Cytokines in Vertebrate Reproduction

Mechanisms determining survival and growth of the semi-allogeneic fetus in the maternal uterus are still not completely defined. Studies in mammals have shown that soluble substances with autocrine/paracrine action (cytokines) have a central role in modulating the maternal immune response and contributing to the expansion of fetal tissues in the maternal uterus. We hypothesized studies on different classes of vertebrates could help clarify the role of cytokines in acceptance of the embryo by the maternal tissues. We examined the presence of the cytokine interleukin-1 beta (IL-1β) and of its functional membrane receptor IL-1 receptor type I (IL-1R tI) in uterine/oviductal tissues of species with different reproductive strategies. In particular, we carried out studies on non-mammalian vertebrates (squamate reptiles, amphibians and elasmobranch fishes), presenting placental or aplacental viviparity, oviparity or ovuliparity. Since in ovuliparity eggs are released and fertilized in the external environment, species adopting this reproductive strategy can be considered a natural negative control in studies on materno-fetal immunotolerance. Findings showed The IL-1 system is expressed in the reproductive tissues of all the species regardless the vertebrate class or the reproductive strategy adopted. However, marked differences exist between ovuliparous species and oviparous and viviparous ones. In fact, expression of IL-1β and IL-1R tI is limited to the luminal epithelium in the ovuliparous species, while it is extended to most cellular components of the uterine wall (including connective tissue, glandular and endothelial cells, and the muscle layer) in oviparous and viviparous specimens. These findings highlight the role of the IL-1 system in the acquisition of the ability to retain the embryo in the female genital tract during the transition from ovuliparity to viviparity and suggest non-mammalian vertebrates as a good animal model for studies on cytokines in materno-fetal immunotolerance

Effects of cigarette smoking on quinine pharmacokinetics in malaria.

OBJECTIVE: Quinine is an important antimalarial drug that is metabolised mainly by the hepatic mixed-function microsomal enzyme cytochrome P(450). Cigarette smoking in healthy volunteers has been reported to enhance quinine clearance. The present study evaluated the effects of smoking on quinine pharmacokinetics in patients with uncomplicated falciparum malaria treated with a 7-day course of oral quinine. Of 22 studied male patients, 10 were regular smokers and 12 were non-smokers. METHODS: All patients were treated with a 7-day oral regimen of quinine sulfate (10 mg salt/kg three times a day). Serial venous blood samples were taken for quinine levels before and during treatment at 12 h and 24 h and then daily until day 7. Plasma quinine and 3-hydroxyquinine concentrations were assayed using high-performance liquid chromatography. Quinine pharmacokinetics were evaluated using non-compartmental modelling. RESULTS: All patients recovered, and there were no significant differences in clinical responses or cure rates between the two studied groups ( P> or =0.32). The median (range) fever clearance time was 51 h (4-152 h) and mean (SD) parasite clearance time was 74+/-28 h. The overall median times to maximum concentrations of quinine and its main metabolite 3-hydroxyquinine were 1.5 days and 4.0 days, respectively. The maximum concentrations of quinine were approximately tenfold higher than 3-hydroxyquinine. There were no significant differences in any pharmacokinetic variables for the parent compound or metabolite between the two groups. The median area under the plasma drug concentration-time curve to day 7 (AUC(0-7)) of quinine in non-smokers was 67.0 micro g/ml/day and in smokers was 51.3 micro g/ml/day, and AUC(0-7) values of 3-hydroxyquinine were 6.2 micro g/ml/day and 4.8 micro g/ml/day, respectively. CONCLUSION: These results indicated that cigarette smoking has no significant effects on quinine pharmacokinetics or the therapeutic response in patients with falciparum malaria

Cytokines in vertebrate reproduction

6Mechanisms determining survival and growth of the semi-allogeneic fetus in the maternal uterus are still not completely defined. Studies in mammals have shown that soluble substances with autocrine/paracrine action (cytokines) have a central role in the maternal-fetal immunotolerance thus, contributing to the expansion of fetal tissues in the maternal uterus. We report here about a methodological approach based on analysis of cytokines in reproductive tissues of vertebrates using different reproductive strategies i.e., placental and aplacental viviparity and oviparity. Most of the studies focused on Interleukin-1 (IL-1), an evolutionarily conserved cytokine with many roles in mammalian reproduction, particularly in uterine receptivity and blastocyst implantation. The presence of IL-1, mainly IL-1β and of its functional membrane receptor IL-1 receptor type I (IL-1R tI) in reproductive tissues of oviparous and viviparous species suggests that this cytokine is a fundamental mediator of maternal-fetal immunotolerance.reservedmixedRicci, Luana; Jantra, SILKE BIRGIT; Ietta, Francesca; Brizzi, R.; Avanzati, ANNA MARIA; Bigliardi, ElisaRicci, Luana; Jantra, SILKE BIRGIT; Ietta, Francesca; R., Brizzi; Avanzati, ANNA MARIA; Bigliardi, Elis

Quinine Pharmacokinetic-Pharmacodynamic Relationships in Uncomplicated Falciparum Malaria

The relationships between the pharmacokinetic properties of quinine during a 7-day treatment course and the therapeutic response were studied in 30 adult patients with uncomplicated falciparum malaria monitored for ≥28 days. All patients received a 7-day oral quinine regimen either alone (n = 22) or in combination with rifampin (n = 8). The median fever clearance time was 58.5 h, and the mean ± standard deviation parasite clearance time was 73 ± 24 h. After recovery, six patients had recrudescences of Plasmodium falciparum malaria and seven had delayed appearances of P. vivax infection between days 16 and 23. Between the patients with and without recrudescences, there were no significant differences either in fever clearance time or parasite clearance time or in the overall pharmacokinetics of quinine and 3-hydroxyquinine. Patients for whom the area under the concentration-time curve from 3 to 7 days for quinine in plasma was <20 μg · day/ml had a relative risk of 5.3 (95% confidence interval = 1.6 to 17.7) of having a subsequent recrudescence of infection (P = 0.016). Modeling of these data suggested an average minimum parasiticidal concentration of quinine in plasma of 3.4 μg/ml and an MIC of 0.7 μg/ml for uncomplicated falciparum malaria in Thailand. To ensure a cure, the minimum parasiticidal concentration must be exceeded during four asexual cycles (>6 days)