Pharmacokinetics and biodistribution of extracellular vesicles administered intravenously and intranasally to Macaca nemestrina.

Extracellular vesicles (EVs) have potential in disease treatment since they can be loaded with therapeutic molecules and engineered for retention by specific tissues. However, questions remain on optimal dosing, administration, and pharmacokinetics. Previous studies have addressed biodistribution and pharmacokinetics in rodents, but little evidence is available for larger animals. Here, we investigated the pharmacokinetics and biodistribution of Expi293F-derived EVs labelled with a highly sensitive nanoluciferase reporter (palmGRET) in a non-human primate model (Macaca nemestrina), comparing intravenous (IV) and intranasal (IN) administration over a 125-fold dose range. We report that EVs administered IV had longer circulation times in plasma than previously reported in mice and were detectable in cerebrospinal fluid (CSF) after 30-60 minutes. EV association with PBMCs, especially B-cells, was observed as early as one minute post-administration. EVs were detected in liver and spleen within one hour of IV administration. However, IN delivery was minimal, suggesting that pretreatment approaches may be needed in large animals. Furthermore, EV circulation times strongly decreased after repeated IV administration, possibly due to immune responses and with clear implications for xenogeneic EV-based therapeutics. We hope that our findings from this baseline study in macaques will help to inform future research and therapeutic development of EVs.

The use of midazolam as an appetite stimulant and anxiolytic in the common marmoset (Callithrix jacchus).

BACKGROUND: Food avoidance secondary to disease or stress can lead to weight loss and rapid deterioration of clinical condition in the common marmoset (Callithrix jacchus). Currently, there are no data supporting the use of any pharmaceuticals as an appetite stimulant in this species; however, benzodiazepines are frequently used for this purpose in other species. METHODS: Six marmosets were used in a crossover study design to evaluate the benzodiazepine midazolam as an appetite stimulant and anxiolytic. Total food intake (TFI) and latency to eat (LTE) were measured following administration of oral and injectable midazolam in non-anxious and anxious states. RESULTS: Injectable midazolam increased TFI and decreased LTE in anxious marmosets, but had no effect in non-anxious animals. Oral midazolam had no effect on appetite in either state. CONCLUSIONS: Injectable midazolam may be an effective treatment for anxiety-induced inappetence in marmosets. Individual response to both oral and injectable midazolam may vary.