J M Midgley

University of Cambridge, Cambridge, ENG, United Kingdom

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Publications (83)184.75 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The metabolism of ethidium bromide by isolated rat hepatocytes is significantly enhanced by pre-treatment of animals with phenobarbitone (PB) and 3-methylcholanthrene (3-MC). Pre-treatment with PB and 3-MC results in a 2.5- and 1.5-fold increase, respectively in the amount of the principal metabolite, ethidium 8-N-glucuronide, compared with that formed by hepatocytes from untreated rats. The formation of ethidium 3-N-glucuronide is not enhanced by pre-treatment with either PB or 3-MC. Two new metabolites, hydroxyethidium glucuronide and a transient unidentified species, have been detected by HPLC and are formed only by hepatocytes from animals pre-treated with 3-MC.
    Chemico-Biological Interactions 12/1999; 123(2):105-15. · 2.97 Impact Factor
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    ABSTRACT: A procedure for the evaluation of chemical equivalence of proprietary formulations of isometamidium is described. The method combines the analysis of the principal component (isometamidium), HPLC profiling of related substances and determination of the inorganic impurity, ammonium chloride, using a modification of the Berthelot (Indophenol) reaction. Application of these procedures to analyses of commercially available sachets from four different batches of Samorin and four different batches of Veridium has demonstrated that there are marked qualitative and quantitative differences between batches from these two sources. Whilst Samorin samples showed inter-batch consistency of composition, there was considerable inter-batch variation between the samples of Veridium.
    Journal of Pharmaceutical and Biomedical Analysis 11/1999; 21(1):1-7. · 2.95 Impact Factor
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    ABSTRACT: To study oral administration of vitamin C on human aqueous humour ascorbate concentration. High performance liquid chromatography (HPLC) coupled with electrochemical detector (ECD) was used. The effect of oral administration of various doses of ascorbic acid, 0 (control), 1.0, 1.5, 2.0, 3.0, and 5.0 g, on its concentration in aqueous humour, obtained from volunteer cataract patients was studied. The concentration of ascorbic acid in aqueous humour of control group (without administration of vitamin-C tablet or drug containing ascorbic acid was (254 +/- 119) mg.L-1. This study revealed that the administration of 2.0 g of ascorbic acid saturate the aqueous humour and further increase in the dose (3.0 g and 5.0 g) did not increase its concentration in aqueous humour, although its concentration was increased in plasma. Oral administration of 2.0 g of Vc is sufficient to saturate the aqueous humour where it may be helpful in controlling the intra-ocular pressure.
    Zhongguo yao li xue bao = Acta pharmacologica Sinica 11/1999; 20(10):879-83.
  • Journal of Veterinary Pharmacology and Therapeutics 09/1999; 22(4):283-5. · 1.35 Impact Factor
  • D G Watson, L L Xin, J M Midgley, D Carr
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    ABSTRACT: A method was developed for the analysis of 4,4'-methylenebiscyclohexylamine (DMDA) and 4,4'-methylenedicyclohexylisocyanate (DMDI) in a pharmaceutical polymer. The DMDA was extracted from the polymer with either buffer (0.1 M potassium phosphate pH 3.1) and the extract was passed through a SCX solid phase extraction cartridge. It was eluted from the cartridge with methanolic ammonia and then converted to its heptafluorobutyramide (HFB) derivative prior to analysis by gas chromatography-negative chemical ionisation mass spectrometry (GC-MS) in the negative ion chemical ionisation (NICI) mode. It was not possible to directly measure DMDI and it was thus analysed by selecting extraction conditions such that it would decompose to DMDA. The quantification of the residues in the polymer was based on the method of standard additions since this gave a better indication of the recovery from the complex matrix.
    Journal of Pharmaceutical and Biomedical Analysis 06/1999; 19(6):917-21. · 2.95 Impact Factor
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    ABSTRACT: 1. Confocal laser scanning microscopy (CLSM) has shown that ethidium (3 ,8-diamino-5-ethyl-6-phenylphenanthridinium) bromide, an aromatic phenanthridinium trypanocide, is taken up rapidly into the nucleoli and nuclear membranes of isolated rat hepatocytes. 2. It is biotransformed by the hepatocytes and at least five metabolites have been detected by high-performance liquid chromatography (HPLC). 3. Two new metabolites, 3- and 8-N-glucuronosylethidium, have been identified by HPLC-electrospray mass spectrometry and they represent the major pathway of metabolism, accounting for 6.4 +/- 0.7 and 19.5 +/- 1.2% respectively of total recovered drug after incubation. A third metabolite, 3,8-diacetylethidium, is formed in trace quantities. 4. The other two metabolites, 3-acetylethidium and 8-acetylethidium, have been reported previously.
    Xenobiotica 05/1999; 29(4):349-60. · 1.98 Impact Factor
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    ABSTRACT: The determination of the phenanthridine trypanocide, isometamidium chloride hydrochloride (ISM), in the presence of four process-related and degradation impurities, by RP-HPLC using a Licrospher-60 RP-select B column with a mobile phase composition of acetonitrile/KH2PO4 (PH 3.0, 20 mM) (25:75 v/v) with UV detection at 320 nm, is described. The method is selective, reproducible and precise with a limit of detection of 45 ng ml-1 for ISM. A HPTLC system (Kieselgel 60 F254, pyridine/acetonitrile/butanol/formic acid, 6:6:4:1, v/v), with UV densitometric evaluation at 320 nm, suitable for the separation of ISM and the related substances is reported.
    Journal of Pharmaceutical and Biomedical Analysis 09/1998; 17(4-5):713-8. · 2.95 Impact Factor
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    ABSTRACT: A method has been developed for the determination of the molecular weight of hyaluronic acid by high performance gel permeation chromatography. The molecular weight distribution was determined using three polymeric columns. Columns were calibrated using Pullulan Polymer molecular weight standards. The average molecular weight (+/- SD) of the hyaluronic acid in bovine vitreous humour and Healon were 1.20 x 10(6) Da (+/- 0.49 x 10(6) and 3.01 x 10(6) Da (+/- 0.14 x 10(6), respectively. Furthermore, the depolymerization of the hyaluronic acid in the presence of ascorbic acid (the concentration found in human eye) was studied. Samples incubated in the presence of atmospheric air showed more depolymerization than those where atmospheric air had been flushed-out with nitrogen.
    International Journal of Clinical Pharmacy 11/1997; 19(5):246-50. · 1.27 Impact Factor
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    ABSTRACT: The expression of a cloned Drosophila octopamine/tyramine receptor (OctyR99AB) is described in Xenopus oocytes. Agonist stimulation of OctyR99AB receptors increased intracellular Ca2+ levels monitored as changes in the endogenous inward Ca2+-dependent chloride current. The receptor is preferentially sensitive to biogenic amines with a single hydroxyl on the aromatic ring. The G-protein, Gαi, appears to be involved in the coupling of the receptor to the production of intracellular calcium signals, since the effect is pertussis-toxin sensitive and is blocked or substantially reduced in antisense knockout experiments using oligonucleotides directed against Gαi but not by those directed against Gαo, Gαq and Gα11. The increase in intracellular calcium levels induced by activation of the OctyR99AB receptor can potentiate the ability of activation of a co-expressed β2-adrenergic receptor to increase oocyte cyclic AMP levels. A comparison of the pharmacological coupling of OctyR99AB to different second messenger systems when expressed in Xenopus oocytes with previous studies on the expression of the receptor in a Chinese hamster ovary cell line suggests that the property of agonist-specific coupling of the receptor to different second messenger systems may be cell-specific, depending upon the G-protein environment of any particular cell type.
    Brain Research 10/1997; · 2.88 Impact Factor
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    ABSTRACT: A method has been developed for the determination of the molecular weight of hyaluronic acid by high performance gel permeation chromatography. The molecular weight distribution was determined using three polymeric columns. Columns were calibrated using Pullulan Polymer molecular weight standards. The average molecular weight ( SD) of the hyaluronic acid in bovine vitreous humour and Healon were 1.20 106 Da ( 0.49 106) and 3.01 106 Da ( 0.14 106), respectively. Furthermore, the depolymerization of the hyaluronic acid in the presence of ascorbic acid (the concentration found in human eye) was studied. Samples incubated in the presence of atmospheric air showed more depolymerization than those where atmospheric air had been flushed-out with nitrogen.
    International Journal of Clinical Pharmacy 08/1997; 19(5):246-250. · 1.27 Impact Factor
  • Zafar Iqbal, John M Midgley, David G Watson
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    ABSTRACT: Perfluorotolyl (PFT)-ether and perfluorotoly-trimethylsilyl (PFT-TMS) ether derivatives of oestrone, 17α- and 17β-oestradiol were prepared under phase transfer conditions. The former derivatives under negative ion chemical ionization conditions gave significant ions in the mass spectrometer but 17α- and 17α-oestradiol gave poor resolution. However, the PFT-TMS derivatives of 17α- and 17β-oestradiol showed good resolution. These derivatives were used for the analysis of oestrogens in bovine aqueous humour, vitreous humour and retina. The mean (±SEM) concentrations of oestrone in bovine aqueous humour (n=18), vitreous humour (n=18) and bovine retina (n=4) were 0.47±0.11, 0.46±0.14 and 1.10±0.24 ng.ml−1, respectively. 17α-Oestradiol was detected in 16 out of 18 samples of bovine aqueous humour and vitreous humour and the mean (±SEM) concentrations were 0.30±0.10 and 0.08±0.02 ng.ml−1, respectively. The mean (±SEM) concentration of 17β-oestradiol in aqueous humour (n=7) and vitreous homour (n=11) 0.83±0.26 ng ml−1 and 0.39±0.09 ng ml−1, respectively. In retina the concentrations of both steroids were below the detection limit.
    Archives of Pharmacal Research 05/1997; 20(3):247-252. · 1.54 Impact Factor
  • J M Midgley, J B Stenlake
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    ABSTRACT: Rapid making and breaking of bonds between quaternary ammonium compounds and cholinergic receptors is typical of ion-pair bonding, which is weak, and ion-pair reactions, which are extremely fast. These properties explain the observed rapid association and dissociation of turbocurarine at receptors. The time course receptor offset is determined by two factors, buffered diffusion due to repetitive bonding, and a potency-related offset-retarding effect. The strength of the latter is a function of chemical structure, which determines the microscopic molecular rate of drug-receptor association and dissociation. Together, buffered diffusion and the potency-related offset-retarding effect provide a complete rational physico-chemical explanation for the marked, yet variable, differences between onset and offset times of non-depolarizing neuromuscular blocking agents. The influence of a potency-related offset-retarding effect together with differing structural requirements for neuromuscular blocking potency and plasma carboxyesterase hydrolysis, suggests that a high potency ultrashort duration block is unlikely to be achieved in a non-depolarizing compound metabolized by plasma esterases alone.
    Journal of Pharmacy and Pharmacology 05/1997; 49(4):416-20. · 2.03 Impact Factor
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    ABSTRACT: The biogenic amines, which include dopamine, noradrenaline, adrenaline, and octopamine, are an important class of signaling molecule utilized by the nervous systems of almost all multicellular animals. In the insect central nervous system (CNS), the presence of some of these amines (dopamine and octopamine) has been inferred by a variety of sensitive, although somewhat nonspecific techniques, including immunohistochemical and histofluorimetric studies (1), radioenzymatic assays (2), and high-performance liquid chromatography coupled to electrochemical detection (HPLC-ECD) (3). This chapter describes the detection of biogenic amines in the insect CNS using gas chromatography-mass spectroscopy (GC-MS). This technique offers a significant advantage in the detection of such biomolecules over similarly sensitive techniques, such as HPLC-ECD, because GC-MS relies not only on chromatographic retention time but also on molecular mass to ascertain identity.
    Methods in molecular biology (Clifton, N.J.) 02/1997; 72:225-37. · 1.29 Impact Factor
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    ABSTRACT: 1. In this study we have compared the abilities of the enantiomers of the structural isomers of the phenolamines, octopamine and synephrine, and the catecholamines, noradrenaline and adrenaline, to couple selectively a human cloned alpha 2A-adrenoceptor, stably expressed in a Chinese hamster ovary (CHO) cell line, to G-protein linked second messenger pathways mediating an increase and a decrease in cyclic AMP production. 2. The catecholamines couple the alpha 2A-adrenoceptor to both an increase and a decrease in the rate of cyclic AMP production. In the absence of pertussis toxin pretreatment both catecholamines tested showed a dose-dependent decrease with a maximum at 100 nM. After pertussis toxin pretreatment they both produced a dose-dependent increase in cyclic AMP production with a maximum at 10 microM. 3. The phenolamines, octopamine and synephrine were only able to couple the alpha 2A-adrenoceptor to a dose-dependent decrease in cyclic AMP production at concentrations up to 1 mM, with the synephrine isomers being more potent than the corresponding octopamine isomers. The meta-isomers of both phenolamines were more potent than the corresponding para-isomers and the (-)-enantiomers were more potent than the (+)-enantiomers. Thus, (-)-meta-synephrine [(-)-phenylephrine] was the most effective isomer tested with an observable decrease occurring between 100 nM and 1 microM. 4. The effects of octopamine and the catecholamines on the decrease in cyclic AMP production were additive at submaximal concentrations, whilst octopamine reduced the stimulant effect of submaximal concentrations of noradrenaline on cyclic AMP production after pertussis toxin pretreatment. 5. The time courses of the inhibitory effects of both meta-octopamine and noradrenaline were parallel and peaked after a 1 min exposure to the agonist. In contrast, the stimulant effects of noradrenaline after pertussis toxin pretreatment were of a much slower time course with a maximum effect occurring after a 5 min incubation period. 6. Since octopamine and synephrine occur naturally in, and are co-released with catecholamines from, mammalian tissues, the results of the present study suggest that the human cloned alpha 2A-adrenoceptor can be coupled selectively by different endogenous agonists to G-protein pathways mediating the regulation of adenylyl cyclase activity.
    British Journal of Pharmacology 01/1997; 122(2):191-198. · 5.07 Impact Factor
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    ABSTRACT: Acyl glycines are normally minor metabolites of fatty acids; however, the excretion of certain acyl glycines is increased in several inborn errors of metabolism. Therefore measurement of the metabolites in body fluids can be used to diagnose these metabolic disorders. The chemical synthesis of a range of acyl glycines is described, together with that of their 13C2-isotopomers for use as internal standards. An analytical method for the measurement of hexanoyl, octanoyl, 3-phenylpropionyl and suberyl glycines in urine, employing gas chromatography-mass spectrometry with negative-ion chemical ionisation was adapted to measure a larger range of acyl glycines in a single blood spot on a standard Guthrie card. Diagnoses of a case of medium-chain acyl-CoA dehydrogenase deficiency and a case of isovaleric acidaemia were confirmed using a single blood spot from each patient.
    Journal of chromatography. B, Biomedical applications 03/1996; 677(1):29-35.
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    ABSTRACT: Nonsymmetrical bisquaternary mono- and diesters combining the potency-enhancing properties of the (1R)-laudanosinium group with a second unhindered quaternary ammonium moiety have been studied as a means of promoting short action with high-potency neuromuscular block. Atracurium-related nonsymmetrical diesters showed high potency, freedom from vagal blockade at neuromuscular blocking doses, and short action. Nonsymmetrical monoesters were short acting but showed varying degrees of vagal block.
    Journal of Medicinal Chemistry 02/1996; 39(2):556-61. · 5.61 Impact Factor
  • Physica A: Statistical Mechanics and its Applications 01/1996; 227(3). · 1.68 Impact Factor
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    ABSTRACT: The two Protocerebral-Medulla 4 neurons (PM4a and b) in the locust brain have adjacent cell bodies in the medial deutocerebrum. They project through the posterior protocerebrum, forming limited arborisations en route, and enter the lobula and medulla of the ipsilateral optic lobe, where they form extensive, overlapping arborisations. The PM4a and b neurons are octopamine immunoreactive. Their octopamine content (approximately 25 pg per cell) is confirmed by gas chromatography-mass spectrometry; each cell contains approximately 25 pg p-octopamine. Simultaneous intracellular recording from exposed PM4a and b cell bodies reveals that the two cells are physiologically indistinguishable. They receive multimodal sensory inputs. Tactile/mechanosensory stimuli to much of the animal's body and head, acoustic stimuli, and simple visual stimuli all give rise to e.p.s.p.s and action potentials in the PM4 cell body. Simultaneous recording from the cell body in the deutocerebrum and the axon in the lobula demonstrates that action potentials are predominantly initiated in the deutocerebrum and propagate centrifugally, towards the optic lobe. Occasionally, bright light flashes will initiate an action potential in the axon in the optic stalk, which probably propagates bidirectionally: centripetally to the cell body, and centrifugally into the optic lobe. The extensive arborisations in the lobula and medulla are therefore likely to be sites of octopamine release. Because PM4 neurons are octopaminergic, project to the optic lobe, and receive modalities of sensory input known to dishabituate the Descending Contralateral Movement Detector (DCMD) visual interneuron, it is proposed that PM4 neurons are neuromodulatory — mediating dishabituation or arousal of the visual system.
    Journal of Comparative Physiology 09/1995; 177(5):611-625. · 1.86 Impact Factor
  • Progress in brain research 02/1995; 106:259-68. · 4.19 Impact Factor
  • Progress in Brain Research - PROG BRAIN RES. 01/1995; 106:259-268.

Publication Stats

684 Citations
184.75 Total Impact Points

Institutions

  • 1989–1997
    • University of Cambridge
      • Department of Zoology
      Cambridge, ENG, United Kingdom
  • 1985–1997
    • University of Strathclyde
      • Strathclyde Institute of Pharmacy and Biomedical Sciences
      Glasgow, Scotland, United Kingdom
  • 1995
    • Babraham Institute
      Cambridge, England, United Kingdom
  • 1993
    • University of Glasgow
      Glasgow, Scotland, United Kingdom
  • 1980–1983
    • The School of Pharmacy
      • Pharmaceutical and Biological Chemistry
      Londinium, England, United Kingdom
    • University of Florida
      • College of Medicine
      Gainesville, Florida, United States
  • 1982
    • University of London
      • The School of Pharmacy
      London, ENG, United Kingdom