CNTO 530: molecular pharmacology in human UT-7EPO cells and pharmacokinetics and pharmacodynamics in mice.

CNTO 530 is a 58 kD antibody Fc domain fusion protein, created using Centocor's MIMETIBODY platform, that contains two EMP1 sequences as a pharmacophore. CNTO 530 has no sequence homology with EPO but acts as a novel erythropoietin receptor agonist. In UT-7(EPO) cells, CNTO 530 caused protein phosporylation of the erythropoietin receptor associated signaling pathway (Jak2, STAT5, AKT and ERK1/2). CNTO 530 also rescued these cells from apoptosis and mediated proliferation. In mice, pharmacokinetic analysis showed that CNTO 530 was slowly cleared from circulation with a t(1/2) approximately 40 h. Pharmacodynamic analysis in mice showed that a single sc dose of CNTO 530 caused a long-lived stimulation of erythropoiesis that translated into increases in red blood cell counts and hemoglobin values that were maintained for at least 28 d. In conclusion, CNTO 530 is a long-lived EPO-R agonist that stimulates erythropoiesis in a manner similar to epoetin-alpha. These data suggest that CNTO 530 may be an effective treatment of anemia in humans.

Characterization of the degradation products of luteinizing hormone releasing hormone.

The degradation products of luteinizing hormone releasing hormone [LH/RH; 1; gonadorelin releasing hormone (GnRH); less than Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2] were determined in aqueous solution (pH 6.5) at 25, 37, 50, and 80 degrees C. The predominant route of degradation involved the cleavage of the less than Glu-His and Trp-Ser peptide bonds to give peptides 5-9 and hydrolysis of the terminal Gly-NH2 to the free acid form in peptides 4 and 10. Racemization of the serine and histidine residues to give peptides 2 and 3 was a second route of degradation.

Characterization of the solution degradation products of etintidine, an H2-receptor antagonist.

The primary solution degradation products of the antiulcer drug etintidine (1, N"-cyano-N-[2-[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethyl]- N'-2-propynylguanidine) were determined to be the guanyl urea 2, the guanidine 3, the amine 4a, and the cyanoamine 4b. These products resulted from nitrile hydrolysis and/or intramolecular cyclization of the guanidino and propargyl groups. The amine 4a was found to be a predominant degradation product in aqueous media of pH 4-7 at 70 +/- 0.2 degrees C.

Characterization of the solution degradation products of histrelin, a gonadotropin releasing hormone (LH/RH) agonist.

The degradation products of histrelin (1, less than Glu-His-Trp-Ser-Tyr-(D-Nim-bzl-His)-Leu-Arg-Pro-NHEt) were determined in aqueous solution at pH 5.4 and 87 degrees C over an 18-day period (47% degradation). These degradation products (2-5) resulted from the cleavage of less than Glu-His and Trp-Ser peptide bonds, His-Trp diketopiperazine formation, and racemization of serine and histidine residues.

The metabolism of etintidine in rat, dog, and human.

The metabolic fate of etintidine, a new H2-receptor antagonist, was studied in the rat, dog, and human. Following oral or iv administration of [14C]etintidine HCl to rats, 63-72% of the dose was eliminated in urine and 15-28% in feces over 3 days. In dogs, 52-70% of the administered dose was excreted in urine and 14-18% in feces over 5 days. In the urine of both species, the major portion (generally greater than 70%) of the radioactivity was associated with parent drug and its sulfoxide metabolite. In rats, a distinct sex-related difference in metabolism was observed following oral administration of 20 mg/kg doses, with males excreting nearly twice the amount of the sulfoxide relative to females. A significant sex-related difference in metabolism was not observed in dogs following oral administration of a comparable dose, nor was it observed in either species following iv drug administration. After oral administration of [14C]etintidine HCl to human volunteers, about 86% of the dose was recovered in urine and 13% in the feces over a 7-day period. In humans, the major urinary metabolite was the N'-glucuronide conjugate. Thus, sulfoxidation does not appear to be the major urinary metabolic pathway of the drug in humans, as it is in animals. The metabolic fate of etintidine and cimetidine, another H2-receptor antagonist, are compared in three species.

Topotecan treatment of adults with primary malignant glioma. The Brain Tumor Center at Duke.

BACKGROUND: Topotecan activity was evaluated for the treatment of malignant glioma. METHODS: Sixty-three patients with newly diagnosed (n = 25) or recurrent (n = 38) malignant glioma were treated with topotecan [AU: Please verify all dosages here and throughout text.]at a dose of 2.6 mg/m2 over a 72-hour period weekly. Recurrent tumors included glioblastoma multiforme (GBM) (n = 28) and anaplastic astrocytoma (AA) (n = 10). Newly diagnosed tumors included GBM (n = 14), AA (n = 8), and anaplastic oligodendroglioma (n = 3). RESULTS: Partial responses were observed in 2 of 14 evaluable patients with newly diagnosed GBM, 1 of 8 patients with newly diagnosed AA, 3 of 10 patients with recurrent AA, and none of 28 patients with recurrent GBM. Four patients with recurrent AA and 7 patients with recurrent GBM demonstrated stable disease (range, 8-52 weeks; median, 21 weeks). Toxicity was limited to infrequent National Cancer Institute Common Toxicity Criteria Grade 3 myelosuppression. CONCLUSIONS: These results suggest that topotecan has modest activity against malignant glioma and continued evaluation of its effectiveness may be warranted when alternative schedules or combination regimens are used.