Antiplatelet Drug Resistance and Drug-Drug Interactions: Role of Cytochrome P450 3A4Lau, Wei; Gurbel, Paul
doi: 10.1007/s11095-006-9084-4pmid: 17061171
Antiplatelet therapy provided pivotal advances in the treatment of cardiovascular disease. Aspirin and thienopyridine, clopidogrel, is currently the treatment of choice in acute coronary syndromes and the prevention of thrombosis after coronary stent implantation. Despite the efficacy of this dual antiplatelet therapy in reduction of adverse coronary events in patients with acute coronary syndromes, complications persist in a subgroup of these patients. Emerging causes of aspirin and clopidogrel resistance may translate to increase risk for recurrent myocardial infarction, stroke, or cardiac related mortality. However, the mechanism of antiplatelet drug resistance remains incompletely characterized, and a sensitive and specific assay of aspirin and clopidogrel effect that reliably predicts treatment failure has not emerged. To date, evidence supporting antiplatelet drug resistance are pharmacokinetic response variability, drug-drug interaction through competitive inhibition a specific enzymatic pathway, genetic variability, and variability in the induction of enzymatic pathway in metabolic activation of prodrugs, like clopidogrel. Further investigation or guidelines are needed to optimize antiplatelet treatment strategies to identify and treat patients resistant to aspirin and/or clopidogrel.
A Review of Poloxamer 407 Pharmaceutical and Pharmacological CharacteristicsDumortier, Gilles; Grossiord, Jean; Agnely, Florence; Chaumeil, Jean
doi: 10.1007/s11095-006-9104-4pmid: 17096184
Poloxamer 407 copolymer (ethylene oxide and propylene oxide blocks) shows thermoreversible properties, which is of the utmost interest in optimising drug formulation (fluid state at room temperature facilitating administration and gel state above sol–gel transition temperature at body temperature promoting prolonged release of pharmacological agents). Pharmaceutical evaluation consists in determining the rheological behaviour (flow curve or oscillatory studies), sol–gel transition temperature, in vitro drug release using either synthetic or physiological membrane and (bio)adhesion characteristics. Poloxamer 407 formulations led to enhanced solubilisation of poorly water-soluble drugs and prolonged release profile for many galenic applications (e.g., oral, rectal, topical, ophthalmic, nasal and injectable preparations) but did not clearly show any relevant advantages when used alone. Combination with other excipients like Poloxamer 188 or mucoadhesive polymers promotes Poloxamer 407 action by optimising sol–gel transition temperature or increasing bioadhesive properties. Inclusion of liposomes or micro(nano)particles in Poloxamer 407 formulations offers interesting prospects, as well. Besides these promising data, Poloxamer 407 has been held responsible for lipidic profile alteration and possible renal toxicity, which compromises its development for parenteral applications. In addition, new findings have demonstrated immuno-modulation and cytotoxicity-promoting properties of Poloxamer 407 revealing significant pharmacological interest and, hence, human trials are in progress to specify these potential applications.
Design for Optimized Topical Delivery: Prodrugs and a Paradigm ChangeSloan, Kenneth; Wasdo, Scott; Rautio, Jarkko
doi: 10.1007/s11095-006-9108-0pmid: 17109215
In theory, topical delivery has substantial potential to treat local and some systemic disease states more effectively than systemic delivery. Unfortunately many, if not most, drug candidates for topical delivery lack the requisite physicochemical properties that would allow them to permeate the skin to a clinically useful extent. One way to overcome this obstacle to effective topical delivery is to make a transient derivative of the drug, a prodrug, with the correct physicochemical properties. But what are those correct properties and can the directives for the design of prodrugs be applied to the design of new drugs, their analogs or homologs? For some time increasing the lipid solubility (S
LIPID) or its surrogate, the partition coefficient between a lipid (LIPID) and water (AQ) (K
LIPID:AQ), has been the standard working paradigm for increasing permeation of the skin, and the permeability coefficient (P = distance/time) has been the quantitative measure of the result. However, even the earliest reports on non-prodrugs such as alcohols showed that working paradigm was incorrect and that P should not be the relevant measure of permeation. The shorter chain and more water soluble alcohols exhibiting lower K
LIPID:AQ values gave the greater flux values (J = amount/area × time; the more clinically relevant measure of permeation), regardless of whether they were applied neat or in an aqueous vehicle, while P showed opposite trends for the two applications. Subsequently a large volume of work has shown that, for prodrugs and non-prodrug homologs or analogs alike, S
AQ (not solubility in the vehicle, S
VEH) as well as S
LIPID should be optimized to give maximum flux from any vehicle, J
MVEH: a new working paradigm. The dependence of J
MVEH on S
AQ is independent of the vehicle so that S
AQ as well as S
LIPID are descriptors of the solubilizing capacity of the skin or S
M1 in Fick’s law. The inverse dependence of J (or P) on molecular weight (MW) or volume (MV) remains. Here we review the literature that leads to the conclusion that a new working paradigm is necessary to explain the experimental data, and argue for its use in the design of new prodrugs or in the selection of candidate analogs or homologs for commercialization.