Special Pharmacokinetic Considerations in Children

Summary: Pediatric patients have greater degrees of pharmacokinetic variability and unpredictability than adults. This variability results from the effects of pharmacogenetics, age and growth, prior and current comedication, and disease. Newborns with seizures have the least predictable dosage requirements, and their needs change as drug-eliminating mechanisms mature in the neonatal period. Infants have the highest relative capacities to eliminate antiepileptics of any age group and require the largest relative doses. In addition to age-related trends, children demonstrate the same drug-specific, pharmacokinetic phenomena that adults do, including nonlinear phenytoin elimination, nonlinear valproate binding, and autoinduction of carbamazepine. Intercurrent illness and drug interactions further modify the age-related pharmacokinetic patterns in children and make dosage requirements even more unpredictable. Recent studies have shown that febrile illness can affect drug elimination, sometimes decreasing drug levels by 50% or more. Intermittent treatment with benzodiazepines administered either orally or rectally can be an important adjunct and help minimize this type of problem for children with marginally controlled epilepsy. Intermittent benzodiazepines are also helpful for children who have febrile seizures and who need only occasional antiepileptic protection.     

Prevention of birth asphyxia: responding appropriately to cardiotocograph (CTG) traces

Birth asphyxia is a broad term that refers to intrapartum asphyxia sufficient to cause neurological damage in some newborns and, rarely, intrapartum or neonatal death. Cerebral palsy and long-term neurological complications such as learning difficulties and motor impairments may be due to causes other than birth asphyxia. Several intrapartum events may cause asphyxia (i.e. hypoxia and metabolic acidosis) leading to the likelihood of neurological injury. The cardiotocograph (CTG) is a screening tool that is used to assess fetal well-being during labour and to identify the possibility of asphyxia. Abnormality of the CTG, sometimes severe enough to be described as a pathological trace, is commonly termed 'fetal distress', although many fetuses with such traces may not have hypoxia and metabolic acidosis. In current practice, the events are appropriately termed 'pathological CTG trace' or 'acidotic pH' rather than 'fetal distress'. Accurate interpretation of CTG is essential, and it is important to recognize a fetus that shows a pathological CTG in labour that may imply possible hypoxia and birth asphyxia. Considering the wider clinical picture in interpreting the CTG, and taking timely and appropriate action based on the findings, may help prevent birth asphyxia.     

In vitro properties of rifapentine (MDL473) relevant to its use in intermittent chemotherapy of tuberculosis

In a comparison of in vitro properties of rifapentine (RIF) and rifampicin (RMP), the minimal inhibitory concentration of RIF against Mycobacterium tuberculosis in Tween-albumin liquid medium was usually 0.02 micrograms/ml, 2-3 times lower than for RMP; the bactericidal activity against a log phase culture was slightly less than that of RMP and the recovery after pulsed exposures to 1 microgram/ml of RIF or RMP lasting 6, 24 and 96 h was identical for the two rifamycins. These findings are used to interpret published data from the chronic experimental murine tuberculosis model and support the view that in the mouse, the efficacy of RIF in widely spaced intermittent chemotherapy is the result of its long half-life.     

Control of pollen hydration in Brassica requires continued protein synthesis, and glycosylation in necessary for intraspecific incompatibility

Pollen hydration and self-incompatibility (SI) in Brassica have been studied by using a combination of in vivo video-microscopy and experiments with metabolic inhibitors. Experiments with cycloheximide confirm earlier observations that pollen hydration is regulated through protein synthesis. No protein or glycoprotein has positively been identified with this event; however, it is unlikely that the total pool of any particular glycoprotein is involved, but rather a newly synthesized or otherwise activated fraction. Micromanipulation of pollen on the stigmatic papillae suggests that access to this hydration regulation system is limited to members of the Brassicaceae: pollen grains of other species—even those possessing dry stigmas—fail to hydrate. It is proposed that an interaction between enzymes of the stigma surface and the superficial layer of the pollen grain coating creates continuity between the content of the papillar wall and the grain protoplast. Inhibition of protein synthesis also overcomes SI, and since the advent of regulated hydration and synthesis of the so-called S-gene glycoproteins coincide with the acquisition of the SI system, there is strong circumstantial evidence that the same molecular species is involved in both processes. Experiments with tunicamycin, which prevents glycosylation of glycoproteins, indicate that the glycosyl groups of the S-gene glycoprotein are required for the operation of the SI system but not for the regulation of hydration. Further experiments suggest that pollen is positively inhibited on incompatible papillae but that this inhibition is biostatic. Recovery from the effects of the SI system appears to involve the metabolism of an inhibitor by the pollen. SI in Brassica thus emerges as a sophisticated process under dynamic control in both the female and male partners. The evolutionary advantages of such a system are discussed.     

Ethical issues in pain management

Dr Albert Schweitzer is reported to have stated, "We must all die. But that I can save ... [someone] from days of torture, that is what I feel is my great and ever new privilege". If, in spite of their anecdotal texture, the reflections in this article challenge my clinical colleagues to further hard reflection, comparison, or contrast with their own professional experience, they will have been worthwhile. If our collective experiences view pain management as a clinical-ethical issue, then no patient should ever have to bear pain due to the ignorance or apathy of well-intentioned but misinformed caregivers. I conclude with the words of Judith Spross, an oncology nurse: Pain is an emergency for the person who experiences it regardless of the urgency of the underlying pathology. I believe we must apply the science and art of pain relief as though life depended upon it. Certainly the quality of life does.     

Phase I study of 4′-deoxydoxorubicin (esorubicin) in children with malignant solid tumors

Summary 4 -Deoxydoxorubicin was given to 15 patients with drug-resistant pediatric malignant solid tumors with the objectives of determining the maximum tolerated dosage and dose-limiting toxicity. Maximum tolerated dosage was 36 mg/m₂ given IV once every 3 weeks. Dose limiting toxicity was myelosuppression, which was severe and prolonged. Therapeutic benefits were not observed for these patients.