Preclinical toxicity and toxicokinetics of GTI-2040, a phosphorothioate oligonucleotide targeting ribonucleotide reductase R2.

Purpose: GTI-2040, a 20-mer phosphorothioate oligonucleotide, was designed to hybridize to the mRNA sequence of human ribonucleotide reductase R2. GTI-2040 has been shown to inhibit human cancer cell proliferation by downregulation of R2 expression in vitro and to significantly inhibit tumor growth in xenograft models of human cancer in mice. As part of the safety evaluation for human clinical trials, the toxicity and toxicokinetics of GTI-2040 were determined in Sprague-Dawley rats and rhesus monkeys.

Non-clinical pharmacology and safety evaluation of TH9507, a human growth hormone-releasing factor analogue.

TH9507, an analogue of human growth hormone-releasing factor (hGRF1-44NH2) minimally modified by addition of a trans-3-hexenoyl moiety to Tyr1 of the amino acid sequence, was found to be resistant to dipeptidyl aminopeptidase-IV deactivation. Compared to natural hGRF1-44NH2, the modification slowed the in vitro degradation of the peptide in rat, dog and human plasma and prolonged the in vivo plasma elimination kinetics of immunoreactive TH9507. Plasma growth hormone and insulin-like growth factor-1 (IGF-1) markedly increased in pigs, rats and dogs after daily repeat intravenous or subcutaneous injections of TH9507 at doses up to 600 microg/kg.

Pulmonary delivery of TH9507, a growth hormone releasing factor analogue, in the dog.

A modified growth hormone releasing factor (GRF; TH9507), a 44 amino acid peptide analogue of natural human growth hormone releasing factor, is being developed for the treatment of age-associated conditions resulting from diminished growth hormone (GH) secretion. The inhalation route of administration is being considered as an alternative to subcutaneous injection. A study was undertaken in dogs to investigate the absorption of TH9507 following pulmonary delivery.

Virulizin(R) - A review of its antineoplastic activity.

Virulizin(R) (registered trademark of Lorus Therapeutics, Inc.) is a novel biological response modifier (BRM) that enhances cell-mediated immune response to tumour cells by direct macrophage activation. The agent, an aqueous solution containing a 5% (w/v) solid material mixture comprised of inorganic salts (95 - 99% of the dry weight) and organic compounds of molecular weight < 3000 Daltons (1 - 5% of the dry weight), is provided as a sterile, injectable formulation.

Virulizin-2gamma, a novel immunotherapeutic agent, in treatment of human pancreatic cancer xenografts.

Virulizin-2gamma, a novel biological response modifier extracted from bovine bile, has shown in clinical studies a significant antitumor activity against pancreatic cancer. We report here the results of preclinical evaluation of Virulizin-2gamma in treatment of human pancreatic cancer xenograft in nude mice. In this in vivo study, 14 daily bolus intraperitoneal administrations of Virulizin-2gamma (0.

Disposition of radioactivity in fischer 344 rats after single and multiple inhalation exposure to [(14)C]Octamethylcyclotetrasiloxane ([(14)C]D(4)).

The retention, distribution, metabolism, and excretion of [(14)C]octamethylcyclotetrasiloxane (D(4)) were studied in Fischer 344 rats after single and multiple exposures to 7, 70, or 700 ppm [(14)C]D(4). Subset groups were established for body burden, distribution, and elimination. Retention of inhaled D(4) was relatively low (5-6% of inhaled D(4)).

Pharmacokinetics and disposition of methyl t-butyl ether in Fischer-344 rats.

Methyl t-butyl ether (MTBE) is a commonly used octane booster in gasoline. This study examines the pharmacokinetics and disposition of MTBE in Fischer-344 rats after i.v.

Pharmacokinetics and disposition of the lipid-lowering drug acifran in normal subjects and in patients with renal failure.

The pharmacokinetics and metabolic fate of the antihyperlipidemic drug acifran were assessed after a single oral dose of the 14C-labeled drug to healthy male volunteers. Peak serum acifran and radioactivity concentrations were attained 1 to 2 hours after dosing, and the drug was eliminated with a half-life of 1.6 hours.

Etodolac, a novel antiinflammatory agent. The syntheses and biological evaluation of its metabolites.

The syntheses of five metabolites of the antiinflammatory drug etodolac (1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid) are described, viz. 6-hydroxyetodolac, N-methyletodolac, 4-ureidoetodolac, 8-(1'-hydroxy)etodolac, and 4-oxoetodolac. These syntheses were used to confirm the identities of the metabolites.

The metabolic disposition of acifran, a new antihyperlipidemic agent, in rats and dogs.

The metabolic disposition of the antihyperlipidemic agent acifran (AY-25, 712) was determined in rats and dogs. The synthesis of 14C-labelled acifran is described. Serum levels of 14C and acifran were measured in rats and dogs after p.

Disposition and biotransformation of 14C-etodolac in man.

Four human subjects were given a capsule containing 200 mg of 14C-etodolac. At the peak (two hours after dosing), most of the radioactivity in serum was due to etodolac; subsequently, metabolites gradually appeared. The elimination half-life of etodolac from serum averaged six hours.

Metabolic disposition and pharmacokinetics of the aldose reductase inhibitor tolrestat in rats, dogs, and monkeys.

The metabolic disposition and pharmacokinetics of the aldose reductase inhibitor tolrestat were studied in rats, dogs, and assamese and capuchin monkeys. In addition, the ocular penetration of tolrestat was examined in rabbits. The bioavailability of tolrestat was 81% in rats and 68% in dogs.

Distribution and excretion of furobufen in rats and dogs.

Groups of male rats and dogs were given single doses of 50 mg of 14C-furobufen per kg orally or intravenously. In rats, tissue radioactivity levels were generally lower than that of serum. Radioactivity accumulated in and was retained by white adipose tissue.

The metabolic disposition of etodolac in rats, dogs, and man.

The metabolic disposition of etodolac (etodolic acid) was studied after oral and intravenous administration of the 14C-labeled or unlabeled drug to rats and dogs, and after oral administration of the drug to man. In all species, peak serum drug levels were attained within 2 hr after dosing. In rats and dogs, virtually all of the oral dose was absorbed; etodolac represented 95% of the serum radioactivity in rats and 75% in dogs.

Studies on the disposition of diosgenin in rats, dogs, monkeys and man.

Rats, dogs and squirrel monkeys were given a single oral dose of [4-(14)C]diosgenin. Virtually all of the radioactivity was excreted in the feces. All of the absorbed radioactivity was eliminated via the bile.

Effect of ring substitution on the metabolic fate and anti-inflammatory activity of some prodolic acid analogs.

Prodolic acid, 1-n-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, exhibits potent anti-inflammatory activity in adjuvant arthritic rats. The potency of prodolic acid is enhanced by indole ring substitution. This increase correlated well with higher and sustained drug concentrations in the serum of normal animals.

Clofibrate and clofibric acid: comparison of the metabolic disposition in rats and dogs.

In rats, equimolar oral doses of [14C]clofibrate and [14c]clofibric acid produced essentially the same profiles of blood levels, tissue distribution and excretion of radioactivity. Both compounds were completely absorbed, and all radioactivity found in the serum was due to clofibric acid (CPIB). Tissues contained readily detectable radioactivity levels, but the concentration was generally lower than in serum.

Synthesis and antihypertensive activity of some thienylethanolamines.

Synthesis of a series of thienylethanolamines having varying substituents on the thiophene ring and on the nitrogen atom is described using the general procedure reported earlier. In the determination of their pharmacological profile, some of the derivatives showed marked antihypertensive activity in the spontaneously hypertensive rat model. Tests are also reported which demonstrated that some of these derivatives antagonized alpha- and/or beta-adrenoreceptor activities.