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Biomedical subjects

D G Harle

Publications and source records attributed to D G Harle.

24 records · Page 2Linked to original sources
PubMed1985

Inhibition of histamine-N-methyltransferase activity by neuromuscular blocking drugs.

On the basis of previous findings that histamine-N-methyltransferase (HMT) activity can be significantly enhanced or inhibited by a number of analogues of histamine and drugs containing dialkylaminoalkyl moieties, we investigated whether the neuromuscular blocking drugs alcuronium, d-tubocurarine, decamethonium, succinylcholine, gallamine and pancuronium each of which contain quaternary ammonium groups, influence the activity of HMT. Our findings showed that all six drugs significantly inhibited HMT activity in the concentration range 10(-7)-10(-3) M with alcuronium being the most potent inhibitor (I.D.50 = 2 X 10(-6) M). Activities at these concentrations reveals that alcuronium, pancuronium, d-tubocurarine and gallamine are more potent inhibitors than two of the most potent histamine analogue inhibitors, N tau-methylhistamine and 2-methylhistamine. Alcuronium proved to be of similar potency to the dimaprit analogue, SKF 91488 regarded as one of the most potent HMT inhibitors known. The structurally similar and chemically least complex straight chain neuromuscular blocking compounds, succinylcholine and decamethonium proved to be the least potent inhibitors.

Alcuronium↗
PubMed1985

In vitro diagnosis and studies on the mechanism(s) of anaphylactoid reactions to muscle relaxant drugs.

By covalently coupling alcuronium, d-tubocurarine and the pancuronium analogue, vecuronium, and using the resultant complexes in radioimmunoassays with patients' sera, we have found high levels of drug-reactive IgE antibodies in some subjects who reacted to these muscle relaxants. This is the first demonstration of IgE antibodies to such compounds. Assays were also developed for the detection of drug-reactive IgE antibodies to the muscle relaxant drugs succinylcholine, decamethonium and gallamine. They involved the coupling of choline and its ethyl analogue, triethylcholine to activated Sepharose. Results of direct binding and inhibition experiments and correlations with clinical findings demonstrated that the assays are relevant to the detection of succinylcholine-, decamethonium- and gallamine-reactive IgE antibodies in patients who experienced adverse reactions to these drugs. Quantitative inhibition studies revealed that IgE antibodies from most patients cross-reacted with all muscle relaxants tested, other quaternary ammonium compounds and some pharmacologically unrelated drugs including promethazine, morphine, neostigmine and pentolinium. Results showed that the specificities of the IgE antibodies are directed towards quaternary or tertiary ammonium ions on the drugs that bind the antibodies. As these ions occur widely in man's environment in drugs, cosmetics, disinfectants, foods and industrial materials, it seems possible that sensitization of patients may occur without previous exposure to muscle relaxant drugs. Thus, we now have assays that will detect antibodies to all six muscle relaxant drugs --alcuronium, d-tubocurarine, pancuronium, succinylcholine, decamethonium and gallamine-- and, for the first time since the work on penicillins, drug-specific IgE antibodies have been found in large numbers of patients and the allergenic determinants have been identified.

Anaphylaxis↗
PubMed1985

Cross-reactivity of metocurine, atracurium, vecuronium and fazadinium with IgE antibodies from patients unexposed to these drugs but allergic to other myoneural blocking drugs.

An inhibition assay was used to determine quantitatively the allergenic cross-reactivity of some myoneural blocking drugs not yet released for use in Australia, in the sera of patients who had experienced anaphylactic reactions to neuromuscular blocking drugs. Two of the compounds, metocurine and atracurium were highly cross-reactive with the currently used myoneural blockers; fazadinium was weakly cross-reactive and vecuronium intermediate in potency between these two extremes. From these results, we predict that anaphylactic reactions to these compounds, and particularly to metocurine and atracurium, will occur in some patients allergic to the currently used neuromuscular blocking agents.

Anaphylaxis↗
PubMed1984

Detection of IgE antibodies to suxamethonium after anaphylactoid reactions during anaesthesia.

Choline covalently coupled to an insoluble support was used in a radioimmunoassay to detect IgE antibodies to suxamethonium in serum samples from patients who experienced life-threatening anaphylactoid reactions after receiving the drug. Direct binding and inhibition experiments and correlations with clinical findings showed that use of choline in such an assay is relevant to the detection of suxamethonium-reactive antibodies. IgE antibodies were found in 9 of 10 patients who reacted to suxamethonium and whose skin-tests to the drug were positive and in 8 other patients who had reactions to other muscle-relaxant drugs. The positive reactions in the latter group were probably due to cross-reacting antibodies that recognise quaternary ammonium groups on more than one muscle relaxant.

Anaphylaxis↗