N.E. Williams

A quantitative gas-liquid chromatographic method for the determination of neostigmine and pyridostigmine in human plasma

A sensitive and selective analytical method was used to measure the concentration of neostigmine and pyridostigmine in human plasma. The procedure involved preliminary ion-pair extraction of the drugs into dichloromethane, followed by concentration and anlysis of the ion-pair complex using a gas-liquid chromatographic system fitted with a nitrogen detector. Using the peak area ratio technique, pyridostigmine bromide was used as the internal standard for the quantitation of neostigmine in plasma; neostigmine bromide was the internal marker for the determination of pyridostigmine. The method depends on the thermal dequaternisation of the quaternary amines, and can be used to detect 5 ng/ml in a 3-ml plasma sample. Accurate measurement can be made at levels of 50-1000 ng/ml. This assay procedure has been applied to the separate determination of the plasma concentration of neostigmine and pyridostigmine after single administration of intravenous doses in aneasthetised patients.

Quantitative capillary column gas chromatographic method for the determination of glycopyrronium in human plasma.

A new sensitive and selective capillary column gas chromatographic method for the anti-cholinergic agent glycopyrronium bromide in human plasma is described. The procedure involves preliminary ion-pair extraction of the drug into dichloromethane, followed by concentration and analysis of the ion-pair complex by capillary column gas chromatography using a nitrogen-sensitive detector. The method depends on the thermal dequaternisation of the quaternary ammonium compound and can be used to detect 5 ng/ml in a 3-ml plasma sample. The assay procedure has been applied to the determination of the plasma concentration of glycopyrronium after intravenous administration to an anaesthetised patient.

PLASMA CONCENTRATION AND URINARY ELIMINATION OF NEOSTIGMINE AFTER INTRAMUSCULAR ADMINISTRATION TO MYASTHENIC PATIENTS

Although intramuscular neostigmine methylsulfate is frequently used during diagnosis or initial therapy in patients with myasthenia gravis, little is known of its metabolism and excretion in these circumstances. The kinetics and disposition of neostigmine methylsulfate ( 1 .O-2.0 mg intramuscularly) was therefore studied in eight myasthenic patients who had a history of voluntary muscle fatiguability for a period of two months to two years. In most subjects, characteristic electromyographic changes were observed and a positive response to edrophonium chloride (“Tensilon”) was obtained. None of the patients were currently taking other compounds or were on anticholinesterase drugs. Studies of the plasma concentration of neostigmine were carried out in five myasthenic patients after intramuscular injection of the drug (2.0 mg). In two subjects, neostigmine was detected in plasma within 15 min. In all five patients, the plasma concentration invariably declined in a monoexponential manner from 21 k 2 ng/ml (mean f S.E.M.) to 9 k 1 ng/ml (mean +S.E.M.) between 30 and 120 min. Small concentrations of neostigmine (5-7 ng/ml) were present in plasma at 150 min in three subjects; in one instance, the drug was stilI detectable at 180 rnin. None of the quaternary amine could be detected in plasma in any of the five patients at 240 min. In other myasthenic patients, the elimination of the drug and its metabolites in urine was studied after intramuscular administration of 14C-neostigmine (1.0 or 2.0 mg neostigmine methylsulfate containing 1.5 pCi of I4C-neostigmine). Unchanged neostigmine and its principal identified metabolites (i.e., 3-hydroxyphenyltrimethylammonium and its 3-oxyglucuronide) were isolated from urine, and identified by both ion exchange and paper chromatography. Approximately 80% of the drug was excreted in urine, either as unchanged neostigmine or its metabolites, within 24 hours. At this time, roughly 50% of the dose was eliminated as the unchanged drug, 15% as 3-hydroxyphenyltrimethylammonium, and 15% as other unidentified metabolites. The decline in the concentration of neostigmine in plasma and urine was interpreted in terms of a one compartment open pharmacokinetic model. Estimates of the plasma half-life of neostigmine varied from 51.1-90.5 min,

Prolonged Release Extradural Morphine

The effects of extradural administration of a microcrystalline preparation of morphine (Duromorph) were studied in 5 patients with postoperative or malignant pain. As assessed by pain scores on a visual analogue scale, the effects of the analgesic were extremely variable; the best results were obtained in patients with postoperative pain. Two patients with chronic pain due to malignant disease developed slow respiratory rates. The plasma concentration of morphine usually followed a biphasic pattern; an initial peak between 0.5 and 1.5 hours was succeeded by a second, large peak between 6 and 12 hours. There was little or no apparent relation between the plasma concentration of morphine and the relief of pain, suggesting that Duromorph may have a local effect on the spinal cord.