ABSTRACT
Professor Bamford was regarded by many as the greatest British polymer chemist of the twentieth century and when Bam passed away in November 1999 tribute was quite rightly made to his considerable achievements in the field of polymer science. The aim of this paper is to highlight Bam's contribution to biomaterials research that occupied his attention for over 15 years after his official retirement. In particular a review of the synthetic methods employed by Bam for the modification of polymers to improve haemocompatibility and to function as affinity separation membranes for protein purification is presented.
Subject(s)
Biochemistry/methods , Biocompatible Materials , Polymers/chemistry , Amino Acids/chemistry , Amino Acids/history , Amino Sugars/chemistry , Amino Sugars/history , Biochemistry/history , Biocompatible Materials/history , Dipyridamole/chemistry , Dipyridamole/history , History, 20th Century , Hydantoins/chemistry , Hydantoins/history , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/history , Polyethylene Glycols/chemistry , Polyethylene Glycols/history , Polymers/history , Theophylline/chemistry , Theophylline/historyABSTRACT
Approximately 30 new derivatives of theophylline and dipyridamole have been prepared and examined as potentiators of the inhibition of platelet aggregation induced by the prostaglandin analogue BW 245C. Potentiating activity has been found to be sensitive to molecular size and also to the presence of specific groups. Polymeric adducts based on dextran, poly(ethylene glycol) or poly(N-vinyl pyrrolidone), and aliphatic esters with alkyl chain-lengths greater than 7 are inactive in potentiation. Derivatives containing carboxyl groups are also inactive. Potentiation is discussed in terms of platelet membrane penetration and extra- and intra-cellular processes. The latter are invoked to account for the enhanced potentiation shown by dipyridamole and derivatives when aggregation is induced by PAF-acether rather than ADP. One derivative of particular interest is the adduct of theophylline with 1,2,5,6-diisopropylidene-D-glucose, containing a furanose ring. This is a more active potentiator than theophylline itself, possibly owing to its molecular resemblance to cAMP. On conversion to the pyranose form all activity is removed.
Subject(s)
Dipyridamole/analogs & derivatives , Hydantoins/pharmacology , Platelet Aggregation Inhibitors , Theophylline/analogs & derivatives , Animals , Dipyridamole/chemical synthesis , Dipyridamole/pharmacology , Drug Synergism , Molecular Structure , Molecular Weight , Platelet Aggregation Inhibitors/chemical synthesis , Polymers/chemical synthesis , Sheep , Structure-Activity Relationship , Theophylline/chemical synthesis , Theophylline/pharmacologyABSTRACT
A study has been made of the behaviour of the drugs dipyridamole and mopidamol (RA 233) attached to poly(N-vinylpyrrolidone). The inhibitory activities towards platelet aggregation induced by ADP or platelet activation factor (PAF) in sheep plasma have been examined and found to exceed the activities of the parent drugs, by factors up to 20. At the same time the abilities of the polymer-bound drugs in potentiating prostaglandin-type anti-aggregatory activities are much lower than those of the unattached drugs. The observations are explained in terms of polymer adsorption on to the platelet membranes, producing a high surface concentration of the drugs with consequent high inhibitory action. Intracellular action, such as the inhibition of phosphodiesterase, is reduced by the difficulty experienced by the polymeric drug in passing through the membrane, so that potentiation of prostaglandin activity, particularly against PAF, becomes small. A terpolymer containing units of dipyridamole and the prostaglandin analogue 5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin (245C) shows a degree of 'self-potentiation'.
Subject(s)
Dipyridamole/analogs & derivatives , Dipyridamole/pharmacology , Platelet Aggregation/drug effects , Polymers/pharmacology , Povidone/analogs & derivatives , Adenosine Diphosphate/pharmacology , Humans , Kinetics , Mass Spectrometry , Mopidamol/pharmacology , Platelet Activating Factor/pharmacology , Polymers/chemical synthesis , Structure-Activity RelationshipABSTRACT
We have studied the inhibition of ADP-induced platelet aggregation in sheep platelet-rich plasma by water-soluble polymers bound to the prostaglandin analogue 5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin ('BW 245' C, (I). The use of unambiguous modes of binding this antiplatelet drug to polymers has enabled us to study some structural features which influence inhibitory activity. Evidence is adduced which indicates that the chemical mechanisms responsible for inhibition by free and coupled BW 245 are similar. The most important observation is a remarkable synergism demonstrated by the greatly enhanced activity of a mixture of a polymer coupled to BW 245 with the uncoupled parent polymer. In some cases (e.g., with high-molecular-weight dextran) the effect may reach (and possibly exceed) two orders of magnitude. The influence of polymer molecular weights and 'cross-polymer' effects have both been examined. A mechanism has been proposed to account for these phenomena, involving adsorption of the added (inactive) polymer on to the platelet membranes, facilitating interaction of the polymer-bound drug with receptors, made more accessible by alteration to the surface geometry. This mechanism is based on physical processes, unlike other explanations of synergistic behaviour, e.g., that of prostaglandins used in conjunction with non-polymeric drugs. The observed dependences of synergistic effects upon polymer molecular weight and type and distribution of drug molecules along chains are typical 'polymer' phenomena which are all consistent with the proposed mechanism.
