ABSTRACT
BACKGROUND: PN 400 is a fixed-dose combination formulated to provide sequential delivery of immediate-release (IR) esomeprazole and enteric-coated (EC) naproxen. AIM: To evaluate gastric acid suppression with three doses of esomeprazole in PN 400 compared with EC esomeprazole 20 mg. METHODS: In this Phase I, randomized, open-label study, 28 healthy adults received PN 400 b.d. (naproxen 500 mg plus esomeprazole 10, 20 and 30 mg) and non-EC naproxen 500 mg b.d. plus EC esomeprazole 20 mg o.d., each for 9 days in a crossover fashion. The primary endpoint was percentage of time on day 9 that intragastric pH was >4.0; secondary endpoints included pharmacokinetics and safety. RESULTS: Day 9 percentage of time where intragastric pH was >4.0 was 76.5%, 71.4%, 40.9% and 56.9% [corrected] for PN 400 containing 30, 20 and 10 mg esomeprazole, and naproxen plus esomeprazole 20 mg respectively. This was significantly greater for PN 400 containing 30 and 20 mg esomeprazole vs. naproxen plus esomeprazole 20 mg (95% CI: 13.0-26.0 and 7.8-20.7 respectively). The pharmacokinetics of PN 400 were consistent with its formulation. No serious adverse events occurred. CONCLUSION: PN 400 containing 20 mg esomeprazole was the lowest dose to achieve gastric acid suppression comparable to EC esomeprazole 20 mg and was selected for further evaluation.
Subject(s)
Anti-Ulcer Agents/therapeutic use , Esomeprazole/therapeutic use , Gastric Acid/metabolism , Magnesium/therapeutic use , Naproxen/therapeutic use , Adolescent , Adult , Anti-Ulcer Agents/pharmacokinetics , Clinical Trials, Phase I as Topic , Cross-Over Studies , Dose-Response Relationship, Drug , Drug Administration Schedule , Esomeprazole/pharmacokinetics , Female , Humans , Magnesium/pharmacokinetics , Male , Middle Aged , Naproxen/pharmacokinetics , Young AdultABSTRACT
UNLABELLED: For antiprogestagens both selectivity (ratio of antiprogestational to antiglucocorticoid activity) and potency are important conditions for their applications in fertility regulation and correction of hormone-dependent irregularities. Org 33628 appears to fulfill both conditions most convincingly. The activities of this new antiprogestagen in various assays are compared with those of RU 38486 and a few other antiprogestagens. The binding of Org 33628 to the progesterone receptor is twice as high as that of RU 38486 whereas the binding to the glucocorticoid receptor is 25 times lower than that of RU 38486. The activity of Org 33628 in the pregnancy interruption test in rats is 16 times higher than that of RU 38486. The antiglucocorticoid activity of Org 33628 in rats is about eight times lower than that of RU 38486. In the ovulation inhibition test in rats Org 33628 is approximately 80 times more potent than RU 38486. For menses induction in the stumptail monkey activity observed for Org 33628 is only twice as high. IN CONCLUSION: Org 33628 is a very potent and selective antiprogestagen with a remarkably high ovulation-inhibitory activity. The magnitude of the potency difference with RU 38486 is species and/or target organ dependent.
Subject(s)
Estrenes/pharmacology , Progestins/antagonists & inhibitors , Adrenal Glands/drug effects , Adrenal Glands/metabolism , Animals , Cell Line , Estrenes/chemistry , Estrenes/metabolism , Female , Furans/pharmacology , Gonanes/pharmacology , Guinea Pigs , Humans , In Vitro Techniques , Mifepristone/pharmacology , Ovulation/drug effects , Pregnancy/drug effects , Receptors, Cell Surface/antagonists & inhibitors , Receptors, Cell Surface/metabolism , Receptors, Progesterone/antagonists & inhibitors , Receptors, Progesterone/metabolism , Structure-Activity RelationshipABSTRACT
Mitosenes of both the pyrrolo- and pyrido[1,2-a]indole type have been prepared via modification of these heterotricyclic compounds. Several mitosenes have been studied for their reactions with nucleophiles under reductive conditions. The results of these experiments show that the biological activity of mitosenes is based on the mechanism of bioreductive activation. When both leaving groups at C-1 and C-10 in the mitosene are the same, the nucleophile preferably adds to C-10 under reductive conditions. All mitosenes were studied for their biological activities in vitro against L1210, WiDr, and A204. On the basis of these results a selection of three mitosenes was made for a more detailed biological evaluation. Several tumor model systems were used, viz. P388, human tumor xenografts, MAC 13, and MAC 16. The results of these studies show that mitosenes have a more limited range of activities than mitomycin C. Surprisingly, the in vivo activities of mitosene diol 8b and mitosene diacetate 10b against the gastric human tumor xenograft GXF 97 were very high and comparable with that of mitomycin C.
Subject(s)
Antineoplastic Agents , Animals , Antineoplastic Agents/chemical synthesis , Chemical Phenomena , Chemistry , Female , Humans , Leukemia L1210/pathology , Mice , Mice, Nude , Mitomycin , Mitomycins/pharmacology , Neoplasm Transplantation , Tumor Cells, Cultured/drug effectsABSTRACT
Mitosenes of both the pyrrolo- and pyrido[1,2-a]indole type have been prepared via a modified Madelung reaction of benzeneacetonitriles ortho-substituted with gamma- and delta-lactam moieties, respectively, followed by modification of the resulting heterotricyclic compounds. Some in vitro anti-tumour activity data of these novel compounds are rearrangement of 2-(1-pyrrolidinyl)-3-vinylquinone derivatives to 5,8-dioxo-1H-pyrrolo[1,2-a]indoles.
