PurposeThe once daily formulation of tacrolimus is an important immunosuppressive drug. Interpatient variability in metabolism has been related to genetic variation in CYP3A4 and CYP3A5. However, in liver transplantation, both donor and recipient genotypes may affect pharmacokinetics. The primary objective of this study was to investigate the effect of CYP3A4*22 and CYP3A5*3 of both donor and recipient on once daily tacrolimus pharmacokinetics. The secondary objective was to develop a limited sampling model able to accurately predict exposure.MethodsStable liver transplant patients receiving once daily tacrolimus (N = 66) were included. Population pharmacokinetic analysis was performed with patients of whom DNA was available (N = 49), and demographic factors, CYP3A4*22 and CYP3A5*3, were tested as covariates. Moreover, a limited sampling model was developed using data of 66 patients.ResultsPharmacokinetics was best described by a two-compartment model with delayed absorption. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 carrying liver had an average 1.7-fold higher clearance compared to non-carriers. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 non-carrying liver or vice versa showed an average 1.3-fold higher clearance compared with non-carriers. CYP3A4*22 was not significantly associated with once daily tacrolimus pharmacokinetics. Using 0, 2, and 3 h postdose as limited sampling model resulted in significantly improved prediction of tacrolimus exposure compared with trough concentration.ConclusionsBoth donor and recipient CYP3A5 genotype significantly influences tacrolimus once daily pharmacokinetics. In contrast, CYP3A4*22 appears not suitable as biomarker. The developed limited sampling model can be used to accurately estimate tacrolimus once daily exposure.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-015-1963-3) contains supplementary material, which is available to authorized users.
BackgroundDuring the last decade, the number of people with ≥1 tattoo has increased noticeably within the European population. Despite this, limited safety information is available for tattoo inks.ObjectivesTo test the skin sensitization potential of 5 tattoo inks in vitro by using reconstructed human skin (RHS) and the contact sensitization biomarker interleukin (IL)‐18.MethodsTwo red and 3 black tattoo inks, 1 additive (Hamamelis virginiana extract) and 1 irritant control (lactic acid) were tested. The culture medium of RHS (reconstructed epidermis on a fibroblast‐populated collagen hydrogel) was supplemented with test substances in a dose‐dependent manner for 24 hours, after which cytotoxicity (histology; thiazolyl blue tetrazolium bromide assay) and skin sensitization potential (IL‐18 secretion; enzyme‐linked immunosorbent assay) were assessed.ResultsAll but 1 ink showed cytotoxicity. Notably, 1 red ink and 1 black ink were able to cause an inflammatory response, indicated by substantial release of IL‐18, suggesting that these inks may be contact sensitizers.ConclusionsThe in vitro RHS model showed that 4 tattoo inks were cytotoxic and 2 were able to cause an inflammatory IL‐18 response, indicating that an individual may develop allergic contact dermatitis when exposed to these tattoo inks, as they contain contact sensitizers.
underserved areas. In the future, these patients could have the ability to scan their lesions so that a dermatologist can print it out at their respective location. However, even in combination with 3D printing, teledermatology does not allow for the assessment of certain portions of the clinical examination, such as induration and warmth. Although 3D technology is studied and utilized in the dermatologic setting, it is not currently being used for the purposes described herein. Skin cells are routinely 3D printed to treat burns and wounds, but not to create replicas of cutaneous disease for the purpose of medical education or teledermatology measures. This article aims to highlight the incredible potential of 3D scanning and 3D printing in an effort to identify gaps in the current application of this useful technology.
Background: Worldwide 10-20% of the population is tattooed. However, tattoo complications can occur, such as allergic tattoo reactions, infections, and manifestations of autoimmune dermatoses. Despite the growing popularity of tattoos and changes in tattoo ink composition over the last decades, little is known about these complications, its clinical aspects, pathomechanism, and relative occurrence.Objective: The aim of this article is to describe the types and clinical aspects of dermatological tattoo complications, its relative occurrence and underlying conditions. Methods:We performed a retrospective cohort study enrolling all patients with tattoo complications from the Tattoo Clinic. Tattoo complications were categorized into infections, inflammatory tattoo reactions, neoplasms, or miscellaneous reactions and correlated to clinical data.Results: Of the total of 326 patients, 301 patients were included with 308 complications. The majority of the complications were chronic: 91.9%. Allergic red tattoo reactions and chronic inflammatory black tattoo reactions (CIBTR) accounted for 50.2% and 18.2%, respectively, of all tattoo complications. Of these CIBTR reactions, extracutaneous involvement was found in 21.4%, including tattoo-associated uveitis (7.1%) and systemic sarcoidosis (14.2%). Of all black tattoo reactions, systemic sarcoidosis was found in 7.8%. Conclusion:Tattoos can cause a wide range in complications that may start years after getting the tattoo. The most frequent tattoo reactions are allergic red tattoo reactions and chronic inflammatory black tattoo reactions, making these the most relevant for the dermatologist. CIBTR have a high percentage of multi-organ involvement, and therefore, screening for sarcoidosis, including ocular involvement, is advised.
) on the gating of native sheep RyR2, reconstituted into bilayers. Suramin displaces CaM from RyR2 and we have used a gel-shift assay to provide evidence of the mechanism underlying this effect. Finally, using suramin to displace endogenous CaM from RyR2 in permeabilized cardiac cells, we have investigated the effects of 50 nmol·L -1 CaM on sarcoplasmic reticulum (SR) Ca 2+-release. Key results: Ca 2+CaM activated or inhibited single RyR2, but activation was much more likely at low (50-100 nmol·L -1 ) concentrations. Also, suramin displaced CaM from a peptide of the CaM binding domain of RyR2, indicating that, like the skeletal isoform (RyR1), suramin directly competes with CaM for its binding site on the channel. Pre-treatment of rat permeabilized ventricular myocytes with suramin to displace CaM, followed by addition of 50 nmol·L -1 CaM to the mock cytoplasmic solution caused an increase in the frequency of spontaneous Ca 2+ -release events. Application of caffeine demonstrated that 50 nmol·L -1 CaM reduced SR Ca 2+ content. Conclusions and implications: We describe for the first time how Ca 2+CaM is capable, not only of inactivating, but also of activating RyR2 channels in bilayers in a CaM kinase II-independent manner. Similarly, in cardiac cells, CaM stimulates SR Ca 2+-release and the use of caffeine suggests that this is a RyR2-mediated effect. Abbreviations: AIP, autocamtide-2-related inhibitory peptide; CaM, calmodulin; CaMKII, CaM kinase II; EC-coupling, excitation-contraction coupling; RyR2, cardiac ryanodine receptor; RyRF, RyR2 peptide (RSKKAVWHKLL-SKQRKRAVVACFRMAPLYNLP); SR, sarcoplasmic reticulum British Journal of Pharmacology IntroductionThe cardiac ryanodine receptor (RyR2; nomenclature follows Alexander et al., 2008) is the pathway for the release of intracellular Ca 2+ during excitation-contraction (EC) coupling. It also acts as a scaffolding protein localizing numerous other proteins to the dyadic cleft regions. Calmodulin (CaM) binds very tightly to RyR2, but the physiological role of this direct association is unclear (Balshaw et al., 2001;Ai et al., 2005). CaM is a Ca 2+ -sensing protein, which contains four Ca 2+ -binding sites, two on the amino and two on the carboxyl lobe. CaM interacts with numerous proteins, usually in the Ca 2+ -bound form (Ca 2+ CaM), but can also modulate certain proteins in the non-Ca 2+ -bound form (apoCaM). It has been well documented that Ca 2+ CaM can cause partial inhibition of both cardiac and skeletal (RyR1) isoforms of RyR (Fruen et al., 2000;Balshaw et al., 2001). Additionally, apoCaM is known to activate RyR1, but has little effect on RyR2 Tripathy et al., 1995;Fruen et al., 2000).The magnitude of the reported inhibition of RyR2 by Ca 2+ CaM is often exceedingly small (Yamaguchi et al., 2004;Xu and Meissner, 2004) and, interestingly, there are also rare reports suggesting that CaM may activate RyR2 (Fruen et al., 2000;Chugun et al., 2007 Xu and Meissner, 2004) and Ca 2+ -spark generation in cardiac cells (Lukyanenko and Gyorke, 1999;Ai et al., 2005;Guo ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.