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1. 5-Hydroxytryptamine receptors in GtoPdb v.2023.1

Author

Andrade, Rodrigo, primary, Barnes, Nicholas M., primary, Baxter, Gordon, primary, Bockaert, Joel, primary, Branchek, Theresa, primary, Butler, Amy, primary, Cohen, Marlene L., primary, Dumuis, Aline, primary, Eglen, Richard M., primary, Göthert, Manfred, primary, Hamblin, Mark, primary, Hamon, Michel, primary, Hartig, Paul R., primary, Hen, René, primary, Hensler, Julie, primary, Herrick-Davis, Katharine, primary, Hills, Rebecca, primary, Hoyer, Daniel, primary, Humphrey, Patrick P. A., primary, Latté, Klaus Peter, primary, Maroteaux, Luc, primary, Martin, Graeme R., primary, Middlemiss, Derek N., primary, Mylecharane, Ewan, primary, Neumaier, John, primary, Peroutka, Stephen J., primary, Peters, John A., primary, Roth, Bryan, primary, Saxena, Pramod R., primary, Sharp, Trevor, primary, Sleight, Andrew, primary, Villalon, Carlos M., primary, and Yocca, Frank, primary

Published
2023
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4. Parkinson's disease: prospects for improved drug therapy

Author

Hagan, Jim J., Middlemiss, Derek N., Sharpe, Paul C., and Poste, George H.

Subjects
Parkinson's disease -- Drug therapy, Dopamine receptors -- Physiological aspects, Biological sciences, Chemistry, Pharmaceuticals and cosmetics industries
Abstract

L-Dopa has long been the mainstay of therapy for Parkinson's disease but its long-term shortcomings, principally uncoordinated, spasmodic or irregular movements (dyskinesias) and fluctuating control of motor symptoms (on/off fluctuations), are well documented. The postulated neuroprotective properties of L-deprenyl, often used as an adjunct to L-dopa, are under scrutiny and doubts have also been raised regarding its safety. Alternative therapeutic approaches are clearly needed. In this review, Jim Hagan, Derek Middlemiss, Paul Sharpe and George Poste outline some new approaches to treatment, with an emphasis on novel, selective dopamine receptor agonists. In addition, Parkinson's disease is commonly thought to be caused by the neurotoxic effects of an unidentified agent but recent data indicate a greater genetic component than previously recognized. Developments in the genetics of Parkinson's disease may provide the key to the next generation of therapeutics.

Published
1997

7. 5-HT1-like receptors: six down and still counting

Author

Beer, Margaret S., Middlemiss, Derek N., and McAllister, George

Subjects
Serotonin -- Receptors, Cloning -- Research, Neurotransmitter receptors -- Research, Biological sciences, Chemistry, Pharmaceuticals and cosmetics industries
Abstract

Pharmacological studies reveal that the application of molecular cloning techniques yielded a diverse set of neurotransmitter receptors which exhibit the capacity for exploitation in the area of selective drug development. These findings are best illustrated by the cloning of 5-HT (serotonin) receptors. Other studies validate these results but indicate biphasic curve solutions to displacement studies.

Published
1993

8. 5-Hydroxytryptamine receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Author

Andrade, Rodrigo, primary, Barnes, Nicholas M., primary, Baxter, Gordon, primary, Bockaert, Joel, primary, Branchek, Theresa, primary, Butler, Amy, primary, Cohen, Marlene L., primary, Dumuis, Aline, primary, Eglen, Richard M., primary, Göthert, Manfred, primary, Hamblin, Mark, primary, Hamon, Michel, primary, Hartig, Paul R., primary, Hen, René, primary, Hensler, Julie, primary, Herrick-Davis, Katharine, primary, Hills, Rebecca, primary, Hoyer, Daniel, primary, Humphrey, Patrick P. A., primary, Latté, Klaus Peter, primary, Maroteaux, Luc, primary, Martin, Graeme R., primary, Middlemiss, Derek N., primary, Mylecharane, Ewan, primary, Neumaier, John, primary, Peroutka, Stephen J., primary, Peters, John A., primary, Roth, Bryan, primary, Saxena, Pramod R., primary, Sharp, Trevor, primary, Sleight, Andrew, primary, Villalon, Carlos M., primary, and Yocca, Frank, primary

Published
2019
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16. Characterization of SB-271046: A potent, selective and orally active 5-HT6 receptor antagonist

Author

Routledge, Carol, Bromidge, Steven M, Moss, Stephen F, Price, Gary W, Hirst, Warren, Newman, Helen, Riley, Graham, Gager, Tracey, Stean, Tania, Upton, Neil, Clarke, Stephen E, Brown, Anthony M, and Middlemiss, Derek N

Subjects
Male, Sulfonamides, Administration, Oral, Brain, Thiophenes, Transfection, Binding, Competitive, Electric Stimulation, Recombinant Proteins, Rats, Rats, Sprague-Dawley, Disease Models, Animal, Radioligand Assay, Cognition, Seizures, Receptors, Serotonin, Papers, Animals, Humans, Serotonin Antagonists, Adenylyl Cyclases, HeLa Cells
Abstract

SB-271046, potently displaced [(3)H]-LSD and [(125)I]-SB-258585 from human 5-HT(6) receptors recombinantly expressed in HeLa cells in vitro (pK(i) 8.92 and 9.09 respectively). SB-271046 also displaced [(125)I]-SB-258585 from human caudate putamen and rat and pig striatum membranes (pK(i) 8.81, 9.02 and 8.55 respectively). SB-271046 was over 200 fold selective for the 5-HT(6) receptor vs. 55 other receptors, binding sites and ion channels. In functional studies on human 5-HT(6) receptors SB-271046 competitively antagonized 5-HT-induced stimulation of adenylyl cyclase activity with a pA(2) of 8.71. SB-271046 produced an increase in seizure threshold over a wide-dose range in the rat maximal electroshock seizure threshold (MEST) test, with a minimum effective dose ofor =0.1 mg kg(-1) p.o. and maximum effect at 4 h post-dose. The level of anticonvulsant activity achieved correlated well with the blood concentrations of SB-271046 (EC(50) of 0.16 microM) and brain concentrations of 0.01-0.04 microM at C(max). These data, together with the observed anticonvulsant activity of other selective 5-HT(6) receptor antagonists, SB-258510 (10 mg kg(-1), 2-6 h pre-test) and Ro 04-6790 (1-30 mg kg(-1), 1 h pre-test), in the rat MEST test, suggest that the anticonvulsant properties of SB-271046 are likely to be mediated by 5-HT(6) receptors. Overall, these studies demonstrate that SB-271046 is a potent and selective 5-HT(6) receptor antagonist and is orally active in the rat MEST test. SB-271046 represents a valuable tool for evaluating the in vivo central function of 5-HT(6) receptors.

Published
2000

17. 5-CT stimulation of adenylyl cyclase activity in guinea-pig hippocampus: evidence for involvement of 5-HT7 and 5-HT1A receptors

Author

Thomas, David R, Middlemiss, Derek N, Taylor, Stephen G, Nelson, Paul, and Brown, Anthony M

Subjects
Male, Serotonin, Cell Membrane, Guinea Pigs, Binding, Competitive, Hippocampus, Serotonin Receptor Agonists, Enzyme Activation, Receptors, Serotonin, Papers, Animals, Serotonin Antagonists, Receptors, Serotonin, 5-HT1, Adenylyl Cyclases
Abstract

1. A number of compounds, including the selective 5-HT7 receptor antagonist SB-258719, were investigated for their effect on [3H]-5-carboxamidotryptamine (5-CT) radioligand binding and 5-CT-stimulated adenylyl cyclase activity in guinea-pig hippocampal membranes, in order to confirm the presence of functionally coupled 5-HT7 receptors in this tissue. 2. The [3H]-5-CT radioligand binding profile was consistent with binding predominantly to 5-HT7 receptors. The affinity of SB-258719 (pKi 7.2+/-0.1) was similar to its reported human 5-HT7 receptor affinity. 3. In the adenylyl cyclase functional assay, 5-CT was a potent and full agonist compared to 5-HT, whereas 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) was a partial agonist (intrinsic activity 0.4+/-0.1). The rank order of potency for agonists (5-CT5-HT approximately 8-OH-DPAT) was consistent with activation of 5-HT7 receptors. SB-258719 (5 microM) and methiothepin (1 microM) surmountably antagonized the response to 5-CT, consistent with competitive antagonism. The pKB for SB-258719 (7.2+/-0.1) was in good agreement with its reported antagonist potency at the human cloned 5-HT7 receptor. 4. In the functional assay, WAY-100635 (100 nM) and cyanopindolol (1 microM) induced a biphasic 5-CT response curve, consistent with selective antagonism of a component of the response to 5-CT. The estimated pKB values for WAY-100635 and cyanopindolol (9.6 and 8.4 respectively) were in good agreement with their reported 5-HT1A receptor affinities. 5. The data are consistent with the presence of 5-HT7 receptors in guinea-pig hippocampus which are positively coupled to adenylyl cyclase. In addition, 5-HT7 receptor-mediated stimulation of adenylyl cyclase activity in this tissue appears to be augmented by a mechanism involving 5-HT1A receptor activation.

Published
1999

18. Functional comparison of muscarinic partial agonists at muscarinic receptor subtypes hM1, hM2, hM3, hM4 and hM5 using microphysiometry

Author

Wood, Martyn D, Murkitt, Karen L, Ho, Michael, Watson, Jeannette M, Brown, Frank, Hunter, A Jacqueline, and Middlemiss, Derek N

Subjects
Quinuclidinyl Benzilate, Receptor, Muscarinic M3, Radioligand Assay, Receptor, Muscarinic M2, Receptor, Muscarinic M4, Cricetinae, Papers, Receptor, Muscarinic M1, Animals, Humans, CHO Cells, Muscarinic Agonists, Receptors, Muscarinic
Abstract

1. This study describes the pharmacological comparison of the muscarinic partial agonists sabcomeline, xanomeline and milameline at human cloned muscarinic receptor subtypes (hM1-5). 2. Radioligand binding studies at the hM1-5 muscarinic receptor subtypes were compared with functional studies using microphysiometry using carbachol as the standard full agonist. 3. In binding assays none of the compounds studied displayed preferential affinity for the M1,3,4 or M5 subtypes although carbachol was less potent at hM1 than hM3,4,5. 4. In functional studies, all of the compounds studied displayed similar levels of efficacy across the muscarinic receptors with the exception of M3, where there was a large apparent receptor reserve and the compounds behaved essentially as full agonists. 5. Sabcomeline was the most potent agonist in functional studies but also showed the lowest efficacy. In terms of potency, xanomeline showed some selectivity for M1 over M2 receptors and milameline showed some selectivity for M2 over M1 receptors. 6. These results show the value of microphysiometry in being able to compare receptor pharmacology across subtypes irrespective of the signal transduction pathway. 7. None of the partial agonists showed functional selectivity for M1 receptors, or indeed any muscarinic receptor, in the present study.

Published
1999

19. ( )-3, -Dimethyl- -[1-methyl-3-(4-methylpiperidin-1-yl)propyl]benzenesulfonamide: The First Selective 5-HT Receptor Antagonist

Author

Forbes, Ian T., Dabbs, Steven, Duckworth, D. Malcolm, Jennings, Andrew J., King, Frank D., Lovell, Peter J., Brown, Anthony M., Collin, Lissa, Hagan, Jim J., Middlemiss, Derek N., Riley, Graham J., Thomas, David R., and Upton, Neil

Subjects
chemistry.chemical_classification, Stereochemistry, Chemistry, Antagonist, Stereoisomerism, Nuclear magnetic resonance spectroscopy, Chemical synthesis, Sulfonamide, 5-HT7 receptor, chemistry.chemical_compound, SB-269970, Drug Discovery, Molecular Medicine, SB-258719
Published
1998
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20. Characterization of the binding of [3H]-SB-204269, a radiolabelled form of the new anticonvulsant SB-204269, to a novel binding site in rat brain membranes

Author

Herdon, Hugh J, Jerman, Jeffrey C, Stean, Tania O, Middlemiss, Derek N, Chan, Wai N, Vong, Antonio K, Evans, John M, Thompson, Mervyn, and Upton, Neil

Subjects
Male, Rats, Sprague-Dawley, Kinetics, Binding Sites, Potassium Channels, Papers, Benzamides, Animals, Brain, Anticonvulsants, Benzopyrans, Tritium, Rats
Abstract

1. SB-204269 (trans-(+)-6-acetyl-4S-(4-fluorobenzoylamino)-3, 4-dihydro-2,2-dimethyl-2H-benzol[b]pyran-3R-ol, hemihydrate) shows potent anticonvulsant activity in a range of animal seizure models, with a lack of neurological or cardiovascular side-effects. The profile of the compound suggests that it may have a novel mechanism of action. This study describes the characteristics of a binding site for [3H]-SB-204269 in rat forebrain membranes. 2. Specific [3H]-SB-204269 binding was saturable and analysis indicated binding to a homogenoeous population of non-interacting binding sites with a dissociation constant (KD) of 32 +/- 1 nM and a maximum binding capacity (Bmax) of 253 +/- 18 fmol mg-1 protein. Kinetic studies indicated monophasic association and dissociation. Binding was similar in HEPES or Tris-HCl buffers and was unaffected by Na+, K+, Ca2+ or Mg2+ ions. Specific binding was widely distributed in brain, but was minimal in a range of peripheral tissues. 3. Specific [3H]-SB-204269 binding was highly stereoselective, with a 1000 fold difference between the affinities of SB-204269 and its enantiomer SB-204268 for the binding site. The affinities of analogues of SB-204269 for binding can be related to their activities in the mouse maximal electroshock seizure threshold (MEST) test of anticonvulsant action. 4. None of the standard anticonvulsant drugs, phenobarbitone, phenytoin, sodium valproate, carbamazepine, diazepam and ethosuximide, or the newer anticonvulsants, lamotrigine, vigabatrin, gabapentin and levetiracetam, showed any affinity for the [3H]-SB-204269 binding site. A wide range of drugs active at amino acid receptors, Na+ or K+ channels or various other receptors did not demonstrate any affinity for the binding site. 5. These studies indicate that SB-204269 possesses a specific CNS binding site which may mediate its anticonvulsant activity. This binding site does not appear to be directly related to the sites of action of other known anticonvulsant agents, but may have an important role in regulating neuronal excitability.

Published
1997

22. 8-Piperazinyl-2,3-dihydropyrrolo[3,2-g]isoquinolines: Potent, selective, orally bioavailable 5-HT1 receptor ligands

Author

Heightman, Tom D., primary, Gaster, Laramie M., additional, Pardoe, Sarah L., additional, Pilleux, Jean-Pierre, additional, Hadley, Michael S., additional, Middlemiss, Derek N., additional, Price, Gary W., additional, Roberts, Claire, additional, Scott, Claire M., additional, Watson, Jeannette M., additional, Gordon, Laurie J., additional, Holland, Vicky A., additional, Powles, Jenifer, additional, Riley, Graham J., additional, Stean, Tania O., additional, Trail, Brenda K., additional, Upton, Neil, additional, Austin, Nigel E., additional, Ayrton, Andrew D., additional, Coleman, Tanya, additional, and Cutler, Leanne, additional

Published
2005
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23. 3,4-Dihydro-2H-benzoxazinones are 5-HT1A receptor antagonists with potent 5-HT reuptake inhibitory activity

Author

Atkinson, Peter J., primary, Bromidge, Steven M., additional, Duxon, Mark S., additional, Gaster, Laramie M., additional, Hadley, Michael S., additional, Hammond, Beverley, additional, Johnson, Christopher N., additional, Middlemiss, Derek N., additional, North, Stephanie E., additional, Price, Gary W., additional, Rami, Harshad K., additional, Riley, Graham J., additional, Scott, Claire M., additional, Shaw, Tracey E., additional, Starr, Kathryn R., additional, Stemp, Geoffrey, additional, Thewlis, Kevin M., additional, Thomas, David R., additional, Thompson, Mervyn, additional, Vong, Antonio K.K., additional, and Watson, Jeannette M., additional

Published
2005
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24. Design and Synthesis of trans-3-(2-(4-((3-(3-(5-Methyl-1,2,4-oxadiazolyl))- phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro- 1H-3-benzazepine (SB-414796): A Potent and Selective Dopamine D3 Receptor Antagonist

Author

Macdonald, Gregor J., primary, Branch, Clive L., additional, Hadley, Michael S., additional, Johnson, Christopher N., additional, Nash, David J., additional, Smith, Alexander B., additional, Stemp, Geoffrey, additional, Thewlis, Kevin M., additional, Vong, Antonio K. K., additional, Austin, Nigel E., additional, Jeffrey, Phillip, additional, Winborn, Kim Y., additional, Boyfield, Izzy, additional, Hagan, Jim J., additional, Middlemiss, Derek N., additional, Reavill, Charlie, additional, Riley, Graham J., additional, Watson, Jeannette M., additional, Wood, Martyn, additional, Parker, Steve G., additional, and Ashby, Charles R., additional

Published
2003
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25. SB-656104-A, a novel selective 5-HT7receptor antagonist, modulates REM sleep in rats

Author

Thomas, David R, primary, Melotto, Sergio, additional, Massagrande, Mario, additional, Gribble, Andrew D, additional, Jeffrey, Phillip, additional, Stevens, Alexander J, additional, Deeks, Nigel J, additional, Eddershaw, Peter J, additional, Fenwick, Susan H, additional, Riley, Graham, additional, Stean, Tania, additional, Scott, Claire M, additional, Hill, Matthew J, additional, Middlemiss, Derek N, additional, Hagan, Jim J, additional, Price, Gary W, additional, and Forbes, Ian T, additional

Published
2003
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33. Cloning and Characterization of Human NTT5 and v7-3: Two Orphan Transporters of the Na+/Cl−-Dependent Neurotransmitter Transporter Gene Family

Author

Farmer, Maurice K., primary, Robbins, Melanie J., additional, Medhurst, Andrew D., additional, Campbell, David A., additional, Ellington, Kathryn, additional, Duckworth, Malcolm, additional, Brown, Anthony M., additional, Middlemiss, Derek N., additional, Price, Gary W., additional, and Pangalos, Menelas N., additional

Published
2000
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34. Characterization of SB-271046: A potent, selective and orally active 5-HT6 receptor antagonist

Author

Routledge, Carol, primary, Bromidge, Steven M, additional, Moss, Stephen F, additional, Price, Gary W, additional, Hirst, Warren, additional, Newman, Helen, additional, Riley, Graham, additional, Gager, Tracey, additional, Stean, Tania, additional, Upton, Neil, additional, Clarke, Stephen E, additional, Brown, Anthony M, additional, and Middlemiss, Derek N, additional

Published
2000
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36. 1-[2-[(Heteroarylmethoxy)aryl]carbamoyl]indolines are selective and orally active 5-HT2C receptor inverse agonists

Author

Bromidge, Steven M., primary, Davies, Susannah, additional, Duckworth, D.Malcolm, additional, Forbes, Ian T., additional, Jones, Graham E., additional, Jones, Jerome, additional, King, Frank D., additional, Blackburn, Thomas P., additional, Holland, Vicky, additional, Kennett, Guy A., additional, Lightowler, Sean, additional, Middlemiss, Derek N., additional, Riley, Graham J., additional, Trail, Brenda, additional, and Wood, Martyn D., additional

Published
2000
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37. 1-[2-[(Heteroaryloxy)heteroaryl]carbamoyl]indolines: novel and selective 5-HT2C receptor inverse agonists with potential as antidepressant/Anxiolytic agents

Author

Bromidge, Steven M., primary, Dabbs, Steven, additional, Davies, Susannah, additional, Duckworth, D.Malcolm, additional, Forbes, Ian T., additional, Jones, Graham E., additional, Jones, Jerome, additional, King, Frank D., additional, Saunders, Damian V., additional, Blackburn, Thomas P., additional, Holland, Vicky, additional, Kennett, Guy A., additional, Lightowler, Sean, additional, Middlemiss, Derek N., additional, Riley, Graham J., additional, Trail, Brenda, additional, and Wood, Martyn D., additional

Published
2000
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38. Characterization of SB-269970-A, a selective 5-HT7receptor antagonist

Author

Hagan, Jim J, primary, Price, Gary W, additional, Jeffrey, Phillip, additional, Deeks, Nigel J, additional, Stean, Tania, additional, Piper, David, additional, Smith, Martin I, additional, Upton, Neil, additional, Medhurst, Andrew D, additional, Middlemiss, Derek N, additional, Riley, Graham J, additional, Lovell, Peter J, additional, Bromidge, Steven M, additional, and Thomas, David R, additional

Published
2000
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40. Design and Synthesis of trans-N-[4-[2-(6-Cyano-1,2,3,4-tetrahydroisoquinolin-2- yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011): A Potent and Selective Dopamine D3 Receptor Antagonist with High Oral Bioavailability and CNS Penetration in the Rat

Author

Stemp, Geoffrey, primary, Ashmeade, Tracey, additional, Branch, Clive L., additional, Hadley, Michael S., additional, Hunter, A. Jacqueline, additional, Johnson, Christopher N., additional, Nash, David J., additional, Thewlis, Kevin M., additional, Vong, Antonio K. K., additional, Austin, Nigel E., additional, Jeffrey, Phillip, additional, Avenell, Kim Y., additional, Boyfield, Izzy, additional, Hagan, Jim J., additional, Middlemiss, Derek N., additional, Reavill, Charlie, additional, Riley, Graham J., additional, Routledge, Carole, additional, and Wood, Martyn, additional

Published
2000
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41. Biarylcarbamoylindolines Are Novel and Selective 5-HT2C Receptor Inverse Agonists: Identification of 5-Methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]- 5-pyridyl]carbamoyl]-6-trifluoromethylindoline (SB-243213) as a Potential Antidepressant/Anxiolytic Agent

Author

Bromidge, Steven M., primary, Dabbs, Steven, additional, Davies, David T., additional, Davies, Susannah, additional, Duckworth, D. Malcolm, additional, Forbes, Ian T., additional, Gaster, Laramie M., additional, Ham, Peter, additional, Jones, Graham E., additional, King, Frank D., additional, Mulholland, Keith R., additional, Saunders, Damian V., additional, Wyman, Paul A., additional, Blaney, Frank E., additional, Clarke, Stephen E., additional, Blackburn, Thomas P., additional, Holland, Vicky, additional, Kennett, Guy A., additional, Lightowler, Sean, additional, Middlemiss, Derek N., additional, Trail, Brenda, additional, Riley, Graham J., additional, and Wood, Martyn D., additional

Published
2000
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42. A Novel, Potent, and Selective 5-HT7 Antagonist: (R)-3-(2-(2-(4-Methylpiperidin-1-yl)ethyl)pyrrolidine-1-sulfonyl)phenol (SB-269970)

Author

Lovell, Peter J., primary, Bromidge, Steven M., additional, Dabbs, Steven, additional, Duckworth, D. Malcolm, additional, Forbes, Ian T., additional, Jennings, Andrew J., additional, King, Frank D., additional, Middlemiss, Derek N., additional, Rahman, Shirley K., additional, Saunders, Damian V., additional, Collin, Lissa L., additional, Hagan, Jim J., additional, Riley, Graham J., additional, and Thomas, David R., additional

Published
2000
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50. 5-Chloro-N-(4-methoxy-3-piperazin-1-yl- phenyl)-3-methyl-2-benzothiophenesulfon- amide (SB-271046): A Potent, Selective, and Orally Bioavailable 5-HT6 Receptor Antagonist

Author

Bromidge, Steven M., primary, Brown, Anthony M., additional, Clarke, Stephen E., additional, Dodgson, Kathy, additional, Gager, Tracey, additional, Grassam, Helen L., additional, Jeffrey, Phil M., additional, Joiner, Graham F., additional, King, Frank D., additional, Middlemiss, Derek N., additional, Moss, Stephen F., additional, Newman, Helen, additional, Riley, Graham, additional, Routledge, Carol, additional, and Wyman, Paul, additional

Published
1999
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