Effects of bromantan on offspring maturation and development of reflexes

Bromantan (N-[2-adamantil]-N-[para-bromphenyl]amine) is an "actoprotective" drug widely used in Russia as a muscle performance-enhancing agent for sportsmen and as an immunostimulator in medicine. Experiments were conducted to determine whether this compound has adverse effects on the reproduction and development of offspring. Sexually mature female rats, weighing 180-200 g, were orally given bromantan at doses of 30 mg/kg (30-mg/kg group), 150 mg/kg (150-mg/kg group) and 600 mg/kg (600-mg/kg group) daily for 16 days, while the controls received the vehicle, amylaceous solution. Afterwards, treated females were mated with untreated males. The body weight change of the pregnant rats was monitored, as well as the length of gestation, litter size, sex ratio and number of stillborn. The offsprings were weighed and observed for external malformations, abnormalities of conditioned and unconditioned reflexes and open-field behaviour. Observation of rat dams revealed that their general state and activity in all groups did not differ significantly both during and after bromantan treatment. Bromantan had no adverse effects on body weight and gestation length of dams. Number of dams delivered per group did not differ from controls. There were stillborn rat pups in all litters, but the control group had less. One dam in the first group delivered a rat pup with a head hematoma. Litter size of the 30- and 600-mg/kg groups was decreased (by 34.9% and 44.2%, respectively) and increased in the 150-mg/kg group (by 45.1%, P< .05) in comparison with controls. Bromantan had insignificant different effects on the sex ratio of newborn in all treatment groups. Survival of pups over the first 3 months showed a loss of 40% for the 150-mg/kg group and 20% for controls. During the remaining time, death rate did not exceed 3-6% and did not differ from those of the controls. Pups in the 30- and 600-mg/kg groups showed significantly higher weight gain during the first week (7th PND) of observation by 83.69% and 58.02%, respectively, compared to controls; subsequently, this difference in the 600-mg/kg group decreased rapidly to insignificant levels, but the 30-mg/kg group remained significantly different until PND 35 and then again at PND 77-112. Dynamics of body weight gain of rat pups in the 150-mg/kg group during the whole (but not on PND 7) period of observation was insignificantly (on PNDs 14, 42 and 49 significantly) lower than that of the control group. Study of the functional state of rat pups' nervous system at different stages of postnatal development revealed insignificant differences in the expression of reflexes compared with those of the control group. Negative geotaxis was completed by the 8th day in controls and in treated groups earlier by an average of 1-2 days. Surface righting was completed by the controls on the 8th day, in the 30-mg/kg group on the 6th day and in other treated groups on the 7th day. Cliff avoidance appeared a day ahead for rat pups in treated groups compared with controls. Air righting reflex in the 30- and 600-mg/kg groups was observed a day earlier than in the controls. Significant differences were observed only for two parameters (negative geotaxis and surface righting); in both cases, rat pups of the 30-mg/kg group differed from the control and 150-mg/kg groups. Early development of physical parameters was also noted, but significant differences from the control group were obtained only in the 30-mg/kg group for incisor eruption. While all pups demonstrated strength of fore and hind limbs by postnatal day 16, treated pups increased their times of maintaining their grasp (PND 15). Open-field testing (PND 40) resulted in an insignificant decrease of exploratory and locomotor behaviors for the 30-, 150- and 600-mg/kg groups. The number of grooming episodes was insignificantly decreased for the 30-mg/kg group and insignificantly increased for the 600-mg/kg group. In the passive avoidance testing, on the retention day (72 h later), entry latency for rat pups in the 30-, 150- and 600-mg/kg groups increased by 259.0%, 175.3% and 160.7%, respectively (P< .05), over their training day, while in the control group, time increased only by 1.8%.