Publications by authors named "Juan C Carril"

11 Publications

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Influence of dopamine, noradrenaline, and serotonin transporters on the pharmacogenetics of Atremorine in Parkinson's disease.

Drug Dev Res 2021 Jan 17. Epub 2021 Jan 17.

EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Bergondo, Spain.

Atremorine is a potent dopamine (DA) enhancer obtained by nondenaturing biotechnological processes from a genetic species of Vicia faba. Atremorine affects the neuronal dopaminergic system by acting as a neuroprotective agent against Parkinson's disease (PD). PD patients (N = 127) responded to a single dose of Atremorine (5 g, p.o.) 1 h after administration in a sex-, time-, dose-, and genotype-dependent fashion. Drug-free patients (N = 81) showed an increase in DA levels from 12.14 ± 0.34 pg/ml to 6463.21 ± 1306.90 pg/ml; and patients chronically treated with anti-PD drugs (N = 46) showed an increase in DA levels from 1321.53 ± 389.94 pg/ml to 16,028.54 ± 4783.98 pg/ml, indicating that Atremorine potentiates the dopaminergic effect of conventional anti-PD drugs. The variability in Atremorine-induced DA response is strongly attributable to pharmacogenetic factors. Polymorphic variants in pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes influence the DA response to Atremorine. Genetic variation in the DA (SLC6A3; rs460000), noradrenaline (NA) (SLC6A2; rs12708954, rs3785143, rs5569), and serotonin (5-HT) transporter (SLC6A4; rs2020934, rs2020936, rs4251417, rs6354) genes exert a genotype-dependent Atremorine-induced DA response in PD, with potential impact on the DA-related pharmacogenetic outcome and minimum effects on NA and 5-HT levels.
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http://dx.doi.org/10.1002/ddr.21784DOI Listing
January 2021

Pharmacogenetics of Atremorine-Induced Neuroprotection and Dopamine Response in Parkinson's Disease.

Planta Med 2019 Nov 26;85(17):1351-1362. Epub 2019 Sep 26.

EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Bergondo, Corunna, Spain.

Atremorine is a novel bioproduct with neuroprotective effects on dopaminergic neurons and a natural L-DOPA donor in Parkinson's disease (PD). In the present study, we show the effects of a single dose of Atremorine (5 g, p. o.) on plasma dopamine (DA) response and brain function in PD (n = 183) and the influence that pathogenic (), metabolic (), transporter (), pleiotropic (), and detoxifying genes () involved in the pharmacogenetic network exerts on Atremorine-induced DA response. Over 90% of PD patients at diagnosis show plasma DA levels below 20 pg/mL. Atremorine induces DA synthesis causing a significant increase in plasma DA levels 1 h after administration in practically 100% of patients. Females tend to show lower basal DA levels than males and the response of DA to Atremorine is stronger in males than in females. Atremorine-induced DA response is pharmacogenotype-specific and lasts from 6 - 12 h depending upon the pharmacogenetic profile of each patient. Genetic variants in pathogenic genes, metabolic genes, and genes involved in the detoxification processes affect the response of DA to Atremorine in a genotype-specific manner. Atremorine or any of its bioactive components can cross the blood-brain barrier and improve brain function and motor function, as revealed by the reduction in slow wave activity in brain mapping and psychometric assessment, respectively. Atremorine is a selective neuroprotective agent for dopaminergic neurons with prophylactic and therapeutic potential in PD.
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http://dx.doi.org/10.1055/a-1013-7686DOI Listing
November 2019

The role of pharmacogenomics in adverse drug reactions.

Expert Rev Clin Pharmacol 2019 May 24;12(5):407-442. Epub 2019 Apr 24.

a EuroEspes Biomedical Research Center , Institute of Medical Science and Genomic Medicine , Corunna , Spain.

Introduction: Adverse drug reactions (ADRs) are a major health concern worldwide. There are multiple causes of ADRs, some of which are preventable. Pharmacogenomics accounts for ≈80% variability in drug efficacy and safety. Over 400 genes are clinically relevant in drug metabolism, and ≈200 pharmagenes are associated with ADRs. The condition of extensive metabolizer in the Caucasian population is lower than 20%, and about 60% of patients are exposed to potential ADRs. Areas covered: Important topics related to pharmacogenomics in drug efficacy and safety are covered, including: (i) major components of the pharmacogenomic machinery; (ii) epigenetic regulation of pharmagene expression; and (iii) pharmacogenomics-related ADRs of different drug categories. Expert opinion: The Regulatory Agencies should make recommendations to the pharmaceutical industry in favor of the introduction of pharmacogenomics in drug development and the inclusion of pharmacogenomic information on drug labels, with specific warnings for the population at risk. Educational programs are fundamental for drug prescribers to become familiar with personalized treatments. Pharmacogenetic testing should be gradually introduced into medical practice. ADRs can be reduced not only by adherence to prescribing guidelines, suitable monitoring and regular medication review, but also by the implementation of pharmacogenomic procedures in the clinical setting.
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http://dx.doi.org/10.1080/17512433.2019.1597706DOI Listing
May 2019

Sirtuins in Alzheimer's Disease: SIRT2-Related GenoPhenotypes and Implications for PharmacoEpiGenetics.

Int J Mol Sci 2019 Mar 12;20(5). Epub 2019 Mar 12.

Department of Psychiatry and Behavioral Science, Stony Brook University, Stony Brook, NY 11794, USA.

Sirtuins (SIRT1-7) are NAD⁺-dependent protein deacetylases/ADP ribosyltransferases with important roles in chromatin silencing, cell cycle regulation, cellular differentiation, cellular stress response, metabolism and aging. Sirtuins are components of the epigenetic machinery, which is disturbed in Alzheimer's disease (AD), contributing to AD pathogenesis. There is an association between the genotype (rs10410544) (50.92%) and AD susceptibility in the -negative population (, 34.72%; 14.36%). The integration of and variants in bigenic clusters yields 18 haplotypes. The 5 most frequent bigenic genotypes in AD are (27.81%), (21.36%), (15.29%), (9.76%) and (7.18%). There is an accumulation of and carriers in > > carriers, and also of and carriers in patients who harbor the genotype. variants influence biochemical, hematological, metabolic and cardiovascular phenotypes, and modestly affect the pharmacoepigenetic outcome in AD. carriers are the best responders, carriers show an intermediate pattern, and carriers are the worst responders to a multifactorial treatment. In bigenic clusters, carriers respond better than and carriers, whereas and carriers behave as the worst responders. CYP2D6 extensive metabolizers (EM) are the best responders, poor metabolizers (PM) are the worst responders, and ultra-rapid metabolizers (UM) tend to be better responders that intermediate metabolizers (IM). In association with genophenotypes, -EMs are the best responders. Some Sirtuin modulators might be potential candidates for AD treatment.
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http://dx.doi.org/10.3390/ijms20051249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429449PMC
March 2019

Pharmacogenetics of Vascular Risk Factors in Alzheimer's Disease.

J Pers Med 2018 Jan 3;8(1). Epub 2018 Jan 3.

EuroEspes Biomedical Research Center, Institute of Medical Science and Genomic Medicine, Bergondo, 15165 La Coruña, Spain.

Alzheimer's disease (AD) is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Pharmacogenetics is a major determinant of therapeutic outcome in AD. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety, including pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes. However, most drugs exert pleiotropic effects that are promiscuously regulated for different gene products. Only 20% of the Caucasian population are extensive metabolizers for tetragenic haplotypes integrating variants. Patients harboring CYP-related poor (PM) and/or ultra-rapid (UM) geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM) or intermediate (IM) metabolizers. Among 111 pentagenic () haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG-AG-CC) exhibit the lowest cholesterol levels, and patients with the H104 haplotype (44-CC-CC-AA-CC) are severely hypercholesterolemic. Furthermore, , , , , and variants influence the therapeutic response to hypotensive drugs in AD patients with hypertension. Consequently, the implementation of pharmacogenetic procedures may optimize therapeutics in AD patients under polypharmacy regimes for the treatment of concomitant vascular disorders.
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http://dx.doi.org/10.3390/jpm8010003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872077PMC
January 2018

Genetic Risk Factors in Cerebrovascular Disorders and Cognitive Deterioration.

Curr Genomics 2017 Oct;18(5):416-429

EuroEspes Biomedical Research Center, Institute of Medical Science and Genomic Medicine. 15165-Bergondo, Corunna, Spain; Genomic Medicine. Camilo José Cela University 28692-Madrid, Spain.

Introduction: The study of variations in genes involved in the different events that trigger the atherogenic process, such as lipid metabolism (modification of LDL-cholesterol), endothelial function and hypertension, immune response (recruitment of macrophages and foam cell formation) and stability of atherosclerotic plaques (thrombosis), established the risk for suffering a vascular disorder. A total of 2455 cases over 50 years of age were genotyped for a panel of 19 SNPs in 15 genes encoding for proteins involved in the atherogenic process. This study shows the relevance of polymorphisms in APOB (odds ratio (OR), 1.17; 95% confidence interval (95% CI), 0.74-1.85), APOC3 (OR, 1.33; 95% CI, 0.82-2.17) and APOE (OR, 1.75; 95% CI, 1.09-2.80), as genetic risk markers for hypercholesterolemia; polymorphisms in ACE (OR, 1.68; 95% CI, 0.32-8.77) and AGT (OR, 1.74; 95% CI, 0.97-3.14) for hypertension; and in APOE*3/*4 (OR, 2.06; 95% CI, 1.70-2.51) and APOE*4/*4 (OR, 3.08; 95% CI, 1.85-5.12) as unambiguous markers of dementia.

Result: Our results also showed the transversal importance of proinflammatory cytokines in different stages of atherogenesis, with special relevance of IL6 (OR, 1.39; 95% CI, 0.56-3.49) and TNF (OR, 1.40; 95% CI, 0.92-2.15) related to hypercholesterolemia and hypertension. The set of markers involved in this genetic risk panel makes it a powerful tool in the management of patients with different vascular disorders.
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http://dx.doi.org/10.2174/1389202918666170426165226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635647PMC
October 2017

Novel Therapeutic Strategies for Dementia.

CNS Neurol Disord Drug Targets 2016 ;15(2):141-241

Department of Genomic Medicine, Camilo José Cela University, Villanueva de la Cañada, 28692-Madrid, Spain.

Dementia represents a major problem of health and disability, with a relevant economic impact on our society. Despite important advances in pathogenesis, diagnosis and treatment, its primary causes still remain elusive, accurate biomarkers are not well characterized, and the available pharmacological treatments are not cost-effective. Alzheimer disease (AD), the most prevalent form of dementia, is a polygenic/multifactorial/complex disorder in which hundreds of defective genes distributed across the human genome may contribute to its pathogenesis. Diverse environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, together with structural and functional genomic dysfunctions lead to amyloid deposition, neurofibrillary tangle formation and premature neuronal death, the major neuropathological hallmarks of AD. For the past 20 years, over 1,000 different compounds have been studied as potential candidate drugs for the treatment of AD. About 50% of these substances are novel molecules obtained from natural sources. The candidate compounds can be classified according to their pharmacological properties and/or the AD-related pathogenic cascade to which they are addressed to halt disease progression. In addition to the Food and Drug Administration (FDA)-approved drugs since 1993 (tacrine, donepezil, rivastigmine, galantamine, memantine), most candidate strategies fall into 6 major categories: (i) novel cholinesterase inhibitors and neurotransmitter regulators, (ii) anti-amyloid beta (Aβ) treatments (amyloid-β protein precursor (APP) regulators, Aβ breakers, active and passive immunotherapy with vaccines and antibodies, β - and γ - secretase inhibitors or modulators), (iii) anti-tau treatments, (iv) pleiotropic products (most of them of natural origin), (v) epigenetic intervention, and (vi) combination therapies. The implementation of pharmacogenomic strategies will contribute to optimize drug development and therapeutics in AD and related disorders.
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http://dx.doi.org/10.2174/1871527315666160202121548DOI Listing
December 2016

Can cloud-based tools accelerate Alzheimer's disease drug discovery?

Expert Opin Drug Discov 2016 3;11(3):215-23. Epub 2016 Feb 3.

a Chair of Genomic Medicine , Camilo José Cela University , Madrid , Spain.

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http://dx.doi.org/10.1517/17460441.2016.1141892DOI Listing
October 2016

Pharmacogenomics of Alzheimer's disease: novel therapeutic strategies for drug development.

Methods Mol Biol 2014 ;1175:323-556

Chair of Genomic Medicine, Camilo José Cela University, 28692, Villanueva de la Cañada, Madrid, Spain,

Alzheimer's disease (AD) is a major problem of health and disability, with a relevant economic impact on our society. Despite important advances in pathogenesis, diagnosis, and treatment, its primary causes still remain elusive, accurate biomarkers are not well characterized, and the available pharmacological treatments are not cost-effective. As a complex disorder, AD is a polygenic and multifactorial clinical entity in which hundreds of defective genes distributed across the human genome may contribute to its pathogenesis. Diverse environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, together with structural and functional genomic dysfunctions, lead to amyloid deposition, neurofibrillary tangle formation, and premature neuronal death, the major neuropathological hallmarks of AD. Future perspectives for the global management of AD predict that genomics and proteomics may help in the search for reliable biomarkers. In practical terms, the therapeutic response to conventional drugs (cholinesterase inhibitors, multifactorial strategies) is genotype-specific. Genomic factors potentially involved in AD pharmacogenomics include at least five categories of gene clusters: (1) genes associated with disease pathogenesis; (2) genes associated with the mechanism of action of drugs; (3) genes associated with drug metabolism (phase I and II reactions); (4) genes associated with drug transporters; and (5) pleiotropic genes involved in multifaceted cascades and metabolic reactions. The implementation of pharmacogenomic strategies will contribute to optimize drug development and therapeutics in AD and related disorders.
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http://dx.doi.org/10.1007/978-1-4939-0956-8_13DOI Listing
May 2015

Genomics of Dementia: APOE- and CYP2D6-Related Pharmacogenetics.

Int J Alzheimers Dis 2012 14;2012:518901. Epub 2012 Mar 14.

EuroEspes Biomedical Research Center, Institute for CNS Disorders and Genomic Medicine, EuroEspes Chair of Biotechnology and Genomics, Camilo José Cela University, 15165 Bergondo, Spain.

Dementia is a major problem of health in developed societies. Alzheimer's disease (AD), vascular dementia, and mixed dementia account for over 90% of the most prevalent forms of dementia. Both genetic and environmental factors are determinant for the phenotypic expression of dementia. AD is a complex disorder in which many different gene clusters may be involved. Most genes screened to date belong to different proteomic and metabolomic pathways potentially affecting AD pathogenesis. The ε4 variant of the APOE gene seems to be a major risk factor for both degenerative and vascular dementia. Metabolic factors, cerebrovascular disorders, and epigenetic phenomena also contribute to neurodegeneration. Five categories of genes are mainly involved in pharmacogenomics: genes associated with disease pathogenesis, genes associated with the mechanism of action of a particular drug, genes associated with phase I and phase II metabolic reactions, genes associated with transporters, and pleiotropic genes and/or genes associated with concomitant pathologies. The APOE and CYP2D6 genes have been extensively studied in AD. The therapeutic response to conventional drugs in patients with AD is genotype specific, with CYP2D6-PMs, CYP2D6-UMs, and APOE-4/4 carriers acting as the worst responders. APOE and CYP2D6 may cooperate, as pleiotropic genes, in the metabolism of drugs and hepatic function. The introduction of pharmacogenetic procedures into AD pharmacological treatment may help to optimize therapeutics.
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http://dx.doi.org/10.1155/2012/518901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312254PMC
August 2012

Results of the 2003-2004 GEP-ISFG collaborative study on mitochondrial DNA: focus on the mtDNA profile of a mixed semen-saliva stain.

Forensic Sci Int 2006 Jul 21;160(2-3):157-67. Epub 2005 Oct 21.

Instituto Nacional de Toxicología y Ciencias Forenses, Servicio de Biología, Barcelona, Spain.

We report here a review of the seventh mitochondrial DNA (mtDNA) exercise undertaken by the Spanish and Portuguese working group (GEP) of the International Society for Forensic Genetics (ISFG) corresponding to the period 2003-2004. Five reference bloodstains from five donors (M1-M5), a mixed stain of saliva and semen (M6), and a hair sample (M7) were submitted to each participating laboratory for nuclear DNA (nDNA; autosomal STR and Y-STR) and mtDNA analysis. Laboratories were asked to investigate the contributors of samples M6 and M7 among the reference donors (M1-M5). A total of 34 laboratories reported total or partial mtDNA sequence data from both, the reference bloodstains (M1-M5) and the hair sample (M7) concluding a match between mtDNA profiles of M5 and M7. Autosomal STR and Y-STR profiling was the preferred strategy to investigate the contributors of the semen/saliva mixture (M6). Nuclear DNA profiles were consistent with a mixture of saliva from the donor (female) of M4 and semen from donor M5, being the semen (XY) profile the dominant component of the mixture. Strikingly, and in contradiction to the nuclear DNA analysis, mtDNA sequencing results yield a more simple result: only the saliva contribution (M4) was detected, either after preferential lysis or after complete DNA digestion. Some labs provided with several explanations for this finding and carried out additional experiments to explain this apparent contradictory result. The results pointed to the existence of different relative amounts of nuclear and mtDNAs in saliva and semen. We conclude that this circumstance could strongly influence the interpretation of the mtDNA evidence in unbalanced mixtures and in consequence lead to false exclusions. During the GEP-ISFG annual conference a validation study was planned to progress in the interpretation of mtDNA from different mixtures.
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http://dx.doi.org/10.1016/j.forsciint.2005.09.005DOI Listing
July 2006