Microvessel Density: Integrating Sex-Based Differences and Elevated Cardiovascular Risks in Metabolic Syndrome.

Metabolic syndrome (MetS) is a complex pathological state consisting of metabolic risk factors such as hypertension, insulin resistance, and obesity. The interconnectivity of cellular pathways within various biological systems suggests that each individual component of MetS may share common pathological sources. Additionally, MetS is closely associated with vasculopathy, including a reduction in microvessel density (MVD) (rarefaction) and elevated risk for various cardiovascular diseases. Microvascular impairments may contribute to perfusion-demand mismatch, where local metabolic needs are insufficiently met due to the lack of nutrient and oxygen supply, thus creating pathological positive-feedback loops and furthering the progression of disease. Sexual dimorphism is evident in these underlying cellular mechanisms, which places males and females at different levels of risk for cardiovascular disease and acute ischemic events. Estrogen exhibits protective effects on the endothelium of pre-menopausal women, while androgens may be antagonistic to cardiovascular health. This review examines MetS and its influences on MVD, as well as sex differences relating to the components of MetS and cardiovascular risk profiles. Finally, translational relevance and interventions are discussed in the context of these sex-based differences.

Development of ALZET® osmotic pump compatible solvent compositions to solubilize poorly soluble compounds for preclinical studies.

CONTEXT: Hydrophilic, non-aqueous solvents are frequently used to solubilize poorly water soluble compounds for use in ALZET® osmotic pumps used during the discovery and preclinical stages. Though these solvents exhibit the potential to solubilize several poorly soluble compounds, the solubilized compounds are prone to crystallization up on contact with aqueous fluids in vitro and in vivo. Crystallization of a compound can potentially cause pain at the release site, erratic blood levels, and uneven or delayed pharmacokinetic profiles. OBJECTIVE: In this study, we discussed the development of ALZET® pump compatible hydrophilic, non-aqueous vehicles that solubilized two poorly soluble model compounds (ELND006 and ELN 481594) and prevented their crystallization from solutions in vitro and in vivo. METHODS: The selected formulations were filled into the pumps at three concentrations for each model compound and investigated for their compatibility with the pumps and the subcutaneous tissue of mice where the pump was inserted. RESULTS AND DISCUSSION: The results showed that the formulations were stable physically with no crystallization and chemically with no degradation and were compatible with the pump and animal tissue. The plasma concentration of ELND006 decreased with time at each dose. The extent of the time-dependent decrease in ELND006 plasma levels increased as the amount of dose delivered increased. This time and dose dependent decrease in ELND006 plasma concentrations was attributed to the known auto-induction of hepatic enzymes by the compound. In contrast, the plasma concentration of ELN 481594 increased significantly at higher dose, likely due to accumulation of the compound.

A formulation strategy for gamma secretase inhibitor ELND006, a BCS class II compound: development of a nanosuspension formulation with improved oral bioavailability and reduced food effects in dogs.

ELND006 is a novel gamma secretase inhibitor previously under investigation for the oral treatment of Alzheimer's disease. ELND006 shows poor solubility and has moderate to high permeability, suggesting it is a Biopharmaceutics Classification System Class II compound. The poor absolute oral bioavailability of the compound in fasted dogs (F ∼11%) is attributed to poor aqueous solubility. In addition, inhibiting amyloid precursor protein but not Notch cleavage is an important goal for gamma secretase inhibitors; therefore, significant variation in bioavailability resulting from food consumption is a potential liability for this class of compounds. The objective of the present study was to determine if an ELND006 nanocrystalline formulation would offer improved and predictable pharmacokinetics. ELND006 was formulated as a nanosuspension with a mean particle size of less than 200 nm, which was stable in particle size and crystallinity for over 1 year. In addition, ELND006 nanosuspension exhibited rapid dissolution in comparison with reference active pharmaceutical ingredient (API). The in vivo performance of the ELND006 nanosuspension was tested in fed and fasted beagle dogs and compared with a gelatin capsule containing reference API. The results show that nanosizing ELND006 profoundly improved the oral bioavailability and virtually eliminated variation resulting from food intake.

The costs and consequences of methicillin-resistant Staphylococcus aureus infection treatments in Canada.

BACKGROUND: A multinational randomized controlled trial has shown a trend toward early discharge of patients taking oral linezolid versus intravenous vancomycin (IV) in the treatment of methicillinresistant Staphylococcus aureus (MRSA) infections. Infection treatments resulting in shorter hospitalization durations are associated with cost savings from the hospital perspective. OBJECTIVE: To determine whether similar economic advantages are associated with oral linezolid, the costs and consequences of linezolid use following vancomycin IV versus the existing practice in the treatment of infections caused by MRSA were compared. METHODS: The charts of all patients admitted to one of three tertiary care teaching hospitals between January 1, 1997 and August 31, 2000 and treated with vancomycin IV for an active MRSA infection (skin and soft tissue only) were reviewed. Based on the vancomycin IV chart review data set and a simulated linezolid data set, the clinical consequences and the associated costs of MRSA treatment with vancomycin IV, and oral and IV forms of linezolid were quantified and compared within the framework of a cost-consequence analysis. RESULTS: Patients treated with oral and IV forms of linezolid compared with the existing practice had a shorter length of stay and required fewer home IV care services, which resulted in a cost savings of $750 (2001 values) to the Canadian health care perspective. CONCLUSIONS: The estimated cost savings associated with linezolid use not only offset the higher acquisition cost of the anti-infective, but may be substantial to health care systems across Canada, especially as the incidence of MRSA continues to rise.

Oral fluoroquinolones in the treatment of pneumonia, bronchitis and sinusitis.

BACKGROUND: Despite a relatively large number of clinical studies comparing oral fluoroquinolones to one antibiotic class comparator, there is limited information on the relative efficacy of different fluoroquinolones. OBJECTIVE: To examine the efficacy and tolerability of oral fluoroquinolones in the treatment of mild to moderate community-acquired pneumonia, acute exacerbations of chronic bronchitis and sinusitis. METHODS: A systematic review was undertaken with a MEDLINE search for antibiotics and indications. Included studies met the following criteria: original study; random allocation to treatment groups; treatment with one of the following oral antibiotics - moxifloxacin, levofloxacin, ciprofloxacin, gatifloxacin; controlled by either placebo or an active comparator medication; double-blind, single-blind or open treatment; men and women (18 years of age and older); diagnosis of one of the three indications; and treatment duration of at least three days. Outcome measures included efficacy and safety. Comparative and single arm meta-analyses were conducted. Statistical differences in antibiotic success rates were evaluated. Pooled point estimates and 95% CIs for the comparative statistics (z-scores, P-values) and the single-arm analysis were examined to evaluate equivalence. RESULTS: The results of the comparative and single meta-analyses revealed no major differences between the new fluoroquinolones. This is not surprising because the clinical studies were designed to show equivalence versus their comparators. Few comparative evaluations were conducted due to a paucity of studies. In relation to other competitors, small differences were seen. CONCLUSIONS: Results indicate that, in general, fluoroquinolones had similar efficacy, overall safety and dropout rates.