PubMed · 3954407
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E W Lanier. 1986. Basic diphenoxylate therapy.. https://pubmed.ncbi.nlm.nih.gov/3954407/
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An increased intake of fruits and vegetables has been shown to be associated with reduced risk of cancer. In epidemiological studies, supplements of beta-carotene, which is abundant in fruits and vegetables, were not found to be beneficial in reducing the incidence of lung cancer in high-risk groups. Epoxycarotenoids are abundant in nature. 5,6-Epoxy-beta-carotene was much more active than beta-carotene in the induction of differentiation of NB4 cells [Duitsman, Becker, Barua and Olson (1996) FASEB J. 10, A732]. Epoxycarotenes may, therefore, have protective effects against cancer. In order to do this, however, epoxycarotenoids must be absorbed by the human body. There is no evidence that epoxycarotenoids, despite their abundance in dietary fruits and vegetables, are absorbed by humans. In this paper, it is demonstrated that orally administered dietary or synthetic epoxy-beta-carotenes are absorbed by humans, as indicated by their appearance in the circulating blood.
Modification of the alpha-carbamate substituent of isoxazoline GPIIb/IIIa (alphaIIb beta3) antagonist DMP 754 (7) led to a series of alpha-sulfonamide and alpha-sulfamide diaminopropionate isoxazolinylacetamides which were found to be potent inhibitors of in vitro platelet aggregation. Aryl- and heteroaryl-alpha-sulfonamide groups, in conjunction with (5R)-isoxazoline (2S)-diaminopropionate stereochemistry, were found to impart a pronounced duration of antiplatelet effect in dogs, potentially due to high affinity for unactivated platelets. Isoxazolylsulfonamide 34b (DMP 802), a highly selective GPIIb/IIIa antagonist, demonstrated a prolonged duration of action after iv and po dosing and high affinity for resting and activated platelets. The prolonged antiplatelet profile of DMP 802 in dogs and the high affinity of DMP 802 for human platelets may be predictive of clinical utility as a once-daily antiplatelet agent.
Selective cyclooxygenase-2 (COX-2) inhibitors have been shown to be potent antiinflammatory agents with fewer side effects than currently marketed nonsteroidal antiinflammatory drugs (NSAIDs). Initial mass screening and subsequent structure-activity relationship (SAR) studies have identified 4b (PD138387) as the most potent and selective COX-2 inhibitor within the thiazolone and oxazolone series of di-tert-butylphenols. Compound 4b has an IC50 of 1.7 microM against recombinant human COX-2 and inhibited COX-2 activity in the J774A.1 cell line with an IC50 of 0.17 microM. It was inactive against purified ovine COX-1 at 100 microM and did not inhibit COX-1 activity in platelets at 20 microM. Compound 4b was also orally active in vivo with an ED40 of 16 mg/kg in the carrageenan footpad edema (CFE) assay and caused no gastrointestinal (GI) damage in rats at the dose of 100 mg/kg but inhibited gastric prostaglandin E2 (PGE2) production in rats' gastric mucosa by 33% following a dose of 100 mg/kg. The SAR studies of this chemical series revealed that the potency and selectivity are very sensitive to minor structural changes. A simple isosteric replacement led to the reversal of selectivity.