Prostatin-Viral Reservoirs Eradication

[tash08]

I would like you guys to take a look at prostatin and viral reservoirs,
http://www.aidsresearch.org/scientific_research/faq_research.html#5

Dr. Paul Alan Cox, an ethnobotanist who routinely explores the world’s ecosystems to study native pharmacology, came across healers in Western Samoa who were using a tea made from the bark of a small native tree known as the mamala to treat a disease they called fava sama sama - hepatitis. Samples of this remedy were sent to scientists at the U.S. National Cancer Institute (NCI), where plant-derived substances are routinely screened against different diseases. Dr. Michael Boyd and his colleagues at NCI isolated the active chemical from the remedy, prostratin, and discovered its powerful effects against HIV. Their initial work suggested that prostratin could be used to activate viral reservoirs.
ARA has initiated a number of research collaborations to examine the potential use of prostratin as part of a Reservoir Ablation Strategy (RAS). These collaborations include Drs. Jerome A. Zack (UCLA Center for AIDS Research), Eric de Clercq (Rega Institute in Belgium), Ivan Hirsch (The French National Institute of Health and Medical Research), Jose Alcami (Spanish Institute of Health) and Michealangelo Foti (University of Geneva, Switzerland). Already, we have convincingly shown in test-tube studies that prostratin, when present at the time of introduction of HIV, prevents the virus from infecting cells and thus acts like an entry inhibitor. This development is exciting because it attacks the virus at a different stage than the other four classes of FDA-approved anti-HIV drugs. It also appears to work on a cellular target rather than a viral target. More importantly, we’ve learned that prostratin can activate dormant virus from a number of different types of cells where HIV reservoirs lurk in the human body. The findings from these studies are moving ARA closer to determining if prostratin’s unique properties in cell cultures can be used to treat HIV in humans.
At the beginning of 2006, AIDS Research Alliance engaged one of the world's largest pharmaceutical research and development services companies to complete pre-clinical research on prostratin (including additional toxicology studies). The experiments included in the study are required for submission of an Investigational New Drug (IND) application to the Food and Drug Administration (FDA) and initiation of a Phase I human clinical trial.  These studies, at a projected cost of $1.2 million, are scheduled to be concluded by Fall 2006. If all goes well, limited Phase I trials will begin, possibly testing of HIV levels in gut-associated lymphoid tissue, in collaboration with Dr. Peter Anton of UCLA (also a member of ARA’s Scientific Advisory Committee).The reservoir of HIV infected cells can be compared to a reservoir of water filled by a stream. The stream that fills the reservoir represents continuing viral replication that occurs in HIV positive individuals, including most of those on HAART. The rate at which the reservoir decreases is related to two factors: Continual filling by the incoming stream and the rate of “evaporation,” or naturally occurring depletion of the reservoirs

[powerpuff]

interesting? latent cells eh? they said that about the valporic acid. i wonder if this one would work.?

[tash08]

Research has been hampered, though, because the compounds are difficult to obtain, particularly in the quantities needed for practical lab work on their mode of action and therapeutic potential. The yield from both plants is low and highly variable; the availability of the plants is limited; and isolating the compound is difficult. Heavy harvesting of the wild plants, especially in Samoa, also could cause ecological damage. But synthetic prostratin and DPP, which now can be readily made in the lab, changes that equation. "We have now minimized, if not eliminated, the issue of availability of prostratin and DPP," Wender said. "But equally, if not more importantly, we have opened access to other compounds that might be similar in structure but superior in function." Previous work done in mice by researchers at the University of California-Los Angeles indicates that prostratin, used in combination with interleukin-7, an immune system stimulator made in bone marrow, managed to flush out and eliminate approximately 80 percent of the dormant virus. But with HIV, 80-percent efficiency is not enough. Anything less than 100 percent means the virus is still lurking in the T-cells and will spring back to action as soon as an opportunity presents itself. But with synthetic prostratin and DPP available, researchers can take the basic compounds and tinker with the structure and related function. "We could find out how to improve them by reverse engineering: figuring out what is important and what isn't important," Wender said. "We could begin to design and synthesize molecules that would never be found in nature but might actually be therapeutically more beneficial than what has been found thus far." In the Science paper, Wender and his team detail how both compounds can be synthesized, but also show the initial phase of designing and making new derivative compounds. Although prostratin has long been used by traditional Samoan healers without their patients experiencing acute side effects, it is possible that undesirable effects could show up in an immune-impaired patient taking prostratin or DPP. But Wender noted that engineering the compounds in a lab would permit scientists to circumvent these problems. "Usually these kinds of side effects are a result of a drug hitting multiple targets. So it hits one target, which is beneficial, but then it hits some other target, too," he said. "But by modifying the structures, you could select for the beneficial activity over the non-beneficial activity." Wender emphasized that the work of his team is the most recent chapter in efforts of a truly global community, starting with the Samoan healers, who willingly shared their knowledge with Paul Cox, an ethnobotanist who saw them prescribing a tea made from Mamala bark for patients with hepatitis-like symptoms. Cox, in turn, sent samples to the National Institutes of Health, in hopes that the bark might have antiviral properties useful in fighting some cancers. Researchers at NIH then analyzed the bark and isolated prostratin. Prostratin belongs to a class of compounds called tiglianes, many of which promote tumor growth, so it had no initially perceived use in fighting cancer. But NIH researchers found that prostratin was not a tumor promoter and checked to see if perhaps it could help combat HIV, which is when its remarkable ability to flush out the dormant virus was discovered. Significantly, prostratin has also been found to block uptake of the purged virus, offering yet another potentially therapeutic benefit.

This practical synthesis produces gram quantities of prostratin, and is a major step forward in pharmaceutical development of prostratin. Phase I human clinical trials of prostratin will be carried out by the AIDS ReSearch Alliance in West Hollywood, California.

[tash08]

I contacted Aids Research Alliance in West Hollywood,CA about Prostatin update as their website has no new updates just the ones from 2006 surprisingly they did respond after my 2nd attempt:

Here is what they said: we are formatting our pre-ind meeting request with the FDA, this  covers what we plan for final toxicology experiments for IND

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