RESUMEN
Outbreaks of emerging diseases, like Mpox in 2022, pose unprecedented challenges to global healthcare systems. Although Mpox cases globally decreased since the end of 2022, numbers are still significant in the African Region, European Region, Region of the Americas, and Western Pacific Region. Rapid and efficient detection of infected individuals by precise screening assays is crucial for successful containment. In these assays, analytical and clinical performance must be assessed to ensure high quality. However, clinical studies evaluating Mpox virus (MPXV) detection kits using patient-derived samples are scarce. This study evaluated the analytical and clinical performance of a new diagnostic MPXV real-time PCR detection kit (Sansure Monkeypox Virus Nucleic Acid Diagnostic Kit) using patient-derived samples collected in Germany during the MPXV clade IIb outbreak in 2022. Our experimental approach determined the Limit of Detection (LoD) to less than 200 cp/mL using whole blood samples and samples derived from vesicles or pustules. Furthermore, we tested potentially inhibiting substances and pathogens with homologous nucleic acid sequences or similar clinical presentation and detected no cross-reactivity or interference. Following this, the assay was compared to a CE-marked test in a clinical performance study and achieved a diagnostic sensitivity of 100.00% and diagnostic specificity of 96.97%. In summary, the investigated real-time PCR assay demonstrates high analytical performance and concurs with the competitor device with high specificity and sensitivity.
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Reacción en Cadena en Tiempo Real de la Polimerasa , Sensibilidad y Especificidad , Humanos , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Alemania/epidemiología , Mpox/diagnóstico , Mpox/virología , Juego de Reactivos para Diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Límite de Detección , Brotes de Enfermedades , Parapoxvirus/aislamiento & purificación , Parapoxvirus/genéticaRESUMEN
OBJECTIVE: The purpose this study was to investigate the reliability of a handheld myotonometer in measuring the mechanical properties of the neck and orofacial muscles in asymptomatic individuals. METHODS: The study included 16 healthy participants. The mechanical properties (frequency, decrement, stiffness, relaxation time, and creep) of the selected muscles were measured with a MyotonPRO myotonometer (Mumeetria Ltd, Tallinn, Estonia). The sternocleidomastoid, upper trapezius, cervical extensor, and masseter muscles were selected to determine the reliability of the device. Measurements were performed by 2 examiners to determine interrater reliability; for intrarater reliability, an examiner repeated the measurements 1 week after the first measurements. RESULTS: The results revealed moderate to excellent intrarater and interrater reliability (intraclass correlation coefficients: 0.50-0.95) in measuring muscle mechanic properties. The standard error of measurement in the tested muscles ranged from 0.3 to 0.8 Hz for frequency, from 7.4 to 20.9 N/m for stiffness, from 0.1 to 0.2 for decrement, and from 0.8 to 1.4 ms for relaxation time. The minimum detectable change ranged from 0.8 to 2.2 Hz for frequency, from 20.5 to 57.9 N/m for stiffness, from 0.2 to 0.6 for decrement, from 2.2 to 3.9 ms for relaxation time, and from 0.2 to 0.3 for creep. In addition, the coefficients of variation were below 9.1% for all the assessed parameters. CONCLUSION: The obtained results demonstrate that the MyotonPRO device is a reliable and repeatable tool to quantify the frequency, stiffness, decrement, relation time, and creep of the neck and orofacial muscles in asymptomatic individuals.
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Electrónica Médica/instrumentación , Músculos del Cuello/fisiología , Músculos Superficiales de la Espalda/fisiología , Adulto , Humanos , Masculino , Manometría/normas , Persona de Mediana Edad , Variaciones Dependientes del Observador , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
Anil et al. (2017) report a patient who presented with drug rash with eosinophilia and systemic symptom (DRESS) syndrome. It may be induced by various drugs. In the mentioned report DRESS syndrome has been attributed to phenytoin use. CYP2C9 is a genetically polymorphic enzyme, and decreased metabolism of many drugs has been reported in the subjects carrying variants of rs1799853 and rs1057910, which were designated as CYP2C9*2 and *3. rs3758581, the variant investigated by Anil et al., is a genetic variant of CYP2C19 (not that of CYP2C9, as stated and discussed in the report). CYP2C19 is also a highly genetically polymorphic enzyme, and rs3758581 may be present in 40 different haplotypes of CYP2C19 including *2 and *17 (for detailed information: www.pharmvar.org/gene/CYP2C19). Detection of rs3758581 is not sufficient because the patient presented by Anil H et al. may have CYP2C19*2, CYP2C19*17, or any other variant due to the co-appearance of other possible genetic variations. It is of importance to perform the correct genetic analysis because CYP2C19*2 is associated with low enzyme activity but CYP2C19*17 is associated with increased enzyme activity. CYP2C9 is a major enzyme responsible for the metabolism of phenytoin. CYP2C9*2 (rs1799853) and *3 (rs1057910) should be considered in a Caucasian subject. CYP2C19 (especially *2 and *17) and ABCB1 polymorphisms may also be considered for the evaluation of the patient. Additionally, serum phenytoin levels would be helpful to understand the contribution of genetic polymorphisms on the pharmacokinetics of phenytoin in the patients presenting side effects like DRESS syndrome.
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Acetamidas , Citocromo P-450 CYP1A2 , Celecoxib , Citocromo P-450 CYP2C9 , Microsomas HepáticosAsunto(s)
Puente de Arteria Coronaria/métodos , Citocromo P-450 CYP2D6/metabolismo , Circulación Extracorporea/métodos , Hígado/metabolismo , Metoprolol/farmacocinética , Disponibilidad Biológica , Citocromo P-450 CYP2D6/deficiencia , Humanos , Errores Innatos del Metabolismo/metabolismo , FarmacocinéticaRESUMEN
Behçet's disease (BD) is a systemic autoimmune disorder. Cytochrome P450 enzymes (CYPs) are responsible for various drug metabolism reactions as well as those of endogenous substances which may be associated with autoimmune disease susceptibility. Recently, we reported that in patients with BD, CYP2C9 seems to be down-regulated due to inflammation. In the same Turkish patients with BD, we investigated whether also CYP2C19 activity is decreased. Lansoprazole (30 mg) was given as a probe drug to evaluate CYP2C19 activity in 59 patients with BD and 27 healthy control volunteers. An HPLC method was used to determine plasma lansoprazole and its metabolite, 5-hydroxy lansoprazole, concentrations. The genotyping for CYP2C19 *2, *3 and *17 polymorphisms was made using PCR-RFLP. The median lansoprazole/5-hydroxy lansoprazole metabolic ratio (MR) in patients with BD was 2.6-fold higher as compared to the healthy control group (p = 0.001, 22.6 (1.3-26) and 8.8 (0.5-140) as median and range, respectively). The CYP2C19*17*17 genotype frequency was found to be significantly less in the BD group as compared to the healthy controls (1.7% versus 14.8% in controls, p = 0.01). Additionally, colchicine treatment did not affect the CYP2C19 enzyme activity in six patients (p = 0.43). In conclusion, the patients with BD had lower CYP2C19 enzyme activity and lower frequency of the CYP2C19*17 allele as compared to those of the healthy controls. Further studies are warranted on the mechanisms underlying this relation. This study should also be applied to other autoimmune diseases similarly characterized by local or systemic inflammation.
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Síndrome de Behçet/enzimología , Síndrome de Behçet/genética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Polimorfismo Genético , 2-Piridinilmetilsulfinilbencimidazoles/sangre , Antiinflamatorios/farmacología , Síndrome de Behçet/sangre , Síndrome de Behçet/tratamiento farmacológico , Biotransformación , Estudios de Casos y Controles , Colchicina/uso terapéutico , Regulación hacia Abajo , Frecuencia de los Genes , Genotipo , Humanos , Hidroxilación , Lansoprazol/sangre , Fenotipo , Especificidad por Sustrato , TurquíaRESUMEN
Pantoprazole is a proton pump inhibitor that is commonly used in the treatment of peptic ulcer disease (PUD) and metabolized by cytochrome P450 (CYP) enzymes CYP2C19 and CYP3A4. Pantoprazole is a substrate for multi-drug resistance protein 1 (MDR1). Single nucleotide polymorphisms (SNPs) in CYP2C19, CYP3A4 and MDR1 affect enzyme activity or gene expression of proteins and may alter plasma pantoprazole concentrations and treatment success in PUD. In this study, we aimed to investigate the association between genetic polymorphisms in CYP2C19, CYP3A4 and MDR1 and pharmacokinetics of pantoprazole and therapeutic outcome in patients with either Helicobacter pylori-associated [H.P.(+)]-PUD or [H.P.(+)]-gastritis. The plasma pantoprazole concentrations were determined by using an HPLC method at the third hour after a 40-mg tablet of pantoprazole administration in 194 newly diagnosed patients with either [H.P.(+)]-PUD or [H.P.(+)]-gastritis. Genotyping was performed by using PCR-RFLP and DNA sequencing. Among patients appearing for follow-up examination (n = 105), the eradication rate for H. pylori was 82.8% (n = 87). The median pantoprazole plasma concentrations in poor metabolizers (PM), rapid metabolizers (RM) and ultrarapid metabolizers (URM) were 2.07, 1.69 and 1.28 µg/ml, respectively (p = 0.04). CYP3A4*1G and *22 polymorphisms did not affect plasma pantoprazole concentrations and H. pylori eradication rate. The MDR1 genetic polymorphisms did not affect plasma pantoprazole concentrations. MDR1 3435CC-2677GG-1236CC haplotype carriers had lower H. pylori eradication rate (60%) than the remaining subjects (84.9%) while the difference was not statistically significant (p = 0.07). In conclusion, while CYP2C19 genetic polymorphisms significantly affected plasma pantoprazole concentrations, polymorphisms of CYP2C19, CYP3A4 and MDR1 did not affect H. pylori eradication rates.
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2-Piridinilmetilsulfinilbencimidazoles/farmacocinética , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/efectos de los fármacos , Polimorfismo de Nucleótido Simple , Inhibidores de la Bomba de Protones/farmacocinética , 2-Piridinilmetilsulfinilbencimidazoles/administración & dosificación , 2-Piridinilmetilsulfinilbencimidazoles/sangre , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Administración Oral , Adulto , Biotransformación , Cromatografía Líquida de Alta Presión , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Monitoreo de Drogas/métodos , Femenino , Gastritis/tratamiento farmacológico , Gastritis/microbiología , Genotipo , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/microbiología , Humanos , Masculino , Pantoprazol , Úlcera Péptica/tratamiento farmacológico , Úlcera Péptica/microbiología , Farmacogenética , Fenotipo , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/sangre , Resultado del TratamientoRESUMEN
OBJECTIVES: Previous investigations on opioid system genetics have identified polymorphisms of the OPRM1 gene expressing µ-opioid receptors to be significantly associated with some features of alcohol dependence (AD). In the present study, we evaluated the relationship between single nucleotide polymorphisms (SNP) in the OPRM1 gene, A118G (rs1799971, Asn40Asp) and C17T (rs1799972, Arg6Val), and AD diagnosis, level of alcohol consumption, and AD severity in a Turkish sample. METHODS: 121 AD patients and 117 healthy male subjects were included in the study. OPRM1 A118G (N40D) and C17T (A6V) polymorphisms were evaluated using PCR - RFLP (polymerase chain reaction - restriction fragment length polymorphism) method. We evaluated the association between the presence of SNPs and AD diagnosis, family history of AD, AD severity evaluated via the Michigan Alcoholism Screening Test (MAST), the daily average and maximum quantity of alcohol consumed. RESULTS: There was no significant difference in OPRM1 A118G genotype frequencies between the AD and control groups. T allele frequency for the OPRM1 C17T SNP was very low (0.006) in the sample population. OPRM1 A118G SNP G118 allele carriers showed significantly higher levels of AD severity as indicated by the MAST. CONCLUSION: The OPRM1 G118 allele was significantly associated with more severe AD in the Turkish population. Similar to other European populations, the frequency of the OPRM1 T17 allele was very low.
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Alcoholismo/genética , Polimorfismo de Nucleótido Simple/genética , Receptores Opioides mu/genética , Adulto , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Humanos , Masculino , Turquía , Población Blanca/genéticaRESUMEN
BACKGROUND: We previously reported on a Swedish patient with Behçet's disease (BD) who was an ultra-rapid metaboliser of drugs catalysed by CYP2C9. Was this extreme metabolism caused by the disease? AIM: This study aims to compare the genotype/phenotype of CYP2C9 in patients with BD and healthy subjects. As the occurrence of BD is high in Turkey, all subjects were recruited from this country. METHODS: Genotyping of CYP2C9 was performed using standard PCR-RFLP and allele-specific PCR methods. Phenotyping of CYP2C9 was performed by administration of a 50-mg single oral dose of losartan and by calculating the urinary metabolic ratio (MR) of probe drug to its metabolite E-3174. Quantitation was performed by HPLC. RESULTS: The frequency of CYP2C9*2 and *3 was not significantly different between the Behçet's disease patients (12.5 and 8.7%) and the healthy subjects (8.9 and 8.2%). The geometric mean losartan MR was higher in the 52 patients (1.75) than in the 96 healthy subjects (1.02) (p = 0.002; t-test). Within the genotypes *1/*1, there was a significant difference of MR between patients and healthy subjects (P = 0.006). All but three of the Behçet's disease patients were treated with colchicine. In nine subsequent patients, we found no significant effect of 2 weeks of treatment with colchicine on the CYP2C9 MR. CONCLUSION: Contrary to expectation, the CYP2C9 activity was lower in Turkish BD patients compared to healthy subjects. As this seems not to be due to colchicine treatment, our hypothesis is that inflammation related to BD might have caused the down-regulation of the CYP2C9 activity due to immune cytokine reactions. The ultra-rapid metabolism of CYP2C9 substrate drugs in the Swedish patient was not due to her BD.
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Síndrome de Behçet/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Adulto , Anciano , Alelos , Síndrome de Behçet/tratamiento farmacológico , Cromatografía Líquida de Alta Presión , Colchicina/uso terapéutico , Citocinas/metabolismo , Regulación hacia Abajo , Femenino , Genotipo , Humanos , Imidazoles/orina , Inflamación/metabolismo , Losartán/farmacocinética , Masculino , Persona de Mediana Edad , Fenotipo , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple , Tetrazoles/orina , TurquíaRESUMEN
BACKGROUND: Polymorphisms in the genes encoding alcohol metabolizing enzymes are associated with alcohol dependence. AIM: To evaluate the association between the alcohol dehydrogenase 1C (ADH1C) Ile350Val and aldehyde dehydrogenase 2 (ALDH2) Glu504Lys polymorphisms and alcohol dependence in a Turkish sample. METHODS: 235 individuals (115 alcohol-dependent patients and 120 controls) were genotyped for ADH1C and ALDH2 with PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism). Association between the polymorphisms and family history, daily and maximum amount of alcohol consumed was investigated. The associations between alcohol dependence, severity of consumption and family history and the polymorphisms were analyzed by chi-square or Fisher's exact test where necessary. Relationship between genotypes and dependence related features was evaluated using analysis of variance (ANOVA). RESULTS: The -350Val allele for ADH1C (ADH1C*2) was increased in alcohol-dependent patients (P = 0.05). In individuals with a positive family history, the genotype distribution differed significantly (P = 0.031) and more patients carried the Val allele compared with controls (P = 0.025). Genotyping of 162 participants did not reveal the -504Lys allele in ALDH2. CONCLUSIONS: These findings suggest that ADH1C*2 is associated with alcohol dependence in the Turkish population displaying a dominant inheritance model. ADH1C*2 allele may contribute to the variance in heritability of alcohol dependence. The ALDH2 -504Lys/Lys or Glu/Lys genotypes were not present in alcohol-dependent patients, similar to that seen in European populations and in contrast to the findings in the Asian populations.
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Alcohol Deshidrogenasa/genética , Alcoholismo/genética , Aldehído Deshidrogenasa/genética , Etnicidad/genética , Adulto , Aldehído Deshidrogenasa Mitocondrial , Alelos , Pueblo Asiatico/genética , Estudios de Casos y Controles , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple , Turquía , Población Blanca/genéticaRESUMEN
Chemotherapy-induced nausea and vomiting (CINV) remains a major adverse effect decreasing quality of life in patients with cancer. Genetic variations among patients may be responsible for part of the lack of efficacy of anti-emetic drugs. The aim of this study was to investigate how the genetic variants of the drug transporter ABCB1 (MDR1) gene affect anti-emetic treatment with 5-HT3 receptor antagonists. Patients (n = 239) receiving moderately or highly emetogenic chemotherapy and ondansetron or granisetron were included in the study. Anti-emetic responses were recorded daily. The primary end-point of the assessment was the total control rates of CINV in the acute and delayed phases after chemotherapy. Genotyping was performed by PCR-RFLP. In the acute phase, patients with ABCB13435TT, 1236TT or 2677TT genotypes had a higher control rate of CINV than other genotype groups: (64.7% in 3435TT versus 45.7% in 3435CC+CT, p = 0.016; 65.1% in 1236TT versus 46.4% in 1236CC+CT, p = 0.027; 66.7% in 2677TT versus 46.5% in other genotypes, p = 0.021). Subjects carrying homozygous variant alleles together (TT-TT-TT) showed a significantly higher protection from nausea and vomiting (67.7% in TT-TT-TT versus 47.1% in other genotypes, p = 0.032). After the logistic regression analysis with adjustment for other known covariates, the total control rate was significantly higher in the 3435TT genotype group during the acute phase (p = 0.021). No significant change was found between the total control rates among genotypes in the delayed phase. Each of three 3435TT, C1236TT, 2677TT genotypes of ABCB1 and their combination was associated with about 50% higher anti-emetic response to 5-HT3 receptor antagonists in the acute phase of chemotherapy in patients with cancer receiving moderately or highly emetogenic chemotherapy. ABCB1 (MDR1) genotypes may contribute to predict the anti-emetic efficacy of 5-HT3 antagonists.
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Antieméticos/uso terapéutico , Neoplasias/complicaciones , Antagonistas del Receptor de Serotonina 5-HT3/uso terapéutico , Vómitos/inducido químicamente , Vómitos/tratamiento farmacológico , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Enfermedad Aguda , Adulto , Anciano , Alelos , Antineoplásicos/efectos adversos , Femenino , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Polimorfismo Genético/genética , Encuestas y CuestionariosRESUMEN
Scholarship knows no geographical boundaries. This science diplomacy and biotechnology journalism article introduces an original concept and policy petition to innovate the global translational science, a Science Peace Corps. Service at the new Corps could entail volunteer work for a minimum of 6 weeks, and up to a maximum of 2 years, for translational research in any region of the world to build capacity manifestly for development and peace, instead of the narrow bench-to-bedside model of life science translation. Topics for translational research are envisioned to include all fields of life sciences and medicine, as long as they are linked to potential or concrete endpoints in development, foreign policy, conflict management, post-crisis capacity building, and/or peace scholarship domains. As a new instrument in the global science and technology governance toolbox, a Science Peace Corps could work effectively, for example, towards elucidating the emerging concept of "one health"--encompassing human, environmental, plant, microbial, ecosystem, and planet health--thus serving as an innovative crosscutting pillar of 21(st) century integrative biology. An interdisciplinary program of this caliber for development would link 21(st) century life sciences to foreign policy and peace, in ways that can benefit many nations despite their ideological differences. We note that a Science Peace Corps is timely. The Intergovernmental Panel on Climate Change (IPCC) of the United Nations released the Fifth Assessment Report on March 31, 2014. Worrisomely, the report underscores that no person or nation will remain untouched by the climate change, highlighting the shared pressing life sciences challenges for global society. To this end, we recall that President John F. Kennedy advocated for volunteer work that has enduring, transgenerational, and global impacts. This culminated in establishment of the Peace Corps in 1961. Earlier, President Abraham Lincoln aptly observed, "nearly all men can stand adversity, but if you want to test a man's character, give him power." We therefore petition President Barack Obama, other world leaders, and international development agencies in positions of power around the globe, to consider deploying a Science Peace Corps to cultivate the essential (and presently missing) ties among life sciences, foreign policy, development, and peace agendas. A Science Peace Corps requires support by a credible and independent intergovernmental organization or development agency for funding, and arbitration in the course of volunteer work when the global versus local (glocal) value-based priorities and human rights intersect in synergy or conflict. In all, Science Peace Corps is an invitation to a new pathway for competence in 21(st) century science that is locally productive and globally competitive. It can open up scientific institutions to broader considerations and broader inputs, and thus cultivate vital translational science in a world sorely in need of solidarity and sustainable responses to the challenges of 21(st) century science and society.
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Biotecnología , Invenciones , Investigación Biomédica Traslacional , África , Humanos , Peace Corps , Investigación , Ciencia/tendencias , Estados UnidosRESUMEN
This article announces the recipient of the 2014 inaugural Werner Kalow Responsible Innovation Prize in Global Omics and Personalized Medicine by the Pacific Rim Association for Clinical Pharmacogenetics (PRACP): Bernard Lerer, professor of psychiatry and director of the Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. The Werner Kalow Responsible Innovation Prize is given to an exceptional interdisciplinary scholar who has made highly innovative and enduring contributions to global omics science and personalized medicine, with both vertical and horizontal (transdisciplinary) impacts. The prize is established in memory of a beloved colleague, mentor, and friend, the late Professor Werner Kalow, who cultivated the idea and practice of pharmacogenetics in modern therapeutics commencing in the 1950s. PRACP, the prize's sponsor, is one of the longest standing learned societies in the Asia-Pacific region, and was founded by Kalow and colleagues more than two decades ago in the then-emerging field of pharmacogenetics. In announcing this inaugural prize and its winner, we seek to highlight the works of prize winner, Professor Lerer. Additionally, we contextualize the significance of the prize by recalling the life and works of Professor Kalow and providing a brief socio-technical history of the rise of pharmacogenetics and personalized medicine as a veritable form of 21(st) century scientific practice. The article also fills a void in previous social science analyses of pharmacogenetics, by bringing to the fore the works of Kalow from 1995 to 2008, when he presciently noted the rise of yet another field of postgenomics inquiry--pharmacoepigenetics--that railed against genetic determinism and underscored the temporal and spatial plasticity of genetic components of drug response, with invention of the repeated drug administration (RDA) method that estimates the dynamic heritabilities of drug response. The prize goes a long way to cultivate transgenerational capacity and broader cognizance of the concept and practice of responsible innovation as an important criterion of 21(st) century omics science and personalized medicine. A new call is presently in place for the 2016 PRACP Werner Kalow prize. Nominations can be made in support of an exceptional individual interdisciplinary scholar, or alternatively, an entire research team, from any region in the world with a record of highly innovative contributions to global omics science and/or personalized medicine, in the spirit of responsible innovation. The application process is straightforward, requiring a signed, 1500-word nomination letter (by the applicant or sponsor) submitted not later than May 31, 2015.
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Distinciones y Premios , Genómica/historia , Farmacogenética/historia , Medicina de Precisión/historia , Alemania , Historia del Siglo XX , Historia del Siglo XXI , Humanos , IsraelRESUMEN
The importance of provision of growth factors in the engineering of tissues has long been shown to control the behavior of the cells within the construct and several approaches were applied toward this end. In nature, more than one type of growth factor is known to be effective during the healing of tissue defects and their peak concentrations are not always simultaneous. One of the most recent strategies includes the delivery of a combination of growth factors with the dose and timing to mimic the natural regeneration cascade. The sequential delivery of bone morphogenetic proteins BMP-2 and BMP-7 which are early and late appearing factors during bone regeneration, respectively, was shown in vitro to enhance osteoblastic differentiation of bone marrow derived mesenchymal stem cells. In the present study, the aim was to study the effectiveness of this delivery strategy in a rabbit iliac crest model. 3D plotted poly(ε-caprolactone) scaffolds were loaded with BMP carrying nanoparticles to achieve: (a) single BMP-2 or BMP-7 delivery, and (b) their combined delivery in a simultaneous or (c) sequential (biomimetic) fashion. After eight weeks of implantation, computed tomography and biomechanical tests showed better mineralized matrix formation and bone-implant union strength at the defect site in the case of sequential delivery compared to single or simultaneous delivery modes. Bone mineral density (BMD) and push-out stress were: 33.65±2.25 g cm(-3) and 14.5±2.28 MPa, respectively, and almost 2.5 fold higher in comparison to those without growth factors (BMD: 14.14±1.21 g cm(-3); PS: 6.59±0.65 MPa). This study, therefore, supports those obtained in vitro and emphasizes the importance of mimicking the natural timing of bioavailability of osteogenic factors in improving the regeneration of critical-sized bone defects.
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Regeneración Ósea/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Ilion/fisiología , Péptidos y Proteínas de Señalización Intercelular/administración & dosificación , Pelvis/fisiología , Andamios del Tejido , Animales , Materiales Biocompatibles/química , Células de la Médula Ósea/citología , Proteína Morfogenética Ósea 2/administración & dosificación , Proteína Morfogenética Ósea 7/administración & dosificación , Huesos/metabolismo , Masculino , Células Madre Mesenquimatosas/citología , Nanopartículas/química , Osteogénesis , Poliésteres/química , Presión , Conejos , Ratas , Ingeniería de Tejidos/métodos , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVES: Interindividual variability in glucuronidation of bilirubin and drugs by UDP-glucuronosyltransferase 1A1 (UGT1A1) is considerable and only partially explained by genetic polymorphisms and enzyme inducers. Here we determined whether a well-known epigenetic modification, cytosine methylation, explains a proportion of this variability in human liver. METHODS: UGT1A1 phenotypes, including UGT1A1 protein and bilirubin glucuronidation, and UGT1A1*28 genotype were determined using a human liver bank (n = 46). Methylation levels were quantified at 5 CpG sites associated with known transcription factor response elements in the UGT1A1 promoter and distal enhancer, as well as a CpG-rich island 1.5 kb further upstream. KEY FINDINGS: Individual CpG sites showed considerable methylation variability between livers, ranging from 10- to 29-fold variation with average methylation levels from 25 to 41%. Multivariate regression analysis identified *28/*28 genotype, -4 CpG site methylation and alcohol history as significant predictors of UGT1A1 protein content. Exclusion of livers with *28/*28 genotype or alcohol history revealed positive correlations of -4 CpG methylation with bilirubin glucuronidation (R = 0.73, P < 0.00001) and UGT1A1 protein content (R = 0.54, P = 0.008). CONCLUSION: These results suggest that differential methylation of the -4 CpG site located within a known USF response element may explain a proportion of interindividual variability in hepatic glucuronidation by UGT1A1.
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Metilación de ADN , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Hígado/enzimología , Hígado/fisiología , Adolescente , Adulto , Anciano , Bilirrubina/metabolismo , Niño , Preescolar , Islas de CpG/genética , Citosina/metabolismo , Epigénesis Genética/genética , Femenino , Genotipo , Humanos , Hígado/metabolismo , Masculino , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Persona de Mediana Edad , Fenotipo , Polimorfismo Genético , Regiones Promotoras Genéticas , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Adulto JovenRESUMEN
PURPOSE: This study was carried out to determine the ocular pharmacokinetics, efficacy and potential endothelial toxicity of moxifloxacin (MF) after a single intracameral bolus injection of 500 µg/0.1 ml in a rabbit model. MATERIALS AND METHODS: Forty-eight eyes of 24 New Zealand White Rabbits were separated into six groups, each including four rabbits. 0.1 ml of 0.5% intracameral moxifloxacin (500 µg) injection was injected to the right eyes and 0.1 ml of balanced salt solution to the left eyes (control). Aqueous humor (AH) and vitreous samples were collected at the 0.5th, 1st, 3rd, 6th, 12th and 24th hours from both eyes of group 1, 2, 3, 4, 5 and 6, respectively. MF concentrations were determined by high performance liquid chromatography. These were compared with the minimum inhibitory concentrations (MIC) and mutant prevention concentrations (MPC) for frequent endophthalmitis pathogens. Electron and light microscopical evaluation of the corneas were performed. RESULTS: Moxifloxacin reaches higher concentration than the MIC of all common endophthalmitis pathogens in the AH and exceeds the mutant prevention concentration levels for Streptococcus pneumonia, Streptococcus viridans, flouroquinolone susceptible Coagulase-negative staphylococcus and flouroquinolone susceptible Staphylococcus aureus for 6 h. The half-life of moxifloxacin in the AH was 2.2 h. Electron and light microscopic evaluation revealed no noticeable sign of toxicity. CONCLUSIONS: Peroperative intracameral moxifloxacin injection for endophthalmitis prophylaxis is a safe and effective method in uncomplicated phacoemulsification surgery.
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Antibacterianos/farmacocinética , Compuestos Aza/farmacocinética , Endoftalmitis/tratamiento farmacológico , Infecciones Bacterianas del Ojo/tratamiento farmacológico , Quinolinas/farmacocinética , Animales , Antibacterianos/farmacología , Antibacterianos/toxicidad , Humor Acuoso/efectos de los fármacos , Humor Acuoso/metabolismo , Compuestos Aza/farmacología , Compuestos Aza/toxicidad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Epitelio Corneal/efectos de los fármacos , Epitelio Corneal/metabolismo , Epitelio Corneal/ultraestructura , Fluoroquinolonas , Inyecciones Intraoculares , Microscopía Electrónica de Transmisión , Moxifloxacino , Facoemulsificación , Quinolinas/farmacología , Quinolinas/toxicidad , Conejos , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estreptocócicas/tratamiento farmacológico , Cuerpo Vítreo/efectos de los fármacos , Cuerpo Vítreo/metabolismoRESUMEN
AIM: Secondary brain injury starts after the initial traumatic impact and marked by an increase in the intracellular calcium concentrations.This cascadeeventually results in membrane lipid peroxidation and neuronal cell death. MATERIAL AND METHODS: We investigated the neuro-protective effects of nimodipine and melatonin in 38 rats after 6 hours of head trauma using the cortical impact injury model of Marmarou. RESULTS: Brain water in the melatonin-given group decreased significantly comparing to that of control group the brain water in the nimodipine given group increased significantly comparing to that of trauma group. Histopathologically, brain edema was significantly low in melatonin-administered group comparing to that of control group while there were no changes in brain edema in the nimodipine given group and in the group that both nimodipine and melatonin were administered in combination. MDA levels in the brain tissues were significantly lower in the melatonin and nimodipine groups comparing to those of trauma and control group however this difference was by far significant in melatonin group comparing to nimodipine group. CONCLUSION: Melatonin appears to have neuro-protective effects on the secondary brain damage while nimodipine and nimodipine plus melatonin combination did not show such neuro-protective effects on the secondary brain injury.
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Edema Encefálico/tratamiento farmacológico , Lesiones Encefálicas/tratamiento farmacológico , Melatonina/farmacología , Fármacos Neuroprotectores/farmacología , Nimodipina/farmacología , Animales , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Combinación de Medicamentos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
This study aimed at investigating the contribution of CYP2C9 and VKORC1 genetic polymorphisms to inter-individual variability of acenocoumarol pharmacokinetics and pharmacodynamics in Black Africans from Benin. Fifty-one healthy volunteers were genotyped for VKORC1 1173C>T polymorphism. All of the subjects had previously been genotyped for CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*9 and CYP2C9*11 alleles. Thirty-six subjects were phenotyped with a single 8 mg oral dose of acenocoumarol by measuring plasma concentrations of (R)- and (S)-acenocoumarol 8 and 24 h after the administration using chiral liquid-chromatography tandem mass-spectrometry. International normalized ratio (INR) values were determined prior to and 24 h after the drug intake. The allele frequency of VKORC1 variant (1173C>T) was 1.96% (95% CI 0.0-4.65%). The INR values did not show statistically significant difference between the CYP2C9 genotypes, but were correlated with body mass index and age at 24 h post-dosing (P < 0.05). At 8 h post dose, the (S)-acenocoumarol concentrations in the CYP2C9*5/*8 and CYP2C9*9/*11 genotypes were about 1.9 and 5.1 fold higher compared with the CYP2C9*1/*1 genotype and 2.2- and 6.0-fold higher compared with the CYP2C9*1/*9 group, respectively. The results indicated that pharmacodynamic response to acenocoumarol is highly variable between the subjects. This variability seems to be associated with CYP2C9*5/*8 and *9/*11 variant and demographic factors (age and weight) in Beninese subjects. Significant association between plasma (S)-acenocoumarol concentration and CYP2C9 genotypes suggested the use of (S)-acenocoumarol for the phenotyping purpose. Larger number of subjects is needed to study the effect of VKORC1 1173C>T variant due to its low frequency in Beninese population.