IL-21 is a Type I cytokine, which uses the common gamma chain (gamma(c)) in its receptor. As members of the gamma(c) cytokine/cytokine receptors family play crucial role in the differentiation, activation, and survival of lymphocytes, we have investigated if IL-21 could promote T cell survival and thus, contribute to T cell homeostasis and expansion. Unlike most gamma(c) cytokine receptors, we report that IL-21R is constitutively expressed by all mature T lymphocytes and that stromal cells of lymphoid organs are a constitutive source of IL-21. These observations are reminiscent of what is observed for IL-7/IL-7R, which control T cell survival and homeostasis and suggest a role for IL-21 in T cell homeostasis. Indeed, our results show that IL-21 is a survival factor for resting and activated T cells. Moreover, the ability of IL-21 to costimulate T cell proliferation is mediated by enhancing T cell viability. Further investigation of how IL-21R signaling induces T cell survival shows for the first time that IL-21 binding to its receptor activates the PI-3K signaling pathway and induces Bcl-2 expression. Moreover, the activation of the PI-3K signaling pathway is essential for IL-21-mediated T cell survival. Our data provide a new role for IL-21 in the immune system, which might be used to improve T cell homeostasis in immunocompromised patients.

Osteomyelitis is an infection located in bone and a notoriously difficult disease to manage, requiring frequent and heavy doses of systemically administered antibiotics. Targeting antibiotics to the bone after systemic administration may provide both greater efficacy of treatment and less frequent administration. By taking advantage of the affinity of the bisphosphonate group for bone mineral, we have prepared a set of 13 bisphosphonated antibacterial prodrugs based on eight different linkers tethered to the free amino functionality on fluoroquinolone antibiotics. While all but one of the prodrugs were shown in vitro to be effective and rapid bone binders (over 90% in 1 h), only eight of them demonstrated the capacity to significantly regenerate the parent drug. In a rat model of the disease, a selected group of agents demonstrated their ability to prevent osteomyelitis when used in circumstances under which the parent drug had already been cleared and is thus inactive.

No abstract

Benzoxazinorifamycins are potent antibacterial agents currently in development. Tethering these antibiotics to a bisphosphonate functional group by a cleavable linker allows the delivery of these agents to osseous tissues, where they can be released over time to treat bone infections. Various linker strategies are presented herein to develop osteotropic prodrugs, the activities of which are examined in vitro and in vivo.

The pharmacokinetics and bone concentrations of oritavancin were investigated after a single intravenous dose was administered to rabbits. The pharmacokinetic profile of oritavancin in rabbits showed that it is rapidly distributed to bone tissues, with concentrations remaining stable for up to 168 h, the last measured time point. Based on these findings, further evaluation of oritavancin for the treatment of infections in bone tissues is warranted. (2) and rapid concentration-dependent bactericidal activity in vitro against a variety of Gram-positive species, including drug-resistant enterococci, staphylococci, and streptococci (3). Oritavancin is characterized by a long half-life (4), which allows for the treatment of ABSSSI with a single dose of the drug (Orbactiv package insert [1]).S. aureus is the most common pathogen responsible for bone and joint infections (5-8); these infections often require long treatment durations with frequent dosing. The high level of activity of oritavancin against S. aureus (including MRSA) and its long half-life are characteristics that warrant further investigations for the treatment of infections caused by Gram-positive infection requiring long-term antibiotic therapy, such as bone and joint infections. This study was conducted to determine the systemic exposure of oritavancin in rabbits relative to human exposure and to evaluate the bone penetration of oritavancin after a humanized dose in rabbits. MATERIALS AND METHODSAntimicrobial agent. Oritavancin was manufactured and provided by The Medicines Company. Oritavancin powder was dissolved in 5% dextrose in water, mixed by vortexing for 1 min, filtered through a sterile 0.22-m filter, and stored at room temperature until administration. Oritavancin was administered as a 5-min intravenous infusion via the marginal ear vein using an indwelling catheter.Animals. Ten-to 12-week-old male New Zealand White rabbits (Charles River Laboratories, Saint-Constant, Canada) weighing 2.1 to 2.5 kg were used. The animal care and use practices in this study were in accordance with the guidelines and policies of the American Association of Laboratory Animal Care and the Canadian Council on Animal Care. All experimental protocols were approved by an institutional animal care and use committee.Pharmacokinetic study in serum. Twelve rabbits (n ϭ 3/dose) were administered 10, 15, 20, or 40 mg/kg of body weight of oritavancin. Blood samples were collected at 0.5, 3, 6, 12, and 24 h after dosing from each rabbit via the central ear artery. It is to be noted that blood collection at 12 h from animals receiving 40 mg/kg was inadvertently not performed.Pharmacokinetic study in bone. Twenty-one rabbits (n ϭ 3/time point) were administered a 20-mg/kg dose of oritavancin. This dose was selected subsequently to the pharmacokinetic study in serum, as it provided an exposure close to the 1,200-mg single dose in humans. Blood samples were collected at 0. 08,3,6,14,24, 48, and 168 h after dosing via the central ear artery. Late blood sampling at 168 h was sele...