The free COOH group of conventional NSAIDs is a structural feature for non-selective cyclooxygenase (COX) inhibition and the molecular cause of their gastrointestinal (GI) toxicity. In this context, an in house database of synthesizable ester prodrugs of some well-known NSAIDs was developed by combining their -COOH group with -OH of a newly identified antioxidant 4-(1H-benzo[d]imidazol-2-yl)phenol (BZ). The antioxidant potential of BZ was unveiled through in silico PASS prediction and in vitro/in vivo evaluation. The in house database of NSAIDs-BZ prodrugs was first subjected to screening with our previously reported pharmacophore models of hCES1 (AAHRR.430) and hCES2 (AHHR.21) for determining hydrolytic susceptibility. Biotransformation behaviour of screened prodrugs was then assessed by using QM/MM and sterimol parameterization, followed by ADMET calculations to predict the drug likeness. On the basis of in silico results, five prodrugs were duly synthesized and the best three were subject to the in vivo evaluation for their anti-inflammatory, analgesic, antioxidant activities, and ulcerogenic index. Among these prodrugs, BN₂ and BN₅ displayed better anti-inflammatory and analgesics potential in comparison to their parent drugs. All the prodrugs were found to be gastro sparing in the rat model and significantly improved the levels of oxidative stress biomarkers in both blood plasma as well as gastric homogenate.

01 Jan 2002·Environmental Toxicology and ChemistryQ3 · ENVIRONMENTAL SCIENCE & ECOLOGY

MONOCLONAL ANTIBODY ENZYME-LINKED IMMUNOSORBENT ASSAY TO QUANTIFY VITELLOGENIN FOR STUDIES ON ENVIRONMENTAL ESTROGENS IN THE RAINBOW TROUT (ONCORHYNCHUS MYKISS)

Q3 · ENVIRONMENTAL SCIENCE & ECOLOGY

Article

Author: Nilsen, Mona V. ; Nilsen, Bente M. ; Goksoyr, Anders ; Hutchinson, Tom H. ; Tyler, Charles R. ; Berg, Karin ; Van Aerle, Ronny ; Maddix, Susan ; Blackwell, Robert

Vitellogenin (VTG) induction has proved to be a valuable biomarker for assessing exposure to environmental estrogens in fish. The widespread use of VTG in this regard has lead to the need for standardized assays to quantify VTG, and monoclonal antibodies have the potential to help accomplish this. A VTG enzyme-linked immunosorbent assay (ELISA) was developed using a monoclonal antibody prepared against Atlantic salmon (Salmo salar) VTG (MAb BN-5) and its ability to quantify VTG in the rainbow trout (Oncorhynchus mykiss) compared with a rainbow trout vitellogenin (rt-VTG) ELISA that employed homologous polyclonal antibodies (PAb). In routine protocols, the working range of the homologous rt-PAb VTG ELISA was between 9 ng/ml and 70 ng/ml (80- 20% relative maximum binding [B/Bo]) with a 50% B/Bo of 25+/-0.9 ng/ml and inter- and intraassay variations at 50% B/Bo of 7% (n = 7) and 8% (n = 15), respectively. The working range of the MAb BN-5 VTG ELISA was between 60 ng/ml and 850 ng/ml (80-20% B/Bo) with a 50% B/Bo of 227+/-22 ng/ml and inter- and intraassay variations at 50% B/Bo of 5% (n = 10) and 9% (n = 12), respectively. In the routine protocols, detection limits for measurement of plasma VTG in rainbow trout (at 80% B/Bo; and given the requirement to dilute plasma to a minimum of 1:10 for the assays) were 90 ng/ml for the polyclonal rt-VTG assay and approximately 600 ng/ml in the monoclonal antibody assay. In juvenile female rainbow trout exposed to a series of doses of estradiol-17beta (E2) and 4-tert nonylphenol (4-NP), there were no differences in the vitellogenic responses measured in the PAb and MAb BN-5 VTG ELISAs. The monoclonal MAb BN-5 VTG ELISA is likely to be of considerable value for studies on environmental estrogens in juvenile female rainbow trout in standardized tests.

01 Jul 1988·British Journal of Clinical PharmacologyQ2 · MEDICINE

Effect of a PAF antagonist, BN52063, on PAF‐induced bronchoconstriction in normal subjects.

Q2 · MEDICINE

Article

Author: M McCusker ; NM Roberts ; KF Chung ; PJ Barnes

1. The effects of an oral platelet activating factor (PAF) antagonist, BN52063, or matched placebo on inhaled PAF challenge were assessed in a double‐blind study in eight normal subjects. 2. PAF (24 micrograms) induced an immediate bronchoconstriction, with a maximum fall in flow at 30% of vital capacity from a partial flow volume manoeuvre (Vp30) of 47.1 +/‐ 7% (mean +/‐ s.e. mean) 5 min after inhalation following placebo treatment. Repeated PAF challenges at 15 min intervals resulted in tachyphylaxis of the bronchoconstrictor response. 3. Two hours after the ingestion of BN52063 (120 mg) the maximum bronchoconstriction induced by inhaled PAF was attenuated (35.9 +/‐ 9% fall at 5 min) with a significant reduction (P less than 0.05) in response after the first and second inhalations. 4. Inhaled PAF induced an immediate neutropenia (73.2 +/‐ 9% fall 5 min after inhalation) followed by a rebound neutrophilia, which were unaffected by pretreatment with BN52063. 5. Oral ingestion of a dose of BN52063 which is effective in reducing skin responses to PAF gave partial protection against the bronchoconstrictor effect of inhaled PAF in normal subjects.

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Indication	Highest Phase	Country/Location	Organization	Date
Arthritis	Preclinical	-	Botanix Pharmaceuticals Ltd.	-
Osteoporosis	Preclinical	-	Botanix Pharmaceuticals Ltd.	-

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