Comparative Toxicology Studies in Sprague-Dawley Rats, Rhesus Monkeys, and New Zealand White Rabbits to Determine a No Observed Adverse Effect Level for 1,1′-Methylenebis[4-[(hydroxyimino)methyl]-pyridinium] Dimethanesulfonate

Abstract

Studies were conducted in Sprague-Dawley rats, New Zealand White (NZW) rabbits, and rhesus monkeys to characterize the toxicity of 1,1'-methylenebis[4-[(hydroxyimino)methyl]-pyridinium] dimethanesulfonate (MMB4 DMS) following intramuscular administration. Rats received MMB4 DMS once daily for 7 days at 100, 200, 400, and 800 mg/kg/d; rabbits received a range of dose levels in 3 separate 7-day studies from 3 to 800 mg/kg/d and in a single-dose study from 50 to 200 mg/kg; and monkeys received MMB4 DMS at 150 to 600 mg/kg/d. Mortality was noted in rats and rabbits administered ≥ 200 mg/kg. All monkeys survived until scheduled termination. Adverse clinical observations were noted in the rats at ≥ 400 mg/kg/d and in rabbits administered ≥ 200 mg/kg; no adverse findings were noted in the monkeys. Clinical pathology changes were noted in the rabbit related to cardiac and renal function. In the rabbit and monkey, elevations in myoglobin, alanine aminotransferase/aspartate aminotransferase, platelets, creatine kinase, and coagulation factors were related to local inflammation at the intramuscular administration site. Light microscopic examination at the injection sites revealed acute skeletal muscle necrosis in vehicle control and treated groups. Target tissues in the rabbit studies were identified as kidney, heart, and lungs at ≥ 100 mg/kg/d. All changes noted in all the species demonstrated partial to complete recovery comparable to control values or to a clinically irrelevant level of effect. The NZW rabbit was the most sensitive species, and the no observed adverse effect level (NOAEL) was determined as 50 mg/kg/d; the NOAEL in the rat was 100 mg/kg/d; and the NOAEL in rhesus monkeys was >600 mg/kg/d.

Inflammatory Cell Findings in the Female Rabbit Heart and Stress-associated Exacerbation with Handling and Procedures Used in Nonclinical Studies

“…The type of infiltrate described in detail here is similar to that described previously in the heart of rabbits (Miller 1924; Osheroff et al 2013; Weber and Van Der Walt 1975). These findings appear to fall along a continuum representing the chronicity of the lesion.…”

“…As compared to other species, rabbits are known for being hyperexcitable and may be uniquely susceptible to the development of stress-associated heart lesions (Osheroff et al 2013). Interestingly, catecholamine concentrations in the rabbit heart have been demonstrated to be notably higher (up to 3 times) than that of other species such as the rat or dog (Angelakos, Fuxe, and Torchiana 1963; Mukherjee et al 1983).…”

Potential protective effect of 3,3′-methylenebis(1-ethyl-4-hydroxyquinolin-2(1H)-one) against bleomycin-induced lung injury in male albino rat via modulation of Nrf2 pathway: biochemical, histological, and immunohistochemical study

“…Group III (3,3′-methylenebis-treated group): Each animal was injected intra-peritoneal with one dose of 3,3′-methylenebis (100 mg /kg) dissolved in 0.1 ml DEXA (Osheroff et al 2013 ).…”

Comparative Toxicokinetics of MMB4 DMS in Rats, Rabbits, Dogs, and Monkeys Following Single and Repeated Intramuscular Administration

“…The dose levels for each species in this study were identical to those used in earlier toxicology studies. 12…”

“…For these reasons, the current study examined the time course of MMB4 concentrations in plasma following IM administration of MMB4 DMS to male and female Sprague-Dawley rats, New Zealand White rabbits, beagle dogs, and rhesus monkeys at the dose levels used in earlier toxicology studies. 12 This study was conducted following Good Laboratory Practice requirements so that experimental data generated from this study can be included in the IND application. The study was conducted in compliance with The American College of Toxicology Policy on the Use of Animals, under the guidance of the Battelle Institutional Animal Care and Use Committee and the Animal Care and Use Review Office of the US Army.…”