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.

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.

Involvement of CYP 3A5 In the Interaction Between Tacrolimus and Nicardipine: A Case Report.

PubMed

Sassi, Mouna B; Gaies, Emna; Salouage, Issam; Trabelsi, Sameh; Lakhal, Mohamed; Klouz, Anis

2015-01-01

Tacrolimus is a calcineurin inhibitor primarily metabolized by CYP3A4 and secondarily by CYP3A5. Several drugs can modify tacrolimus blood levels as calcium channel blockers (CCBs). Interaction with nicardipine was reported in some cases. A man with a history of malignant arterial hypertension treated with nicardipine, underwent kidney transplantation. After transplantation, he was treated with tacrolimus, mycophenolate mofetil and corticoids. Therapeutic drug monitoring of tacrolimus was done regularly showing a mean trough concentration (C0) of 24.39 ng/mL with some concentrations reaching 52 ng/mL. After changing nicardipine by prazosine, the first tacrolimus C0 after stopping nicardipine was 3.2 ng/mL. Increase of tacrolimus trough concentrations is due to the inhibition of CYP3A4. Very high levels of tacrolimus suggest the non expression of CYP3A5. Thus, because of the possible lack of the secondary pathway, therapeutic drug monitoring of tacrolimus is highly recommended at the introduction of CCBs and also at its stopping.

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

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

Analysis of tacrolimus and creatinine from a single dried blood spot using liquid chromatography tandem mass spectrometry.

PubMed

Koop, Dennis R; Bleyle, Lisa A; Munar, Myrna; Cherala, Ganesh; Al-Uzri, Amira

2013-05-01

Long term therapeutic drug monitoring and assessment of renal function are required in renal transplant recipients on immunosuppressant therapy such as tacrolimus. Dry blood spots (DBS) have been used successfully in the clinic for many years and offers a convenient, simple and non-invasive method for repeated blood tests. We developed and performed a preliminary validation of a method for the analysis of tacrolimus and creatinine from a single DBS using liquid chromatography-tandem mass spectrometric (LC-MS/MS). Tacrolimus and creatinine were extracted from a 6mm punch with a mixture of methanol/acetonitrile containing ascomycin and deuterated creatinine as internal standards. A 10 μl aliquot of the extract was analyzed directly after dilution for creatinine with normal phase high performance liquid chromatography and multiple reaction monitoring. The remainder of the extract was processed and analyzed for tacrolimus. The lower limit of quantification for tacrolimus was 1 ng/ml with accuracy of 0.34% bias and precision (CV) of 11.1%. The precision ranged from 1.33% to 7.68% and accuracy from -4.44% to 11.6% bias for the intra- and inter-day analysis. The lower limit of quantification of creatinine was 0.01 mg/dL with precision of 7.94%. Accuracy was based on recovery of additional creatinine spiked into whole blood samples and ranged from -2.45% bias at 5 mg/dL to 3.75% bias at 0.5 mg/dL. Intra- and inter-day precision was from 3.48 to 4.11%. The assay was further validated with DBS prepared from pediatric renal transplant recipients. There was excellent correlation between the levels of tacrolimus and creatinine obtained from the clinical laboratory and the DBS method developed. After additional validation, this assay may have a significant impact on compliance with medication intake as well as potentially lowering the cost associated with intravenous blood draws in clinical laboratories. Copyright © 2013 Elsevier B.V. All rights reserved.

Efficacy of tacrolimus/mycophenolate mofetil as acute graft-versus-host disease prophylaxis and the impact of subtherapeutic tacrolimus levels in children after matched sibling donor allogeneic hematopoietic cell transplantation.

PubMed

Offer, Katharine; Kolb, Michelle; Jin, Zhezhen; Bhatia, Monica; Kung, Andrew L; George, Diane; Garvin, James H; Robinson, Chalitha; Sosna, Jean; Karamehmet, Esra; Satwani, Prakash

2015-03-01

Only a few studies in children have evaluated the efficacy of prophylactic regimens using tacrolimus on acute graft-versus-host disease (aGVHD). As a result, optimal tacrolimus levels in children after matched sibling donor allogeneic hematopoietic cell transplantation (alloHCT) are not well defined. We measured the association between subtherapeutic levels (<10 ng/mL) during weeks 1 to 4 after alloHCT and the cumulative incidence of grades II to IV aGVHD in children. Additionally, we identified optimal lower cutoff levels for tacrolimus. Sixty patients (median age, 8 years) received tacrolimus/mycophenolate mofetil between March 2003 and September 2012. Twenty-three had a malignant disease and 37 nonmalignant disorders. The stem cell source included peripheral blood stem cells (n = 12) and bone marrow or cord blood (n = 48). Conditioning regimen varied. Specifically, 38.3% received a myeloablative regimen, 36.7% receiving a reduced-toxicity regimen, and 25% receiving a reduced-intensity regimen. Tacrolimus was initiated at .03 mg/kg/day via continuous i.v. infusion or .12 mg/kg/day orally. The dose was adjusted to maintain daily steady state concentrations within a range of 10 to 20 ng/mL. The overall incidence of grades II to IV aGVHD was 33.3%. On multivariate analysis, a mean tacrolimus level < 10 ng/mL during week 3 (P = .042; 95% confidence interval, 1.051 to 14.28) was significantly associated with increased incidence of grades II to IV aGVHD. Using weekly receiver operator curves, the optimal lower cutoff for tacrolimus levels was 10 to 11.2 ng/mL. Further prospective studies are warranted to study the incidence of aGVHD comparing the conventional tacrolimus levels of 5 to 15 versus 10 to 15 ng/mL. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

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

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.

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

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.

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.

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.

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.

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

Erratic tacrolimus exposure, assessed using the standard deviation of trough blood levels, predicts chronic lung allograft dysfunction and survival.

PubMed

Gallagher, Harry M; Sarwar, Ghulam; Tse, Tracy; Sladden, Timothy M; Hii, Esmond; Yerkovich, Stephanie T; Hopkins, Peter M; Chambers, Daniel C

2015-11-01

Erratic tacrolimus blood levels are associated with liver and kidney graft failure. We hypothesized that erratic tacrolimus exposure would similarly compromise lung transplant outcomes. This study assessed the effect of tacrolimus mean and standard deviation (SD) levels on the risk of chronic lung allograft dysfunction (CLAD) and death after lung transplantation. We retrospectively reviewed 110 lung transplant recipients who received tacrolimus-based immunosuppression. Cox proportional hazard modeling was used to investigate the effect of tacrolimus mean and SD levels on survival and CLAD. At census, 48 patients (44%) had developed CLAD and 37 (34%) had died. Tacrolimus SD was highest for the first 6 post-transplant months (median, 4.01; interquartile range [IQR], 3.04-4.98 months) before stabilizing at 2.84 μg/liter (IQR, 2.16-4.13 μg/liter) between 6 and 12 months. The SD then remained the same (median, 2.85; IQR, 2.00-3.77 μg/liter) between 12 and 24 months. A high mean tacrolimus level 6 to 12 months post-transplant independently reduced the risk of CLAD (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.63-0.86; p < 0.001) but not death (HR, 0.96; 95% CI, 0.83-1.12; p = 0.65). In contrast, a high tacrolimus SD between 6 and 12 months independently increased the risk of CLAD (HR, 1.46; 95% CI, 1.23-1.73; p < 0.001) and death (HR, 1.27; 95% CI, 1.08-1.51; p = 0.005). Erratic tacrolimus levels are a risk factor for poor lung transplant outcomes. Identifying and modifying factors that contribute to this variability may significantly improve outcomes. Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

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.

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.

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

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 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.

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.

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

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...

Correlation between viral load of cytomegalovirus and tacrolimus and sirolimus levels in transplanted pediatric patients.

PubMed

Reyes-Pérez, Herlinda; Sánchez-Huerta, José Luis; Varela-Fascinetto, Gustavo; Romo-Vázquez, José Carlos; Morales-Sánchez, Abigail; Fuentes-Pananá, Ezequiel M; Parra-Ortega, Israel; Ramírez-Ramírez, Graciela; López-Martínez, Briceida

Survival of transplant patients and grafts depends largely on the use of immunosuppressive drugs. However, a balance remains to be established among immunosuppression, transplant rejection and cytomegalovirus (CMV) infection, which results in a high rate of morbidity and mortality. The aim of this study was to define a better strategy for monitoring transplanted patients based on the analysis of the blood concentration of sirolimus and tacrolimus and the burden of CMV. Fifty five post-transplant (kidney and liver) pediatric patients, nine treated with sirolimus and 46 treated with tacrolimus, were included. A total of 541 measurements were obtained. In each measurement the concentration of immunosuppressant in whole blood and CMV viral load in plasma and whole blood was quantified by real-time PCR. Pearson correlation coefficient (r) was estimated. Values of r ≤0.0747 were found for the relationship between dose and concentration of immunosuppressant; r = 0.9406 for the relationship between viral load in whole blood and plasma, and r ≤0.4616 for the relationship between concentration of immunosuppressant and viral load. These data support that the doses of immunosuppressive drugs do not correlate with the levels of the same in whole blood. Therefore, systemic levels of immunosuppressant should be constantly monitored together with CMV load. Meanwhile, a high correlation between viral load measured in whole blood and plasma was found. Copyright © 2016 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

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.

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).

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

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.

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.

Different Influences on Tacrolimus Pharmacokinetics by Coadministrations of Zhi Ke and Zhi Shi in Rats

PubMed Central

Lin, Shiuan-Pey; Wu, Ping-Ping; Hou, Yu-Chi; Tsai, Shang-Yuan; Wang, Meng-Ju; Fang, Shih-Hua; Chao, Pei-Dawn Lee

2011-01-01

Tacrolimus, an immunosuppressant with narrow therapeutic window, has been used widely in transplant patients. Grapefruit juice and pomelo have been reported to increase the blood levels of tacrolimus. Zhi Ke and Zhi Shi, the ripe peels and unripe fruits of Citrus aurantium which is chemotaxonomically related to grapefruit and pomelo, are in wide use in clinical Chinese medicine. To investigate the possible interaction of these two Citrus herbs with tacrolimus, male Sprague-Dawley rats were orally given tacrolimus (1.5 mg/kg) with and without Zhi Ke and Zhi Shi decoctions in a cross-over design. Blood samples were withdrawn via cardiopuncture at specific time and quantitated by a microparticle enzyme immunoassay. In addition, to explore the mechanism of interaction, LS 180 cell line was used for the transport study of rhodamine 123, a typical substrate of P-glycoprotein (P-gp). The results showed that Zhi Shi significantly decreased the C max and AUC0−t of tacrolimus by 72.4% and 72.0%, respectively, whereas Zhi Ke did not affect tacrolimus pharmacokinetics. LS 180 cell line study indicated that Zhi Shi increased the efflux activity of P-gp, enabling us to explain the decreased oral bioavailability of tacrolimus caused by Zhi Shi. Hence, we suggest that Zhi Shi be contraindicated for transplant patients treated with tacrolimus to reduce the risk of allograft rejection. PMID:21318106

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.

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

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�

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 .

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.

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

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.

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.

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

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

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.

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.

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.

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.

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.

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.

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 ...

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.

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.

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.

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.

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

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

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.

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.

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.

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.

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

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.

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.

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.

The influence of genetic polymorphisms of cytochrome P450 3A5 and ABCB1 on starting dose- and weight-standardized tacrolimus trough concentrations after kidney transplantation in relation to renal function.

PubMed

Mourad, Michel; Wallemacq, Pierre; De Meyer, Martine; Brandt, Dimitri; Van Kerkhove, Valérie; Malaise, Jacques; Chaïb Eddour, Djamila; Lison, Dominique; Haufroid, Vincent

2006-01-01

Cytochrome P450 3A5 (CYP3A5) and ABCB1 polymorphisms have been shown to influence tacrolimus (Tc) blood concentrations in the stable phase after organ transplantation. We hypothesized that Tc pharmacokinetics may be affected by genetic mutations subsequent to starting doses. We retrospectively analyzed data from a cohort of 59 kidney transplant recipients, in whom CYP3A5 (intron 3) and ABCB1 (exons 12, 21 and 26) genotypes were correlated to dose- and weight-standardized Tc trough concentrations obtained after initial Tc doses. Renal function, expressed as glomerular filtration rate (GFR) (MDRD equation), on days 7 and 14 after transplantation was evaluated and its relationship with Tc concentrations was analyzed. Dose- and weight-standardized Tc trough concentrations were lower in patients carrying the CYP3A5 *1 allele (p<0.01). There was no statistically significant association with ABCB1 polymorphisms. In a multivariate analysis, both the presence of at least one CYP3A5 *1 allele (p=0.006) and age at the time of transplantation (p=0.010) were significant independent variables affecting Tc trough blood concentrations standardized to the first dosages (model r2=0.23). GFR was not affected by Tc concentrations. Prospective trials are needed to prove that a genetic approach to Tc pharmacokinetics and its related side effects during the early period after grafting may improve patient outcome.

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.

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

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.

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.

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

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

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.

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

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.

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.

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 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

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.

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.

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.

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.

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.

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

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.

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.

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].

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.

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.

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.

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.

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.

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.

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.

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.

Clinical and genetic factors affecting tacrolimus trough levels and drug-related outcomes in Korean kidney transplant recipients.

PubMed

Kim, In-Wha; Moon, Yoo Jin; Ji, Eunhee; Kim, Kyung Im; Han, Nayoung; Kim, Sung Ju; Shin, Wan Gyoon; Ha, Jongwon; Yoon, Jeong-Hyun; Lee, Hye Suk; Oh, Jung Mi

2012-05-01

The purpose of this study was to characterize the effects of clinical and genetic variables on the pharmacokinetics and complications of tacrolimus during the first year after kidney transplantation. One hundred and thirty-two Korean kidney recipients who received tacrolimus were genotyped for ABCB1 (exons 12, 21, and 26) and CYP3A5 (intron 3). Tacrolimus trough levels, dose, or dose-adjusted trough levels and complications were compared among patients during the early stage (3, 7, 14, 30, and 90 days) and up to 1 year according to the genotypes. A donor source-adjusted linear mixed model with multilevel analysis adjusting for age, body weight, hematocrit, and serum creatinine showed that CYP3A5 genotype is associated with dose-adjusted level of tacrolimus (p < 0.001). The influence of ABCB1 polymorphisms on the pharmacokinetics or complications of tacrolimus was less certain in our study. The incidence of acute rejections was significantly higher in recipients of cadaveric donor kidney (p < 0.05). A generalized estimating equation model analysis showed that alopecia and hyperlipidemia were associated with dose-adjusted level of tacrolimus (p < 0.001). Genotype of CYP3A5 variants along with significant clinical covariates may be useful in individualizing tacrolimus therapy in kidney transplantation patients.

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 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.

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

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.

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.

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.

Nitrobenzodiazepines: Postmortem brain and blood reference concentrations.

PubMed

Skov, Louise; Holm, Karen Marie Dollerup; Linnet, Kristian

2016-11-01

Reference concentrations are needed to evaluate postmortem toxicology results and usually femoral blood is the specimen of choice. However, brain tissue has been suggested as a viable alternative specimen, since postmortem blood concentrations can be difficult to interpret due to postmortem redistribution, among other factors. Here we present reference concentrations of postmortem brain and femoral blood of the nitrobenzodiazepines clonazepam, flunitrazepam, and nitrazepam that are of particular interest since they commonly are converted to their corresponding 7-aminometabolites in the postmortem situation. The drugs and metabolites were quantified in both matrices using LC-MS-MS in 69 cases. In 63 cases the compounds were judged not to have been of significance for the death (C cases), whereas they were considered to have been a contributing factor in 6 cases (B cases). No cases were observed with a nitrobenzodiazepine being the sole cause of death (A cases). The brain-blood ratios for clonazepam and nitrazepam were 5.5 and 4.7, respectively, while the brain-blood ratios for the 7-aminometabolites ranged from 0.4 to 0.5. Flunitrazepam only occurred as the 7-aminometabolite. A positive correlation between brain and blood concentrations was found with Spearman's rank correlation coefficients (r s ) ranging from 0.77 to 0.96. The measured femoral blood concentrations agree with literature values, but only few brain concentrations were available for comparison. The drug-metabolite ratios for clonazepam and nitrazepam were 10-12 times higher in brain than in blood. The pre-analytical variation in brain of 5.9% was fairly low, suggesting that brain tissue is a useful alternative to blood. The reported brain and femoral blood concentrations serve as reference values in postmortem investigations. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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.

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.

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.

[Blood clots in erythrocyte concentrates during transfusion].

PubMed

Wagner, T; Drexler, C; Kröll, W; Jüngling, G; Lanzer, G; Gabriel, C

2008-12-01

The presence of multiple blood clots in leucocyte-depleted erythrocyte concentrates during a transfusion gave rise to an investigation to find the exact cause. Determination of the various blood group systems was carried out using the gel centrifugation method and also the polymerase chain reaction (PCR) using sequence-specific primers. In addition the human leucocyte antigens (HLA) class 1 and class 2 markers were determined with molecular biological methods. The erythrocytes in the blood bags containing the blood clots showed a mixed-field agglutination in each blood group where the donor and recipient had different phenotypes. The HLA groups, however, could be solely attributed to the patient, since during the preparation of erythrocyte concentrates all leucocytes are removed and only very few residual cells containing DNA are present. To the best of our knowledge, this is the first detailed report on blood clots from patient blood in erythrocyte concentrates, which occurred during a transfusion. The retrograde filling of the blood bag with patient blood during the transfusion led to coagulation in the bag. Therefore, careful attention must be taken when dealing with stored blood and corresponding training must be regularly carried out.

[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.

Effect of dosage increments on blood phenytoin concentrations

PubMed Central

Bochner, F.; Hooper, W. D.; Tyrer, J. H.; Eadie, M. J.

1972-01-01

Blood phenytoin (diphenylhydantoin) concentrations were measured after each dosage change in 12 epileptic patients who were given increasing oral doses of phenytoin. In each of these patients a dosage increment beyond the dosage that produced a blood phenytoin level of 6-9 μg/ml. caused a disproportionately great increase in the blood concentration of drug. This effect might be expected if the limit of the body's capacity to metabolize phenytoin were being reached. As oral dosages were increased in one patient, measurements of the rate of urinary excretion of phenytoin metabolite showed that the phase of rapid rise in blood phenytoin concentration coincided with a failure to increase the rate of phenytoin metabolite excretion. Awareness of the non-linear relation between oral dose and blood concentration of phenytoin in the individual patient, and realization that the phase of rapid rise in blood phenytoin concentration occurs through the `therapeutic' range of 10-20 μg/ml., is of importance to those who use blood phenytoin levels as a guide to the adequacy of anticonvulsant therapy. PMID:4647859

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.

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.

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

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.

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.

[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.

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.

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.

Blood Selenium Concentration and Blood Cystatin C Concentration in a Randomly Selected Population of Healthy Children Environmentally Exposed to Lead and Cadmium.

PubMed

Gać, Paweł; Pawlas, Natalia; Wylężek, Paweł; Poręba, Rafał; Poręba, Małgorzata; Pawlas, Krystyna

2017-01-01

This study aimed at evaluation of a relationship between blood selenium concentration (Se-B) and blood cystatin C concentration (CST) in a randomly selected population of healthy children, environmentally exposed to lead and cadmium. The studies were conducted on 172 randomly selected children (7.98 ± 0.97 years). Among participants, the subgroups were distinguished, manifesting marginally low blood selenium concentration (Se-B 40-59 μg/l), suboptimal blood selenium concentration (Se-B: 60-79 μg/l) or optimal blood selenium concentration (Se-B ≥ 80 μg/l). At the subsequent stage, analogous subgroups of participants were selected separately in groups of children with BMI below median value (BMI <16.48 kg/m 2 ) and in children with BMI ≥ median value (BMI ≥16.48 kg/m 2 ). In all participants, values of Se-B and CST were estimated. In the entire group of examined children no significant differences in mean CST values were detected between groups distinguished on the base of normative Se-B values. Among children with BMI below 16.48 kg/m 2 , children with marginally low Se-B manifested significantly higher mean CST values, as compared to children with optimum Se-B (0.95 ± 0.07 vs. 0.82 ± 0.15 mg/l, p < 0.05). In summary, in a randomly selected population of healthy children no relationships could be detected between blood selenium concentration and blood cystatin C concentration. On the other hand, in children with low body mass index, a negative non-linear relationship was present between blood selenium concentration and blood cystatin C concentration.

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

21 CFR 868.1120 - Indwelling blood oxyhemoglobin concentration analyzer.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Indwelling blood oxyhemoglobin concentration... Indwelling blood oxyhemoglobin concentration analyzer. (a) Identification. An indwelling blood oxyhemoglobin... hemoglobin in blood to aid in determining the patient's physiological status. (b) Classification. Class III...

21 CFR 868.1120 - Indwelling blood oxyhemoglobin concentration analyzer.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Indwelling blood oxyhemoglobin concentration... Indwelling blood oxyhemoglobin concentration analyzer. (a) Identification. An indwelling blood oxyhemoglobin... hemoglobin in blood to aid in determining the patient's physiological status. (b) Classification. Class III...

21 CFR 868.1120 - Indwelling blood oxyhemoglobin concentration analyzer.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Indwelling blood oxyhemoglobin concentration... Indwelling blood oxyhemoglobin concentration analyzer. (a) Identification. An indwelling blood oxyhemoglobin... hemoglobin in blood to aid in determining the patient's physiological status. (b) Classification. Class III...

21 CFR 868.1120 - Indwelling blood oxyhemoglobin concentration analyzer.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Indwelling blood oxyhemoglobin concentration... Indwelling blood oxyhemoglobin concentration analyzer. (a) Identification. An indwelling blood oxyhemoglobin... hemoglobin in blood to aid in determining the patient's physiological status. (b) Classification. Class III...

21 CFR 868.1120 - Indwelling blood oxyhemoglobin concentration analyzer.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Indwelling blood oxyhemoglobin concentration... Indwelling blood oxyhemoglobin concentration analyzer. (a) Identification. An indwelling blood oxyhemoglobin... hemoglobin in blood to aid in determining the patient's physiological status. (b) Classification. Class III...

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.

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

Determinants of hydroxychloroquine blood concentration variations in systemic lupus erythematosus.

PubMed

Jallouli, M; Galicier, L; Zahr, N; Aumaître, O; Francès, C; Le Guern, V; Lioté, F; Smail, A; Limal, N; Perard, L; Desmurs-Clavel, H; Le Thi Huong, D; Asli, B; Kahn, J-E; Pourrat, J; Sailler, L; Ackermann, F; Papo, T; Sacré, K; Fain, O; Stirnemann, J; Cacoub, P; Leroux, G; Cohen-Bittan, J; Sellam, J; Mariette, X; Blanchet, B; Hulot, J S; Amoura, Z; Piette, J C; Costedoat-Chalumeau, N

2015-05-01

Blood concentrations of hydroxychloroquine (HCQ) vary widely among patients with systemic lupus erythematosus (SLE). A pharmacokinetic/pharmacodynamic relationship has been found in different situations, and a very low blood concentration of HCQ is a simple marker of nonadherence to treatment. Therefore, interest in blood HCQ concentration measurement has increased, but little is known about factors that influence blood HCQ concentration variability. This study was undertaken to analyze determinants of blood HCQ concentrations. We conducted a retrospective analysis of patient data, including data from the Plaquenil Lupus Systemic (PLUS) study, to determine the association of epidemiologic, clinical, and biologic factors with blood HCQ concentrations. Data for nonadherent patients (blood HCQ concentration <200 ng/ml) were excluded. To examine homogeneous pharmacologic data, we restricted the analyses of the PLUS data to the 509 SLE patients receiving 400 mg/day. We found no association of ethnicity or smoking with blood HCQ concentrations and no pharmacokinetic drug-drug interaction with antacids or with inhibitors or inducers of cytochrome P450 enzymes. On multivariate analysis, high body mass index (P = 0.008), no treatment with corticosteroids (P = 0.04), increased time between the last tablet intake and measurement of blood HCQ concentrations (P = 0.017), low platelet count (P < 0.001), low neutrophil count (P < 0.001), and high estimated creatinine clearance (P < 0.001) were associated with low blood HCQ concentrations. In 22 SLE patients with chronic renal insufficiency (median serum creatinine clearance 52 ml/minute [range 23-58 ml/minute]) who received 400 mg/day HCQ, the median blood HCQ concentration was significantly higher than that in the 509 patients from the PLUS study (1,338 ng/ml [range 504-2,229 ng/ml] versus 917 ng/ml [range 208-3316 ng/ml]) (P < 0.001). We provide a comprehensive analysis of determinants of blood HCQ concentrations

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.

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

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

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

Cardiac and peripheral blood similarities in the comparison of nordiazepam and bromazepam blood concentrations.

PubMed

Pos Pok, P-Rop; Haddouche, Djamel; Mauras, Michel; Kuhlmann, Erika; Burle, Joëlle; Salmon, Thierry; Berland, Emilie; Coiffait, P-Emmanuel; Viala, Alain

2008-01-01

Concomitant heart and peripheral blood determinations were performed on 40 fatal cases involving nordiazepam (20 cases) and bromazepam (20 cases). The heart blood concentration for the two drugs (588 ng/mL for nordiazepam and 802 ng/mL for bromazepam) does not differ from the corresponding peripheral blood concentration (587 ng/mL for nordiazepam and 883 ng/mL for bromazepam). The mean ratios for the heart and peripheral blood concentrations were 0.95 for nordiazepam and 0.86 for bromazepam. No postmortem redistribution was observed for these two benzodiazepines. The authors thus suggest that corresponding heart blood can be proposed in the quantitative analysis of these drugs when peripheral blood is unavailable. The present study also shows the stability of the two drugs after a year of storage.

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.

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.

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.

Drug concentrations in post-mortem femoral blood compared with therapeutic concentrations in plasma

PubMed Central

Launiainen, Terhi; Ojanperä, Ilkka

2014-01-01

Therapeutic drug concentrations measured in plasma are of limited value as reference intervals for interpretation in post-mortem (PM) toxicology. In this study, drug concentration distributions were studied in PM femoral venous blood from 57 903 Finnish autopsy cases representing all causes of death during an 11-year period. Cause-of-death information was obtained from death certificates issued by forensic pathologists. Median, mean, and upper percentile (90th, 95th, 97.5th) concentrations were calculated for 129 drugs. To illustrate how PM median concentrations relate to established therapeutic ranges in plasma, a PM blood/plasma relationship was calculated for each drug. Males represented 75% of the subjects and showed a lower median age (55 yrs) than females (59 yrs). In 43% of these cases, blood alcohol concentration was higher than 0.2‰, and the median was 1.8‰. Sixty-one (47%) of the 129 drugs showed a PM blood/plasma relationship of 1. For 22 drugs (17%), the relationship was <1, and for 46 drugs (35%), the relationship was >1. No marked correlation was found between the PM blood/plasma relationship and the volume of distribution (Vd). For 36 drugs, more than 10% of cases were fatal poisonings attributed to this drug as the main finding. These drug concentration distributions based on a large database provide a helpful reference not only to forensic toxicologists and pathologists but also to clinical pharmacologists in charge of interpreting drug concentrations in PM cases. © 2013 The Authors. Drug Testing and Analysis published by John Wiley & Sons, Ltd. PMID:23881890

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.

Validation of an LC-MS/MS method to measure tacrolimus in rat kidney and liver tissue and its application to human kidney biopsies.

PubMed

Noll, Benjamin D; Coller, Janet K; Somogyi, Andrew A; Morris, Raymond G; Russ, Graeme R; Hesselink, Dennis A; Van Gelder, Teun; Sallustio, Benedetta C

2013-10-01

Tacrolimus (TAC) has a narrow therapeutic index and high interindividual and intraindividual pharmacokinetic variability, necessitating therapeutic drug monitoring to individualize dosage. Recent evidence suggests that intragraft TAC concentrations may better predict transplant outcomes. This study aimed to develop a method for the quantification of TAC in small biopsy-sized samples of rat kidney and liver tissue, which could be applied to clinical biopsy samples from kidney transplant recipients. Kidneys and livers were harvested from Mrp2-deficient TR- Wistar rats administered TAC (4 mg·kg·d for 14 days, n = 8) or vehicle (n = 10). Tissue samples (0.20-1.00 mg of dry weight) were solubilized enzymatically and underwent liquid-liquid extraction before analysis by liquid chromatography tandem mass spectrometry method. TAC-free tissue was used in the calibrator and quality control samples. Analyte detection was accomplished using positive electrospray ionization (TAC: m/z 821.5 → 768.6; internal standard ascomycin m/z 809.3 → 756.4). Calibration curves (0.04-2.6 μg/L) were linear (R > 0.99, n = 10), with interday and intraday calibrator coefficients of variation and bias <17% at the lower limit of quantification and <15% at all other concentrations (n = 6-10). Extraction efficiencies for TAC and ascomycin were approximately 70%, and matrix effects were minimal. Rat kidney TAC concentrations were higher (range 109-190 pg/mg tissue) than those in the liver (range 22-53 pg/mg of tissue), with median tissue/blood concentrations ratios of 72.0 and 17.6, respectively. In 2 transplant patients, kidney TAC concentrations ranged from 119 to 285 pg/mg of tissue and were approximately 20 times higher than whole blood trough TAC concentrations. The method displayed precision and accuracy suitable for application to TAC measurement in human kidney biopsy tissue.

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 performance of five different dried blood spot cards for the analysis of six immunosuppressants.

PubMed

Koster, Remco A; Botma, Rixt; Greijdanus, Ben; Uges, Donald R A; Kosterink, Jos G W; Touw, Daan J; Alffenaar, Jan-Willem C

2015-01-01

The relation between hematocrit, substance concentration, extraction recovery and spot formation of tacrolimus, sirolimus, everolimus, ascomycin, temsirolimus and cyclosporin A was investigated for Whatman 31 ET CHR, Whatman FTA DMPK-C, Whatman 903, Perkin Elmer 226 and Agilent Bond Elut DMS DBS cards. We found that all DBS cards showed the same hematocrit and concentration-dependent recovery patterns for sirolimus, everolimus and temsirolimus. At high concentrations, the total hematocrit effects were much more pronounced than at low concentrations for tacrolimus, sirolimus, everolimus, ascomycin and temsirolimus. The tested card types showed differences in performance, especially at extreme concentrations and hematocrit values. It may be useful to investigate the performance of different types of DBS cards prior to analytical method validation.

[Dynamic determination of the medicine concentration of poisoned blood of acephate].

PubMed

Chu, Jian-Xin; Shen, Ju-Hua; Jiang, Wen-Hui

2006-06-01

To observe rule of medicine concentration of blood and the last concentration that through hemoperfusion after poisoned by acephate. Utilizeng the patient annual bonus venous blood in hospital emergency room, the content of acephate in plasma was analyzed by gas chromatography. After hemoperfusion, the concentration of acephate showed a rapid drop and the characteristic that the concentration drops quicker if medicine concentration of blood before hemoperfusion is higher. Hemoperfusion is able to rapidly reduce the concentration of acephate in blood, its speed is determined by initial concentration and the beginning time of hemoperfusion etc.

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.

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.

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

the US Food and Drug Administration (FDA) average bioequivalence (ABE) acceptance criteria of a 90% confidence interval contained within the confidence limits of 80.00% and 125.00%. Within-subject variability was similar for the area under the curve (AUC) (range 12.11–15.81) and the concentration maximum (Cmax) (range 17.96–24.72) for all products. The within-subject variability was utilized to calculate the scaled average bioequivalence (SCABE) 90% confidence interval. The calculated SCABE 90% confidence interval was 84.65%–118.13% and 80.00%–125.00% for AUC and Cmax, respectively. The more stringent SCABE acceptance criteria were met for all product comparisons for AUC and Cmax in both individuals with a kidney transplant and those with a liver transplant. European Medicines Agency (EMA) acceptance criteria for narrow therapeutic index drugs were also met, with the only exception being in the case of Brand versus Generic Lo, in which the upper limits of the 90% confidence intervals were 111.30% (kidney) and 112.12% (liver). These were only slightly above the upper EMA acceptance criteria limit for an AUC of 111.11%. SCABE criteria were also met for the major tacrolimus metabolite 13-O-desmethyl tacrolimus for AUC, but it failed the EMA criterion. No acute rejections, no differences in renal function in all individuals, and no differences in liver function were observed in individuals with a liver transplant using the Tukey honest significant difference (HSD) test for multiple comparisons. Fifty-two percent and 65% of all individuals with a kidney or liver transplant, respectively, reported an adverse event. The Exact McNemar test for paired categorical data with adjustments for multiple comparisons was used to compare adverse event rates among the products. No statistically significant differences among any pairs of products were found for any adverse event code or for adverse events overall. Limitations of this study include that the observations were made

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

(FDA) average bioequivalence (ABE) acceptance criteria of a 90% confidence interval contained within the confidence limits of 80.00% and 125.00%. Within-subject variability was similar for the area under the curve (AUC) (range 12.11-15.81) and the concentration maximum (Cmax) (range 17.96-24.72) for all products. The within-subject variability was utilized to calculate the scaled average bioequivalence (SCABE) 90% confidence interval. The calculated SCABE 90% confidence interval was 84.65%-118.13% and 80.00%-125.00% for AUC and Cmax, respectively. The more stringent SCABE acceptance criteria were met for all product comparisons for AUC and Cmax in both individuals with a kidney transplant and those with a liver transplant. European Medicines Agency (EMA) acceptance criteria for narrow therapeutic index drugs were also met, with the only exception being in the case of Brand versus Generic Lo, in which the upper limits of the 90% confidence intervals were 111.30% (kidney) and 112.12% (liver). These were only slightly above the upper EMA acceptance criteria limit for an AUC of 111.11%. SCABE criteria were also met for the major tacrolimus metabolite 13-O-desmethyl tacrolimus for AUC, but it failed the EMA criterion. No acute rejections, no differences in renal function in all individuals, and no differences in liver function were observed in individuals with a liver transplant using the Tukey honest significant difference (HSD) test for multiple comparisons. Fifty-two percent and 65% of all individuals with a kidney or liver transplant, respectively, reported an adverse event. The Exact McNemar test for paired categorical data with adjustments for multiple comparisons was used to compare adverse event rates among the products. No statistically significant differences among any pairs of products were found for any adverse event code or for adverse events overall. Limitations of this study include that the observations were made under strictly controlled conditions that did

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

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.

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.

Relationship between maternal sodium intake and blood lead concentration during pregnancy.

PubMed

Lee, Yo A; Hwang, Ji-Yun; Kim, Hyesook; Kim, Ki Nam; Ha, Eun-Hee; Park, Hyesook; Ha, Mina; Kim, Yangho; Hong, Yun-Chul; Chang, Namsoo

2013-03-14

Pb is released from bone stores during pregnancy, which constitutes a period of increased bone resorption. A high Na intake has been found to be negatively associated with Ca and adversely associated with bone metabolism. It is possible that a high Na intake during pregnancy increases the blood Pb concentration; however, no previous study has reported on the relationship between Na intake and blood Pb concentration. We thus have investigated this relationship between Na intake and blood Pb concentrations, and examined whether this relationship differs with Ca intake in pregnant Korean women. Blood Pb concentrations were analysed in 1090 pregnant women at mid-pregnancy. Dietary intakes during mid-pregnancy were estimated by a 24 h recall method covering the use of dietary supplements. Blood Pb concentrations in whole-blood samples were analysed using graphite furnace atomic absorption spectrophotometry. Multiple regression analysis performed after adjustment for covariates revealed that maternal Na intake was positively associated with blood Pb concentration during pregnancy, but only when Ca intake was below the estimated average requirement for pregnant Korean women (P= 0·001). The findings of the present study suggest that blood Pb concentration during pregnancy could be minimised by dietary recommendations that include decreased Na and increased Ca intakes.

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.

32 CFR 634.34 - Blood alcohol concentration standards.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 4 2010-07-01 2010-07-01 true Blood alcohol concentration standards. 634.34... ENFORCEMENT AND CRIMINAL INVESTIGATIONS MOTOR VEHICLE TRAFFIC SUPERVISION Traffic Supervision § 634.34 Blood... evaluated as follows: (1) If the percentage of alcohol in the person's blood is less than 0.05 percent...

32 CFR 634.34 - Blood alcohol concentration standards.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 4 2012-07-01 2011-07-01 true Blood alcohol concentration standards. 634.34... ENFORCEMENT AND CRIMINAL INVESTIGATIONS MOTOR VEHICLE TRAFFIC SUPERVISION Traffic Supervision § 634.34 Blood... evaluated as follows: (1) If the percentage of alcohol in the person's blood is less than 0.05 percent...

32 CFR 634.34 - Blood alcohol concentration standards.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 4 2013-07-01 2013-07-01 false Blood alcohol concentration standards. 634.34... ENFORCEMENT AND CRIMINAL INVESTIGATIONS MOTOR VEHICLE TRAFFIC SUPERVISION Traffic Supervision § 634.34 Blood... evaluated as follows: (1) If the percentage of alcohol in the person's blood is less than 0.05 percent...

32 CFR 634.34 - Blood alcohol concentration standards.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 4 2014-07-01 2013-07-01 true Blood alcohol concentration standards. 634.34... ENFORCEMENT AND CRIMINAL INVESTIGATIONS MOTOR VEHICLE TRAFFIC SUPERVISION Traffic Supervision § 634.34 Blood... evaluated as follows: (1) If the percentage of alcohol in the person's blood is less than 0.05 percent...

32 CFR 634.34 - Blood alcohol concentration standards.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 4 2011-07-01 2011-07-01 false Blood alcohol concentration standards. 634.34... ENFORCEMENT AND CRIMINAL INVESTIGATIONS MOTOR VEHICLE TRAFFIC SUPERVISION Traffic Supervision § 634.34 Blood... evaluated as follows: (1) If the percentage of alcohol in the person's blood is less than 0.05 percent...

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

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

21 CFR 868.1170 - Indwelling blood hydrogen ion concentration (pH) analyzer.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Indwelling blood hydrogen ion concentration (pH... Indwelling blood hydrogen ion concentration (pH) analyzer. (a) Identification. An indwelling blood hydrogen... used to measure, in vivo, the hydrogen ion concentration (pH) in blood to aid in determining the...

21 CFR 868.1170 - Indwelling blood hydrogen ion concentration (pH) analyzer.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Indwelling blood hydrogen ion concentration (pH... Indwelling blood hydrogen ion concentration (pH) analyzer. (a) Identification. An indwelling blood hydrogen... used to measure, in vivo, the hydrogen ion concentration (pH) in blood to aid in determining the...

21 CFR 868.1170 - Indwelling blood hydrogen ion concentration (pH) analyzer.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Indwelling blood hydrogen ion concentration (pH... Indwelling blood hydrogen ion concentration (pH) analyzer. (a) Identification. An indwelling blood hydrogen... used to measure, in vivo, the hydrogen ion concentration (pH) in blood to aid in determining the...

21 CFR 868.1170 - Indwelling blood hydrogen ion concentration (pH) analyzer.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Indwelling blood hydrogen ion concentration (pH... Indwelling blood hydrogen ion concentration (pH) analyzer. (a) Identification. An indwelling blood hydrogen... used to measure, in vivo, the hydrogen ion concentration (pH) in blood to aid in determining the...

21 CFR 868.1170 - Indwelling blood hydrogen ion concentration (pH) analyzer.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Indwelling blood hydrogen ion concentration (pH... Indwelling blood hydrogen ion concentration (pH) analyzer. (a) Identification. An indwelling blood hydrogen... used to measure, in vivo, the hydrogen ion concentration (pH) in blood to aid in determining the...

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.

[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.

Blood glucose concentrations in prehospital trauma patients with traumatic shock: A retrospective analysis.

PubMed

Kreutziger, Janett; Lederer, Wolfgang; Schmid, Stefan; Ulmer, Hanno; Wenzel, Volker; Nijsten, Maarten W; Werner, Daniel; Schlechtriemen, Thomas

2018-01-01

Deranged glucose metabolism after moderate to severe trauma with either high or low concentrations of blood glucose is associated with poorer outcome. Data on prehospital blood glucose concentrations and trauma are scarce. The primary aim was to describe the relationship between traumatic shock and prehospital blood glucose concentrations. The secondary aim was to determine the additional predictive value of prehospital blood glucose concentration for traumatic shock when compared with vital parameters alone. Retrospective analysis of the predefined, observational database of a nationwide Helicopter Emergency Medical Service (34 bases). Emergency trauma patients treated by Helicopter Emergency Medical Service between 2005 and 2013 were investigated. All adult trauma patients (≥18 years) with recorded blood glucose concentrations were enrolled. Primary outcome: upper and lower thresholds of blood glucose concentration more commonly associated with traumatic shock. Secondary outcome: additional predictive value of prehospital blood glucose concentrations when compared with vital parameters alone. Of 51 936 trauma patients, 20 177 were included. In total, 220 (1.1%) patients died on scene. Hypoglycaemia (blood glucose concentration 2.8 mmol l or less) was observed in 132 (0.7%) patients, hyperglycaemia (blood glucose concentration exceeding 15 mmol l) was observed in 265 patients (1.3%). Blood glucose concentrations more than 10 mmol l (n = 1308 (6.5%)) and 2.8 mmol l or less were more common in patients with traumatic shock (P < 0.0001). The Youden index for traumatic shock ((sensitivity + specificity) - 1) was highest when blood glucose concentration was 3.35 mmol l (P < 0.001) for patients with low blood glucose concentrations and 7.75 mmol l (P < 0.001) for those with high blood glucose concentrations. In logistic regression analysis of patients with spontaneous circulation on scene, prehospital blood glucose

Association of Cord Blood Magnesium Concentration and Neonatal Resuscitation

PubMed Central

Johnson, Lynn H.; Mapp, Delicia C.; Rouse, Dwight J.; Spong, Catherine Y.; Mercer, Brian M.; Leveno, Kenneth J.; Varner, Michael W.; Iams, Jay D.; Sorokin, Yoram; Ramin, Susan M.; Miodovnik, Menachem; O'Sullivan, Mary J.; Peaceman, Alan M.; Caritis, Steve N.

2014-01-01

Objective Assess the relationship between umbilical cord blood magnesium concentration and level of delivery room resuscitation received by neonates. Study design Secondary analysis of a controlled fetal neuroprotection trial that enrolled women at imminent risk for delivery between 24 and 31 weeks’ gestation and randomly allocated them to receive intravenous magnesium sulfate or placebo. The cohort included 1507 infants for whom total cord blood magnesium concentration and delivery room resuscitation information were available. Multivariable logistic regression was used to estimate the association between cord blood magnesium concentration and highest level of delivery room resuscitation, using the following hierarchy: none, oxygen only, bag-mask ventilation with oxygen, intubation or chest compressions. Results There was no relationship between cord blood magnesium and delivery room resuscitation (odds ratio [OR] 0.92 for each 1.0 mEq/L increase in magnesium; 95% confidence interval [CI]: 0.83-1.03). Maternal general anesthesia was associated with increased neonatal resuscitation (OR 2.51; 95% CI: 1.72-3.68). Each 1-week increase in gestational age at birth was associated with decreased neonatal resuscitation (OR 0.63; 95% CI: 0.60 – 0.66). Conclusion Cord blood magnesium concentration does not correlate with the level of delivery room resuscitation of infants exposed to magnesium sulfate for fetal neuroprotection. PMID:22056282

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

Lead reduction of petrol and blood lead concentrations of athletes

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

Maresky, L.S.; Kotze, T.J.V.W.; Grobler, S.R.

In 1984, it was determined that the blood of long-distance runners in South Africa contained unacceptably high concentrations of lead. Subsequently, the petrol lead level in South Africa was reduced from 0.8 g/l to 0.4 g/l. In view of this reduction, a follow-up investigation of its effect on the blood lead concentration of South African runners was undertaken. Blood lead samples were analyzed by graphite furnace atomic absorption spectrophotometry. The mean values of blood lead concentrations dropped from 52 to 13 {mu}g/dl and from 20 to 8.5 {mu}g/dl for the urban and rural trainers, respectively. A highly significant decrease inmore » blood lead levels was found and was mainly attributable to the reduction in the petrol lead levels. The blood lead results for rural trainers indicated that there still exists a certain degree of lead pollution in athletes from nonremote areas.« less

Effect of blood thiamine concentrations on mortality: Influence of nutritional status.

PubMed

Leite, Heitor Pons; de Lima, Lúcio Flávio Peixoto; Taddei, José Augusto de A C; Paes, Ângela Tavares

2018-04-01

To test the hypothesis that low blood thiamine concentrations in malnourished critically ill children are associated with higher risk of 30-d mortality. Prospective cohort study in 202 consecutively admitted children who had whole blood thiamine concentrations assessed on admission and on days 5 and 10 of intensive care unit (ICU) stay. The primary outcome variable was 30-d mortality. Mean blood thiamine concentrations within the first 10 d of ICU stay, age, sex, malnutrition, C-reactive protein concentration, Pediatric Index of Mortality 2 score, and severe sepsis/septic shock were the main potential exposure variables for outcome. Thiamine deficiency was detected in 61 patients within the first 10 d of ICU stay, 57 cases being diagnosed on admission and 4 new cases on the 5th d. C-reactive protein concentration during ICU stay was independently associated with decreased blood thiamine concentrations (P = 0.003). There was a significant statistical interaction between mean blood thiamine concentrations and malnutrition on the risk of 30-d mortality (P = 0.002). In an adjusted analysis, mean blood thiamine concentrations were associated with a decrease in the mortality risk in malnourished patients (odds ratio = 0.85; 95% confidence interval [CI]: 0.73-0.98; P = 0.029), whereas no effect was noted for well-nourished patients (odds ratio: 1.03; 95% CI: 0.94-1.13; P = 0.46). Blood thiamine concentration probably has a protective effect on the risk of 30-d mortality in malnourished patients but not in those who were well nourished. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

Significant decreases in blood propofol concentrations during adrenalectomy for phaeochromocytoma.

PubMed

Watanabe, Tatsunori; Hiraoka, Haruhiko; Araki, Takuya; Nagano, Daisuke; Aomori, Tohru; Nakamura, Tomonori; Yamamoto, Koujirou; Baba, Hiroshi

2017-10-01

The kinetics of propofol are influenced by cardiac output. The aim of this study was to examine changes in blood propofol concentrations during phaeochromocytoma surgery using target-controlled infusion (TCI) anaesthesia with propofol. This is a prospective observational study. Ten patients with phaeochromocytoma who underwent unilateral adrenalectomy were included. Cardiac output was measured using an arterial pressure-based cardiac output analysis method. The target blood propofol concentrations were adjusted to maintain an approximate bispectral index (BIS) value of 40 before initiating surgery. The settings remained constant during surgery. Blood samples for propofol concentrations were collected from the radial artery at seven time points: two before tumour manipulation (T1, 2), two during tumour manipulation (T3, 4), and three after tumour vein ligation (T4-7). BIS values, the arterial pressure cardiac index (APCI) and haemodynamic parameters were measured at the same time points as the blood samples. The prop-ratio was calculated by dividing blood propofol concentrations by target concentrations of TCI. APCI increased during tumour manipulation and after tumour vein ligation. The prop-ratio was reduced significantly by approximately 40% and showed a significant negative correlation with APCI. BIS values increased significantly and showed a significant negative correlation with the prop-ratio. The increased APCI during tumour manipulation and after tumour vein ligation was associated with markedly reduced blood propofol concentrations. These results reveal that significant decreases in the anaesthetic effect may be observed in patients undergoing phaeochromocytoma surgery even if TCI anaesthesia is used with propofol. © 2017 The British Pharmacological Society.

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.

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.

Ammonia concentrations in arterial blood, venous blood, and cerebrospinal fluid of dogs with and without congenital extrahepatic portosystemic shunts.

PubMed

Or, Matan; Devriendt, Nausikaa; Kitshoff, Adriaan M; Peremans, Kathelijne; Vandermeulen, Eva; Paepe, Dominique; Polis, Ingeborgh; Martlé, Valentine; de Rooster, Hilde

2017-11-01

OBJECTIVE To compare ammonia concentrations in arterial blood, venous blood, and CSF samples of dogs with and without extrahepatic portosystemic shunts (EHPSS). ANIMALS 19 dogs with congenital EHPSS and 6 healthy control dogs. PROCEDURES All dogs underwent a physical examination and then were anesthetized for transsplenic portal scintigraphy to confirm the presence or absence of EHPSS. While dogs were anesthetized, arterial and venous blood samples and a CSF sample were simultaneously collected for determination of ammonia concentration, which was measured by use of a portable blood ammonia analyzer (device A) and a nonportable biochemical analyzer (device B). Results were compared between dogs with EHPSS and control dogs. RESULTS Arterial, venous, and CSF ammonia concentrations for dogs with EHPSS were significantly greater than those for control dogs. For dogs with EHPSS, ammonia concentrations in both arterial and venous blood samples were markedly increased from the reference range. There was a strong positive correlation between arterial and venous ammonia concentrations and between blood (arterial or venous) and CSF ammonia concentrations. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that blood and CSF ammonia concentrations in dogs with EHPSS were greater than those for healthy dogs and were strongly and positively correlated, albeit in a nonlinear manner. This suggested that the permeability of the blood-brain barrier to ammonia may be abnormally increased in dogs with EHPSS, but further investigation of the relationship between blood or CSF ammonia concentration and clinical signs of hepatic encephalopathy or the surgical outcome for dogs with EHPSS is warranted.

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...

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.

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.

Blood concentrations of new designer benzodiazepines in forensic cases.

PubMed

Høiseth, Gudrun; Tuv, Silja Skogstad; Karinen, Ritva

2016-11-01

A number of new designer benzodiazepines have reached the illegal drug market over the past years. Toxicological interpretation of concentrations of these drugs in blood is quite challenging as very limited human data have previously been published. The aim of this study was to report blood concentrations of new designer benzodiazepines in a population of drugged drivers as well as some other criminal offenders, and to relate this to clinical impairment. The present material represents cases involving new designer benzodiazepines (clonazolam, diclazepam, flubromazepam, flubromazolam and pyrazolam) and etizolam, submitted for analyses during the period July 1, 2013-May 31, 2016. Analyses were performed using an ultra-performance liquid chromatography-tandem mass spectrometry method. Blood concentrations and results from the clinical test of impairment are reported. New designer benzodiazepines were detected in 77 cases during the study period. The median (range) concentrations were 0.012mg/L (0.00048-0.10) for flubromazolam (n=25), 0.055mg/L (0.0047-1.2) for flubromazepam (n=24), 0.013mg/L (0.0021-0.057) for diclazepam (n=15), 0.050mg/L (0.019-0.17) for etizolam (n=14), 0.0053mg/L (0.0019-0.011) for clonazolam (n=7) and 0.074mg/L for pyrazolam (n=1). In six cases, designer benzodiazepines were the only drugs detected in blood, and in two of those cases, the physician had given the conclusion of "considerably impaired" upon performing the clinical test for impairment. Given the lack of previously published data on human concentrations, results presented in this study could be helpful in interpretation of blood concentrations of new designer benzodiazepines. This is crucial for the assessment of the importance of toxicological results in suspected drugged drivers, rape victims, etc. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Predictors of blood trihalomethane concentrations in NHANES 1999-2006.

PubMed

Riederer, Anne M; Dhingra, Radhika; Blount, Benjamin C; Steenland, Kyle

2014-07-01

Trihalomethanes (THMs) are water disinfection by-products that have been associated with bladder cancer and adverse birth outcomes. Four THMs (bromoform, chloroform, bromodichloromethane, dibromochloromethane) were measured in blood and tap water of U.S. adults in the National Health and Nutrition Examination Survey (NHANES) 1999-2006. THMs are metabolized to potentially toxic/mutagenic intermediates by cytochrome p450 (CYP) 2D6 and CYP2E1 enzymes. We conducted exploratory analyses of blood THMs, including factors affecting CYP2D6 and CYP2E1 activity. We used weighted multivariable regressions to evaluate associations between blood THMs and water concentrations, survey year, and other factors potentially affecting THM exposure or metabolism (e.g., prescription medications, cruciferous vegetables, diabetes, fasting, pregnancy, swimming). From 1999 to 2006, geometric mean blood and water THM levels dropped in parallel, with decreases of 32%-76% in blood and 38%-52% in water, likely resulting, in part, from the lowering of the total THM drinking water standard in 2002-2004. The strongest predictors of blood THM levels were survey year and water concentration (n = 4,232 total THM; n = 4,080 bromoform; n = 4,582 chloroform; n = 4,374 bromodichloromethane; n = 4,464 dibromochloromethane). We detected statistically significant inverse associations with diabetes and eating cruciferous vegetables in all but the bromoform model. Medications did not consistently predict blood levels. Afternoon/evening blood samples had lower THM concentrations than morning samples. In a subsample (n = 230), air chloroform better predicted blood chloroform than water chloroform, suggesting showering/bathing was a more important source than drinking. We identified several factors associated with blood THMs that may affect their metabolism. The potential health implications require further study.

Vitamin D receptor Fok1 polymorphism and blood lead concentration in children.

PubMed Central

Haynes, Erin N; Kalkwarf, Heidi J; Hornung, Richard; Wenstrup, Richard; Dietrich, Kim; Lanphear, Bruce P

2003-01-01

Variation in blood lead concentration is caused by a complex interaction of environmental, social, nutritional, and genetic factors. We evaluated the association between blood lead concentration and a vitamin D receptor (VDR) gene polymorphism. Environmental samples and blood were analyzed for lead, nutritional and behavioral factors were assessed, and VDR -Fok1 genotype was determined in 245 children. We found a significant interaction between floor dust lead and genotype on blood lead concentration. For every 1 microg/ft(2) increase in floor dust, children with VDR -FF genotype had a 1.1% increase in blood lead [95% confidence interval (CI), 0.69-1.5], VDR -Ff, 0.53% increase (95% CI, 0.1-0.92), and VDR -ff, 3.8% increase (95% CI, 1.2-6.3); however, at floor dust levels < 10 microg/ft(2), children with VDR -ff had the lowest blood lead concentrations. These data suggest that VDR -Fok1 is an effect modifier of the relationship of floor dust lead exposure and blood lead concentration. PMID:14527848

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

Cancer and blood concentrations of the comutagen harmane in essential tremor.

PubMed

Louis, Elan D; Pellegrino, Kathryn M; Factor-Litvak, Pam; Rios, Eileen; Jiang, Wendy; Henchcliffe, Claire; Zheng, Wei

2008-09-15

Blood concentrations of harmane, a tremor-producing neurotoxin, are elevated in essential tremor (ET). Harmane is also a comutagen. Using a case-control design, we compared the prevalence of cancer in ET cases vs. controls, and determined whether blood harmane concentrations are elevated among ET cases with cancer. 66/267 (24.7%) ET cases vs. 55/331 (16.6%) controls had cancer (adjusted OR 1.52, 95% CI 1.01-2.30, P = 0.04). Among specific cancer types, colon cancer was more prevalent in ET cases than controls (2.6% vs. 0.6%, P = 0.04). Log blood harmane concentration was higher in ET cases vs. controls (P = 0.02) and in participants with vs. without cancer (P = 0.02). Log blood harmane concentration was highest in ET cases with cancer when compared with other groups (P = 0.009). These links between cancer and ET and between high blood harmane and cancer in ET deserve further study. (c) 2007 Movement Disorder Society.

Optical sensor for remote estimation of alcohol concentration in blood stream

NASA Astrophysics Data System (ADS)

Shenhav, Asaf; Brodie, Ziv; Beiderman, Yevgeny; Garcia, Javier; Mico, Vicente; Zalevsky, Zeev

2013-02-01

The purpose of this manuscript is to validate our recently developed novel optical approach for extraction of remote vibration sources as a successful technique to estimate the alcohol concentration in blood stream. This technique is based on the tracking of temporal changes of reflected secondary speckle patterns produced in human skin when being illuminated by a laser beam. Since the skin's vibrations profile is changed due to the alcohol in the blood stream, the extraction of the vibration profile can be translated into the corresponding alcohol concentration values by means of defining several parameters acting as indicators for the presence of alcohol in the blood stream. We have conducted several experimental tests showing a good correlation with conventional breath alcohol concentration measurement device when determining alcohol concentration in blood. The presented preliminary results validate the proposed optical sensor as a potentially useful device for measuring alcohol in blood stream with subjects that can be car drivers inspected by police authorities or medically monitored patients.

Predictors of Blood Trihalomethane Concentrations in NHANES 1999–2006

PubMed Central

Dhingra, Radhika; Blount, Benjamin C.; Steenland, Kyle

2014-01-01

Background: Trihalomethanes (THMs) are water disinfection by-products that have been associated with bladder cancer and adverse birth outcomes. Four THMs (bromoform, chloroform, bromodichloromethane, dibromochloromethane) were measured in blood and tap water of U.S. adults in the National Health and Nutrition Examination Survey (NHANES) 1999–2006. THMs are metabolized to potentially toxic/mutagenic intermediates by cytochrome p450 (CYP) 2D6 and CYP2E1 enzymes. Objectives: We conducted exploratory analyses of blood THMs, including factors affecting CYP2D6 and CYP2E1 activity. Methods: We used weighted multivariable regressions to evaluate associations between blood THMs and water concentrations, survey year, and other factors potentially affecting THM exposure or metabolism (e.g., prescription medications, cruciferous vegetables, diabetes, fasting, pregnancy, swimming). Results: From 1999 to 2006, geometric mean blood and water THM levels dropped in parallel, with decreases of 32%–76% in blood and 38%–52% in water, likely resulting, in part, from the lowering of the total THM drinking water standard in 2002–2004. The strongest predictors of blood THM levels were survey year and water concentration (n = 4,232 total THM; n = 4,080 bromoform; n = 4,582 chloroform; n = 4,374 bromodichloromethane; n = 4,464 dibromochloromethane). We detected statistically significant inverse associations with diabetes and eating cruciferous vegetables in all but the bromoform model. Medications did not consistently predict blood levels. Afternoon/evening blood samples had lower THM concentrations than morning samples. In a subsample (n = 230), air chloroform better predicted blood chloroform than water chloroform, suggesting showering/bathing was a more important source than drinking. Conclusions: We identified several factors associated with blood THMs that may affect their metabolism. The potential health implications require further study. Citation: Riederer AM, Dhingra R

Anthroposophic lifestyle influences the concentration of metals in placenta and cord blood

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

Fagerstedt, Sara; Kippler, Maria; Scheynius, Annika

Allergic diseases develop in genetically susceptible individuals in a complex interplay with the environment, usually early in life. We have previously shown that the anthroposophic lifestyle is associated with reduced risk of allergic disease in children, but details on the influencing environmental factors are largely unknown. This study aims to elucidate if anthroposophic lifestyle influences fetal exposure to selected toxic and essential elements. Randomly selected non-smoking mothers with (n=40) and without (n=40) anthroposophic lifestyle from the prospective birth cohort ALADDIN were included. Concentrations of 12 toxic and essential elements were analyzed in full term placentas and in the erythrocyte fractionsmore » of maternal peripheral blood and of umbilical cord blood, using inductively coupled plasma mass spectrometry. Cadmium concentrations in maternal blood and placenta were significantly higher in mothers with an anthroposophic lifestyle (p<0.001), while concentrations in cord blood were generally low, irrespective of lifestyle. Cobalt concentrations were higher in both maternal blood, placenta and cord blood in the anthroposophic group. Lead concentrations were higher in maternal blood and cord blood, but not placenta, of mothers with anthroposophic lifestyle. Analysis of covariance, including lifestyle, parity, maternal age, gestational age, vegetarian diet, use of herbal medicine and occupation in the model, showed that mainly the anthroposophic lifestyle was significantly associated with cadmium concentrations. In conclusion, women with an anthroposophic lifestyle had higher concentrations of cadmium, cobalt and lead concentrations. Cadmium concentrations might have been influenced by a diet rich in vegetables and/or low iron status of the mothers. - Highlights: • Toxic elements in mother–newborn pairs in relation to anthroposophic lifestyle. • Anthroposophic lifestyle was associated with higher levels of cadmium, cobalt and lead. • A

Factors associated with total mercury concentrations in maternal blood, cord blood, and breast milk among pregnant women in Busan, Korea.

PubMed

Song, Yoojun; Lee, Chae-Kwan; Kim, Kun-Hyung; Lee, Jong-Tae; Suh, Chunhui; Kim, Se-Yeong; Kim, Jeong-Ho; Son, Byung-Chul; Kim, Dae-Hwan; Lee, Sangyoon

2016-01-01

This study investigated the concentration of total mercury (THg) in maternal blood, cord blood, and breast milk, and its association with dietary factors. A total of 127 pregnant women in Busan, Korea were recruited. Maternal blood, cord blood, and breast milk were collected at 36 weeks of gestation, at delivery, and at one week after birth, respectively. Information about dietary habits and other factors were obtained from each subject. The mean THg concentrations in maternal blood, cord blood, and breast milk were 3.12±1.36 μg/L, 5.46±2.41 μg/L, and 0.91±2.08 μg/L, respectively. Positive correlations were found between log-transformed THg concentrations in maternal blood and cord blood (r=0.829, p<0.001), and between maternal blood and breast milk (r=0.296, p=0.001). Multiple linear regression analysis showed that the log-transformed concentration of THg in maternal blood was positively correlated with fish consumption (β=0.345, p<0.0001) and negatively correlated with bean consumption (β=-0.055, p=0.048). Fish consumption (β=0.482, p<0.0001) and maternal age (β=0.025, p=0.033) were positively associated with the concentration of THg in cord blood, while negative correlations were found for bean consumption (β=-0.134, p=0.027) and parity (β=-0.172, p=0.015). Beef consumption (β=0.031, p=0.007) was positively associated with log-transformed THg concentrations in breast milk, while negative correlations were found for bean consumption (β=-0.019, p=0.003) and maternal age (β=-0.083, p=0.004). Our study found that both the dietary and demographic factors differently affected to THg concentrations among samples of maternal blood, cord blood, and breast milk.

Post-mortem quetiapine concentrations in hair segments of psychiatric patients - Correlation between hair concentration, dose and concentration in blood.

PubMed

Günther, Kamilla Nyborg; Johansen, Sys Stybe; Nielsen, Marie Katrine Klose; Wicktor, Petra; Banner, Jytte; Linnet, Kristian

2018-04-01

Drug analysis in hair is useful when seeking to establish drug intake over a period of months to years. Segmental hair analysis can also document whether psychiatric patients are receiving a stable intake of antipsychotics. This study describes segmental analysis of the antipsychotic drug quetiapine in post-mortem hair samples from long-term quetiapine users by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis. The aim was to obtain more knowledge on quetiapine concentrations in hair and to relate the concentration in hair to the administered dose and the post-mortem concentration in femoral blood. We analyzed hair samples from 22 deceased quetiapine-treated individuals, who were divided into two groups: natural hair colour and dyed/bleached hair. Two to six 1cm long segments were analyzed per individual, depending on the length of the hair, with 6cm corresponding to the last six months before death. The average daily quetiapine dose and average concentration in hair for the last six months prior to death were examined for potential correlation. Estimated doses ranged from 45 to 1040mg quetiapine daily over the period, and the average concentration in hair ranged from 0.18 to 13ng/mg. A significant positive correlation was observed between estimated daily dosage of quetiapine and average concentration in hair for individuals with natural hair colour (p=0.00005), but statistical significance was not reached for individuals with dyed/bleached hair (p=0.31). The individual coefficient of variation (CV) of the quetiapine concentrations between segments ranged from 3 to 34% for individuals with natural hair colour and 22-62% for individuals with dyed/bleached hair. Dose-adjusted concentrations in hair were significantly lower in females with dyed/bleached hair than in individuals with natural hair colour. The quetiapine concentrations in post-mortem femoral blood and in the proximal hair segment, segment 1 (S1), representing

Comparison of Oseltamivir and Oseltamivir Carboxylate Concentrations in Venous Plasma, Venous Blood, and Capillary Blood in Healthy Volunteers

PubMed Central

Instiaty, Insti; Lindegardh, Niklas; Jittmala, Podjanee; Hanpithakpong, Warunee; Blessborn, Daniel; Pukrittayakamee, Sasithon; White, Nicholas J.

2013-01-01

Oseltamivir and oseltamivir carboxylate concentrations were measured in venous plasma, venous blood, and capillary blood taken simultaneously from 24 healthy volunteers. Median (range) venous-blood-to-plasma ratios were 1.42 (0.920 to 1.97) for oseltamivir and 0.673 (0.564 to 0.814) for oseltamivir carboxylate. Capillary blood/venous plasma ratios were 1.32 (0.737 to 3.16) for oseltamivir and 0.685 (0.502 to 1.34) for oseltamivir carboxylate. Oseltamivir concentrations in venous and capillary blood were similar. Oseltamivir carboxylate showed a time-dependent distribution between venous and capillary blood. PMID:23507284

Phenothiaziniums as putative photobactericidal agents for red blood cell concentrates.

PubMed

Wainwright, M; Phoenix, D A; Smillie, T E; Wareing, D R

2001-10-01

The antibacterial activities of Methylene Blue and several of its congeners were measured against Yersinia enterocolitica, a gram-negative pathogen known to exhibit significant growth at 4 degrees C and thus constituting a threat to red blood cell concentrates which are stored at this temperature. None of the derivatives was highly active in dark conditions, as expected, but on illumination using a lamp emitting light in the waveband 615-645 nm, considerable bactericidal activity was noted using similar photosensitizer concentrations to those used elsewhere to inactivate blood-borne viruses. Two novel compounds in this area, the phenothiazinium New Methylene Blue N and the phenoxazinium Brilliant Cresyl Blue, exhibited bactericidal activity at lower concentrations than both of the established phenothiaziniums, Methylene Blue and Toluidine Blue O and the recently published blood photovirucidal agent 1,9-Dimethyl Methylene Blue. The photoactivity of these compounds was undiminished in the presence of red blood cells.

Influence of artificial sweetener on human blood glucose concentration.

PubMed

Skokan, Ilse; Endler, P Christian; Wulkersdorfer, Beatrix; Magometschnigg, Dieter; Spranger, Heinz

2007-10-05

Artificial sweeteners, such as saccharin or cyclamic acid are synthetically manufactured sweetenings. Known for their low energetic value they serve especially diabetic and adipose patients as sugar substitutes. It has been hypothesized that the substitution of sugar with artificial sweeteners may induce a decrease of the blood glucose. The aim of this study was to determine the reliability of this hypothesis by comparing the influence of regular table sugar and artificial sweeteners on the blood glucose concentration. In this pilot-study 16 patients were included suffering from adiposity, pre-diabetes and hypertension. In the sense of a cross-over design, three test trials were performed at intervals of several weeks. Each trial was followed by a test free interval. Within one test trial each patient consumed 150 ml test solution (water) that contained either 6 g of table sugar ("Kandisin") with sweetener free serving as control group. Tests were performed within 1 hr after lunch to ensure conditions comparable to patients having a desert. Every participant had to determine their blood glucose concentration immediately before and 5, 15, 30 and 60 minutes after the intake of the test solution. For statistics an analysis of variance was performed. The data showed no significant changes in the blood glucose concentration. Neither the application of sugar (F(4;60) = 1.645; p = .175) nor the consumption of an artificial sweetener (F(2.068;31.023) = 1.551; p > .05) caused significant fluctuations in the blood sugar levels. Over a time frame of 60 minutes in the control group a significant decrease of the blood sugar concentration was found (F(2.457;36.849) = 4.005; p = .020) as a physiological reaction during lunch digestion.

The Effect of Fasting Duration on Baseline Blood Glucose Concentration, Blood Insulin Concentration, Glucose/Insulin Ratio, Oral Sugar Test, and Insulin Response Test Results in Horses.

PubMed

Bertin, F R; Taylor, S D; Bianco, A W; Sojka-Kritchevsky, J E

2016-09-01

Published descriptions of the oral sugar test (OST) and insulin response test (IRT) have been inconsistent when specifying the protocol for fasting horses before testing. The purpose of our study was to examine the effect of fasting duration on blood glucose concentration, blood insulin concentration, glucose/insulin ratio, OST, and IRT results in horses. Ten healthy adult horses. Both OST and IRT were performed on horses without fasting and after fasting for 3, 6, and 12 hours. Thus, 8 tests were performed per horse in a randomized order. Blood collected at the initial time point of the OST was analysed for both blood glucose and serum insulin concentrations so that baseline concentrations and the glucose/insulin ratio could be determined. Unless fasted, horses had free-choice access to grass hay. There was no effect of fasting and fasting duration on blood glucose concentration, serum insulin concentration, glucose/insulin ratio, or the OST. Response to insulin in the IRT was decreased in fasted horses. The effect increased with fasting duration, with the least response to insulin administration after a 12-hour fast. These data indicate that insulin sensitivity is not a fixed trait in horses. Fasting a horse is not recommended for a glucose/insulin ratio or IRT, and fasting a horse for 3 hours is recommended for the OST. Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Methods for estimating expected blood alcohol concentration

DOT National Transportation Integrated Search

1980-08-01

Estimates of blood alcohol concentration (BAC) typically are based on the amount of alcohol consumed per pound bodyweight. This method fails to consider either food intake or body composition, factors which significantly affect BAC. A laboratory expe...

Prevalence of driving with blood drug concentrations above proposed new legal limits in Norway: estimations based on drug concentrations in oral fluid.

PubMed

Gjerde, Hallvard; Normann, Per T; Christophersen, Asbjørg S; Mørland, Jørg

2011-07-15

To estimate the prevalence of driving with blood drug concentrations above the recently proposed Norwegian legal limits for drugged driving in random traffic. The results from a roadside survey of 10,816 drivers was used as basis for the estimation, and the most prevalent drugs were included. Three approaches were used to estimate the prevalence of drug concentrations above the proposed legal limits in blood based on drug concentrations in oral fluid: comparison with drug concentrations observed in oral fluid and blood in pharmacokinetic studies, estimating the prevalence of drug concentrations in blood by calculating the prevalence of drug concentrations in oral fluid that were larger than the limit in blood multiplied with mean oral fluid/blood ratios, and a mathematical simulation mimicking the relationship between drug concentration distributions in blood and oral fluid for populations of drug users. In total, alcohol or drugs were detected in 5.7% of the samples of oral fluid from drivers in normal traffic; 3.8% (n=410) were positive for the drugs that we included in the assessment. The estimation of drug concentrations in blood suggested that about 1.5% had concentrations above the proposed legal limits in blood for the studied drugs, which is about 40% of those who were positive for the drugs in oral fluid. The estimated prevalence of driving with concentrations of psychoactive drugs in blood above the proposed legal limits was for illegal drugs 0.4% and for medicinal drugs 1.1%. These may be regarded as minimum estimates as some drugs were not included in the assessment. These prevalences are higher than the prevalence of driving with blood alcohol concentrations above the legal limit of 0.2g/kg in Norway. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

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

Methods for estimating expected blood alcohol concentration.

DOT National Transportation Integrated Search

1980-12-01

Estimates of blood alcohol concentration (BAC) typically are based on the amount of alcohol consumed per pound body weight. This method fails to consider food intake and body composition, which significantly affect BAC. A laboratory experiment was co...

Determinants of bone and blood lead concentrations in the early postpartum period

PubMed Central

Brown, M. J.; Hu, H.; Gonzales-Cossio, T.; Peterson, K.; Sanin, L.; Kageyama, M. d.; Palazuelos, E.; Aro, A.; Schnaas, L.; Hernandez-Avila, M.

2000-01-01

OBJECTIVE—This study investigated determinants of bone and blood lead concentrations in 430 lactating Mexican women during the early postpartum period and the contribution of bone lead to blood lead.
METHODS—Maternal venous lead was measured at delivery and postpartum, and bone lead concentrations, measured with in vivo K-x ray fluorescence, were measured post partum. Data on environmental exposure, demographic characteristics, and maternal factors related to exposure to lead were collected by questionnaire. Linear regression was used to examine the relations between bone and blood lead, demographics, and environmental exposure variables.
RESULTS—Mean (SD) blood, tibial, and patellar lead concentrations were 9.5 (4.5) µg/dl, 10.2 (10.1) µg Pb/g bone mineral, and 15.2 (15.1) µg Pb/g bone mineral respectively. These values are considerably higher than values for women in the United States. Older age, the cumulative use of lead glazed pottery, and higher proportion of life spent in Mexico City were powerful predictors of higher bone lead concentrations. Use of lead glazed ceramics to cook food in the past week and increased patellar lead concentrations were significant predictors of increased blood lead. Patellar lead concentrations explained one third of the variance accounted for by the final blood lead model. Women in the 90th percentile for patella lead had an untransformed predicted mean blood lead concentration 3.6 µg/dl higher than those in the 10th percentile.
CONCLUSIONS—This study identified the use of lead glazed ceramics as a major source of cumulative exposure to lead, as reflected by bone lead concentrations, as well as current exposure, reflected by blood lead, in Mexico. A higher proportion of life spent in Mexico City, a proxy for exposure to leaded gasoline emissions, was identified as the other major source of cumulative lead exposure. The influence of bone lead on blood lead coupled with the long half life of lead in bone has

Effect of new Vacutainer blood collection tubes on plasma lidocaine concentrations.

PubMed

Lopez, L M; Sen, A; Robinson, J D; Curry, R W

1987-12-01

This study was designed to establish whether plasma lidocaine concentrations changed subsequent to contact with a new formulation of rubber-stopper Vacutainer collection tubes. Plasma lidocaine concentrations from blood samples exposed to rubber stoppers for one hour were compared with concentrations from blood samples which were not exposed to rubber stoppers. Plasma lidocaine concentrations remained essentially unchanged following one-hour exposure to Vacutainer rubber stoppers. The new formulation of "red-top" Vacutainer may be used reliably in lidocaine therapeutic drug monitoring.

Increased blood carboxyhaemoglobin concentrations in inflammatory pulmonary diseases

PubMed Central

Yasuda, H; Yamaya, M; Yanai, M; Ohrui, T; Sasaki, H

2002-01-01

Background: Exhaled carbon monoxide has been reported to increase in inflammatory pulmonary diseases and to be correlated with blood carboxyhaemoglobin (Hb-CO) concentration. A study was undertaken to determine whether arterial blood Hb-CO increases in patients with inflammatory pulmonary diseases. Methods: The Hb-CO concentration in arterial blood was measured with a spectrophotometer in 34 normal control subjects, 24 patients with bronchial asthma, 52 patients with pneumonia, and 21 patients with idiopathic pulmonary fibrosis (IPF). Results: The mean (SE) Hb-CO concentrations in patients with bronchial asthma during exacerbations (n=24, 1.05 (0.05)%), with pneumonia at the onset of illness (n=52, 1.08 (0.06)%), and with IPF (n=21, 1.03 (0.09)%) were significantly higher than those in control subjects (n=34, 0.60 (0.07)%) (mean difference 0.45% (95% confidence interval (CI) 0.23 to 0.67), p<0.01 in patients with bronchial asthma, mean difference 0.48% (95% CI 0.35 to 0.60), p<0.0001 in patients with pneumonia, and mean difference 0.43% (95% CI 0.26 to 0.61) p<0.001 in patients with IPF). In 20 patients with bronchial asthma the Hb-CO concentration decreased after 3 weeks of treatment with oral glucocorticoids (p<0.001). In 20 patients with pneumonia the Hb-CO concentration had decreased after 3 weeks when patients showed evidence of clinical improvement (p<0.001). The values of C-reactive protein (CRP), an acute phase protein, correlated with Hb-CO concentrations in patients with pneumonia (r=0.74, p<0.0001) and in those with IPF (r=0.46, p<0.01). In patients with bronchial asthma changes in Hb-CO concentrations were significantly correlated with those in forced expiratory volume in 1 second (FEV1) after 3 weeks (r=0.67, p<0.01). Exhaled carbon monoxide (CO) concentrations were correlated with Hb-CO concentrations (n=33, r=0.80, p<0.0001). Conclusions: Hb-CO concentrations are increased in inflammatory pulmonary diseases including bronchial asthma, pneumonia, and

Cadmium blood concentrations in relation to nutrition.

PubMed

Krajcovicová-Kudládková, Marica; Ursínyová, Monika; Masánová, Vlasta; Béderová, Alzbeta; Valachovicová, Martina

2006-09-01

Cadmium is a toxic element ubiquitous in the environment, which damages biological systems in various ways. The major source of cadmium exposure is food. High cadmium content in the soil leads to high cadmium concentrations in certain plants such as grains (above all surface layers and germs), oil or non-oil seeds, fruit and vegetables. These food commodities are the crucial components of a vegetarian nutrition. Blood cadmium concentrations were measured in two non-smoking population groups: the vegetarian group (n = 80) and the non-vegetarian (control) group of general population on traditional mixed diet (n = 84). The significantly higher blood cadmium content (1.78 +/- 0.22 vs. 0.45 +/- 0.04 microg/l) was measured in vegetarian group. Healthy risk values > 5 microg/l were found in 6 vegetarians vs. no non-vegetarian. The highest cadmium concentration (3.15 +/- 0.77 microg/l) was measured in vegan subgroup (plant food only, n = 10) and that value decreased with increasing animal food consumption (1.75 +/- 0.36 microg/l, lactovegetarian and lactoovovegetarian subgroup/added dairy products and eggs, n = 41/, 1.34 +/- 0.21 microg/I, semivegetarian subgroup /as a previous subgroup and added white meat, n = 291). Risk vegetarians vs. non-risk vegetarians consume significantly higher amounts of whole grain products, grain sprouts and oil seeds. Blood cadmium content is directly influenced by age (r = 0.32, p < 0.001), by whole grain product intake (r = 0.66, p < 0.001) and by duration of vegetarianism (r = 0.5, p < 0.001). Oxidative stress plays a major role in chronic cadmium induced hepatic and renal toxicity as well as in other consequences of cadmium injuries. Vegetarians have significantly higher plasma concentrations of natural antioxidants. The sufficient antioxidative protection against cadmium induced free radical formation in vegetarians may inhibit the harmful effects of greater cadmium intake from plant food.

Organohalogen concentrations in blood and adipose tissue of Southern Beaufort Sea polar bears.

PubMed

Bentzen, T W; Muir, D C G; Amstrup, S C; O'Hara, T M

2008-11-15

We analyzed 151 organohalogen chemicals (OHCs) in whole blood and subcutaneous fat of 57 polar bears sampled along the Alaskan Beaufort Sea coast in spring, 2003. All major organochlorine pesticides, PCBs, PBDEs and their congeners were assessed. Concentrations of most OHCs continue to be lower among Southern Beaufort Sea polar bears than reported for other populations. Additionally, toxaphenes and related compounds were assessed in adipose tissue, and 8 perflourinated compounds (PFCs) were examined in blood. Perfluorooctane sulfonate (PFOS) concentrations exceeded those of any other contaminant measured in blood. SigmaChlordane concentrations were higher in females, and both SigmaPCBs and SigmaChlordane concentrations in adipose tissue decreased significantly with age. The rank order of OHC mean concentrations; SigmaPCB>Sigma10PCB>PCB153>SigmaChlordane>Oxychlordane>PCB180>SigmaHCH>beta-HCH>SigmaDDT>p,p-DDE>SigmaPBDE>HCB>Toxaphene was similar for compounds above detection limits in both fat and blood. Although correlation between OHC concentrations in blood and adipose tissue was examined, the predictability of concentrations in one matrix for the other was limited.

Organohalogen concentrations in blood and adipose tissue of Southern Beaufort Sea polar bears

USGS Publications Warehouse

Bentzen, T.W.; Muir, D.C.G.; Amstrup, Steven C.; O'Hara, T. M.

2008-01-01

We analyzed 151 organohalogen chemicals (OHCs) in whole blood and subcutaneous fat of 57 polar bears sampled along the Alaskan Beaufort Sea coast in spring, 2003. All major organochlorine pesticides, PCBs, PBDEs and their congeners were assessed. Concentrations of most OHCs continue to be lower among Southern Beaufort Sea polar bears than reported for other populations. Additionally, toxaphenes and related compounds were assessed in adipose tissue, and 8 perflourinated compounds (PFCs) were examined in blood. Perfluorooctane sulfonate (PFOS) concentrations exceeded those of any other contaminant measured in blood. ??Chlordane concentrations were higher in females, and both ??PCBs and ??Chlordane concentrations in adipose tissue decreased significantly with age. The rank order of OHC mean concentrations; ??PCB > ??10PCB > PCB153 > ??Chlordane > Oxychlordane > PCB180 > ??HCH > ??-HCH > ??DDT > p,p-DDE > ??PBDE > HCB > Toxaphene was similar for compounds above detection limits in both fat and blood. Although correlation between OHC concentrations in blood and adipose tissue was examined, the predictability of concentrations in one matrix for the other was limited. ?? 2008 Elsevier B.V.

Cancer and Blood Concentrations of the Co-mutagen Harmane in Essential Tremor

PubMed Central

Louis, Elan D.; Pellegrino, Kathryn M.; Factor-Litvak, Pam; Rios, Eileen; Jiang, Wendy; Henchcliffe, Claire; Zheng, Wei

2008-01-01

Background Blood concentrations of harmane, a tremor-producing neurotoxin, are elevated in essential tremor (ET). Harmane is also a co-mutagen. Objective To compare the prevalence of cancer in ET cases vs. controls, and determine whether blood harmane concentrations are elevated among ET cases with cancer. Methods Case-control design. Results 66/267 (24.7%) ET cases vs. 55/331 (16.6%) controls had cancer (adjusted OR 1.52, 95% CI 1.01 – 2.30, p = 0.04). Among specific cancer types, colon cancer was more prevalent in ET cases than controls (2.6% vs. 0.6%, p = 0.04). Log blood harmane concentration was higher in ET cases vs. controls (p = 0.02) and in participants with vs. without cancer (p = 0.02). Log blood harmane concentration was highest in ET cases with cancer when compared with other groups (p = 0.009). Discussion These links between cancer and ET and between high blood harmane and cancer in ET deserve further study. PMID:18709680

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.

Evaluation of two portable meters for determination of blood triglyceride concentration in dogs.

PubMed

Kluger, Elissa K; Dhand, Navneet K; Malik, Richard; Ilkin, William J; Snow, David H; Govendir, Merran

2010-02-01

To evaluate agreement between 2 portable triglyceride meters and a veterinary laboratory for measurement of blood triglyceride concentrations in dogs and evaluate effects of Hct and blood volume analyzed. 97 blood samples collected from 60 dogs. Triglyceride concentrations were measured in blood by use of 2 meters and compared with serum triglyceride concentrations determined by a veterinary laboratory. Within- and between-day precision, accuracy, and effects of blood volume and Hct were analyzed. Accuracy of both meters varied with triglyceride concentration, although both accurately delineated dogs with triglyceride concentrations < 180 mg/dL versus > or = 180 mg/dL. One meter had results with excellent overall correlation with results of the standard laboratory method, with a concordance correlation coefficient of 0.94 and mean difference of 20.3 mg/dL. The other meter had a good overall concordance correlation coefficient of 0.86 with a higher absolute mean difference of -27.7 mg/dL. Results were only affected by blood volume; triglyceride concentrations determined via both meters were significantly lower when 7 microL of EDTA-anticoagulated blood was used, compared with larger volumes. 1 meter had greater accuracy in the range of 140 to 400 mg/dL and was therefore well suited to detect hypertriglyceridemia. The other meter was accurate with triglyceride values < 140 mg/dL and yielded results similar to those of the veterinary laboratory in the range of 140 to 400 mg/dL, therefore being suitable for determination of triglyceride concentrations in nonfed dogs and dogs with mildly high concentrations.

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.

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

Method for measuring lead concentrations in blood

DOEpatents

Nogar, Nicholas S.

2001-01-01

Method for measuring lead concentrations in blood. The present invention includes the use of resonant laser ablation to analyze .ltoreq.1 .mu.L (or equivalent mass) samples of blood for lead content. A typical finger prick, for example, yields about 10 .mu.L. Solid samples may also readily be analyzed by resonant laser ablation. The sample is placed on a lead-free, electrically conducting substrate and irradiated with a single, focused laser beam which simultaneously vaporizes, atomizes, and resonantly ionizes an analyte of interest in a sample. The ions are then sorted, collected and detected using a mass spectrometer.

Cadmium Concentration in Mother's Blood, Milk, and Newborn's Blood and Its Correlation with Fatty Acids, Anthropometric Characteristics, and Mother's Smoking Status.

PubMed

Olszowski, Tomasz; Baranowska-Bosiacka, Irena; Rębacz-Maron, Ewa; Gutowska, Izabela; Jamioł, Dominika; Prokopowicz, Adam; Goschorska, Marta; Chlubek, Dariusz

2016-11-01

The aim of this study was to determine cadmium concentration in mothers' blood, milk, and newborns' blood from Szczecin (Poland) as a result of environmental cadmium exposure and evaluate the correlation (1) between cadmium levels in analyzed matrices, (2) between cadmium and fatty acids in those matrices, and (3) between cadmium and some selected personal variables, such as anthropometric characteristics, mothers' smoking status, and fruit and fish consumption by mothers. The concentration of cadmium in whole blood and milk of mothers and in the umbilical cord blood of newborns was determined by atomic absorption spectrometry with graphite furnace atomization and Zeeman correction. The fatty acid concentrations were determined by gas chromatography in our previous study. The mean concentrations of cadmium in maternal blood, newborn's blood, and breast milk were 0.61 ± 0.62 μg/L, 0.05 ± 0.04 μg/L, and 0.11 ± 0.07 μg/L, respectively, and differed significantly between analyzed matrices. Cadmium concentrations in the umbilical cord blood were 15 % (range 0-83 %) of the concentration in maternal blood, whereas cadmium concentrations in breast milk constituted 35 % (range 3-142 %) of the concentration in mothers' blood. No correlation was found between cadmium levels in three analyzed matrices. The correlation analysis revealed significant low positive correlation between maternal blood cadmium concentrations and concentrations of elaidic, oleic, and cis-vaccenic acids in mothers' milk (correlation coefficients 0.30, 0.32, and 0.31, respectively). Mothers' blood cadmium correlated with mothers' age (r = -0.26, p = 0.03), maternal smoking before pregnancy (r = 0.55, p < 0.000), maternal smoking during pregnancy (r = 0.58, p < 0.000), and fruit consumption by mothers after delivery (r = -0.44, p = 0.003). Mothers' height was the only variable that correlated significantly with breast milk cadmium levels. Newborns

Blood concentrations of amino acids, glucose and lactate during experimental swine dysentery.

PubMed

Jonasson, R; Essén-Gustavsson, B; Jensen-Waern, M

2007-06-01

The aim of this study was to examine blood concentrations of amino acids, glucose and lactate in association with experimental swine dysentery. Ten pigs (approximately 23kg) were orally inoculated with Brachyspira hyodysenteriae. Eight animals developed muco-haemorrhagic diarrhoea with impaired general appearance, changes in white blood cell counts and increased levels of the acute phase protein Serum Amyolid A. Blood samples were taken before inoculation, during the incubation period, during clinical signs of dysentery and during recovery. Neither plasma glucose nor lactate concentrations changed during the course of swine dysentery, but the serum concentrations of gluconeogenic non-essential amino acids decreased during dysentery. This was mainly due to decreases in alanine, glutamine, serine and tyrosine. Lysine increased during dysentery and at the beginning of the recovery period, and leucine increased during recovery. Glutamine, alanine and tyrosine levels show negative correlations with the numbers of neutrophils and monocytes. In conclusion, swine dysentery altered the blood concentrations of amino acids, but not of glucose or lactate.

Rapid Microbial Sample Preparation from Blood Using a Novel Concentration Device

PubMed Central

Boardman, Anna K.; Campbell, Jennifer; Wirz, Holger; Sharon, Andre; Sauer-Budge, Alexis F.

2015-01-01

Appropriate care for bacteremic patients is dictated by the amount of time needed for an accurate diagnosis. However, the concentration of microbes in the blood is extremely low in these patients (1–100 CFU/mL), traditionally requiring growth (blood culture) or amplification (e.g., PCR) for detection. Current culture-based methods can take a minimum of two days, while faster methods like PCR require a sample free of inhibitors (i.e., blood components). Though commercial kits exist for the removal of blood from these samples, they typically capture only DNA, thereby necessitating the use of blood culture for antimicrobial testing. Here, we report a novel, scaled-up sample preparation protocol carried out in a new microbial concentration device. The process can efficiently lyse 10 mL of bacteremic blood while maintaining the microorganisms’ viability, giving a 30‑μL final output volume. A suite of six microorganisms (Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae, Pseudomonas aeruginosa, and Candida albicans) at a range of clinically relevant concentrations was tested. All of the microorganisms had recoveries greater than 55% at the highest tested concentration of 100 CFU/mL, with three of them having over 70% recovery. At the lowest tested concentration of 3 CFU/mL, two microorganisms had recoveries of ca. 40–50% while the other four gave recoveries greater than 70%. Using a Taqman assay for methicillin-sensitive S. aureus (MSSA)to prove the feasibility of downstream analysis, we show that our microbial pellets are clean enough for PCR amplification. PCR testing of 56 spiked-positive and negative samples gave a specificity of 0.97 and a sensitivity of 0.96, showing that our sample preparation protocol holds great promise for the rapid diagnosis of bacteremia directly from a primary sample. PMID:25675242

Circadian melatonin concentration rhythm is lost in pregnant women with altered blood pressure rhythm.

PubMed

Tranquilli, A L; Turi, A; Giannubilo, S R; Garbati, E

2004-03-01

We assessed the correlation between the rhythm of melatonin concentration and circadian blood pressure patterns in normal and hypertensive pregnancy. Ambulatory 24-h blood pressure and blood samples every 4 h were monitored in 16 primigravidae who had shown an abnormal circadian blood pressure pattern (eight pre-eclamptic and eight normotensive) in pregnancy and 6-12 months after pregnancy. The circadian rhythm was analyzed by chronobiological measures. Eight normotensive women with maintained blood pressure rhythm served as controls. During pregnancy, melatonin concentration was significantly higher in pre-eclamptic than in normotensive women (pre-eclampsia, 29.4 +/- 1.9 pg/ml, normotensin, altered rhythm, 15.6 +/- 2.1; controls, 22.7 +/- 1.8; p < 0.001). This difference faded after pregnancy, owing to the fall observed in pre-eclampsia (11.8 +/- 3.2 pg/ml, 9.8 +/- 2.1, and 11.1 +/- 2.0, respectively; NS). The rhythm of melatonin concentration was lost in all pregnant women with loss of blood pressure rhythm. After pregnancy, normotensive women showed a reappearance of both melatonin and blood pressure rhythm, whereas pre-eclamptic women showed a reappearance of blood pressure but not melatonin rhythm. The loss of blood pressure rhythm in pregnancy is consistent with the loss of melatonin concentration rhythm. In pre-eclamptic women, the normalization of blood pressure rhythm, while melatonin rhythm remained altered, suggests a temporal or causal priority of circadian concentration of melatonin in the determination of blood pressure trend.

Concentrations of zolpidem and zopiclone in venous blood samples from impaired drivers compared with femoral blood from forensic autopsies.

PubMed

Jones, Alan Wayne; Holmgren, Anita

2012-10-10

The concentrations of zolpidem and zopiclone were determined in peripheral blood samples in two forensic materials collected over a 10-year period (2001-2010). The z-hypnotics were determined in venous blood from living subjects (impaired drivers) and in femoral blood from deceased persons (forensic autopsies), with the latter classified as intoxication or other causes of death. The z-hypnotics were determined in blood by capillary column gas chromatography (GC) with a nitrogen-phosphorous (N-P) detector after solvent extraction with n-butyl acetate. The analytical limit of quantitation (LOQ) was 0.02 mg/L for zopiclone and 0.05 mg/L for zolpidem and these have remained unchanged throughout the study. When death was attributed to drug intoxication (N=918), the median concentration of zopiclone in blood was 0.20 mg/L compared with 0.06 mg/L for other causes of death (N=1215) and 0.07 mg/L in traffic offenders (N=691) (p<0.001). Likewise, a higher median concentration (0.30 mg/L) was found in intoxication deaths involving zolpidem (N=357) compared with 0.13 mg/L for other causes of death (N=397) or 0.19 mg/L in impaired drivers (N=837) (p<0.001). Median concentration in blood of both z-hypnotics were appreciably higher in intoxication deaths when no other substances were identified; 0 70 mg/L (N=12) for zopiclone and 1.35 mg/L (N=12) for zolpidem. The median concentrations of z-hypnotics in blood decreased as the number of co-ingested substances increased for intoxication deaths but not other causes of death. The most prevalent co-ingested substances were ethanol in autopsy cases and diazepam in the motorists. This large compilation of forensic cases should prove useful when toxicologists are required to interpret concentrations of z-hypnotics in blood samples in relation to cause of death. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

A review on therapeutic drug monitoring of immunosuppressant drugs.

PubMed

Mohammadpour, Niloufar; Elyasi, Sepideh; Vahdati, Naser; Mohammadpour, Amir Hooshang; Shamsara, Jamal

2011-11-01

: Immunosuppressants require therapeutic drug monitoring because of their narrow therapeutic index and significant inter-individual variability in blood concentrations. This variability can be because of factors like drug-nutrient interactions, drug-disease interactions, renal-insufficiency, inflammation and infection, gender, age, polymorphism and liver mass. Drug monitoring is widely practiced especially for cyclosporine, tacrolimus, sirolimus and mycophenolic acid. CYCLOSPORINE: Therapeutic monitoring of immunosuppressive therapy with cyclosporine is a critical requirement because of intra- and inter-patient variability of drug absorption, narrow therapeutic window and drug induced nephrotoxicity. MYCOPHENOLIC ACID MPA: Some reasons for therapeutic drug monitoring of MPA during post-transplant period include: relationship between MPA pharmacokinetic parameters and clinical outcomes, Inter-patient pharmacokinetic variability for MPA despite fixed MMF doses, alternations of MPA pharmacokinetics during the first months after transplantation, drug- drug interaction and influence of kidney function on MPA pharmacokinetic. SIROLIMUS: A recent review of the pharmacokinetics of sirolimus suggested a therapeutic range of 5 to 10 μg l(-1) in whole blood. However, the only consensus guidelines published on the therapeutic monitoring of sirolimus concluded that there was not enough information available about the clinical use of the drug to make recommendations. TACROLIMUS: Sudies have shown, in kidney and liver transplant patients, significant associations of low tacrolimus concentrations with rejection and of high concentrations with nephrotoxicity. Although the feasibility of a limited sampling scheme to predict AUC has been demonstrated, as yet, trough, or pre-dose, whole blood concentration monitoring is still the method of choice.

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.

Impact of Low Blood Lead Concentrations on IQ and School Performance in Chinese Children

PubMed Central

Liu, Jianghong; Li, Linda; Wang, Yingjie; Yan, Chonghuai; Liu, Xianchen

2013-01-01

Objectives Examine the relationships between blood lead concentrations and children's intelligence quotient (IQ) and school performance. Participants and Methods Participants were 1341 children (738 boys and 603 girls) from Jintan, China. Blood lead concentrations were measured when children were 3–5 years old. IQ was assessed using the Chinese version and norms of the Wechsler Preschool and Primary Scale of Intelligence – Revised when children were 6 years old. School performance was assessed by standardized city tests on 3 major subjects (Chinese, Math, and English [as a foreign language]) when children were age 8–10 years. Results Mean blood lead concentration was 6.43 µg/dL (SD = 2.64). For blood lead concentrations, 7.8% of children (n = 105) had ≥10.0 µg/dL, 13.8% (n = 185) had 8.0 to <10.0 µg/dL, and 78.4% (n = 1051) had <8.0 µg/dL. Compared to children with blood lead concentrations <8 µg/dL, those with blood lead concentrations ≥8 µg/dL scored 2–3 points lower in IQ and 5–6 points lower in school tests. There were no significant differences in IQ or school tests between children with blood lead concentrations groups 8–10 and ≥10 µg/dL. After adjustment for child and family characteristics and IQ, blood lead concentrations ≥10 µg/dL vs <8 µg/dL at ages 3–5 years was associated with reduced scores on school tests at age 8–10 years (Chinese, β = −3.54, 95%CI = −6.46, −0.63; Math, β = −4.63, 95%CI = −7.86, −1.40; English, β = −4.66, 95%CI = −8.09, −1.23). IQ partially mediated the relationship between elevated blood lead concentrations and later school performance. Conclusions Findings support that blood lead concentrations in early childhood, even <10 µg/dL, have a long-term negative impact on cognitive development. The association between blood lead concentrations 8–10 µg/dL and cognitive development needs further study in Chinese children and children from

Blood cadmium concentration and lipid profile in Korean adults

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

Kim, Kisok, E-mail: kimkisok@kmu.ac.kr

Although animal experiments have shown that cadmium exposure induces alterations in lipid profiles, no epidemiological study of this relationship has been performed. The objective of this study was to evaluate the association between blood cadmium concentration and blood lipid levels in Korean adults. A cross-sectional study comprising participants (n=3903) aged 20 years or older from the 2005, 2008, and 2009 Korea National Health and Nutrition Examination Surveys was conducted. Demographic characteristics and dietary intake were obtained from the participants by questionnaire, and cadmium and lipid levels were determined by analysis of blood samples. After adjusting for demographic and dietary factors,more » blood concentration of cadmium was positively associated with the risk of low high-density lipoprotein cholesterol (HDL-C) in a dose-dependent manner (p for trend <0.001). In addition, the odds ratios (ORs) of a high triglyceride to HDL-C ratio was significantly increased in the high blood cadmium groups [OR=1.36; 95% confidence interval (CI), 1.03-1.79 for fourth quintile and OR=1.41; 95% CI, 1.07-1.86 for fifth quintile] compared with the lowest quintile group. However, high blood cadmium was not associated with a risk of high total cholesterol, high low-density lipoprotein cholesterol, or high triglycerides. These data suggest that an increased cadmium body burden increases the risk of dyslipidemia, mainly due to the increased risk of low HDL-C and the high ratio of triglycerides to HDL-C.« less

Venous blood provides lower GLP-1 concentrations than arterialised blood in the postprandial, but not fasted state: Consequences of sampling methods.

PubMed

Chen, Yung-Chih; Edinburgh, Robert M; Hengist, Aaron; Smith, Harry A; Walhin, Jean-Philippe; Betts, James A; Thompson, Dylan; Gonzalez, Javier T

2018-06-27

What is the central question of this study? Glucagon-like peptide-1 (GLP-1) is an important obesity/diabetes target, with effects dependent on circulating GLP-1 concentrations. Peripheral tissues extract GLP-1, therefore sampling venous versus arterialised blood may provide different GLP-1 concentrations. This study examined whether arterialisation alters GLP-1 concentrations during fasting and feeding. What is the main finding and its importance? This study demonstrates that venous blood provides lower postprandial, but not fasting, GLP-1 concentrations versus arterialised blood. Therefore, when accurate assessment of postprandial peripheral availability of GLP-1 is required, blood sampling methods should be carefully considered, clearly reported, and arterialisation is recommended. Glucagon-like peptide-1 (GLP-1) displays concentration-dependent effects on metabolism, appetite and angiogenesis, so accurate determination of circulating GLP-1 concentrations is important. This study compared GLP-1 concentrations in venous versus arterialised blood under both fasted and fed conditions. Venous and arterialised blood samples were simultaneously drawn from ten, young, healthy men before, and 30, 60 and 120 min after, ingestion of 75 g glucose. Plasma GLP-1 concentrations increased in response to glucose ingestion (time effect: p < 0.01) and to a lesser extend in venous versus arterialised plasma (time x arterialisation interaction: p < 0.01). Accordingly, the plasma incremental area under the curve was lower in venous versus arterialised plasma (974 ± 88 versus 1214 ± 115 pmol·L x 120 min -1 , respectively, p = 0.049). In the postprandial state, there was a positive relationship between arterialised GLP-1 concentrations and the venous-arterialised difference in GLP-1 concentrations (r 2  = 0.51; p < 0.01). Both arterialised and venous peak GLP-1 concentrations showed positive relationships with peak arterialised insulin concentrations (both r 2 �

Blood mercury concentrations in CHARGE Study children with and without autism.

PubMed

Hertz-Picciotto, Irva; Green, Peter G; Delwiche, Lora; Hansen, Robin; Walker, Cheryl; Pessah, Isaac N

2010-01-01

Some authors have reported higher blood mercury (Hg) levels in persons with autism, relative to unaffected controls. We compared blood total Hg concentrations in children with autism or autism spectrum disorder (AU/ASD) and typically developing (TD) controls in population-based samples, and determined the role of fish consumption in differences observed. The Childhood Autism Risk from Genetics and the Environment (CHARGE) Study enrolled children 2-5 years of age. After diagnostic evaluation, we analyzed three groups: AU/ASD, non-AU/ASD with developmental delay (DD), and population-based TD controls. Mothers were interviewed about household, medical, and dietary exposures. Blood Hg was measured by inductively coupled plasma mass spectrometry. Multiple linear regression analysis was conducted (n = 452) to predict blood Hg from diagnostic status controlling for Hg sources. Fish consumption strongly predicted total Hg concentration. AU/ASD children ate less fish. After adjustment for fish and other Hg sources, blood Hg levels in AU/ASD children were similar to those of TD children (p = 0.75); this was also true among non-fish eaters (p = 0.73). The direct effect of AU/ASD diagnosis on blood Hg not through the indirect pathway of altered fish consumption was a 12% reduction. DD children had lower blood Hg concentrations in all analyses. Dental amalgams in children with gum-chewing or teeth-grinding habits predicted higher levels. After accounting for dietary and other differences in Hg exposures, total Hg in blood was neither elevated nor reduced in CHARGE Study preschoolers with AU/ASD compared with unaffected controls, and resembled those of nationally representative samples.

The complexity of hair/blood mercury concentration ratios and its implications.

PubMed

Liberda, Eric N; Tsuji, Leonard J S; Martin, Ian D; Ayotte, Pierre; Dewailly, Eric; Nieboer, Evert

2014-10-01

The World Health Organization (WHO) recommends a mercury (Hg) hair-to-blood ratio of 250 for the conversion of Hg hair levels to those in whole blood. This encouraged the selection of hair as the preferred analyte because it minimizes collection, storage, and transportation issues. In spite of these advantages, there is concern about inherent uncertainties in the use of this ratio. To evaluate the appropriateness of the WHO ratio, we investigated total hair and total blood Hg concentrations in 1333 individuals from 9 First Nations (Aboriginal) communities in northern Québec, Canada. We grouped participants by sex, age, and community and performed a 3-factor (M)ANOVA for total Hg in hair (0-2 cm), total Hg in blood, and their ratio. In addition, we calculated the percent error associated with the use of the WHO ratio in predicting blood Hg concentrations from hair Hg. For group comparisons, Estimated Marginal Means (EMMS) were calculated following ANOVA. At the community level, the error in blood Hg estimated from hair Hg ranged -25% to +24%. Systematic underestimation (-8.4%) occurred for females and overestimation for males (+5.8%). At the individual level, the corresponding error range was -98.7% to 1040%, with observed hair-to-blood ratios spanning 3 to 2845. The application of the ratio endorsed by the WHO would be unreliable for determining individual follow-up. We propose that Hg exposure be assessed by blood measurements when there are human health concerns, and that the singular use of hair and the hair-to-blood concentration conversion be discouraged in establishing individual risk. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

[Blood PCB concentrations and their tendencies examined in Fukuoka 2007-2010 annual inspections for Yusho].

PubMed

Hori, Tsuguhide; Yasutake, Daisuke; Ashizuka, Yuki; Takahashi, Koji; Kajiwara, Jumboku; Hirata, Teruaki; Uchi, Hiroshi; Furue, Masutaka

2011-04-01

We performed PCB congener specific analysis using HRGC/HRMS and determined their concentrations and blood chromatogram classifications in 275 individual blood samples collected during annual Yusho examinations between 2007 and 2010. When both blood total PCB concentrations and blood chromatogram classifications were compared among eleven Yusho patients undergoing examinations between 2007 and 2010, the longitudinal concentrations and classifications in the respective individuals hardly changed over these years. In a subset of persons suspected of Yusho, it was found that the mean total blood concentrations of three index congeners, that is, 2, 3', 4, 4', 5-pentaCB (PCB118), 2, 2', 4, 4', 5, 5'-hexaCB (PCB153), 2, 3, 3', 4, 4', 5-hexaCB (PCB156) and mean blood total PCB concentrations gradually decreased between 2007 and 2010. Mean concentration of PCB118 in blood from persons suspected of Yusho was calculated as 0.035 ng/g in the 2010 examination, which was 36% lower than the mean value of 0.054 ng/g in the 2007 examination: the concentration of PCB118 showed the highest degree of decrease among the three index congeners. Among persons suspected of Yusho, occupational rates of persons with blood PCB concentrations below one ppb in the entire population increased from approx. 50% in 2007 to approx. 70% in 2010. The lowest concentration of PCB156 in blood of persons suspected of Yusho in 2010 was 0.43 pg/g, which was almost equivalent to the limit of the determination value on HRGC/HRMS, S/N = 10.

Blood lead exposure concentrations in mottled ducks (Anas fulvigula) on the upper Texas coast

USGS Publications Warehouse

McDowell, Stephen K.; Conway, Warren C.; Haukos, David A.; Moon, Jena A.; Comer, Christopher E.; Hung, I-Kuai

2015-01-01

The mottled duck (Anas fulvigula) is a non-migratory waterfowl species dependent upon coastal marsh systems, including those on the Texas Chenier Plain National Wildlife Refuge (NWR) Complex, and considered a regional indicator species of marsh habitat quality. Research from the early 1970s, 1990s, and early-2000s indicated that mottled ducks continued to exhibit elevated wing-bone lead (Pb) concentrations, decades after implementation of non-toxic shot regulations. However, wing-bone concentrations reflect lifetime accumulation of Pb, whereas blood Pb concentrations reflect more recent exposure. To identify current potentially relevant temporal windows of Pb exposure, we collected 260 blood samples from mottled ducks during summer (n=124) and winter (n=136) from 2010–2012 on the Texas Chenier Plain NWR Complex. We quantified baseline blood Pb concentrations for all ages of mottled ducks, and hypothesized that blood lead concentrations would remain elevated above background levels (200 µg L–1) despite the 1983 and 1991 lead shot bans. Blood Pb concentrations ranged from below detection limits to >12,000 µg L–1, where >200 µg L–1 was associated with exposure levels above background concentrations. Male mottled ducks had the greatest blood Pb concentrations (30 times greater than females) with concentrations greater during winter than summer. Likewise, the proportion of exposed (>200 µg L–1) females increased from 14%–47% from summer to winter, respectively. Regardless of sex, adult mottled duck blood Pb concentrations were five times greater than juveniles, particularly during winter. We identified five plausible models that influenced blood Pb levels where year, site, and interactions among age*sex*season and between age*season were included in the top-ranked models. Frequency of exposure was greatest during winter, increasing from 12% in summer to 55% in winter, indicating that a temporal exposure window to environmental Pb exists between nesting

Rapid measurement of fibrinogen concentration in whole blood using a steel ball coagulometer

PubMed Central

Schlimp, Christoph J.; Khadem, Anna; Klotz, Anton; Solomon, Cristina; Hochleitner, Gerald; Ponschab, Martin; Redl, Heinz; Schöchl, Herbert

2015-01-01

BACKGROUND Fibrinogen plays a key role in hemostasis and is the first coagulation factor to reach critical levels in bleeding patients. Current European guidelines on the management of traumatic or perioperative bleeding recommend fibrinogen supplementation at specific threshold levels. Whole blood viscoelastic tests provide fast evaluation of fibrin deficits. Fast measurement of plasma fibrinogen concentration is not yet available. We investigated a method to rapidly determine whole blood fibrinogen concentration using standard Clauss assays and a steel ball coagulometer and provide an estimate of the “plasma-equivalent” fibrinogen concentration within minutes by adjustment of the measured whole blood fibrinogen concentration with a quickly measureable hemoglobin-derived hematocrit. METHODS The feasibility of this approach was tested with a Clauss assay using multiple porcine fresh blood samples obtained during in vivo bleeding, hemodilution, and after treatment with hemostatic therapy. Two different Clauss assays were then tested using multiple human volunteers’ blood samples diluted in vitro and supplemented with fibrinogen concentrate. Comparative measurements with fibrin-based thromboelastometry tests were performed. RESULTS Regression and Bland-Altman analyses of derived “plasma-equivalent” fibrinogen and measured plasma fibrinogen concentration was excellent in porcine and human blood samples, especially in the ranges relevant to traumatic or perioperative bleeding. CONCLUSION Fast whole blood fibrinogen measurements could be considered as an alternative to plasma fibrinogen measurement for acute bleeding management in trauma and perioperative care settings. Further studies are needed to prove this concept and determine the turnaround times for its clinical application in emergency departments and operating theaters. PMID:25742256

BLOOD LEAD CONCENTRATION AND DELAYED PUBERTY IN GIRLS

EPA Science Inventory

Background
Environmental lead exposure has been linked to alterations in growth and endocrine function. It is not known whether such exposure affects pubertal development.

Methods
We analyzed the relations between blood lead concentration and pubertal...

Association of selenium status and blood glutathione concentrations in blacks and whites

PubMed Central

Richie, John P.; Muscat, Joshua E.; Ellison, Irina; Calcagnotto, Ana; Kleinman, Wayne; El-Bayoumy, Karam

2011-01-01

Selenium deficiency has been linked with increased cancer risk and, in some studies, selenium supplementation was protective against certain cancers. Previous studies suggest that selenium chemoprevention may involve reduced oxidative stress through enhanced glutathione (GSH). Our objectives were to examine the relationships between selenium and GSH in blood and modifying effects of race and sex in free living adults and individuals supplemented with selenium. Plasma selenium concentrations and free and bound GSH concentrations and γ-glutamyl cysteine ligase (GCL) activity in blood were measured in 336 healthy adults, (161 blacks, 175 whites). Plasma selenium and blood GSH were also measured in 36 healthy men from our previously conducted placebo-controlled trial of selenium-enriched yeast (247 μg/day for 9 months). In free-living adults, selenium concentrations were associated with increased blood GSH concentration and GCL activity (P<0.05). Further, selenium was significantly higher in whites than in blacks (P<0.01). After 9 months of supplementation, plasma selenium was increased 114% in whites and 50% in blacks (P<0.05) and blood GSH was increased 35% in whites (P<0.05) but was unchanged in blacks. These results indicate a direct association between selenium and GSH in blood of both free-living and selenium-supplemented individuals, with race being an important modifying factor. PMID:21462082

Predicting high blood metal ion concentrations following hip resurfacing.

PubMed

Matharu, Gulraj S; Berryman, Fiona; Brash, Lesley; Pynsent, Paul B; Treacy, Ronan B C; Dunlop, David J

2015-01-01

To determine whether gender, femoral head size, acetabular inclination, and time since surgery predicted high blood metal ion concentrations following Birmingham Hip Resurfacing (BHR). BHR patients with unilateral bearings at one specialist centre with blood cobalt and chromium concentrations measured up to May 2013 were included. This comprised a mixed (at-risk) group including symptomatic patients and asymptomatic individuals with specific clinical and/or radiological findings. Blood sampling was at a mean of 7.5 years (range 1-15.4 years) postoperatively. Of 319 patients (mean age 49.3 years; 53% male), blood metal ions greater than 7 µg/l were observed in 9% (n = 28). Blood metal ions were significantly higher in females (p<0.001), femoral head sizes ≤48 mm (p<0.01), and cup inclinations >55° (p<0.001). Linear regression demonstrated femoral head size was responsible for the highest proportion of variance in blood metal ions (cobalt p<0.001, R2 = 8%; chromium p<0.001, R2 = 11%). Analysis of femoral head size and inclination together demonstrated 36% of BHRs with head sizes of 38-44 mm and inclination >55° had blood metal ions >7 µg/l. BHR 10-year survival for this at-risk group was 91% (95% confidence intervals 86.0%-95.0%) with 30 hips revised. If blood metal ions are used to screen hip resurfacing patients for adverse reactions to metal debris it is recommended those with small femoral head sizes (38-44 mm) and high acetabular inclinations (>55°) are targeted. These findings require validation in other cohorts as they may not be applicable to all hip resurfacing devices given the differences in radial clearance, coverage arc, and metallurgy.

Impairment related to blood amphetamine and/or methamphetamine concentrations in suspected drugged drivers.

PubMed

Gustavsen, Ingebjørg; Mørland, Jørg; Bramness, Jørgen G

2006-05-01

Experimental studies have investigated effects of low oral doses of amphetamine and methamphetamine on psychomotor functions, while less work has been done on effects of high doses taken by abusers in real-life settings. There are indications that intake of high doses may impair traffic related skills, and that abuse of amphetamines may cause hypersomnolence at the end-of-binge. The present study aimed at investigating the concentration-effect relationship between blood amphetamines concentrations and impairment in a population of real-life users. Eight hundred and seventy-eight cases with amphetamine or methamphetamine as the only drugs present in the blood samples were selected from the impaired driver registry at The Norwegian Institute of Public Health. In each case the police physician had concluded on whether the driver was impaired or not. 27% of the drivers were judged as not impaired, while 73% were judged as impaired. There was a positive relationship between blood amphetamines concentrations and impairment. The relationship reached a ceiling at blood amphetamines concentrations of 0.27-0.53 mg/l. Younger drivers were more often judged impaired than older drivers at similar concentrations. Despite the performance enhancing qualities of amphetamines demonstrated in some low dose laboratory experiments; this study revealed a positive relationship between blood amphetamines concentration and traffic related impairment.

Heterogeneity in cord blood DHA concentration: towards an explanation.

PubMed

Muhlhausler, B S; Gibson, R A; Yelland, L N; Makrides, M

2014-10-01

This paper aimed to identify the dietary and non-dietary determinants of docosahexaenoic acid (DHA) levels in umbilical cord blood at delivery. DHA was measured in cord blood plasma phospholipids of 1571 participants from the DOMInO (DHA to Optimize Mother Infant Outcome) randomized controlled trial. Socioeconomic, lifestyle and clinical data relating to the mother and current pregnancy were obtained from all women and their relationships with cord blood DHA assessed. DHA concentrations in the cord plasma phospholipids at delivery covered a 3-4 fold range in both control and DHA groups. The total number of DHA-rich intervention supplement capsules consumed over the course of pregnancy and gestational age at delivery individually explained 21% and 16% respectively of the variation in DHA abundance in the cord blood plasma phospholipids at delivery, but no other clinical or life-style factors explored in this study could account for >2% of the variation. Indeed, more than 65% of the variation remained unaccounted for even when all factors were included in the analysis. These data suggest that factors other than maternal DHA intake have an important role in determining cord blood DHA concentrations at delivery, and may at least partially explain the variation in the response of infants to maternal DHA supplementation reported in published trials. Copyright © 2014 Elsevier Ltd. All rights reserved.

Rapid separation of very low concentrations of bacteria from blood.

PubMed

Buchanan, Clara M; Wood, Ryan L; Hoj, Taalin R; Alizadeh, Mahsa; Bledsoe, Colin G; Wood, Madison E; McClellan, Daniel S; Blanco, Rae; Hickey, Caroline L; Ravsten, Tanner V; Husseini, Ghaleb A; Robison, Richard A; Pitt, William G

2017-08-01

A rapid and accurate diagnosis of the species and antibiotic resistance of bacteria in septic blood is vital to increase survival rates of patients with bloodstream infections, particularly those with carbapenem-resistant enterobacteriaceae (CRE) infections. The extremely low levels in blood (1 to 100CFU/ml) make rapid diagnosis difficult. In this study, very low concentrations of bacteria (6 to 200CFU/ml) were separated from 7ml of whole blood using rapid sedimentation in a spinning hollow disk that separated plasma from red and white cells, leaving most of the bacteria suspended in the plasma. Following less than a minute of spinning, the disk was slowed, the plasma was recovered, and the bacteria were isolated by vacuum filtration. The filters were grown on nutrient plates to determine the number of bacteria recovered from the blood. Experiments were done without red blood cell (RBC) lysis and with RBC lysis in the recovered plasma. While there was scatter in the data from blood with low bacterial concentrations, the mean average recovery was 69%. The gender of the blood donor made no statistical difference in bacterial recovery. These results show that this rapid technique recovers a significant amount of bacteria from blood containing clinically relevant low levels of bacteria, producing the bacteria in minutes. These bacteria could subsequently be identified by molecular techniques to quickly identify the infectious organism and its resistance profile, thus greatly reducing the time needed to correctly diagnose and treat a blood infection. Copyright © 2017 Elsevier B.V. All rights reserved.

Detection of propofol concentrations in blood by Raman spectroscopy

NASA Astrophysics Data System (ADS)

Wróbel, M. S.; Gnyba, M.; UrniaŻ, R.; Myllylä, T. S.; Jedrzejewska-Szczerska, M.

2015-07-01

In this paper we present a proof-of-concept of a Raman spectroscopy-based approach for measuring the content of propofol, a common anesthesia drug, in whole human blood, and plasma, which is intended for use during clinical procedures. This method utilizes the Raman spectroscopy as a chemically-sensitive method for qualitative detection of the presence of a drug and a quantitative determination of its concentration. A number of samples from different patients with added various concentrations of propofol IV solution were measured. This is most equivalent to a real in-vivo situation. Subsequent analysis of a set of spectra was carried out to extract qualitative and quantitative information. We conclude, that the changes in the spectra of blood with propofol, overlap with the most prominent lines of the propofol solution, especially at spectral regions: 1450 cm-1, 1250- 1260 cm-1, 1050 cm-1, 875-910 cm-1, 640 cm-1. Later, we have introduced a quantitative analysis program based on correlation matrix closest fit, and a LOO cross-validation. We have achieved 36.67% and 60% model precision when considering full spectra, or specified bands, respectively. These results prove the possibility of using Raman spectroscopy for quantitative detection of propofol concentrations in whole human blood.

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.

The effect of interior lead hazard controls on children's blood lead concentrations: a systematic evaluation.

PubMed Central

Haynes, Erin; Lanphear, Bruce P; Tohn, Ellen; Farr, Nick; Rhoads, George G

2002-01-01

Dust control is often recommended to prevent children's exposure to residential lead hazards, but the effect of these controls on children's blood lead concentrations is uncertain. We conducted a systematic review of randomized, controlled trials of low-cost, lead hazard control interventions to determine the effect of lead hazard control on children's blood lead concentration. Four trials met the inclusion criteria. We examined mean blood lead concentration and elevated blood lead concentrations (> or = 10 microg/dL, > or = 15 microg/dL, and > or = 20 microg/dL) and found no significant differences in mean change in blood lead concentration for children by random group assignment (children assigned to the intervention group compared with those assigned to the control group). We found no significant difference between the intervention and control groups in the percentage of children with blood lead > or = 10 microg/dL, 29% versus 32% [odds ratio (OR), 0.85; 95% confidence interval (CI), 0.56-1.3], but there was a significant difference in the percentage of children with blood lead > or = 15 microg/dL between the intervention and control groups, 6% versus 14% (OR, 0.40; 95% CI, 0.21-0.80) and in the percentage of children with blood lead > or = 20 microg/dL between the intervention and control groups, 2% versus 6% (OR, 0.29; 95% CI, 0.10-0.85). We conclude that although low-cost, interior lead hazard control was associated with 50% or greater reduction in the proportion of children who had blood lead concentrations exceeding 15 microg/dL and > or = 20 microg/dL, there was no substantial effect on mean blood lead concentration. PMID:11781171

The effect of interior lead hazard controls on children's blood lead concentrations: a systematic evaluation.

PubMed

Haynes, Erin; Lanphear, Bruce P; Tohn, Ellen; Farr, Nick; Rhoads, George G

2002-01-01

Dust control is often recommended to prevent children's exposure to residential lead hazards, but the effect of these controls on children's blood lead concentrations is uncertain. We conducted a systematic review of randomized, controlled trials of low-cost, lead hazard control interventions to determine the effect of lead hazard control on children's blood lead concentration. Four trials met the inclusion criteria. We examined mean blood lead concentration and elevated blood lead concentrations (> or = 10 microg/dL, > or = 15 microg/dL, and > or = 20 microg/dL) and found no significant differences in mean change in blood lead concentration for children by random group assignment (children assigned to the intervention group compared with those assigned to the control group). We found no significant difference between the intervention and control groups in the percentage of children with blood lead > or = 10 microg/dL, 29% versus 32% [odds ratio (OR), 0.85; 95% confidence interval (CI), 0.56-1.3], but there was a significant difference in the percentage of children with blood lead > or = 15 microg/dL between the intervention and control groups, 6% versus 14% (OR, 0.40; 95% CI, 0.21-0.80) and in the percentage of children with blood lead > or = 20 microg/dL between the intervention and control groups, 2% versus 6% (OR, 0.29; 95% CI, 0.10-0.85). We conclude that although low-cost, interior lead hazard control was associated with 50% or greater reduction in the proportion of children who had blood lead concentrations exceeding 15 microg/dL and > or = 20 microg/dL, there was no substantial effect on mean blood lead concentration.

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.

Consumption of lead-shot cervid meat and blood lead concentrations in a group of adult Norwegians.

PubMed

Meltzer, H M; Dahl, H; Brantsæter, A L; Birgisdottir, B E; Knutsen, H K; Bernhoft, A; Oftedal, B; Lande, U S; Alexander, J; Haugen, M; Ydersbond, T A

2013-11-01

Several recent investigations have reported high concentrations of lead in samples of minced cervid meat. This paper describes findings from a Norwegian study performed in 2012 among 147 adults with a wide range of cervid game consumption. The main aim was to assess whether high consumption of lead-shot cervid meat is associated with increased concentration of lead in blood. A second aim was to investigate to what extent factors apart from game consumption explain observed variability in blood lead levels. Median (5 and 95 percentile) blood concentration of lead was 16.6 µg/L (7.5 and 39 µg/L). An optimal multivariate linear regression model for log-transformed blood lead indicated that cervid game meat consumption once a month or more was associated with approximately 31% increase in blood lead concentrations. The increase seemed to be mostly associated with consumption of minced cervid meat, particularly purchased minced meat. However, many participants with high and long-lasting game meat intake had low blood lead concentrations. Cervid meat together with number of bullet shots per year, years with game consumption, self-assembly of bullets, wine consumption and smoking jointly accounted for approximately 25% of the variation in blood lead concentrations, while age and sex accounted for 27% of the variance. Blood lead concentrations increased approximately 18% per decade of age, and men had on average 30% higher blood lead concentrations than women. Hunters who assembled their own ammunition had 52% higher blood lead concentrations than persons not making ammunition. In conjunction with minced cervid meat, wine intake was significantly associated with increased blood lead. Our results indicate that hunting practices such as use of lead-based ammunition, self-assembling of lead containing bullets and inclusion of lead-contaminated meat for mincing to a large extent determine the exposure to lead from cervid game consumption. © 2013 Elsevier Inc. All rights

Effects of exposure to malathion on blood glucose concentration: a meta-analysis.

PubMed

Ramirez-Vargas, Marco Antonio; Flores-Alfaro, Eugenia; Uriostegui-Acosta, Mayrut; Alvarez-Fitz, Patricia; Parra-Rojas, Isela; Moreno-Godinez, Ma Elena

2018-02-01

Exposure to malathion (an organophosphate pesticide widely used around the world) has been associated with alterations in blood glucose concentration in animal models. However, the results are inconsistent. The aim of this meta-analysis was to evaluate whether malathion exposure can disturb the concentrations of blood glucose in exposed rats. We performed a literature search of online databases including PubMed, EBSCO, and Google Scholar and reviewed original articles that analyzed the relation between malathion exposure and glucose levels in animal models. The selection of articles was based on inclusion and exclusion criteria. The database search identified thirty-five possible articles, but only eight fulfilled our inclusion criteria, and these studies were included in the meta-analysis. The effect of malathion on blood glucose concentration showed a non-monotonic dose-response curve. In addition, pooled analysis showed that blood glucose concentrations were 3.3-fold higher in exposed rats than in the control group (95% CI, 2-5; Z = 3.9; p < 0.0001) in a random-effect model. This result suggested that alteration of glucose homeostasis is a possible mechanism of toxicity associated with exposure to malathion.

What is the concentration of hydrogen peroxide in blood and plasma?

PubMed

Forman, Henry Jay; Bernardo, Angelito; Davies, Kelvin J A

2016-08-01

The concentration of hydrogen peroxide (H2O2) in blood and plasma is a measurement that has often been made, but the absolute values remain unsettled due the great variability of results actually published in the literature. As in every tissue, the concentration of H2O2 in blood and plasma is determined by the dynamics of its production versus its removal. The major sources of H2O2 in cells will only be briefly described as they are already well documented, The production of H2O2 in red blood cells will be described as it is less well known. But, the concentration of H2O2 within cells is more problematic. Intracellular H2O2 concentration has been estimated based on the kinetics of production and elimination, while its determination is technically difficult. Furthermore, compartmentalization and gradients result in its quantitation only as an average. The sources of extracellular H2O2, particularly in plasma, will also be described briefly. The major question addressed here however, is the actual concentration of H2O2 in plasma, which has been studied extensively, but still remains controversial. Copyright © 2016 Elsevier Inc. All rights reserved.

Impact of intraoperative factor concentrates on blood product transfusions during orthotopic liver transplantation.

PubMed

Colavecchia, A Carmine; Cohen, David A; Harris, Jesse E; Thomas, Jeena M; Lindberg, Scott; Leveque, Christopher; Salazar, Eric

2017-12-01

Major bleeding in orthotopic liver transplantation is associated with significant morbidity and mortality. Limited literature exists regarding comparative effectiveness of prothrombin complex concentrate and fibrinogen concentrate during orthotopic liver transplantation on blood product utilization. This retrospective, single-institution study evaluated the impact of prothrombin complex concentrate and fibrinogen concentrate on blood product utilization during orthotopic liver transplantation from December 2013 to April 2016. This study included patients age 18 years or older and excluded patients who received simultaneous heart or lung transplantation or did not meet documentation criteria. A propensity score matching technique was used to match patients who were exposed to prothrombin complex concentrate with unexposed patients, at a 2 to 1 ratio, to control for selection bias. During this study, 212 patients received orthotopic liver transplantation with 39 prothrombin complex concentrate exposures. The matched study population included 39 patients who were exposed to prothrombin complex concentrate and 78 unexposed patients. Overall, 84.6% of patients who were exposed to prothrombin complex concentrate also received concomitant fibrinogen concentrate, whereas only 2% of patients in the control group received fibrinogen concentrate. After propensity score matching, no other factors that were included in the model differed significantly or had a standardized mean difference of 0.11 or greater. There was no statistical difference in the utilization of red blood cells or fresh frozen plasma for the exposed group versus the unexposed group after matching (mean ± standard deviation: red blood cell units, 12.4 ± 8.0 units vs. 9.7 ± 5.6 units [p = 0.058]; fresh-frozen plasma units, 10.0 ± 6.3 vs. 12.7 ± 9.7 units [p = 0.119], respectively). The intraoperative use of prothrombin complex concentrate and fibrinogen concentrate during

Blood harmane concentrations and dietary protein consumption in essential tremor.

PubMed

Louis, E D; Zheng, W; Applegate, L; Shi, L; Factor-Litvak, P

2005-08-09

Beta-carboline alkaloids (e.g., harmane) are highly tremorogenic chemicals. Animal protein (meat) is the major dietary source of these alkaloids. The authors previously demonstrated that blood harmane concentrations were elevated in patients with essential tremor (ET) vs controls. Whether this difference is due to greater animal protein consumption by patients or their failure to metabolize harmane is unknown. The aim of this study was to determine whether patients with ET and controls differ with regard to 1) daily animal protein consumption and 2) the correlation between animal protein consumption and blood harmane concentration. Data on current diet were collected with a semiquantitative food frequency questionnaire and daily calories and consumption of animal protein and other food types was calculated. Blood harmane concentrations were log-transformed (logHA). The mean logHA was higher in 106 patients than 161 controls (0.61 +/- 0.67 vs 0.43 +/- 0.72 g(-10)/mL, p = 0.035). Patients and controls consumed similar amounts of animal protein (50.2 +/- 19.6 vs 49.4 +/- 19.1 g/day, p = 0.74) and other food types (animal fat, carbohydrates, vegetable fat) and had similar caloric intakes. In controls, logHA was correlated with daily consumption of animal protein (r = 0.24, p = 0.003); in patients, there was no such correlation (r = -0.003, p = 0.98). The similarity between patients and controls in daily animal protein consumption and the absence of the normal correlation between daily animal protein consumption and logHA in patients suggests that another factor (e.g., a metabolic defect) may be increasing blood harmane concentration in patients.

Evaluation of blood glucose concentration measurement using photoacoustic spectroscopy in near-infrared region

NASA Astrophysics Data System (ADS)

Namita, Takeshi; Sato, Mitsuki; Kondo, Kengo; Yamakawa, Makoto; Shiina, Tsuyoshi

2017-03-01

Diabetes, a typical lifestyle-related disease, is an important disease presenting risks of various complications such as retinopathy, kidney failure, and nervous neuropathy. To treat diabetes, regular and continual self-measurement of blood glucose concentrations is necessary to maintain blood glucose levels and to prevent complications. Usually, daily measurements are taken using invasive methods such as finger-prick blood sampling. Some non-invasive optical techniques have been proposed to reduce pain and infection risk, however, few practical techniques exist today. To realize highly accurate and practical measurement of blood glucose concentrations, the feasibility of a photoacoustic method using near-infrared light was evaluated. A photoacoustic signal from a solution of glucose in water (+0-5 g/dl) or equine blood (+0-400 mg/dl) was measured using a hydrophone (9 mm diameter) at 800-1800 nm wavelengths. We investigated the relation between the glucose solution concentration and the photoacoustic signal intensity or peak position of the received photoacoustic signal (i.e. speed of sound in solutions). Results show that the signal intensity and sound speed of the glucose solution increase with increased glucose concentration for wavelengths at which light absorbance of glucose is high. For quantitative estimation of the glucose solution concentration, the photoacoustic signal intensity ratio between two wavelengths, at which dependence of the signal intensity on glucose concentration is high and low, was calculated. Results confirmed that the signal intensity ratios increase linearly with the glucose concentration. These analyses verified the feasibility of glucose level estimation using photoacoustic measurement in the near-infrared region.

Physical characteristics, blood hormone concentrations, and plasma lipid concentrations in obese horses with insulin resistance.

PubMed

Frank, Nicholas; Elliott, Sarah B; Brandt, Laura E; Keisler, Duane H

2006-05-01

To compare obese horses with insulin resistance (IR) with nonobese horses and determine whether blood resting glucose, insulin, leptin, and lipid concentrations differed between groups and were correlated with combined glucose-insulin test (CGIT) results. 7 obese adult horses with IR (OB-IR group) and 5 nonobese mares. Physical measurements were taken, and blood samples were collected after horses had acclimated to the hospital for 3 days. Response to insulin was assessed by use of the CGIT, and maintenance of plasma glucose concentrations greater than the preinjection value for > or = 45 minutes was used to define IR. Area under the curve values for glucose (AUC(g)) and insulin (AUC(i)) concentrations were calculated. Morgan, Paso Fino, Quarter Horse, and Tennessee Walking Horse breeds were represented in the OB-IR group. Mean neck circumference and BCS differed significantly between groups and were positively correlated with AUC values. Resting insulin and leptin concentrations were 6 and 14 times as high, respectively, in the OB-IR group, compared with the nonobese group, and were significantly correlated with AUC(g) and AUC(i). Plasma nonesterified fatty acid, very low-density lipoprotein, and high-density lipoprotein-cholesterol (HDL-C) concentrations were significantly higher (86%, 104%, and 29%, respectively) in OB-IR horses, and HDL-C concentrations were positively correlated with AUC values. Measurements of neck circumference and resting insulin and leptin concentrations can be used to screen obese horses for IR. Dyslipidemia is associated with IR in obese horses.

Acoustofluidic, label-free separation and simultaneous concentration of rare tumor cells from white blood cells.

PubMed

Antfolk, Maria; Magnusson, Cecilia; Augustsson, Per; Lilja, Hans; Laurell, Thomas

2015-09-15

Enrichment of rare cells from peripheral blood has emerged as a means to enable noninvasive diagnostics and development of personalized drugs, commonly associated with a prerequisite to concentrate the enriched rare cell population prior to molecular analysis or culture. However, common concentration by centrifugation has important limitations when processing low cell numbers. Here, we report on an integrated acoustophoresis-based rare cell enrichment system combined with integrated concentration. Polystyrene 7 μm microparticles could be separated from 5 μm particles with a recovery of 99.3 ± 0.3% at a contamination of 0.1 ± 0.03%, with an overall 25.7 ± 1.7-fold concentration of the recovered 7 μm particles. At a flow rate of 100 μL/min, breast cancer cells (MCF7) spiked into red blood cell-lysed human blood were separated with an efficiency of 91.8 ± 1.0% with a contamination of 0.6 ± 0.1% from white blood cells with a 23.8 ± 1.3-fold concentration of cancer cells. The recovery of prostate cancer cells (DU145) spiked into whole blood was 84.1 ± 2.1% with 0.2 ± 0.04% contamination of white blood cells with a 9.6 ± 0.4-fold concentration of cancer cells. This simultaneous on-chip separation and concentration shows feasibility of future acoustofluidic systems for rapid label-free enrichment and molecular characterization of circulating tumor cells using peripheral venous blood in clinical practice.

Concentrations of selenium, mercury, and lead in blood of emperor geese in western Alaska

USGS Publications Warehouse

Franson, J.C.; Schmutz, J.A.; Creekmore, L.H.; Fowler, A.C.

1999-01-01

We found up to 10 ppm wet weight of selenium in blood samples collected from emperor geese (Chen canagica) on their breeding grounds on the Yukon‐Kuskokwim Delta in western Alaska, USA. Incubating adult females captured in late May through mid‐June 1997 had significantly higher concentrations of selenium in their blood (mean = 5.60 ppm) than adult females captured during wing molt in late July 1996 (mean = 2.78 ppm). Females that nested early or were in good body condition had higher concentrations of selenium in their blood than did other nesting females. Blood samples from 4 of 29 goslings had detectable levels of selenium (mean = 0.14 ppm). Our findings suggest that emperor geese are exposed to more selenium in the marine environment of their wintering and staging areas on the Alaska Peninsula than on the breeding grounds. The highest concentration of mercury found in the blood of emperor geese was 0.24 ppm. One bird had a blood lead concentration of 0.67 ppm, but 82% had no detectable lead in their blood, suggesting that lead exposure from the ingestion of lead shot poses little threat for emperor geese in western Alaska, contrary to findings reported for sympatric spectacled eiders (Somateria fischeri).

Cocaine and metabolite concentrations in DBS and venous blood after controlled intravenous cocaine administration

PubMed Central

Ellefsen, Kayla N; da Costa, Jose Luiz; Concheiro, Marta; Anizan, Sebastien; Barnes, Allan J; Pirard, Sandrine; Gorelick, David A; Huestis, Marilyn A

2015-01-01

Background: DBS are an increasingly common clinical matrix. Methods & results: Sensitive and specific methods for DBS and venous blood cocaine and metabolite detection by LC–HRMS and 2D GC–MS, respectively, were validated to examine correlation between concentrations following controlled intravenous cocaine administration. Linear ranges from 1 to 200 µg/l were achieved, with acceptable bias and imprecision. Authentic matched specimens’ (392 DBS, 97 venous blood) cocaine and benzoylecgonine concentrations were qualitatively similar, but DBS had much greater variability (21.4–105.9 %CV) and were lower than in blood. Conclusion: DBS offer advantages for monitoring cocaine intake; however, differences between capillary and venous blood and DBS concentration variability must be addressed. PMID:26327184

Blood harmane concentrations and dietary protein consumption in essential tremor

PubMed Central

Louis, E.D.; Zheng, W.; Applegate, L.; Shi, L.; Factor-Litvak, P.

2016-01-01

Background β-Carboline alkaloids (e.g., harmane) are highly tremorogenic chemicals. Animal protein (meat) is the major dietary source of these alkaloids. The authors previously demonstrated that blood harmane concentrations were elevated in patients with essential tremor (ET) vs controls. Whether this difference is due to greater animal protein consumption by patients or their failure to metabolize harmane is unknown. Objective The aim of this study was to determine whether patients with ET and controls differ with regard to 1) daily animal protein consumption and 2) the correlation between animal protein consumption and blood harmane concentration. Methods Data on current diet were collected with a semiquantitative food frequency questionnaire and daily calories and consumption of animal protein and other food types was calculated. Blood harmane concentrations were log-transformed (logHA). Results The mean logHA was higher in 106 patients than 161 controls (0.61 ± 0.67 vs 0.43 ± 0.72 g−10/mL, p = 0.035). Patients and controls consumed similar amounts of animal protein (50.2 ± 19.6 vs 49.4 ± 19.1 g/day, p = 0.74) and other food types (animal fat, carbohydrates, vegetable fat) and had similar caloric intakes. In controls, logHA was correlated with daily consumption of animal protein (r = 0.24, p = 0.003); in patients, there was no such correlation (r = −0.003, p = 0.98). Conclusions The similarity between patients and controls in daily animal protein consumption and the absence of the normal correlation between daily animal protein consumption and logHA in patients suggests that another factor (e.g., a metabolic defect) may be increasing blood harmane concentration in patients. PMID:16087903

Vitamin blood concentration and vitamin supplementation in bottlenose dolphins (Tursiops truncatus) in European facilities.

PubMed

Gimmel, Angela Emilia Ricarda; Baumgartner, Katrin; Liesegang, Annette

2016-09-05

As fish eaters bottlenose dolphins (Tursiops truncatus) in human care need to receive daily vitamin supplementation, because whole thawed fish lacks certain vitamins. However, the exact concentration of supplementation has not been established and is a matter of discussion. To ensure adequate vitamin supplementation in pets, vitamin blood concentrations are measured. This is not a common practice in dolphins. The objective of the present study was to collect information about vitamin supplementation in bottlenose dolphins and on vitamin blood concentrations of healthy animals in European facilities. In addition, these results were compared with blood levels of wild animals. Conclusions on how to provide bottlenose dolphins in human care with an effective vitamin supplementation will then be drawn. Initially, fish-handling techniques and vitamin supplementation were evaluated by questionnaire, which was sent to 25 European facilities that house bottlenose dolphins. Secondly, blood samples from 57 dolphins living in 10 facilities were taken and sent by mail to a reference laboratory. They were analysed for retinol, thiamine pyrophosphate, cobalamin, calcidiol and tocopherol. The blood concentrations were then correlated with vitamin supplementation, fish handling techniques and pre-existing blood concentrations of free-ranging dolphins. Finally, the data was subjected to a standard analysis of variance techniques (ANOVA) and a linear model analysis. Fish was mainly thawed in a refrigerator. Further, the 95 % confidence interval for retinol blood concentrations was 0.048 to 0.059 mg/l and for tocopherol 17.95 to 20.76 mg/l. These concentrations were 27 and 53 %, respectively, higher than those found in free-ranging animals. In contrast, calcidiol concentrations (143.9-174.7 ng/ml) of the dolphins in human care were lower than in blood found for free-ranging animals. Regarding thiamine pyrophosphate and cobalamin, concentrations ranged between 0.42 and 0.55�

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

Seafood Consumption and Blood Mercury Concentrations in Jamaican Children With and Without Autism Spectrum Disorders

PubMed Central

Samms-Vaughan, Maureen; Loveland, Katherine A.; Ardjomand-Hessabi, Manouchehr; Chen, Zhongxue; Bressler, Jan; Shakespeare-Pellington, Sydonnie; Grove, Megan L.; Bloom, Kari; Pearson, Deborah A.; Lalor, Gerald C.; Boerwinkle, Eric

2014-01-01

Mercury is a toxic metal shown to have harmful effects on human health. Several studies have reported high blood mercury concentrations as a risk factor for autism spectrum disorders (ASDs), while other studies have reported no such association. The goal of this study was to investigate the association between blood mercury concentrations in children and ASDs. Moreover, we investigated the role of seafood consumption in relation to blood mercury concentrations in Jamaican children. Based on data for 65 sex- and age-matched pairs (2–8 years), we used a General Linear Model to test whether there is an association between blood mercury concentrations and ASDs. After controlling for the child’s frequency of seafood consumption, maternal age, and parental education, we did not find a significant difference (P = 0.61) between blood mercury concentrations and ASDs. However, in both cases and control groups, children who ate certain types of seafood (i.e., salt water fish, sardine, or mackerel fish) had significantly higher (all P <0.05) geometric means blood mercury concentration which were about 3.5 times that of children living in the US or Canada. Our findings also indicate that Jamaican children with parents who both had education up to high school are at a higher risk of exposure to mercury compared to children with at least one parent who had education beyond high school. Based on our findings, we recommend additional education to Jamaican parents regarding potential hazards of elevated blood mercury concentrations, and its association with seafood consumption and type of seafood. PMID:22488160

Do capillary dried blood spot concentrations of gamma-hydroxybutyric acid mirror those in venous blood? A comparative study.

PubMed

Sadones, Nele; Archer, John R H; Ingels, Ann-Sofie M E; Dargan, Paul I; Wood, David M; Wood, Michelle; Neels, Hugo; Lambert, Willy E; Stove, Christophe P

2015-04-01

Gamma-hydroxybutyric acid (GHB) is a well-known illicit club and date-rape drug. Dried blood spot (DBS) sampling is a promising alternative for classical venous sampling in cases of (suspected) GHB intoxication since it allows rapid sampling, which is of interest for the extensively metabolized GHB. However, there is limited data if -and how- capillary DBS concentrations correlate with venous concentrations. We conducted a comparative study in 50 patients with suspected GHB intoxication, to determine and to correlate GHB concentrations in venous DBS (vDBS) and capillary DBS (cDBS). This is the first study that evaluates in a large cohort the correlation between capillary and venous concentrations of an illicit drug in real-life samples. Of the 50 paired samples, 7 were excluded: the vDBS concentration was below the LLOQ of 2 µg/mL in 3 cases and 4 samples were excluded after visual inspection of the DBS. Bland-Altman analysis revealed a mean % difference of -2.8% between cDBS and vDBS concentrations, with the zero value included in the 95% confidence interval of the mean difference in GHB concentration. A paired sample t-test confirmed this observation (p = 0.17). Also the requirement for incurred sample reproducibility was fulfilled: for more than two-thirds of the samples the concentrations obtained in cDBS and those in vDBS were within 20% of their mean. Since equivalent concentrations were observed in cDBS and vDBS, blood obtained by fingerprick can be considered a valid alternative for venous blood for GHB determination. Copyright © 2015 John Wiley & Sons, Ltd.

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

Melanin and blood concentration in human skin studied by multiple regression analysis: experiments

NASA Astrophysics Data System (ADS)

Shimada, M.; Yamada, Y.; Itoh, M.; Yatagai, T.

2001-09-01

Knowledge of the mechanism of human skin colour and measurement of melanin and blood concentration in human skin are needed in the medical and cosmetic fields. The absorbance spectrum from reflectance at the visible wavelength of human skin increases under several conditions such as a sunburn or scalding. The change of the absorbance spectrum from reflectance including the scattering effect does not correspond to the molar absorption spectrum of melanin and blood. The modified Beer-Lambert law is applied to the change in the absorbance spectrum from reflectance of human skin as the change in melanin and blood is assumed to be small. The concentration of melanin and blood was estimated from the absorbance spectrum reflectance of human skin using multiple regression analysis. Estimated concentrations were compared with the measured one in a phantom experiment and this method was applied to in vivo skin.

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

Carbohydrate Ingestion Before and During Soccer Match Play and Blood Glucose and Lactate Concentrations

PubMed Central

Russell, Mark; Benton, David; Kingsley, Michael

2014-01-01

Context: The ingestion of carbohydrate (CHO) before and during exercise and at halftime is commonly recommended to soccer players for maintaining blood glucose concentrations throughout match play. However, an exercise-induced rebound glycemic response has been observed in the early stages of the second half of simulated soccer-specific exercise when CHO-electrolyte beverages were consumed regularly. Therefore, the metabolic effects of CHO beverage consumption throughout soccer match play remain unclear. Objective: To investigate the blood glucose and blood lactate responses to CHOs ingested before and during soccer match play. Design: Crossover study. Setting: Applied research study. Patients or Other Participants: Ten male outfield academy soccer players (age = 15.6 ± 0.2 years, height = 1.74 ± 0.02 m, mass = 65.3 ± 1.9 kg, estimated maximal oxygen consumption = 58.4 ± 0.8 mL·kg−1·min−1). Intervention(s): Players received a 6% CHO-electrolyte solution or an electrolyte (placebo) solution 2 hours before kickoff, before each half (within 10 minutes), and every 15 minutes throughout exercise. Blood samples were obtained at rest, every 15 minutes during the match (first half: 0–15, 15–30, and 30–45 minutes; second half: 45–60, 60–75, and 75–90 minutes) and 10 minutes into the halftime break. Main Outcome Measure(s): Metabolic responses (blood glucose and blood lactate concentrations) and markers of exercise intensity (heart rate) were recorded. Results: Supplementation influenced the blood glucose response to exercise (time × treatment interaction effect: P ≤ .05), such that glucose concentrations were higher at 30 to 45 minutes in the CHO than in the placebo condition. However, in the second half, blood glucose concentrations were similar between conditions because of transient reductions from peak values occurring in both trials at halftime. Blood lactate concentrations were elevated above those at rest in the first 15 minutes of exercise

Carbohydrate ingestion before and during soccer match play and blood glucose and lactate concentrations.

PubMed

Russell, Mark; Benton, David; Kingsley, Michael

2014-01-01

The ingestion of carbohydrate (CHO) before and during exercise and at halftime is commonly recommended to soccer players for maintaining blood glucose concentrations throughout match play. However, an exercise-induced rebound glycemic response has been observed in the early stages of the second half of simulated soccer-specific exercise when CHO-electrolyte beverages were consumed regularly. Therefore, the metabolic effects of CHO beverage consumption throughout soccer match play remain unclear. To investigate the blood glucose and blood lactate responses to CHOs ingested before and during soccer match play. Crossover study. Applied research study. Ten male outfield academy soccer players (age = 15.6 ± 0.2 years, height = 1.74 ± 0.02 m, mass = 65.3 ± 1.9 kg, estimated maximal oxygen consumption = 58.4 ± 0.8 mL·kg(-1)·min(-1)). Players received a 6% CHO-electrolyte solution or an electrolyte (placebo) solution 2 hours before kickoff, before each half (within 10 minutes), and every 15 minutes throughout exercise. Blood samples were obtained at rest, every 15 minutes during the match (first half: 0-15, 15-30, and 30-45 minutes; second half: 45-60, 60-75, and 75-90 minutes) and 10 minutes into the halftime break. Metabolic responses (blood glucose and blood lactate concentrations) and markers of exercise intensity (heart rate) were recorded. Supplementation influenced the blood glucose response to exercise (time × treatment interaction effect: P ≤ .05), such that glucose concentrations were higher at 30 to 45 minutes in the CHO than in the placebo condition. However, in the second half, blood glucose concentrations were similar between conditions because of transient reductions from peak values occurring in both trials at halftime. Blood lactate concentrations were elevated above those at rest in the first 15 minutes of exercise (time-of-sample effect: P < .001) and remained elevated throughout exercise. Supplementation did not influence the pattern of

CSF and blood oxytocin concentration changes following intranasal delivery in macaque.

PubMed

Dal Monte, Olga; Noble, Pamela L; Turchi, Janita; Cummins, Alex; Averbeck, Bruno B

2014-01-01

Oxytocin (OT) in the central nervous system (CNS) influences social cognition and behavior, making it a candidate for treating clinical disorders such as schizophrenia and autism. Intranasal administration has been proposed as a possible route of delivery to the CNS for molecules like OT. While intranasal administration of OT influences social cognition and behavior, it is not well established whether this is an effective means for delivering OT to CNS targets. We administered OT or its vehicle (saline) to 15 primates (Macaca mulatta), using either intranasal spray or a nebulizer, and measured OT concentration changes in the cerebral spinal fluid (CSF) and in blood. All subjects received both delivery methods and both drug conditions. Baseline samples of blood and CSF were taken immediately before drug administration. Blood was collected every 10 minutes after administration for 40 minutes and CSF was collected once post-delivery, at the 40 minutes time point. We found that intranasal administration of exogenous OT increased concentrations in both CSF and plasma compared to saline. Both delivery methods resulted in similar elevations of OT concentration in CSF, while the changes in plasma OT concentration were greater after nasal spray compared to nebulizer. In conclusion our study provides evidence that both nebulizer and nasal spray OT administration can elevate CSF OT levels.

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

Factors associated with elevated blood lead concentrations in children in Karachi, Pakistan.

PubMed Central

Rahbar, Mohammad Hossein; White, Franklin; Agboatwalla, Mubina; Hozhabri, Siroos; Luby, Stephen

2002-01-01

OBJECTIVES: To confirm whether blood lead concentrations in Karachi were as high as reported in 1989 and to identify which types of exposure to lead contribute most to elevated blood lead concentrations in children in Karachi. METHODS: A total of 430 children aged 36-60 months were selected through a geographically stratified design from the city centre, two suburbs, a rural community and an island situated within the harbour at Karachi. Blood samples were collected from children and a pretested questionnaire was administered to assess the effect of various types of exposure. Cooked food, drinking-water and house dust samples were collected from households. FINDINGS: About 80% of children had blood lead concentrations 10 g/dl, with an overall mean of 15.6 g/dl. At the 5% level of significance, houses nearer to the main intersection in the city centre, application of surma to children's eyes, father's exposure to lead at workplace, parents' illiteracy and child's habit of hand- to-mouth activity were among variables associated with elevated lead concentrations in blood. CONCLUSION: These findings are of public health concern, as most children in Karachi are likely to suffer some degree of intellectual impairment as a result of environmental lead exposure. We believe that there is enough evidence of the continuing problem of lead in petrol to prompt the petroleum industry to take action. The evidence also shows the need for appropriate interventions in reducing the burden due to other factors associated with this toxic element. PMID:12471396

Power law relation between particle concentrations and their sizes in the blood plasma

NASA Astrophysics Data System (ADS)

Kirichenko, M. N.; Chaikov, L. L.; Zaritskii, A. R.

2016-08-01

This work is devoted to the investigation of sizes and concentrations of particles in blood plasma by dynamic light scattering (DLS). Blood plasma contains many different proteins and their aggregates, microparticles and vesicles. Their sizes, concentrations and shapes can give information about donor's health. Our DLS study of blood plasma reveals unexpected dependence: with increasing of the particle sizes r (from 1 nm up to 1 μm), their concentrations decrease as r-4 (almost by 12 orders). We found also that such dependence was repeated for model solution of fibrinogen and thrombin with power coefficient is -3,6. We believe that this relation is a fundamental law of nature that shows interaction of proteins (and other substances) in biological liquids.

The relationship between exsanguination blood lactate concentration and carcass quality in slaughter pigs.

PubMed

Edwards, L N; Engle, T E; Correa, J A; Paradis, M A; Grandin, T; Anderson, D B

2010-07-01

A group of 128 cross-bred barrows were used to determine the relationship between exsanguination blood lactate concentration ([LAC]) and carcass quality following commercial marketing conditions. After 10h of feed withdrawal, pigs were loaded on a truck with a hydraulically lifted second deck and transported approximately 1h to the slaughter facility. Pigs were rested for 8h and stunned with carbon dioxide. Blood lactate concentration was measured on exsanguination blood. Fourteen pork quality measurements were obtained following normal post-mortem processing. Pearson correlations were used to determine the relationships between [LAC] and the meat quality parameters. Exsanguination blood lactate concentration ranged from 4 to 19.7 mM. Higher lactate was associated with lower 60 min pH (P=0.0004) and higher drip loss (P=0.02). These results suggest that under low-stress loading and standard marketing conditions, exsanguination [LAC] is predictive of the rate of early post-mortem metabolism. Copyright 2010 Elsevier Ltd. All rights reserved.

Neonatal blood cultures: effect of delayed entry into the blood culture machine and bacterial concentration on the time to positive growth in a simulated model.

PubMed

Jardine, Luke Anthony; Sturgess, Barbara Ruth; Inglis, Garry Donald Trevor; Davies, Mark William

2009-04-01

To determine if: time from blood culture inoculation to positive growth (total time to positive) and time from blood culture machine entry to positive growth (machine time to positive) is altered by delayed entry into the automated blood culture machine, and if the total time to positive differs by the concentration of organisms inoculated into blood culture bottles. Staphylococcus epidermidis, Escherichia coli and group B beta-haemolytic streptococci were chosen as clinically significant representative organisms. Two concentrations (> or =10 colony-forming units per millilitre and <1 colony-forming units per millilitre) were inoculated into PEDS BacT/Alert blood culture bottles and randomly allocated to one of three delayed automated blood culture machine entry times (30 min/8.5 h/15.5 h). For all organisms at all concentrations, except the Staphylococcus epidermidis, the machine time to positive was significantly decreased by delayed entry. For all organisms at all concentrations, the mean total time to positive significantly increased with increasing delayed entry into the blood culture machine. Higher concentrations of group B beta-haemolytic streptococci and Escherichia coli grew significantly faster than lower concentrations. Bacterial growth in inoculated bottles, stored at room temperature, continues although at a slower rate than in those blood culture bottles immediately entered into the machine. If a blood culture specimen has been stored at room temperature for greater than 15.5 h, the currently allowed safety margin of 36 h (before declaring a result negative) may be insufficient.

Blood vitamin concentrations in privately owned dogs fed non-standardized commercial diets and after intake of diets with specified vitamin concentrations.

PubMed

Tran, J L; Horvath, C; Krammer, S; Höller, U; Zentek, J

2007-02-01

The objective was to investigate in a survey study the blood vitamin concentrations in healthy dogs fed non-specified commercial complete diets and in an intervention study to determine the effects of defined dietary vitamin intakes on blood vitamin levels and hair and skin condition. Sixty-four privately owned dogs, aged from 1 to 8 years, without history of skin or coat problems were included. All animals were fed commercial complete diets with uncertain vitamin concentrations before enrolment. The animals were assigned, according to weight and gender, to four groups with graded vitamin intakes. The blood vitamin levels and skin and coat quality of the dogs were investigated at days 0 and day 122. Coat and hair condition was not influenced by the experimental diets. The retinol concentrations were reduced at the end of the experiment compared with the baseline levels, retinyl esters were not influenced. 25-Hydroxycholecalciferol decreased in all groups, alpha-tocopherol was constant or tended to decrease. Ascorbic acid, thiamine pyrophosphate and riboflavin concentrations were not affected by treatment, flavin adenine dinucleotide and pyridoxal-5'-phosphate were partially reduced on day 122. Cobalamin, pantothenate and biotin concentrations increased with higher dietary intakes, folate levels in tendency. In conclusion, this study gives a survey of blood vitamin concentrations in healthy dogs and provides a data base for the evaluation of the vitamin status in health and disease.

Individual and environmental risk factors for high blood lead concentrations in Danish indoor shooters.

PubMed

Grandahl, Kasper; Suadicani, Poul; Jacobsen, Peter

2012-08-01

International studies have shown blood lead at levels causing health concern in recreational indoor shooters. We hypothesized that Danish recreational indoor shooters would also have a high level of blood lead, and that this could be explained by shooting characteristics and the physical environment at the shooting range. This was an environmental case study of 58 male and female shooters from two indoor shooting ranges with assumed different ventilation and cleaning conditions. Information was obtained on general conditions including age, gender, tobacco and alcohol use, and shooting conditions: weapon type, number of shots fired, frequency of stays at the shooting range and hygiene habits. A venous blood sample was drawn to determine blood lead concentrations; 14 non-shooters were included as controls. Almost 60% of the shooters, hereof five out of 14 women, had a blood lead concentration above 0.48 micromol/l, a level causing long-term health concern. All controls had blood lead values below 0.17 micromol/l. Independent significant associations with blood lead concentrations above 0.48 micromol/l were found for shooting at a poorly ventilated range, use of heavy calibre weapons, number of shots and frequency of stays at the shooting range. A large proportion of Danish recreational indoor shooters had potentially harmful blood lead concentrations. Ventilation, amounts of shooting, use of heavy calibre weapons and stays at the shooting ranges were independently associated with increased blood lead. The technical check at the two ranges was performed by the Danish Technological Institute and costs were defrayed by the Danish Rifle Association. To pay for the analyses of blood lead, the study was supported by the The Else & Mogens Wedell-Wedellsborg Foundation. The Danish Regional Capital Scientific Ethics Committee approved the study, protocol number H-4-2010-130.

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.

Blood selenium concentrations and enzyme activities related to glutathione metabolism in wild emperor geese

USGS Publications Warehouse

Franson, J. Christian; Hoffman, David J.; Schmutz, Joel A.

2002-01-01

In 1998, we collected blood samples from 63 emperor geese (Chen canagica) on their breeding grounds on the Yukon-Kuskokwim Delta (YKD) in western Alaska, USA. We studied the relationship between selenium concentrations in whole blood and the activities of glutathione peroxidase and glutathione reductase in plasma. Experimental studies have shown that plasma activities of these enzymes are useful biomarkers of selenium-induced oxidative stress, but little information is available on their relationship to selenium in the blood of wild birds. Adult female emperor geese incubating their eggs in mid-June had a higher mean concentration of selenium in their blood and a greater activity of glutathione peroxidase in their plasma than adult geese or goslings that were sampled during the adult flight feathermolting period in late July and early August. Glutathione peroxidase activity was positively correlated with the concentration of selenium in the blood of emperor geese, and the rate of increase relative to selenium was greater in goslings than in adults. The activity of glutathione reductase was greatest in the plasma of goslings and was greater in molting adults than incubating females but was not significantly correlated with selenium in the blood of adults or goslings. Incubating female emperor geese had high selenium concentrations in their blood, accompanied by increased glutathione peroxidase activity consistent with early oxidative stress. These findings indicate that further study of the effects of selenium exposure, particularly on reproductive success, is warranted in this species.

Evaluation of the agreement among three handheld blood glucose meters and a laboratory blood analyzer for measurement of blood glucose concentration in Hispaniolan Amazon parrots (Amazona ventralis).

PubMed

Acierno, Mark J; Mitchell, Mark A; Schuster, Patricia J; Freeman, Diana; Sanchez-Migallon Guzman, David; Tully, Thomas N

2009-02-01

To determine the degree of agreement between 3 commercially available point-of-care blood glucose meters and a laboratory analyzer for measurement of blood glucose concentrations in Hispaniolan Amazon parrots (Amazona ventralis). 20 healthy adult Hispaniolan Amazon parrots. A 26-gauge needle and 3-mL syringe were used to obtain a blood sample (approx 0.5 mL) from a jugular vein of each parrot. Small volumes of blood (0.6 to 1.5 microL) were used to operate each of the blood glucose meters, and the remainder was placed into lithium heparin microtubes and centrifuged. Plasma was harvested and frozen at -30 degrees C. Within 5 days after collection, plasma samples were thawed and plasma glucose concentrations were measured by means of the laboratory analyzer. Agreement between pairs of blood glucose meters and between each blood glucose meter and the laboratory analyzer was evaluated by means of the Bland-Altman method, and limits of agreement (LOA) were calculated. None of the results of the 3 blood glucose meters agreed with results of the laboratory analyzer. Each point-of-care blood glucose meter underestimated the blood glucose concentration, and the degree of negative bias was not consistent (meter A bias, -94.9 mg/dL [LOA, -148.0 to -41.7 mg/dL]; meter B bias, -52 mg/dL [LOA, -107.5 to 3.5 mg/dL]; and meter C bias, -78.9 mg/dL [LOA, -137.2 to -20.6 mg/dL]). On the basis of these results, use of handheld blood glucose meters in the diagnosis or treatment of Hispaniolan Amazon parrots and other psittacines cannot be recommended.

Blood mineral concentrations in manatees (Trichechus manatus latirostris and Trichechus manatus manatus)

USGS Publications Warehouse

Siegal-Willott, J.; Harr, Kendal E.; Hall, Jeffery O.; Hayek, Lee-Ann C.; Auil-Gomez, Nicole; Powell, James A.; Bonde, Robert K.; Heard, Darryl

2013-01-01

Limited information is available regarding the role of minerals and heavy metals in the morbidity and mortality of manatees. Whole-blood and serum mineral concentrations were evaluated in apparently healthy, free-ranging Florida (Trichechus manatus latirostris, n = 31) and Belize (Trichechus manatus manatus, n = 14) manatees. Toxicologic statuses of the animals and of their environment had not been previously determined. Mean mineral whole-blood (WB) and serum values in Florida (FL) and Belize (BZ) manatees were determined, and evaluated for differences with respect to geographic location, relative age, and sex. Mean WB and serum silver, boron, cobalt, magnesium, molybdenum, and WB cadmium concentrations were significantly higher in BZ versus FL manatees (P ≤ 0.05). Mean WB aluminum, calcium, manganese, sodium, phosphorus, vanadium, and serum zinc concentrations were significantly lower in BZ versus FL manatees. Adult manatees had significant and higher mean WB aluminum, manganese, sodium, antimony, vanadium, and serum manganese and zinc concentrations compared to juvenile animals. Significant and lower mean WB and serum silver, boron, cobalt, and serum copper and strontium concentrations were present in adults compared to juveniles (P ≤ 0.05). Females had significant and higher mean WB nickel and serum barium compared to males (P ≤ 0.05). Mean WB arsenic and zinc, and mean serum iron, magnesium, and zinc concentrations fell within toxic ranges reported for domestic species. Results reveal manatee blood mineral concentrations differ with location, age, and sex. Influence from diet, sediment, water, and anthropogenic sources on manatee mineral concentration warrant further investigation.

Blood mineral concentrations in manatees (Trichechus manatus latirostris and Trichechus manatus manatus).

PubMed

Siegal-Willott, Jessica L; Harr, Kendal E; Hall, Jeffery O; Hayek, Lee-Ann C; Auil-Gomez, Nicole; Powell, James A; Bonde, Robert K; Heard, Darryl

2013-06-01

Limited information is available regarding the role of minerals and heavy metals in the morbidity and mortality of manatees. Whole-blood and serum mineral concentrations were evaluated in apparently healthy, free-ranging Florida (Trichechus manatus latirostris, n = 31) and Belize (Trichechus manatus manatus, n = 14) manatees. Toxicologic statuses of the animals and of their environment had not been previously determined. Mean mineral whole-blood (WB) and serum values in Florida (FL) and Belize (BZ) manatees were determined, and evaluated for differences with respect to geographic location, relative age, and sex. Mean WB and serum silver, boron, cobalt, magnesium, molybdenum, and WB cadmium concentrations were significantly higher in BZ versus FL manatees (P < 0.05). Mean WB aluminum, calcium, manganese, sodium, phosphorus, vanadium, and serum zinc concentrations were significantly lower in BZ versus FL manatees. Adult manatees had significant and higher mean WB aluminum, manganese, sodium, antimony, vanadium, and serum manganese and zinc concentrations compared to juvenile animals. Significant and lower mean WB and serum silver, boron, cobalt, and serum copper and strontium concentrations were present in adults compared to juveniles (P < or = 0.05). Females had significant and higher mean WB nickel and serum barium compared to males (P < or = 0.05). Mean WB arsenic and zinc, and mean serum iron, magnesium, and zinc concentrations fell within toxic ranges reported for domestic species. Results reveal manatee blood mineral concentrations differ with location, age, and sex. Influence from diet, sediment, water, and anthropogenic sources on manatee mineral concentration warrant further investigation.

Use of dried blood spots for the determination of serum concentrations of tamoxifen and endoxifen.

PubMed

Jager, N G L; Rosing, H; Schellens, J H M; Beijnen, J H; Linn, S C

2014-07-01

The anti-estrogenic effect of tamoxifen is suggested to be mainly attributable to its metabolite (Z)-endoxifen, and a minimum therapeutic threshold for (Z)-endoxifen in serum has been proposed. The objective of this research was to establish the relationship between dried blood spot (DBS) and serum concentrations of tamoxifen and (Z)-endoxifen to allow the use of DBS sampling, a simple and patient-friendly alternative to venous sampling, in clinical practice. Paired DBS and serum samples were obtained from 50 patients using tamoxifen and analyzed using HPLC-MS/MS. Serum concentrations were calculated from DBS concentrations using the formula calculated serum concentration = DBS concentration/([1-haematocrit (Hct)] + blood cell-to-serum ratio × Hct). The blood cell-to-serum ratio was determined ex vivo by incubating a batch of whole blood spiked with both analytes. The average Hct for female adults was imputed as a fixed value. Calculated and analyzed serum concentrations were compared using weighted Deming regression. Weighted Deming regression analysis comparing 44 matching pairs of DBS and serum samples showed a proportional bias for both analytes. Serum concentrations were calculated using [Tamoxifen] serum, calculated  = [Tamoxifen] DBS /0.779 and [(Z)-Endoxifen] serum, calculated = [(Z)-Endoxifen] DBS /0.663. Calculated serum concentrations were within 20 % of analyzed serum concentrations in 84 and 100 % of patient samples for tamoxifen and (Z)-endoxifen, respectively. In conclusion, DBS concentrations of tamoxifen and (Z)-endoxifen were equal to serum concentrations after correction for Hct and blood cell-to-serum ratio. DBS sampling can be used in clinical practice.

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.

Elevated Blood Lead Concentrations in Essential Tremor: A Case–Control Study in Mersin, Turkey

PubMed Central

Dogu, Okan; Louis, Elan D.; Tamer, Lulufer; Unal, Ozgur; Yilmaz, Arda; Kaleagasi, Hakan

2007-01-01

Background Essential tremor (ET) is one of the most common neurologic disorders. Aside from underlying susceptibility genes, recent studies have also begun to focus on environmental toxic factors. Yet there remains a paucity of information on such factors, making studies of environmental factors important. A recent study in New York City found blood lead concentrations to be elevated in ET cases compared with matched controls. Chronic exposure to lead produces cerebellar damage, and this could predispose individuals to develop ET. Objective The aim of this study was to determine whether the elevation in blood lead concentrations observed in a single study in New York was similarly present in ET cases sampled from a completely different geographic region. Methods Blood lead concentrations were measured in 105 ET cases and 105 controls at Mersin University, Mersin, Turkey. Results The median blood lead concentration was 2.7 μg/dL in ET cases compared with 1.5 μg/dL in controls (p < 0.001). In an unadjusted logistic regression model, blood lead concentration was associated with diagnosis: odds ratio (OR) = 4.01; 95% confidence interval (CI), 2.53–6.37; p < 0.001 (i.e., each 1-μg/dL increase in blood lead concentration was associated with a 4-fold increased odds of ET). This association was more robust when cases were compared with a subsample of controls who did not share the same home environment (OR = 8.13; 95% CI, 3.05–21.65; p < 0.001). In adjusted models, results were similar. Conclusions These data replicate those of a previous study in New York and demonstrate an association between the environmental toxicant lead and a common neurologic disorder. PMID:18007985

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.

Fat induced hypertension in rabbits. Effects of dietary fibre on blood pressure and blood lipid concentration.

PubMed

Burstyn, P G; Husbands, D R

1980-04-01

Rabbits were fed diets containing 200 g.kg-1 coconut oil, palm oil, or safflower oil. Some of the diets also contained 200 g.kg-1 cellulose. The blood pressure was measured daily by a non-invasive technique for the 2 month duration of the experiment. Blood samples were drawn after an overnight fast at intervals during the experiment and analysed for lipids. Blood pressure was always increased by a fat-enriched diet. This effect was diminished and delayed by adding cellulose to the diets, though cellulose itself had no effect on the blood pressure in the absence of fat. There was a modest negative correlation between fasting serum triglyceride concentration and the blood pressure in animals fed fat enriched diets without added cellulose, but not in animals fed diets containing both fat and cellulose. These results coupled with those of Wright, Burstyn and Gibney may serve partly to explain the observation that vegetarians have lower blood pressures than omnivores, the latter consuming diets which are relatively richer in fats and poorer in fibre than the former.

Blood lead concentration after a shotgun accident.

PubMed

Gerhardsson, Lars; Dahlin, Lars; Knebel, Richard; Schütz, Andrejs

2002-01-01

In an accidental shooting, a man in his late forties was hit in his left shoulder region by about 60 lead pellets from a shotgun. He had injuries to the vessels, the clavicle, muscles, and nerves, with total paralysis of the left arm due to axonal injury. After several surgical revisions and temporary cover with split skin, reconstructive surgery was carried out 54 days after the accident. The brachial plexus was swollen, but the continuity of the nerve trunks was not broken (no neuroma present). We determined the blood lead (BPb) concentration during a follow-up period of 12 months. The BPb concentration increased considerably during the first months. Although 30 lead pellets were removed during the reconstructive surgery, the BPb concentration continued to rise, and reached a peak of 62 microg/dL (3.0 micromol/L) on day 81. Thereafter it started to decline. Twelve months after the accident, BPb had leveled off at about 30 microg/dL. At that time, muscle and sensory functions had partially recovered. The BPb concentration exceeded 30 microg/dL for 9 months, which may have influenced the recovery rate of nerve function. Subjects with a large number of lead pellets or fragments embedded in the body after shooting accidents should be followed for many years by regular determinations of BPb. To obtain a more stable basis for risk assessment, the BPb concentrations should be corrected for variations in the subject's hemoglobin concentration or erythrocyte volume fraction.

Effects of sample handling methods on substance P concentrations and immunoreactivity in bovine blood samples.

PubMed

Mosher, Ruby A; Coetzee, Johann F; Allen, Portia S; Havel, James A; Griffith, Gary R; Wang, Chong

2014-02-01

To determine the effects of protease inhibitors and holding times and temperatures before processing on the stability of substance P in bovine blood samples. Blood samples obtained from a healthy 6-month-old calf. Blood samples were dispensed into tubes containing exogenous substance P and 1 of 6 degradative enzyme inhibitor treatments: heparin, EDTA, EDTA with 1 of 2 concentrations of aprotinin, or EDTA with 1 of 2 concentrations of a commercially available protease inhibitor cocktail. Plasma was harvested immediately following collection or after 1, 3, 6, 12, or 24 hours of holding at ambient (20.3° to 25.4°C) or ice bath temperatures. Total substance P immunoreactivity was determined with an ELISA; concentrations of the substance P parent molecule, a metabolite composed of the 9 terminal amino acids, and a metabolite composed of the 5 terminal amino acids were determined with liquid chromatography-tandem mass spectrometry. Regarding blood samples processed immediately, no significant differences in substance P concentrations or immunoreactivity were detected among enzyme inhibitor treatments. In blood samples processed at 1 hour of holding, substance P parent molecule concentration was significantly lower for ambient temperature versus ice bath temperature holding conditions; aprotinin was the most effective inhibitor of substance P degradation at the ice bath temperature. The ELISA substance P immunoreactivity was typically lower for blood samples with heparin versus samples with other inhibitors processed at 1 hour of holding in either temperature condition. Results suggested that blood samples should be chilled and plasma harvested within 1 hour after collection to prevent substance P degradation.

Heavy metal and trace element concentrations in blood and follicular fluid affect ART outcome.

PubMed

Tolunay, Harun Egemen; Şükür, Yavuz Emre; Ozkavukcu, Sinan; Seval, Mehmet Murat; Ateş, Can; Türksoy, Vugar Ali; Ecemiş, Tolga; Atabekoğlu, Cem Somer; Özmen, Batuhan; Berker, Bülent; Sönmezer, Murat

2016-03-01

To assess the effects of heavy metal and trace element concentrations in blood and follicular fluid on assisted reproductive technology cycle outcome. A prospective study was conducted between January 2012 and July 2012 in a university hospital infertility clinic. One hundred and one patients with unexplained infertility who underwent intracytoplasmic sperm injection using GnRH-antagonist protocol were recruited. Concentrations of four toxic metals (Cd, Pb, Hg, As) and three trace elements (Cu, Zn, Fe) were measured both in blood and follicular fluid specimens. Patients were evaluated in two groups; the study group consisted of patients with ongoing pregnancy (n=20) and the reference group consisted of patients experienced assisted reproductive technology failure, miscarriage or biochemical pregnancy (n=81). Demographics and cycle parameters were comparable between the groups except for median number of day 3 Grade A embryos. Statistically significant negative correlations were found between blood Pb levels and number of MII oocytes, implantation, clinical pregnancy and ongoing pregnancy rates. Results of the log binomial regression revealed 2.2% lower risk for ongoing pregnancy for each 1μg/dL higher blood Pb concentration while holding the other variables in the model constant (RR 0.978; 95% CI 0.956-0.998; P=.041). Also, the results revealed 71.9% lower risk for ongoing pregnancy for each 1μg/dL higher follicular fluid Cu concentration while holding the other variables in the model constant (RR 0.288; 95% CI 0.085-0.92; P=.039). Blood concentrations of Pb and follicular fluid concentrations of Cu seem to have significant impacts on assisted reproductive technology cycle outcome. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

White blood cell concentrations during lower body negative pressure and blood loss in humans.

PubMed

van Helmond, Noud; Johnson, Blair D; Curry, Timothy B; Cap, Andrew P; Convertino, Victor A; Joyner, Michael J

2016-10-01

What is the central question of this study? Is lower body negative pressure a useful surrogate to study white blood cell responses to haemorrhage in humans? What is the main finding and its importance? We found that lower body negative pressure appears to be a useful surrogate to study the early white blood cell mobilization response during blood loss. Hypovolaemia has been associated with an immune response that might be secondary to sympathoexcitation. We tested the hypothesis that simulated hypovolaemia using lower body negative pressure (LBNP) and real hypovolaemia induced via experimental blood loss (BL) cause similar increases in the white blood cell concentration ([WBC]). We measured [WBC] and catecholamine concentrations in 12 men who underwent an LBNP and a BL protocol in a randomized order. We compared 45 mmHg of LBNP with 1000 ml of BL; therefore, [WBC] and catecholamine concentrations were plotted against central venous pressure to obtain stimulus-response relationships using the linear regression line slopes for both protocols. Mean regression line slopes were similar for total [WBC] (LBNP 183 ± 4 μl -1  mmHg -1 versus BL 155 ± 109 μl -1  mmHg -1 , P = 0.15), neutrophils (LBNP 110 ± 2 μl -1  mmHg -1 versus BL 96 ± 72 μl -1  mmHg -1 , P = 0.15) and lymphocytes (LBNP 65 ± 21 μl -1  mmHg -1  versus BL 59 ± 38 μl -1  mmHg -1 , P = 0.90). Mean regression line slopes for adrenaline were similar (LBNP 15 ± 5 pg ml -1  mmHg -1 versus BL 16 ± 4 pg ml -1  mmHg -1 , P = 0.84) and were steeper during LBNP for noradrenaline (LBNP 28 ± 6 pg ml -1  mmHg -1 versus BL 9 ± 6 pg ml -1  mmHg -1 , P = 0.01). These data indicate that central hypovolaemia elicits a relative leucocytosis with a predominantly neutrophil-based response. Additionally, our results indicate that LBNP models the stimulus-response relationship between central venous pressure and [WBC] observed during BL. © 2016 The Authors

Alteration of chaotic advection in blood flow around partial blockage zone: Role of hematocrit concentration

NASA Astrophysics Data System (ADS)

Maiti, Soumyabrata; Chaudhury, Kaustav; DasGupta, Debabrata; Chakraborty, Suman

2013-01-01

Spatial distributions of particles carried by blood exhibit complex filamentary pattern under the combined effects of geometrical irregularities of the blood vessels and pulsating pumping by the heart. This signifies the existence of so called chaotic advection. In the present article, we argue that the understanding of such pathologically triggered chaotic advection is incomplete without giving due consideration to a major constituent of blood: abundant presence of red blood cells quantified by the hematocrit (HCT) concentration. We show that the hematocrit concentration in blood cells can alter the filamentary structures of the spatial distribution of advected particles in an intriguing manner. Our results reveal that there primarily are two major impacts of HCT concentrations towards dictating the chaotic dynamics of blood flow: changing the zone of influence of chaotic mixing and determining the enhancement of residence time of the advected particles away from the wall. This, in turn, may alter the extent of activation of platelets or other reactive biological entities, bearing immense consequence towards dictating the biophysical mechanisms behind possible life-threatening diseases originating in the circulatory system.

The fluctuation of blood glucose, insulin and glucagon concentrations before and after insulin therapy in type 1 diabetes

NASA Astrophysics Data System (ADS)

Arif, Idam; Nasir, Zulfa

2015-09-01

A dynamical-systems model of plasma glucose, insulin and glucagon concentrations has been developed to investigate the effects of insulin therapy on blood glucose, insulin and glucagon regulations in type 1 diabetic patients. Simulation results show that the normal regulation of blood glucose concentration depends on insulin and glucagon concentrations. On type 1 diabetic case, the role of insulin on regulating blood glucose is not optimal because of the destruction of β cells in pancreas. These β cells destructions cause hyperglycemic episode affecting the whole body metabolism. To get over this, type 1 diabetic patients need insulin therapy to control the blood glucose level. This research has been done by using rapid acting insulin (lispro), long-acting insulin (glargine) and the combination between them to know the effects of insulin therapy on blood glucose, insulin and glucagon concentrations. Simulation results show that these different types of insulin have different effects on blood glucose concentration. Insulin therapy using lispro shows better blood glucose control after consumption of meals. Glargin gives better blood glucose control between meals and during sleep. Combination between lispro and glargine shows better glycemic control for whole day blood glucose level.

Cutpoints for screening blood glucose concentrations in healthy senior cats.

PubMed

Reeve-Johnson, Mia K; Rand, Jacquie S; Vankan, Dianne; Anderson, Stephen T; Marshall, Rhett; Morton, John M

2017-12-01

Objectives The objectives of this study were to determine the reference interval for screening blood glucose in senior cats, to apply this to a population of obese senior cats, to compare screening and fasting blood glucose, to assess whether screening blood glucose is predicted by breed, body weight, body condition score (BCS), behaviour score, fasting blood glucose and/or recent carbohydrate intake and to assess its robustness to changes in methodology. Methods The study included a total of 120 clinically healthy client-owned cats aged 8 years and older of varying breeds and BCSs. Blood glucose was measured at the beginning of the consultation from an ear/paw sample using a portable glucose meter calibrated for cats, and again after physical examination from a jugular sample. Fasting blood glucose was measured after overnight hospitalisation and fasting for 18-24 h. Results The reference interval upper limit for screening blood glucose was 189 mg/dl (10.5 mmol/l). Mean screening blood glucose was greater than mean fasting glucose. Breed, body weight, BCS, behaviour score, fasting blood glucose concentration and amount of carbohydrate consumed 2-24 h before sampling collectively explained only a small proportion of the variability in screening blood glucose. Conclusions and relevance Screening blood glucose measurement represents a simple test, and cats with values from 117-189 mg/dl (6.5-10.5 mmol/l) should be retested several hours later. Cats with initial screening blood glucose >189 mg/dl (10.5 mmol/l), or a second screening blood glucose >116 mg/dl (6.4 mmol/l) several hours after the first, should have fasting glucose and glucose tolerance measured after overnight hospitalisation.

Range of therapeutic prothipendyl and prothipendyl sulfoxide concentrations in clinical blood samples.

PubMed

Krämer, Michael; Heese, Peter; Banger, Markus; Madea, Burkhard; Hess, Cornelius

2018-06-01

Due to a lack of reference blood concentrations in the literature, the forensic evaluation of prothipendyl findings in blood samples is difficult. Interpretations with regard to the assessment of blood concentrations as well as an estimation of the ingested prothipendyl amounts were often vague. To describe a concentration range in clinical samples, prothipendyl and prothipendyl sulfoxide concentrations were determined in serum samples of 50 psychiatric patients receiving 40 mg, 80 mg, or 160 mg doses of prothipendyl. The analyses of prothipendyl and prothipendyl sulfoxide were carried out using validated methods of high performance liquid chromatography coupled to triple quadrupole mass spectrometry (LC-QQQ-MS), respectively. 40 mg doses caused average prothipendyl serum concentrations of 18.0 ng/mL (1 hour after intake) and 7.9 ng/mL (10.5 hours after intake), while 80 mg doses caused averages of 42.6 ng/mL and 15.2 ng/mL at the mentioned times of sampling. Irrespective of the given dose, prothipendyl concentrations below 30 ng/mL were observed in 80% of the patient samples taken 1 hour after ingestion as well as in 90% of the samples collected 10.5 hours after administration. Serum concentrations of the Phase I metabolite prothipendyl sulfoxide averaged 4.3 ng/mL (1 hour after intake) and 3.6 ng/mL (10.5 hours after intake). Possible drug-drug interactions regarding absorption and metabolism of prothipendyl are discussed. Results of the herein presented study are useful for the interpretation of analytical prothipendyl findings in forensic toxicology. The utility of the described concentration range is demonstrated by discussing two death cases involving prothipendyl findings. Copyright © 2017 John Wiley & Sons, Ltd.

Rational and timely haemostatic interventions following cardiac surgery - coagulation factor concentrates or blood bank products.

PubMed

Tang, Mariann; Fenger-Eriksen, Christian; Wierup, Per; Greisen, Jacob; Ingerslev, Jørgen; Hjortdal, Vibeke; Sørensen, Benny

2017-06-01

Cardiac surgery may cause a serious coagulopathy leading to increased risk of bleeding and transfusion demands. Blood bank products are commonly first line haemostatic intervention, but has been associated with hazardous side effect. Coagulation factor concentrates may be a more efficient, predictable, and potentially a safer treatment, although prospective clinical trials are needed to further explore these hypotheses. This study investigated the haemostatic potential of ex vivo supplementation of coagulation factor concentrates versus blood bank products on blood samples drawn from patients undergoing cardiac surgery. 30 adults were prospectively enrolled (mean age=63.9, females=27%). Ex vivo haemostatic interventions (monotherapy or combinations) were performed in whole blood taken immediately after surgery and two hours postoperatively. Fresh-frozen plasma, platelets, cryoprecipitate, fibrinogen concentrate, prothrombin complex concentrate (PCC), and recombinant FVIIa (rFVIIa) were investigated. The haemostatic effect was evaluated using whole blood thromboelastometry parameters, as well as by thrombin generation. Immediately after surgery the compromised maximum clot firmness was corrected by monotherapy with fibrinogen or platelets or combination therapy with fibrinogen. At two hours postoperatively the coagulation profile was further deranged as illustrated by a prolonged clotting time, a reduced maximum velocity and further diminished maximum clot firmness. The thrombin lagtime was progressively prolonged and both peak thrombin and endogenous thrombin potential were compromised. No monotherapy effectively corrected all haemostatic abnormalities. The most effective combinations were: fibrinogen+rFVIIa or fibrinogen+PCC. Blood bank products were not as effective in the correction of the coagulopathy. Coagulation factor concentrates appear to provide a more optimal haemostasis profile following cardiac surgery compared to blood bank products. Copyright © 2017

Homeostasis of the Intraparenchymal-Blood Glutamate Concentration Gradient: Maintenance, Imbalance, and Regulation

PubMed Central

Bai, Wei; Zhou, Yuan-Guo

2017-01-01

It is widely accepted that glutamate is the most important excitatory neurotransmitter in the central nervous system (CNS). However, there is also a large amount of glutamate in the blood. Generally, the concentration gradient of glutamate between intraparenchymal and blood environments is stable. However, this gradient is dramatically disrupted under a variety of pathological conditions, resulting in an amplifying cascade that causes a series of pathological reactions in the CNS and peripheral organs. This eventually seriously worsens a patient’s prognosis. These two “isolated” systems are rarely considered as a whole even though they mutually influence each other. In this review, we summarize what is currently known regarding the maintenance, imbalance and regulatory mechanisms that control the intraparenchymal-blood glutamate concentration gradient, discuss the interrelationships between these systems and further explore their significance in clinical practice. PMID:29259540

Evaluation of 99mtechnetium-radiopharmaceutical binding to blood elements using different trichloroacetic acid concentrations.

PubMed

Freitas, R S; Gutfilen, B; da Fonseca, L M; Bernardo-Filho, M

1996-01-01

Secure determination of the binding of 99mTc-radiopharmaceuticals to plasma (P) and blood cell (BC) constituents can help to understand the biodistribution of radiophamaceuticals. The reported precipitation studies of blood with radiopharmaceuticals have shown that the results can not be easily compared between studies. We decided to determine the "gold standard" concentration of trichloroacetic acid (TCA) to evaluate the binding to blood elements for several radiopharmaceuticals used in routine nuclear medicine. We have studied phytic (99mTc-PHY), diethylenetriaminepentaacetic (99mTc-DTPA), glucoheptonic (99mTc-GHA) and dimercaptosuccinic (99mTc-DMSA) acids. Blood was incubated with radiopharmaceuticals, centrifuged and P and BC separated. Samples of P and BC were also precipitated with TCA concentrations (20.0, 10.0, 5.0, 1.0, 0.5 and 0.1 percent) and soluble (SF) and insoluble fractions (IF) were isolated. The percent radioactivity (percent rad) in IF-P depends on TCA concentration. It varied from 36.4 to 65.0 (99mTc-PHY), from 17.9 to 32.0 (99mTc-DTPA), from 11.5 to 38.8 (99mTc-GHA) and from 52.8 to 66.2 (99mTc-DMSA). The results for the binding of 99mTc-PHY to IF-P show that there was no differences in the percent rad when TCA concentrations of 0.1 to 1.0 percent were used. For 99mTc-DTPA, 5.0 percent is the best TCA concentration. For 99mTc-GHA, low values of percent rad bound to IF-P is found with TCA concentrations of 0.1, 0.5 and 1.0. Interestingly, with 99mTc-DMSA, high values of bound radioactivity are not dependent on TCA concentrations (0.1 to 10.0). Radioactivity in IF-BC depends on TCA concentration and it varied for 99mTc-PHY (80.1 to 54.1) and for 99mTc-GHA (85.5 to 61.7). With 99mTc-DTPA and with 99mTc-DMSA the percent rad in IF-BC seems independent of TCA concentration. We suggest that the evaluation of the binding of the various 99mTc-radiopharmaceuticals to blood constituents, using only one TCA concentration, should be avoided.

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.

Blood lead concentration after a shotgun accident.

PubMed Central

Gerhardsson, Lars; Dahlin, Lars; Knebel, Richard; Schütz, Andrejs

2002-01-01

In an accidental shooting, a man in his late forties was hit in his left shoulder region by about 60 lead pellets from a shotgun. He had injuries to the vessels, the clavicle, muscles, and nerves, with total paralysis of the left arm due to axonal injury. After several surgical revisions and temporary cover with split skin, reconstructive surgery was carried out 54 days after the accident. The brachial plexus was swollen, but the continuity of the nerve trunks was not broken (no neuroma present). We determined the blood lead (BPb) concentration during a follow-up period of 12 months. The BPb concentration increased considerably during the first months. Although 30 lead pellets were removed during the reconstructive surgery, the BPb concentration continued to rise, and reached a peak of 62 microg/dL (3.0 micromol/L) on day 81. Thereafter it started to decline. Twelve months after the accident, BPb had leveled off at about 30 microg/dL. At that time, muscle and sensory functions had partially recovered. The BPb concentration exceeded 30 microg/dL for 9 months, which may have influenced the recovery rate of nerve function. Subjects with a large number of lead pellets or fragments embedded in the body after shooting accidents should be followed for many years by regular determinations of BPb. To obtain a more stable basis for risk assessment, the BPb concentrations should be corrected for variations in the subject's hemoglobin concentration or erythrocyte volume fraction. PMID:11781173

Effects of high and low blood lactate concentrations on sweat lactate response.

PubMed

Green, J M; Bishop, P A; Muir, I H; McLester, J R; Heath, H E

2000-11-01

Sweat lactate results from eccrine gland metabolism, however, the possible clearance of blood lactate through sweat has not been resolved. On separate days in an environmental chamber (32 +/- 1 C) 12 subjects completed a constant load (CON) (30 min at 40% VO2 max) and an interval cycling trial (INT) (15 one-min intervals at 80% VO2 max, each separated by one min rest) each designed to elicit different blood lactate responses. Each 30 min cycling trial was preceded by 15 min warm-up (30 watts) and followed by 15 min passive rest. Sweat and blood were analyzed for lactate concentration at 15, 25, 35, 45, and 60 min during CON and INT. Total body water loss was used to calculate sweat rate (ml/hr). Blood lactate was significantly greater (p < or = 0.05) at 25, 35, 45, and 60 min during INT compared to CON (approximately 5 mmol/L vs 1.5 mmol/L). Sweat lactate was not significantly different (p>0.05) between trials at any time (approximately 10 mmol/L). Sweat rates (approximately 600ml/hr) and estimated total lactate secretion were not significantly different (CON vs. INT) (p > 0.05). Elevated blood lactate was not associated with changes in sweat lactate concentration. Sweat lactate seems to originate in eccrine glands independent of blood lactate.

A method for estimating radioactive cesium concentrations in cattle blood using urine samples.

PubMed

Sato, Itaru; Yamagishi, Ryoma; Sasaki, Jun; Satoh, Hiroshi; Miura, Kiyoshi; Kikuchi, Kaoru; Otani, Kumiko; Okada, Keiji

2017-12-01

In the region contaminated by the Fukushima nuclear accident, radioactive contamination of live cattle should be checked before slaughter. In this study, we establish a precise method for estimating radioactive cesium concentrations in cattle blood using urine samples. Blood and urine samples were collected from a total of 71 cattle on two farms in the 'difficult-to-return zone'. Urine 137 Cs, specific gravity, electrical conductivity, pH, sodium, potassium, calcium, and creatinine were measured and various estimation methods for blood 137 Cs were tested. The average error rate of the estimation was 54.2% without correction. Correcting for urine creatinine, specific gravity, electrical conductivity, or potassium improved the precision of the estimation. Correcting for specific gravity using the following formula gave the most precise estimate (average error rate = 16.9%): [blood 137 Cs] = [urinary 137 Cs]/([specific gravity] - 1)/329. Urine samples are faster to measure than blood samples because urine can be obtained in larger quantities and has a higher 137 Cs concentration than blood. These advantages of urine and the estimation precision demonstrated in our study, indicate that estimation of blood 137 Cs using urine samples is a practical means of monitoring radioactive contamination in live cattle. © 2017 Japanese Society of Animal Science.

Blood selenium concentrations in female Pacific black brant molting in Arctic Alaska: Relationships with age and habitat salinity.

PubMed

Franson, J Christian; Flint, Paul L; Schmutz, Joel A

2016-10-15

Blood samples collected from 81 female Pacific black brant (Branta bernicla nigricans) molting near Teshekpuk Lake, Alaska, were analyzed for selenium concentration. The concentration of selenium in blood of after second year (hatched two or more years ago) females (0.84μg/g wet weight) was significantly greater than the concentration in second year (hatched the previous year) females (0.61μg/g wet weight). The concentrations of selenium we found in blood of black brant were 1.5 to 2 times greater than baseline values typical of freshwater birds, but considerably lower than reported in other marine waterfowl sampled in Alaska. This finding may be attributable in part to the nearly exclusive herbivorous diet of black brant. No relationship was noted between blood selenium concentration and molting habitat salinity. We are unaware of any previous reports of blood selenium concentrations in black brant. Published by Elsevier Ltd.

Blood selenium concentrations in female Pacific black brant molting in Arctic Alaska: Relationships with age and habitat salinity

USGS Publications Warehouse

Franson, J. Christian; Flint, Paul L.; Schmutz, Joel A.

2016-01-01

Blood samples collected from 81 female Pacific black brant (Branta bernicla nigricans) molting near Teshekpuk Lake, Alaska, were analyzed for selenium concentration. The concentration of selenium in blood of after second year (hatched two or more years ago) females (0.84 μg/g wet weight) was significantly greater than the concentration in second year (hatched the previous year) females (0.61 μg/g wet weight). The concentrations of selenium we found in blood of black brant were 1.5 to 2 times greater than baseline values typical of freshwater birds, but considerably lower than reported in other marine waterfowl sampled in Alaska. This finding may be attributable in part to the nearly exclusive herbivorous diet of black brant. No relationship was noted between blood selenium concentration and molting habitat salinity. We are unaware of any previous reports of blood selenium concentrations in black brant.

Differences in iron concentration in whole blood of animal models using NAA

NASA Astrophysics Data System (ADS)

Bahovschi, V.; Zamboni, C. B.; Lopes Silva, L. F. F.; Metairon, S.; Medeiros, I. M. M. A.

2015-07-01

In this study Neutron Activation Analysis technique (NAA) was applied to determine Fe concentration in whole blood samples of several animal models such as: mice (Mus musculus), Golden Hamster (Mesocricetus auratus), Wistar rats, Albinic Rabbits of New Zealand, Golden Retriever dogs and Crioulabreed horses. These results were compared with human whole blood estimation to check their similarities.

Associations between blood BTEXS concentrations and hematologic parameters among adult residents of the U.S. Gulf States.

PubMed

Doherty, Brett T; Kwok, Richard K; Curry, Matthew D; Ekenga, Christine; Chambers, David; Sandler, Dale P; Engel, Lawrence S

2017-07-01

Studies of workers exposed to benzene at average air concentrations below one part per million suggest that benzene, a known hematotoxin, causes hematopoietic damage even at low exposure levels. However, evidence of such effects outside of occupational settings and for other volatile organic compounds (VOCs) is limited. To investigate associations between ambient exposures to five VOCs, including benzene, and hematologic parameters among adult residents of the U.S. Gulf Coast. Blood concentrations of selected VOCs were measured in a sample of adult participants in the Gulf Long-term Follow-up Study (GuLF STUDY) during 2012 and 2013. Complete blood counts with differentials were also performed on a subset of participants (n=406). We used these data together with detailed questionnaire data to estimate adjusted associations between blood BTEXS (benzene, toluene, ethylbenzene, o-xylene, m/p-xylene, and styrene) concentrations and hematologic parameters using generalized linear models. We observed inverse associations between blood benzene concentrations and hemoglobin concentration and mean corpuscular hemoglobin concentration, and a positive association with red cell distribution width among tobacco smoke-unexposed participants (n=146). Among tobacco smoke-exposed participants (n=247), we observed positive associations between blood VOC concentrations and several hematologic parameters, including increased white blood cell and platelet counts, suggestive of hematopoietic stimulation typically associated with tobacco smoke exposure. Most associations were stronger for benzene than for the other VOCs. Our results suggest that ambient exposure to BTEXS, particularly benzene, may be associated with hematologic effects, including decreased hemoglobin concentration, mean corpuscular hemoglobin concentration, and increased red cell distribution width. Published by Elsevier Inc.

Impact of Ficoll density gradient centrifugation on major and trace element concentrations in erythrocytes and blood plasma.

PubMed

Lu, Ying; Ahmed, Sultan; Harari, Florencia; Vahter, Marie

2015-01-01

Ficoll density gradient centrifugation is widely used to separate cellular components of human blood. We evaluated the suitability to use erythrocytes and blood plasma obtained from Ficoll centrifugation for assessment of elemental concentrations. We determined 22 elements (from Li to U) in erythrocytes and blood plasma separated by direct or Ficoll density gradient centrifugation, using inductively coupled plasma mass spectrometry. Compared with erythrocytes and blood plasma separated by direct centrifugation, those separated by Ficoll had highly elevated iodine and Ba concentration, due to the contamination from the Ficoll-Paque medium, and about twice as high concentrations of Sr and Mo in erythrocytes. On the other hand, the concentrations of Ca in erythrocytes and plasma were markedly reduced by the Ficoll separation, to some extent also Li, Co, Cu, and U. The reduced concentrations were probably due to EDTA, a chelator present in the Ficoll medium. Arsenic concentrations seemed to be lowered by Ficoll, probably in a species-specific manner. The concentrations of Mg, P, S, K, Fe, Zn, Se, Rb, and Cs were not affected in the erythrocytes, but decreased in plasma. Concentrations of Mn, Cd, and Pb were not affected in erythrocytes, but in plasma affected by EDTA and/or pre-analytical contamination. Ficoll separation changed the concentrations of Li, Ca, Co, Cu, As, Mo, I, Ba, and U in erythrocytes and blood plasma, Sr in erythrocytes, and Mg, P, S, K, Fe, Zn, Se, Rb and Cs in blood plasma, to an extent that will invalidate evaluation of deficiencies or excess intakes. Copyright © 2014 Elsevier GmbH. All rights reserved.

Altering plasma sodium concentration rapidly changes blood pressure during haemodialysis.

PubMed

Suckling, Rebecca J; Swift, Pauline A; He, Feng J; Markandu, Nirmala D; MacGregor, Graham A

2013-08-01

Plasma sodium is increased following each meal containing salt. There is an increasing interest in the effects of plasma sodium concentration, and it has been suggested that it may have direct effects on blood pressure (BP) and possibly influences endothelial function. Experimental increases of plasma sodium concentration rapidly raise BP even when extracellular volume falls. Ten patients with end-stage renal failure established on haemodialysis were studied during the first 2 h of dialysis without fluid removal during this period. They were randomized to receive haemodialysis with (i) dialysate sodium concentration prescribed to 135 mmol/L and (ii) 145 mmol/L in random order in a prospective, single-blinded crossover study. BP measurements and blood samples were taken every 30 min. Pre-dialysis sitting BP was 137/76 ± 7/3 mmHg. Lower dialysate sodium concentration (135 mmol/L) reduced plasma sodium concentration [139.49 ± 0.67 to 135.94 ± 0.52 mmol/L (P < 0.001)], whereas plasma sodium concentration was not altered by higher dialysate sodium (145 mmol/L) (140.17 ± 0.66 mmol/L at baseline to 140.72 ± 0.43 mmol/L at 120 min). Systolic BP was lower with dialysate sodium concentration 135 mmol/L [area under the curve (AUC) 15823.50 ± 777.15 (mmHg)min] compared with 145 mmol/L [AUC 17018.20 ± 1102.17 (mmHg)min], mean difference 1194.70 ± 488.41 (mmHg)min, P < 0.05. There was a significant positive relationship between change in plasma sodium concentration and change in systolic BP. This direct relationship suggests that a fall of 1 mmol/L in plasma sodium concentration would be associated with a 1.7 mmHg reduction in systolic BP (P < 0.05). The potential mechanism for the increase in BP seen with salt intake may be through small but significant changes in plasma sodium concentration.

Metal and selenium concentrations in blood and feathers of petrels of the genus Procellaria.

PubMed

Carvalho, Paloma Calábria; Bugoni, Leandro; McGill, Rona A R; Bianchini, Adalto

2013-07-01

Concentrations of copper (Cu), zinc (Zn), cadmium (Cd), lead (Pb), mercury (Hg), and selenium (Se) were determined in blood and feathers of spectacled (Procellaria conspicillata) and white-chinned (Procellaria aequinoctialis) petrels, species that are phylogenetically related, but with distinct ecological niches. In winter, they feed on similar foods, indicated by an overlapping range of whole-blood stable isotopes values (δ(15) N; δ(13) C). No relation was found between blood metal concentration and stable isotope values. In spectacled petrels, metal concentrations appeared lower in blood (Cu = 0.79-20.77 µg/g; Zn = 10.95-28.02 µg/g; Cd = 1.73-10.11 µg/g; Pb = 5.02-26.03 µg/g; Hg = 0.84-9.86 µg/g) than in feathers (Cu = 1.05-21.57 µg/g; Zn = 45.30-81.49 µg/g; Cd = 3.76-10.44 µg/g; Pb = 16.53-59.00 µg/g; Hg = 4.24-24.03 µg/g). In white-chinned petrels, metal concentrations also appeared lower in blood (Cu = 0.62-10.4 µg/g; Zn = 10.73-24.69 µg/g; Cd = 2.00-6.31 µg/g; Pb = 5.72-24.03 µg/g) than in feathers (Cu = 2.68-23.92 µg/g; Zn = 48.96-93.54 µg/g; Cd = 5.72-24.03 µg/g; Pb = 18.62-55.51 µg/g), except for Hg (blood = 0.20-15.82 µg/g; feathers = 0.19-8.91 µg/g). Selenium (0.24-14.18 µg/g) and Hg (0.22-1.44 µg/g) concentrations showed a positive correlation in growing feathers of spectacled petrels. Blood and feather Hg levels were higher in spectacled petrels while feathers Cu and Zn concentrations were greater in white-chinned petrels. Juvenile white-chinned petrels exhibited greater blood Hg concentrations than adults. In the south Atlantic Ocean, discards from commercial fishing operations consumed by spectacled petrels year-round and by white-chinned petrels during the wintering period have elevated Hg concentrations. Because Hg toxicity is associated with behavioral and reproductive changes in birds, it could

Copeptin concentration in cord blood in infants with early-onset sepsis, chorioamnionitis and perinatal asphyxia.

PubMed

Schlapbach, Luregn J; Frey, Stefanie; Bigler, Susanna; Manh-Nhi, Chiem; Aebi, Christoph; Nelle, Mathias; Nuoffer, Jean-Marc

2011-05-19

Vasopressin is one of the most important physiological stress and shock hormones. Copeptin, a stable vasopressin precursor, is a promising sepsis marker in adults. In contrast, its involvement in neonatal diseases remains unknown. The aim of this study was to establish copeptin concentrations in neonates of different stress states such as sepsis, chorioamnionitis and asphyxia. Copeptin cord blood concentration was determined using the BRAHMS kryptor assay. Neonates with early-onset sepsis (EOS, n = 30), chorioamnionitis (n = 33) and asphyxia (n = 25) were compared to a control group of preterm and term (n = 155) neonates. Median copeptin concentration in cord blood was 36 pmol/l ranging from undetectable to 5498 pmol/l (IQR 7 - 419). Copeptin cord blood concentrations were non-normally distributed and increased with gestational age (p < 0.0001). Neonates born after vaginal compared to cesarean delivery had elevated copeptin levels (p < 0.0001). Copeptin correlated strongly with umbilical artery pH (Spearman's Rho -0.50, p < 0.0001), umbilical artery base excess (Rho -0.67, p < 0.0001) and with lactate at NICU admission (Rho 0.54, p < 0.0001). No difference was found when comparing copeptin cord blood concentrations between neonates with EOS and controls (multivariate p = 0.30). The highest copeptin concentrations were found in neonates with asphyxia (median 993 pmol/l). Receiver-operating-characteristic curve analysis showed that copeptin cord blood concentrations were strongly associated with asphyxia: the area under the curve resulted at 0.91 (95%-CI 0.87-0.96, p < 0.0001). A cut-off of 400 pmol/l had a sensitivity of 92% and a specifity of 82% for asphyxia as defined in this study. Copeptin concentrations were strongly related to factors associated with perinatal stress such as birth acidosis, asphyxia and vaginal delivery. In contrast, copeptin appears to be unsuitable for the diagnosis of EOS.

Copeptin concentration in cord blood in infants with early-onset sepsis, chorioamnionitis and perinatal asphyxia

PubMed Central

2011-01-01

Background Vasopressin is one of the most important physiological stress and shock hormones. Copeptin, a stable vasopressin precursor, is a promising sepsis marker in adults. In contrast, its involvement in neonatal diseases remains unknown. The aim of this study was to establish copeptin concentrations in neonates of different stress states such as sepsis, chorioamnionitis and asphyxia. Methods Copeptin cord blood concentration was determined using the BRAHMS kryptor assay. Neonates with early-onset sepsis (EOS, n = 30), chorioamnionitis (n = 33) and asphyxia (n = 25) were compared to a control group of preterm and term (n = 155) neonates. Results Median copeptin concentration in cord blood was 36 pmol/l ranging from undetectable to 5498 pmol/l (IQR 7 - 419). Copeptin cord blood concentrations were non-normally distributed and increased with gestational age (p < 0.0001). Neonates born after vaginal compared to cesarean delivery had elevated copeptin levels (p < 0.0001). Copeptin correlated strongly with umbilical artery pH (Spearman's Rho -0.50, p < 0.0001), umbilical artery base excess (Rho -0.67, p < 0.0001) and with lactate at NICU admission (Rho 0.54, p < 0.0001). No difference was found when comparing copeptin cord blood concentrations between neonates with EOS and controls (multivariate p = 0.30). The highest copeptin concentrations were found in neonates with asphyxia (median 993 pmol/l). Receiver-operating-characteristic curve analysis showed that copeptin cord blood concentrations were strongly associated with asphyxia: the area under the curve resulted at 0.91 (95%-CI 0.87-0.96, p < 0.0001). A cut-off of 400 pmol/l had a sensitivity of 92% and a specifity of 82% for asphyxia as defined in this study. Conclusions Copeptin concentrations were strongly related to factors associated with perinatal stress such as birth acidosis, asphyxia and vaginal delivery. In contrast, copeptin appears to be unsuitable for the diagnosis of EOS. PMID:21595972

Triazolam blood concentrations in forensic cases in Canada.

PubMed

Joynt, B P

1993-01-01

Triazolam has been a controversial drug since its appearance on world markets as a hypnotic more than ten years ago. Whole blood concentrations of triazolam as found in forensic cases are cited in several categories; that is, impaired driving: 17 cases; sexual assault: four cases; death due to drugs: 45 cases; drug-related death (drugs contributed to the death but were not the ultimate cause): 20 cases; drug-involved death (drugs were present but were not felt to be a contributing factor): six cases; miscellaneous: one case. The data was gleaned from a forensic toxicology database designed and used by the Forensic Toxicology Sections of the Royal Canadian Mounted Police (RCMP) laboratories in Canada. Triazolam concentrations from selected references are included for comparison.

Concentrations of pentosidine, an advanced glycation end-product, in umbilical cord blood.

PubMed

Tsukahara, Hirokazu; Ohta, Naoko; Sato, Shuko; Hiraoka, Masahiro; Shukunami, Ken-Ichi; Uchiyama, Mayumi; Kawakami, Hisako; Sekine, Kyouichi; Mayumi, Mitsufumi

2004-07-01

Advanced glycation end-products (AGEs) are formed over several weeks to months by non-enzymatic glycation and oxidation ("glycoxidation") reactions between carbohydrate-derived carbonyl groups and protein amino groups, known as the Maillard reaction. Pentosidine is one of the best-characterized AGEs and is accepted as a satisfactory marker for glycoxidation in vivo. The present study was intended to measure pentosidine concentrations in umbilical cord blood from newborns with various gestational ages using our recently established high-performance liquid chromatography method [Tsukahara, H. et al. (2003) Pediatr. Res. 54, 419-424]. Our study demonstrates, for the first time, that pentosidine is detected in most of the umbilical blood samples. This study also shows that the umbilical blood concentrations of pentosidine are considerably lower than normal adult values, but that they increase with gestation progression and fetal growth. Umbilical pentosidine concentrations were significantly elevated in newborns of mothers with preeclampsia compared to those of mothers without preeclampsia. We conclude that accumulation of AGEs and oxidative stress occurs in fetal tissues and organs in utero at the early stage of human life and that their accumulation is augmented in the maternal preeclampsic condition.

Concentrations of Water-Soluble Vitamins in Blood and Urinary Excretion in Patients with Diabetes Mellitus.

PubMed

Iwakawa, Hiromi; Nakamura, Yasuyuki; Fukui, Tomiho; Fukuwatari, Tsutomu; Ugi, Satoshi; Maegawa, Hiroshi; Doi, Yukio; Shibata, Katsumi

2016-01-01

We examined the concentrations of water-soluble vitamins in blood and urinary excretion of 22 patients with type 2 diabetes mellitus (type 2DM) and 20 healthy control participants. Macronutrient and vitamin intakes of type 2DM subjects were measured using a weighed food record method. Control participants consumed a semipurified diet for eight days. Multiple linear regression models were used to determine whether significant differences existed in vitamin concentrations in blood independent of age, sex, and other confounding factors. Concentrations of vitamins B2, B6, C, niacin, and folate in blood were significantly lower in type 2DM subjects than in controls, independent of confounding factors. Renal clearances of vitamins B6, C, niacin, and folate were significantly higher in type 2DM subjects than in controls. In conclusion, concentrations of vitamins B2, B6, C, niacin, and folate in blood were significantly lower in type 2DM subjects than in controls, independent of confounding factors; based on the evidence of increased urinary clearance of these vitamins, the lower levels were likely due to impaired reabsorption processes.

[Effects of ciclosporin and tacrolimus on replication of hepatitis B virus in vitro: a comparative study].

PubMed

Xia, Wei-liang; Xie, Hai-yang; Shen, Yan; Wu, Li-ming; Zhang, Feng; Zheng, Shu-sen

2006-01-10

To investigate the effects of ciclosporin (CsA) and tacrolimus (FK506) on replication of hepatitis B virus (HBV) in vitro. HBV genome permanently transfected human liver cancer cells of the line HepG2.2.15 were cultured. CsA and FK506 at different concentrations were added into the culture fluid so as to identify the nontoxic concentrations by MTT method. Then the HepG2.2.15 cells were treated by CsA and FK506 at different nontoxic concentrations respectively for 4 days. ELISA was used to detect the HB surface antigen (HBsAg) and HB e antigen (HBeAg) in the supernatant. The relative replication level of HBV DNA was detected by slot blot analysis. MTT method confirmed that the nontoxic concentrations of CsA and FK506 were 0-40.0 microg/ml and 0-400 ng/ml respectively. After the treatment of CsA at the concentration of 1.3, 2.5, and 5.0 microg/ml, in comparison to the control group, the suppression rates of HBsAg expression in the HepG2.2.15 cells were 16.5% +/- 9.4%, 21.5% +/- 8.9%, and 33.1% +/- 5.3% respectively (all P < 0.05); the suppression rates of HBeAg expression in the HepG2.2.15 cells were 7.8% +/- 2.2%, 11.0% +/- 2.3%, and 20.8% +/- 1.5% respectively (all P < 0.05); and the HBV DNA replication levels were 56 +/- 16, 42 +/- 11, and 40 +/- 10 respectively (P > 0.05, P < 0.05, and P > 0.05). However, FK506 at different nontoxic concentrations showed no significant inhibitory effect on the levels of HBsAg, HBeAg, and HBV DNA. CsA dose-dependently inhibits the HBV replication in vitro, and FK506 does not exercise similar effects.

Study on the mechanism of human blood glucose concentration measuring using mid-infrared spectral analysis technology

NASA Astrophysics Data System (ADS)

Li, Xiang

2016-10-01

All forms of diabetes increase the risk of long-term complications. Blood glucose monitoring is of great importance for controlling diabetes procedure, preventing the complications and improving the patient's life quality. At present, the clinical blood glucose concentration measurement is invasive and could be replaced by noninvasive spectroscopy analytical techniques. The mid-infrared spectral region contains strong characteristic and well-defined absorption bands. Therefore, mid-infrared provides an opportunity for monitoring blood glucose invasively with only a few discrete bonds. Although the blood glucose concentration measurement using mid-infrared spectroscopy has a lot of advantages, the disadvantage is also obvious. The absorption in this infrared region is fundamental molecular group vibration. Absorption intensity is very strong, especially for biological molecules. In this paper, it figures out that the osmosis rate of glucose has a certain relationship with the blood glucose concentration. Therefore, blood glucose concentration could be measured indirectly by measuring the glucose exudate in epidermis layer. Human oral glucose tolerance tests were carried out to verify the correlation of glucose exudation in shallow layer of epidermis layer and blood glucose concentration. As it has been explained above, the mid-infrared spectral region contains well-defined absorption bands, the intensity of absorption peak around 1123 cm-1 was selected to measure the glucose and that around 1170 cm-1 was selected as reference. Ratio of absorption peak intensity was recorded for each set of measurement. The effect and importance of the cleaning the finger to be measured before spectrum measuring are discussed and also verified by experiment.

Blood alcohol concentration testing and reporting by the states : traffic tech.

DOT National Transportation Integrated Search

2012-08-01

Accurate and complete data on blood alcohol concentration : (BAC) levels for drivers in fatal crashes are critical in monitoring : alcohol-impaired-driving rates across the country, developing : alcohol-impaired-driving programs, and evaluating : the...

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.

Discrepant post filter ionized calcium concentrations by common blood gas analyzers in CRRT using regional citrate anticoagulation.

PubMed

Schwarzer, Patrik; Kuhn, Sven-Olaf; Stracke, Sylvia; Gründling, Matthias; Knigge, Stephan; Selleng, Sixten; Helm, Maximilian; Friesecke, Sigrun; Abel, Peter; Kallner, Anders; Nauck, Matthias; Petersmann, Astrid

2015-09-08

Ionized calcium (iCa) concentration is often used in critical care and measured using blood gas analyzers at the point of care. Controlling and adjusting regional citrate anticoagulation (RCA) for continuous renal replacement therapy (CRRT) involves measuring the iCa concentration in two samples: systemic with physiological iCa concentrations and post filter samples with very low iCa concentrations. However, modern blood gas analyzers are optimized for physiological iCa concentrations which might make them less suitable for measuring low iCa in blood with a high concentration of citrate. We present results of iCa measurements from six different blood gas analyzers and the impact on clinical decisions based on the recommendations of the dialysis' device manufacturer. The iCa concentrations of systemic and post filter samples were measured using six distinct, frequently used blood gas analyzers. We obtained iCa results of 74 systemic and 84 post filter samples from patients undergoing RCA for CRRT at the University Medicine of Greifswald. The systemic samples showed concordant results on all analyzers with median iCa concentrations ranging from 1.07 to 1.16 mmol/L. The medians of iCa concentrations for post filter samples ranged from 0.21 to 0.50 mmol/L. Results of >70% of the post filter samples would lead to major differences in decisions regarding citrate flow depending on the instrument used. Measurements of iCa in post filter samples may give misleading information in monitoring the RCA. Recommendations of the dialysis manufacturer need to be revised. Meanwhile, little weight should be given to post filter iCa. Reference methods for low iCa in whole blood containing citrate should be established.

Geographic and temporal patterns of variation in total mercury concentrations in blood of harlequin ducks and blue mussels from Alaska

USGS Publications Warehouse

Savoy, Lucas; Flint, Paul L.; Zwiefelhofer, Denny; Brant, Heather; Perkins, Christopher R.; Taylor, Robert J.; Lane, Oksana P.; Hall, Jefferson S.; Evers, David C.; Schamber, Jason

2017-01-01

We compared total mercury (Hg) concentrations in whole blood of harlequin ducks (Histrionicus histrionicus) sampled within and among two geographically distinct locations and across three years in southwest Alaska. Blue mussels were collected to assess correlation between Hg concentrations in locally available forage and birds. Mercury concentrations in harlequin duck blood were significantly higher at Unalaska Island (0.31 ± 0.19 mean ± SD, μg/g blood) than Kodiak Island (0.04 ± 0.02 mean ± SD, μg/g blood). We found no evidence for annual variation in blood Hg concentration between years at Unalaska Island. However, blood Hg concentration did vary among specific sampling locations (i.e., bays) at Unalaska Island. Findings from this study demonstrate harlequin ducks are exposed to environmental sources of Hg, and whole blood Hg concentrations are associated with their local food source.

In Vitro Interactions between Tacrolimus and Azoles against Candida albicans Determined by Different Methods▿

PubMed Central

Sun, Shujuan; Li, Yan; Guo, Qiongjie; Shi, Changwen; Yu, Jinlong; Ma, Lin

2008-01-01

Combination therapy could be of use for the treatment of fungal infections, especially those caused by drug-resistant fungi. However, the methods and approaches used for data generation and result interpretation need further optimizing. The fractional inhibitory concentration index (FICI) is the most commonly used method, but it has several drawbacks in characterizing antifungal drug interaction. Alternatively, some new methods can be used such as the ΔE model (difference between the predicted and measured fungal growth percentages) and the response surface approach, which uses the concentration-effect relationship over the whole concentration range instead of just the MIC. In the present study, in vitro interactions between tacrolimus (FK506) and three azoles—fluconazole (FLC), itraconazole (ITR), and voriconazole (VRC)-against Candida albicans were evaluated by the checkerboard microdilution method and time-killing test. The intensity of the interactions was determined by visual reading and the spectrophotometric method in a checkerboard assay, and the nature of the interactions was assessed by nonparametric models of FICI and ΔE. Colony counting and colorimetric viable detection methods (2,3-bis {2-methoxy-4-nitro-5-[(sulfenylamino) carbonyl]-2H-tetrazolium hydroxide} [XTT] reduction test) were used for evaluating the combination antifungal effects over time. Synergistic and indifferent effects were found for the combination of FK506 and azoles against azole-sensitive strains, while strong synergy was found against azole-resistant strains analyzed by FICI. The ΔE model gave more consistent results with FICI. The positive interactions were also confirmed by the time-killing test. Our findings suggest a potential role for combination therapy with calcineurin pathway inhibitors and azoles to augment activity against resistant C. albicans. PMID:18056277

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.

Overweight Kidney Transplant Recipients Are at Risk of Being Overdosed Following Standard Bodyweight-Based Tacrolimus Starting Dose.

PubMed

Andrews, Louise M; de Winter, Brenda C M; Tang, Jiang-Tao; Shuker, Nauras; Bouamar, Rachida; van Schaik, Ron H N; Koch, Birgit C P; van Gelder, Teun; Hesselink, Dennis A

2017-02-01

Bodyweight-based dosing of tacrolimus (Tac) is considered standard care, even though the available evidence is thin. An increasing proportion of transplant recipients is overweight, prompting the question if the starting dose should always be based on bodyweight. For this analysis, data were used from a randomized-controlled trial in which patients received either a standard Tac starting dose or a dose that was based on CYP3A5 genotype. The hypothesis was that overweight patients would have Tac overexposure following standard bodyweight-based dosing. Data were available for 203 kidney transplant recipients, with a median body mass index (BMI) of 25.6 (range, 17.2-42.2). More than 50% of the overweight or obese patients had a Tac predose concentration above the target range. The CYP3A5 nonexpressers tended to be above target when they weighed more than 67.5 kg or had a BMI of 24.5 or higher. Dosing guidelines were proposed with a decrease up to 40% in Tac starting doses for different BMI groups. The dosing guideline for patients with an unknown genotype was validated using the fixed-dose versus concentration controlled data set. This study demonstrates that dosing Tac solely on bodyweight results in overexposure in more than half of overweight or obese patients.

Fatal fentanyl patch misuse in a hospitalized patient with a postmortem increase in fentanyl blood concentration.

PubMed

Moore, Philip W; Palmer, Robert B; Donovan, Joseph Ward

2015-01-01

Opioid-related mortality happens, even in healthcare settings. We describe serial postmortem fentanyl blood concentrations in a hospital inpatient who fatally abused transdermal fentanyl. This is a single-patient case report. A 42-year-old man with lymphoma was started on transdermal fentanyl therapy while hospitalized for chronic abdominal pain. The patient was last seen awake 1.3 h prior to being found apneic and cyanotic. During the resuscitation attempt, a small square-shaped film was removed from the patient's oropharynx. Femoral blood was collected 0.5 and 2 h postmortem, and the measured fentanyl concentration increased from 1.6 to 14 ng/mL. Study limitations include potential laboratory or collection errors and missing data. (i) Providers must be vigilant for signs of fentanyl patch abuse. (ii) Postmortem blood concentrations are not static postmortem, likely secondary to decreasing pH, increased aqueous solubility, and tissue redistribution, and are therefore unlikely to accurately represent antemortem blood concentrations. © 2014 American Academy of Forensic Sciences.

Comparison of accuracy of pregnancy-associated glycoprotein (PAG) concentration in blood and milk for early pregnancy diagnosis in cows.

PubMed

Gajewski, Z; Petrajtis-Gołobów, M; Melo de Sousa, N; Beckers, J F; Pawliński, B; Wehrend, A

2014-12-01

The aim of this study was to compare two methods of early pregnancy diagnosis by determining pregnancy-associated glycoprotein (PAG) concentration in blood and PAG concentration in milk. Blood and milk samples were obtained on days 0 (AI day), 14, 21, 28, 35, 49, 63, 77, 91 and 105 of gestation from 60 lactating Holstein Frisian cows from one herd, carrying live fetuses. To determine PAG concentration a specific RIA system (RIA-706) was used. PAG concentration in blood and milk increased after 28 days of pregnancy, with blood concentrations being significantly higher than in milk. However, the accuracy of both tests at this time point was similar (sensitivity: 92 % in blood, 93 % in milk; specificity 53 % and 60 % respectively). None of the tests were able to detect open cows properly at this stage. On day 35 of gestation sensitivity (100 % for blood, 97 % for milk) and specificity (100 % for blood, 100 % for milk) were high enough to be used for reliable pregnancy diagnosis. The accuracy (sensitivity and specificity) for PAG concentrations in blood and milk for the rest of the study was 100 %. Our investigation shows that PAG determination in milk is a stress-free and non-invasive method for early pregnancy diagnosis in cattle.

Factors associated with blood lead concentrations of children in Jamaica

PubMed Central

RAHBAR, MOHAMMAD H.; SAMMS-VAUGHAN, MAUREEN; DICKERSON, AISHA S.; LOVELAND, KATHERINE A.; ARDJOMAND-HESSABI, MANOUCHEHR; BRESSLER, JAN; SHAKESPEARE-PELLINGTON, SYDONNIE; GROVE, MEGAN L.; BOERWINKLE, ERIC

2015-01-01

Lead is a heavy metal known to be detrimental to neurologic, physiologic, and behavioral health of children. Previous studies from Jamaica reported that mean lead levels in soil are four times that of lead levels in some other parts of the world. Other studies detected lead levels in fruits and root vegetables, which were grown in areas with lead contaminated soil. In this study, we investigate environmental factors associated with blood lead concentrations in Jamaican children. The participants in this study comprised 125 typically developing (TD) children (ages 2–8 years) who served as controls in an age- and sex-matched case-control study that enrolled children from 2009 – 2012 in Jamaica. We administered a questionnaire to assess demographic and socioeconomic information as well as potential exposures to lead through food. Using General Linear Models (GLMs), we identified factors associated with blood lead concentrations in Jamaican children. The geometric mean blood lead concentration (GMBLC) in the sample of children in this study was 2.80 μg/dL. In univariable GLM analyses, GMBLC was higher for children whose parents did not have education beyond high school compared to those whose parents had attained this level (3.00 μg/dL vs. 2.31 μg/dL; P = 0.05), children living near a high traffic road compared to those who did not (3.43 μg/dL vs. 2.52 μg/dL; P < 0.01), and children who reported eating ackee compared to those who did not eat this fruit (2.89 μg/dL vs. 1.65 μg/dL; P < 0.05). In multivariable analysis, living near a high traffic road was identified as an independent risk factor for higher adjusted GMBLC (3.05 μg/dL vs. 2.19 μg/dL; P = 0.01). While our findings indicate that GMBLC in Jamaican children has dropped by at least 62% during the past two decades, children living in Jamaica still have GMBLC that is twice that of children in more developed countries. In addition, we have identified significant risk factors for higher blood lead

Bi-phasic trends in mercury concentrations in blood of Wisconsin common loons during 1992–2010

USGS Publications Warehouse

Meyer, Michael W.; Rasmussen, Paul W.; Watras, Carl J.; Fevold, Brick M.; Kenow, Kevin P.

2011-01-01

Wisconsin Department of Natural Resources (WDNR) assessed the ecological risk of mercury (Hg) in aquatic systems by monitoring common loon (Gavia immer) population dynamics and blood Hg concentrations. We report temporal trends in blood Hg concentrations based on 334 samples collected from adults recaptured in subsequent years (resampled 2-9 times) and from 421 blood samples of chicks collected at lakes resampled 2-8 times 1992-2010.. Temporal trends were identified with generalized additive mixed effects models (GAMMs) and mixed effects models to account for the potential lack of independence among observations from the same loon or same lake. Trend analyses indicated that Hg concentrations in the blood of Wisconsin loons declined over the period 1992-2000, and increased during 2002-2010, but not to the level observed in the early 1990s. The best fitting linear mixed effects model included separate trends for the two time periods. The estimated trend in Hg concentration among the adult loon population during 1992-2000 was -2.6% per year and the estimated trend during 2002-2010 was +1.8% per year; chick blood Hg concentrations decreased by -6.5% per year during 1992-2000, but increased 1.8% per year during 2002-2010. This bi-phasic pattern is similar to trends observed for concentrations of methylmercury (meHg) and SO4 in lake water of a well studied seepage lake (Little Rock Lake, Vilas County) within our study area. A cause-effect relationship between these independent trends is hypothesized.

Elevated blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations in essential tremor.

PubMed

Louis, Elan D; Jiang, Wendy; Pellegrino, Kathryn M; Rios, Eileen; Factor-Litvak, Pam; Henchcliffe, Claire; Zheng, Wei

2008-03-01

Essential tremor (ET) is a widespread late-life neurological disease. Genetic and environmental factors likely play an etiological role. Harmane (1-methyl-9H-pyrido[3,4-b]indole) is a potent tremor-producing neurotoxin. In 2002, we demonstrated elevated blood harmane concentrations in an initial sample of 100 ET cases compared to 100 controls. Between 2002 and 2007, we assembled a new and larger sample of ET cases and controls. We now attempt to replicate our previous findings. Cases and controls were frequency-matched on age, gender, and race. Blood harmane concentrations were quantified by high-performance liquid chromatography. Subjects comprised 150 ET cases and 135 controls (mean age 65.3+/-15.5 vs. 65.5+/-14.2 years, p=0.94). Mean log blood harmane concentration was approximately 50% higher in cases than controls (0.50+/-0.54g(-10)/ml vs. 0.35+/-0.62g(-10)/ml, p=0.038). In a logistic regression analysis, log blood harmane concentration was associated with ET (OR(adjusted) 1.56, 95% CI 1.01-2.42, p=0.04), and odds of ET was 1.90 (95% CI 1.07-3.39, p=0.029) in the highest versus lowest log blood harmane tertile. Log blood harmane was highest in ET cases with familial ET (0.53+/-0.57g(-10)/ml), intermediate in cases with sporadic ET (0.43+/-0.45g(-10)/ml) and lowest in controls (0.35+/-0.62g(-10)/ml) (test for trend, p=0.026). Blood harmane appears to be elevated in ET. The higher concentrations in familial ET suggests that the mechanism may involve genetic factors.

The Correlation of Blood Glucose Concentration and the Movement of Laser Secondary Speckle Pattern of the Artery

NASA Astrophysics Data System (ADS)

Saputra, M. A.; Prajitno, P.

2018-04-01

Blood glucose is the molecule needed for human life, it usually measured invasively (by taking blood). but that measurement is still very vulnerable. The alternative method namely the non-invasive method is very interesting. In addition, the article [1] explains the relationship between the movement of the arterial pulse with glucose concentration, therefore the research study to investigate the correlation between the blood glucose and the movement of laser speckle pattern resulted from the arterial movement will be promising as the non-invasive method for measuring the blood glucose concentration. In this study, the laser speckle pattern imaging method, where the microscopically movement of the object is illuminated by a laser beam and recorded by the high-speed camera in a certain interval time, are used to identify the movement patterns of the artery. From the image processing, the graphs such as electrocardiograph (ECG) can be extracted. The average of the maximum peaks of the graph can be correlated with the blood glucose concentration in the blood, as the same as shown in the article [2]. From the data that has been obtained in this research, the movement of the speckle tends to increase in accordance with the rise of blood glucose concentration.

Investigating the impact of oxygen concentration and blood flow variation on photodynamic therapy

NASA Astrophysics Data System (ADS)

Penjweini, Rozhin; Kim, Michele M.; Finlay, Jarod C.; Zhu, Timothy C.

2016-03-01

Type II photodynamic therapy (PDT) is used for cancer treatment based on the combined action of a photosensitizer, a special wavelength of light, oxygen (3O2) and generation of singlet oxygen (1O2). Intra-patient and inter-patient variability of oxygen concentration ([3O2]) before and after the treatment as well as photosensitizer concentration and hemodynamic parameters such as blood flow during PDT has been reported. Simulation of these variations is valuable, as it would be a means for the rapid assessment of treatment effect. A mathematical model has been previously developed to incorporate the diffusion equation for light transport in tissue and the macroscopic kinetic equations for simulation of [3O2], photosensitizers in ground and triplet states and concentration of the reacted singlet oxygen ([1O₂]rx) during PDT. In this study, the finite-element based calculation of the macroscopic kinetic equations is done for 2-(1- Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH)-mediated PDT by incorporating the information of the photosensitizer photochemical parameters as well as the tissue optical properties, photosensitizer concentration, initial oxygen concentration ([3O2]0), blood flow changes and Φ that have been measured in mice bearing radiation-induced fibrosarcoma (RIF) tumors. Then, [1O2]rx calculated by using the measured [3O2] during the PDT is compared with [1O2]rx calculated based on the simulated [3O₂]; both calculations showed a reasonably good agreement. Moreover, the impacts of the blood flow changes and [3O2]0 on [1O2]rx have been investigated, which showed no pronounced effect of the blood flow changes on the long-term 1O2 generation. When [3O2]0 becomes limiting, small changes in [3O₂] have large effects on [1O2]rx.

Measurement of tissue optical properties with optical coherence tomography: Implication for noninvasive blood glucose concentration monitoring

NASA Astrophysics Data System (ADS)

Larin, Kirill V.

Approximately 14 million people in the USA and more than 140 million people worldwide suffer from diabetes mellitus. The current glucose sensing technique involves a finger puncture several times a day to obtain a droplet of blood for analysis. There have been enormous efforts by many scientific groups and companies to quantify glucose concentration noninvasively using different optical techniques. However, these techniques face limitations associated with low sensitivity, accuracy, and insufficient specificity of glucose concentrations over a physiological range. Optical coherence tomography (OCT), a new technology, is being applied for noninvasive imaging in tissues with high resolution. OCT utilizes sensitive detection of photons coherently scattered from tissue. The high resolution of this technique allows for exceptionally accurate measurement of tissue scattering from a specific layer of skin compared with other optical techniques and, therefore, may provide noninvasive and continuous monitoring of blood glucose concentration with high accuracy. In this dissertation work I experimentally and theoretically investigate feasibility of noninvasive, real-time, sensitive, and specific monitoring of blood glucose concentration using an OCT-based biosensor. The studies were performed in scattering media with stable optical properties (aqueous suspensions of polystyrene microspheres and milk), animals (New Zealand white rabbits and Yucatan micropigs), and normal subjects (during oral glucose tolerance tests). The results of these studies demonstrated: (1) capability of the OCT technique to detect changes in scattering coefficient with the accuracy of about 1.5%; (2) a sharp and linear decrease of the OCT signal slope in the dermis with the increase of blood glucose concentration; (3) the change in the OCT signal slope measured during bolus glucose injection experiments (characterized by a sharp increase of blood glucose concentration) is higher than that measured in

A Bayesian network for modelling blood glucose concentration and exercise in type 1 diabetes.

PubMed

Ewings, Sean M; Sahu, Sujit K; Valletta, John J; Byrne, Christopher D; Chipperfield, Andrew J

2015-06-01

This article presents a new statistical approach to analysing the effects of everyday physical activity on blood glucose concentration in people with type 1 diabetes. A physiologically based model of blood glucose dynamics is developed to cope with frequently sampled data on food, insulin and habitual physical activity; the model is then converted to a Bayesian network to account for measurement error and variability in the physiological processes. A simulation study is conducted to determine the feasibility of using Markov chain Monte Carlo methods for simultaneous estimation of all model parameters and prediction of blood glucose concentration. Although there are problems with parameter identification in a minority of cases, most parameters can be estimated without bias. Predictive performance is unaffected by parameter misspecification and is insensitive to misleading prior distributions. This article highlights important practical and theoretical issues not previously addressed in the quest for an artificial pancreas as treatment for type 1 diabetes. The proposed methods represent a new paradigm for analysis of deterministic mathematical models of blood glucose concentration. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Blood folate concentrations among women of childbearing age by race/ethnicity and acculturation, NHANES 2001-2010.

PubMed

Marchetta, Claire M; Hamner, Heather C

2016-01-01

Hispanic women have higher rates of neural tube defects and report lower total folic acid intakes than non-Hispanic white (NHW) women. Total folic acid intake, which is associated with neural tube defect risk reduction, has been found to vary by acculturation factors (i.e. language preference, country of origin, or time spent in the United States) among Hispanic women. It is unknown whether this same association is present for blood folate status. The objective of this research was to assess the differences in serum and red blood cell (RBC) folate concentrations between NHW women and Mexican American (MA) women and among MA women by acculturation factors. Cross-sectional data from the 2001-2010 National Health and Nutrition Examination Survey (NHANES) were used to investigate how blood folate concentrations differ among NHW or MA women of childbearing age. The impact of folic acid supplement use on blood folate concentrations was also examined. MA women with lower acculturation factors had lower serum and RBC folate concentrations compared with NHW women and to their more acculturated MA counterparts. Consuming a folic acid supplement can minimize these disparities, but MA women, especially lower acculturated MA women, were less likely to report using supplements. Public health efforts to increase blood folate concentrations among MA women should consider acculturation factors when identifying appropriate interventions. © 2014 John Wiley & Sons Ltd.

Gender Differences in Alcohol Beliefs and Usual Blood-Alcohol Concentration.

ERIC Educational Resources Information Center

Lo, Celia C.; Globetti, Gerald

2000-01-01

Male (n=59) and female (n=65) high school students were interviewed concerning their beliefs about moderate and heavy drinking and their usual blood-alcohol concentrations were obtained. Results indicate that most heavy-drinking males believe that alcohol makes them lose physical and emotional control. Females who abstain or are light drinkers…

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

Blood alcohol concentration measurement using a salivary reagent stick: a reliable tool for emergency departments?

PubMed

Phair, I C; Mardel, S; Bodiwala, G G

1990-06-01

Measurements of blood alcohol concentration (BAC) were made on patients who presented to an accident and emergency department with acute alcohol intoxication. A correlation of r = 0.418 was noted to exist between BAC as measured by sampling saliva and blood. Blood alcohol concentrations as measured by salivary reagent strip (ALCO-SCREEN, Chem Elec.) were significantly lower (p less than 0.0001) than those determined by gas chromatography of serum. Although such reagent strips offer a rapid measurement of BAC, it is concluded that they are unreliable for the quantitative measurement of BAC in accident and emergency departments.

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

Indiana Residents' Perceptions of Driving and Lower Blood Alcohol Concentration

ERIC Educational Resources Information Center

Seo, Dong-Chul; Torabi, Mohammed R.

2005-01-01

Since Congress passed .08 blood alcohol concentration (BAC) as the national standard for impaired driving in October 2000, 28 U.S. States including Indiana have enacted .08 BAC law. This study investigated perceived impact of the .08 law among Indiana residents and their attitudinal and perceptional changes since the enforcement of the law. The…

ELEVATED BLOOD HARMANE (1-METHYL-9H-PYRIDO[3,4-B]INDOLE) CONCENTRATIONS IN ESSENTIAL TREMOR

PubMed Central

Louis, Elan D.; Jiang, Wendy; Pellegrino, Kathryn M.; Rios, Eileen; Factor-Litvak, Pam; Henchcliffe, Claire; Zheng, Wei

2008-01-01

Essential tremor (ET) is a widespread late-life neurological disease. Genetic and environmental factors likely play an etiological role. Harmane (1-methyl-9H-pyrido[3,4-b]indole) is a potent tremor-producing neurotoxin. In 2002, we demonstrated elevated blood harmane concentrations in an initial sample of 100 ET cases compared to 100 controls. Between 2002 and 2007, we assembled a new and larger sample of ET cases and controls. We now attempt to replicate our previous findings. Cases and controls were frequency-matched on age, gender, and race. Blood harmane concentrations were quantified by high performance liquid chromatography. Subjects comprised 150 ET cases and 135 controls (mean age 65.3 ± 15.5 vs. 65.5 ± 14.2 years, p = 0.94). Mean log blood harmane concentration was ∼50% higher in cases than controls (0.50 ± 0.54 g -10/ml vs. 0.35 ± 0.62 g-10/ml, p = 0.038). In a logistic regression analysis, log blood harmane concentration was associated with ET (ORadjusted 1.56, 95% CI 1.01 - 2.42, p = 0.04), and odds of ET was 1.90 (95% CI 1.07 - 3.39, p = 0.029) in the highest vs. lowest log blood harmane tertile. Log blood harmane was highest in ET cases with familial ET (0.53 ± 0.57 g -10/ml), intermediate in cases with sporadic ET (0.43 ± 0.45 g -10/ml) and lowest in controls (0.35 ± 0.62 g-10/ml) (test for trend, p = 0.026). Blood harmane appears to be elevated in ET. The higher concentrations in familial ET suggests that the mechanism may involve genetic factors. PMID:18242711

Non-invasive method to detect the changes of glucose concentration in whole blood using photometric technique.

PubMed

Rajan, Shiny Amala Priya; Towe, Bruce C

2014-01-01

A non-invasive method is developed to monitor rapid changes in blood glucose levels in diabetic patients. The system depends on an optical cell built with a LED that emits light of wavelength 535nm, which is a peak absorbance of hemoglobin. As the glucose concentration in blood decreases, its osmolarity also decreases and the Red Blood Cells (RBCs) swell and decrease the path length absorption coefficient. Decreasing absorption coefficient increases the transmission of light through the whole blood. The system was tested with a constructed optical cell that held whole blood in a capillary tube. As expected the light transmitted to the photodiode increases with decreasing glucose concentration. The average response time of the system was between 30-40 seconds.

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

Organochlorine residues in Baluchistan/Pakistan: Blood and fat concentrations in humans

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

Krawinkel, M.B.; Plehn, G.; Kruse, H.

1989-12-01

Organochlorine (OC)-residues are detected in measurable concentrations in various tissues of human beings because of the worldwide pollution of air, water, soil, and foods. The concentrations vary from region to region according to chemical, climatic, socio-economic, and geographic factors. Persisting pesticides used in agriculture are found in relevant concentrations in agriculture products, meat, and fish. As developing countries face economic pressure to increase their agricultural exports cheap pesticides are sometimes used without the precautions necessary to prevent contaminations of water and food. The authors conducted a small survey monitoring the OC-concentrations in human blood and fat tissue under the aimmore » to detect more recent as well as elder expositions.« less

sCD30, interleukin-1beta-converting enzyme and anti-Annexin V autoantibodies concentrations in heart transplant recipients.

PubMed

Zeglen, Sławomir; Zakliczyński, Michał; Nozyński, Jerzy; Rogala, Barbara; Zembala, Marian

2006-11-01

sCD30 and ICE/caspase-1 as apoptosis-regulating factors are suspected to be involved in the survival rate of immunocompetent cells during immunosuppression after allotransplantation. Serum CD30 and ICE/caspase-1 concentrations were estimated and associated with unspecific serum apoptosis marker--anti-Annexin V antibodies and myocardial biopsies results. 28 clinically stabile patients--heart transplant recipients at least 3 months after cardiac transplantation performed due to heart failure caused by ischaemic and/or congestive cardiomyopathy or/and primary valvular heart disease (26 men and 2 women, mean age=36.8 years, S.D.=7.6) with normal heart function assessed by use of ultrasound scan--were involved in the trial. The patients were divided and analyzed in two ways: first according to the results of elective endomyocardial biopsies and second to main immunosuppressive agent used. The enzyme immunoassay (CD30, Dako; interleukin-1beta-converting enzyme (ICE)/Caspase-1 ELISA and anti-Annexin V BENDER MedSystem) for soluble CD30, caspase-1 and anti-Annexin V autoantibodies serum levels was used. sCD30 and caspase-1 concentrations were non-significantly up-regulated in all analysed groups--with or without rejection signs or immunosuppressed with cyclosporine or especially tacrolimus. In contrast anti-Annexin V autoantibodies concentration was non-significantly down-regulated also in all studied groups. Moreover in the group with signs of transplant rejection, strong negative correlation between anti-Annexin antibodies and rejection grade was observed (-0.65, p<0.05). Biopsy results were comparable in groups treated with tacrolimus and cyclosporine A. The increasing tendency of sCD30 and caspase-1 as well as the decrease in anti-Annexin V autoantibodies concentrations in heart recipients could be the result of post-transplant apoptosis disturbances. This tendency seems to be inhibited in a greater degree by tacrolimus than by cyclosporine. Anti-Annexin V

Hyperventilation accelerates the rise of arterial blood concentrations of desflurane in gynecologic patients.

PubMed

Lu, Chih-Cherng; Lin, Tso-Chou; Hsu, Che-Hao; Yu, Mu-Hsien; Chen, Ta-Liang; Chen, Ruei-Ming; Ku, Chih-Hung; Ho, Shung-Tai

2012-09-01

Under a constant inspired concentration, the uptake of a volatile anesthetic into the arterial blood should mainly be governed by alveolar ventilation, according to the assumption that the patient's cardiac output remains stable during anesthesia. We investigated whether ventilation volume affects the rate of desflurane uptake by examining arterial blood concentrations. Thirty female patients were randomly allocated into the following three groups: hyperventilation, normal ventilation and hypoventilation. Hemodynamic variables were measured using a Finometer, inspiratory and end-tidal concentrations of desflurane were measured by infrared analysis, and the desflurane concentration in the arterial blood (Ades) was analyzed by gas chromatography. During the first 10 minutes after the administration of desflurane, the Ades was highest in the hyperventilation group, and this value was significantly different from those obtained for the normal and hypoventilation groups. In addition, hyperventilation significantly increased the slope of Ades-over-time during the first 5 minutes compared with patients experiencing normal ventilation and hypoventilation, but there were no differences in these slopes during the periods from 5-10, 10-20 and 20-40 minutes after the administration of desflurane. This finding indicates that there were no differences in desflurane uptake between the three groups after the first 5 minutes within desflurane administration. Hyperventilation accelerated the rate of the rise in Ades following desflurane administration, which was time-dependent with respect to different alveolar ventilations levels.

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

Blood Lead Concentrations in Jamaican Children with and without Autism Spectrum Disorder

PubMed Central

Rahbar, Mohammad H.; Samms-Vaughan, Maureen; Dickerson, Aisha S.; Loveland, Katherine A.; Ardjomand-Hessabi, Manouchehr; Bressler, Jan; Shakespeare-Pellington, Sydonnie; Grove, Megan L.; Pearson, Deborah A.; Boerwinkle, Eric

2014-01-01

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder manifesting by early childhood. Lead is a toxic metal shown to cause neurodevelopmental disorders in children. Several studies have investigated the possible association between exposure to lead and ASD, but their findings are conflicting. Using data from 100 ASD cases (2–8 years of age) and their age- and sex-matched typically developing controls, we investigated the association between blood lead concentrations (BLC) and ASD in Jamaican children. We administered a questionnaire to assess demographic and socioeconomic information as well as exposure to potential lead sources. We used General Linear Models (GLM) to assess the association of BLC with ASD status as well as with sources of exposure to lead. In univariable GLM, we found a significant difference between geometric mean blood lead concentrations of ASD cases and controls (2.25 μg/dL cases vs. 2.73 μg/dL controls, p < 0.05). However, after controlling for potential confounders, there were no significant differences between adjusted geometric mean blood lead concentrations of ASD cases and controls (2.55 μg/dL vs. 2.72 μg/dL, p = 0.64). Our results do not support an association between BLC and ASD in Jamaican children. We have identified significant confounders when assessing an association between ASD and BLC. PMID:25546274