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Inhaled drug delivery is a promising approach to achieving high lung drug concentrations to facilitate efficient treatment of tuberculosis (TB) and to reduce the overall duration of treatment. Rifampicin is a good candidate for delivery via the pulmonary route. There have been no clinical studies yet at relevant inhaled doses despite the numerous studies investigating its formulation and preclinical properties for pulmonary delivery. This review discusses the clinical implications of pulmonary drug delivery in TB treatment, the drug delivery systems reported for pulmonary delivery of rifampicin, animal models, and the animal studies on inhaled rifampicin formulations, and the research gaps hindering the transition from preclinical development to clinical investigation. A review of reports in the literature suggested there have been minimal attempts to test inhaled formulations of rifampicin in laboratory animals at relevant high doses and there is a lack of appropriate studies in animal models. Published studies have reported testing only low doses (≤ 20 mg/kg) of rifampicin, and none of the studies has investigated the safety of inhaled rifampicin after repeated administration. Preclinical evaluations of inhaled anti-TB drugs, such as rifampicin, should include high-dose formulations in preclinical models, determined based on allometric conversions, for relevant high-dose anti-TB therapy in humans. Graphical abstract
Inhaled drug delivery is a promising approach to achieving high lung drug concentrations to facilitate efficient treatment of tuberculosis (TB) and to reduce the overall duration of treatment. Rifampicin is a good candidate for delivery via the pulmonary route. There have been no clinical studies yet at relevant inhaled doses despite the numerous studies investigating its formulation and preclinical properties for pulmonary delivery. This review discusses the clinical implications of pulmonary drug delivery in TB treatment, the drug delivery systems reported for pulmonary delivery of rifampicin, animal models, and the animal studies on inhaled rifampicin formulations, and the research gaps hindering the transition from preclinical development to clinical investigation. A review of reports in the literature suggested there have been minimal attempts to test inhaled formulations of rifampicin in laboratory animals at relevant high doses and there is a lack of appropriate studies in animal models. Published studies have reported testing only low doses (≤ 20 mg/kg) of rifampicin, and none of the studies has investigated the safety of inhaled rifampicin after repeated administration. Preclinical evaluations of inhaled anti-TB drugs, such as rifampicin, should include high-dose formulations in preclinical models, determined based on allometric conversions, for relevant high-dose anti-TB therapy in humans. Graphical abstract
Statins form a class of drugs often administered in a variety of cardiovascular diseases, for which their antioxidant capacity appears particularly relevant. Although experiments have long provided empirical evidence that statins can suppress various oxidation pathways, theoretical attempts to quantify the antioxidant activity of statins (read, atorvastatin ATV, because this is the only one studied so far) were not published until last year. Molecular and clinical differences of stains trace back to the ring attached to the active moiety of the statin. This can be, e.g., a pyrrole, as the case of the aforementioned ATV or a quinoline, as the case of pitavastatin (PVT), which represents the focus of the present work. Extensive results reported here for PVT and derivative include the thermodynamic antioxidant descriptors (bond dissociation enthalpy BDE, adiabatic ionization potential IP, proton dissociation enthalpy PDE, proton affinity PA, and electron transfer enthalpy ETE) related to the three antioxidant mechanisms (hydrogen atom transfer HAT, stepwise electron transfer proton transfer SETPT, sequential proton loss electron transfer SPLET). Our particular emphasis is on the PVT hydroxylated derivatives wherein a hydroxy group replaces a hydrogen atom either on the quinoline core (Q-hydroxylated metabolites) or on the fluorophenyl ring (F-hydroxylated metabolites). Our calculations indicate that both the Q- and F-hydroxylated metabolites possess antioxidant properties superior to the parent PVT molecule. Given the fact that, to the best of our knowledge, no experimental data for the antioxidant potency of PVT and its hydroxylated derivatives exist, this is a theoretical prediction, and we Given the fact that, to the best of our knowledge, no experimental data for the antioxidant potency of PVT and its hydroxylated derivatives exist, this is a theoretical prediction for the validation of which we aim hereby to stimulate companion experimental in vivo and in vitro investigations and inspire pharmacologists in further drug developments.
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