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Biomedical subjects

G Frazer

Publications and source records attributed to G Frazer.

7 recordsLinked to original sources
PubMed1992

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American Speech-Language-Hearing Association↗
PubMed1988

Identification of cyclophilin as the erythrocyte ciclosporin-binding protein.

Previous studies on the distribution of circulating ciclosporin have shown that the majority of the drug is associated with erythrocytes. In order to investigate the nature of ciclosporin-erythrocyte binding, binding studies were performed on isolated erythrocytes. At therapeutic concentrations (approx. 0.5 microgram/ml in whole blood) greater than 90% of the erythrocyte associated ciclosporin was found in the cytosol. The cytosolic binding capacity was approximately (2-2.5).10(5) molecules of ciclosporin per cell. A lower affinity binding of the drug to the plasma membrane occurred only at higher ciclosporin concentrations. The ciclosporin-binding species was purified from erythrocyte cytosol using ciclosporin-Affigel affinity chromatography. This revealed a 16 kDa protein, similar in size to the ciclosporin-binding protein, cyclophilin, previously identified in lymphocyte cytosol. Immunochemical analysis using rabbit anti-bovine spleen cyclophilin antisera revealed that the erythrocyte ciclosporin-binding protein was either cyclophilin or a closely related protein. It is concluded that intracellular ciclosporin-binding within erythrocytes is mostly attributable to the presence of a single protein or protein family represented by cyclophilin. The presence of (2-2.5).10(5) copies of this binding protein within each erythrocyte is responsible for the ciclosporin found associated with erythrocytes.

Binding, Competitive↗
PubMedDate not supplied

[3H]Digoxin in the optic tract in digoxin intoxication.

Normal and chronically hypokalemic dogs were infused with [3H]digoxin until ventricular tachycardia occurred, at which point the concentration of digoxin was measured in all tissues involved in vision. The highest concentration was found in the choroid-retina of the eye, and this was considered the most likely site for the various visual changes seen in digitalis intoxication in man. Chronic hypokalemia did not influence the concentration or distribution of digoxin in the optic tract. It is speculated that the increased digoxin level in the extracranial part of the optic nerve is due to a weakness in the blood-retina barrier where the optic nerve fibers pass through the retina. One eye was left in situ for 3 days after death to study post-mortem changes in digoxin distribution. Vitreous humor analysis is being used to study the cause of death in man, but we found an increase in the vitreous humor digoxin level after death due to loss from its primary binding site in the choroid-retina. A similar effect would be expected with any drug bound to the retina and would have to be taken into account when considering the cause of death forensic pathology.

Animals↗
PubMedDate not supplied

3H-digoxin distribution in the nervous system in ventricular tachycardia.

The distribution of 3H-digoxin has been measured in a large number of tissues from the central, autonomic, and peripheral nervous system after the induction of ventricular tachycardia by infusing digoxin into anesthetized dogs. In most parts of the nervous system the tissue digoxin concentration was close to that in the cerebrospinal fluid. Digoxin accumulation in the choroid plexus probably represented a labeling of adenosine triphosphatase. There was a markedly higher concentration of digoxin in the neurohypophysis than in the adenohypophysis, and the very high levels in the neurohypophysis are hard to explain. There may be a relationship between the pituitary and the hypothalamic digoxin levels, although the concentration in the latter was unimpressive. The fornix showed a modest increase in 3H-digoxin concentration and may play a role, as its efferent discharge goes to the hypothalamus. The high concentration of digoxin in the area postrema suggests that this central nervous system structure is responsible, at least in part, for producing digoxin-induced cardiac arrhythmias. It may act as a sensing organ sensitive to blood digoxin concentration. Either it is the only central nervous structure implicated, or it is involved together with the fornix-hypothalamus-hypophysis pathways. Further proof is given for the importance of the autonomic nervous system in cardiac arrhythmias by the high digoxin levels in the superior cervical sympathetic ganglion and adrenal medulla.

Animals↗
PubMedDate not supplied

Ischemic brain edema: comparative effects of barbiturates and hypothermia.

The effect of pentobarbital and hypothermia on the development of ischemic brain edema was studied in 23 rhesus monkeys undergoing transorbital middle cerebral artery occlusion. Fifteen additional animals served as unclipped controls. Regional cortical cerebral blood flow (rCBF), arteriovenous oxygen content difference (AVDO2), and regional cortical metabolic rate of O2 (rCMRO2) were measured hourly until sacrifie 11 hours postocclusion, at which time ischemic cerebral edema was measured. In 8 animals no treatment followed the occlusion, and these developed edema. In 7 animals pentobarbial 14 mg/kg was administered intravenously 30 min after occlusion and 7 mg/kg every 2 hours thereafter. In this group ischemic brain edema was negligible. In 8 animals, hypothermia to 25.9 +/- 0.5 degrees C was started 30 min after occlusion and maintained until sacrifice; ischemic brain edema was not significantly altered from untreated-clipped animals. On the basis that both pentobarbital and hypothermia produced similar changes in rCBF, AVDO2, and rCMRO2, but only pentobarbital prevented edema, it is postulated that the mode of action of barbiturates in preventing ischemic brain edema is not entirely related to their known effect on blood flow and metabolism.

Animals↗