Background Factors limiting the efficacy of conventional antiretroviral therapy for HIV-1 infection include treatment adherence, pharmacokinetics and penetration into viral sanctuaries. These affect the rate of viral mutation and drug resistance. In attempts to bypass such limitations, nanoparticles containing ritonavir, indinavir and efavirenz (described as nanoART) were manufactured to assess macrophage-based drug delivery. Methods NanoART were made by high-pressure homogenization of crystalline drug with various surfactants. Size, charge and shape of the nanoparticles were assessed. Monocyte-derived macrophage nanoART uptake, drug release, migration and cytotoxicity were determined. Drug levels were measured by reverse-phase high-performance liquid chromatography. Results Efficient monocyte-derived macrophage cytoplasmic vesicle uptake in less than 30 min based on size, charge and coating was observed. Antiretroviral drugs were released over 14 days and showed dose-dependent reduction in progeny virion production and HIV-1 p24 antigen. Cytotoxicities resulting from nanoART carriage were limited. Conclusion These results support the continued development of macrophage-mediated nanoART carriage for HIV-1 disease.

We posit that improvements in pharmacokinetics and biodistributions of antiretroviral therapies (ART) for human immunodeficiency virus-type one infected people can be achieved through developments in nanoformulations. To this end, we manufactured nanoparticles of atazanavir, efavirenz, and ritonavir (termed nanoART) and treated human monocyte-derived macrophages (MDM) in combination therapies. This resulted in improved drug uptake, release and antiretroviral efficacy over monotherapy. MDM rapidly, within minutes, ingested nanoART combinations, at equal or similar rates, as individual formulations. Combination nanoART ingested by MDM facilitated drug release from 15 to > 20 days. These findings are noteworthy as a nanoART cell-mediated drug delivery provides a means to deliver therapeutics to viral sanctuaries, such as the central nervous system during progressive human immunodeficiency virus-type one infection. The work brings us yet another step closer to realizing the utility of nanoART for virus-infected people.

A tandem reaction sequence involving relay metathesis-induced enyne RCM and metallotropic [1,3]shift is an effective tool to construct cyclic alkenes with embedded 1,5-dien-3-yne moieties from acyclic precursors containing a 1,3-diyne. Total syntheses of (+)-asperpentyn, (-)-harveynone and (-)-tricholomenyn A have been accomplished by implementing this metathesis-based tandem reaction sequence as the key step.Epoxyquinoids, a subclass of naturally occurring cyclohexane epoxides, display a broad range of structural variation and impressive biological activities, and thus have elicited significant synthetic and biological studies. 1 Among many naturally occurring epoxyquinoids, (+)-asperpentyn, 2 (-)-harveynone 3 and its prenylated homolog (-)-tricholomenyn A 4 have an embedded 1,5-dien-3-yne moiety (Scheme 1). Due to this structural characteristic, Ogasawara, 5 Johnson, 6 Taylor, 7 Maycock, 8 Negishi, 9 and Kitahara 10 utilized Pd-catalyzed Sonagashira or Stille coupling between the preformed 2-bromo-or iodocyclo-hexenone derivatives (bromoxone or its iodo analogue) 11 and appropriate 1,3-enyne counterparts for their total syntheses.We envisioned a conceptually new strategy relying on enyne metathesis 12 -based construction of the cyclohexene core with concommitant installation of the 1,3-enyne moieties starting from the corresponding acyclic precursors. This new approach will harness a streamlined sequence of enyne ring-closing metathesis followed by metallotropic [1,3]-shift, 13 whereby the 1,5-dien-3-yne moiety will be directly installed on the incipient epoxycyclohexene ring. Herein we describe a successful application of this powerful tandem reaction to the concise syntheses of (+)-asperpentyn, (-)-harveynone and (-)-tricholomenyn A. Retrosynthetically, we envisaged that cyclohexene derivative 1 with an appropriate R substituent would serve as a common advanced intermediate for all three natural product targets: (+)-asperpentyn, (-)-harveynone and (-)-tricholomenyn A (Scheme 2). A direct precursor of 1 would be an acyclic 1,3-diyne-contaning compound 2 or its simpler variant lacking the relay device. The pivotal metathesis substrate 2 would be prepared through flouoride-catalyzed addition of silylated 1,3-diyne 4 to epoxy aldehyde 3, which in turn would be derived from aldehyde 5 14 and allyl propargyl ether 6. To test the feasibility of the key step, alkene-tethered 1,3-diyne 11 was prepared from commercially available cis-2-buten-1,4-diol 7 in 8 steps (Scheme 3). Following the known procedure involving the Sharpless asymmetric epoxidation 15 , the diol 7 was elaborated to epoxide 8. Oxidation of the primary alcohol with PCC to generate aldehyde 5 was followed by addition of vinyl magnesium bromide, MOMprotection of the resultant secondary alcohol (1:1 mixture) and removal of the TBS group afforded primary alcohol 9. After Dess-Martin oxidation 16 of the primary alcohol, a lithiated diyne derived from 10 was added to provide RCM substrate 11. Disappointingly, however, treatment of 11 with Grubb's se...

Pre-filled syringes are convenient devices for the delivery of parenteral medications. They are small which makes them easy to carry and are dependable for delivering a precise dose of medication. These and many other reasons are leading to their growth in the pharmaceutical market. There are a number of review articles that describe the advantages and disadvantages of pre-filled syringes. However, there are few journal articles that present information on their manufacturing and challenges. The intent of this review article is to provide information on the history of the pre-filled syringe, methods of their manufacture, methods of filling syringes as a drug product and to examine the types of syringes available. This type of knowledge can familiarize the formulation scientist with the choices available and their possible challenges.

Two consecutive ruthenium-catalyzed reactions have been achieved for the synthesis of siloxacycles from terminal alkenyl carbenols and alkynylsilanes. The metal-catalyzed dehydrogenative condensation between alcohols and silanes, generating molecular hydrogen as the only byproduct, allows for the subsequent enyne metathesis without isolating the intermediate silyl ethers. This system provides a streamlined synthesis of synthetically useful building blocks. [reaction: see text]