A comparison of the in vivo effects of ketotifen, clemastine, chlorpheniramine and sodium cromoglycate on histamine and allergen induced weals in human skin.

The effect of ketotifen was compared with that of clemastine and chlorpheniramine, known antihistamines, and sodium cromoglycate, a drug considered to have mast cell "stabilizing' properties on histamine and allergen wealing reactions in human skin, in random order, double-blind, placebo controlled studies. Ketotifen was significantly more potent in the inhibition of both histamine (P less than 0.001) and allergen (P less than 0.001) skin wealing reactions than either clemastine or chlorpheniramine. Sodium cromoglycate had no significant effect on either histamine or allergen skin wealing reactions in any of the concentrations tested. However ketotifen, like clemastine, had a significantly greater inhibitory effect on histamine than on allergen induced weals (P less than 0.001) and both drugs were shown to act as competitive antagonists of histamine. Ketotifen has been shown to be a potent anti-histamine but there is no evidence from these in vivo studies to suggest that it has any additional inhibitory activity on release of mediators from mast cells in human skin.     

How independent are "independent" effects? Relative risk estimation when correlated exposures are measured imprecisely

A relative risk estimate which relates an exposure to risk of disease will tend to be estimated too close to unity if that exposure is subject to random measurement error or intra-subject variability. "Independent" relative risk estimates, for the effect of one exposure after adjusting for confounding exposures, may be biased in either direction, depending on the amount of measurement imprecision in the exposure of interest and in the confounders. We describe two methods which estimate the bias in multivariate relative risk estimates due to the effect of measurement imprecision in one or more of the exposure variables in the model. Results from the two methods are compared in an example involving HDL cholesterol, triglycerides and coronary heart disease. In this example, the degree of bias in relative risk estimates is shown to be highly dependent on the amount of measurement imprecision ascribed to the exposures. It is concluded that when two exposures are substantially correlated, and one or both is subject to sizeable measurement imprecision, a study in which exposures are measured only once will be inadequate for investigating the independent effect of the exposures. Where feasible, epidemiologists should seek study populations where the correlation between the exposures is smaller.     

The application of population pharmacokinetic analysis to large scale clinical efficacy trials

Summary Results have been presented that demonstrate the ability to conduct population pharmacokinetic analysis as a component of clinical efficacy and safety trials. This method of analysis offers the potential to determine the pharmacokinetics of a drug in the actual patients receiving medication and to evaluate relationships between pharmacokinetics and drug action. However, active involvement in the protocol design, and data collection process are required to ensure the quality of the resultant data set.     

Measuring teaching intensity with the resident-to-average daily census ratio

This article analyzes a change in the measure of teaching intensity when calculating Medicare's indirect medical education (IME) adjustment: It looks at the potential for replacing, in the denominator of the ratio, beds with the average daily census (ADC). Among the findings are: (1) Hospitals with small teaching programs would benefit from this switch more than hospitals with larger programs because of their generally lower occupancy rates, (2) The adjustment formula currently used for the capital prospective payment system (PPS) would alleviate this effect relative to the adjustment formula used for the operating PPS, (3) Although ADC appears to vary more on average, the weighted average rates of change in the resident-to-ADC ratios for a matched group of teaching hospitals are equal to the rates of change for the resident-to-bed ratios.     

Geriatric planning: planning for our elderly

The objective of this article is to persuade policy-makers that we can improve planning for our elderly. An alternative model is presented--The Geriatric Centre--with location based upon city neighbourhoods, suburban and rural communities, and having neighbourhood responsibility, accountability and a comprehensive service delivery.     

Influence of the cardioprotective agent dexrazoxane on doxorubicin pharmacokinetics in the dog

Summary The influence of dexrazoxane on doxorubicin pharmacokinetics was investigated in four dogs using the two treatment sequences of saline/doxorubicin or dexrazoxane/doxorubicin. Intravenous doses of 1.5 mg/kg doxorubicin and 30 mg/kg (the 20-fold multiple) dexrazoxane were given separately, with doxorubicin being injected within 1 min of the dexrazoxane dose. Both doxorubicin and its 13-dihydro metabolite doxorubicinol were quantified in plasma and urine using a validated high-performance liquid chromatographic (HPLC) fluorescence assay. The doxorubicin plasma concentration versus time data were adequately fit by a three-compartment model. The mean half-lives calculated for the fast and slow distributive and terminal elimination phases in the saline/doxorubicin group were 3.0±0.5 and 32.2±12.8 min and 30.0±4.0 h, respectively. The model-predicted plasma concentrations were virtually identical for the saline and dexrazoxane treatment groups. Analysis of variance of the area under the plasma concentration-time curve (AUC_0–), terminal elimination rate (_Z), systemic clearance (CL _s), and renal clearance (CL _r) for the parent drug showed no statistically significant difference (P<0.05) between the two treatments. Furthermore, the doxorubicinol plasma AUC_0– value and the doxorubicinol-to-doxorubicin AUC_0– ratio showed no significant difference, demonstrating that dexrazoxane had no effect on the metabolic capacity for formation of the 13-dihydro metabolite. The total urinary excretion measured as parent drug plus doxorubicinol and the metabolite-to-parent ratio in urine were also unaffected by the presence of dexrazoxane. The myelosuppressive effects of doxorubicin as determined by WBC monitoring revealed no apparent difference between the two treatments. In conclusion, these results show that drug exposure was similar for the two treatment arms. No kinetic interaction with dexrazoxane suggests that its coadministration is unlikely to modify the safety and/or efficacy of doxorubicin.     

Effects of valproate on xenobiotic biotransformation in rat liver

Male Wistar rats werein vivo exposed for 2 weeks to 100 g/ml sodium valproate by subcutaneous implantation of osmotic pumps and hepatocytes were isolated. As anin vitro model co-cultures of rat hepatocytes with epithelial cells were daily treated with valproate (25, 50, 100, 200g/ml) for 2 weeks. In both models the cytochrome P-450 content and the enzymatic activities of 7-ethoxycoumarinO-deethylase, aldrin epoxidase and glutathioneS-transferase were determined in valproate-treated hepatocytes, in controls and in phenobarbital-induced cells. It appeared that in both systems the cytochrome P-450 content and the 7-ethoxycoumarinO-deethylase activity increased significantly after valproate treatment. On the other hand, the activities of aldrin epoxidase and glutathioneS-transferase decreased. A cDNA probe, encoding rat P450IIB2 was used to determine whether mRNAs encoding the P450IIB subfamily were induced by valproate. It became clear that the inducing effect of valproate was even more pronouncedin vitro thanin vivo.