[Obstruction of the nose in newborns]. / Neusobstructie bij de pasgeborene.

Five newborns, 4 girls and 1 boy, presented with breathing and feeding difficulties caused by obstruction of the nose. The causes were choanal atresia, apertura pyriformis stenosis, teratoma, glioma and haemangioma. Following surgical treatment the children were symptom-free. Rapid diagnosis and treatment of these conditions are essential. An alternative airway should be created if a newborn suffers from breathing problems. Diagnostic work-up includes flexible laryngo-endoscopy followed by MRI- or CT-scan. Treatment is usually surgical.

Mechanisms of drug transfer across the human placenta.

In this review we summarized literature data on the mechanisms of human placental drug transport studied in the isolated perfused placental cotyledon, placental membrane vesicles or trophoblastic cell cultures. Overall human placental drug transport rarely exceeds the transfer of flow-dependent and membrane-limited marker compounds. Interestingly, relatively often placental drug transfer appeared to be much smaller, indicating impaired trans-placental transport, depending on the physico-chemical characteristics of the drug or placental factors such as tissue binding or metabolism. Although in perfusion studies overall human placental drug transport occurs by simple diffusion, at the membrane level several drug transport systems have been found, mainly for drugs structurally related to endogenous compounds.

Uptake of cimetidine into syncytial microvillus membrane vesicles of human term placenta.

Uptake of the H2-receptor antagonist, cimetidine, into syncytial microvillus membrane vesicles of human term placenta was investigated to clarify whether an active transport mechanism can be responsible for the observed barrier of the human placenta for cimetidine. Imposition of an outwardly directed H(+)-gradient stimulated cimetidine uptake, resulting in a small transient overshoot. The H(+)-gradient-dependent peak uptake was decreased under voltage-clamped conditions by carbonyl cyanide p-trifluoromethoxy-phenylhydrazone, suggesting the presence of an organic cation-proton exchange mechanism. Uptake was partially, but significantly, inhibited by organic cation transport inhibitors, H2-receptor antagonists and several other cationic drugs, providing further evidence for mediated uptake. H(+)-gradient-dependent cimetidine uptake was saturable and characterized by a low-affinity (Km) of 6.3 mM and Vmax of 17.5 nmol/mg protein/10 sec. We conclude that the system cannot play an important role in the barrier function of the human placenta in the transport of cimetidine. Rather than active transport, other factors, as for instance the degree of ionization of cimetidine at physiological pH, seem to be a more likely explanation for the low clearance of cimetidine across the human placenta.

Inhibition of choline uptake in syncytial microvillus membrane vesicles of human term placenta. Specificity and nature of interaction.

The potency and nature of the inhibitory effect of various cationic drugs on the transport of choline across the placental syncytial microvillus membrane was investigated. Tetraethylammonium, a model substrate for organic cation transport, was a poor inhibitor. Enlarging the degree of alkylation of the quaternary ammonium increased the inhibitory effect, in proportion with increasing lipophilicity. Log concentration vs % control uptake curves showed marked differences in inhibitory potency for the different cationic drugs. Hemicholinium-3 inhibited mediated choline uptake in the micromolar range, whereas atropine and mepiperphenidol were less potent. The H2-receptor antagonists cimetidine, ranitidine, and famotidine inhibited choline uptake in the millimolar ranges. Dixon analysis revealed a competitive nature of inhibition for hemicholinium-3 and atropine (Ki = 40 microM and 1.2 mM, respectively). Cimetidine interacted noncompetitively (Ki = 3.4 mM). Since relatively high concentrations were needed to reach half maximal inhibition, impairment of fetal choline supply due to maternal drug use during pregnancy is not to be expected.

Isolation of syncytial microvillous membrane vesicles from human term placenta and their application in drug-nutrient interaction studies.

The initial step in placental uptake of nutrients occurs across the syncytial microvillous membrane of the trophoblast. This study was designed to isolate syncytial microvillous membrane vesicles (SMMV) of human term placenta, to validate their purity and viability, and to investigate the interaction of several commonly used drugs with the transport of two essential nutrients: alanine and choline. SMMV were isolated according to an established procedure, but instead of homogenization the initial preparation step was replaced by mincing of placental tissue followed by gently stirring to loosen the microvilli. These modifications doubled the protein recovery and increased the enrichment in alkaline phosphatase, whereas no substantial contamination with basal membranes nor interfering subcellular organelles was found. The functional viability of the vesicles was evaluated through the transport of alanine. In accordance with literature, uptake was sodium-dependent, inhibitable by structural analogues, and saturable. A number of cationic drugs were were able to able to inhibit choline uptake, whereas no effect on alanine transport was observed. Anionic drugs, drugs of abuse, and catecholamines did not interfere with alanine transport either. In conclusion, our isolated SMMV provide a suitable tool for screening drug-nutrient interactions at the level of membrane transport. In view of the very low susceptibility of the alanine transporter to drug inhibition and the relatively high drug concentrations necessary to inhibit choline transport, it seems unlikely that clinically important drug interactions may occur with these nutrients.

p-aminohippurate uptake by syncytial microvillous membrane vesicles of human term placenta.

The mechanism of uptake of p-aminohippurate (PAH) by syncytial microvillous membrane vesicles of human term placenta was investigated. Initial PAH uptake and efflux were increased in the presence of a pH-gradient and a Cl(-)-gradient, respectively. Forced negative and positive membrane potentials did not influence the uptake, which indicated that the transport is not electrogenic. The pH-dependent increase is probably the result of a higher rate of diffusion due to a lower degree of dissociation of PAH. Because several organic anions failed to transstimulate PAH uptake and FCCP did not decrease the uptake in the presence of an inwardly directed H(+)-gradient, ruling out a PAH/OH- antiport, an anion exchange system does not appear to be present in these membranes. Since electrogenicity and anion exchange seem not to be involved in the Cl(-)-dependent increase, an allosteric effect of Cl- on the transporter might be possible. Various organic anions were able to inhibit pH-stimulated PAH uptake significantly. Kinetic analysis of the probenecid sensitive part of uptake provided further evidence for mediated transport of PAH (Km = 7.4 +/- 2.6 mM and Vmax = 2.0 +/- 0.4 nmol/mg/15 s). Non-inhibitable diffusion accounted for the main part of total transport. Concentration dependent inhibition of PAH transport by probenecid showed a Ki of 2.5 +/- 0.9 mM. It is concluded that human placental syncytial microvillous membrane vesicles possess a low affinity transport mechanism for PAH with low specificity. The importance of this system, for placental excretion of anionic drugs, will depend on the intrasyncytial concentration of these drugs, caused by the transport across the basal membrane.

Uptake of choline into syncytial microvillus membrane vesicles of human term placenta.

The uptake of the quaternary ammonium compound choline was studied in syncytial microvillus membrane vesicles of human term placenta. Uptake was stimulated by an inside negative membrane potential and by loading the vesicles with unlabeled choline. Imposition of an inwardly directed Na+ or outwardly directed H+ gradient did not stimulate choline uptake. Several organic cations were able to inhibit choline transport in the following order: hemicholinium-3 > or = choline > or = mepiperphenidol > cimetidine > or = famotidine. The kinetics of uptake involved a saturable process for choline with high affinity (Km = 550 microM). Our results confirm the presence of a carrier mediated transport system in human placental syncytial microvillus membranes. The system appears to be electrogenic, and able to transport choline efficiently from the maternal circulation into the placenta.