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Driving Drug Discovery: The Fundamental Role of Academic Labs

Researchers at academic labs make almost all of the basic science discoveries that underlie the creation of innovative new medicines. Academic labs have been responsible for virtually all of the basic science discoveries that translate into the discovery and development of innovative new medicines. There is a growing concern that large pharmaceutical and biotechnology companies are not able to sustain research pipelines that bring new compounds into drug development that translate into innovative new medicines, especially in areas with high unmet medical need. To address the needs of patients, caregivers, and society, academic labs have played and can continue to play an important role at one or more stages in the development of innovative medicines, both directly and through collaborations with researchers in pharmaceutical and biotechnology companies. Collaboration is in the best interests of patients and society if it accelerates the translation of basic science discoveries to new medicines that address unmet medical needs.

The pharmacokinetics of cefixime in the fasted and fed state

SummaryTwenty healthy adult volunteers received single 400 mg oral doses of cefixime in an open, randomized, crossover study, administered twice in the fasted state and twice with a standard breakfast. The study design allowed both an evaluation of a potential food effect and also an analysis of both intrasubject and intersubject variability in the fasted and fed state.There was a small but significantly longer (∼1 h) time to peak concentration when the drug was given with food. Peak serum concentrations, area under the curve, and 24 h urinary recovery values were unchanged in the fed and fasted states. The terminal elimination half-life of the drug given after a meal (3.6 h) was slightly longer than that observed after dosing in the fasting condition (3.5 h).The intrasubject and intersubject variabilities were less than 12% and 33% respectively, for both area under the curve and 24 h urinary recovery, and were virtually the same for the fasted and fed occasions. Therefore, the drug may be administered with or without food.

Optimization of Aryl Amides that Extend Survival in Prion-Infected Mice

Developing therapeutics for neurodegenerative diseases (NDs) prevalent in the aging population remains a daunting challenge. With the growing understanding that many NDs progress by conformational self-templating of specific proteins, the prototypical prion diseases offer a platform for ND drug discovery. We evaluated high-throughput screening hits with the aryl amide scaffold and explored the structure–activity relationships around three series differing in their N-aryl core: benzoxazole, benzothiazole, and cyano. Potent anti-prion compounds were advanced to pharmacokinetic studies, and the resulting brain-penetrant leads from each series, together with a related N-aryl piperazine lead, were escalated to long-term dosing and efficacy studies. Compounds from each of the four series doubled the survival of mice infected with a mouse-passaged prion strain. Treatment with aryl amides altered prion strain properties, as evidenced by the distinct patterns of neuropathological deposition of prion protein and associated astrocytic gliosis in the brain; however, none of the aryl amide compounds resulted in drug-resistant prion strains, in contrast to previous studies on compounds with the 2-aminothiazole (2-AMT) scaffold. As seen with 2-AMTs and other effective anti-prion compounds reported to date, the novel aryl amides reported here were ineffective in prolonging the survival of transgenic mice infected with human prions. Most encouraging is our discovery that aryl amides show that the development of drug resistance is not an inevitable consequence of efficacious anti-prion therapeutics.

Dose-dependent pharmacokinetics of a new oral cephalosporin, cefixime, in the dog.

Cefixime (CL 284,635; FK 027) is a new third-generation oral cephalosporin. To study dose-dependent pharmacokinetics of cefixime in dogs, two balanced four-way crossover studies were conducted. In the first study, oral doses of 50, 100, and 200 mg/kg and an intravenous dose of 50 mg/kg cefixime were administered. In the second study, oral doses of 6.25, 12.5, and 25 mg/kg and an intravenous dose of 12.5 mg/kg cefixime were administered to the same dogs. A period of 1 month separated the two studies. When the two intravenous doses were compared (i.e., 12.5 and 50 mg/kg), a twofold increase in clearance and volume of distribution was observed after the higher dose. The oral systemic bioavailability in the dose range 6.25–50 mg/kg was 55%. It decreased to 44% at 100 mg/kg and 27% at 200 mg/kg. The average peak serum concentrations ranged from 15.8 µg/ml at 6.25 mg/kg to 119 µg/ml at 200 mg/kg. Within this concentration range, the fraction of free drug in serum (unbound to proteins) increased from 7 to 25%. This concentration-dependent protein binding was primarily responsible for changes in total clearance, volume of distribution, and bioavailability of the drug in dogs.

Nonlinear formation of propranolol metabolites in dogs after portacaval transpositions.

The formation of four major metabolites of propranolol by the liver was examined at steady state in three dogs that had undergone surgical portacaval transposition, following which injection of drug into the hindlimb delivers the total dose to the liver. Propranolol was infused directly into the liver via a hindlimb vein at dose rates ranging from 1.01 to 6.3 mg/min. In all dogs the formation of 4-hydroxypropranolol, α-naphthoxylactic acid, and propranolol glycol was saturable. Vmax and Km values were determined at steady state by relating the rate of excretion of each metabolite into bile and urine to the blood concentration of propranolol. The formation of propranolol glucuronide was a first order process. The use of a dog with a portacaval transposition has permitted development of a method to estimate, in vivo,the kinetic properties of enzymes responsible for hepatic first-pass metabolism of drugs.

Pharmacokinetics of Nilvadipine After Multiple Oral Dosing to Steady-State

AbstractForty-four healthy male volunteers were randomly assigned to receive one of four dosing regimens: placebo or a dose of 6, 8, 10 or 12 mg of nilvadipine administered at 0, 7 and 14 hr each day for 19 doses over seven days. There was a proportional relationship between the maximum plasma concentration of nilvadipine after the first dose and the last dose and the dose administered. There was also a proportional relationship between the area under the plasma concentration-time curve during the last dosing interval and the administered dose. Results showed that there was no accumulation of drug in plasma at steady-state. In addition, there was no dose-dependency in the oral clearance, elimination rate constant or terminal elimination half-life values. The pharmacokinetics of nilvadipine are linear upon multiple dosign over the dosing range studied