ABSTRACT
PURPOSE: A new aminothiol, PrC-210, was tested for orally conferred radioprotection (rats, mice; 9.0 Gy whole-body, which was otherwise lethal to 100% of the animals) and presence of the debilitating side effects (nausea/vomiting, hypotension/fainting) that restrict use of the current aminothiol, amifostine (Ethyol, WR-2721). METHODS AND MATERIALS: PrC-210 in water was administered to rats and mice at times before irradiation, and percent-survival was recorded for 60 days. Subcutaneous (SC) amifostine (positive control) or SC PrC-210 was administered to ferrets (Mustela putorius furo) and retching/emesis responses were recorded. Intraperitoneal amifostine (positive control) or PrC-210 was administered to arterial cannulated rats to score drug-induced hypotension. RESULTS: Oral PrC-210 conferred 100% survival in rat and mouse models against an otherwise 100% lethal whole-body radiation dose (9.0 Gy). Oral PrC-210, administered by gavage 30-90 min before irradiation, conferred a broad window of radioprotection. The comparison of PrC-210 and amifostine side effects was striking because there was no retching or emesis in 10 ferrets treated with PrC-210 and no induced hypotension in arterial cannulated rats treated with PrC-210. The tested PrC-210 doses were the ferret and rat equivalent doses of the 0.5 maximum tolerated dose (MTD) PrC-210 dose in mice. The human equivalent of this mouse 0.5 MTD PrC-210 dose would likely be the highest PrC-210 dose used in humans. By comparison, the mouse 0.5 MTD amifostine dose, 400 µg/g body weight (equivalent to the human amifostine dose of 910 mg/m(2)), when tested at equivalent ferret and rat doses in the above models produced 100% retching/vomiting in ferrets and 100% incidence of significant, progressive hypotension in rats. CONCLUSIONS: The PrC-210 aminothiol, with no detectable nausea/vomiting or hypotension side effects in these preclinical models, is a logical candidate for human drug development to use in healthy humans in a wide variety of radioprotection settings, including medical radiation, space travel, and nuclear accidents.
Subject(s)
Diamines/administration & dosage , Hypotension/chemically induced , Nausea/chemically induced , Radiation Injuries, Experimental/prevention & control , Radiation-Protective Agents/administration & dosage , Sulfhydryl Compounds/administration & dosage , Vomiting/chemically induced , Administration, Oral , Amifostine/administration & dosage , Animals , Diamines/adverse effects , Diamines/chemistry , Diamines/pharmacokinetics , Drug Evaluation, Preclinical , Female , Ferrets , Infusions, Intra-Arterial , Infusions, Parenteral , Injections, Subcutaneous , Male , Maximum Tolerated Dose , Mice , Mice, Inbred ICR , Radiation-Protective Agents/adverse effects , Radiation-Protective Agents/chemistry , Radiation-Protective Agents/pharmacokinetics , Rats , Rats, Sprague-Dawley , Sulfhydryl Compounds/adverse effects , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/pharmacokineticsABSTRACT
OBJECTIVE: To seek a mechanism linking tobacco smoking with the increased incidence and severity of rheumatoid arthritis, deduced from many retrospective surveys, by studying arthritis/fibrosis development in rats. METHODS: Rats (>300) received low levels of sodium/potassium thiocyanate (10 or 25 mmol/l) in their drinking water to raise their blood thiocyanate levels, mimicking the elevated levels of blood, salivary and urinary thiocyanate found in smokers. RESULTS: Thiocyanate supplements increased the severity of experimental arthritis induced by tailbase injection of (1) Freund's complete adjuvants (mycobacteria plus various adjuvant-active oils), (2) collagen type-II with Freund's incomplete adjuvant (no mycobacteria), (3) the synthetic lipid amine, avridine in an oil and (4) the natural hydrocarbons squalene (C(30)H(50)) and pristane (C(19)H(40)). This pro-arthritic effect was independent of sex, rat strain or changing diet and housing facilities. Thiocyanate supplements also amplified the acute/persisting inflammatory responses to paw injections of pristane, zymosan and microcrystalline hydroxyapatite. Iodide salts also mimicked some of these effects of thiocyanate. CONCLUSION: Thiocyanate, a detoxication product of HCN present in tobacco smoke, increased (or even induced) inflammatory responses to several agents causing arthritis or fibrotic inflammation in rats. It, therefore, can act as a co-arthritigen, or 'virulence factor' and could be a therapeutic target to reduce arthritis expression and morbidity.
Subject(s)
Arthritis, Experimental/metabolism , Hydrogen Cyanide/metabolism , Inflammation/metabolism , Smoking/adverse effects , Thiocyanates/metabolism , Administration, Oral , Animals , Arthritis, Experimental/chemically induced , Arthritis, Experimental/microbiology , Collagen/adverse effects , Diamines/adverse effects , Disease Models, Animal , Female , Hydrocarbons/adverse effects , Male , Mycobacterium , Rats , Rats, Wistar , Severity of Illness Index , Thiocyanates/administration & dosage , Thiocyanates/adverse effectsABSTRACT
We aimed our studies toward gaining an understanding of some of the reactions and pathways involved in the metabolism and activation of the aromatic diamines used in hair dyes and of phenacetin used in analgesic mixtures. Comparison of the data obtained from human and animal tissues established that animal tissues can serve as suitable models for evaluation of the activity of these compounds in humans.