Tolerability and pharmacokinetic evaluation of inhaled dry powder hydroxychloroquine in healthy volunteers

RATIONALE: Inhaled antimicrobials enable high local concentrations where needed and, compared to orally administration, greatly reduce the potential for systemic side effects. In SARS-CoV-2 infections, hydroxychloroquine sulphate (HCQ) administered as dry powder via inhalation could be safer than oral HCQ allowing higher and therefore more effective pulmonary concentrations without dose limiting toxic effects. OBJECTIVES: To assess the local tolerability, safety and pharmacokinetic parameters of HCQ inhalations in single ascending doses of 5, 10 and 20 mg using the Cyclops dry powder inhaler. METHODS: Twelve healthy volunteers were included in the study. Local tolerability and safety were assessed by pulmonary function tests, electrocardiogram and recording adverse events. To estimate systemic exposure, serum samples were collected before and 0.5, 2 and 3.5 h after inhalation. RESULTS AND DISCUSSION: Dry powder HCQ inhalations were well tolerated by the participants, except for transient bitter taste in all participants and minor coughing irritation. There was no significant change in QTc-interval or drop in FEV1 post inhalation. The serum HCQ concentration remained below 10 μg/L in all samples. CONCLUSION: Single doses of inhaled dry powder HCQ up to 20 mg are safe and well tolerated. Our data support that further studies with inhaled HCQ dry powder to evaluate pulmonary pharmacokinetics and efficacy are warranted

Theory change as dimensional change: Conceptual spaces applied to the dynamics of empirical theories

This paper offers a novel way of reconstructing conceptual change in empirical theories. Changes occur in terms of the structure of the dimensions-that is to say, the conceptual spaces-underlying the conceptual framework within which a given theory is formulated. Five types of changes are identified: (1) addition or deletion of special laws, (2) change in scale or metric, (3) change in the importance of dimensions, (4) change in the separability of dimensions, and (5) addition or deletion of dimensions. Given this classification, the conceptual development of empirical theories becomes more gradual and rationalizable. Only the most extreme type-replacement of dimensions-comes close to a revolution. The five types are exemplified and applied in a case study on the development within physics from the original Newtonian mechanics to special relativity theory. © 2012 Springer Science+Business Media B.V