Summary
The alimentary symptoms found in 107 consecutive cases of Parkinsonism have been compared with those found in 96 control subjects. Chewing difficulty, drooling of saliva, dysphagia, frequent heartburn and constipation all occurred significantly more often in Parkinsonism than in controls, and of these symptoms only the incidences of dysphagia and heartburn did not correlate with increasing disability from Parkinsonism. There was relatively little correlation between alimentary symptoms and ætiological type of Parkinsonism, though chewing difficulty occurred particularly in Parkinsonism following encephalitis lethargica, and constipation in paralysis agitans. The alimentary symptoms of Parkinsonism may be due to dorsal vagal nuclear and basal ganglia lesions, and to side effects of drug therapy.
The in vitro binding of diphenylhydantoin (DPH) to the lJrotein in plasma from 97 volunteers has been studied using ultrafiltration at 37° C. The capacity of plasma protein to bind DPH did not ditfer significantly between pregnant women (11.6 ± 1.7% of total drug unbound), women taking oral contraceptives (9.9 ± 1.7% unbound), healthy males (10.6 ± 1.3% unbound), and healthy females (11.0 ± 3.2% unbound). However, in plasma trom patients with renal disease (15.8 ± 3.9% unbound), hepatic disease (15.9 ± 6.0%) or hepatorenal disease (15.6 ± 5.4%), the protein binding of DPH was significantly decreased. These changes in protein binding were found to correlate better with changes in albumin and bilirubin levels in plasma than with any of 13 other biochemical parameters examined.
The binding of carbamazepine to the proteins of human plasma has been studied using ultrafiltration techniques. In vitro studies at 37 degrees C showed the relation between concentration of unbound drug and total drug to be linear through the range of total concentration of 5 to 50 mug/ml. The per cent unbound drug increased slightly as concentration increased. There was little difference between the extent of binding at 4 degrees C and 20 degrees C, but more carbamazepine was unbound at 37 degrees C. Under in vitro conditions, 6 other anticonvulsants, and aspirin, were tested individually, each at high therapeutic or toxic concentration, and shown not to displace carbamazepine from plasma proteins to a significant degree. The extent of binding of carbamazepine in vivo was determined in a total of 54 plasma samples collected from treated patients; 26.9 plus or minus SD 9.4 percent of the drug was unbound. In blood samples from 23 of these patients, the red cell concentration of carbamazepine averaged 38.3 plus or minus SD 17.9 percent of the plasma concentration. The effects of hepatic and renal diseases on the carbamazepine binding capacity of plasma proteins were assessed by comparing the binding capacity of plasma from disease persons with that from normal subjects. There was no significant difference in binding capacity between plasma from patients with renal disease and that from normal subjects. However, the plasma from patients with hepatic disease bound a slightly lower percentage of carbamazepine than did normal plasma (p smaller than 0.05). This alteration did not correlate with changes in any of 15 biochemical parameters measured in these patients. The clinical significance of these results is discussed.
SUMMARY Blood phenytoin (diphenylhydantoin) concentrations were measured after each dosage change in 12 epileptic patients who were given increasing oral doses of phenytoin. In each of these patients a dosage increment beyond the dosage that produced a blood phenytoin level of 6-9 [kg/ml. caused a disproportionately great increase in the blood concentration of drug. This effect might be expected if the limit of the body's capacity to metabolize phenytoin were being reached. As oral dosages were increased in one patient, measurements of the rate of urinary excretion of phenytoin metabolite showed that the phase of rapid rise in blood phenytoin concentration coincided with a failure to increase the rate of phenytoin metabolite excretion. Awareness of the non-linear relation between oral dose and blood concentration of phenytoin in the individual patient, and realization that the phase of rapid rise in blood phenytoin concentration occurs through the 'therapeutic' range of 10-20 ,g/ml., is of importance to those who use blood phenytoin levels as a guide to the adequacy of anticonvulsant therapy.
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