have contributed equally to the present paper.Precis: Melatonin encapsulated in solid lipid nanoparticles enterally administered in critically ill patients has useful pharmacokinetics; transdermal microemulsion has concentration-time profile more similar to endogenous one. AbstractBackground and objectives: Critically ill patients present reduced endogenous melatonin blood levels, and they might benefit from its exogenous supplementation. The aim of this research was to evaluate the feasibility of different routes of administration and drug formulations of melatonin. The efficiency of absorption was assessed as well as the adequacy in achieving and maintaining the physiological nocturnal blood peak.Methods: Twenty-one high-risk critically ill patients were randomly assigned to receive melatonin either: (a) per os, as a standard tablet (ST-OS), (b) per os, as a suspension in solid lipid nanoparticles (SLN-OS) or c) transdermal (TD), by applying a jellified melatonin microemulsion (μE) on the skin (μE-TD). SLN-OS and μE-TD were lipidbased colloidal systems. The endogenous melatonin blood values were observed for 24 hours; subsequently, melatonin 3 mg was administered and pharmacokinetics was studied for 24 hours further. Results:In both groups that received ST-OS and SLN-OS, the median time-topeak blood concentration was 0.5 hours; however, the area under the curve (AUC) after administration of SLN-OS was significantly higher than after ST-OS (157386 [65732-193653] vs 44441 [22319-90705] pg/mL*hours, P = 0.048). μE-TD presented a delayed time-to-peak blood concentration (4 hours), a lower bioavailability (AUC: 3142 [1344-14573] pg/mL*hours) and reached pharmacological peak concentration (388 [132-1583] pg/mL).Conclusions: SLN-melatonin enterally administered offers favourable pharmacokinetics in critically ill patients, with higher bioavailability with respect to the standard formulation; μE-TD provided effective pharmacological blood levels, with a time-concentration profile more similar to the physiological melatonin pattern. K E Y W O R D Scritically ill patients, lipid nanovector encapsulation, melatonin, microemulsion, transdermal absorption

No abstract

No abstract

No abstract

Antibody-drug conjugates (ADCs) delivering pyrrolobenzodiazepine (PBD) DNA crosslinkers are currently being evaluated in clinical trials with encouraging results in Hodgkin and non-Hodgkin lymphomas. The first example of an ADC delivering a PBD DNA crosslinker (loncastuximab tesirine) has been recently approved by the U.S. Food and Drug Administration for the treatment of relapsed and refractory diffuse large B-cell lymphoma. There has also been considerable interest in mono-alkylating PBD analogues. We conducted a head-to-head comparison of a conventional PBD bis-imine and a novel PBD mono-imine. Key Mitsunobu chemistry allowed clean and convenient access to the mono-imine class. Extensive DNA binding studies revealed that the mono-imine mediated a type of DNA interaction that is described as “pseudo-crosslinking,” as well as alkylation. The PBD mono-imine ADC demonstrated robust antitumor activity in mice bearing human tumor xenografts at doses threefold higher than those that were efficacious for the PBD bis-imine ADC. A single-dose toxicology study in rats demonstrated that the maximum tolerated dose of the PBD mono-alkylator ADC was approximately threefold higher than that of the ADC bearing a bis-imine payload, suggesting a comparable therapeutic index for this molecule. However, although both ADCs caused myelosuppression, renal toxicity was observed only for the bis-imine after repeated dosing, indicating possible differences in toxicological profiles that could influence tolerability and therapeutic index. These data show that mono-amine PBDs have physicochemical and pharmaco-toxicological properties distinct from their crosslinking analogues and support their potential utility as a novel class of ADC payload.