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Franklin Cerasoli

Publications and source records attributed to Franklin Cerasoli.

3 recordsLinked to original sources

Developing the ideal inhaled corticosteroid.

Inhaled corticosteroids (ICS) are considered the most effective asthma therapy, but concerns remain about side effects. The ideal ICS would have a larger therapeutic ratio than currently available agents, allowing doses to be increased but without greatly increasing the frequency or severity of adverse events. The ideal ICS would possess the following pharmacokinetic properties to maximize efficacy and minimize side effects: high pulmonary deposition, conversion to an active metabolite, high receptor potency, high pulmonary retention, low oral bioavailability, extensive metabolism, and rapid elimination. The new ICS ciclesonide has been shown to possess many of these characteristics. Ciclesonide has also been shown to improve lung function, to treat the underlying inflammation, to be effective as monotherapy in patients with persistent asthma, to have reduced side effects compared with other ICS, and to be easy to use with once-daily dosing. However, as with all new products, the advantages witnessed in clinical trials still have to be demonstrated to be beneficial long-term in general clinical use. ICS with an improved therapeutic index may have the potential to increase patient adherence, enhance the use of ICS monotherapy in the primary care setting, and increase the range of patients for whom ICS monotherapy would be appropriate.

Administration, Inhalation↗

Safety of inhaled corticosteroids: room for improvement.

Inhaled corticosteroids (ICS) are the standard of care in asthma and are widely used in the treatment of patients with chronic obstructive pulmonary disease. High-dose regimens and long-term use of ICS in predisposed individuals may be associated with a variety of side effects, similar to those observed with systemic corticosteroid therapy. Side effects associated with long-term ICS use include reduction in growth velocity, cataracts, glaucoma, osteoporosis, and fractures. Fear of unwanted complications may be of concern in all patients using ICS, particularly in age- and gender-specific populations that are more prone to develop side effects or to reduce treatment adherence because of physical, behavioral, or psychological problems. In addition to concerns about ICS safety, dosing regimens that are difficult to follow may further reduce a patient's ability to comply with treatment. Ciclesonide, a new-generation ICS with unique pharmacokinetic properties, was developed to provide effective anti-inflammatory control for asthma with once-daily administration to improve patient adherence and a high safety profile to reduce the occurrence of local and systemic side effects.

Administration, Inhalation↗

Pharmacodynamic evaluation of the neutralization of endotoxin by PMX622 in mice.

Polymyxin B (PMB) binds to and neutralizes endotoxin, but its systemic clinical utility is limited by neuro- and nephrotoxicity. PMX622 is a covalent conjugate of PMB and Dextran-70 designed to retain the ability of PMB to neutralize endotoxin and to retain the favorable colloidal, pharmacokinetic, and metabolic properties of Dextran-70. PMX622 has demonstrated efficacy in a number of animal models and effectively neutralized endotoxin in phase I clinical trials. Here, we systematically evaluated the pharmacodynamic properties of PMX622 in a murine model of endotoxin-induced lethality in galactosamine-sensitized mice. PMX622 completely and dose dependently inhibited lethality in this model. A stoichiometric relationship was found between the endotoxin challenge dose and the dose of PMX622 needed for protection. PMX622 neutralized endotoxin from four different genera of gram-negative bacteria but not Neisseria meningitidis. PMX622 was significantly less toxic than PMB in the mouse, suggesting that PMX622 has a better margin of safety than PMB. The timing of PMX622 administration relative to endotoxin was crucial. PMX622 was active for several hours prior to the endotoxin challenge; however, PMX622 did not protect mice if administered >/=15 min after endotoxin challenge. This suggests that PMX622 would best be clinically used prophylactically rather than therapeutically. These studies will be crucial in designing and interpreting human clinical trials assessing PMX622 efficacy.

Animals↗