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1.
Invest New Drugs ; 38(5): 1463-1471, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32157599

RESUMO

Cisplatin is a widely used chemotherapy for the treatment of certain solid tumors. Ototoxicity and subsequent permanent hearing loss remain a serious dose-limiting side effect associated with cisplatin treatment. To date, no therapies have been approved to prevent or treat cisplatin-induced hearing loss (CIHL). Sodium thiosulfate effectively inactivates cisplatin through covalent binding and may provide protection against cisplatin-induced ototoxicity. DB-020 is being developed as a novel formulation of sodium thiosulfate pentahydrate in 1% sodium hyaluronate for intratympanic injection (IT), enabling the delivery of high concentrations of thiosulfate into the cochlea prior to cisplatin administration. In the DB-020-002 phase 1a single-ascending dose study, healthy volunteers were enrolled into 5 cohorts to receive different doses of DB-020 via IT injection. Cohorts 1-4 received unilateral injections while Cohort 5 received bilateral injections. Plasma thiosulfate pharmacokinetics was measured, and safety and audiometric data were collected throughout the study. This study has demonstrated that intratympanic administration of DB-020 results in nominal systemic increases in thiosulfate levels, hence it should not compromise cisplatin anti-tumor efficacy. Furthermore, DB-020 was safe and well tolerated with most adverse events reported as transient, of mild-to-moderate severity and related to the IT administration procedure. These results support the design and execution of the ongoing proof-of-concept study, DB-020-002, to assess otoprotection using DB-020 in cancer patients receiving cisplatin without negatively impacting cisplatin anti-tumor efficacy.


Assuntos
Antineoplásicos/administração & dosagem , Perda Auditiva/prevenção & controle , Tiossulfatos/administração & dosagem , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cisplatino/farmacocinética , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Perda Auditiva/induzido quimicamente , Humanos , Injeção Intratimpânica , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Tiossulfatos/efeitos adversos , Tiossulfatos/sangue , Tiossulfatos/farmacocinética , Adulto Jovem
2.
Psychon Bull Rev ; 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38361106

RESUMO

It is well known that contextual predictability facilitates word identification, but it is less clear whether the uncertainty associated with the current context (i.e., its lexical entropy) influences sentence processing. On the one hand, high entropy contexts may lead to interference due to greater number of lexical competitors. On the other hand, predicting multiple lexical competitors may facilitate processing through the preactivation of shared semantic features. In this study, we examined whether entropy measured at the trial level (i.e., for each participant, for each item) corresponds to facilitatory or inhibitory effects. Trial-level entropy captures each individual's knowledge about specific contexts and is therefore a more valid and sensitive measure of entropy (relative to the commonly employed item-level entropy). Participants (N = 112) completed two experimental sessions (with counterbalanced orders) that were separated by a 3- to 14-day interval. In one session, they produced up to 10 completions for sentence fragments (N = 647). In another session, they read the same sentences including a target word (whose entropy value was calculated based on the produced completions) while reading times were measured. We observed a facilitatory (not inhibitory) effect of trial-level entropy on lexical processing over and above item-level measures of lexical predictability (including cloze probability, surprisal, and semantic constraint). Extra analyses revealed that greater semantic overlap between the target and the produced responses facilitated target processing. Thus, the results lend support to theories of lexical prediction maintaining that prediction involves broad activation of semantic features rather than activation of full lexical forms.

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