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Lenacapavir is a novel, first-in-class, multistage inhibitor of HIV-1 capsid function approved for the treatment of multidrug-resistant HIV-1 infection in combination with other antiretrovirals for heavily treatment-experienced people with HIV. Two Phase 1, open-label, parallel-group, single-dose studies assessed the pharmacokinetics (PK) of lenacapavir in participants with moderate hepatic impairment [Child-Pugh-Turcotte (CPT) Class B: score 7-9] or severe renal impairment [15 ≤ creatinine clearance (CLcr) ≤29 mL/min] to inform lenacapavir dosing in HIV-1-infected individuals with organ impairment. In both studies, a single oral dose of 300 mg lenacapavir was administered to participants with normal (n = 10) or impaired (n = 10) hepatic/renal function who were matched for age (±10 years), sex, and body mass index (±20%). Lenacapavir exposures [area under the plasma concentration-time curve from time 0 to infinity (AUCinf) and maximum concentration (Cmax)] were approximately 1.47- and 2.61-fold higher, respectively, in participants with moderate hepatic impairment compared to those with normal hepatic function, whereas lenacapavir AUCinf and Cmax were approximately 1.84- and 2.62-fold higher, respectively, in participants with severe renal impairment compared to those with normal renal function. Increased lenacapavir exposures with moderate hepatic or severe renal impairment were not considered clinically meaningful. Lenacapavir was considered generally safe and well tolerated in both studies. These results support the use of approved lenacapavir dosing regimen in patients with mild (CPT Class A: score 5-6) or moderate hepatic impairment as well as in patients with mild (60 ≤ CLcr ≤ 89 mL/min), moderate (30 ≤ CLcr ≤ 59 mL/min), and severe renal impairment.
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Hepatopatías , Insuficiencia Renal , Humanos , Área Bajo la Curva , Insuficiencia Renal/metabolismo , Riñón/metabolismo , Hepatopatías/tratamiento farmacológico , Hepatopatías/metabolismoRESUMEN
Bictegravir (BIC) is a potent small-molecule integrase strand-transfer inhibitor (INSTI) and a component of Biktarvy®, a single-tablet combination regimen that is currently approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. The absorption, metabolism, distribution, and elimination (ADME) characteristics of BIC were determined through in vivo nonclinical and clinical studies (IND 121318).[14C]BIC was rapidly absorbed orally in mice, rats, monkeys and human. The cumulative dose recovery was high in nonclinical species (>80%) and humans (95.3%), with most of the excreted dose recovered in faeces. Quantifiable radioactivity with declining concentration was observed in rat tissues suggesting reversible binding. Unchanged BIC was the most abundant circulating component in all species along with two notable metabolites M20 (a sulphate conjugate of hydroxylated BIC) and M15 (a glucuronide conjugate of BIC). BIC was primarily eliminated by hepatic metabolism followed by excretion of the biotransformed products into faeces. In vitro drug-drug interaction (DDI) studies with M15 and M20 demonstrated that no clinically relevant interactions were expected.Overall, BIC is a novel and potent INSTI with a favourable resistance, PK, and ADME profile that provides important improvements over other currently available INSTIs for the treatment of HIV-1.
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Infecciones por VIH , Inhibidores de Integrasa VIH , VIH-1 , Humanos , Animales , Ratones , Ratas , Inhibidores de Integrasa VIH/farmacología , Inhibidores de Integrasa VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Piridonas , Amidas , Compuestos Heterocíclicos con 3 Anillos/farmacología , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos , Integrasas/uso terapéuticoRESUMEN
BACKGROUND: Capnocytophaga canimorsus is a facultative anaerobic, slow-growing, capnophilic, Gram-negative bacillus, that is commonly found in the microflora of canine and feline oral cavities. Capnocytophaga infections are an emerging zoonotic disease that can cause fatal systemic infections in immunocompromised individuals. Localized ocular Capnocytophaga infections, including keratitis, blepharitis, and endophthalmitis, can lead to severe eye threatening situations. To our knowledge, there is currently no documented case of Capnocytophaga canimorsus blebitis with bleb perforation after trabeculectomy. CASE PRESENTATION: Our case report and literature review features a novel case of Capnocytophaga blebitis that occurred after trabeculectomy, associated with close dog contact (i.e. face licking). The patient had underwent trabeculectomy 10 years prior and presented with conjunctival injection, perforated bleb, and hypotony. Overall, patient was medically treated subconjunctival vancomycin, gentamicin and moxifloxacin drops. Trabeculectomy revision was performed with good visual outcome. Bacterial cultures grew Capnocytophaga canimorsus. CONCLUSIONS: We discuss the strategies for diagnosis, treatment, and common risk factors for ocular Capnocytophaga infections. At-risk patients with ocular infections should be asked about close contact with dogs and cats; and treated promptly with the proper antibiotic regimen.
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Enfermedades de los Gatos , Enfermedades de los Perros , Infecciones por Bacterias Gramnegativas , Animales , Capnocytophaga , Gatos , Perros , Infecciones por Bacterias Gramnegativas/diagnóstico , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , HumanosRESUMEN
BACKGROUND: Supported self-management (SSM) is a recognized approach for people with long-term conditions but, despite the prevalence of unmet needs, little is known about its role for people with traumatic brain injury (TBI). OBJECTIVES: To codesign an SSM intervention with people with TBI and evaluate feasibility of implementation through multidisciplinary staff across a trauma pathway. SETTING AND PARTICIPANTS: People who had previously been admitted to a Major Trauma Centre following TBI and family members participated in a series of codesign activities. Staff attended SSM workshops and used the intervention with patients in acute and rehabilitation settings. METHODS: We used Normalization Process Theory constructs to guide and interpret implementation. Knowledge, beliefs and confidence of staff in SSM were assessed through pre- and post-training questionnaires, and staff, patients' and families' experiences were explored through semi-structured interviews. Qualitative data were analysed thematically, and clinical measures were mapped against a matched sample. RESULTS: Codesigned resources were created and used within an SSM approach for which 110 staff participated in training. Evaluation demonstrated significant differences in staff SSM confidence and skills, following training. Qualitative evaluation revealed adoption by staff, and patients' and families' experiences of using the resources. Challenges included reaching staff across complex pathways to achieve collective implementation. CONCLUSION: This is the first project to demonstrate feasibility of SSM for people after TBI starting in an acute trauma setting. Through an open approach to codesign with a marginalized group, the SSM resources were valued by them and held meaning and relevance for staff.
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Lesiones Traumáticas del Encéfalo/terapia , Grupo de Atención al Paciente/organización & administración , Automanejo/métodos , Familia , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Masculino , Rol Profesional , Apoyo SocialRESUMEN
Momelotinib (MMB), a small-molecule inhibitor of Janus kinase (JAK)1/2 and of activin A receptor type 1 (ACVR1), is in clinical development for the treatment of myeloproliferative neoplasms. The pharmacokinetics and disposition of [14C]MMB were characterized in a single-dose, human mass-balance study. Metabolism and the pharmacologic activity of key metabolites were elucidated in multiple in vitro and in vivo experiments. MMB was rapidly absorbed following oral dosing with approximately 97% of the radioactivity recovered, primarily in feces with urine as a secondary route. Mean blood-to-plasma [14C] area under the plasma concentration-time curve ratio was 0.72, suggesting low association of MMB and metabolites with blood cells. [14C]MMB-derived radioactivity was detectable in blood for ≤48 hours, suggesting no irreversible binding of MMB or its metabolites. The major circulating human metabolite, M21 (a morpholino lactam), is a potent inhibitor of JAK1/2 and ACVR1 in vitro. Estimation of pharmacological activity index suggests M21 contributes significantly to the pharmacological activity of MMB for the inhibition of both JAK1/2 and ACVR1. M21 was observed in disproportionately higher amounts in human plasma than in rat or dog, the rodent and nonrodent species used for the general nonclinical safety assessment of this molecule. This discrepancy was resolved with additional nonclinical studies wherein the circulating metabolites and drug-drug interactions were further characterized. The human metabolism of MMB was mediated primarily by multiple cytochrome P450 enzymes, whereas M21 formation involved initial P450 oxidation of the morpholine ring followed by metabolism via aldehyde oxidase.
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Benzamidas/farmacocinética , Pirimidinas/farmacocinética , Adolescente , Adulto , Animales , Línea Celular , Línea Celular Tumoral , Sistema Enzimático del Citocromo P-450/metabolismo , Perros , Interacciones Farmacológicas/fisiología , Femenino , Células Hep G2 , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Ratas , Adulto JovenRESUMEN
Preclinical characterization of velpatasvir (VEL; GS-5816), an inhibitor of the hepatitis C virus (HCV) NS5A protein, demonstrated that it has favorable in vitro and in vivo properties, including potent antiviral activity against hepatitis C virus genotype 1 to 6 replicons, good metabolic stability, low systemic clearance, and adequate bioavailability and physicochemical properties, to warrant clinical evaluation. The phase 1 (first-in-human) study evaluated the safety, tolerability, and pharmacokinetics of VEL in healthy human subjects following administration of single and multiple (n = 7) once-daily ascending doses and of VEL in the presence and absence of food. Following administration of single and multiple doses, VEL was safe and well tolerated when administered at up to 450 mg and when administered with food. The pharmacokinetic behavior of VEL observed in humans was generally in agreement with that seen during preclinical characterization. Following administration of multiple doses, VEL trough concentrations were significantly greater than the protein-adjusted half-maximal (50%) effective concentration of VEL against HCV genotype 1 to 6 replicons at all evaluated doses greater than 5 mg. The pharmacokinetics of VEL were not significantly affected by administration with food. Collectively, the results of this study support the further clinical investigation of VEL administered once daily as part of a regimen with other pangenotypic direct-acting antivirals for the treatment of HCV infection.
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Antivirales/uso terapéutico , Carbamatos/farmacocinética , Carbamatos/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Proteínas no Estructurales Virales/antagonistas & inhibidores , Adulto , Animales , Antivirales/efectos adversos , Carbamatos/efectos adversos , Perros , Femenino , Voluntarios Sanos , Hepatitis C/virología , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Humanos , Macaca fascicularis , Masculino , Microsomas Hepáticos/metabolismo , Persona de Mediana Edad , Ratas , Ratas Sprague-Dawley , Replicación Viral/efectos de los fármacos , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVE: Lenacapavir (LEN) is a novel, first-in-class, multistage, selective inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function recently approved for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. The purpose of this multicohort study was to evaluate the pharmacokinetics, metabolism, excretion, safety, and tolerability of LEN following a single intravenous (IV) infusion of 10 mg LEN or 20 mg [14C]LEN in healthy participants. METHODS: Twenty-one healthy adult participants were enrolled into the study and received either a single IV dose of 10 mg LEN (n = 8 active, n = 3 placebo; cohort 1) or a single IV dose of 20 mg [14C]LEN containing 200 µCi (n = 10; cohort 2). Blood, urine, and feces samples (when applicable) were collected after dosing, and radioactivity (cohort 2) was assessed using liquid scintillation counting in both plasma and excreta. LEN in plasma was quantified by liquid chromatography (LC) tandem mass spectroscopy (MS/MS) method bioanalysis. Metabolite profiling in plasma and excreta were performed using LC-fraction collect (FC)-high-resolution MS and LC-FC-accelerator mass spectrometry in plasma. RESULTS: Between the 10 mg and 20 mg doses of LEN, the observed plasma exposure of LEN doubled, while the elimination half-life was similar. Following administration of 20 mg [14C]LEN (200 µCi), the mean cumulative recovery of [14C] radioactivity was 75.9% and 0.24% from feces and urine, respectively. The mean whole [14C] blood-to-plasma concentration ratio was 0.5-0.7, which showed a low distribution of LEN to red blood cells. Intact LEN was the predominant circulating species in plasma (representing 68.8% of circulating radioactivity), and no single metabolite contributed to > 10% of total radioactivity exposure through 1176 h postdose. Similarly, intact LEN was the most abundant component (32.9% of administered dose; 75.9% of recovered dose) measured in feces, with metabolites accounting for trace amounts. These results suggest metabolism of LEN is not a primary pathway of elimination. Of the metabolites observed in the feces, the three most abundant metabolites were direct phase 2 conjugates (glucuronide, hexose, and pentose conjugates), with additional metabolites formed to a lesser extent via other pathways. The administered LEN IV doses were generally safe and well-tolerated across participants in this study. CONCLUSIONS: The results of this mass balance study indicated that LEN was majorly eliminated as intact LEN via the feces. The renal pathway played a minor role in LEN elimination (0.24%). In addition, no major circulating metabolites in plasma or feces were found, indicating minimal metabolism of LEN.
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Fármacos Anti-VIH , VIH-1 , Adulto , Humanos , Infusiones Intravenosas , Cápside , Voluntarios Sanos , Espectrometría de Masas en Tándem , Biotransformación , Heces/química , Administración OralRESUMEN
BACKGROUND: Checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway are effective therapies in a range of immunogenic cancer types. Blocking this pathway with an oral therapy could benefit patients through greater convenience, particularly in combination regimens, and allow flexible management of immune-mediated toxicities. METHODS: PD-L1 binding activity was assessed in engineered dimerization and primary cell target occupancy assays. Preclinical antitumor activity was evaluated in ex vivo and in vivo human PD-L1-expressing tumor models. Human safety, tolerability, pharmacokinetics, and biomarker activity were evaluated in an open-label, multicenter, sequential dose-escalation study in patients with advanced solid tumors. Biomarkers evaluated included target occupancy, flow cytometric immunophenotyping, plasma cytokine measurements, and T-cell receptor sequencing. RESULTS: GS-4224 binding caused dimerization of PD-L1, blocking its interaction with PD-1 and leading to reversal of T-cell inhibition and increased tumor killing in vitro and in vivo. The potency of GS-4224 was dependent on the density of cell surface PD-L1, with binding being most potent on PD-L1-high cells. In a phase 1 dose-escalation study in patients with advanced solid tumors, treatment was well tolerated at doses of 400-1,500 mg once daily. Administration of GS-4224 was associated with a dose-dependent increase in plasma GS-4224 exposure and reduction in free PD-L1 on peripheral blood T cells, an increase in Ki67 among the PD-1-positive T-cell subsets, and elevated plasma cytokines and chemokines. CONCLUSIONS: GS-4224 is a novel, orally bioavailable small molecule inhibitor of PD-L1. GS-4224 showed evidence of expected on-target biomarker activity, including engagement of PD-L1 and induction of immune-related pharmacodynamic responses consistent with PD-L1 blockade. TRIAL REGISTRATION NUMBER: NCT04049617.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antígeno B7-H1 , Receptor de Muerte Celular Programada 1 , Neoplasias/tratamiento farmacológico , Linfocitos T/metabolismoRESUMEN
A woman in her 30s was referred to an otolaryngologist with an acute onset of aural fullness, noise sensitivity, unilateral sudden onset hearing loss, vertigo and tinnitus. She had a confirmed COVID-19 infection 5 weeks prior. A pure tone audiogram confirmed sensorineural hearing loss. MRI identified an empty sella of the pituitary gland and without an obvious cause for hearing loss. Oral prednisolone and betahistine were prescribed, and her audiovestibular symptoms slowly improved over the subsequent months. The patient continues to experience intermittent tinnitus.
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COVID-19 , Pérdida Auditiva Sensorineural , Pérdida Auditiva Súbita , Acúfeno , Femenino , Humanos , Acúfeno/tratamiento farmacológico , Acúfeno/etiología , COVID-19/complicaciones , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/tratamiento farmacológico , Pérdida Auditiva Sensorineural/etiología , Pérdida Auditiva Súbita/diagnóstico , Pérdida Auditiva Súbita/tratamiento farmacológico , Pérdida Auditiva Súbita/etiología , VértigoRESUMEN
Patients with POTS (postural tachycardia syndrome) have excessive orthostatic tachycardia (>30 beats/min) when standing from a supine position. HR (heart rate) and BP (blood pressure) are known to exhibit diurnal variability, but the role of diurnal variability in orthostatic changes of HR and BP is not known. In the present study, we tested the hypothesis that there is diurnal variation of orthostatic HR and BP in patients with POTS and healthy controls. Patients with POTS (n=54) and healthy volunteers (n=26) were admitted to the Clinical Research Center. Supine and standing (5 min) HR and BP were obtained in the evening on the day of admission and in the following morning. Overall, standing HR was significantly higher in the morning (102±3 beats/min) than in the evening (93±2 beats/min; P<0.001). Standing HR was higher in the morning in both POTS patients (108±4 beats/min in the morning compared with 100±3 beats/min in the evening; P=0.012) and controls (89±3 beats/min in the morning compared with 80±2 beats/min in the evening; P=0.005) when analysed separately. There was no diurnal variability in orthostatic BP in POTS. A greater number of subjects met the POTS HR criterion in the morning compared with the evening (P=0.008). There was significant diurnal variability in orthostatic tachycardia, with a great orthostatic tachycardia in the morning compared with the evening in both patients with POTS and healthy subjects. Given the importance of orthostatic tachycardia in diagnosing POTS, this diurnal variability should be considered in the clinic as it may affect the diagnosis of POTS.
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Ritmo Circadiano/fisiología , Síndrome de Taquicardia Postural Ortostática/fisiopatología , Postura/fisiología , Taquicardia/fisiopatología , Adulto , Presión Sanguínea/fisiología , Epinefrina/sangre , Femenino , Frecuencia Cardíaca/fisiología , Hemodinámica/fisiología , Humanos , Masculino , Norepinefrina/sangre , Síndrome de Taquicardia Postural Ortostática/sangre , Posición Supina/fisiologíaAsunto(s)
Traumatismos por Radiación/etiología , Retina/efectos de la radiación , Enfermedades de la Retina/etiología , Luz Solar/efectos adversos , Atrofia , Angiografía con Fluoresceína , Humanos , Masculino , Persona de Mediana Edad , Células Fotorreceptoras de Vertebrados/patología , Traumatismos por Radiación/diagnóstico , Enfermedades de la Retina/diagnóstico , Segmento Externo de las Células Fotorreceptoras Retinianas/patología , Epitelio Pigmentado de la Retina/patología , Tomografía de Coherencia Óptica , Agudeza VisualRESUMEN
Objective This study attempts to use the Myers-Briggs Type Indicator (MBTI) to analyze personality types among current and recent ophthalmology residents. We aimed to evaluate the prevalence rates of each specific personality type in ophthalmology, and whether these changed by level of training, training program, or fellowship selection. The study aimed to evaluate whether certain personality types are more prevalent in ophthalmology as a unique medical specialty. This can help understand specialty choice and potentially predict trends in specialty selection. Study Design After obtaining institutional review board approval from Howard University Hospital, an electronic version of the MBTI questionnaire, form M, was sent to participants. In addition to the questionnaire, participants responded to four questions inquiring about home program, postgraduate training level, subspecialty interest, and work environment (if applicable). The anonymous responses of the surveys were automatically scored on google forms, and the results were analyzed by using StatView statistical analysis. Setting This study was conducted at Howard University, Georgetown University, George Washington University, University of Texas Medical Branch at Galveston, and Kresge Eye Institute. Participants A total of 66 current residents and recent graduates of five residency programs were involved in this study. Main Outcomes and Measures This study evaluated four-letter personality type from each participant. Results Ophthalmology residents were statistically more likely to be identified in the categories of extroversion (E) than introversion (I) ( p = 0.049), thinking (T) than feeling (F) ( p = 0.027), and judging (J) than perceiving (P) ( p = 0.007), with no statistically significant difference between sensing (S) and intuition (N). ENTP, ESTJ, and ISTJ were the most common personality types, each comprising 13.6% of the sample population. The ratio of J:P was found to increase as training level increased, beginning with postgraduate 2nd year until graduate level. Conclusion Certain personality types are more common among ophthalmology residents in our cohort from five different training programs. It is possible that individual types change over the course of residency training and career. Understanding that these findings exist can be used as a baseline for future research in terms of potential predictors for applicants, of resident knowledge base, and personality changes over the course of one's training.
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Remdesivir (RDV, Veklury®) is a once-daily, nucleoside ribonucleic acid polymerase inhibitor of severe acute respiratory syndrome coronavirus 2 replication. Remdesivir has been granted approvals in several countries for use in adults and children hospitalized with severe coronavirus disease 2019 (COVID-19). Inside the cell, remdesivir undergoes metabolic activation to form the intracellular active triphosphate metabolite, GS-443902 (detected in peripheral blood mononuclear cells), and ultimately, the renally eliminated plasma metabolite GS-441524. This review discusses the pre-clinical pharmacology of RDV, clinical pharmacokinetics, pharmacodynamics/concentration-QT analysis, rationale for dose selection for treatment of patients with COVID-19, and drug-drug interaction potential based on available in vitro and clinical data in healthy volunteers. Following single-dose intravenous administration over 2 h of an RDV solution formulation across the dose range of 3-225 mg in healthy participants, RDV and its metabolites (GS-704277and GS-441524) exhibit linear pharmacokinetics. Following multiple doses of RDV 150 mg once daily for 7 or 14 days, major metabolite GS-441524 accumulates approximately 1.9-fold in plasma. Based on pharmacokinetic bridging from animal data and available human data in healthy volunteers, the RDV clinical dose regimen of a 200-mg loading dose on day 1 followed by 100-mg maintenance doses for 4 or 9 days was selected for further evaluation of pharmacokinetics and safety. Results showed high intracellular concentrations of GS-443902 suggestive of efficient conversion from RDV into the triphosphate form, and further supporting this clinical dosing regimen for the treatment of COVID-19. Mathematical drug-drug interaction liability predictions, based on in vitro and phase I data, suggest RDV has low potential for drug-drug interactions, as the impact of inducers or inhibitors on RDV disposition is minimized by the parenteral route of administration and extensive extraction. Using physiologically based pharmacokinetic modeling, RDV is not predicted to be a clinically significant inhibitor of drug-metabolizing enzymes or transporters in patients infected with COVID-19 at therapeutic RDV doses.
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Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Antivirales/farmacología , Tratamiento Farmacológico de COVID-19 , Adenosina/análogos & derivados , Adenosina Monofosfato/farmacocinética , Adenosina Monofosfato/farmacología , Adenosina Monofosfato/uso terapéutico , Adulto , Alanina/farmacocinética , Alanina/farmacología , Alanina/uso terapéutico , Animales , Antivirales/farmacocinética , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Furanos/metabolismo , Semivida , Humanos , Tasa de Depuración Metabólica , Pirroles/metabolismo , SARS-CoV-2 , Triazinas/metabolismoRESUMEN
PURPOSE: To present an association between acquired pits of the optic nerve (APON) and prior laser-assisted in situ keratomileusis (LASIK). MATERIALS AND METHODS: A retrospective case series of patients with an optic disc pit on clinical exam and a history of LASIK. Spectralis Optical Coherence Tomography images and Humphrey Visual Fields were reviewed from prior visits. Extended-depth optical coherence tomography was performed of the optic nerve head at subsequent visits after patients were identified. RESULTS: Seven patients, aged 45-73 years, were identified each with unilateral optic disc pits. Optic disc pits were located inferior in six patients and centrally in one patient. All demonstrated thinning on optical coherence tomography and six patients had corresponding visual field defects. Four patients identified these defects after their LASIK procedure while two patients were unaware of their reproducible visual field defects. All patients were treated with drops initially. One patient underwent laser trabeculoplasty, and three underwent a trabeculectomy after demonstrating progression on maximum tolerated medical therapy. CONCLUSION: This series describes a possible association between LASIK and APON. Given the similarity and severity of vision loss associated with the optic nerve pits in these patients after LASIK, increased awareness and caution is suggested while considering LASIK in susceptible individuals. HOW TO CITE THIS ARTICLE: Smith AK, Bussel I, Ling J, et al. Acquired Optic Pits Associated with Laser-assisted In Situ Keratomileusis: A Case Series. J Curr Glaucoma Pract 2020;14(3):106-108.
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BACKGROUND: Selonsertib is a first-in-class inhibitor of apoptosis signal-regulating kinase 1 (ASK1) with therapeutic potential for fibrotic diseases. This phase I study evaluated the safety, tolerability, pharmacokinetics (PK), and food effect of selonsertib in healthy subjects. METHODS: This was a double-blinded, randomized, placebo-controlled dose-escalation study. Healthy subjects received 1, 3, 10, 30, or 100 mg of selonsertib or placebo as single or multiple doses once daily for 14 days in the fasted state, or 30 mg or placebo single dose in the fed state. Blood and urine (single-dose cohorts only) samples for selonsertib PK were collected and safety was assessed throughout the study. Ex vivo pharmacodynamic (PD) assessment was performed in blood from a separate cohort of healthy donors using an auranofin-stimulated C-X-C motif chemokine ligand 1 (CXCL1) assay. RESULTS: Overall, 107 subjects (83 active, 24 placebo) were enrolled and randomized to 11 cohorts. Selonsertib was generally well tolerated; adverse events were generally mild to moderate. Selonsertib was rapidly absorbed with dose-proportional PK of both parent and inactive metabolite GS-607509. There was no food effect on selonsertib PK. Renal excretion was a minor pathway of selonsertib elimination. Selonsertib half maximal effective concentration (EC50) in human whole blood was determined to be 56 ng/mL. CONCLUSIONS: Selonsertib exhibited a favorable PK profile amenable to once-daily dosing without regard to food. PD data suggest pharmacologically relevant exposures were achieved in the dose range evaluated. Study results support further clinical development of selonsertib.
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Benzamidas/farmacocinética , Imidazoles/farmacocinética , MAP Quinasa Quinasa Quinasa 5 , Piridinas/farmacocinética , Área Bajo la Curva , Benzamidas/administración & dosificación , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Interacciones Alimento-Droga , Voluntarios Sanos , Humanos , Imidazoles/administración & dosificación , MAP Quinasa Quinasa Quinasa 5/antagonistas & inhibidores , Piridinas/administración & dosificaciónRESUMEN
Remdesivir (RDV), a single diastereomeric monophosphoramidate prodrug that inhibits viral RNA polymerases, has potent in vitro antiviral activity against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). RDV received the US Food and Drug Administration (FDA)'s emergency use authorization in the United States and approval in Japan for treatment of patients with severe coronavirus disease 2019 (COVID-19). This report describes two phase I studies that evaluated the safety and pharmacokinetics (PKs) of single escalating and multiple i.v. doses of RDV (solution or lyophilized formulation) in healthy subjects. Lyophilized formulation was evaluated for potential future use in clinical trials due to its storage stability in resource-limited settings. All adverse events were grade 1 or 2 in severity. Overall, RDV exhibited a linear profile following single-dose i.v. administration over 2 hours of RDV solution formulation across the dose range of 3-225 mg. Both lyophilized and solution formulations provided comparable PK parameters. High intracellular concentrations of the active triphosphate (~ 220-fold to 370-fold higher than the in vitro half-maximal effective concentration against SARS-CoV-2 clinical isolate) were achieved following infusion of 75 mg or 150 mg lyophilized formulation over 30 minutes or 2 hours. Following multiple-doses of RDV 150 mg once daily for 7 or 14 days, RDV exhibited a PK profile similar to single-dose administration. Metabolite GS-441524 accumulated ~ 1.9-fold after daily dosing. Overall, RDV exhibited favorable safety and PK profiles that supported once-daily dosing.
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Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Antivirales/efectos adversos , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Adenosina Monofosfato/administración & dosificación , Adenosina Monofosfato/efectos adversos , Adenosina Monofosfato/farmacocinética , Administración Intravenosa , Adulto , Alanina/administración & dosificación , Alanina/efectos adversos , Alanina/farmacocinética , Antivirales/administración & dosificación , Antivirales/farmacocinética , Área Bajo la Curva , Betacoronavirus/patogenicidad , COVID-19 , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/virología , Femenino , Voluntarios Sanos , Humanos , Japón , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/sangre , Neumonía Viral/epidemiología , Neumonía Viral/virología , SARS-CoV-2 , Adulto Joven , Tratamiento Farmacológico de COVID-19RESUMEN
BACKGROUND: Selgantolimod is a novel oral, selective Toll-like receptor 8 (TLR8) agonist in development for the treatment of chronic hepatitis B (CHB). TLR8 is an endosomal innate immune receptor and a target for treatment of viral infections. This first-in-human study investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of selgantolimod in healthy volunteers. METHODS: Of 71 subjects enrolled, 59 received a single dose of selgantolimod (0.5, 1.5, 3 or 5 mg) or placebo, and 12 were evaluated for food effect. Safety, PK and PD activity by induction of cytokines, chemokines and acute phase proteins were assessed. PK/PD analyses were conducted. RESULTS: Single doses of 0.5-5 mg were generally safe. No serious adverse events (AEs) or AEs leading to discontinuation were reported, and most were Grade 1 in severity. Selgantolimod displayed rapid absorption and dose-proportional PK and PD activity. Food had minimal effect on PK but resulted in diminished PD activity. In PK/PD analyses, near-saturation of induction for most evaluated biomarkers occurred at the 5-mg dose. CONCLUSIONS: Single doses of up to 5 mg selgantolimod were safe and induced dose-dependent PD responses. These data support evaluation of selgantolimod in combination with other agents in future clinical studies of CHB. Australian New Zealand Clinical Trials Registration: ACTRN12616001646437.
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Antivirales/farmacología , Hexanoles/farmacología , Pirimidinas/farmacología , Receptor Toll-Like 8/agonistas , Administración Oral , Adulto , Antivirales/administración & dosificación , Antivirales/efectos adversos , Antivirales/farmacocinética , Quimiocinas/sangre , Relación Dosis-Respuesta a Droga , Femenino , Hepatitis B Crónica/tratamiento farmacológico , Hexanoles/administración & dosificación , Hexanoles/efectos adversos , Hexanoles/farmacocinética , Humanos , Proteína Antagonista del Receptor de Interleucina 1/sangre , Interleucina-12/sangre , Masculino , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Adulto JovenRESUMEN
OBJECTIVE: To investigate the dental arch width of the Southern Chinese across buccal cusps, central fossae, or lingual cusps and compare these values with study findings in different populations and using different definitions. MATERIALS AND METHODS: The dental arch dimensions of study casts of an unselected sample from a 12-year-old Hong Kong Oral Health Survey of 12-year-old children (n = 358; 210 boys and 148 girls) were measured. RESULTS: When compared with Caucasians, the Southern Chinese were characterized by a wider dental arch width. However, variations were great. All maxillary and mandibular male arch widths were significantly larger than female arch widths, except at the incisor regions. CONCLUSION: This study yielded a database about dental arch widths by which different studies on these widths can be compared.
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Pueblo Asiatico , Arco Dental/anatomía & histología , Cefalometría , Niño , China , Bases de Datos Factuales , Femenino , Humanos , Masculino , Valores de Referencia , Caracteres Sexuales , Población BlancaRESUMEN
This study evaluated the effect of supratherapeutic exposure of the anti-HCV drug ledipasvir on the QTc interval in healthy subjects. Sixty healthy volunteers were randomized to receive twice-daily blinded ledipasvir (120 mg) or placebo, administered for 10 days each, or single doses of open-label moxifloxacin (400 mg). Serial plasma samples for ledipasvir concentration analysis were collected after each treatment. Triplicate time-matched electrocardiograms were collected at baseline and after each treatment. Change from baseline in the QTc for ledipasvir or moxifloxacin versus placebo was determined using several correction formulas (primary: QTcF [Fridericia's]; secondary: QTcN [population] and QTcI [individual]). Pharmacokinetics and exposure-QTc relationships were evaluated. Ledipasvir AUC0-24 and Cmax achieved approximately 3.7-fold and 4.2-fold, respectively, above exposures observed following administration of ledipasvir/sofosbuvir (90/400 mg) to HCV-infected patients. There was a lack of effect of supratherapeutic ledipasvir on QTc intervals using all correction methods (upper bound of the 2-sided 90%CIs for the mean difference in time-matched baseline-corrected QTc between ledipasvir versus placebo < 10 milliseconds at all times). The lower bound of the 2-sided 96.67%CI for the mean difference in moxifloxacin versus placebo was >5 milliseconds, thereby establishing assay sensitivity. Categorical analyses did not demonstrate clinically relevant effects of ledipasvir on QTc intervals or other electrocardiogram parameters. No relationships between ledipasvir plasma concentration and QTc interval were observed. Ledipasvir does not prolong QTc interval. Based on these results and a previous TQT evaluation for sofosbuvir, the fixed-dose combination regimen of ledipasvir/sofosbuvir is not expected to prolong the QTc interval.
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Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Electrocardiografía/efectos de los fármacos , Fluorenos/administración & dosificación , Fluorenos/efectos adversos , Adolescente , Adulto , Fármacos Anti-VIH/sangre , Área Bajo la Curva , Bencimidazoles/sangre , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Fluorenos/sangre , Voluntarios Sanos , Humanos , Síndrome de QT Prolongado/inducido químicamente , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Tenofovir alafenamide (TAF), a prodrug of the nucleotide analogue tenofovir (TFV), is an antiretroviral (ARV) agent approved either as a complete regimen [elvitegravir/cobicistat/emtricitabine (F)/TAF, rilpivirine/F/TAF, bictegravir/F/TAF], or for use with other ARVs (F/TAF), for treatment of HIV. TAF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. Disposition of TAF may be altered by comedications that can inhibit or induce P-gp or BCRP transporters. The effects of ARVs on the pharmacokinetics of TAF were evaluated in 3 studies. METHODS: Healthy participants received TAF administered alone or with rilpivirine in study 1, with dolutegravir, ritonavir-boosted atazanavir (ATV + RTV), lopinavir (LPV/RTV), or darunavir (DRV + RTV) in study 2, and with the pharmacokinetic enhancer cobicistat or efavirenz in study 3. RESULTS: Across the 3 studies, 98 participants received treatment with TAF and a coadministered agent (n = 10-34/cohort). All study treatments were well tolerated. TAF and TFV exposures were unaffected after co-administration with rilpivirine and dolutegravir. Coadministration with P-gp/BCRP inhibitors such as cobicistat or PI-based regimens (ATV + RTV, LPV/r, or DRV + RTV) resulted in a range of 6%-183% increases in TAF and 105%-316% increases in TFV exposure, whereas coadministration with a P-gp inducer, efavirenz, resulted in a 15%-24% decrease in TAF and TFV exposure. CONCLUSIONS: Evaluation of the drug interaction between TAF and other commonly prescribed boosted and unboosted ARVs provides characterization of the susceptibility of TAF and/or TFV pharmacokinetics to inhibitors or inducers of P-gp/BCRP transporters.