Metabolism and Pharmacokinetics of SP-8356, a Novel (1S)-(-)-Verbenone Derivative, in Rats and Dogs and Its Implications in Humans.

(1S,5R)-4-((E)-3,4-dihydroxy-5-methoxystryryl)-6,6-dimethylbicylco[3.1.1]hept-3-en-2-one (SP-8356) is a novel (1S)-(-)-verbenone derivative that is currently in preclinical development for the treatment of ischemic stroke and atherosclerosis. This report aimed at characterization of the metabolism and pharmacokinetic properties of SP-8356. Following intravenous dose in rats and dogs, plasma concentrations of SP-8356 declined rapidly with high clearance (CL) and short half-life; after oral administration in both species, its plasma levels were below the quantitation limit. Fourteen circulating metabolites, formed by mono-oxygenation, demethylation, glucuronidation, catechol O-methylation, sulfation and oxidation (bioactivation) followed by glutathione (GSH) conjugation, were tentatively identified in both species. Urinary excretion of SP-8356 appeared to be minimal in rats, compared to its metabolites. GSH conjugate of SP-8356 was also formed during incubation with rat liver S9 fraction consistent with oxidative bioactivation; this bioactivation was almost completely inhibited by the cofactors for glucuronidation, sulfation and methylation, indicating that it may be abolished by competing metabolic reactions in the body. The human pharmacokinetics of SP-8356 was predicted to be similar to that of the animals based on the current in vitro metabolic stability results. In summary, rapid phase II metabolism appears to be mainly responsible for its suboptimal pharmacokinetics, such as high CL and low oral absorption. Because of competing metabolic reactions, potential safety risks related to SP-8356 bioactivation may be low.

New Synergistic Combination Therapy of Mupirocin and α-Pinene Against Multidrug-Resistant Clinical Strains of Methicillin-Resistant Staphylococcus aureus.

OBJECTIVE: Increased mupirocin use leads to mupirocin resistance and is associated with persistence of methicillin-resistant Staphylococcus aureus (MRSA) carriers, prolonged hospitalization, and significant economic burdens for health systems. The study aimed to investigate the antimicrobial activity of compounds of Salvia rosmarinus L. ("rosemary", formerly Rosmarinus officinalis), alone or in combination with mupirocin, against multidrug resistant MRSA using isolates obtained from pediatric patients. METHODS: The in vitro antibacterial activity of the monoterpene α-pinene (α-Pi), a rosemary essential oil constituent, alone and in combination with mupirocin, was evaluated by determining the minimum inhibitory concentrations and minimum bactericidal concentrations (MBCs) and the fractional inhibitory concentration indices (FICIs) and fractional bactericidal concentration indices against multidrug-resistant clinical MRSA strains. The in vivo efficacy of α-Pi, alone and in combination with mupirocin, to eradicate MRSA infection was determined using an optimized mouse model of MRSA-infected wounds. Mouse skin samples (obtained via biopsy) were assessed for toxicity, and rabbit skin samples for irritation. RESULTS: Both in vitro and in vivo, α-Pi was active against MRSA strains and acted synergistically with mupirocin against MRSA strains. Mupirocin-monoterpene combinations exhibited FICI values of 0.2 to 0.4, reducing the MBC of topical mupirocin 33-fold. A topical formulation containing α-Pi and mupirocin enhanced the efficacy of mupirocin in an in vivo MRSA-infected mouse skin model without significantly harming the skin of mice and rabbits. CONCLUSIONS: A topical formulation combining mupirocin and α-Pi may aid in the development of innovative agents for treating MRSA infections.

Effects of α-pinene on the pinewood nematode (Bursaphelenchus xylophilus) and its symbiotic bacteria.

The pinewood nematode (PWN), Bursaphelenchus xylophilus, is an important plant-parasitic nematode that can cause severe mortality of pine trees. This PWN-induced harm to plants may be closely related to the abundance and diversity of the symbiotic microorganisms of the parasitic nematode. In this study, nematodes were divided into untreated and antibiotic-treated groups. Nematodes were treated by fumigation with different amounts of α-pinene, and the resultant mortality rates were analyzed statistically. Concentrations of symbiotic bacteria were calculated as colony-forming units per nematode. High-throughput sequencing was used to investigate the bacterial community structure. The results showed that the mortality of nematodes increased slightly with an increasing concentration of α-pinene, and nematodes untreated with antibiotics were more sensitive to α-pinene than those treated with antibiotics. The highest abundance of symbiotic bacteria was obtained via medium and low levels of α-pinene, but for which community diversity was the lowest (Shannon and Simpson indexes). The proportion of Pseudomonas spp. in the symbiotic bacteria of nematodes without antibiotics was relatively high (more than 70%), while that of Stenotrophomonas spp. was low (6%-20%). However, the proportion of Stenotrophomonas spp. was larger than that of Pseudomonas spp in the symbiotic bacteria associated with the antibiotic-treated nematodes. Pseudomonas sp. increased after pinene treatment, whereas Stenotrophomonas spp. decreased. These results indicate that although α-pinene has low toxicity to PWNs over a short time period, α-pinene ultimately influences the abundance and community diversity of the symbiotic bacteria of these nematodes; this influence may potentially disturb the development and reproduction of nematodes in the process of infecting pine trees.