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We present the case of a 34-year-old Japanese man with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer and brain metastases. After central nervous system (CNS) disease progression with alecintib and brigatinib, treatment with lorlatinib resulted in a good intracranial response. In this case, we investigated brain penetration ratio of brigatinib using cerebrospinal fluid and paired serum samples, and the ratio was 0.012. Further, we investigated resistance mechanisms via next-generation sequencing (NGS) using lung biopsy at lung cancer diagnosis and brain biopsy sample at progressive disease of brigatinib. No apparent resistance mechanism of known ALK resistance, such as ALK mutations, amplifications, epithelial-mesenchymal transition (EMT) and bypass pathway activation were detected. Taken together, we speculate that the low CNS penetration rate of brigatinib confers CNS progression. Further studies are warranted to reveal the resistance mechanism and propose a treatment strategy for CNS progression in ALK-positive patients.
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The blood-brain barrier (BBB) is one of several barriers between the brain and the peripheral blood system to maintain homeostasis. Understanding the interactions between infectious agents such as human immunodeficiency virus type 1 (HIV-1), which are capable of traversing the BBB and causing neuroinflammation requires modeling an authentic BBB in vitro. Such an in vitro BBB model also helps develop means of targeting viruses that reside in the brain via natural immune effectors such as antibodies. The BBB consists of human brain microvascular endothelial cells (HBMECs), astrocytes, and pericytes. Here we report in vitro methods to establish a dual-cell BBB model consisting of primary HBMECs and primary astrocytes to measure the integrity of the BBB and antibody penetration of the BBB, as well as a method to establish a single cell BBB model to study the impact of HIV-1 infected medium on the integrity of such a BBB.
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Astrocitos , Barrera Hematoencefálica , Células Endoteliales , Infecciones por VIH , VIH-1 , Barrera Hematoencefálica/virología , Barrera Hematoencefálica/metabolismo , Humanos , Astrocitos/virología , Astrocitos/metabolismo , Astrocitos/inmunología , Células Endoteliales/virología , Células Endoteliales/metabolismo , Células Endoteliales/inmunología , VIH-1/inmunología , VIH-1/fisiología , Infecciones por VIH/virología , Infecciones por VIH/inmunología , Pericitos/virología , Pericitos/metabolismo , Pericitos/inmunología , Enfermedades Neuroinflamatorias/virología , Enfermedades Neuroinflamatorias/inmunología , Técnicas de Cocultivo/métodos , Células Cultivadas , Encéfalo/virología , Encéfalo/inmunología , Encéfalo/metabolismoRESUMEN
The treatment of various disorders of the central nervous system (CNS) is often impeded by the limited brain exposure of drugs, which is regulated by the human blood-brain barrier (BBB). The screening of lead compounds for CNS penetration is challenging due to the biochemical complexity of the BBB, while experimental determination of permeability is not feasible for all types of compounds. Here we present a novel method for rapid preclinical screening of libraries of compounds by utilizing advancements in computing hardware, with its foundation in transition-based counting of the flux. This method has been experimentally validated for in vitro permeabilities and provides atomic-level insights into transport mechanisms. Our approach only requires a single high-temperature simulation to rank a compound relative to a library, with a typical simulation time converging within 24 to 72 h. The method offers unbiased thermodynamic and kinetic information to interpret the passive transport of small-molecule drugs across the BBB.
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Barrera Hematoencefálica , Humanos , Transporte Biológico/fisiología , Permeabilidad , Simulación por Computador , EndotelioRESUMEN
Structural optimization of a previously reported agonist of µOR, PZM21 is described resulting in the discovery of a novel series of amides with at least 4-folds enhanced CNS penetration in rat. Furthermore, these efforts yielded compounds with varying levels of efficacy on the receptor ranging from high efficacy agonists such as compound 20 to antagonists, such as 24. The correlation between in vitro activation of µOR and relative activity in models of analgesia for these compounds is discussed. The compelling results obtained in these studies demonstrate the potential utility of these newly discovered compounds in the treatment of pain and opioid use disorder.
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Trastornos Relacionados con Opioides , Dolor , Ratas , Animales , Dolor/tratamiento farmacológico , Amidas , Encéfalo/metabolismo , Receptores Opioides mu/agonistas , Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéuticoRESUMEN
Heterogeneous neurocognitive impairment remains an important issue, even in the era of combination antiretroviral therapy (cART), with an incidence ranging from 15% to 65%. Although ART drugs with higher penetration scores to the central nervous system (CNS) show better HIV replication control in the CNS, the association between CNS penetration effectiveness (CPE) scores and neurocognitive impairment remains inconclusive. To explore whether ART exposure is associated with the risk of neurological diseases among patients with HIV/AIDS, this study in Taiwan involved 2,571 patients with neurological diseases and 10,284 matched, randomly selected patients without neurological diseases between 2010 and 2017. A conditional logistic regression model was used in this study. The parameters for ART exposure included ART usage, timing of exposure, cumulative defined daily dose (DDD), adherence, and cumulative CPE score. Incident cases of neurological diseases, including CNS infections, cognitive disorders, vasculopathy, and peripheral neuropathy, were obtained from the National Health Insurance Research Database in Taiwan. Odds ratios (ORs) for the risk of neurological diseases were conducted using a multivariate conditional logistic regression model. Patients with a history of past exposure (OR: 1.68, 95% confidence interval [CI]:1.22-2.32), low cumulative DDDs (< 2,500) (OR: 1.28, 95% CI: 1.15-1.42), low adherence (0 < adherence (ADH) ≤ 0.8) (OR: 1.46, 95% CI: 1.30-1.64), or high cumulative CPE scores (>14) (OR: 1.34, 95% CI: 1.14-1.57) had a high risk of neurological diseases. When stratified by classes of ART drugs, patients with low cumulative DDDs or low adherence had a high risk of neurological diseases, including NRTIs, PIs, NNRTIs, INSTIs, and multi-drug tablets. Subgroup analyses also suggested that patients with low cumulative DDDs or low adherence had a high risk of neurological diseases when they had high cumulative CPE scores. Patients with high cumulative DDDs or medication adherence were protected against neurological diseases only when they had low cumulative CPE scores (≤ 14). Patients may be at risk for neurological diseases when they have low cumulative DDDs, low adherence, or usage with high cumulative CPE scores. Continuous usage and low cumulative CPE scores of ART drugs may benefit neurocognitive health in patients with HIV/AIDS.
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INTRODUCTION: Siponimod, a potent and selective sphingosine-1-phosphate (S1P1,5) agonist, is the only therapeutic agent that has shown efficacy against disability progression, decline in cognitive processing speed, total brain volume loss, gray matter atrophy and signs of demyelination in patients with secondary progressive multiple sclerosis (SPMS). Although the pathophysiology of progression in SPMS and primary progressive MS (PPMS) is thought to be similar, fingolimod, the prototype S1P1,3,45 agonist, failed to show efficacy against disability progression in PPMS. Differentiating siponimod from fingolimod at the level of their central effects is believed to be the key to a better understanding of the underlying characteristics that could make siponimod uniquely efficacious in progressive MS (PMS). METHODS: Here, we compared the central vs. peripheral dose-dependent drug exposures for siponimod and fingolimod in healthy mice and mice with experimental autoimmune encephalomyelitis (EAE). RESULTS: Siponimod treatment achieved dose-dependent efficacy and dose-proportional increases in steady-state drug blood levels, with a central nervous system (CNS)/blood drug-exposure ratio (CNS/bloodDER) of ~ 6 in both healthy and EAE mice. In contrast, fingolimod treatments achieved dose-proportional increases in fingolimod and fingolimod-phosphate blood levels, with respective CNS/bloodDER that were markedly increased (≥ threefold) in EAE vs. healthy mice. CONCLUSION: If proven to have translational value, these observations would suggest that CNS/bloodDER may be a key differentiator for siponimod over fingolimod for clinical efficacy in PMS.
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The brain penetration of methotrexate (MTX) and its metabolite 7-hydroxymethotrexate (7OHMTX) was characterized in non-tumor bearing mice and mice bearing orthotopic Group 3 medulloblastoma. Plasma pharmacokinetic studies and cerebral and ventricular microdialysis studies were performed in animals dosed with 200 or 1000 mg/kg MTX by IV bolus. Plasma, brain/tumor extracellular fluid (ECF) and lateral ventricle cerebrospinal fluid (CSF) MTX and 7OHMTX concentration-time data were analyzed by validated LC-MS/MS methods and modeled using a population-based pharmacokinetic approach and a hybrid physiologically-based model structure for the brain compartments. Brain penetration was similar for MTX and 7OHMTX and was not significantly different between non-tumor and tumor bearing mice. Overall, mean (±SD) model-derived unbound plasma to ECF partition coefficient Kp,uu were 0.17 (0.09) and 0.17 (0.12) for MTX and 7OHMTX, respectively. Unbound plasma to CSF Kp,uu were 0.11 (0.06) and 0.18 (0.09) for MTX and 7OHMTX, respectively. The plasma and brain model were scaled to children using allometric principles and pediatric physiological parameters. Model-based simulations were adequately overlaid with digitized plasma and CSF lumbar data collected in children receiving different MTX systemic infusions. This model can be used to further explore and optimize methotrexate dosing regimens in children with brain tumors.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , Ratones , Animales , Meduloblastoma/metabolismo , Metotrexato , Cromatografía Liquida , Espectrometría de Masas en Tándem , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologíaRESUMEN
Glioblastoma (GBM) remains one of the most difficult tumors to treat. The mean overall survival rate of 15 months and the 5-year survival rate of 5% have not significantly changed for almost 2 decades. Despite progress in understanding the pathophysiology of the disease, no new effective treatments to combine with radiation therapy after surgical tumor debulking have become available since the introduction of temozolomide in 1999. One of the main reasons for this is the scarcity of compounds that cross the blood-brain barrier (BBB) and reach the brain tumor tissue in therapeutically effective concentrations. In this review, we focus on the role of the BBB and its importance in developing brain tumor treatments. Moreover, we discuss drug repurposing, a drug discovery approach to identify potential effective candidates with optimal pharmacokinetic profiles for central nervous system (CNS) penetration and that allows rapid implementation in clinical trials. Additionally, we provide an overview of repurposed candidate drug currently being investigated in GBM at the preclinical and clinical levels. Finally, we highlight the importance of phase 0 trials to confirm tumor drug exposure and we discuss emerging drug delivery technologies as an alternative route to maximize therapeutic efficacy of repurposed candidate drug.
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P-glycoprotein (P-gp, MDR1) is expressed at the blood-brain barrier (BBB) and restricts penetration of its substrates into the central nervous system (CNS). In vitro MDR1 assays are frequently used to predict the in vivo relevance of MDR1-mediated efflux at the BBB. It has been well established that drug candidates with high MDR1 efflux ratios (ERs) display poor CNS penetration. Following a comparison of MDR1 transporter function between the MDR1-MDCKI cell line from National Institutes of Health (NIH) and our internal MDR1-MDCKII cell line, the former was found to provide better predictions of in vivo brain penetration than our in-house MDR1-MDCKII cell line. In particular, the NIH MDR1 assay has an improved sensitivity to differentiate the compounds with ERs of <3 in our internal cell line and is able to reduce the risk of false negatives. A better correlation between NIH MDR1 ERs and brain penetration in rat and non-human primate (NHP) was demonstrated. Additionally, a comparison of brain penetration time course of MDR1 substrates and an MDR1 non-substrate in NHP demonstrated that MDR1 interaction can delay the time to equilibrium of drug concentration in the brain with plasma. It is recommended to select highly permeable compounds without MDR1 interaction for rapid brain penetration to produce the maximal pharmacological effect in the CNS with a quicker onset.
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Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Preparaciones Farmacéuticas/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Perros , Evaluación Preclínica de Medicamentos/métodos , Humanos , Macaca fascicularis , Células de Riñón Canino Madin Darby , Masculino , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie , Factores de Tiempo , Distribución TisularRESUMEN
Primary central nervous system lymphoma (PCNSL) is a rare form and aggressive type of diffuse large B-cell lymphoma (DLBCL) that occurs in both immunocompetent and immunocompromised adults. While adding rituximab to chemotherapeutic regimens resulted in dramatic improvement in both progression-free survival and overall survival in patients with non-central nervous system (CNS) DLBCL, the outcomes of PCNSL are generally poor due to the immune-privileged tumor microenvironment or suboptimal delivery of systemic agents into tumor tissues. Therefore, more effective therapy for PCNSL generally requires systemic therapy with sufficient CNS penetration, including high-dose intravenous methotrexate with rituximab or high-dose chemotherapy followed by autologous stem cell transplantation. However, overall survival is usually inferior in comparison to non-CNS lymphomas, and treatment options are limited for elderly patients or patients with relapsed/refractory disease. Chimeric antigen receptor T (CAR-T) cell therapy has emerged as a cutting-edge cancer therapy, which led to recent FDA approvals for patients with B-cell malignancies and multiple myeloma. Although CAR-T cell therapy in patients with PCNSL demonstrated promising results without significant toxicities in some small cohorts, most cases of PCNSL are excluded from the pivotal CAR-T cell trials due to the concerns of neurotoxicity after CAR-T cell infusion. In this review, we will provide an overview of PCNSL and highlight current approaches, resistance mechanisms, and future perspectives of CAR-T cell therapy in patients with PCNSL.
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BACKGROUND: Siponimod (BAF312), a selective S1P1/S1P5 agonist, reduces disability progression in secondary progressive MS. Recent observations suggest it could act via S1P1/S1P5-dependent anti-inflammatory and pro-myelination effects on CNS-resident cells. OBJECTIVE: Generate preclinical evidence confirming siponimod's CNS penetration and activity. METHODS: Siponimod's CNS penetration and distribution was explored in rodents and non-human primates (NHPs) using: Liquid Chromatography coupled to tandem Mass Spectrometry (LC-MS/MS), quantitative whole-body autoradiography (QWBA) using 14C-radiolabeled siponimod or non-invasive single-photon emission CT (SPECT) with a validated 123I-radiolabeled siponimod analog. Functional CNS activity was investigated by S1P1 receptor quantification in brain homogenates. RESULTS: In mice/rats, siponimod treatments achieved dose-dependent efficacy and dose-proportional increase in drug blood levels, with mean brain/blood drug-exposure ratio (Brain/BloodDER) of 6-7. Efficacy in rat brain tissues was revealed by a dose-dependent reduction in brain S1P1 levels. QWBA distribution analysis in rats indicated that [14C]siponimod related radioactivity could readily penetrate CNS, with particularly high uptakes in white matter of cerebellum, corpus callosum, and medulla oblongata versus lower exposures in other areas such as olfactory bulb. SPECT monitoring in NHPs revealed CNS distribution with a brain/bloodDER of â¼6, as in rodents. CONCLUSION: Findings demonstrate siponimod's CNS penetration and distribution across species, with high translational potential to human.
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Despite increasing knowledge of the biologic drivers of central nervous system tumors, most targeted agents trialed to date have not shown activity against these tumors in clinical trials. To effectively treat central nervous system tumors, an active drug must achieve and maintain an effective exposure at the tumor site for a long enough period of time to exert its intended effect. However, this is difficult to assess and achieve due to the constraints of drug delivery to the central nervous system. To address this complex problem, an understanding of pharmacokinetic principles is necessary. Pharmacokinetics is classically described as the quantitative study of drug absorption, distribution, metabolism, and elimination. The innate chemical properties of a drug, its administration (dose, route and schedule), and host factors all influence these four key pharmacokinetic phases. The central nervous system adds a level of complexity to standard plasma pharmacokinetics as it is a coupled drug compartment. This review will discuss special considerations of pharmacokinetics in the context of therapeutic development for central nervous system tumors.
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PURPOSE OF REVIEW: To describe the possible neuroinvasion pathways of Severe Acute Respiratory Syndrome-related Coronavirus-2 (SARS-CoV-2), the virus responsible for the Coronavirus disease-19 (Covid-19) pandemic. RECENT FINDINGS: We present data regarding the family of Coronaviruses (CoVs) and the central nervous system (CNS), and describe parallels between SARS-CoV-2 and other members of the family, which have been investigated in more depth and combine these findings with the recent advancements regarding SARS-CoV-2. SUMMARY: SARS-CoV-2 like other CoVs is neuroinvasive, neurotropic and neurovirulent. Two main pathways of CNS penetration seem to be the strongest candidates, the hematogenous and the neuronal. Τhe olfactory route in particular appears to play a significant role in neuroinvasion of coronaviruses and SARS-CoV-2, as well. However, existing data suggest that other routes, involving the nasal epithelium in general, lymphatic tissue and the CSF may also play roles in SARS-CoV-2 invasion into the CNS.
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Now, it has been evidenced that Covid19 (SARS-CoV-2) infects the brain tissues. Along with this, a challenge has been raised for research professionals to find effective drugs for its treatment since the recent spread of this virus from Wuhan, China. Targeting the treatment of brain infection, it has also been a challenge that the clinical drug should have good CNS penetration ability to cross the blood-brain barrier.
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Betacoronavirus , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/metabolismo , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/metabolismo , Adenosina Monofosfato/administración & dosificación , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/metabolismo , Alanina/administración & dosificación , Alanina/análogos & derivados , Alanina/metabolismo , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/metabolismo , Antivirales/administración & dosificación , Antivirales/metabolismo , Betacoronavirus/efectos de los fármacos , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/virología , Encéfalo/efectos de los fármacos , COVID-19 , Fármacos del Sistema Nervioso Central/administración & dosificación , Fármacos del Sistema Nervioso Central/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Humanos , Metilprednisolona/administración & dosificación , Metilprednisolona/metabolismo , Pandemias , SARS-CoV-2 , Resultado del TratamientoRESUMEN
HIV-associated neurocognitive disorder (HAND) can be represented by neurological and neuropathological abnormalities with a consequence of motor and cognitive loss. It has become a critical unmet medical need for infected people, and the number continues to rise every year. Pathological investigations have revealed its occurrence due to the release of free radicals from the HIV infected microglia and macrophages. So far, no effective clinical trials have been conducted for its treatment other than the use of some antiretroviral therapies which have failed to show good results due to poor CNS penetration and hence low CNS distribution. This collective information from the updated literature reports motivated us to share the idea of conjugated products of antiretroviral agents and antioxidants leading to better brain penetration abilities due to higher logâ¯p values, higher molecular weight and possibly low toxicity and better neuroprotective action. In this Viewpoint, we have attempted to analyze the chemical and pharmacological classes of antiretroviral agents (ARAs) and their clinical failures for the treatment of cognitive dysfunction due to HIV infection. As the causes of clinical insufficiency of antiretroviral agents and neuropathological mechanisms of HAND have been well established, it would be a good opportunity for medicinal chemists to develop new potential antiretroviral agents or to improve their molecular properties for better therapeutic implications. Furthermore, in silico based molecular properties have been investigated correlating them to the brain penetration abilities.
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Disfunción Cognitiva , Infecciones por VIH , Antirretrovirales/uso terapéutico , Encéfalo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Trastornos Neurocognitivos/tratamiento farmacológicoRESUMEN
Central nervous system (CNS) histoplasmosis occurs in 5-20% of all cases and is most commonly seen in immunosuppressed patients who have acquired immunodeficiency syndrome (AIDS) or have received organ transplant. The prevalence of histoplasmosis in patients greater than 65 years old between the years of 1999-2008 in the state of Texas was about 2-3 cases per 100,000 patients year. Since 1990 with the discovery of Triazoles, itraconazole (ICZ) has become the standard initial and suppressive therapy in patients with mild-moderate histoplasmosis without CNS involvement. However, poor penetration of ICZ into the brain, in vitro fluconazole resistance and lack of controlled-trials pose challenge in the treatment of cerebral histoplasmosis.
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Anidulafungin and micafungin were quantified in cerebrospinal fluid (CSF) of critically ill adults and in cerebral cortex of deceased patients. In CSF, anidulafungin levels (<0.01 to 0.66 µg/ml) and micafungin levels (<0.01 to 0.16 µg/ml) were lower than those in plasma concentrations (0.77 to 5.07 and 1.21 to 8.70 µg/ml, respectively) drawn simultaneously. In cerebral cortex, anidulafungin and micafungin levels were 0.21 to 2.34 and 0.18 to 2.88 µg/g, respectively. Thus, MIC values of several pathogenic Candida strains exceed concentrations in CSF and in brain.
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Antifúngicos , Equinocandinas , Adulto , Anidulafungina , Antifúngicos/uso terapéutico , Corteza Cerebral , Humanos , Lipopéptidos , Micafungina , Pruebas de Sensibilidad MicrobianaRESUMEN
Introduction: Disease-modifying treatment for Parkinson's disease (PD) to halt or revert the disease progression remains an unmet medical need. LRRK2 kinase activity is abnormally elevated in PD patients carrying LRRK2 mutations, with G2019S as the most frequent one. Small molecules to inhibit LRRK2 kinase activity might provide a potential disease-modifying strategy for PD.Areas covered: This review provides an update of small molecule LRRK2 inhibitors in patents published from January 2014 to October 2019. The molecules are classified by their structural scaffolds.Expert opinion: Despite the tremendous efforts to push small molecule LRRK2 inhibitors toward clinical trials, the overall progress is somewhat disappointing due to the challenges in compound optimization and the putative concern of target-related adverse effects. It is challenging to optimize multiple parameters including kinase selectivity, CNS penetration, and unbound fraction in brain simultaneously. In addition, the on-target effect of morphologic changes observed in lung/kidney in pre-clinical studies for several frontrunner ATP-competitive inhibitors prevented their further development. With this regard, non-ATP-competitive inhibitors may provide a different safety profile for development. DNL201 and DNL151 have entered early clinical trials to evaluate tolerability and target engagement biomarkers. This will pave the way for the development for future LRRK2 inhibitors.
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Antiparkinsonianos/farmacología , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Animales , Antiparkinsonianos/uso terapéutico , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Patentes como AsuntoRESUMEN
The carboxylesterase Notum is a key negative regulator of the Wnt signaling pathway by mediating the depalmitoleoylation of Wnt proteins. Our objective was to discover potent small molecule inhibitors of Notum suitable for exploring the regulation of Wnt signaling in the central nervous system. Scaffold-hopping from thienopyrimidine acids 1 and 2, supported by X-ray structure determination, identified 3-methylimidazolin-4-one amides 20-24 as potent inhibitors of Notum with activity across three orthogonal assay formats (biochemical, extra-cellular, occupancy). A preferred example 24 demonstrated good stability in mouse microsomes and plasma, and cell permeability in the MDCK-MDR1 assay albeit with modest P-gp mediated efflux. Pharmacokinetic studies with 24 were performed in vivo in mouse with single oral administration of 24 showing good plasma exposure and reasonable CNS penetration. We propose that 24 is a new chemical tool suitable for cellular studies to explore the fundamental biology of Notum.
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Acetilesterasa/antagonistas & inhibidores , Amidas/química , Pirimidinas/química , Acetilesterasa/metabolismo , Amidas/metabolismo , Amidas/farmacología , Animales , Sitios de Unión , Permeabilidad de la Membrana Celular/efectos de los fármacos , Cristalografía por Rayos X , Perros , Semivida , Concentración 50 Inhibidora , Células de Riñón Canino Madin Darby , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas/metabolismo , Simulación de Dinámica Molecular , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
The New World alphaviruses Venezuelan, Eastern, and Western equine encephalitis viruses (VEEV, EEEV and WEEV, respectively) commonly cause a febrile disease that can progress to meningoencephalitis, resulting in significant morbidity and mortality. To address the need for a therapeutic agent for the treatment of Alphavirus infections, we identified and pursued preclinical characterization of a ribonucleoside analog EIDD-1931 (ß-D-N4-hydroxycytidine, NHC), which has shown broad activity against alphaviruses in vitro and has a very high genetic barrier for development of resistance. To be truly effective as a therapeutic agent for VEEV infection a drug must penetrate the blood brain barrier and arrest virus replication in the brain. High plasma levels of EIDD-1931 are rapidly achieved in mice after oral dosing. Once in the plasma EIDD-1931 is efficiently distributed into organs, including brain, where it is rapidly converted to its active 5'-triphosphate. EIDD-1931 showed a good safety profile in mice after 7-day repeated dosing with up to 1000â¯mg/kg/day doses. In mouse model studies, EIDD-1931 was 90-100% effective in protecting mice against lethal intranasal infection when therapeutic treatment was started as late as 24â¯h post-infection, and partial protection was achieved when treatment was delayed for 48â¯h post-infection. These results support further preclinical development of EIDD-1931 as a potential anti-alphavirus drug.