ABSTRACT
Mixed lymphocyte reactions (MLRs) were measured in 25 HLA-A, B and DR compatible sibling bone marrow transplants. Only four of 25 MLRs were positive and in these the low reactivity was of doubtful clinical importance. There was no correlation between MLR and the subsequent development or severity of graft versus host disease (GVHD). A survey of bone marrow transplant units in the United Kingdom showed that most centres perform HLA-DR typing as well as an assessment of the MLR. Factors other than histocompatibility are important in the pathogenesis of GVHD and the data from this study suggest that conventional MLRs can be omitted in HLA-A, B and DR compatible sibling bone marrow transplants.
Subject(s)
Bone Marrow Transplantation , Graft vs Host Disease/pathology , HLA-DR Antigens/analysis , Lymphocyte Culture Test, Mixed , Adult , Female , HLA-A Antigens/analysis , HLA-B Antigens/analysis , Humans , Male , Sex FactorsSubject(s)
Alprostadil/analogs & derivatives , Prostaglandins E, Synthetic/chemical synthesis , Stomach Ulcer/prevention & control , Animals , Indomethacin/adverse effects , Magnetic Resonance Spectroscopy , Prostaglandins E, Synthetic/therapeutic use , Rats , Rats, Inbred Strains , Stomach Ulcer/chemically induced , Structure-Activity RelationshipABSTRACT
Rat uterine stimulant activity has been determined in vivo for a series of (+)-11-deoxyprostaglandins. The most active members of the series. 11-deoxy-15 methyl-PGE1, 11-deoxy-16,16-dimethyl - PGE1 and its 1-alcohol were 2-3 times more potent than PGE1. Gastrointestinal side effects assessed by the antagonism of morphine-induced constipation in the mouse, were generally relatively low with these compounds and consequently several members of the series had a more favourable relative selectivity than 16,16-dimethyl-PGE2 methyl ester.
Subject(s)
Prostaglandins, Synthetic/pharmacology , Uterine Contraction/drug effects , Animals , Constipation/chemically induced , Cricetinae , Female , Gastrointestinal Motility/drug effects , Luteolytic Agents , Male , Mice , Morphine/antagonists & inhibitors , Prostaglandins, Synthetic/chemical synthesis , Rats , Rats, Inbred StrainsABSTRACT
Some omega-chain phenyl- and 16-phenoxy- analogues of (+/-)-11-deoxyprostaglandin F1 alpha have been synthesized and evaluated for anti-fertility activity in the hamster. 11-Deoxy-16-phenoxy-17,18,19,20-tetranor-PGF1 alpha was the most active member of the series with an ED50 equal to that of PGF2 alpha. 11-Deoxy-17-phenyl-18,19,20-trinor-PGF1 alpha, which was one third as active as PGF2 alpha, was more potent than the corresponding 16- and 18-phenyl compounds. Aryl ring substitution was found to lower activity, except that with the 16-phenyl compound, p-bromo and m-trifluoromethyl substitution increased the potency. The antifertility activity of the phenoxy compounds, which were poor substrates for 15-hydroxyprostaglandin dehydrogenase, was shown to correlate well with the binding affinity for the bovine corpus luteum PGF2 alpha receptor. Some quantitative structure-activity data supporting this finding are presented.
Subject(s)
Luteolytic Agents , Prostaglandins F, Synthetic/pharmacology , Animals , Cattle , Corpus Luteum/metabolism , Cricetinae , Female , Hydroxyprostaglandin Dehydrogenases/metabolism , In Vitro Techniques , Lung/enzymology , Male , Pregnancy , Prostaglandins F, Synthetic/chemical synthesis , Prostaglandins F, Synthetic/metabolism , Receptors, Prostaglandin/metabolism , Structure-Activity RelationshipABSTRACT
The synthesis and gastrointestinal pharmacology of some 11-deoxyprostaglandin E1 analogues are described with results analysed for selectivity from side effects. 11-Deoxygenation reduced potency relative to PGE2 but, as has been reported for natural PGs, 15- or 16-methyl analogues were more potent than the unsubstituted parent compound in the order 16-methyl greater than 15-methyl greater than 16,16-dimethyl. The results suggest that a complex interaction between C-15 and C-16 in methyl analogues affects their profile of activity, but that none of the modifications studied conferred a substantial potency or selectivity advantage over PGE2.
Subject(s)
Digestive System/drug effects , Prostaglandins E, Synthetic/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Constipation/chemically induced , Drug Evaluation, Preclinical , Gastric Juice/metabolism , Indomethacin/antagonists & inhibitors , Male , Mice , Morphine/antagonists & inhibitors , Morphine/pharmacology , Pentagastrin/antagonists & inhibitors , Pentagastrin/pharmacology , Prostaglandins E, Synthetic/pharmacology , Rats , Stomach Ulcer/chemically induced , Stomach Ulcer/drug therapyABSTRACT
The synthesis and antiallergic activity in the rat passive cutaneous anaphylactic reaction of a series of 2-phenyl-8-azapurin-6-ones are described. Early in the investigation, a linear free-energy equation was established in which the activity was related to the size and hydrogen bonding capacity of the ortho substituent in the phenyl ring. This relationship was used to provide guidance and limits for subsequent work leading to 2-o-propoxyphenyl-8-azapurin-6-one which is 40 times more potent than disodium cromoglycate. It is suggested that good antiallergic activity in this series is associated with coplanarity of the phenyl group with the azapurin-6-one which would be favored by a high degree of hydrogen bonding.
