Pharmacokinetics and pharmacodynamics of anticancer agents: contributions to the therapy of childhood cancer

Strategies for treating pediatric malignancies have not only been successful (i.e., curative) for several disseminated childhood cancers, they have also served as paradigms for the therapy of many adult cancers. Initial strategies included combined treatment modalities (chemotherapy, surgery, radiotherapy) and combinations of different pharmacologic classes of anticancer drugs given in the appropriate schedules. Despite the currently successful therapy for some malignancies (e.g., 70% 4-year disease-free survival in acute lymphocytic leukemia), many children die without known reason. Recent advances in the clinical pharmacology of anticancer drugs have identified relationships between dose intensity and response (efficacy, toxicity). Traditional methods of measuring dose intensity (prescribed dose) have evolved to more sophisticated approaches in maximizing the intensity of treatment, with good response rates. Other methods of optimizing chemotherapy for individual patients include bone marrow support procedures and therapy with biologic response modifiers. Relatively few clinically useful new anticancer drugs have been discovered in the past several years. Fortunately, the potential to improve therapy with currently available agents has come about through enhanced knowledge of the biochemical and clinical pharmacology of anticancer drugs and biologic response modifiers, as well as improved understanding drug resistance biology.     

Titration of duration discrimination in behavioral pharmacology and toxicology

This study investigated a discrete-trial, titration duration discrimination procedure in behavioral pharmacology. Pentobarbital and d-amphetamine, measured with this procedure, selectively affected discrimination more than response tendencies. Pentobarbital also tended to affect selectively discrimination of longer durations, whereas d-amphetamine did not. Further experiments showed that (1) other algorithms for modulating stimulus duration are useful in behavioral pharmacology and toxicology, (2) threshold estimates are similar with the method of constant stimuli and the method of titration, and (3) this titration procedure permits the separate examination of drug effects upon discrimination and upon response tendencies; the fixed-interval procedure does not. Baseline variability was an important correlate of drug effects in that the endpoints with more variable baselines were also more sensitive to drugs.     

Relationship between structure and function of dietary fibre: a comparative study of the effects of three galactomannans on cholesterol metabolism in the rat.

Male adult rats were fed on diets containing 80 g/kg galactomannans with different galactose (G): mannose (M) ratios/kg. The galactomannans were compared with purified cellulose (Solkaflok) and the animal were also fed on a basal diet free from fibre. All diets contained cholesterol (10 g/kg) and sodium cholate (2 g/kg). The three galactomannans were fenugreek gum (1G:1M), guar gum (1G:2M) and locust-bean gum (1G:4M). In comparison with the fibre-free and Solkaflok diets, all three galactomannans lowered the concentrations of cholesterol in both liver and blood plasma. The galactomannans also decreased the rate of hepatic synthesis of cholesterol. Dietary galactomannans increased caecal volatile fatty acids, particularly propionic, increased the weight of the caecum and its contents and increased the amount of water in the faeces. The increase in propionic acid production was significantly related to a decrease in caecal pH, but not to changes in plasma cholesterol or hepatic cholesterol synthesis. These effects were significantly influenced by chemical composition and structure of the galactomannan; they were most evident when the proportion of galactose in the galactomannan was highest (i.e. fenugreek gum). The three galactomannans also differed markedly in their effects on the viscosity of the digesta, but the galactomannan which gave the highest viscosity was least effective in lowering plasma cholesterol. A separate experiment with perfused loops of small intestine in vivo showed that the most effective galactomannan, fenugreek gum, had no direct effect on cholesterol absorption.     

Differences in hip axis and femoral neck length in premenopausal women of Polynesian, Asian and European origin

There are substantial inter-racial differences in hip fracture incidence. Studies in several different ethnic groups have suggested that differences in the length of the femoral neck may contribute to these. The present study assesses femoral neck and hip axis lengths in three ethnic groups in which it has not been documented previously (Chinese, Indians and Polynesians) and compares these values with those in Europeans. Lengths were measured from dual-energy X-ray absorptiometry scans of the proximal femur in normal premenopausal women (n=225). The Polynesian (1.65 m) and European (1.64 m) women were significantly taller than the two Asian groups (mean height in each, 1.58 m). There were also differences in mean body weight, the Polynesians being the heaviest (76 kg) and the Chinese the lightest (53 kg). Femoral neck lengths were (mean + SD) Chinese 61.5+4.4 mm, Indian 61.5+5.1 mm, Polynesian 68.2+4.3 mm and Europeans 66.0+4.8 mm. Hip axis lengths were Chinese 98.0+5.6 mm, Indian 94.5+5.2 mm, Polynesian 106.4 ± 5.3 mm and European 102.3+5.3 mm. Each of the other groups were significantly different from the Europeans for both variables and, in general, this remained so after height adjustment. These data suggest that shorter femoral necks are common to the major Asian racial groups. However, in contrast to all other ethnic groups studied, Polynesians have longer femoral necks than Europeans and their low incidence of hip fracture is not explicable, therefore, in terms of their femoral neck length. This suggests that either higher bone density or other more subtle differences in proximal femoral geometry must account for the low hip fracture incidence in Polynesians.     

Nutritional issues in pediatric inflammatory bowel disease.

Malnutrition, characterized by weight loss, growth failure and micronutrient depletion, are prominent features of inflammatory bowel disease (IBD) in the pediatric age group. Accurate evaluation of the patient's nutritional status and appropriate nutritional support, whether enteral or parenteral, constitute integral parts of the management of the growing child with IBD. Over the past two decades, a number of studies have supported the potential use of nutritional therapy to induce remission and to control disease activity in symptomatic Crohn's disease. More recently, preliminary studies on the use of dietary supplements of marine-oil-derived omega-3 fatty acids have also indicated a beneficial effect in IBD patients. In parallel with these clinical trials, scientific research has recently focused on the concept that specific dietary alterations can modulate the immune response. Components of the diet that may have particular relevance to mucosal immunity and the pathogenesis of IBD include polyunsaturated fatty acids, nucleotides, and amino acids such as glutamine and arginine. Future research in the interactions between specific nutrients and the immune system will likely increase our understanding of the causes of IBD, as well as enhance the development of novel nutritional therapies for IBD patients.     

Differential effects of monoclonal antibodies to tumor necrosis factor alpha and gamma interferon on induction of hepatic nitric oxide synthase in experimental gram-negative sepsis.

To investigate the stimuli required for the induction of nitric oxide synthase (NOS) in sepsis, we have analyzed the levels of this enzyme in the livers of mice infected with a 90% lethal dose of Escherichia coli in a model of gram-negative sepsis. Hepatic NOS levels are markedly induced in this model, with peak values occurring 12 to 22 h following infection. Treatment with TN3-19.12, a neutralizing monoclonal antibody to tumor necrosis factor alpha (TNF-alpha), resulted in complete protection from death in this model of sepsis but had no significant effect on the level of induction of hepatic NOS. Treatment with H22, a monoclonal antibody to gamma interferon (IFN-gamma), also gave significant protection against death and, in addition, did lead to a decrease in the level of induction of the hepatic NOS. Treatment of mice with pure TNF-alpha (0.2 microgram), IFN-gamma (2,000 U), or a combination of the two did not induce the hepatic NOS, but treatment with the combination led to significant mortality (probability of survival at 22 h, 0.32). Thus, the level of induction of NOS within the liver either in sepsis or by the coadministration of TNF-alpha and IFN-gamma does not correlate with death.