Current uncertainties and challenges of publicly available pharmaceutical environmental risk assessment data.

Pharmaceutical residues are widely detected in aquatic environment worldwide mainly arising from human excretions in sewage systems. Presently, publicly available, high quality environmental risk assessment (ERA) data for pharmaceuticals are limited. However, databases like the Swedish Fass offer valuable resources aiding healthcare professionals and environmental scientists in identifying substances of significant concern. In this review, we provide a concise overview of the regulatory ERA process for medicinal products intended for human use. We explore its key assumptions and uncertainties using a subset of 37 pharmaceuticals. First, we compare the consistency of their predicted no-effect concentrations reported in the Fass database with those by marketing authorisation holders. Second, we compare the predicted environmental concentrations (PEC) calculated based on sales data between European and national drug consumption statistics as well as with measured environmental concentrations (MEC), to demonstrate their impact on the regional risk quotients. Finally, we briefly discuss the prevailing uncertainties and challenges of current ecotoxicity testing, especially outcomes of chronic and nonlethal effects.

Toxicokinetics of the food-toxin IQ in human placental perfusion is not affected by ABCG2 or xenobiotic metabolism.

Metabolizing enzymes and transporters affect toxicokinetics of foreign compounds (e.g. drugs and carcinogens) in human placenta. The heterocyclic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a food-borne carcinogen being metabolically activated by cytochrome P450 (CYP) enzymes, especially by CYP1A1/2. IQ is also a substrate for ABCG2 transporter. Placental transfer of (14)C-IQ was evaluated in 4-6 h ex vivo human placental perfusions in Finland and Denmark. In Finland placentas were perfused with (14)C-IQ alone (0.5 microM, n = 6) or in combination with GF120918 (inhibitor of ABCG2, 1 microM, n = 6) or Ko143 (specific inhibitor of ABCG2, 2 microM, n = 4) to study the role of ABCG2 inhibition in transfer while in Denmark perfusions were performed with (14)C-IQ alone. Critical parameters (leak from fetal to maternal circulation, pH values, blood gases, glucose consumption, the production of hCG hormone and transport of antipyrine) were analyzed during the perfusions. (14)C-IQ on maternal and fetal sides was determined by liquid scintillation counting. In Finland IQ and its metabolites in final perfusates were determined also by LC/TOF-MS. ABCG2 expression and EROD activity (CYP1A1/2) were analyzed from perfused tissues. (14)C-IQ was easily transferred through the placenta from maternal to fetal side in both laboratories. Neither significant EROD activity nor IQ metabolites were found in placentas from non-smoking mothers. Inhibition of ABCG2 by GF120918 (FM-ratio of IQ 0.95) or Ko143 (FM-ratio of IQ 0.94) did not affect (14)C-IQ transfer (FM-ratio of IQ in IQ only perfusions 0.97), which indicates that placental ABCG2 does not have a significant role in protecting fetus from IQ.

Oxcarbazepine (GP 47 680) in the treatment of intractable seizures.

A single blind, within-patient clinical study was carried out on sixteen profoundly mentally retarded in-patients. Five of them had primary generalized, four had partial, six secondary generalized and one had mixed epileptic seizures. With the exception of two patients, all had for months or years been on CBZ combined with other anticonvulsive drugs. Eleven cases had received diphenylhydantoin, eight valproate, six had been given phenobarbital and five nitrazepam. Without changing other anticonvulsive therapy, CBZ was replaced by ox-CBZ up to a dosage of 30 mg/kg b.w. in two or three daily doses. The anticonvulsive efficacy of ox-CBZ was considered better than that of CBZ in eight patients. In three cases, CBZ was preferred and in the remaining five no preference could be stated. A desirable psychotropic effect was found in three patients on ox-CBZ. Unwanted side effects occurred in seven patients. Two of them had their first episode of status epilepticus during the trial. Two out of sixteen patients had to discontinue the therapy. One of them experienced several episodes of status epilepticus, and the other patient lost appetite and had to be fed by tube. No signs of hepatitis occurred in any patient. Three patients are still on ox-CBZ, three and a half years from the start of the trial.