Therapeutic drug monitoring in pediatrics: a need for improvement

Therapeutic drug monitoring (TDM) is practiced for a number of frequently used drugs in infants and children. It is believed that monitoring drug levels will increase the probability of a therapeutic response and minimize the probability of adverse drug sequelae. Dose adjustments are based on measured drug levels interpreted relative to published therapeutic ranges which may or may not reflect the true relationship with either therapeutic or adverse effects. Potential errors derive from many sources, some amenable to solutions based on current knowledge, others awaiting improved understanding of the causes and consequences of unreliable therapeutic ranges.     

Transforming growth factor beta: a matter of life and death

A wide variety of functions, many of which represent opposing activities, have been attributed to TGF-beta, a molecule implicated in embryogenesis, development, and immune and inflammatory processes. This paradoxical behavior of promoting or inhibiting cell growth and function, while important in normal physiology and homeostasis, can contribute to or interrupt pathologic sequelae, making TGF-beta a particularly intriguing molecule for study. New transgenic mouse models displaying targeted alterations in TGF-beta 1 expression offer novel and unique opportunities to determine the essential function(s) of TGF-beta.     

Energy-transducing thylakoid membranes remain highly impermeable to ions during protein translocation

We investigated the operation of a posttranslational protein translocation pathway to determine whether ions are excluded from the translocase during protein transport. The membrane capacitance during protein translocation across chloroplast thylakoid membranes was monitored via electric-field-indicating carotenoid electrochromic bandshift measurements. Evidence is presented that shows that the membrane ion conductance is not increased during the complete cycle of binding, transport, and substrate release by the DeltapH-dependent translocase; i.e., the membrane remains ion-tight during protein translocation. We further demonstrate that a synthetic targeting peptide that directs proteins across this membrane does not gate translocation pores. We conclude that protein transport across the thylakoid membrane does not compromise its ability to maintain ion gradients and is, thus, unlikely to affect its functions in energy transduction.     

Photoaffinity labeling of the human erythrocyte nucleoside transporter by N6-(p-Azidobenzyl)adenosine and nitrobenzylthioinosine. Evidence that the transporter is a band 4.5 polypeptide

N6-(p-Azidobenzyl)adenosine (ABA) and nitrobenzylthioinosine (NBMPR) were employed as covalent probes of the nucleoside transport mechanism in human erythrocytes. NBMPR, a potent inhibitor of nucleoside transport, binds tightly (KD 0.3-1 nM) to specific sites on nucleoside transporter elements. ABA, a less potent inhibitor of uridine influx, competitively inhibited NBMPR binding (Ki 15 nM). [3H]ABA was bound tightly (KD 13.4 nM) but reversibly to sites on erythrocytes which appeared to be those which bind NBMPR. ABA binding was inhibited by uridine and adenosine. Irradiation with UV light caused site-bound [3H]ABA on erythrocyte membranes to become covalently bound and, similarly, photoactivation resulted in covalent attachment of membrane-bound [3H]NBMPR. In the presence of dithiothreitol, a free radical scavenger, photoactivation of the site-bound 3H-ligand on membranes depleted of extrinsic membrane proteins resulted in selective incorporation of 3H into band 4.5 of the membrane polypeptides which were resolved on sodium dodecyl sulfate-polyacrylamide gel electropherograms. This result, when considered with previous findings, indicates that the NBMPR-binding component of the nucleoside transport mechanism (or the entire mechanism, if the NBMPR site is an integral part) is a band 4.5 polypeptide.     

Salivary theophylline estimation in the management of asthma in children

Simultaneous sampling was performed to determine whether saliva could replace plasma in the monitoring of theophylline dosages. Forty-eight children with moderate to severe asthma received oral theophylline preparation (usually sustained release) on a daily basis. They provided simultaneous saliva and plasma samples at routine out-patient visits. Saliva and plasma theophylline concentrations showed a wide variation between individuals, and their ratios also differed. Saliva theophylline concentrations below 7 micrograms/ml reflect plasma concentrations below 10 micrograms/ml, i.e. sub-therapeutic, while saliva concentrations above 7 micrograms/ml are consistent with therapeutic dosage. Estimation of saliva theophylline concentration on routine visits avoids the discomfort of blood sampling. It reflects whether daily oral theophylline dosage in childhood asthma is below or within the therapeutic range. The need for changes in dosage and the degree of patient-compliance with therapy can be usefully indicated.     

Sodium oxacillin in the horse: serum, synovial fluid, peritoneal fluid, and urine concentrations after single-dose intramuscular administration

Six healthy adult mares were given a single dose (25 mg/kg of body weight) of sodium oxacillin IM. Oxacillin concentrations in serum, synovial fluid, peritoneal fluid, and urine were measured serially over a 48-hour period. The mean peak serum oxacillin concentration was 9.75 microgram/ml at 0.5 hour after injection. Mean peak oxacillin concentrations in synovial and peritoneal fluids were 1.45 microgram/ml and 2.60 microgram/ml at 1 hour and 2 hours, respectively. These concentrations decreased in parallel with serum values and were not measurable at 48 hours. Urine concentrations of oxacillin were high, with a mean peak concentration of 2,790.2 microgram/ml at 0.5 hour.