Difficulties in using animal data to predict pharmacological response in man

Variation among species in their response to xenobiotic agents depends upon two sets of factors: pharmacokinetic and pharmacodynamic. Pharmacokinetic factors, of which the rate of metabolic transformation is the most important, determine the concentration of the agent in plasma and tissues as a function of time after it is administered, while pharmacodynamic factors define the tissue response to a given concentration. Both are subject to considerable uncertainty when dealing with a new compound, so that it is not in general possible to predict reliably the response of human subjects to a new compound solely from studies on experimental animals. This uncertainty can be reduced substantially by understanding its mechanisms of action. Greater accuracy in predicting the metabolism of foreign compounds in man is also likely to be achieved by studies of the species variation of cytochrome P450s, and by the use of human hepatocytes and other cell lines to study xenobiotic metabolism.     

Genetic factors for the span of apprehension test: a study of normal twins.

The Partial Report Span of Apprehension test has been found to detect cognitive deficits in some first degree relatives of schizophrenic patients. To assess the relative contribution of genetic vs. environmental factors on this measure, 19 monozygotic and 14 dizygotic female twin pairs, selected from a normal population, were tested on the Span of Apprehension test and an IQ test. Both Span of Apprehension test performance and IQ score had high heritabilities: 0.65 and 0.71, respectively. The mode of transmission for performance on the Span of Apprehension test appears to operate in a nonadditive manner. A multivariate behavioral-genetic model applied to the Span of Apprehension and IQ measures indicated that slightly less than half of the genetic effects important for the Span of Apprehension test are found in common with the genetic factors important for IQ. The phenotypic correlation between the Span of Apprehension and IQ measures can be attributed entirely to genetic factors. The influence of unique genetic components in the performance of the Span of Apprehension test in the general population heightens the promise of this measure as a genetic marker for schizophrenia.     

Immediate effects of intravenous clomipramine on sleep and sleep-related secretion in depressed patients

An i.v. challenge dose of clomipramine (12.5 mg) was given to eight outpatients with major depression. The procedure facilitated the examination of all-night sleep and sleep-related neuroendocrine changes (cortisol, growth hormone, and prolactin). In comparison to baseline saline nights, the patients experienced a profound suppression of rapid eye movement (REM) sleep throughout the night with no rebound recovery in the second half of the night. Furthermore, REM-suppressing effects were noted on the following no-drug night. In contrast, little effect on delta wave sleep was found, except for increased consolidation of delta waves within stage 3 and 4 sleep. Delta sleep measures were significantly correlated with levels of cortisol and growth hormone.     

Surgical implications of cerebral dysgenesis

Cerebral dysgenesis encompasses varied disorders of brain development. Based on the understanding of these conditions provided by histopathologists, embryologists, radiologists and developmental pediatricians, surgeons are able to appropriately assist in the care of these patients. The surgeon can offer assessment of the ventriculomegaly that commonly accompanies cerebral dysgenesis in addition to providing methods to control hydrocephalus, to reconstruct cranial and facial malformations and to remove dysfunctional tissue. For most patients, surgical intervention is only one of the many factors that determine developmental prognosis. Based on the foundation built by other specialists, this review discusses cerebral dysgenesis from the perspective of historical and current surgical interventions.     

Studies on the contact system of coagulation during therapy with high doses of recombinant IL-2: implications for septic shock

Patients treated with high doses of interleukin-2 (IL-2) because of cancer, develop hemodynamic and vasopermeability changes, that resemble those observed in sepsis. These patients thus provide a unique opportunity to study the early events in the development of septic shock. We analysed the changes that occurred in the contact system of coagulation in plasma from 4 patients, who together received seven 12-day cycles of high doses of IL-2. Levels of factor XII and prekallikrein during the cycles progressively fell to 50 and 30% of their initial levels, respectively, whereas significant increases in plasma factor XIIa- and kallikrein-C1-inhibitor complexes were not observed (in 3 out of 211 samples slightly increased levels of both complexes were found). The reductions in factor XII and prekallikrein were only in part due to protein leakage, since levels were still significantly lower, i.e., 80 and 50%, respectively, when corrected for albumin decreases. Levels of high molecular weight kininogen (HMWK) also decreased during IL-2 therapy, however, this decrease paralleled that of albumin. SDS-PAGE analysis of plasma HMWK did not reveal increased cleavage of this protein. The reduction of factor XII and prekallikrein, corrected for protein leakage, significantly correlated with albumin levels and inversely with daily cumulative weight gain in the patients. Thus, we demonstrate that factor XII and prekallikrein decrease during IL-2 therapy. As these decreases, already observed after 1 day treatment, were disproportional to that of albumin, a negative acute phase reactant, and correlated with signs of the vascular leak syndrome, we favor the explanation that they reflected activation rather than a decreased synthesis of the contact system proteins.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dependence of blood clot lysis on the mode of transport of urokinase into the clot--a magnetic resonance imaging study in vitro

Magnetic resonance imaging was employed to study the dependence of clot lysing patterns on two different modes of transport of urokinase into whole blood clots. In one group of clots (nonperfused clots, n1 = 10), access of urokinase to the fibrin network was possible by diffusion only, whereas in the other group (perfused clots, n2 = 10) bulk flow of plasma containing urokinase was instituted through occlusive clots by a pressure difference of 3.7 kPa (37 cm H2O) across 3 cm long clots with a diameter of 4 mm. It was determined separately that this pressure difference resulted in a volume flow rate of 5.05 +/- 2.4 x 10(-2) ml/min through occlusive clots. Perfused clots diminished in size significantly in comparison to nonperfused ones already after 20 min (p less than 0.005). Linear regression analysis of two-dimensional clot sizes measured by MRI showed that the rate of lysis was more than 50-times faster in the perfused group in comparison to the nonperfused group. It was concluded that penetration of the thrombolytic agent into clots by perfusion is much more effective than by diffusion. Our results might have some implications for understanding the differences in lysis of arterial and venous thrombi.     

Cerebral hemorrhagic risk of aspirin or heparin therapy with thrombolytic treatment in rabbits

We studied the incidence of cerebral hemorrhage in an animal model of embolic stroke to determine the safety of aspirin, heparin, and tissue plasminogen activator therapies. We occluded the middle cerebral arteries of rabbits with labeled blood clots and administered either tissue plasminogen activator, heparin, aspirin, tissue plasminogen activator plus aspirin, tissue plasminogen activator plus heparin, or saline at various times after stroke. Compared to saline controls, both the aspirin-only and the tissue plasminogen activator-plus-aspirin groups had a significantly higher incidence of cerebral hemorrhage, whereas the heparin and tissue plasminogen activator combination groups did not. We conclude that aspirin antiplatelet therapy alone may increase the risk of hemorrhagic infarction, whereas heparin or tissue plasminogen activator therapy appears to be relatively safe.     

Reference values of anthropometric measurements in Dutch children. The Oosterwolde Study

In the period 1979-1980 the following anthropometric measurements were recorded in 2351 healthy Dutch children from 0-17 years of age: height, weight, sitting height, arm span, lengths of upper-arm, lower-arm and hand, tibial length, foot length, biacromial diameter, biiliacal diameter, and head circumference. Corresponding percentile values were constructed on the basis of normality assumptions, the mean and standard deviation at age t being determined by a cubic spline approximation. The results are compared with other studies and given in the form of growth charts.     

Dental and periodontal disturbances due to magnesium deficit

Experimental results in female rats with marginal magnesium deficiency a and clinical results in over 100 female tetanic patients suggest the deleterious influence of magnesium on oro-facial tissues.