Therapeutic doses of paracetamol with co-administration of cysteine and mannitol during early development result in long term behavioral changes in laboratory rats

Abstract

Based on several lines of evidence, numerous investigators have suggested that paracetamol exposure during early development can induce neurological disorders. We had previously postulated that paracetamol exposure early in life, if combined with antioxidants that prevent accumulation of NAPQI, the toxic metabolite of paracetamol, might be innocuous. In this study, we administered paracetamol at or below the currently recommended therapeutic dose to male laboratory rat pups aged 4-10 days. The antioxidants cysteine and mannitol were included to prevent accumulation of NAPQI. In addition, animals were exposed to a cassette of common stress factors: an inflammatory diet, psychological stress, antibiotics, and mock infections using killed bacteria. At age 37-49 days, observation during introduction to a novel conspecific revealed increased rearing behavior, an asocial behavior, in animals treated with paracetamol plus antioxidants, regardless of their exposure to oxidative stress factors (2-way ANOVA; P < 0.0001). This observation would suggest that the initial hypothesis is incorrect, and that oxidative stress mediators do not entirely eliminate the effects of paracetamol on neurodevelopment. This study provides additional cause for caution when considering the use of paracetamol in the pediatric population, and provides evidence that the effects of paracetamol on neurodevelopment need to be considered both in the presence and in the absence of oxidative stress.

Paracetamol (acetaminophen) use in infants and children was never shown to be safe for neurodevelopment: a systematic review with citation tracking

“…This case-controlled, survey-based study raised substantial concerns, as mentioned in the Introduction. Further, studies in animal models evaluating the issue have been conducted [19][20][21]36], all indicating that the drug is not safe for neurodevelopment despite a wide range of study designs. In addition, as described in the Introduction, at least 14 cohort analyses [5][6][7][8][9][10][11][12][13][14][15][16][17][18] have indicated that exposure to paracetamol during pregnancy is not safe for neurodevelopment of the fetus.…”

“…Since this antidote is not present in the commonly used oral formulation, the University of Oulu study, even if it had been much larger and controlled for drug exposure over a period of years, would still not apply to most cases of paracetamol use. It should be noted that, in laboratory animals, exposure during the postpartum period to currently accepted levels of the intravenous formulation of paracetamol with the antidote present causes dramatic increases in asocial behavior later in life [36]. Thus, the argument is not that use of paracetamol with the antidote is safe, but rather that, hypothetically, some of the more serious adverse effects might be prevented by inclusion of the antidote with the drug.…”