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BACKGROUND: Bafiertam® (monomethyl fumarate [MMF]) and Vumerity® (diroximel fumarate [DRF]) are two FDA approved drug products for the treatment of relapsing forms of multiple sclerosis (MS) to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Vumerity® is a prodrug of MMF which requires enzymatic conversion of DRF to the active drug MMF, the moiety responsible for the therapeutic efficacy; whereas Bafiertam® contains MMF, providing the active drug directly without any need for enzymatic conversion. OBJECTIVE: The objective of this study was to evaluate the pharmacokinetics and relative bioavailability of MMF from oral administration of two Bafiertam® capsules each containing 95 mg of MMF in comparison to two Vumerity® capsules each containing 231 mg of DRF, the therapeutic doses of each product. METHODS: This was a single-dose, open-label, randomized, 2-way crossover study evaluating two treatments over two periods with a washout interval between treatments. Forty-four healthy male or female subjects were planned to receive each of the two treatments to assure 40 completed dosing: a single dose of 2 × 95 mg Bafiertam® capsules and a single dose of 2 × 231 mg Vumerity® capsules under fasting conditions in a randomized crossover fashion. Blood samples were obtained prior to dosing and at prespecified time points through 24 h post-dose to determine plasma concentrations of MMF. MMF pharmacokinetic [PK] parameters were calculated and included maximum observed concentration (Cmax), time to reach Cmax (tmax), apparent half-life of MMF in plasma (t1/2), AUC0-t which is the area under the plasma concentration vs. time curve (AUC) from time zero (dosing time) to the last time point, t, with quantifiable MMF concentration, and AUC0-inf which is AUC0-t plus the extrapolated AUC from time t to infinity. RESULTS: Forty-one subjects completed the study as planned. MMF in Bafiertam® capsules was well and readily absorbed with a median tmax occurring at 4 h post dose, approximately 1 h later than that of Vumerity® capsules. However, the mean MMF Cmax from Bafiertam® (1969 ng/mL) was higher than that from Vumerity® (1121 ng/mL). The mean MMF AUC0-t and AUC0-inf from Bafiertam® (3503 and 3531 h*ng/mL) were also higher than those from Vumerity® (3123 and 3227 h*ng/mL), respectively. The geometric least-squares mean (GLSM) ratios (90% confidence interval), Bafiertam® vs. Vumerity®, for MMF Cmax, AUC0-t and AUC0-inf were 181.8 (158.2 - 208.8)%, 116.8 (107.9-126.5)% and 113.8 (105.3 - 123.0)%, respectively. Both products were safe and well tolerated, as expected, with flushing being the most common adverse event for both products. CONCLUSIONS: The mean MMF AUC0-t and AUC0-inf were 14-17% higher after administration of Bafiertam® as compared to Vumerity® at their respective therapeutic doses under fasting conditions, however, this difference was not statistically or clinically significant. Although more clinical studies would be needed before making strong recommendations, results of this study may help with selecting appropriate fumarate products, especially when administering the product with food is clinically recommended.
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Fumaratos , Adulto , Humanos , Masculino , Feminino , Disponibilidade Biológica , Estudos Cross-Over , Administração OralRESUMO
Frequent recombination is a hallmark of retrovirus replication. In rare cases, recombination occurs between distantly related retroviruses, generating novel viruses that may significantly impact viral evolution and public health. These recombinants may initially have substantial replication defects due to impaired interactions between proteins and/or nucleic acids from the two parental viruses. However, given the high mutation rates of retroviruses, these recombinants may be able to evolve improved compatibility of these viral elements. To test this hypothesis, we examined the adaptation of chimeras between two distantly related human pathogens: HIV-1 and HIV-2. We constructed HIV-1-based chimeras containing the HIV-2 nucleocapsid (NC) domain of Gag or the two zinc fingers of HIV-2 NC, which are critical for specific recognition of viral RNA. These chimeras exhibited significant defects in RNA genome packaging and replication kinetics in T cells. However, in some experiments, the chimeric viruses replicated with faster kinetics when repassaged, indicating that viral adaptation had occurred. Sequence analysis revealed the acquisition of a single amino acid substitution, S18L, in the first zinc finger of HIV-2 NC. This substitution, which represents a switch from a conserved HIV-2 residue to a conserved HIV-1 residue at this position, partially rescued RNA packaging and replication kinetics. Further analysis revealed that the combination of two substitutions in HIV-2 NC, W10F and S18L, almost completely restored RNA packaging and replication kinetics. Our study demonstrates that chimeras of distantly related retroviruses can adapt and significantly enhance their replication by acquiring a single substitution. IMPORTANCE Novel retroviruses can emerge from recombination between distantly related retroviruses. Most notably, HIV-1 originated from zoonotic transmission of a novel recombinant (SIVcpz) into humans. Newly generated recombinants may initially have significant replication defects due to impaired interactions between viral proteins and/or nucleic acids, such as between cis- and trans-acting elements from the two parental viruses. However, provided that the recombinants retain some ability to replicate, they may be able to adapt and repair the defective interactions. Here, we used HIV-1 and HIV-2 Gag chimeras as a model system for studying the adaptation of recombinant viruses. We found that only two substitutions in the HIV-2 NC domain, W10F and S18L, were required to almost fully restore RNA genome packaging and replication kinetics. These results illustrate the extremely flexible nature of retroviruses and highlight the possible emergence of novel recombinants in the future that could pose a significant threat to public health.
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HIV-1 , Humanos , HIV-1/metabolismo , HIV-2/genética , RNA Viral/metabolismo , Quimera/metabolismo , Sequência de Aminoácidos , Replicação Viral , Proteínas Virais/metabolismo , Montagem de Vírus , Genoma ViralRESUMO
The assessment in real-life conditions of the safety and efficacy of new antimalarial drugs is of greatest interest. This study aimed to monitor and evaluate both clinical and biological safety of pyronaridine-artesunate (PA) in real-life conditions in Burkina Faso's health system. This was a single-arm, open-label study, where patients attending Nanoro health facilities with uncomplicated malaria were consented to be part of a cohort event monitoring (CEM). At inclusion (day-0), PA was administered orally once a day for 3 days. Patients spontaneous reported any clinical adverse events (AEs) occurring within 28 days following the treatment. Additionally, the study focused on AEs of special interest (AESI), namely clinical signs related to hepatotoxicity and increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST). A nested subset of patients with blood sample collection at day-0 and day-7 were monitored to investigate the effect of PA on biochemistry parameters. From September 2017 to October 2018, 2786 patients were treated with PA. About 97.8% (2720/2786) of patients did not report any AE. The most commonly reported events were respiratory, thoracic, and mediastinal disorders (8.3 per 1000), infections and infestations (7.9 per 1000), and gastrointestinal disorders (7.2 per 1000). No clinical or biological hepatotoxicity event related to PA was reported during the follow-up. Changes in biochemistry parameters remained within laboratory reference ranges. The study showed that PA is a well-tolerated drug and should be considered as a good option by malaria control programs in countries where existing first-line antimalarial drugs are continuously threatened by the emergence of drug resistance.
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Antimaláricos , Artemisininas , Doença Hepática Induzida por Substâncias e Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Malária , Antimaláricos/efeitos adversos , Artemisininas/efeitos adversos , Artesunato , Burkina Faso/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Humanos , Malária/induzido quimicamente , Malária/tratamento farmacológico , Naftiridinas , Saúde da População RuralRESUMO
We identified a human embryonic stem cell subline that fails to respond to the differentiation cues needed to obtain endoderm derivatives, differentiating instead into extra-embryonic mesoderm. RNA-sequencing analysis showed that the subline has hyperactivation of the WNT and BMP4 signalling. Modulation of these pathways with small molecules confirmed them as the cause of the differentiation impairment. While activation of WNT and BMP4 in control cells resulted in a loss of endoderm differentiation and induction of extra-embryonic mesoderm markers, inhibition of these pathways in the subline restored its ability to differentiate. Karyotyping and exome sequencing analysis did not identify any changes in the genome that could account for the pathway deregulation. These findings add to the increasing evidence that different responses of stem cell lines to differentiation protocols are based on genetic and epigenetic factors, inherent to the line or acquired during cell culture.
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Proteína Morfogenética Óssea 4/genética , Diferenciação Celular/genética , Células-Tronco Embrionárias Humanas/fisiologia , Proteínas Wnt/genética , Proteína Morfogenética Óssea 4/metabolismo , Células Cultivadas , Endoderma/citologia , Endoderma/fisiologia , Membranas Extraembrionárias/citologia , Membranas Extraembrionárias/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Mesoderma/citologia , Mesoderma/fisiologia , Transdução de Sinais/genética , Transcriptoma , Proteínas Wnt/metabolismoRESUMO
BACKGROUND: Tecfidera® (dimethyl fumarate [DMF]) is an approved product for the treatment of relapsing forms of multiple sclerosis. Monomethyl fumarate (MMF) is the only active metabolite of DMF and is responsible for its therapeutic efficacy. OBJECTIVE: The objective of this study was to determine whether two Bafiertam™ capsules each containing 95 mg of MMF is bioequivalent to one Tecfidera® capsule containing 240 mg of DMF, a prodrug of MMF. METHODS: This was a single-dose, open-label, randomized, two-way crossover study evaluating two treatments over two periods with a washout interval between treatments. Fifty healthy subjects were randomized to receive a single dose of the test drug MMF 190 mg as 2 × 95 mg delayed-release capsules or the reference drug DMF 240 mg as a 1 × 240-mg delayed-release capsule. Blood samples were obtained prior to dosing and at prespecified time points through 24 h post-dose to determine plasma concentrations of MMF. The pharmacokinetic parameters of MMF were calculated including maximum observed concentration, time to reach maximum observed concentration, apparent half-life of the drug in plasma, AUC0-t which is the area under the plasma concentration-time curve (AUC) from time zero (dosing time) to the last time point, t, with measurable analyte concentration, and AUC0-inf, which is AUC0-t plus the extrapolated AUC from time t to infinity. RESULTS: The geometric least-squares mean ratios (90% confidence interval) of the test drug MMF vs the reference drug DMF were 96.80% (92.18-101.64), 96.35% (91.81-101.12), and 104.84% (95.54-115.05) for AUC0-t, AUC0-inf, and maximum observed concentration, respectively. Two capsules of Bafiertam™ was safe and generally well tolerated. The most common adverse event for both products was flushing, 60% and 51%, for Bafiertam™ and Tecfidera®, respectively. CONCLUSIONS: Based on the statistical analysis results of the pharmacokinetic parameters of MMF, a single oral dose of two Bafiertam™ DR 95 mg capsules is bioequivalent to a single oral dose of one Tecfidera® DR 240 mg capsule. CLINICAL TRIAL REGISTRATION: This study was retrospectively registered with ClinicalTrials.gov (NCT04570670) on 30 September, 2020.
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Fumarato de Dimetilo/administração & dosagem , Fumaratos/administração & dosagem , Imunossupressores/administração & dosagem , Administração Oral , Adulto , Área Sob a Curva , Disponibilidade Biológica , Cápsulas , Estudos Cross-Over , Preparações de Ação Retardada , Fumarato de Dimetilo/efeitos adversos , Fumarato de Dimetilo/farmacocinética , Feminino , Fumaratos/efeitos adversos , Fumaratos/farmacocinética , Meia-Vida , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Masculino , Pessoa de Meia-Idade , Equivalência TerapêuticaRESUMO
BACKGROUND: Monomethyl fumarate (MMF) is the pharmacologically active metabolite of dimethyl fumarate (DMF). MMF formulated as Bafiertam™ 190 mg and DMF formulated as Tecfidera 240 mg deliver bioequivalent exposure of MMF and therefore possess the same efficacy/safety profiles. DMF is a widely used oral treatment for relapsing-remitting forms of multiple sclerosis (RRMS) but is limited in some patients, primarily female, by issues with gastrointestinal (GI) tolerability. METHODS: This was a randomized, double-blind, head-to-head, 5-week study evaluating the GI tolerability of MMF 190 mg vs DMF 240 mg, administered twice daily in healthy subjects, using a derivative of the self-administered Modified Overall Gastrointestinal Symptom Scale (MOGISS). Subjects were stratified (3:1, female:male) and randomized (1:1) to the treatments. The primary endpoint was the Area Under the Curve (AUC) in each of the individual symptoms in the MOGISS over the 5-week treatment period. Other endpoints included the AUC over the 5-week treatment period in the MOGISS composite and total scores; duration and severity of GI events; Number and percentage of subjects reporting GI events during the overall treatment period, and assessment of safety/tolerability. RESULTS: Inferential analysis of the hierarchical testing of overall treatment differences in each MOGISS symptom AUC occurred in a predefined sequence starting with Abdominal Pain. For each symptom, LSMean AUC values were lower for MMF than DMF, however, the first primary endpoint, Abdominal Pain, was not statistically different between treatments; thus, all subsequent statistical analyses were considered exploratory. The side effects and safety profiles observed were consistent with the known profiles of DMF, with no new or unique safety concerns noted. CONCLUSIONS: Bafiertam showed an improved gastrointestinal tolerability profile compared with Tecfidera, with less severe GI events and fewer days of self-assessed GI symptoms, fewer GI adverse events, and lower discontinuation rates because of GI adverse events.
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Fumarato de Dimetilo , Esclerose Múltipla Recidivante-Remitente , Fumarato de Dimetilo/efeitos adversos , Feminino , Fumaratos/efeitos adversos , Humanos , Imunossupressores , MasculinoRESUMO
PURPOSE: In 2005, Burkina Faso changed its first-line treatment for uncomplicated malaria from chloroquine to artemisinin-based combination therapies (ACTs). Patient adherence to ACTs regimen is a keystone to achieve the expected therapeutic outcome and prevent the emergence and spread of parasite resistance. Eleven years after the introduction of ACTs in the health system, this study aimed to measure adherence level of patients in rural settlement and investigate the determinants of nonadherence. PATIENTS AND METHODS: The study was carried out at public peripheral health facilities from May 2017 to August 2017 in Nanoro health district, Burkina Faso. An electronic semi-structured questionnaire was used for data collection from patients with an ACT prescription at their medical consultation exit visit and during home visit at day 5±2. Adherence level was measured through self-report and pill counts. Logistic regression was performed to identify factors for nonadherence. RESULTS: The analysis was conducted on 199 outpatients who received ACT as prescription. About 92.5% of ACT prescriptions included artemether-lumefantrine tablets. Adherence level was measured in 97.0% of included patients at day 5±2. Of these, 86.0% were classified as "complete adherent" and 14.0% as "nonadherent". In univariate analysis, patients/caregivers who considered that affordability of ACTs was easy seemed to be less adherent to the treatment regimen (OR: 0.26; 95% CI: 0.07-0.70). In univariate and multivariable analyses, patients/caregivers who did not receive advices from health care workers (HCWs) were more likely to be nonadherent to the prescribed ACTs (adjusted OR: 3.21; 95% CI: 1.13-9.12). CONCLUSION: This study demonstrates that majority of those who get an ACT prescription comply with the recommended regimen. This emphasizes that in rural settings where ACTs are provided free of charge or at a subsidized price, patient adherence to ACTs is high, thus minimizing the risk of subtherapeutic concentrations of the drug in blood which is known to increase resistance and susceptibility to new infections. Therefore, to address the problem of patient nonadherence, strategy to strengthen communication between HCWs and patients should be given greater consideration.
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BACKGROUND: For hormone receptor-positive (HR+) human epidermal growth factor receptor 2 (HER2-) negative metastatic breast cancer (MBC), international guidelines recommend endocrine therapy as first-line treatment, except in case of 'visceral crisis'. In the latter case, chemotherapy is preferred. Few studies have compared these two strategies. We used the Epidemiological Strategy and Medical Economics (ESME) programme, UNICANCER, a large national observational database (NCT03275311), to address this question. METHODS: All patients who initiated treatment for a newly diagnosed HR+ HER2-negative MBC between January 2008 and December 2014 in any of the 18 French Comprehensive Cancer Centers participating to ESME were selected. Patients should be aromatase inhibitor (AI)-sensitive (no previous AI or relapse occurring more than 1 year after last adjuvant AI). Objectives of the study were evaluation of progression-free and overall survival (OS) according to the type of first-line treatment adjusted on main prognostic factors using a propensity score. RESULTS: Six thousand two hundred sixty-five patients were selected: 2733 (43.6%) received endocrine therapy alone, while 3532 (56.4%) received chemotherapy as first-line therapy. Among the latter, 2073 (58.7%) received maintenance endocrine therapy. Median OS was 60.78 months (95% confidence interval [CI], 57.16-64.09) and 49.64 months (95% CI, 47.31-51.64; p < 0.0001) for patients receiving endocrine therapy alone and chemotherapy ± maintenance endocrine therapy, respectively. However, this difference was not significant after adjusting on the propensity score (hazard ratio: 0.943, 95% CI 0.863-1.030, p = 0.19). CONCLUSION: In this large retrospective cohort of patients with AI-sensitive metastatic luminal BC, OS was similar, whether first-line treatment was chemotherapy or endocrine therapy. In agreement with international guidelines, endocrine therapy should be the first choice for first-line systemic treatment for MBC in the absence of visceral crisis.
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Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama Masculina/mortalidade , Neoplasias da Mama Masculina/patologia , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Metástase Neoplásica , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Análise de Sobrevida , Adulto JovemRESUMO
The derivation of gametes from patient-specific pluripotent stem cells may provide new perspectives for genetic parenthood for patients currently facing sterility. We use current data to assess the gamete differentiation potential of patient-specific pluripotent stem cells and to determine which reprogramming strategy holds the greatest promise for future clinical applications. First, we compare the two best established somatic cell reprogramming strategies: the production of induced pluripotent stem cells (iPSC) and somatic cell nuclear transfer followed by embryonic stem cell derivation (SCNT-ESC). Recent reports have indicated that these stem cells, though displaying a similar pluripotency potential, show important differences at the epigenomic level, which may have repercussions on their applicability. By comparing data on the genetic and epigenetic stability of these cell types during derivation and in-vitro culture, we assess the reprogramming efficiency of both technologies and possible effects on the subsequent differentiation potential of these cells. Moreover, we discuss possible implications of mitochondrial heteroplasmy. We also address the ethical aspects of both cell types, as well as the safety considerations associated with clinical applications using these cells, e.g. the known genomic instability of human PSCs during long-term culture. Secondly, we discuss the role of the stem cell pluripotency state in germ cell differentiation. In mice, success in germ cell development from pluripotent stem cells could only be achieved when starting from a naive state of pluripotency. It remains to be investigated if the naive state is also crucial for germ cell differentiation in human cells and to what extent human naive pluripotency resembles the naive state in mouse.
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Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Animais , Diferenciação Celular/fisiologia , Linhagem Celular , Células Cultivadas , Reprogramação Celular/fisiologia , Epigênese Genética/genética , Epigenômica , Células Germinativas/citologia , Células Germinativas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Mitocôndrias/metabolismo , Técnicas de Transferência NuclearRESUMO
PREMISE OF THE STUDY: Microsatellite primers (simple sequence repeats [SSRs]) were developed in Guibourtia ehie (Fabaceae, Detarioideae) to study population genetic structure and the history of African vegetation. METHODS AND RESULTS: We isolated 18 polymorphic SSRs from a nonenriched genomic library. This set of primer pairs was tested on four populations, and the results showed two to 16 alleles per locus with mean observed and expected heterozygosities of 0.27 ± 0.05 and 0.57 ± 0.05, respectively. Cross-amplification tests in 13 congeneric species were successful for the four taxa belonging to the subgenus Gorskia. CONCLUSIONS: This set of microsatellite markers will be useful to investigate the phylogeography and population genetics of G. ehie, a key representative of African semideciduous moist forests.
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PREMISE OF THE STUDY: Multiplexes of nuclear microsatellite primers were developed to investigate population genetic structure and diversity in two exploited African rainforest trees: Entandrophragma candollei and E. utile (Meliaceae). METHODS AND RESULTS: Microsatellite isolation was performed simultaneously on two nonenriched genomic libraries after next-generation sequencing. We developed 16 and 22 polymorphic markers for E. candollei and E. utile in three and four multiplexes, respectively. The number of alleles ranged from two to 17 for E. candollei and from three to 19 for E. utile. Mean expected and observed heterozygosity ranged between 0.75 ± 0.13 and 0.55 ± 0.23 for E. candollei and between 0.73 ± 0.10 and 0.49 ± 0.2 for E. utile. CONCLUSIONS: These sets of nuclear microsatellite markers constitute useful tools for exploring gene flow patterns in these two Entandrophragma species.
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BACKGROUND: Effective treatment of acromegaly with pegvisomant (PEGV), a growth hormone receptor antagonist, requires an appropriate dose titration. PEGV doses vary widely among individual patients, and various covariates may affect its dosing and pharmacokinetics. OBJECTIVE: To identify predictors of the PEGV dose required to normalize insulin-like growth factor I (IGF-I) levels during PEGV monotherapy and in combination with long-acting somatostatin analogues (LA-SSAs). DESIGN: Two retrospective cohorts (Rotterdam + Liège Acromegaly Survey (LAS), total n = 188) were meta-analyzed as a form of external replication to study the predictors of PEGV dosing in addition to LA-SSA, the LAS (n = 83) was used to study the predictors of PEGV monotherapy dosing. Multivariable regression models were used to identify predictors of the PEGV dose required to normalize IGF-I levels. RESULTS: For PEGV dosing in combination with LA-SSA, IGF-I levels, weight, height and age, were associated with the PEGV normalization dosage (P ≤ 0.001, P ≤ 0.001, P = 0.028 and P = 0.047 respectively). Taken together, these characteristics predicted the PEGV normalization dose correctly in 63.3% of all patients within a range of ±60 mg/week (21.3% within a range of ±20 mg/week). For monotherapy, only weight was associated with the PEGV normalization dose (P ≤ 0.001) and predicted this dosage correctly in 77.1% of all patients within a range of ±60 mg/week (31.3% within a range of ±20 mg/week). CONCLUSION: In this study, we show that IGF-I levels, weight, height and age can contribute to define the optimal PEGV dose to normalize IGF-I levels in addition to LA-SSA. For PEGV monotherapy, only the patient's weight was associated with the IGF-I normalization PEGV dosage.
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Acromegalia/tratamento farmacológico , Hormônio do Crescimento Humano/análogos & derivados , Modelos Biológicos , Somatostatina/análogos & derivados , Somatostatina/administração & dosagem , Acromegalia/sangue , Adulto , Quimioterapia Combinada , Feminino , Hormônio do Crescimento Humano/administração & dosagem , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Treatment of acromegaly with monotherapy long-acting somatostatin analogues (LA-SSA) as primary treatment or after neurosurgery can only achieve complete normalization of insulin-like growth factor I (IGF-I) in roughly 40 % of patients. Recently, one of the acromegaly consensus groups has recommended switching to combined treatment of LA-SSA and pegvisomant (PEGV) in patients with partial response to LA-SSAs. This combination of LA-SSA and PEGV, a growth hormone receptor antagonist, can normalize IGF-I levels in virtually all patients, requiring that the adequate dose of PEGV is used. The required PEGV dose varies significantly between individual acromegaly patients. One of the advantages of the combination therapy is that tumor size control or even tumor shrinkage can be observed in a vast majority of patients. The main side effects of the combination treatment are gastrointestinal symptoms, lipohypertrophy and transient elevated liver transaminases. In this review we provide an overview of the efficacy and safety of the combined treatment of LA-SSAs with PEGV.
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Acromegalia/tratamento farmacológico , Hormônio do Crescimento Humano/análogos & derivados , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Quimioterapia Combinada , Hormônio do Crescimento Humano/farmacologia , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Tamanho do Órgão/efeitos dos fármacos , Hipófise/efeitos dos fármacos , Qualidade de Vida , Somatostatina/farmacologia , Resultado do TratamentoRESUMO
BACKGROUND: Doses of the GH receptor (GHR) antagonist pegvisomant (PEGV) that normalize insulin-like growth factor 1 (IGF1) levels vary widely among acromegaly patients. Predictors for PEGV response are baseline IGF1 levels, sex, body weight and previous radiotherapy. A GHR polymorphism lacking exon 3 (d3-GHR) is frequent in the general population. The influence of d3-GHR on PEGV responsiveness in acromegaly is unclear. OBJECTIVE: To assess the influence of d3-GHR on IGF1 levels and PEGV responsiveness in acromegaly patients using combined PEGV and long-acting somatostatin receptor ligand (LA-SRIF) treatment. DESIGN: Data were collected at the Rotterdam Pituitary Centre between 2004 and 2013. Patients with elevated IGF1 levels (>1.2 upper limit of normal; n=112) and over 6 months of high-dose LA-SRIF treatment were co-treated with PEGV. GHR genotype was assessed using genomic DNA in 104 patients. RESULTS: D3-GHR was observed in 51 (49.0%) of the patients (7.7% homozygous, 41.3% heterozygous) and was in Hardy-Weinberg equilibrium (P=0.859). Baseline characteristics were similar in d3-GHR and full-length (fl)-GHR genotypes. During PEGV/LA-SRIF treatment IGF1 levels were not different between d3-carriers and non-carriers. Similarly, no difference in PEGV dose required to normalize IGF1 (P=0.337) or PEGV serum levels (P=0.433) was observed between the two groups. However, adenoma size decreased significantly (>20% of largest diameter) in 25.6% of the fl-GHR genotype but only in 7.5% of d3-carriers (P=0.034, OR: 4.6 (CI: 1.1-18.9)). CONCLUSIONS: GHR genotype does not predict the IGF1 normalizing dose of PEGV in acromegaly patients using combination PEGV/LA-SRIF treatment. However, fewer d3-carriers showed significant reductions in adenoma size.
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Acromegalia/tratamento farmacológico , Adenoma/tratamento farmacológico , Hormônio do Crescimento Humano/análogos & derivados , Fator de Crescimento Insulin-Like I/metabolismo , Proteínas de Membrana/genética , Neoplasias Hipofisárias/tratamento farmacológico , Somatostatina/farmacologia , Adulto , Preparações de Ação Retardada , Quimioterapia Combinada , Éxons , Feminino , Hormônio do Crescimento Humano/farmacologia , Humanos , Masculino , Proteínas de Membrana/antagonistas & inibidores , Pessoa de Meia-Idade , Somatostatina/análogos & derivados , Resultado do TratamentoRESUMO
BACKGROUND: Treatment for acromegaly patients with long-acting somatotropin release-inhibiting factor (LA-SRIF) often does not result in complete normalization of IGF-1. Addition of pegvisomant (PEGV), a GH receptor antagonist, could improve this; however, the literature has not described long-term follow-up. OBJECTIVE: To assess long-term efficacy and safety of this combined treatment in the largest current single-center cohort of patients, from 2004-2013. DESIGN: Acromegaly patients were treated for at least 6 months with a high-dose LA-SRIF. To patients with persistently elevated IGF-1 levels (>1.2 × upper limit of normal) or poor quality of life, PEGV was added as one weekly injection. RESULTS: The patients (n = 141) were treated with PEGV and LA-SRIFs for a median period of 4.9 years (range, 0.5-9.2). Efficacy, defined as the lowest measured IGF-1 level during treatment, was 97.0%. The median PEGV dose to achieve this efficacy was 80 mg weekly (interquartile range, 60-120 mg). Combination treatment-related adverse events were recorded in 26 subjects (18.4%). Pituitary tumor size increase was observed in one patient. Injection-site reactions were observed in four subjects. In 19 patients (13.5%), transiently elevated liver transaminases of more than three times the upper limit of normal were observed, of which 83% occurred within the first year of combination treatment. Eight patients died, at a mean age of 71 years; none of them were considered treatment-related. CONCLUSIONS: The combination treatment with LA-SRIFs and PEGV was effective in 97% of the patients, it appears to be a safe medical treatment and it reduces the required dose of PEGV.
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Acromegalia/tratamento farmacológico , Hormônio do Crescimento Humano/análogos & derivados , Somatostatina/análogos & derivados , Acromegalia/etiologia , Acromegalia/genética , Adulto , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Seguimentos , Glucuronosiltransferase/genética , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/efeitos adversos , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Receptores da Somatotropina/antagonistas & inibidores , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Centros de Atenção Terciária , Tempo , Resultado do TratamentoRESUMO
We present a technique for the multi-sensor registration of featureless datasets based on the photogrammetric tracking of the acquisition systems in use. This method is developed for the in situ study of cultural heritage objects and is tested by digitizing a small canvas successively with a 3D digitization system and a multispectral camera while simultaneously tracking the acquisition systems with four cameras and using a cubic target frame with a side length of 500 mm. The achieved tracking accuracy is better than 0.03 mm spatially and 0.150 mrad angularly. This allows us to seamlessly register the 3D acquisitions and to project the multispectral acquisitions on the 3D model.
RESUMO
UNLABELLED: In nonalcoholic steatohepatitis (NASH), the extent of hepatocyte apoptosis correlates with disease severity. Reducing hepatocyte apoptosis with the selective caspase inhibitor GS-9450 has a potential for altering the course of the liver disease. In this phase 2, double-blind study, 124 subjects with biopsy-proven NASH were randomized to once-daily placebo or 1, 5, 10, or 40 mg GS-9450 for 4 weeks. Absolute and percent changes from baseline in ALT levels, AST levels, and caspase-3-cleaved cytokeratin (CK)-18 fragments at week 4 were assessed by an analysis of covariance model with adjustment for baseline values. In the 40-mg group, mean (SD) ALT decreased by 47 (43) U/L from baseline to week 4 (P < 0.0001 versus placebo), and the proportion of subjects with normal ALT increased from 0% to 35% at week 4. In the 40-mg group, mean AST decreased by 13 U/L from baseline (not significant), and the proportion with normal AST increased from 20% at baseline to 48% at week 4. By week 4, mean CK-18 fragment levels had decreased to 393 (723) U/L in the GS-9450 10-mg group and 125 (212) U/L in the 40-mg group, but these reductions were not statistically significant. No serious adverse events were reported during treatment, and the percentage of subjects with at least one treatment-emergent grade 3 or 4 laboratory abnormality ranged from 11.5% to 17% across the GS-9450 treatment groups versus 35% in the placebo group. CONCLUSION: GS-9450 treatment induced significant reductions in ALT levels in NASH patients. Reductions in CK-18 fragment levels also occurred, although they were not statistically significant. At appropriate therapeutic indices, selective caspase inhibitors may be a promising treatment option in patients with NASH.
Assuntos
Inibidores de Caspase , Fígado Gorduroso/tratamento farmacológico , Adulto , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Método Duplo-Cego , Fígado Gorduroso/sangue , Feminino , Humanos , Queratina-18/sangue , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
The unexpected diversity of exoplanets includes a growing number of super-Earth planets, i.e., exoplanets with masses of up to several Earth masses and a similar chemical and mineralogical composition as Earth. We present a thermal evolution model for a 10 Earth-mass planet orbiting a star like the Sun. Our model is based on the integrated system approach, which describes the photosynthetic biomass production and takes into account a variety of climatological, biogeochemical, and geodynamical processes. This allows us to identify a so-called photosynthesis-sustaining habitable zone (pHZ), as determined by the limits of biological productivity on the planetary surface. Our model considers solar evolution during the main-sequence stage and along the Red Giant Branch as described by the most recent solar model. We obtain a large set of solutions consistent with the principal possibility of life. The highest likelihood of habitability is found for "water worlds." Only mass-rich water worlds are able to realize pHZ-type habitability beyond the stellar main sequence on the Red Giant Branch.
Assuntos
Evolução Planetária , Meio Ambiente Extraterreno , Origem da Vida , Planetas , Sistema Solar , Temperatura , ÁguaRESUMO
OBJECTIVES: To evaluate the pharmacodynamics and safety of escalating doses of amdoxovir (DAPD) monotherapy administered to treatment-naive and experienced HIV-1-infected patients over 15 days. DESIGN: Ninety patients with plasma HIV-1 RNA levels between 5000 and 250,000 copies/ml were randomized to DAPD 25, 100, 200, 300 or 500 mg twice daily or 600 mg once daily monotherapy [antiretroviral therapy (ART)-naive and ART-experienced] or to add DAPD 300 or 500 mg twice daily to existing ART. After 15 days of dosing, patients were followed for an additional 7 days. METHODS: Antiviral activity was compared between treatment arms using log10 HIV-1 RNA based on average area under the curve minus baseline to day 15. Safety and tolerability was analyzed by incidence of grade 1 to 4 clinical and laboratory adverse events. RESULTS: In ART-naive patients receiving short-term DAPD monotherapy, a median reduction in plasma HIV-1 RNA of 1.5 log10 copies/ml at the highest doses was observed. In ART-experienced patients, the reduction in viral load observed at each dose was less than that observed in treatment-naive patients (reduction of 0.7 log10 at 500 mg twice daily). The incidence of adverse events was similar across groups with the majority of adverse events reported as mild or moderate in severity. Steady-state plasma concentrations of DAPD and dioxolane guanosine followed linear kinetics. CONCLUSIONS: DAPD was well tolerated and produced antiviral activity in treatment-naive and in some treatment-experienced patients. In ART-experienced patients, the antiviral activity was significant in those with no thymidine-analogue mutations and higher baseline CD4+ cell counts.
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Fármacos Anti-HIV/administração & dosagem , Dioxolanos/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1 , Nucleosídeos de Purina/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/sangue , Terapia Antirretroviral de Alta Atividade , Dioxolanos/efeitos adversos , Dioxolanos/sangue , Relação Dose-Resposta a Droga , Feminino , Genótipo , Infecções por HIV/sangue , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Mutação , Nucleosídeos de Purina/efeitos adversos , Nucleosídeos de Purina/sangue , RNA Viral/sangue , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/sangue , Resultado do TratamentoRESUMO
Emtricitabine (FTC) is a potent deoxycytidine nucleoside analogue that was recently approved for the treatment of HIV infection. Emtricitabine is activated by intracellular phosphorylation to its 5'-triphosphate (FTC5'-TP), a competitive inhibitor of the HIV reverse transcriptase (RT). Early clinical studies incorporating pharmacokinetic-pharmacodynamic (PK-PD) analyses provided a sound rationale for developing FTC as a once daily drug. A short-term open-label monotherapy trial in therapy naive HIV-infected subjects evaluated various dosage regimens of FTC, i.e., 25, 100, and 200 mg qd and/or bid, with serial measurements of plasma HIV RNA, plasma FTC, and intracellular (PBMC) FTC-5'-TP levels over the 14 days of treatment. PK data were augmented by other steady-state studies, one in healthy volunteers and the other in HIV-infected patients receiving 200 mg FTC qd, with measurements of plasma FTC and/or intracellular FTC-5'-TP levels. Correlation between anti-HIV activity and FTC-5'-TP levels was examined with dose- and concentration-response relationships determined. The once daily dosing schedule is supported by the relatively long half-lives of plasma FTC (8-10 hr) and PBMC FTC-TP (39 hr) and the high plasma FTC and PBMC FTC-5'-TP concentrations. HIV RNA suppression (PD) correlates well with PBMC FTC-5'-TP levels (PK), both reaching a plateau at doses > or = 200 mg/day. The PK and PD characteristics of FTC demonstrate that it is a once daily nucleoside RT inhibitor.