Replies to post #19779 on RespireRx Pharmaceuticals Inc (fka RSPI)

[atheroprevent]

re limiting <<consumption of grapefruit juice during the trial>>
helps limit dosing variability of some drugs by preventing enhanced absorption (increased bioavailability). The effects are not predictable because of individual patient variation and variations in the fruit, pulp and mix of juice. I have heard that the white pulp may carry more of the substances that block the oxidation (degradation) of some drugs (in the intestinal lining where absorption takes place). More commonly known effected drugs include simvastatin, felopidine and cyclosporin, leading to potentially highly significant clinical effects from the higher drug levels in the body.

http://www.ncbi.nlm.nih.gov/pubmed/9260034

Clin Pharmacokinet. 1997 Aug;33(2):103-21.Links
Drug interactions with grapefruit juice.Ameer B, Weintraub RA.
Princeton Junction, New Jersey, USA.

Some drugs demonstrate a significantly greater (up to 3-fold) mean oral bioavailability on coadministration with grapefruit juice. With some calcium antagonists, the benzodiazepines midazolam and triazolam and the antihistamine terfenadine, changes in bioavailability are accompanied by altered drug action. Study design factors possibly contribute to the magnitude of changes in drug bioavailability; they include the source of the citrus, its intake schedule, drug formulations and individual metabolising capacity. The components of citrus juice that are responsible for clinical drug interactions have yet to be fully determined. Based on the flavonoid naringin's unique distribution in the plant kingdom, abundance in grapefruit and ability to inhibit metabolic enzymes, naringin is likely to be one of the grapefruit components influencing drug metabolism. Other components present in citrus fruit, such as furanocoumarins, may be more potent inhibitors than flavonoids and are under investigation. Conclusions drawn from clinical drug interaction studies should be considered specific to the citrus fruit products evaluated because of the variation in their natural product content. The predominant mechanism for enhanced bioavailability is presumably the inhibition of oxidative drug metabolism in the small intestine. The consistent findings across studies of diverse cytochrome P450 (CYP) 3A substrates support the mechanistic hypothesis that 1 or more grapefruit juice components inhibit CYP3A enzymes in the gastrointestinal tract. The evaluation of the need to avoid the concomitant intake of grapefruit products with drugs is best done on an individual drug basis rather than collectively by drug class. Based on the narrow therapeutic range of cyclosporin and research experience in organ transplant recipients, its interaction with grapefruit juice is likely to be clinically significant.

[spyderboi]

I cant tell you anything about that compound, but the grapefruit juice exclusion is likely to mean the drug can be metabolised by Cytochrome P-450 3A4 and may have a narrow therapeutic window.
CYP-3A4 is responsible for metabolism of 70% of drugs in the liver, but also occurs in the intestine. It has been found that grapefruit juice can inhibit 3A4 and therefore affect the drug bioavialabilty. This is usually not important, but if a drug only has efficacy close to its toxic level then such variability in its bioavailablity can be very significant.
Im not sure your guess of high potency is necessarily accurate- they are starting at 0.25mg then rising from there. That suggests they just dont know.

My best guess would be- Hi impact since only cortex seems to work on LI And the concern about starting dose and tight controls of bioavailablity suggests a concern with toxicity- probably seizure- again a feature of HI ampakines.

Hope that helps

[ombowstring]

gfp, please correct me if I'm wrong,

but doesn't Cortex hold the patent for AMPA upmodulation? What are the "North American rights" that have been talked so much about on this board?