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BACKGROUND: Establishing adequate reference intervals (RIs) for vitamins A and E is essential for diagnosing and preventing deficiencies. Due to the current boom in data mining and its easy applicability, more laboratories are establishing RIs using indirect methods. Our study aims to obtain RIs using four indirect data-mining procedures (Bhattacharya, Hoffmann, Kosmic, and RefineR) for vitamins A and E. MATERIAL AND METHODS: 8943 individuals were collected to establish the RIs. After using different data cleaning steps and checking whether these data should be divided according to age and gender based on multiple linear regression and variance component analyses, indirect RIs were calculated using specific Excel spreadsheets or R-packages software. RESULTS: A total of 2004 records were eligible. For vitamin A, the RIs obtained were (1.11 - 2.68) µmol/L, (1.13 - 2.70) µmol/L, (1.13 - 2.71) µmol/L, and (1.17 - 2.66) µmol/L using the Bhattacharya, Hoffmann, Kosmic and RefineR approaches, respectively. For vitamin E, these intervals were (17.3 - 49.9) µmol/L (Bhattacharya), (17.3 - 48.9) µmol/L (Hoffmann), (19.6 - 50.3) µmol/L (Kosmic), and (19.4 - 50.9) µmol/L (RefineR). In all cases, the RIs were comparable. CONCLUSIONS: Suitable RIs for vitamins A and E were calculated using four indirect methods that are suitable and adapted to our population's demographic characteristics.
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Mineração de Dados , Vitamina A , alfa-Tocoferol , Humanos , Vitamina A/sangue , alfa-Tocoferol/sangue , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Valores de Referência , Adulto Jovem , Adolescente , Idoso , Criança , Pré-Escolar , Idoso de 80 Anos ou maisRESUMO
Tacrolimus (Tac) is pivotal in preventing acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). It has been reported that genetic factors, including CYP3A5*3 and CYP3A4*22 polymorphisms, have an impact on Tac metabolism, dose requirement, and response to Tac. There is limited information regarding this topic in alloHSCT. The CYP3A5 genotype and a low Tac trough concentration/dose ratio (Tac C0/D ratio) can be used to identify fast metabolizers and predict the required Tac dose to achieve target concentrations earlier. We examined 62 Caucasian alloHSCT recipients with a fast metabolizer phenotype (C0/dose ratio ≤ 1.5 ng/mL/mg), assessing CYP3A5 genotypes and acute GVHD incidence. Forty-nine patients (79%) were poor metabolizers (2 copies of the variant *3 allele) and 13 (21%) were CYP3A5 expressers (CYP3A5*1/*1 or CYP3A5*1/*3 genotypes). CYP3A5 expressers had lower C0 at 48 h (3.7 vs. 6.2 ng/mL, p = 0.03) and at 7 days (8.6 vs. 11.4 ng/mL, p = 0.04) after Tac initiation, tended to take longer to reach Tac therapeutic range (11.8 vs. 8.9 days, p = 0.16), and had higher incidence of both global (92.3% vs. 38.8%, p < 0.001) and grade II-IV acute GVHD (61.5% vs. 24.5%, p = 0.008). These results support the adoption of preemptive pharmacogenetic testing to better predict individual Tac initial dose, helping to achieve the therapeutic range and reducing the risk of acute GVHD earlier.
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Liver transplantation is the most effective treatment for end-stage liver disease. Transplant indications have been progressively increasing, with a huge discrepancy between the supply and demand of optimal organs. In this context, the use of extended criteria donor grafts has gained importance, even though these grafts are more susceptible to ischemic reperfusion injury (IRI). Hepatic IRI is an inherent and inevitable consequence of all liver transplants; it involves ischemia-mediated cellular damage exacerbated upon reperfusion and its severity directly affects graft function and post-transplant complications. Strategies for organ preservation have been constantly improving since they first emerged. The current gold standard for preservation is perfusion solutions and static cold storage. However, novel approaches that allow extended preservation times, organ evaluation, and their treatment, which could increase the number of viable organs for transplantation, are currently under investigation. This review discusses the mechanisms associated with IRI, describes existing strategies for liver preservation, and emphasizes novel developments and challenges for effective organ preservation and optimization.
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Transplante de Fígado , Traumatismo por Reperfusão , Humanos , Perfusão , Reperfusão , CriopreservaçãoRESUMO
Introduction: The use of noninvasive biomarkers may avoid the need for liver biopsy (LB) and could guide immunosuppression adjustment in liver transplantation (LT). The aims of this study were: to confirm the predictive and diagnostic capacity of plasmatic expression of miR-155-5p, miR-181a-5p, miR-122-5p and CXCL-10 for assessing T-cell mediated rejection (TCMR) risk; to develop a score based on a panel of noninvasive biomarkers to predict graft rejection risk and to validate this score in a separate cohort. Methods: A prospective, observational study was conducted with a cohort of 79 patients followed during the first year after LT. Plasma samples were collected at predetermined time points for the analysis of miRNAs and the CXCL-10. Patients with LFTs abnormalities were submitted to a LB to rule out rejection, assessing previous and concurrent expression of the biomarkers to evaluate their predictive and diagnostic ability. Information from 86 patients included in a previous study was collected and used as a validation cohort. Results: Twenty-four rejection episodes were diagnosed in 22 patients. Plasmatic CXCL-10 concentration and the expression of the three miRNAs were significantly elevated prior to and at the moment of the diagnosis of rejection. We developed a logistic model for rejection prediction and diagnosis, which included CXCL-10, miR-155-5p and miR-181a-5p. The area under the ROC curve (AUROC) for rejection prediction was 0.975 (79.6% sensitivity, 99.1% specificity, 90,7% PPV; 97.7% NPV; 97.1% correctly classified) and 0.99 for diagnosis (87.5% sensitivity, 99.5% specificity, 91.3% PPV; 99.3% NPV; 98.9% correctly classified). In the validation cohort (n=86; 14 rejections), the same cut-off points were used obtaining AUROCs for rejection prediction and diagnosis of 0.89 and 0.92 respectively. In patients with graft dysfunction in both cohorts the score could discriminate those with rejection regarding other causes with an AUROC of 0.98 (97.3% sensitivity, 94.1%specificity). Conclusion: These results suggest that the clinical implementation of the monitoring of this noninvasive plasmatic score may allow the prediction and diagnosis of rejection and identify patients with graft dysfunction due to rejection, helping with a more efficient guide for immunosuppressive therapy adjustment. This finding warrants the development of prospective biomarker-guided clinical trials.
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MicroRNAs , Humanos , MicroRNAs/genética , Fígado , Transplante Homólogo , Biomarcadores , AloenxertosRESUMO
Analysis of the genotype that predicts the phenotypic characteristics of a cohort of glaucoma and ocular hypertension patients, and the correlation with their personal pharmacological response to beta-blockers (BB) and prostaglandin analogues (PGA). Prospective study that included 139 eyes from 72 patients under BB and/or PGA treatment, and in some cases other types of ocular hypotensive treatments. Five single-nucleotide polymorphisms were genotyped by real-time PCR assays: prostaglandin-F2α receptor (rs3766355, rs3753380); cytochrome-P450 2D6 (rs16947, rs769258); and beta-2-adrenergic receptor (rs1042714). Other studied variables were mean deviation (MD) of visual field, previous ocular interventions, medical treatment, baseline (bIOP), and treated intraocular pressure (tIOP). From a total of 139 eyes, 71 (51.1%) were left eyes. The main diagnosis was primary open angle glaucoma (66.2%). A total of 57 (41%) eyes were under three or more medications (PGA + BB + other) and, additionally, 57 eyes (41%) had had some kind of glaucoma surgery. The mean bIOP and tIOP were 26.55 ± 8.19 and 21.01 ± 5.54 mmHg, respectively. Significant differences in tIOP were found between heterozygous (HT) (21.07 ± 0.607 mmHg) and homozygous (HM) (20.98 ± 0.639 mmHg) rs3766355 with respect to wildtype individuals (16 ± 1.08 mmHg) (p = 0.031). The MD values presented significant differences between wildtype rs3766355 (-2 ± 2.2 dB), HT (-3.87 ± 4 dB), and HM carriers (-9.37 ± 9.51 dB) (p = 0.009). Significant differences were also observed between the MD in wildtype rs3753380 (-6.1 ± 8.67 dB), HT (-9.02 ± 8.63 dB), and HM carriers (-9.51 ± 7.44 dB) (p = 0.017). Patients carrying the variant rs3766355 in HM or HT presented clinically-significantly higher tIOP than wildtype patients. Additionally, some differences in MD were found in rs3766355 and rs3753380 carriers, and the more alleles that were affected, the worse the MD value, meaning greater severity of the glaucoma. Poor response to treatment and more visual field damage may be associated with being a carrier of these mutated alleles.
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Glaucoma de Ângulo Aberto , Glaucoma , Hipertensão Ocular , Humanos , Glaucoma de Ângulo Aberto/tratamento farmacológico , Glaucoma de Ângulo Aberto/genética , Estudos Prospectivos , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Glaucoma/tratamento farmacológico , Glaucoma/genética , Hipertensão Ocular/tratamento farmacológico , Hipertensão Ocular/genética , Pressão Intraocular , Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/uso terapêutico , Genótipo , Fenótipo , Prostaglandinas Sintéticas/farmacologia , Prostaglandinas Sintéticas/uso terapêuticoRESUMO
OBJECTIVES: To review the drug-drug interactions between tacrolimus and lopinavir/ritonavir in 23 patients who received solid organ transplant during the first wave of COVID-19 and to determine the efficacy as well as safety of prednisone monotherapy. METHODS: Observational study performed between March and June 2020 in solid organ transplant recipients admitted with an established diagnosis of SARS-CoV-2 infection who received lopinavir/ritonavir (≥2 doses). Once lopinavir/ritonavir therapy was initiated, calcineurin inhibitor treatment was temporarily switched to prednisone monotherapy (15-20 mg/d) to avoid drug-drug interactions and toxicity. After lopinavir/ritonavir treatment completion, immunosuppressive treatment was restarted with reduced doses of prednisone-tacrolimus (target minimum blood concentration -C0- approximately 5 ng/mL). Patients were observed for 3 months to confirm the absence of rejection. RESULTS: The median time from discontinuation of tacrolimus to initiation of lopinavir/ritonavir was 14 hours (interquartile range [IQR], 12-15) and from discontinuation of lopinavir/ritonavir to resumption of tacrolimus 58 hours (IQR, 47-81). The duration of lopinavir/ritonavir treatment was 7 days (IQR, 5-7). Nine of the 21 (42.8%) patients on tacrolimus treatment had C0 above the cutoff point after lopinavir/ritonavir initiation, despite having been substituted with prednisone before lopinavir/ritonavir initiation. Three patients had very high concentrations (>40 ng/mL) and developed toxicity. No episodes of acute rejection were diagnosed. DISCUSSION: We did not observe toxicity in patients for whom tacrolimus was discontinued 24 hours before starting lopinavir/ritonavir and reintroduced at half dose 48 to 72 hours after lopinavir/ritonavir discontinuation. Prednisone monotherapy during lopinavir/ritonavir therapy was safe with no episodes of acute rejection. Experience with lopinavir/ritonavir may be applicable to the use of nirmatrelvir/ritonavir, but larger multicentre studies are needed to confirm these findings.
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COVID-19 , Transplante de Órgãos , Humanos , Ritonavir/efeitos adversos , Lopinavir/efeitos adversos , SARS-CoV-2 , Inibidores de Proteases , Tacrolimo/efeitos adversos , Prednisona/efeitos adversos , Tratamento Farmacológico da COVID-19 , Interações Medicamentosas , TransplantadosRESUMO
ABSTRACT: Nirmatrelvir/ritonavir (Paxlovid) consists of a peptidomimetic inhibitor (nirmatrelvir) of the SARS-CoV-2 main protease and a pharmacokinetic enhancer (ritonavir). It is approved for the treatment of mild-to-moderate COVID-19. This combination of nirmatrelvir and ritonavir can mediate significant and complex drug-drug interactions (DDIs), primarily due to the ritonavir component. Indeed, ritonavir inhibits the metabolism of nirmatrelvir through cytochrome P450 3A (CYP3A) leading to higher plasma concentrations and a longer half-life of nirmatrelvir. Coadministration of nirmatrelvir/ritonavir with immunosuppressive drugs (ISDs) is particularly challenging given the major involvement of CYP3A in the metabolism of most of these drugs and their narrow therapeutic ranges. Exposure of ISDs will be drastically increased through the potent ritonavir-mediated inhibition of CYP3A, resulting in an increased risk of adverse drug reactions. Although a decrease in the dosage of ISDs can prevent toxicity, an inappropriate dosage regimen may also result in insufficient exposure and a risk of rejection. Here, we provide some general recommendations for therapeutic drug monitoring of ISDs and dosing recommendations when coadministered with nirmatrelvir/ritonavir. Particularly, tacrolimus should be discontinued, or patients should be given a microdose on day 1, whereas cyclosporine dosage should be reduced to 20% of the initial dosage during the antiviral treatment. Dosages of mammalian target of rapamycin inhibitors (m-TORis) should also be adjusted while dosages of mycophenolic acid and corticosteroids are expected to be less impacted.
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COVID-19 , Ritonavir , Humanos , Ritonavir/uso terapêutico , Monitoramento de Medicamentos , Citocromo P-450 CYP3A , Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Imunossupressores/efeitos adversosRESUMO
Tacrolimus (Tac) is a pivotal immunosuppressant agent used to prevent graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloHSCT). Tac is characterized by a narrow therapeutic window and a high inter-patient and intra-patient pharmacokinetic variability (IPV). Although high IPV of Tac concentrations has been associated with adverse post-transplant outcomes following solid organ transplantation, the effects of Tac IPV on alloHSCT recipients have not been determined. Tac IPV was therefore retrospectively evaluated in 128 alloHSCT recipients receiving high-dose post-transplant cyclophosphamide (PTCy) and the effects of Tac IPV on the occurrence of acute GVHD (aGVHD) were analyzed. Tac IPV was calculated from pre-dose concentrations (C0) measured during the first month after Tac initiation. The cumulative rates of grades II-IV and grades III-IV aGVHD at day +100 were 22.7% and 7%, respectively. Higher Tac IPV was associated with a greater risk of developing GVHD, with patients having IPV > 50th percentile having significantly higher rates of grades II-IV (34.9% vs. 10.8%; hazard ratio [HR] 3.858, p < 0.001) and grades III-IV (12.7% vs. 1.5%; HR 9.69, p = 0.033) aGVHD than patients having IPV ≤ 50th percentile. Similarly, patients with IPV > 75th percentile had higher rates of grades II-IV (41.9% vs. 16.5%; HR 3.30, p < 0.001) and grades III-IV (16.1% vs. 4.1%; HR 4.99, p = 0.012) aGVHD than patients with IPV ≤ 75th percentile. Multivariate analyses showed that high Tac IPV (>50th percentile) was an independent risk factor for grades II-IV (HR 2.99, p = 0.018) and grades III-IV (HR 9.12, p = 0.047) aGVHD. Determination of Tac IPV soon after alloHSCT could be useful in identifying patients at greater risk of aGVHD.
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INTRODUCTION: Therapeutic Drug Monitoring (TDM) of antipsychotics in schizophrenia is a powerful tool that allows tailoring the treatment in an individualized approach. Our goals are to develop and validate a Dried Blood Spot (DBS) method for monitoring some commonly used antipsychotics (aripiprazole, clozapine, and paliperidone) and to evaluate its usefulness as a compliance biomarker, as well as in drug-dose adjustment to personalize the antipsychotic treatment to improve its efficacy and safety. METHODS: 31 first-psychotic episode (FEP) and schizophrenia patients were included; 5 refer to naïve FEP who started antipsychotic treatment; 26, to patients with more than one episode and under antipsychotic treatment: aripiprazole (7 cases), clozapine (17), paliperidone (11). For DBS sample collection, 25µl of capillary blood were placed in the spot of a FTA™DMPK-C-card. After completely dryness, antipsychotics were extracted and analyzed by a validated UHPLC-MS/MS-method. DBS antipsychotic results were compared with those obtained in venous blood/plasma. RESULTS: Aripiprazole, paliperidone and clozapine showed from good to excellent correlations between concentrations in venous blood and DBS capillary blood (r2, from 0.500 to 0.721). The correlation between conventional plasma and DBS concentrations for paliperidone, aripiprazole, clozapine, and their metabolites were moderate, suggesting that optimal drug target concentrations should be established for DBS. CONCLUSIONS: In this study, for aripiprazole, dehydroaripiprazole, paliperidone, clozapine and desmethylclozapine, DBS has provided good analytical performance for TDM. Thus, DBS sampling can offer a great alternative over conventional sampling for plasma measurement. The assay provides good analytical performances for TDM and clinical research applicability, suggesting that DBS is a promising clinical application in TDM in psychiatry.
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Antipsicóticos , Clozapina , Humanos , Aripiprazol/uso terapêutico , Clozapina/uso terapêutico , Palmitato de Paliperidona/uso terapêutico , Antipsicóticos/uso terapêutico , Espectrometria de Massas em Tandem/métodosRESUMO
The influence of pharmacogenetics in tacrolimus pharmacokinetics and pharmacodynamics needs further investigation, considering its potential in assisting clinicians to predict the optimal starting dosage and the need for a personalized adjustment of the dose, as well as to identify patients at a high risk of rejection, drug-related adverse effects, or poor outcomes. In the past decade, new pharmacokinetic strategies have been developed to improve personalized tacrolimus treatment. Several studies have shown that patients with tacrolimus doses C0/D < 1 ng/mL/mg may demonstrate a greater incidence of drug-related adverse events and infections. In addition, C0 tacrolimus intrapatient variability (IPV) has been identified as a potential biomarker to predict poor outcomes related to drug over- and under-exposure. With regard to tacrolimus pharmacodynamics, inconsistent genotype-phenotype relationships have been identified. The aim of this review is to provide a concise summary of currently available data regarding the influence of pharmacogenetics on the clinical outcome of patients with high intrapatient variability and/or a fast metabolizer phenotype. Moreover, the role of membrane transporters in the interindividual variability of responses to tacrolimus is critically discussed from a transporter scientist's perspective. Indeed, the relationship between transporter polymorphisms and intracellular tacrolimus concentrations will help to elucidate the interplay between the biological mechanisms underlying genetic variations impacting drug concentrations and clinical effects.
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PURPOSE: Polyethylene glycol drug-eluting microspheres (PEG-DEMs) can be loaded to elute doxorubicin. The current study evaluated the pharmacokinetic profile and safety of PEG-DEMs in the treatment of patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The current prospective, multicenter, dose-escalation study enrolled 25 patients (68% men) with early or intermediate stage HCC and a performance status of 0. Patients in Cohort I were assigned to receive target doxorubicin doses of 75, 100, or 150 mg. Analyses were performed on the basis of the specific dose of doxorubicin that the patients received because some patients received less than the assigned dose. Patients in Cohort II received the maximum safe tested dose. Adverse events were classified according to the Common Terminology Criteria for Adverse Events version 4.03. The tumor response was evaluated every 3 months according to the European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors. RESULTS: The maximum tested safe dose of doxorubicin was 150 mg. For the groups that received ≤75, 75-100, and 101-150 mg of doxorubicin, the peak plasma concentrations were 286.7 ng/mL ± 220.1, 157.1 ng/mL ± 94.6, and 245.4 ng/mL ± 142.8, respectively; the areas under the curves calculated from 0 to 24 h were 421.7 (ng × h)/mL ± 221.2, 288.1 (ng × h)/mL ± 100.9, and 608.3 (ng × h)/mL ± 319.3, respectively, with almost complete clearance at 24 h. There was no death within 30 d. The best objective response rate was 81%, and the disease control rate was 91%. The median overall survival was 27.2 months (95% confidence interval [CI], 17.5 months to not evaluated [n.e.]); the median progression-free survival was 9.8 months (95% CI, 5.5 months to n.e.). CONCLUSIONS: PEG-DEMs demonstrated a favorable safety profile with low systemic concentration of doxorubicin, and promising efficacy.
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Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Antibióticos Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/efeitos adversos , Doxorrubicina/efeitos adversos , Estudos de Viabilidade , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Microesferas , Polietilenoglicóis/efeitos adversos , Resultado do TratamentoRESUMO
OBJECTIVES: Physiopathological changes in advanced cirrhosis could alter tigecycline pharmacokinetics (PK), thus affecting serum drug concentrations and compromising target attainment. We aimed to describe tigecycline PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target. METHODS: Serum concentrations and covariates were obtained from patients with severe infections under tigecycline treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate tigecycline exposure to assess the PTA. RESULTS: Twenty critically ill patients were enrolled in the study. Data were best described by a two-compartment linear model. Mean ± SD parameter estimates for clearance (CL), intercompartmental clearance (Q), central and peripheral volumes of distribution (V1 and V2) were 14.8 ± 11â L/h, 38.4 ± 24â L/h, 63.7 ± 14â L and 233 ± 30â L, respectively. MELD score significantly influenced tigecycline CL, and total serum proteins significantly affected V1. Monte Carlo simulations showed that tigecycline elimination is hampered as MELD score values increase, consequently requiring lower drug doses. Patients with hypoproteinaemia would have lower peak tigecycline concentrations but similar steady-state concentrations compared with patients with normoproteinaemia. CONCLUSIONS: Our study confirms that tigecycline dose adjustment is needed in severe hepatic dysfunction and suggests using the MELD score for dose optimization since it is identified as a covariate that significantly influences tigecycline CL. Dosing regimens are recommended to reach several PK/PD targets considering this clinical variable and any MIC within the susceptibility range.
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Infecções Bacterianas , Estado Terminal , Antibacterianos/farmacologia , Infecções Bacterianas/tratamento farmacológico , Estado Terminal/terapia , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Tigeciclina/farmacocinéticaRESUMO
Monitoring of graft function is essential during the first months after liver transplantation (LT), but current liver function tests (LFTs) lack the specificity and sensitivity to ensure an efficient diagnosis of acute rejection (AR). Recently, donor-derived cell-free DNA (ddcfDNA) has emerged as a noninvasive biomarker to assess graft integrity. This study evaluated the feasibility of measuring the ddcfDNA through short tandem repeat (STR) analysis by quantitative fluorescent-polymerase chain reaction (QF-PCR) and to assess the role of the concentration and fragment size of total cfDNA as AR biomarkers. The total concentration and fragment size of cfDNA and the ddcfDNA percentage were monitored in plasma of 20 patients without rejection and 7 patients with T-cell-mediated AR during the first 3 months after LT. The median ddcfDNA percentage was 3-fold higher before AR diagnosis (34.8%; P < 0.001) and moderately higher at AR confirmatory diagnosis (23.8%; P = 0.049) compared with that of nonrejector patients (10.6%), showing a better performance (area under the curve = 84.6%) than conventional LFTs to predict the risk of rejection within the first 2 weeks following LT. The fraction of 100-250-bp cfDNA fragments was higher at AR diagnosis compared with that of nonrejector patients (68.0% versus 57.9%, P = 0.02). STR amplification by QF-PCR may be an alternative strategy for rapid ddcfDNA quantification, which is easily implementable in clinical laboratories. The results of this pilot study indicate that ddcfDNA increases very early, even 1-2 weeks before the diagnosis of AR, and so it could be useful as a prognostic biomarker in improving patient risk stratification.
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Ácidos Nucleicos Livres , Transplante de Fígado , Biomarcadores , Rejeição de Enxerto/diagnóstico , Humanos , Transplante de Fígado/efeitos adversos , Repetições de Microssatélites , Projetos Piloto , Medição de RiscoRESUMO
INTRODUCTION: Actually, immunosuppression selection isn't based on individual immune alloreactivity, and immunosuppressive drug dosing is mainly based on the development of toxicity and the achievement of specific target concentrations. Since a successful outcome requires optimal patient risk stratification and treatment, several groups have evaluated candidate biomarkers that have shown promise in the assessment of individual immune responses, the prediction of personal pharmacodynamic effects of immunosuppressive drugs and the prognosis and diagnosis of graft outcomes.. AREAS COVERED: This review includes biomarkers that the Scientific Community in Solid Organ Transplantation currently considers to have potential as diagnostic and prognostic biomarkers of graft evolution. We have focused on recent scientific advances and expert recommendations regarding the role of specific and non-specific pharmacodynamic biomarkers that are mainly involved in the T-cell-mediated response. EXPERT OPINION: Integral pharmacologic monitoring that combines pharmacokinetics, pharmacogenetics and predictive pharmacodynamic biomarkers may provide crucial information and allow personal adjustment of immunosuppressive drugs at an early stage before severe adverse events ensue. Multicentre, randomized, prospective and interventional trials are needed to fine tune the established cut-off values for each biomarker and the optimal monitoring frequency for each biomarker and to accurately evaluate possible clinical confounding factors to enable correct clinical qualification.
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Transplante de Órgãos , Biomarcadores , Rejeição de Enxerto/prevenção & controle , Humanos , Terapia de Imunossupressão/efeitos adversos , Imunossupressores/efeitos adversos , Transplante de Órgãos/efeitos adversos , Estudos ProspectivosRESUMO
This study evaluate the potential of plasmatic CXCL-10 (pCXCL-10) as a pre&post transplantation prognostic and diagnostic biomarker of T-cell-mediated rejection (TCMR), antibody-mediated rejection (ABMR) and subclinical rejection (SCR) risk in adult kidney recipients considering BKV and CMV infections as possible clinical confounder factors. Twenty-eight of 100 patients included experienced rejection (TCMR:14; ABMR:14); 8 SCR; 13 and 16 were diagnosed with BKV and CMV infection, respectively. Pre-transplantation pCXCL-10 was significantly increased in TCMR and ABMR and post-transplantation in TCMR, ABMR and SCR compared with nonrejectors. All CMV+ patients showed pCXCL-10 levels above the cutoff values established for rejection whereas the 80% of BKV+ patients showed pCXCL-10 concentration < 100 pg/mL. pCXCL-10 could improve pre-transplantation patient stratification and immunosuppressive treatment selection according to rejection risk; and after kidney transplantation could be a potential early prognostic biomarker for rejection. Clinical confounding factor in BKV+ and particularly in CMV+ patients must be discarded.
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Quimiocina CXCL10/sangue , Rejeição de Enxerto/sangue , Rejeição de Enxerto/diagnóstico , Transplante de Rim/efeitos adversos , Adulto , Idoso , Vírus BK , Biomarcadores/sangue , Quimiocina CXCL10/urina , Infecções por Citomegalovirus/complicações , Feminino , Rejeição de Enxerto/etiologia , Humanos , Isoanticorpos/imunologia , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/complicações , Prognóstico , Estudos Prospectivos , Fatores de Risco , Linfócitos T/imunologia , Infecções Tumorais por Vírus/complicaçõesRESUMO
People living with HIV should be considered candidates for solid-organ transplantation (SOT). However, managing HIV-infected patients undergoing SOT represents a major challenge due to the potential drug-drug interactions between antiretroviral drugs and immunosuppressive agents, particularly when resorting to antiretroviral drugs that require pharmacokinetic enhancers. We report three cases of cobicistat-tacrolimus co-administration, two of which also include the co-administration of mTOR inhibitors, in HIV-positive patients undergoing SOT (2 kidney and 1 liver recipient). We review previously reported cases and provide recommendations for initial management following transplantation.
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Acute intermittent porphyria (AIP) is a rare metabolic disease caused by mutations within the hydroxymethylbilane synthase gene. Previous studies have reported increased levels of plasma total homocysteine (tHcy) in symptomatic AIP patients. In this study, we present long-term data for tHcy and related parameters for an AIP patient cohort (n = 37) in different clinical disease-states. In total, 25 patients (68%) presented with hyperhomocysteinemia (HHcy; tHcy > 15 µmol/L) during the observation period. HHcy was more frequent in AIP patients with recurrent disease receiving heme arginate, than in nonrecurrent (median tHcy: 21.6 µmol/L; range: 10-129 vs median tHcy: 14.5 µmol/L; range 6-77). Long-term serial analyses showed a high within-person tHcy variation, especially among the recurrent patients (coefficient of variation: 16.4%-78.8%). HHcy was frequently associated with low blood concentrations of pyridoxal-5'-phosphate and folate, while cobalamin concentration and the allele distribution of the methylene-tetrahydrofolate-reductase gene were normal. Strikingly, 6 out of the 9 recurrent patients who were later included in a regime of givosiran, a small-interfering RNA that effectively reduced recurrent attacks, showed further increased tHcy (median tHcy in 9 patients: 105 µmol/L; range 16-212). Screening of amino acids in plasma by liquid-chromatography showed co-increased levels of methionine (median 71 µmol/L; range 23-616; normal <40), suggestive of acquired deficiency of cystathionine-ß-synthase. The kynunerine/tryptophan ratio in plasma was, however, normal, indicating a regular metabolism of tryptophan by heme-dependent enzymes. In conclusion, even if HHcy was observed in AIP patients receiving heme arginate, givosiran induced an aggravation of the dysregulation, causing a co-increase of tHcy and methionine resembling classic homocystinuria.
Assuntos
Acetilgalactosamina/análogos & derivados , Arginina/deficiência , Heme/deficiência , Hiper-Homocisteinemia/etiologia , Porfiria Aguda Intermitente/tratamento farmacológico , Pirrolidinas/uso terapêutico , Acetilgalactosamina/efeitos adversos , Acetilgalactosamina/uso terapêutico , Adulto , Arginina/uso terapêutico , Cistationina beta-Sintase/genética , Feminino , Ácido Fólico/sangue , Heme/uso terapêutico , Homeostase , Homocisteína/metabolismo , Homocistinúria/complicações , Humanos , Hidroximetilbilano Sintase/sangue , Hidroximetilbilano Sintase/genética , Masculino , Metionina/sangue , Pessoa de Meia-Idade , Porfiria Aguda Intermitente/sangue , Porfiria Aguda Intermitente/complicações , Porfiria Aguda Intermitente/genética , Fosfato de Piridoxal/sangue , Pirrolidinas/efeitos adversos , Adulto JovemRESUMO
ABSTRACT: When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.
Assuntos
Monitoramento de Medicamentos , Imunossupressores/administração & dosagem , Ácido Micofenólico/administração & dosagem , Transplante de Órgãos , Área Sob a Curva , Consenso , Rejeição de Enxerto/prevenção & controle , HumanosRESUMO
AIMS: Calcineurin inhibitors (CNI) have a small therapeutic window, and drug monitoring is required. Pharmacokinetic monitoring does not correlate sufficiently with clinical outcome. Therefore, the expression of nuclear factor of activated T cells (NFAT)-regulated genes in the peripheral blood has been suggested as a potentially useful immune monitoring tool to optimize CNI therapy. NFAT-regulated gene expression (RGE) was evaluated in renal allograft recipients as predictive biomarker to detect patients at risk of acute rejection or infections. METHODS: NFAT-RGE (interleukin-2, interferon-γ, granular-macrophage colony-stimulating factor) was evaluated by quantitative real-time polymerase chain reaction in whole blood samples at day 7, day 14, month 1, 3, and 6 after transplantation in 64 de novo renal allograft recipients from 3 European centres. Immunosuppression consisted of tacrolimus (Tac), mycophenolic acid, and corticosteroids. RESULTS: Tac concentrations (C0 and C1.5) correlated inversely with NFAT-RGE (P < .01). NFAT-RGE showed a high interindividual variability (1-61%). Patients with high residual gene expression (NFAT-RGE ≥30%) were at the increased risk of acute rejection in the following months (35 vs. 5%, P = .02), whereas patients with low residual gene expression (NFAT-RGE <30%) showed a higher incidence of viral complications, especially cytomegalovirus and BK virus replication (52.5 vs. 10%, P = .01). CONCLUSIONS: NFAT-RGE was confirmed as a potential noninvasive early predictive biomarker in the immediate post-transplant period to detect patients at risk of acute rejection and infectious complications in Tac-treated renal allograft recipients. Monitoring of NFAT-RGE may provide additional useful information for physicians to achieve individualized Tac treatment.