Studies on tolerance. I. The role of the interval between doses on the development of tolerance to morphine.

The effect of varying the interval between doses on the rate of development of tolerance to a series of injections of morphine was studied in two strains of rats. Morphine sulfate injections (15 mg/kg s.c.) were given at intervals of 1, 2, 3, 7, 10, 14 or 21 days to adult male Wistar/Furth or Wistar-Lewis rats and drug effect was measured by means of the hot-plate assay technique. A diminution of morphine effect on the second or subsequent injections of drug was considered to be the result of the development of tolerance. Little or no tolerance was observed with the Wistar/Furth animals when a second injection or morphine was administered 7 days after the first, although there was marked tolerance when there were shorter or longer intervals between the first two injections. Subsequent injections of morphine sulfate, given to the animals at the predetermined intervals, resulted in wiping out out the differences between all interval groups, with the exception of the 1-day group, by the fifth injection. Although the differences between the 7-day and longer or shorter intervals were not as great with the Wistar-Lewis animals, they were significant and may reflect a slightly different rate of tolerance development in the latter strain. These observations are consistent with the hypothesis that there may be two types of tolerance, one appearing very rapidly, the other taking a longer period of time to develop.     

Comparison of the mode of immunopotentiating action of BCG and wax D. I. Effect on the immune response to SRBC.

The immunopotentiating action of BCG and wax D was comparatively evaluated as the immune response to sheep red blood cells (SRBC) in mice. The immunopotentiation of BCG varied with the interval between its priming and subsequent antigen injection. BCG increased delayed type hypersensitivity (DTH) at early stage but enhanced antibody formation at later stage. DTH reached its maximum about 5 weeks after BCG inoculation. In contrast, wax D increased antibody formation at early stage but increased DTH at later stage. Freund complete adjuvant (FCA) containing wax D stimulated much antibody formation rather than induction of DTH in mice. Cord factor and even Drakeol 6VR could induce DTH at early stage of prior inoculation.     

Effect of acute hypoxia on vascular responsiveness in man: I. Responsiveness to lower body negative pressure and ice on the forehead. II. Responses to norepinephrine and angiotensin. III. Effect of hypoxia and hypocapnia

An effect of hypoxemia on vascular responsiveness and blood pressure regulation has not been demonstrated in man. The response of forearm resistance vessels to several vasoconstrictor stimuli was compared during normoxia and acute hypoxia. Forearm vasoconstrictor responses to lower body negative pressure and to the application of ice to the forehead, which are neurogenic stimuli, were decreased during acute hypoxia. Lower body negative pressure caused a decrease in mean arterial pressure during hypoxia, but not during normoxia. Because norepinephrine is the neurotransmitter released during reflex vasoconstriction, we considered the possibility that decreased responsiveness to norepinephrine might be one mechanism for diminished responses to lower body negative pressure and ice on the forehead during hypoxia. Hypoxia decreased the response of forearm resistance vessels to infusions of norepinephrine and angiotensin into the brachial artery. In addition, the effectiveness of intravenous infusions of norepinephrine in elevating mean arterial pressure was decreased during hypoxia. Since exposure to acute hypoxia stimulates hyperventilation and hypocapnia, experiments were done to determine the contribution of hypocapnia during hypoxia to the decreased vasoconstriction. The results indicate that hypocapnia may diminish the vascular response to some stimuli, but the reduction in oxygen appears to be the primary mechanism for decreased vasoconstrictor responses during acute hypoxia.     

Using protocols to improve the outcomes of mechanically ventilated patients. Focus on weaning and sedation.

The use of nonphysician-directed protocols and guidelines for the management of sedation and weaning has been shown to reduce the duration of mechanical ventilation for patients with acute respiratory failure when compared with conventional physician-directed practices. Practitioners in ICUs frequently are needed to perform multiple tasks and to evaluate numerous elements of clinical information in the care of the critically ill. In this complex environment, protocols and guidelines are one strategy for ensuring that specific tasks are carried out in a timely manner. Simple-to-employ methods for facilitating changes and improvements in the care of hospitalized patients recently have been proposed. These methods emphasize the importance of developing a culture of cooperation within the ICU so protocols and guidelines can be implemented successfully. Such a culture should embrace changes in medical practices in the ICU if they are associated with improved clinical outcomes. The results of studies evaluating the use of protocols and guidelines have important implications for general critical care practices, because many ICUs do not have physicians who are constantly at the patient's bedside. The need for effective communication from the bedside caregiver (e.g., nurse, respiratory therapist, pharmacist, technician) to the physician, so that treatment orders can be changed appropriately, usually results in some delay in the implementation of treatment changes. Protocols are one method for potentially reducing those delays and ensuring that medical care is administered in a more standardized and efficient manner.     

Studies on the specificity of human IgE-antibodies to the plant proteases papain and bromelain.

The sera of seven patients clinically hypersensitive to papain--in one case also to baromelain--and the sera of sixty asthmatic patients with allergies to other inhalant and food allergens were investigated for IgE antibody activity to the plant proteases papain and bromelain and to common allergens by RAST, confirmed in some sera by RAST inhibition. There seems to be a relation between the antibody reactions to papain and bromelain, in several cases also between the reactions to these proteases and to grass pollen and flour. Studies by RAST inhibition showed that papain, bromelain, wheat flour, rye flour, grass pollen and birch pollen mutually inhibit IgE antibody to each antigen; but the degree of inhibition varies among the different sera and allergens. Our results suggest that these allergens from various plants, besides having specific antigenic determinants, also possess similar or even identical antigenically active regions, leading to immunological cross-reactivity.