Most methods used for the extraction of quaternary amines in biological fluids have been based on ion-pair extraction techniques. In this study, a sensitive and selective chromatographic procedure is described to measure the concentration of pyridostigmine, neostigmine and their major metabolites in the plasma and urine. The methods involve a preliminary selective ion-pair extraction of the unchanged drugs and their metabolites into dichloromethane and dichloromethane-acetone mixture respectively. Quantitation is possible down to 3 ng/ml for parent drugs and 50 ng/ml for the metabolites. The present work also described a modified procedure to measure neostigmine and pyridostigmine in plasma simultaneously, using a specially synthesized pyridostigmine analogue as a common internal marker. The plasma concentration of pyridostigmine was measured after three different doses of the quaternary amine (36.2 Ng/kg, 72.4 pg/kg and 144.8 )tg/kg) were given intravenously to twenty five surgical patients during anaesthesia. The relation between the plasma concentration of pyridostigmine and time was invariably expressed as a bi-exponential equation, and the data was interpreted in terms of a two compartment model. The slow disposition halflife of the drug was progressively prolonged as the dose of the drug was raised from 36.2 Ng/kg to 144.8 jig/kg. A similar increase in the half-life was observed in cross-over studies. The clearance of the quaternary amine was enhanced at intermediate dose (72.4 )xg/kg) but significantly reduced after high dose (144.8 pg/kg). It was suggested that these results may partially account for the observed differences in the duration of action of neostigmine and pyridostigmine in man. The dose of pyridostigmine used to reverse non-depolarizing neuromuscular block is 4-5 times greater than neostigmine. After intramuscular administration of neostigmine to five myasthenic patients, the plasma concentration of the drug declined monoexponentially from 21 ±2 no/ml to 9t1 ng/ml between 30 and 120 minutes and data was interpreted in terms of a one-compartment model. Estimates of the plasma half-life varied from 56.9 - 100.1 minutes. The oral administration of pyridostigmine alone and of both neostigmine and pyridostigmine in two different groups of myasthenic patients, were also studied. There was a direct linear relation between area, under the plasma concentration - time curve and total daily dose of pyridostigmine in the first group of patients (r = 0.95), but no such observation was noticed in either all patients (two groups; r=0.15) or in the second group who were treated with both drugs (r =-0.08). It was suggested that there might be a drug-drug interaction between pyridostigmine and neostigmine during oral absorption. The relation between plasma levels of pyridostigmine to clinical evaluation of muscle power was examined in nine myasthenic patients during treatment with pyridostigmine in doses of 60 to 1080 mg per day. Five of the nine subjects demonstrated a trend towards a positive correlation and in two of them was this significant at pt0.05. In addition, the presence or absence of a possible correlation between muscle power and plasma concentration was not related to the duration of disease, additional prednisolone therapy or thymectomy.
Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:255744 |
Date | January 1981 |
Creators | Dehghan, A. |
Publisher | Liverpool John Moores University |
Source Sets | Ethos UK |
Detected Language | English |
Type | Electronic Thesis or Dissertation |
Source | http://researchonline.ljmu.ac.uk/4927/ |
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