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Selective catalytic reduction of nitrogen oxides with NH3 at low temperatures remains a key goal for industrial applications. However, effective catalysts operating at 90 oC are rarely reported, limiting SCR scenarios to high-temperature conditions. Herein, we report a unique MnO2 nanofilament catalyst grown on activated semi-coke synthesized via a one-step in situ hydrothermal approach, which exhibits a stable and marked 100% conversion rate of NO to N2 with 100% selectivity at 90 oC, superior to the other prepared structures (nanowires, nanorods, and nanotubes). Temperature-programmed desorption shows a large number of acid sites on MnO2(NFs)/ASC, benefiting the formation of NH4+ ions. Meanwhile, diffuse reflectance infrared Fourier transform spectroscopy reveals the activation of NO with O2 to form bidentate nitrate/bridging nitrate NO2 intermediates via bidentate nitrate species, triggering the Fast SCR with NH3 at low temperatures. Such an effective, easy-to-prepare, and low-cost catalyst paves a new pathway for low-temperature SCR for a wide range of application scenarios.
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Cholesteryl ester transfer protein (CETP) inhibitor is a target for both lowering low-density lipoproteins and raising high-density lipoproteins. Anacetrapib was the lead compound in our cholesteryl ester transfer protein inhibitor program. Preclinical studies were initiated to support the safety of anacetrapib deposition in adipose tissue, followed by a clinical trial to evaluate the effects of anacetrapib in people with vascular disease. An ultra-high performance liquid chromatography/tandem mass spectrometry method was developed to determine tissue anacetrapib concentrations in the adipose of three animal species and humans. The assays were validated in the concentration ranges of 5-5000 ng/ml and 0.1-100 µg/ml. The anacetrapib concentrations in adipose tissue from preclinical and clinical studies were determined.
[Box: see text].
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BACKGROUND: Clesrovimab (MK-1654) is an investigational, half-life extended human monoclonal antibody (mAb) against RSV F glycoprotein in clinical trials as a prophylactic agent against RSV infection for infants. METHODS: This adult study measured clesrovimab concentrations in the serum and nasal epithelial lining fluid (ELF) to establish the partitioning of the antibody after dosing. Clesrovimab concentrations in the nasal ELF were normalized for sampling dilution using urea concentrations from ELF and serum. Furthermore, in vitro RSV neutralization of human nasal ELF following dosing was also measured to examine the activity of clesrovimab in the nasal compartment. FINDINGS: mAbs with YTE mutations are reported in literature to partition â¼1-2 % of serum antibodies into nasal mucosa. Nasal: serum ratios of 1:69-1:30 were observed for clesrovimab in two separate adult human trials after urea normalization, translating to 1.4-3.3 % of serum concentrations. The nasal PK and estimates of peripheral volume of distribution correlated with higher extravascular distribution of clesrovimab. These higher concentration of the antibody in the nasal ELF corroborated with the nasal sample's ability to neutralize RSV ex vivo. An overall trend of decreased viral plaque AUC was also noted with increasing availability of clesrovimab in the nasal ELF from a human RSV challenge study. INTERPRETATION: Along with its extended half-life, the higher penetration of clesrovimab into the nasal epithelial lining fluid and the associated local increase in RSV neutralization activity could offer infants better protection against RSV infection.
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Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Humanos , Adulto , Anticuerpos Monoclonales/uso terapéutico , Semivida , Anticuerpos Antivirales , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , UreaRESUMEN
Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.
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Epilepsia/genética , Genes Recesivos , Mutación con Pérdida de Función/genética , Oxidorreductasas/genética , Uridina Difosfato Glucosa Deshidrogenasa/genética , Adolescente , Alelos , Animales , Niño , Preescolar , Femenino , Humanos , Lactante , Cinética , Masculino , Organoides/patología , Oxidorreductasas/química , Linaje , Dominios Proteicos , Síndrome , Pez CebraRESUMEN
Hepatocellular carcinoma (HCC) is one of the most severe cancer types and many genetic and environmental factors contribute to the development of HCC. Androgen receptor (AR) signaling is increasingly recognized as one of the important factors associated with HCC. Previously, we have developed an inducible HCC model in kras transgenic zebrafish. In the present study, to investigate the role of AR in liver tumor development, we specifically knocked out ar gene in the liver of zebrafish via the CRISPR/Cas9 system and the knockout zebrafish was named L-ARKO for liver-specific ar knockout. We observed that liver-specific knockout of ar attenuated liver tumor development in kras transgenic zebrafish at the early stage (one week of tumor induction). However, at the late stage (two weeks of tumor induction), essentially all kras transgenic fish continue to develop HCC irrespective of the absence or presence of ar gene, indicating an overwhelming role of the driver oncogene kras over ar knockout. Consistently, cell proliferation was reduced at the early stage, but not the late stage, of liver tumor induction in the kras/L-ARKO fish, indicating that the attenuant effect of ar knockout was at least in part via cell proliferation. Furthermore, androgen treatment showed acceleration of HCC progression in kras fish but not in kras/L-ARKO fish, further indicating the abolishment of ar signalling. Therefore, we have established a tissue-specific ar knockout zebrafish and it should be a valuable tool to investigate AR signalling in the liver in future.
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Carcinogénesis/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Hígado/metabolismo , Receptores Androgénicos/genética , Proteínas de Pez Cebra/genética , Pez Cebra/genética , Animales , Animales Modificados Genéticamente , Proliferación Celular/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Técnicas de Inactivación de Genes , Masculino , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptores Androgénicos/metabolismo , Proteínas de Pez Cebra/metabolismoRESUMEN
Hepatocellular carcinoma (HCC) shows clear sex disparity with men being more prone to developing HCC and having higher mortality than women. Previous studies have indicated that sex hormones play important roles in HCC initiation and development, but the effects of sex hormones on HCC in clinical trials remain inconsistent. Using zebrafish liver tumor model co-induced by oncogenes Myc and xmrk, we observed similar sex disparity between male and female zebrafish in liver tumor progression and regression; i.e. male Myc/xmrk transgenic zebrafish developed HCC significantly faster and regressed HCC significantly slower than female Myc/xmrk transgenic zebrtafish. To investigate the effects of sex hormones on liver tumor progression and regression, Myc/xmrk fish were treated with either androgen or estrogen, we observed that androgen promoted HCC progression and retarded HCC regression in females, while estrogen attenuated HCC progression and accelerated HCC regression in males. Furthermore, androgen promoted cell proliferation while estrogen inhibited it. Overall, the present study suggested that sex hormones affected liver tumor progression and regression in the Myc/xmrk transgenic zebrafish.
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Progresión de la Enfermedad , Hormonas Esteroides Gonadales/farmacología , Neoplasias Hepáticas/patología , Oncogenes , Proteínas de Pez Cebra/metabolismo , Pez Cebra/genética , Animales , Animales Modificados Genéticamente , Carcinoma Hepatocelular/patología , Proliferación Celular/efectos de los fármacos , Femenino , Masculino , Caracteres Sexuales , Proteínas de Pez Cebra/genéticaRESUMEN
Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is mainly due to genetic changes in hepatocytes. However, molecular expression in hepatocytes during hepatocarcinogenesis has not been characterized. In this study, using an inducible kras transgenic zebrafish models for HCC, transcriptomic profiles of oncogenic hepatocytes from larvae, male and female adult fish following a brief induction of oncogenic kras were investigated. We found that oncogenic hepatocytes from all the three sources possess most of the cancer hallmarks at molecular level, including Sustaining proliferative signaling, Evading growth suppressors, Resisting cell death, Avoiding immune destruction, Inflammation, Reprogramming of energy metabolism, Angiogenesis, and Activating invasion and metastasis, suggesting the malignant transformation at molecular level could occur at the early stage of hepatocarcinogensis and can be captured in hepatocytes. However, each group of oncogenic hepatocytes also had their own characteristics. Larval oncogenic hepatocytes have cancer stem cell features. Female oncogenic hepatocytes showed resemblance to a mild human HCC subtype while male oncogenic hepatocytes resembled a severe HCC subtype, consistent with the observed sex disparity of HCC in both zebrafish and human. Finally, the two adult groups were more similar to each other than to the larval group, indicating an overwhelming effect of development over the gender.
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Carcinogénesis/genética , Carcinoma Hepatocelular/genética , Hepatocitos/patología , Neoplasias Hepáticas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas de Pez Cebra/genética , Pez Cebra/genética , Animales , Animales Modificados Genéticamente/genética , Carcinogénesis/patología , Carcinoma Hepatocelular/patología , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Hepatocitos/metabolismo , Neoplasias Hepáticas/patología , Masculino , Mutación Puntual , TranscriptomaRESUMEN
We have previously demonstrated the pro-tumoral role of neutrophils using a kras-induced zebrafish hepatocarcinogenesis model. To further illustrate the molecular basis of the pro-tumoral role, Tumor-associated neutrophils (TANs) were isolated by fluorescence-activated cell sorting (FACS) and transcriptomic analyses were carried out by RNA-Seq. Differentially expressed gene profiles of TANs from larvae, male and female livers indicate great variations during liver tumorigenesis, but the common responsive canonical pathways included an immune pathway (Acute Phase Response Signaling), a liver metabolism-related pathway (LXR/RXR Activation) and Thrombin Signaling. Consistent with the pro-tumoral role of TANs, gene module analysis identified a consistent down-regulation of Cytotoxicity module, which may allow continued proliferation of malignant cells. Gene Set Enrichment Analysis indicated up-regulation of several genes promoting angiogenesis. Consistent with this, we found decreased density of blood vessels accompanied with decreased oncogenic liver sizes in neutrophil-depleted larvae. Collectively, our study has indicated some molecular mechanisms of the pro-tumoral roles of TANs in hepatocarcinogenesis, including weakened immune clearance against tumor cells and enhanced function in angiogenesis.
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Carcinogénesis/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas Experimentales/irrigación sanguínea , Neoplasias Hepáticas Experimentales/genética , Neovascularización Patológica/genética , Neutrófilos/patología , Transcriptoma , Animales , Carcinogénesis/patología , Perfilación de la Expresión Génica , Humanos , Neoplasias Hepáticas Experimentales/patología , Ratones , Neutrófilos/metabolismo , Transducción de Señal , Pez CebraRESUMEN
Environmental pollutants may cause adverse effects on the immune system of aquatic organisms. However, the cellular effects of pollutants on fish immune system are largely unknown. Here, we exploited the transgenic zebrafish Tg(lysC:DsRed2) larva as a preliminary screening system to evaluate the potential inflammatory effects of environmental pollutants. Tg(lysC:DsRED2) larvae aged 7-day-postfertilization (7 dpf) were treated with selected environmental chemicals for 24â¯h (24â¯h) and the number of neutrophils were quantified using both image analysis and fluorescence activated cell sorting (FACS). We found that the numbers of neutrophils in the Tg(lysC:DsRED2) larvae were significantly increased by most of the organic chemicals tested, including E2 (17ß-estradiol), BPA (Bisphenol-A), NDEA (N-nitrosodiethylamine), 4-NP (4-Nitrophenol) and Lindane (γ-hexachlorocyclohexane). Neutrophil numbers were also increased by all the metals tested (Na2HAsO4· 7H2O, Pb(NO3)2, HgCl2, CdCl2, CuSO4·5H2O, ZnSO4, and K2Cr2O7). The only exception was TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), which significantly reduced the number of neutrophils after exposure. Additionally, the transcription of genes (lyz, mpo, tnfα and il8) related to fish immune system were significantly modulated upon exposure to some of the selected chemicals such as E2, TCDD, Cu and Cd. This study revealed that representatives of major categories of environmental pollutants could cause an acute inflammatory response in zebrafish larvae as shown by alterations in the neutrophils, which may imply a common immunotoxicity mechanism for most environmental pollutants. This study has also demonstrated that Tg(lyz:DsRed2) transgenic zebrafish is an excellent tool for screening environmental chemicals with potential inflammatory effects through FACS-facilitated neutrophil counting.
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Contaminantes Ambientales/toxicidad , Neutrófilos/metabolismo , Pez Cebra/inmunología , Animales , Animales Modificados Genéticamente , Modelos Animales de Enfermedad , Exposición a Riesgos Ambientales/análisis , Regulación de la Expresión Génica/efectos de los fármacos , Inmunidad Celular/efectos de los fármacos , Inflamación/patología , Larva/efectos de los fármacos , Larva/genética , Larva/inmunología , Neutrófilos/efectos de los fármacos , Reproducibilidad de los Resultados , Transcripción Genética/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Pez Cebra/genéticaRESUMEN
Previously we have generated inducible liver tumor models by transgenic expression of an oncogene and robust tumorigenesis can be rapidly induced by activation of the oncogene in both juvenile and adult fish. In the present study, we aimed at chemical intervention of tumorigenesis for understanding molecular pathways of tumorigenesis and for potential development of a chemical screening tool for anti-cancer drug discovery. Thus, we evaluated the roles of several major signaling pathways in krasV12- or Myc-induced liver tumors by using several small molecule inhibitors: SU5402 and SU6668 for VEGF/FGF signaling; IWR1 and cardionogen 1 for Wnt signaling; and cyclopamine and Gant61 for Hedgehog signaling. Inhibition of VEGF/FGF signaling was found to deter both Myc- and krasV12-induced liver tumorigenesis while suppression of Wnt signaling relaxed only Myc- but not krasV12-induced liver tumorigenesis. Inhibiting Hedgehog signaling did not suppress either krasV12 or Myc-induced tumors. The suppression of liver tumorigenesis was accompanied with a decrease of cell proliferation, increase of apoptosis, distorted liver histology. Collectively, our observations suggested the requirement of VEGF/FGF signaling but not the hedgehog signaling in liver tumorigenesis in both transgenic fry. However, Wnt signaling appeared to be required for liver tumorigenesis only in Myc but not krasV12 transgenic zebrafish.
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Carcinoma Hepatocelular/metabolismo , Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Genes myc , Neoplasias Hepáticas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Proteínas de Pez Cebra/genética , Animales , Animales Modificados Genéticamente , Modelos Animales de Enfermedad , Neoplasias Hepáticas Experimentales/genética , Neoplasias Hepáticas Experimentales/metabolismo , Transducción de Señal , Pez CebraRESUMEN
Hepatocellular carcinoma (HCC) is more prevalent in men than women, but the reason for this gender disparity is not well understood. To investigate whether zebrafish could be used to study the gender disparity of HCC, we compared the difference of liver tumorigenesis between female and male fish during early tumorigenesis and long-term tumor progression in our previously established inducible and reversible HCC model - the krasV12 transgenic zebrafish. We found that male fish developed HCC faster than females. The male tumors were more severe from the initiation stage, characteristic of higher proliferation, activation of WNT/ß-catenin pathway and loss of cell adhesion. During long-term tumor progression, the male tumors developed into more advanced multi-nodular tumors, whereas the female tumors remain uniform and homogenous. Moreover, regression of male tumors required longer time. We further investigated the role of sex hormones in krasV12 transgenic fish. Estrogen treatment showed tumor suppressing effect during early tumorigenesis through inhibiting cell proliferation, whereas androgen accelerated tumor growth by promoting cell proliferation. Overall, our study presented the zebrafish as a useful animal model for study of gender disparity of HCC.
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Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas de Pez Cebra/genética , Pez Cebra/genética , Animales , Animales Modificados Genéticamente , Cadherinas/metabolismo , Carcinogénesis/metabolismo , Carcinogénesis/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Proliferación Celular , Progresión de la Enfermedad , Doxiciclina/farmacología , Doxiciclina/uso terapéutico , Femenino , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Oncogenes , beta Catenina/metabolismoRESUMEN
Intraoral (IO) administration is a unique route that takes advantage of transmucosal absorption in the oral cavity to deliver a drug substance locally or systemically. IO delivery can also enhance or enable oral administration, providing a better therapeutic benefit/safety risk profile for patient compliance. However, there are relatively few systematic biopharmaceutics assessments for IO delivery to date. Therefore, the goals of this study were to i) identify the most relevant in vitro permeability models as alternatives to porcine oral tissues (gold standard) for predicting human IO absorption and ii) establish guidelines for biopharmaceutics assessment during early drug development for IO delivery. Porcine kidney LLC-PK1 cells provided the strongest correlation of transmucosal permeability with porcine oral tissues followed by human Caco-2 cells. Furthermore, cultured human buccal tissues predicted high/low permeability classification and correlated well with porcine oral tissues, which are used for predicting clinical IO absorption. In the meantime, we introduced maximum absorbable dose and dose number in the oral cavity for IO delivery assessment as well as a decision tree to provide guidance for biopharmaceutics assessment during early drug development for IO delivery.
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Mucosa Bucal/metabolismo , Administración Oral , Animales , Células CACO-2 , Humanos , Técnicas In Vitro , Células LLC-PK1 , Modelos Biológicos , Permeabilidad , Preparaciones Farmacéuticas/metabolismo , PorcinosRESUMEN
Previously we have generated inducible liver tumor models by transgenic expression of Myc or xmrk (activated EGFR homolog) oncogenes in zebrafish. To investigate the interaction of the two oncogenes, we crossed the two transgenic lines and observed more severe and faster hepatocarcinogenesis in Myc/xmrk double transgenic zebrafish than either single transgenic fish. RNA-Seq analyses revealed distinct changes in many molecular pathways among the three types of liver tumors. In particular, we found dramatic alteration of cancer metabolism based on the uniquely enriched pathways in the Myc/xmrk tumors. Critical glycolytic genes including hk2, pkm and ldha were significantly up-regulated in Myc/xmrk tumors but not in either single oncogene-induced tumors, suggesting a potential Warburg effect. In RT-qPCR analyses, the specific pkm2 isoformin Warburg effect was found to be highly enriched in the Myc/xmrk tumors but not in Myc or xmrk tumors, consistent with the observations in many human cancers with Warburg effect. Moreover, the splicing factor genes (hnrnpa1, ptbp1a, ptbp1b and sfrs3b) responsible for generating the pkm isoform were also greatly up-regulated in the Myc/xmrk tumors. As Pkm2 isoform is generally inactive and causes incomplete glycolysis to favor anabolism and tumor growth, by treatment with a Pkm2-specific activator, TEPP-46, we further demonstrated that activation of Pkm2 suppressed the growth of oncogenic liver as well as proliferation of liver cells. Collectively, our Myc/xmrk zebrafish model suggests synergetic effect of EGFR and MYC in triggering Warburg effect in the HCC formation and may provide a promising in vivo model for Warburg effect.
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Carcinoma Hepatocelular/metabolismo , Proteínas de Peces/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Animales , Animales Modificados Genéticamente , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Proteínas de Peces/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Tirosina Quinasas Receptoras/genética , Pez CebraRESUMEN
Recent studies utilizing transcriptome sequences generated by next-generation sequencing (NGS) technologies have demonstrated the ability to rapidly detect and characterize thousands of gene-based microsatellites from different plants. However, these simple sequence repeats (SSRs) were seldom used directly to test interspecific transferability in the populations of closely related species. Aspidistra Ker-Gawl. is a monocot genus with high species richness and diversity in flower structure, but its fresh floral materials are not easy to obtain. Until now, little is known about genetic background in the species of Aspidistra, quite apart from the fearful reduction of their natural habitats. In this study, the floral transcriptome of Aspidistra saxicola was obtained using NGS. Based on these data, a total of 5527 SSRs were identified in the unigenes. Among these SSRs, the proportions of di- and tri-nucleotide repeats were quite close (49.6% verse 46.8%), and the most tri-nucleotide repeats were AGG/CCT followed by AAG/CTT and AGC/GCT in A. saxicola, showing distinct differences with other angiosperm species. To assess genetic diversity in the species of Aspidistra, 48 SSR loci were tested in four available populations of A. elatior. The results revealed that more than a third of the loci were polymorphic. The majority of these primers could be amplified in 24 species representing the main clades of Aspidistra. The primer subsets from transcriptome data proved highly useful for detecting polymorphisms in the related species, supporting the finding that NGS is an efficient approach to molecular marker development at both intra- and interspecies levels, especially in endangered nonmodel species.
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Liliaceae/genética , Repeticiones de Microsatélite , Transcriptoma , Cartilla de ADN/genética , Marcadores Genéticos , Variación Genética , Liliaceae/clasificación , Especificidad de la EspecieRESUMEN
HIV-1 integrase strand transfer inhibitors are an important class of compounds targeted for the treatment of HIV-1 infection. Microdosing has emerged as an attractive tool to assist in drug candidate screening for clinical development, but necessitates extremely sensitive bioanalytical assays, typically in the pg/mL concentration range. Currently, accelerator mass spectrometry is the predominant tool for microdosing support, which requires a specialized facility and synthesis of radiolabeled compounds. There have been few studies attempted to comprehensively assess a liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach in the context of microdosing applications. Herein, we describe the development of automated LC-MS/MS methods to quantify five integrase inhibitors in plasma with the limits of quantification at 1 pg/mL for raltegravir and 2 pg/mL for four proprietary compounds. The assays involved double extractions followed by UPLC coupled with negative ion electrospray MS/MS analysis. All methods were fully validated to the rigor of regulated bioanalysis requirements, with intraday precision between 1.20 and 14.1% and accuracy between 93.8 and 107% at the standard curve concentration range. These methods were successfully applied to a human microdose study and demonstrated to be accurate, reproducible, and cost-effective. Results of the study indicate that raltegravir displayed linear pharmacokinetics between a microdose and a pharmacologically active dose.
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Cromatografía Liquida/métodos , Inhibidores de Integrasa VIH/administración & dosificación , Inhibidores de Integrasa VIH/sangre , Espectrometría de Masas en Tándem/métodos , Adolescente , Adulto , Cálculo de Dosificación de Drogas , Humanos , Límite de Detección , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Taranabant (N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide or MK-0364) is an orally active inverse agonist of the cannabinoid 1 (CB-1) receptor that was under development for the management of obesity. The metabolism and excretion of taranabant were investigated following a single oral dose of 5 mg/201 µCi [14C]taranabant to six healthy male subjects. The overall excretion recovery of the administered radioactivity was nearly quantitative (â¼92%), with the majority of the dose (â¼87%) excreted into faeces and a much smaller fraction (â¼5%) into urine. Taranabant was absorbed rapidly, with C(max) of radioactivity attained at 1-2-h postdose. The parent compound and its monohydroxylated metabolite, M1, were the major radioactive components circulating in plasma and comprised â¼12-24% and 33-42%, respectively, of the plasma radioactivity for up to 48 h. A second monohydroxylated metabolite, designated as M1a, represented â¼10-12% of the radioactivity in the 2- and 8-h postdose plasma profiles. Metabolite profiles of the faeces samples consisted mainly of the (unabsorbed) parent compound and multiple diastereomeric carboxylic acid derivatives derived from oxidation of the geminal methyl group of the parent compound and of the hydroxylated metabolite/s. These data suggest that, similar to rats and monkeys, taranabant is primarily eliminated in humans via oxidative metabolism and excretion of metabolites via the biliary/faecal route.
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Amidas/farmacocinética , Piridinas/farmacocinética , Receptor Cannabinoide CB1/agonistas , Amidas/análisis , Amidas/metabolismo , Radioisótopos de Carbono/análisis , Agonismo Inverso de Drogas , Heces/química , Humanos , Masculino , Piridinas/análisis , Piridinas/metabolismoRESUMEN
Taranabant is a cannabinoid-1 receptor inverse agonist developed for the treatment of obesity. A population model was constructed to facilitate the estimation of pharmacokinetic parameters and to identify the influence of selected covariates. Data from 12 phase 1 studies and one phase 2 study were pooled from subjects administered single and multiple oral doses of taranabant ranging from 0.5 to 8 mg. A total of 6,834 taranabant plasma concentrations from 187 healthy and 385 obese subjects were used to develop the population model in NONMEM. A standard covariate analysis using forward selection (α = 0.05) and backward elimination (α = 0.001) was conducted. A three-compartment model with first-order absorption and elimination adequately described plasma taranabant concentrations. The population mean estimates for apparent clearance and apparent steady-state volume of distribution were 25.4 L/h and 2,578 L, respectively. Statistically significant covariate effects were modest in magnitude and not considered clinically relevant (the effects of body mass index (BMI) and creatinine clearance (CrCL) on apparent clearance; BMI, age, CrCL, and gender on apparent volume of the peripheral compartment and age on apparent intercompartmental clearance). The pharmacokinetic profile of taranabant can adequately be described by a three-compartment model with first-order absorption and elimination. Clinical dose adjustment based on covariates effects is not warranted.
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Amidas/farmacocinética , Piridinas/farmacocinética , Receptor Cannabinoide CB1/antagonistas & inhibidores , Adulto , Amidas/sangre , Área Bajo la Curva , Índice de Masa Corporal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Piridinas/sangreRESUMEN
This study assessed the potential pharmacokinetic interaction and safety/tolerability of taranabant and phentermine coadministration. This was a randomized, double-blind, 3-panel, fixed-sequence study in healthy participants. Panels A, B, and C evaluated the safety/tolerability of phentermine 15 mg coadministered with taranabant 0.5, 1, and 2 mg for 7 days (panel A) and 28 days (panels B and C). In panels A and C, phentermine 15 mg was administered both with (7 days, panel A; 28 days, panel C) and without (7 days) taranabant 0.5 mg or 2 mg to evaluate pharmacokinetics. The primary endpoint was phentermine AUC(0-24 h) in panels A and C. Secondary endpoints were changes from baseline in blood pressure and heart rate for all panels. The geometric mean ratios and 90% confidence intervals for phentermine AUC(0-24 h) in the presence/absence of taranabant 0.5 mg and 2 mg were 1.08 (0.99, 1.17) and 1.04 (0.98, 1.10), respectively. No significant differences in blood pressure and heart rate were observed with any treatment versus placebo. Coadministration of taranabant 0.5 mg, 1 mg, and 2 mg with phentermine was well tolerated with no pharmacokinetic interaction and did not result in meaningful changes in blood pressure or heart rate versus placebo.
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Amidas/efectos adversos , Fármacos Antiobesidad/farmacocinética , Agonismo Inverso de Drogas , Fentermina/efectos adversos , Fentermina/farmacocinética , Piridinas/efectos adversos , Receptor Cannabinoide CB1/antagonistas & inhibidores , Adolescente , Adulto , Amidas/administración & dosificación , Fármacos Antiobesidad/efectos adversos , Presión Sanguínea/efectos de los fármacos , Esquema de Medicación , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Fentermina/administración & dosificación , Piridinas/administración & dosificaciónRESUMEN
Taranabant is a cannabinoid-1 receptor inverse agonist for the treatment of obesity. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of taranabant (5, 7.5, 10, or 25 mg once daily for 14 days) in 60 healthy male subjects. Taranabant was rapidly absorbed, with a median t(max) of 1.0 to 2.0 hours and a t(1/2) of approximately 74 to 104 hours. Moderate accumulation was observed in C(max) (1.18- to 1.40-fold) and AUC(0-24 h) (1.5- to 1.8-fold) over 14 days for the 5-, 7.5-, and 10-mg doses, with an accumulation half-life ranging from 15 to 21 hours. Steady state was reached after 13 days. After multiple-dose administration, plasma AUC(0-24 h) and C(max) of taranabant increased dose proportionally (5-10 mg) and increased somewhat less than dose proportionally for 25 mg. Taranabant was generally well tolerated up to doses of 10 mg and exhibited multiple-dose pharmacokinetics consistent with once-daily dosing.