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1.
Antimicrob Agents Chemother ; 68(5): e0161523, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38526047

RESUMEN

AT-752 is a novel guanosine nucleotide prodrug inhibitor of the dengue virus (DENV) polymerase with sub-micromolar, pan-serotype antiviral activity. This phase 1, double-blind, placebo-controlled, first-in-human study evaluated the safety, tolerability, and pharmacokinetics of ascending single and multiple oral doses of AT-752 in healthy subjects. AT-752 was well tolerated when administered as a single dose up to 1,500 mg or when administered as multiple doses up to 750 mg three times daily (TID). No serious adverse events occurred, and the majority of treatment-emergent adverse events were mild in severity and resolved by the end of the study. In those receiving single ascending doses of AT-752, no pharmacokinetic sensitivity was observed in Asian subjects, and no food effect was observed. Plasma exposure of the guanosine nucleoside metabolite AT-273, the surrogate of the active triphosphate metabolite of the drug, increased with increasing dose levels of AT-752 and exhibited a long half-life of approximately 15-25 h. Administration of AT-752 750 mg TID led to a rapid increase in plasma levels of AT-273 exceeding the target in vitro 90% effective concentration (EC90) of 0.64 µM in inhibiting DENV replication, and maintained this level over the treatment period. The favorable safety and pharmacokinetic results support the evaluation of AT-752 as an antiviral for the treatment of dengue in future clinical studies.Registered at ClinicalTrials.gov (NCT04722627).


Asunto(s)
Antivirales , Dengue , Nucleótidos de Guanina , Profármacos , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Antivirales/efectos adversos , Antivirales/farmacocinética , Dengue/tratamiento farmacológico , Método Doble Ciego , Semivida , Profármacos/efectos adversos , Profármacos/farmacocinética , Adolescente
2.
Future Virol ; 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37928891

RESUMEN

Aim: This phase III study assessed the efficacy/safety/antiviral activity/pharmacokinetics of bemnifosbuvir, a novel, oral nucleotide analog to treat COVID-19. Patients & methods: Outpatient adults/adolescents with mild-to-moderate COVID-19 were randomized 2:1 to bemnifosbuvir/placebo. Time to symptom alleviation/improvement (primary outcome), risk of hospitalization/death, viral load and safety were evaluated. Results: Although the study was discontinued prematurely and did not meet its primary end point, bemnifosbuvir treatment resulted in fewer hospitalizations (71% relative risk reduction), COVID-19-related medically attended hospital visits, and COVID-19-related complications compared with placebo. No reduction in viral load was observed. The proportion of patients with adverse events was similar; no deaths occurred. Conclusion: Bemnifosbuvir showed hospitalization reduction in patients with variable disease progression risk and was well tolerated. Clinical Trial Registration: NCT04889040 (ClinicalTrials.gov).

3.
Contemp Clin Trials Commun ; 23: 100830, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34401600

RESUMEN

BLZ-100 (tozuleristide) is an intraoperative fluorescent imaging agent that selectively detects malignant tissue and can be used in real time to guide tumor resection. The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of BLZ-100 and to explore the pharmacodynamics of fluorescence imaging of skin tumors. In this first-in-human study, BLZ-100 was administered intravenously to 21 adult patients 2 days before excising known or suspected skin cancers. Doses were 1, 3, 6, 12, and 18 mg, with 3-6 patients/cohort. Fluorescence imaging was conducted before and up to 48 h after dosing. BLZ-100 was well tolerated. There were no serious adverse events, deaths, or discontinuations due to adverse events, and no maximum tolerated dose (MTD) was identified. Headache (n = 2) and nausea (n = 2) were the only BLZ-100 treatment-related adverse events reported for >1 patient. Median time to maximal serum concentration was <0.5 h. Exposure based on maximal serum concentrations increased in a greater than dose-proportional manner. For intermediate dose-levels (3-12 mg), 4 of 5 basal cell carcinomas and 4 of 4 melanomas were considered positive for BLZ-100 fluorescence. BLZ-100 was well tolerated at all dose levels tested and these results support further clinical testing of this imaging agent in surgical oncology settings. Clinicaltrials.gov: NCT02097875.

4.
Neurosurgery ; 85(4): E641-E649, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31069381

RESUMEN

BACKGROUND: Fluorescence-guided surgery (FGS) can improve extent of resection in gliomas. Tozuleristide (BLZ-100), a near-infrared imaging agent composed of the peptide chlorotoxin and a near-infrared fluorophore indocyanine green, is a candidate molecule for FGS of glioma and other tumor types. OBJECTIVE: To perform a phase 1 dose-escalation study to characterize the safety, pharmacokinetics, and fluorescence imaging of tozuleristide in adults with suspected glioma. METHODS: Patients received a single intravenous dose of tozuleristide 3 to 29 h before surgery. Fluorescence images of tumor and cavity in Situ before and after resection and of excised tissue ex Vivo were acquired, along with safety and pharmacokinetic measures. RESULTS: A total of 17 subjects received doses between 3 and 30 mg. No dose-limiting toxicity was observed, and no reported adverse events were considered related to tozuleristide. At doses of 9 mg and above, the terminal serum half-life for tozuleristide was approximately 30 min. Fluorescence signal was detected in both high- and low-grade glial tumors, with high-grade tumors generally showing greater fluorescence intensity compared to lower grade tumors. In high-grade tumors, signal intensity increased with increased dose levels of tozuleristide, regardless of the time of dosing relative to surgery. CONCLUSION: These results support the safety of tozuleristide at doses up to 30 mg and suggest that tozuleristide imaging may be useful for FGS of gliomas.


Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Glioma/diagnóstico por imagen , Verde de Indocianina/análogos & derivados , Recurrencia Local de Neoplasia/diagnóstico por imagen , Imagen Óptica/métodos , Venenos de Escorpión/administración & dosificación , Venenos de Escorpión/farmacocinética , Adulto , Anciano , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/cirugía , Relación Dosis-Respuesta a Droga , Femenino , Colorantes Fluorescentes/administración & dosificación , Colorantes Fluorescentes/farmacocinética , Glioma/metabolismo , Glioma/cirugía , Humanos , Verde de Indocianina/administración & dosificación , Verde de Indocianina/farmacocinética , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/cirugía
5.
Arch Pathol Lab Med ; 143(9): 1076-1083, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-30550350

RESUMEN

CONTEXT.­: Resection of breast carcinoma with adequate margins reduces the risk of local recurrence and reoperation. Tozuleristide (BLZ-100) is an investigational peptide-fluorophore agent that may aid in intraoperative tumor detection and margin assessment. In this study, fluorescence imaging was conducted ex vivo on gross breast pathology specimens. OBJECTIVES.­: To determine the potential of tozuleristide to detect breast carcinoma in fresh pathology specimens and the feasibility of fluorescence-guided intraoperative pathology assessment of surgical margins. DESIGN.­: Twenty-three patients received an intravenous bolus dose of 6 or 12 mg of tozuleristide at least 1 hour before surgery. Fifteen lumpectomy and 12 mastectomy specimens were evaluated for fluorescence by the site's clinical pathology staff using the SIRIS, an investigational near-infrared imaging device. The breast tissue was then processed per usual procedures. Fluorescent patterns were correlated with the corresponding hematoxylin-eosin-stained sections. Clinical pathology reports were used to correlate fluorescent signal to grade, histotype, prognostic marker status, and margin measurements. RESULTS.­: Tozuleristide fluorescence was readily observed in invasive and in situ breast carcinoma specimens. Most invasive carcinomas were bright and focal, whereas in situ lesions demonstrated a less intense, more diffuse pattern. Tozuleristide was detected in ductal and lobular carcinomas with a similar fluorescent pattern. Fluorescence was detected in high- and low-grade lesions, and molecular marker/hormone receptor status did not affect signal. Fluorescence could be used to identify the relationship of carcinoma to margins intraoperatively. CONCLUSIONS.­: Tumor targeting with tozuleristide allowed visual real-time distinction between pathologically confirmed breast carcinoma and normal tissue.


Asunto(s)
Carcinoma de Mama in situ/diagnóstico por imagen , Neoplasias de la Mama/diagnóstico por imagen , Carcinoma Ductal de Mama/diagnóstico por imagen , Carcinoma Lobular/diagnóstico por imagen , Colorantes Fluorescentes , Verde de Indocianina/análogos & derivados , Venenos de Escorpión , Carcinoma de Mama in situ/patología , Carcinoma de Mama in situ/cirugía , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/cirugía , Carcinoma Lobular/patología , Carcinoma Lobular/cirugía , Femenino , Humanos , Cuidados Intraoperatorios/métodos , Márgenes de Escisión , Mastectomía , Mastectomía Segmentaria , Invasividad Neoplásica/diagnóstico por imagen , Invasividad Neoplásica/patología , Pronóstico
6.
Blood ; 108(1): 57-62, 2006 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-16556896

RESUMEN

Congenital factor XIII (FXIII) deficiency is associated with a tendency for severe bleeding, a risk for spontaneous abortion, and a high rate of spontaneous intracranial hemorrhage. This phase 1 escalating-dose study was developed to evaluate the safety and pharmacokinetics of a single administration of human recombinant FXIII-A2 (rFXIII-A2) homodimer in adults with congenital FXIII deficiency. Pharmacokinetics and activity of rXIII and changes in endogenous B subunit levels were assessed. Recombinant FXIII-A2 homodimer were complexed with endogenous FXIII-B subunits to form an FXIII-A2B2 heterotetramer with a half-life of 8.5 days, similar to that of endogenous FXIII. The median dose response was a 2.4% increase in FXIII activity based on unit per kilogram rFXIII administered. After the administration of rFXIII-A2, clot solubility normalized as measured by clot lysis in urea. Clot strength and resistance to fibrinolysis, as assessed by thromboelastography, also improved. Safety reviews were conducted before each dose escalation; no serious adverse events, including bleeding or thrombosis, were noted during the study. In addition, there was no evidence of the generation of specific antibodies to rFXIII or yeast proteins. Recombinant FXIII appears to be a safe and potentially effective alternative for FXIII replacement in patients with FXIII deficiency.


Asunto(s)
Deficiencia del Factor XIII/tratamiento farmacológico , Factor XIII , Factor XIIIa/farmacocinética , Proteínas Recombinantes/farmacocinética , Adulto , Anciano , Coagulación Sanguínea/efectos de los fármacos , Pruebas de Coagulación Sanguínea , Dimerización , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Factor XIII/análisis , Deficiencia del Factor XIII/congénito , Deficiencia del Factor XIII/inmunología , Factor XIIIa/administración & dosificación , Factor XIIIa/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Solubilidad , Tromboelastografía , Factores de Tiempo
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