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Biotech / Medical : Biotech Lock-Up Expiration Hell Portfolio -- Ignore unavailable to you. Want to Upgrade?

To: tuck who wrote (105)	6/13/2001 4:24:41 PM
From: Biomaven	Read Replies (2) \| Respond to of 1005

<<PTIE>> Valtran (Tilidine-naloxone) is used in Europe, but is not approved in the US. It differs from the PTIE drug in that the dose of naloxone it uses is way higher in Valtran (perhaps by a factor of 100 or more, although as tilidine is a pro-drug I'm not quite sure precisely how its dosage compares). Paradoxically, for reasons certainly not understood by me, the much smaller dose produces better analgesia. PTIE measures its naltrexone dose in ng/kg!(Biotech Jim is the guy on SI who best understands this stuff - he's the one for you to try to get some informed comments from). As I understand it, Valtran was principally designed to avoid abuse - if you take too much the naltrexone kicks in and you don't get a high. The PTIE drug is principally designed to reduce the narcotic dose while maintaining efficacy. Here's one abstract (by the PTIE guys) that illustrates the remarkable effect of a miniscule dose of naltrexone in a morphine combo. Note that you these rats apparently didn't develop tolerance and dependence: Brain Res 1997 May 23;757(2):176-90 Related Articles, Books, LinkOut Ultra-low doses of naltrexone or etorphine increase morphine's antinociceptive potency and attenuate tolerance/dependence in mice. Shen KF, Crain SM. Department of Neuroscience, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA. In previous studies we showed that low (pM) concentrations of naloxone (NLX), naltrexone (NTX) or etorphine selectively antagonize excitatory, but not inhibitory, opioid receptor-mediated functions in nociceptive types of sensory neurons in culture. Cotreatment of these neurons with pM NTX or etorphine not only results in marked enhancement of the inhibitory potency of acutely applied nM morphine [or other bimodally-acting (inhibitory/excitatory) opioid agonists], but also prevents development of cellular manifestations of tolerance and dependence during chronic exposure to microM morphine. These in vitro studies were confirmed in vivo by demonstrating that acute cotreatment of mice with morphine plus a remarkably low dose of NTX (ca. 10 ng/kg) does, in fact, enhance the antinociceptive potency of morphine, as measured by hot-water tail-flick assays. Furthermore, chronic cotreatment of mice with morphine plus low doses of NTX markedly attenuates development of naloxone-precipitated withdrawal-jumping in physical dependence assays. The present study provides systematic dose-response analyses indicating that NTX elicited optimal enhancement of morphine's antinociceptive potency in mice when co-administered (i.p.) at about 100 ng/kg together with morphine (3 mg/kg). Doses of NTX as low as 1 ng/kg or as high as 1 microg/kg were still effective, but to a lesser degree. Oral administration of NTX in the drinking water of mice was equally effective as i.p. injections in enhancing the antinociceptive potency of acute morphine injections and even more effective in attenuating development of tolerance and NLX-precipitated withdrawal-jumping during chronic cotreatment. Cotreatment with a subanalgesic dose of etorphine (10 ng/kg) was equally effective as NTX in enhancing morphine's antinociceptive potency and attenuating withdrawal-jumping after chronic exposure. These studies provide a rationale for the clinical use of ultra-low-dose NTX or etorphine so as to increase the antinociceptive potency while attenuating the tolerance/dependence liability of morphine or other conventional bimodally-acting opioid analgesics.