Pharmacodynamic comparison of LY3023703, a novel microsomal prostaglandin e synthase 1 inhibitor, with celecoxib.

To assess the safety, tolerability, and pharmacology of LY3023703, a microsomal prostaglandin E synthase 1 (mPGES1) inhibitor, a multiple ascending dose study was conducted. Forty-eight subjects received LY3023703, celecoxib (400 mg), or placebo once daily for 28 days. Compared with placebo, LY3023703 inhibited ex vivo lipopolysaccharide-stimulated prostaglandin E2 (PGE2 ) synthesis 91% and 97% on days 1 and 28, respectively, after 30-mg dosing, comparable to celecoxib's effect (82% inhibition compared to placebo). Unlike celecoxib, which also inhibited prostacyclin synthesis by 44%, LY3023703 demonstrated a maximal increase in prostacyclin synthesis of 115%. Transient elevations of serum aminotransferase were observed in one subject after 30-mg LY3023703 dosing (10× upper limit of normal (ULN)), and one subject after 15-mg dosing (about 1.5× ULN). Results from this study suggest that mPGES1 inhibits inducible PGE synthesis without suppressing prostacyclin generation and presents a novel target for inflammatory pain.

Disposition of LY333531, a selective protein kinase C beta inhibitor, in the Fischer 344 rat and beagle dog.

1. Studies were conducted in the Fischer 344 rat and beagle dog to determine the disposition of LY333531 and its equipotent active des-methyl metabolite, LY338522, both potent and selective inhibitors of the beta-isozyme of protein kinase C. 2. Male Fischer 344 rats and female beagle dogs received a single 5-mg kg(-1) oral dose of (14)C-LY333531. Urine, faeces, bile and plasma were collected and analysed for (14)C, LY333531 and LY338522. 3. LY333531 was eliminated primarily in the faeces (91% by 120 h in rat, 90% by 96 h in dog). Bile contributed the majority of the radioactivity excreted in the faeces in rat (66% in the cannulated bile duct study) and a variable but significant proportion in dog. 4. Pharmacokinetics following a single 5 mg kg(-1) oral dose of (14)C-LY333531 to the male rat produced C(max) and AUC(0-infinity ) for LY333531 of 14.7 ng ml(-1) and 60.8 ng h ml(-1), respectively, with a half-life of 2.5 h. LY338522 and total radioactivity showed similar profiles. 5. In the female dog at the same dose, C(max) and AUC(0-infinity ) of LY333531 were higher, producing 245 +/- 94 ng ml(-1) and 1419 +/- 463 ng h ml(-1), respectively, with a half-life of 5.7 h. 6. The data indicate that the disposition of LY333531 is similar in rat and dog.

Viracept (nelfinavir mesylate, AG1343): a potent, orally bioavailable inhibitor of HIV-1 protease.

Using a combination of iterative structure-based design and an analysis of oral pharmacokinetics and antiviral activity, AG1343 (Viracept, nelfinavir mesylate), a nonpeptidic inhibitor of HIV-1 protease, was identified. AG1343 is a potent enzyme inhibitor (Ki = 2 nM) and antiviral agent (HIV-1 ED50 = 14 nM). An X-ray cocrystal structure of the enzyme-AG1343 complex reveals how the novel thiophenyl ether and phenol-amide substituents of the inhibitor interact with the S1 and S2 subsites of HIV-1 protease, respectively. In vivo studies indicate that AG1343 is well absorbed orally in a variety of species and possesses favorable pharmacokinetic properties in humans. AG1343 (Viracept) has recently been approved for marketing for the treatment of AIDS.

Nasal delivery of polypeptides I: nasal absorption of enkephalins in rats.

The serum levels of two enkephalins after various routes of administration were compared in rats. The results indicated that serum levels of metkephamid after nasal administration were not significantly different than levels after intravenous injection. The oral administration of metkephamid resulted in undetectable serum levels. The effects of a promoter and variations in the peptide dose on nasal absorption were studied. Depending on the stability of the polypeptide and its susceptibility to enzymatic degradation, nasal absorption of peptides can be influenced by the presence of a promoting agent in the formulation. A linear relationship between the dose and the AUC was observed in the range of concentrations studied. The absorption mechanism appears to be passive diffusion. Microscopic examinations of nasal mucosa in rats revealed degrees of irritation which, considering the experimental exposure, were slight and probably repairable. The data indicate that enkephalins can be absorbed through the nasal mucosa into the systemic circulation, and the onset of absorption was rapid. Nasal administration may offer an attractive alternative for the delivery of proteins and/or polypeptides which are, in general, absorbed poorly when given orally.

Nonaqueous cephalosporin suspension for parenteral administration: cefazolin sodium.

The flocculation-deflocculation behavior of cefazolin sodium (I) in nonaqueous media and the effect of surfactants as measured by zeta potential, sedimentation, and porosity were studied. A significant difference in zeta potential was observed when the particles were suspended in different nonaqueous media. The addition of surfactant produced a deflocculated state. The surfactant deflocculated the particles by a process of supersaturation and crystallization involving a surfactant-cefazolin complex. The shielding effect of the surfactant on the surface of the particles also apparently affected their electrophoretic properties. Kinetic studies on the stability of the drug as a function of temperature were conducted; it appears that the chemical stability in ethyl oleate at room temperature is adequate for a reasonable shelf life. The efficiency of absorption of the drug from the ethyl oleate suspension was evaluated after intramuscular administration in dogs. The area under the plasma concentration versus time curve and urinary recovery indicated that cefazolin was 100% bioavailable from this nonaqueous preparation.

Nasal drug delivery system of a quaternary ammonium compound: clofilium tosylate.

The blood levels of the [14C]clofilium ion in rats after various routes of administration of clofilium tosylate were compared. The results indicate that the blood levels after nasal administration were not statistically different from levels after intravenous administration (p greater than 0.05). Administration by the oral route resulted in considerably lower blood levels. Nasal administration of clofilium tosylate appeared to be superior to oral administration. Histological examinations of nasal mucosa were conducted. At the lower concentration, mild necrosis was observed, and large areas of mucosa were unaffected. However, necrosis of large areas of mucosa occurred after exposure to the higher concentration. Levels of radioactivity in heart, liver, lung, and kidney tissue, as a function of time, were also studied. Unlike the blood levels after nasal administration, the levels of radioactivity were persistent in heart tissue. The data suggest that the [14C]clofilium ion and/or metabolite concentrate in the heart and that blood levels of radioactivity may not be an accurate index of cardiac levels or biological response.