Effects of prenatal exposure to combination of acetaminophen, isopropylantipyrine and caffeine on intrauterine development in rats

Abstract

<jats:p> The common effects of acetaminophen (paracetamol), isopropylantipyrine (propyphenazone) and caffeine on fetal development were examined in rats. The mixture was given in Tween 80 solution once daily, in a constant proportion of 5:3:1, during days 8–14 of gestation in three different doses. Dose S<jats:sub>1</jats:sub>–3.5 mg/kg acetaminophen, 2.14 mg/kg isopropylantipyrine, 0.7 mg/kg caffeine. Dose S<jats:sub>2</jats:sub> was 10 times higher, and S<jats:sub>3</jats:sub> 100 times higher than dose S<jats:sub>1</jats:sub>. On day 21 of gestation, the dams were sacrificed and the fetuses were removed. The corpora lutea, resorptions, live and dead fetuses were counted. The pre-and postimplantation mortality were calculated. The weight of fetuses and placentas, and the length of fetuses and their tails were measured. Two-thirds of each litter was processed for Alizarin Red S staining. The remaining third was fixed in Bouin's solution for subsequent visceral examination by using modified Wilson's technique. A significant decrease in body weight in S<jats:sub>1</jats:sub> group, and fetal length and placental weight in group S<jats:sub>3</jats:sub> were recorded. A significant increase in tail length in group S<jats:sub>2</jats:sub> was observed. The number ofcorpora lutea, fetuses, resorptions, preimplantation and postimplantation mortality did not exhibit any significant difference. Nonsignificant incidence of fetal anomalies was found. </jats:p>

Developmental effects of propyphenazone in analgesic and antipyretic combination with caffeine or paracetamol

“…24 ] 26 Similar kinds and rates of spontaneous bone abnormality were found in rats exposed to the mixture of propyphenazone, caffeine and paracetamol, when all three compounds were administered in the constant proportion 3:1:5. 31 Intrauterine exposure to the highest dose of such mixture caused statistically significant decrease of fetal length, as well as fetal and placental weight. 31 Unlike single compound studies 23 ] 28 and current reported groups treated with propyphenazone1/ paracetamol, a dose-dependent liver injury was seen in dams exposed to the mixture of propyphenazone and caffeine, and the mixture containing all three ingredients.…”

“…31 Intrauterine exposure to the highest dose of such mixture caused statistically significant decrease of fetal length, as well as fetal and placental weight. 31 Unlike single compound studies 23 ] 28 and current reported groups treated with propyphenazone1/ paracetamol, a dose-dependent liver injury was seen in dams exposed to the mixture of propyphenazone and caffeine, and the mixture containing all three ingredients. 33 The hepatotoxic effect and decrease of maternal body weight were seen in the middle and highest dose groups of a three-compound study; no indication of teratogenicity was found.…”

Evaluation of the reproductive and developmental risks of caffeine

“…The initial objective was to evaluate the effects of caffeine on skeletal development, when administered by gavage during gestation (Burdan et al, 2000). The later studies were designed to evaluate the effects of over‐the‐counter preparations of various mixtures of propyphenazone, caffeine, and paracetamol, with the purpose of determining liver toxicity (Burdan et al, 2001) and the prenatal risk of COX inhibitors administered with or without caffeine (Burdan, 2002, 2003, 2004). The studies were conducted in general conformance with evaluations performed for testing pharmaceuticals, but used fewer rats than are usually utilized in studies designed for regulatory use (generally 15 per group, rather than the recommended 16–20 litters), an abbreviated treatment period p.c.ds.…”

“…The next series of studies of combined drugs in over‐the‐counter products evaluated acetaminophen, isopropylantipyrine, and caffeine (Burdan, 2002). There were 29 control rats and 15 to 19 per group in those administered the caffeine mixture.…”

Congenital ventricular septal defects and prenatal exposure to cyclooxygenase inhibitors

“…The initial body weight of the dams on insemination day (gestational day 1, GD 1), ranged from 200 to 250 g. Commercial laboratory rat chow (LSM ® ; Agropol, Motycz, Poland) and filtered municipal tap water (Lublin, Poland) were provided ad libitum. All dams were intragastrically exposed to various selective, i.e., DuP-697 (5-bromo-2- (16), and non-selective COX-2 inhibitors, i.e., ibuprofen (15), paracetamol (25), piroxicam (16), propyphenazone (26), and tolmetin (15) with or without caffeine (25,(27)(28)(29). Detailed characteristics of all treated groups are presented in Table 1.…”