Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target.

Malarial dihydrofolate reductase (DHFR) is the target of antifolate antimalarial drugs such as pyrimethamine and cycloguanil, the clinical efficacy of which have been compromised by resistance arising through mutations at various sites on the enzyme. Here, we describe the use of cocrystal structures with inhibitors and substrates, along with efficacy and pharmacokinetic profiling for the design, characterization, and preclinical development of a selective, highly efficacious, and orally available antimalarial drug candidate that potently inhibits both wild-type and clinically relevant mutated forms of Plasmodium falciparum (Pf) DHFR. Important structural characteristics of P218 include pyrimidine side-chain flexibility and a carboxylate group that makes charge-mediated hydrogen bonds with conserved Arg122 (PfDHFR-TS amino acid numbering).

Lymphatic absorption of subcutaneously administered proteins: influence of different injection sites on the absorption of darbepoetin alfa using a sheep model.

The relative contribution of the lymph and blood in the absorption of darbepoetin alfa (DA) from different s.c. injection sites was determined using a central lymph-cannulated sheep model.

The absorption of darbepoetin alfa occurs predominantly via the lymphatics following subcutaneous administration to sheep.

Purpose: To determine the contribution of the lymphatics to the systemic availability of darbepoetin alfa (DA) using an established sheep model.

Materials And Methods: DA was administered either by intravenous (IV) injection (0.2, 0.

Subcutaneous drug delivery and the role of the lymphatics.

Subcutaneous injections are widely utilised as a delivery route for compounds with limited oral bioavailability or as a means to modify or extend the release profile. In this review, factors affecting absorption from the subcutaneous space are discussed with particular emphasis on differential drug absorption into either the underlying blood or lymphatic capillaries. Formulation and targeted delivery approaches, which utilise the subcutaneous administration route, are reviewed with reference to associated technologies and future challenges.

Lymphatic absorption is the primary contributor to the systemic availability of epoetin Alfa following subcutaneous administration to sheep.

The contribution of the lymphatics to the absorption and systemic availability of recombinant human epoetin alfa (rHuEPO) following s.c. injection was examined using a cannulated sheep model.

Pharmacokinetic model to describe the lymphatic absorption of r-metHu-leptin after subcutaneous injection to sheep.

Purpose: The purpose of this work was to develop a pharmacokinetic model to describe the contribution of the lymphatics to the absorption and bioavailability of r-metHu-Leptin administered by subcutaneous (SC) injection to sheep.

Methods: r-metHu-Leptin was administered either by bolus intravenous injection (0.1 mg/kg) into the jugular vein or by SC injection (0.