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

Abstract

<jats:p> The aim of the study was to determine the influence of an over-the-counter (OTC) mixture of propyphenazone with caffeine or paracetamol on prenatal development. Propyphenazone:caffeine and propyphenazone:paracetamol mixtures were prepared with constant 3:1 and 3:5 ratios, respectively. Three dose levels of each of the mixtures were administered separately in Tween-80 water suspension once a day to pregnant Wistar rats on gestation days 8-14. The low dose was similar to the OTC preparations, 2.1 mg/kg of propyphenazone, 0.7 mg/kg of caffeine or 3.5 mg/kg of paracetamol. The middle dose was 21.0, 7.0 or 35.0 mg/kg, and the highest 210.0, 70.0 or 350.0 mg/kg for propyphenazone, caffeine or paracetamol, respectively. On day 21 of gestation the fetuses were delivered by hysterectomy. Dead or live fetuses, resorptions and the number of implantation sites were counted. Live fetuses were examined for external, visceral and skeletal malformation. Postimplantation mortality was calculated. Dose-dependent effects in the middle and high dose groups on fetal body weight/length and placental weight were found. No increase in external or internal congenital anomalies was found in any of the mixture-exposed groups. Prenatal coadministration of propyphenazone with caffeine or paracetamol caused intrauterine growth retardation but did not increase external or internal congenital anomalies. The risk of midline defects (umbilical hernia and gastroschisis) is discussed. </jats:p>

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.…”

“…Finally, Burdan (2004) administered maternal dosages of 2.1:0.7, 21:7, or 210:70 mg/kg prophyphenazone:caffeine on p.c.ds. 8 to 14.…”

Determinação Rápida E Simultânea De Propifenazona, Paracetamol E Cafeína Utilizando Análise Por Injeção Em Batelada Com Detecção Amperométrica

“…9,10 A combinação dos três princípios ativos (PRO, PAR e CAF) gera uma atividade terapêutica mais eficiente devido a atuação de cada droga em sítios ativos diferentes no organismo proporcionando maior eficácia analgésica e maior rapidez no início de ação quando compara-se com as drogas administradas separadamente. 11,12 Assim, é possível concluir que o uso de formulações farmacêuticas contendo mais de um princípio ativo apresenta vantagens. Dessa forma, no controle de qualidade deste tipo de medicamento, o uso de metodologias analíticas que permitem determinações simultâneas é altamente desejável.…”

Organ and prenatal toxicity of nonsteroidal anti-inflammatory drugs

“…Their popularity is facilitated by accessibility, as they are available for purchase in pharmacies, as well as in kiosks, grocery stores and petrol stations. The drugs in question are used so often because they have antiplatelet, analgesic, antipyretic, anti-inflammatory and tocolytic effects [13,15,40]. In contrast to the well-researched organ toxicity in adults, the adverse effects of COX inhibitors in pregnancy have not yet been fully explained [4,34].…”