Zilascorb(2H), a new reversible protein synthesis inhibitor: clinical study of an oral preparation.
The new anti-cancer drug zilascorb(2H) has shown promising activity in preclinical models. Its putative mechanism of action is reversible protein synthesis inhibition and long-term treatment is required. As a clinical treatment modality, long-term daily zilascorb(2H) infusions, as used in previous studies, are not regarded feasible. Therefore, an oral formulation of the drug was developed, and pharmacokinetic profile, toxicity and antitumor activity of zilascorb(2H) tablets were studied. Thirteen patients with advanced solid cancer not amenable to established therapy, but with adequate performance status and organ functions, were included. The treatment was given as a daily i.v. zilascorb(2H) infusion for 5 days, followed by zilascorb(2H) tablets twice daily for 3 months. Blood and urine sampling was performed when estimated plasma steady-state level was reached for each formulation, respectively. Analyses of drug concentrations in plasma and urine were performed by high performance liquid chromatography. Zilascorb(2H) in tablet formulation had a bioavailability of 32%, was quickly absorbed and slowly eliminated. Concomitant use of the H2-blocker ranitidine possibly enhanced bioavailability. Zilascorb(2H) was well tolerated. Two patients experienced drug-related fever, disturbing the treatment schedule for one of them. Moderate nausea was reported. One objective response was obtained. The bioavailability of zilascorb(2H) tablets was satisfactory. The principle of oral administration of zilascorb(2H) is feasible for long-term treatment and the side effects are acceptable. The mechanisms of action and the very low toxicity of the drug makes it a candidate for combination with other anticancer agents.
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K A
KA
Department of Oncology, Norwegian Radium Hospital, Montebello, Norway.
Fodstad
O
O
Klem
B
B
Bibow
K
K
Osmundsen
K
K
Aamdal
S
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001597:Benzylidene Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy
D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D001205:Ascorbic Acid; C070680:zilascorb