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Ion Channels Open Doors to New Drugs Increased R&D Efforts Are Overcoming Obstacles and Showing Potential

Last Updated on Thursday, 8 July 2010 03:20 Written by Editor Thursday, 8 July 2010 03:20

  • Nina Flanagan
Ion channels make good drug targets—they reside on the cell surface and are fast switching mechanisms. They act like cell transistors, controlling many cell processes. There are close to 500 types of ion channels, yet many remain undiscovered. This was mainly attributed to technology restraints, however, with the recent introduction of HT patch clamping, as well as new assays that facilitate faster, more robust screening, there are more ion channel receptors being detected.

Researchers at the recent Society for Biomolecular Screening conference and CHI’s upcoming “Pharmacology Driven Assays for GPCRs and Ion Channels” shared information on a cornucopia of topics, including the latest enabling technologies, new screening paradigms, and novel approaches to generate GPCRs.

The IonFlux system from Fluxion Biosciences was recently beta tested by scientists at Novartis Institutes for Biomedical Research (NIBR). “Compounds, buffers, and waste are contained on a single 96-well plate, eliminating robotic handling. Air pressure drives experiments in microfluidic channels in a layer below the wells. This is a novel approach in automated electrophysiology,” explained Andrew Golden, Ph.D., post-doc fellow.

Robustness is enhanced via recordings taken from 20-cell ensembles (IonFlux HT), and pharmacology improved by recording a full range of concentrations from the same group of cells, according to the company. There are two available systems—the IonFlux 16, which uses 96-well plates, and the IonFlux HT, which uses 384-well plates.

Analysis of the prototype (alpha and beta testing) was initially focused on whether IonFlux could reproduce results demonstrated on other platforms. “The microfluidic approach could be helpful for ligand-gated ion channels—especially for subsets of those for fast desensitizing ligand-gated ion channels where you only add a short pulse of the ligand or neurotransmitter,” explained Mats Holmqvist, Ph.D., research investigator in the center for proteomic chemistry at NIBR.

In addition, Dr. Holmqvist said the hope for the new platform is that it should provide selectivity not only by target but also by function. “You can utilize ‘use dependency’—the accumulation of inhibition with repetitive depolarizations. If an ion channel is active, the drug may be much more potent.” With this new technology, one should be able to refine and understand how a compound affects an ion channel. However, it’s still too early to show whether this will be the case.

Since HT platforms for ion channels are fairly new, standardization across different instruments hasn’t been addressed. “There are different quality control parameters, including the way of recording a single cell per well or ensemble recording in parallel. Some machines use Oracle database versus file formats. We’ve been trying to address that in safety profiling. A quick answer is that we make a summary PDF file of every compound in each experiment that can be accessed any time,” noted Dr. Holmqvist.

Parallel Screening

The traditional screening paradigm involves one target for primary HTS. However, this process “wastes a considerable amount of time to get results, and also wastes efforts on compound management in order to get those compounds ready for testing,” said Peter Hodder, Ph.D., senior director of lead identification for the translation research institute at the Scripps Institute, Florida.

His group uses a parallel screening process that screens compounds against the target and antitarget simultaneously. “Antitarget is an all-encompassing name for any assay you would run that’s different from the target—usually to remove compounds from further consideration,” Dr. Hodder explained. “We found most of those compounds are junk compounds anyway.” The antitarget becomes important for the hit compounds, because it provides information on whether it is something specific to the target or whether it is something nonspecific to the assay format.

Time saved via parallel screening can be four to five weeks per target. In addition, and what is more important and what is harder to gauge, he noted, is saved efforts following false trails, which result in smaller, cleaner datasets. Relevant structure  activity relationships emerge early in a campaign. For example, Dr. Hodder performed an SF1 (transcription factor) assay and ran the antitarget ROR against it and found potent compounds. “If we had relied on primary screening alone, those compounds would not have been selected.”

The parallel-screening format is not specific to any target class. “What’s more important is how to apply it to different target classes or different assay formats.” His group was successful in screening ion channels, including TRPML3 with TRPN1 as the antitarget (TRP is transient-receptor potential). HTS probes confirmed that the target is not located on plasma membranes in native cells.

Dr. Hodder added that this approach can be used to help focus on the most important compounds for drug or probe discovery, but it’s key is in choosing the right antitarget. “If it’s too close in relationship to the target, you’re going to start throwing out compounds you don’t want to during the campaign.”

His group is now performing more sophisticated screening using two or three antitargets and trying to find the overlap of hits that are specific in all three versus two or one of those targets and antitargets. “This challenges us to think about how we present and analyze our data.”

Novel Assays

Some of the challenges of working with ion channels include controlling activity, whether with a small molecule ligand or voltage. Many ion channels inactivate within milliseconds, making HTS difficult.

David Weaver, Ph.D., director at Vanderbilt Institute of Chemical Biology HTS, has been focusing his research efforts on ion channels—especially 7TM (7-Transmembrane) receptors.

“We are interested in looking at some of the effector systems that are more physiologically relevant and one of these is the GIRK (G-protein regulated inwardly rectifying potassium (K+) channel).” His group developed this assay to measure the activity of GI-coupled 7TM receptors. “The idea was whether we could see any differences in the pharmacology and the fact that we may be using a more physiologically relevant end effector rather than using mutant G proteins to couple the change in intracellular calcium.”

The success of the GIRK assay encouraged Dr. Weaver to examine ion channels as end effectors that could be used to generate new assays with physiological relevance. Preliminary data demonstrates the ability to detect changes in M-current (muscarinic-modulated potassium current, usually studied in the brain and peripheral nervous system) activity.

He developed an HTS-compatible assay that can measure and quantify the modulation of M-current downstream from the 7TM receptor using thallium-flux. This optical assay platform can use a commercially available kinetic imaging plate reader.

According to Dr. Weaver, the only nonstandard part of the assay is that he extracts a slope from the initial measurement, instead of fitting a peak amplitude. His hope is to use this assay to further understand the pharmacology of 7TM receptors. “It’s my intent that we can demonstrate that these are good, robust assays for use in HT screens to discover novel modulators of 7TM receptors or the ion channels we’re using as effectors.”

Novel Targets

“Ion channels are terrific molecular targets, and many drugs have been targeted to them,” stated David Clapham, M.D., Ph.D., Aldo R. Castenada professor of cardiovascular research at Children’s Hospital Boston. Yet, one of the biggest challenges is the gold standard assay—the patch clamp.

This is a time-consuming technique—single cell membranes must be broken open and the current must be recorded while controlling voltage in the cell. Although HT assays exist, not all ion channels are suited to them. “The most promising are the very fast, voltage-dependent channels with large, rapid changes and ones less amenable are ones that are similar to each other in their properties, like TRP channels—these are more difficult.”

Dr. Clapham also presented information on what he thought were good, fairly recent, ion-channel targets and included some recent data on some of his work with these targets.

Many TRP channels are involved in sensory functions, like smell, taste, and hearing. TRPV3 is an ion channel that is well expressed in skin. Dr. Clapham demonstrated that both skin barrier formation and some aspects of hair formation are altered by this ion-channel’s activation or block.

It is activated by subtle temperature changes—temperatures about 32ºC—indicating TRPV3 is sensing heat at the skin surface and relating that to the nerves. This indicates it may help regulate body temperature. Growth factors such as EPGR potentiates TRPV3 to bring calcium into karatinocytes, and, in turn, TRPV3 potentiates EPGR, so there’s a positive feedback loop.

“This is important for the proper formation of skin barriers, so that there is normally a cycle of karatinocytes maturing from deeper in the skin to the surface of the skin.” Dr. Clapham added that TRP channels are difficult to work with because they are fairly slow and their properties are often difficult to distinguish. In addition, they are often small in size, and there is a lack of known ways to activate them.

Additional ion channels that Dr. Clapham thought were worth pursuing were the NAV1.7 to NAV1.9 pain targets, which are voltage-gated sodium channels. A new chloride channel, TMAM16-A, and the ORAI channel, which is important in the immune system, were also on the list. An interesting new target for contraception, called CATSPER, is an ion channel only present in mature sperm and required for male fertility. “This may be a good method of contraception without hormones,” said Dr. Clapham.

“Our job is to find new targets and new molecules, and then other people can work with those molecules to target diseases.”

New Approach

There are many challenges for the generation of new GPCRs, said Michel Bouvier, Ph.D., professor and chairman in the department of biochemistry at the University of Montreal. These include selectivity and ligand-biased signaling, where one receptor can couple to different signaling pathways in a cell.

“The problem with this is that you are trying to monitor the efficacy of a compound toward one signaling pathway, but since there are multiple ones, we don’t necessarily know which one to follow that will correlate with a disease or particular activity.” His approach is to develop one assay that could encapsulate in one reading all the signaling pathways and by dissecting the signatures, provide information about the pathways being engaged by a receptor.

Utilizing Roche’s label-free xCELLigence platform, his group is able to measure cell impedence. Each well of the plate has electrodes. As the cells grow, the impedance increases, and when the cells are treated with compounds that bind to receptors, many different pathways are triggered.

The readout reflects changes in impedance from the compound over time—providing a global assessment of the various pathways. Different compounds generate different curve shapes. “We can use this technology to differentiate classes of compounds that have different relative selectivity toward different pathways. It’s generating a simpler way to classify compounds in different efficacy profiles toward different signaling pathways.”

Dr. Bouvier added that they can now, using selective inhibitors of different pathways  such as the generation of cyclic AMP, show how the inhibition influences the shape of the impedance curve. “Not only can we start classifying the ligands in different categories or compounds, but we can start making predictions on which pathways these compounds will be actively inhibiting. His group is planning to develop algorithms to apply to the curve and thus, provide a response as to which pathway is being affected. “We first need to confirm which portion of the curve informs us about each pathway.”

This approach can be used for almost any receptors, reported Dr. Bouvier. It provides a big time savings—one assay instead of four or five. However, he added, “we don’t know yet if all signaling pathways will respond to changes in impedance—from our data so far, we haven’t encountered such a pathway.”

source: genengnews.com

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Leading the way

Last Updated on Friday, 14 May 2010 11:06 Written by Editor Friday, 14 May 2010 11:06

Successful drug research depends on high-quality hits in early screening. Trevor Perrior, research director at Domainex, explains why researchers are adopting a new method that turns high-throughput screening on its head

To some people, high-throughput screening (HTS) is synonymous with finding hits. But is it the best and only system? More and more drug researchers say they are looking for a faster and more cost-effective replacement. LeadBuilder was developed as an alternative to HTS that saves time and money because only compounds likely to become a drug are screened. HTS works the opposite way round – it ploughs through an enormous, random library of compounds and the hits are tested afterwards to find the most ‘drug-like’.

HTS is like searching for a needle in a vast haystack using a bulldozer. It is expensive because – paradoxically – the chance of finding the needle increases if you have more hay in which to look. Hundreds of thousands, or even millions, of compounds must be collected before HTS can begin. You also need to buy the bulldozer. Equipment like assay platforms and automated machinery must be purchased. HTS has high ongoing costs too, such as reagents, supplying proteins or cells, and replenishing the compound collection over time.

Once the equipment is running, screening seems very fast at first glance. Some estimates claim 10,000–100,000 compounds a day can pass through an HTS system. But preparing for HTS is an often forgotten time-sink. It takes time to establish a robust assay suitable for HTS and to obtain enough high-quality protein or cells to screen the whole compound collection.

Analysing HTS results is also time-consuming. Bulldozing your way randomly through any old compounds means hits often are not very ‘drug-like’. Hundreds of hits must be exhaustively tested for safety, bioavailability, novelty and affinity for the target.

A decade ago, it was less important that HTS was expensive and hard to set up. Big pharmaceutical companies with large budgets and laboratories did most drug discovery. Now, spin-off companies, small biotechs, research institutions and academic labs are increasingly getting in on the act. Many cannot afford to run an HTS operation in-house or pay perhaps £100,000–£250,000 to outsource a screen.

LeadBuilder turns HTS on its head. Instead of screening everything, the system physically screens only compounds that look like drugs or hits. Returning to our haystack idea, the system only picks short “needle-like” straws, making it easier to find the ones that really shine

Based on state-of-the-art virtual modelling and screening software, LeadBuilder has four main modules: LibraryBuilder, CompoundProfiler, ScreenBuilder and StructureBuilder


The system starts with CATS (Compounds Available To Screen). These are a set of commercially available compounds sourced from reliable suppliers stored in the LibraryBuilder module.

ranked by drug potential

CompoundProfiler finds NICE (Interesting Chemical Entities) CATS by calculating each CATS’ molecular properties and predicting its physiochemical, pharmacokinetic and toxicity profile
CATS are then ranked by how ‘drug-like’ they are. NICE CATS meet every criterion for the ‘perfect’ screening hit – they have excellent molecular properties, good ADME, low toxicity and interact well with a target protein.

Choosing NICE CATS involves creative thinking about what makes a ‘drug-like’ compound. For example, after reviewing 37 hit-to-lead programmes, we found that high ligand efficiency (binding energy per atom) predicted hits that were easy to optimise into drug candidates. Higher ligand efficiencies resulted from certain structural features like charged groups (e.g. N+). So Domainex developed an algorithm that predicts a ligand efficiency from a compound’s structural features. We use this to eliminate poorly performing CATS.

The next stage in building leads is ScreenBuilder – a virtual screening engine that works on NICE CATS. Using information about the target protein, any known ligands or both of these, this module can screen by a com­bination of docking, pharmacophore searches and privileged fragment recognition. If the target protein is unknown, the system can identify a surrogate with a similar active siteThree real-life examples can illustrate how ScreenBuilder works: first, screening with pharmacophores derived from a known ligand, followed by docking into the x-ray structure of a protein; second, searching with ligand-based pharmacophores; and third, using only information about the target protein structure.

Example 1: Finding small molecules to inhibit protein-protein or peptide-peptide interactions is notoriously difficult. But LeadBuilder managed it. ScreenBuilder found 47 compounds that blocked a growth factor – natural peptide – from binding to its protein receptor. Aberrant growth factor signalling often drives tumour growth.

Domainex was given an x-ray structure of the ligand-binding pocket of the growth factor receptor with an oligopeptide fragment of the growth factor ligand bound to it. LeadBuilder analysed the ligand-binding pocket to define search criteria. Several structural features of the oligopeptide – H-bond donors and acceptors and a lipophilic group – seemed essential for binding to the receptor.

Next, the NICE database was virtually screened for compounds that contained these features and could be ‘docked’ into the protein’s active site. Domainex’s client lined up a subset of these compounds for further screening.

The project is currently in its hit-to-lead phase. Altogether, LeadBuilder identified 950 compounds for screening, delivering a 5% hit rate over several structural types. This made it 10 times more productive than another vendor’s focused library of 1000 compounds, which found only five hits (0.5% hit rate).

Example 2: A patent was filed on several compounds identified during another LeadBuilder project because they had commercially interesting activity levels. Domainex had been just given one known ligand to work with. The client was interested in compounds that would stimulate bone growth to accelerate the healing of fractures. It had developed a cell-based assay to look for compounds that switched on a signalling pathway that would cause deposition of bone. The ligand given to Domainex as a starting point was the only stimulator it had found for the pathway – it was keen to find others as potential drugs and for mechanism-of-action studies.

Domainex screened the NICE database using three pharmacophoric features based on the known ligand. Around 100 compounds were selected for screening, with the emphasis being on cellular penetration. During screening, our client found a hit with five times the activity of the known ligand. We are now helping it with a follow-up medicinal chemistry programme to find even better compounds.

Example 3: Protein kinases are important drug targets for a number of diseases. Many of the known inhibitors work by competing with the kinase substrate ATP. The problem with this approach is that it is difficult to find compounds that stop ATP binding to one kinase, but have no effect on the binding of ATP to other kinases. This selectivity problem means that kinase inhibitors often have side-effects caused by them blocking non-target kinase enzymes.

Our client wanted to find a selective inhibitor of a kinase that is a well-known cancer target, and had a novel hypothesis – did this protein kinase have a natural regulatory site that they could exploit with small-molecule drugs? The answer was yes. The client has patented the IP and is using it to secure funds. Domainex is now helping it develop a programme to turn its hits into leads.

An x-ray structure of the kinase showed that, in the naturally occurring inactive form, part of the enzyme ‘loops’ around to block the substrate protein binding site. On activation, this loop must move away to reveal a groove on the enzyme where the protein substrate can bind. An inhibitor that sits in this groove would stop catalysis by the kinase.

LeadBuilder found a four-point pharmaco-phore based on the key features of the “autoinhibitory loop” and an analysis of its binding groove on the surface of the enzyme (see Fig. 5). Using ScreenBuilder, potential ligands were selected from the NICE database using this pharmacophore and were docking into the hypothesised binding pocket.

Domainex recommended that the client screen 450 compounds based on this research. When tested against the kinase, this gave a 6% hit rate – 27 hits in four structural classes. Four of these showed promise in a follow-up cell-based screen.

In conclusion, dissatisfaction with HTS is growing. To many, finding hits seems like looking for a needle in a haystack. LeadBuilder is a smarter alternative. It may not yet offer pinpoint accuracy, but it can deliver ten times more hits during drug development.

source: manufacturingchemist.com

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AFraxis CEO Outlines Biotech’s Success With Ultra-Lean Pre-Clinical R&D in Russia

Last Updated on Wednesday, 12 May 2010 02:49 Written by Editor Wednesday, 12 May 2010 02:49

AFraxis, a mostly stealthy San Diego biotech, is getting ready to come out with a big announcement in the next week or so, but CEO Jay Lichter previewed some key parts of the story yesterday during a presentation before the San Diego Venture Group. He says the biotech has completed pre-clinical testing of a promising compound for treating a form of autism related to Fragile X syndrome.

Lichter, who does double duty as a managing partner of San Diego-based Avalon Ventures, founded aFraxis in 2007—shortly after researchers identified a possible drug target for Fragile X, a family of related mental disorders caused by a defect (or multiple defects) in a single gene on the X chromosome.

Of course, finding a compound that fits a single molecular target (the way a key fits into a lock) is no simple matter. The process can require screening millions of compounds, and then researchers must determine if candidate compounds are reasonably safe for initial use in humans and show the relevant pharmacological activity that justifies commercial development.

“The goal is to make a single exploratory compound and test it in a mouse, and we’ve done that,” Lichter says. The aFraxis CEO didn’t provide a lot of new details about the science. The target, which was identified at MIT in Nobel laureate Susumu Tonegawa’s laboratory, is PAK, a specific group of enzymes that catalyze neural reactions. Lichter says the same mechanism appears to be in play with schizophrenia. As Denise reported earlier this month, Fragile X Syndrome, which is the most common known cause of autism, is believed to be caused by defects in the gene that produces this group of enzymes.

Lichter’s presentation was instead focused mostly on the ultra-lean company-building approach aFraxis has taken to get this far. After three years, he says the biotech has only a handful of employees, and Avalon has invested a total of roughly $6 million to basically get to a stage where the company could submitt an application to begin clinical trials. “We started from scratch from a paper in PNAS (Proceedings of the National Academy of Sciences,” Lichter says.

The pre-clinical research was done in record time—and at a savings of roughly $4 million—by joining forces with Torrey Pines Investment, Lichter says. Torrey Pines Investment, a San Diego life sciences investment firm, happens to own a full-service contract research organization near Moscow. AFraxis plans to begin tests in Russia in 2011 to evaluate the drug’s safety in humans, Lichter says. If all goes as planned, he says tests in Fragile X patients in Moscow will follow.

Nicolay Savchuk, a Russian-born mathematician and director of Torrey Pines Investment who also participated in the presentation, says his firm uses its ties with the Moscow-based Chemical Diversity Research Institute to focus “on the gap where [potential drug] compounds are and where they need to be.” Savchuk says his firm likes to invest in potential drug candidate “assets” and use its R&D capabilities to produce “data packages” that provide the validation necessary to eventually turn its assets into drugs.

Savchuk says the deal with Avalon and aFraxis was “unusual and out-of-the-box thinking” made possible because “Jay was very seductive” and offered Torrey Pines an opportunity to make a direct investment in aFraxis. In exchange for an equity stake in the San Diego biotech, Savchuk says his firm guaranteed to cover the costs of the pre-clinical research and development that was done by the Russian CRO.

“I would not say it’s a one-size-fits-all model,” Savchuk says. “But it is a way to do more.”

Lichter added that he personally reviewed the capabilities of the Russian CRO, and was deeply impressed by the institute’s “top-notch’ capabilities in medicinal chemistry, biology, and related fields of drug research and development. He says he also was assured by the fact that Savchuk lives and works “just down the street.” Lichter says the Russian CRO’s cost was competitive with Asian firms, but that Savchuk’s personal involvement was a crucial factor—and a principal reason why Lichter could not envision doing the same work with an unfamiliar CRO in India or China.

“There’s something to be said about good neighbors,” Savchuk agreed. “We saw these target-to-clinic capabilities [that we have] as a convenient way to de-risk [biotech] investments. It made sense to us and our partners to streamline costs as much as possible.”

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« Community Group Loses City Funding More Restaurants on Noe Valley’s 24th Street? » UCSF Lab Uses Brains & Street Smarts to Fight Deadly Parasite

Last Updated on Wednesday, 12 May 2010 02:46 Written by Editor Wednesday, 12 May 2010 02:46

A few years ago a chemist made an offer under the table to Jim McKerrow, a professor at UC San Francisco’s Mission Bay campus. McKerrow accepted and drove down to South San Francisco, backed his car up to a loading dock, filled the trunk, and drove away.

“Suddenly I think, oh wow. What if I get stopped by the highway patrol and they open the trunk and there’s all these vials with white powder,” he said, recalling the incident recently. “Now officer, these are protease inhibitors,” he joked.

Back in the mid-1990s, McKerrow adopted another protease inhibitor, K777, in a similarly altruistic maneuver with Jim Palmer, a chemist then working at the now defunct Khepri Pharmaceuticals.

Today, that compound has become a promising candidate in the fight against an infectious parasite that has been found in the Bay Area blood supply and affects millions of victims in Latin America. The culprit—Trypanosoma cruzi (trip-PAN-o-soma CREW-see) —causes the potentially-fatal Chagas disease.

If K777 is successful, which won’t be known until it goes through lengthy clinical trials, it will be the first drug out of UCSF developed independently from industry. In this case, that research was conducted by McKerrow’s lab and its collaborators at the Sandler Center for Basic Research into Parasitic Diseases, a consortium devoted to drug development for neglected diseases.

The latter are infections that are endemic but primarily affect poor people. With Chagas, it’s 8 to 12 million of them, nearly all having lived in rural Latin America at some point in their lives.

An obsolete Brazilian 10,000 cruzado note reflects the importance of the disease in that country, where it was first discovered.

“Instead of on American money – e pluribus unum – here is the life cycle of the parasite sucking blood from someone’s skin,” McKerrow said, pulling a bill out of his desk drawer and pointing to money, which shows a drawing of a benchuca and the skin of its victim, complete with bite mark and parasite-rich feces.

Spread By A Bloodsucking Vector

The T. cruzi parasite – a single-celled eukaryote – is spread by a bloodsucking subfamily of assassin bug called a benchuca, or kissing bug. It bites near a sleeping victim’s eye or mouth, hence its name.

Every time a benchuca has a blood meal, it also defecates. T. cruzi moves from bug to human host when the victim inadvertently scratches the its poop into the bite wound or a mucus membrane.

The Centers for Disease Control and Prevention believe that almost all infections happen outside of the United States, but the parasite, and the insect that spreads it, live in the Southwest and some parts of California. It can also infect animals.

If untreated, 20 to 30 percent of its victims will develop significant, sometimes fatal heart disease, according to the CDC.

No Financial Incentives to Study Chagas

Because the poor are most affected, Chagas isn’t an interesting investment for pharmaceutical development, but it remains important to researchers and countries like Brazil, Argentina, and Bolivia, which have pockets of very high incidence. It’s that importance that leads some to make calls to fellow chemists like McKerrow.

Labs have no financial incentive to look into alternatives to the available treatment for the parasite — nasty drug regimens developed around WWII that have serious side effects including vomiting, psychiatric effects, and nerve damage. But still, scientists remain interested and aware that the latter might be improved on.

So when lawyers for the closing South San Francisco life sciences company told their scientists to destroy the compounds they had been working on to avoid any legal problems, the chemist thought it worth the risk to call McKerrow.

Some of these otherwise doomed compounds, he or she suspected, might be useful to the Sandler Center in fighting parasitic diseases like Chagas and malaria. McKerrow declined to name the chemist.

“It would be a terrible shame to waste stuff in which millions of dollars had been poured into,” Jim Palmer said generally about drugs developed in industry that might get thrown away.

Years earlier, Palmer made a batch of K777 for McKerrow in his free time, hoping the compound would have potential to help treat parasitic infections.

Palmer now works in Australia and said that everything he did with McKerrow was above board, though there are indications that some higher ups in his company at the time – long since dissolved – were uninformed about the relationship initially. “I don’t know anything about that – I don’t remember,” Palmer said.

Palmer was happy about the compound´s progress. He said he named after he saw the very first Boeing 777 airplane waiting to enter service at Dulles International Airport. “It’s like my child,” he said.

K777 was one of about 20 compounds – initially investigated for applications like cancer and arthritis – that were handed over to McKerrow to match against a chemical produced by the Chagas disease parasite.

McKerrow said that the compound has since been legally secured, safe from anyone being able to take out a patent and charge huge sums for it if it.

Though getting drug company throwaways helps, having promising compounds is merely one of many steps in a long and expensive drug development process.

Sandler Center researcher at a chemical hood.

Researchers screened thousands of compounds along the way. Tests for the disease had to be created, as did an animal model, which were designed through the devoted efforts of scientist couple Patricia Doyle-Engle and Juan Engle, according to McKerrow.

The Sandler Center targeted Chagas in particular because Latin American countries have basic infrastructure, like clinics, to distribute medicines once they are developed.

McKerrow said there won’t be a vaccine, since vaccines function to boost immune function, and in later stages of the disease, the host’s own immune response to T. cruzi helps damage heart tissue. Furthermore, there are wild animals like armadillos that are reservoirs for the disease. It’s impossible to eradicate.

Instead, researchers at the Sandler Center are looking at possible drug treatment – protease inhibitors – that stop the action of a chemical the parasite requires throughout its life cycle.

So far, K777 has been shown to be effective in animal tests. The next step is a clinical trial in humans. McKerrow said that the next hurdle is raising roughly $350,000 to pay for manufacturing the drug for such a study according to FDA standards.

Parasites in the Blood Supply

Meanwhile, on the local level, other researchers are tracking Chagas through blood donations.

Studies conducted by San Francisco-based Blood Systems Research Institute found that one out of every 16,000 donors in the San Francisco area tested positive for the parasite. That’s about double the overall U.S. rate.

The CDC estimates roughly 300,000 immigrants have the parasite in the United States.

“Nobody is legally required to screen for T. cruzi in the U.S.,” said Brian Custer, an associate investigator at the institute. He estimated 75 to 80 percent of blood banks nationwide are screening for it, and probably all California blood banks screen for it.

He said he didn’t know anybody that was doing really good outreach, adding that the institute tried to form outreach partnerships with local organizations and clinics, but it was “very, very unsuccessful.”

The American Red Cross and the institute are the largest blood research entities in the country and the only blood banks studying the infection. Custer said the Blood Systems Research Institute is in an ongoing study of the parasite in Brazil, because little data exists on how Chagas disease progresses after initial infection.

“We really don’t know how it’s contributing to the overall burden of heart disease in the United States,” Custer said.

Rare cases of transmission have occurred in this country. However, infection is closely associated with substandard housing – the benchuca likes crevices that exist in thatched housing – and the vast majority of infections are linked to time spent in certain rural areas of Latin America.

Areas of Argentina have some of the highest prevalence of infection, yet “the likelihood of someone in Buenos Aires having T. cruzi is about the same as someone in San Francisco having the infection,” Custer cautioned.

It’s a disease, like many, with a long tail and may have felled one of the most famous scientists of all.

Charles Darwin wrote about being bitten by a benchuca and suffered from a mysterious illness his whole life. He died from heart failure, and some believe he may have had Chagas.

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Pharmatek Laboratories Receives DEA Registration for Handling Controlled Substances

Last Updated on Wednesday, 12 May 2010 02:35 Written by Editor Wednesday, 12 May 2010 02:35

Pharmatek Expands its Capabilities in Providing Comprehensive Drug Development and Manufacturing Services
SAN DIEGO, Feb. 17 /PRNewswire/ — Pharmatek Laboratories, Inc., a premier contract development and manufacturing organization supporting the pharmaceutical industry, announced that it has successfully met Drug Enforcement Agency (DEA) requirements to be registered for the development and manufacture of Schedule IV and V controlled substances.”Based on the needs of our clients, Pharmatek has put significant systems in place for the handling, inventory, development and manufacture of controlled substances,” said Kevin Rosenthal, Director of Manufacturing.   “Being registered by the DEA validates our facility design, security systems, and procedures for manufacturing, handling, storage and disposal meet the stringent requirements of the DEA.”

Controlled substances are designated as Schedule I-V according to their medical use, potential for abuse and safety or dependence liability.  In order to research, manufacture or distribute a controlled substance, a person or entity must be audited and registered by the DEA.

“Our goal is to continue to strive to meet the needs of our existing and prospective clients by adding to our capabilities in pharmaceutical chemistry development and manufacturing,” said Timothy Scott, President at Pharmatek.  “As a client-centric organization, our success is predicated on our ability to serve our clients.  We are happy to bring this additional capability to Pharmatek in order to serve that purpose.”

About Pharmatek Laboratories, Inc.

Pharmatek Laboratories Inc. is a premier pharmaceutical chemistry development company providing full-service pharmaceutical chemistry product development for the pharmaceutical industry.  Pharmatek focuses on bringing client compounds from discovery to the clinic with services that include compound selection, analytical development, preformulation testing, formulation development, GMP manufacturing, stability storage and testing, and cytotoxic and high-potency development.

Statements contained in this media release which are not historical facts may constitute forward-looking statements.  All forward-looking statements are subject to risks and uncertainties which could cause actual results to differ from those projected including sales forecasts and strategic expansion.  The trademarks Pharmatek, Pharmatek Laboratories, Inc., Hot Rod Chemistry, Pharmatek Formulation Screening, Pharmatek University and PTEK U are all property of Pharmatek Laboratories, Inc.  Additional information about Pharmatek Laboratories may be obtained at the Web site http://www.pharmatek.com or by calling 858-805-6383.

source: fiercebiotech.com

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Nausea drug may treat heart disease

Last Updated on Wednesday, 12 May 2010 01:53 Written by Editor Wednesday, 12 May 2010 01:53

American scientists have identified new effects of drugs approved by Food and Drug Administration (FDA), which can help shift cellular energy metabolism and may even come useful in the treatment of cardiovascular disease.

The findings of the study team, led by Massachusetts General Hospital (MGH) researchers, have appeared in Nature Biotechnology . One of the key findings of the study was meclisine, a well-known nausea drug, may help treat heart disease and stroke. Initial studies in animals using meclisine, a drug commonly used to treat nausea and vertigo, have given favourable results in treating cardiovascular diseases and stroke. Vamsi Mootha of the MGH Center for Human Genetic Research, who led the study, said, ‘Shifts in cells’ energy production pathways take place naturally during development and in response to demanding activities – like sprinting versus long-distance running. They are also known to be involved in several disease states.

“We wanted to identify compounds that can safely induce this shift – those that have previously been discovered are too toxic – and investigate their therapeutic potential in animal models.” Usually cells convert nutrients into energy by relying on two cellular processes. One involves the uptake of sugars that are broken down in the cytoplasm into a molecule called lactate by a process called glycolysis, which quickly yields a small amount of ATP, the enzyme that provides cellular energy. Alternatively, sugars and proteins can be processed in cellular structures called mitochondria to release greater amounts of ATP through a more efficient process called cellular respiration.

In cancer cells and other rapidly proliferating cells, energy is produced predominantly by glycolysis, suggesting that a shift away from that mechanism might suppress tumour growth. Previous animal studies suggested that a reduction in mitochondrial respiration could mimic a process called ischemic preconditioning, in which brief episodes of ischemia – a reduction in blood flow – actually protect tissue against being damaged if its blood supply is later cut off completely.

To look for compounds that shift cells from respiration to glycolysis, Mootha’s team devised a unique screening strategy. The scientists cultured skin cells in two different nutrient environments – glucose, which provides energy through both glycolysis and respiration, or galactose, which forces cells to rely on mitochondrial respiration alone. A drug that redirects energy metabolism from respiration to glycolysis would stop growth in the galactose- cultured cells while having little effect on cells grown in glucose. Their initial screen of almost 3,700 compounds, including nearly half of all FDA-approved drugs, found several drugs known to inhibit cellular respiration on one end of the scale and several anti-cancer drugs that halt the growth of rapidly proliferating cells at the other, which verified the approach.

Because most agents known to mimic ischemic preconditioning in animal models are too toxic to use in human patients, the researchers were quite eager to find drugs that cause subtle metabolic shifts. The screen identified eight approved drugs that produced a less pronounced but still significant shift away from cellular respiration. One of those agents was meclisine.

To study meclisine’s potential to prevent tissue damage in heart attack or stroke, Mootha’s team joined hands with University of Rochester researchers who had developed rat models of heart attack damage and an MGH Pathology group with a mouse model of stroke damage. Blinded experiments using both animal models showed that pretreatment with meclisine dramatically reduced ischemic damage to cardiac cells in the heart attack model and to brain cells in the stroke model. They also discovered that meclisine’s ischemia protective effects do not appear to involve its known mechanisms.

While the study results suggest that treatment with drugs like meclisine may someday be useful for reducing the damage associated with heart attack or stroke, Mootha believes much additional study is needed. He said, “Before we can think about human studies, we need to do rigorous animal testing to determine optimal, safe dosing regimens and learn more about how this drug works.”
source: indiatimes.com

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Experimental drug shows some benefit for Huntington’s disease

Last Updated on Wednesday, 12 May 2010 01:32 Written by Editor Wednesday, 12 May 2010 01:32

An experimental drug call latrepirdine has produced a small improvement in the mental abilities of some patients with Huntington’s disease, a finding that sets the stage for a larger clinical trial. Although the improvement was modest, the study marks the first time that a drug has been shown to improve brain function in the disorder.

Huntington’s is one of the more common inherited brain disorders. About 25,000 Americans have it and an additional 60,000 carry the defective gene that causes it and will develop the disorder as they age. It strikes between age 30 and 50 and is characterized by jerky, involuntary movements called chorea; loss of control of bodily functions; and dementia, a progressive deterioration of memory and thought processes. The only drug formally approved for treatment of Huntington’s is tetrabenazine, which improves chorea but does nothing for mental faculties.

Latrepirdine was originally developed in Russia nearly three decades ago as a treatment for hay fever, but it is no longer sold anywhere. Russian researchers screening compounds for potential effects on the brain found that it appears to stabilize mitochondria, the power source of brain and other cells. Because of that activity, Medivation Inc. of San Francisco and Pfizer Inc, which purchased the rights to the drug, conducted a Phase 2 clinical trial of the drug in Alzheimer’s patients and found some benefit. A larger Phase 3 trial, required for Food and Drug Administration approval, is now under way and results are expected later this year.

They also began testing it against Huntington’s, which is marked by a deterioration of mitochondria in brain cells. In a Phase 2 trial, Dr. Kurt Kieburtz of the University of Rochester Medical Center and his colleagues studied the drug in 91 Huntington’s patients over a 90-day period. Half received the drug in three daily doses and half received a placebo. The study was primarily a safety trial and the researchers concluded that the drug posed no untoward risks: About 70% of patients receiving the drug reported adverse side effects, but so did 80% of those receiving a placebo.

The drug produced no benefits on motor function, but it did yield an improvement in a mental test called the Mini-Mental State Examination, in which patients answer questions about what year it is and where they are, count backward, and try to recall words they haver recently heard. Patients receiving the drug showed an average improvement of 0.86 point on the 30-point scale, while those on placebo showed an 0.12-point decline. Kieburtz said he was surprised to see the improvement because the exam is a relatively crude test of mental function.

The trial was sponsored by Medivation and Pfizer, which hope to market the drug under the brand name Dimebon. The company now has a larger trial of 350 Huntington’s patients in progress as a final step toward winning FDA approval.
source: latimesblogs.latimes.com

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Eiger BioPharmaceuticals Announces Identification of a Novel Class of HCV Inhibitors

Last Updated on Thursday, 6 May 2010 03:10 Written by Editor Thursday, 6 May 2010 03:10

PALO ALTO, Calif., Jan. 20, 2010 /PRNewswire/ — Eiger BioPharmaceuticals, Inc., a biotechnology company developing antiviral therapies, announced today the publication of research from the labs of Stanford scientist and Eiger Founder, Dr. Jeffrey Glenn, M.D., Ph.D. and colleagues entitled, “Identification of a Novel Class of HCV Inhibitors”.  Published in the January 20th edition of Science and Translational Medicine, the research validates a domain, termed 4BAH2, within the non-structural protein (NS4B) of the HCV genome, as essential for HCV replication and describes the development of a high-throughput screen leading to the identification of small molecule inhibitors of 4BAH2.

“The 4BAH2 is the second new domain within NS4B now proven necessary and essential for HCV replication, and which has been shown to be susceptible to pharmacologic inhibition.  Eiger is developing small molecule inhibitors of both NS4B-RNA binding and small molecule inhibitors of NS4B-AH2, each of which has significant activity alone and significant synergy when combined,” said David Cory, President and CEO of Eiger. “Inhibiting these NS4B functions represents an exciting new approach toward developing new classes of virus-specific agents to treat HCV.”

“The discovery of a new class of HCV inhibitors against a novel target that is described in this paper paves the way for the development of novel anti-HCV strategies. This is of particular benefit because, like AIDS and tuberculosis, future effective therapy for HCV is expected to require a cocktail of several independent classes of drugs, each designed against a different viral target.  As such, the types of inhibitors described in this paper represent ideal components of future anti-HCV drug cocktails,” said Jeffrey Glenn, M.D., Ph.D., Founder of Eiger.  ”I am particularly excited to be working with the Eiger team because they have proven their ability to rapidly develop potent derivatives of the initial compounds described in my lab, and to efficiently move leads to the clinic.”

About 4BAH2

Representing a second target of interest to Eiger within NS4B, 4BAH2 has been genetically-validated and consists of a conserved amphipathic helix (AH) essential for viral genome replication. 4BAH2 has a dramatic specific biochemical activity of promoting the aggregation of lipid vesicles, with likely relevance to the establishment of the membranous web, the site of HCV replication.  This biochemical activity was leveraged into a new high throughput screening assay for pharmacologic inhibitors of 4BAH2 function.  Analysis of these inhibitors reveals a mechanism of action involving inhibition of 4BAH2 induced vesicle aggregation.  Eiger has developed a next generation series of potent 4BAH2 inhibitors that are highly active as single agents against HCV, and highly synergistic when combined with the NS4B-RNA inhibitor, clemizole.

About Eiger BioPharmaceuticals, Inc. www.eigerbio.com

Eiger is focused on the discovery and development of new antiviral agents against novel targets for the treatment of hepatitis virus infections. Eiger’s pipeline includes repurposed clinical stage therapeutic agents as well as preclinical NCEs from discovery that exhibit antiviral activity against Hepatitis C, Hepatitis D, and other viruses. Eiger investors include InterWest Partners www.interwest.com and Vivo Ventures www.vivoventures.com.

source: prnewswire.com

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Fast Forward, Juvenile Diabetes Research Foundation and Axxam SpA Join Forces to Accelerate Development of Treatments for Multiple Sclerosis and Type 1 Diabetes

Last Updated on Thursday, 6 May 2010 02:46 Written by Editor Thursday, 6 May 2010 02:46

NEW YORK and MILAN, Italy, Jan. 19 /PRNewswire-USNewswire/ — Fast Forward, LLC, the commercial drug development arm of the National Multiple Sclerosis Society, and the Juvenile Diabetes Research Foundation (JDRF), the leader in research leading to a cure for type 1 diabetes in the world today announced a collaborative partnership with Axxam SpA — a leading company in conducting early-stage discovery research programs for the life science industry — to develop new treatments for two autoimmune diseases, multiple sclerosis (MS) and type 1 diabetes (T1D).

Under the terms of the agreement, Axxam will screen its extensive chemical library to identify compounds that can target specific ion channels in the immune system. Ion channels are tiny pores on the surface of immune cells that control the influx of charged particles and allow the cells to become activated to perform their natural surveillance and protection functions.  Recent studies have found that immune cells in MS and T1D contain high levels of a specific ion channel, Kv1.3, and that the hyperactivity of this channel contributes to the dysfunction of the immune system in MS and T1D.  If the initial research is successful, Axxam will have identified compounds that modulate Kv1.3 ion channel activities, and these will be further developed by the company as potential therapies for MS and T1D.

The agreement with Axxam is the first of its kind between cross-disciplinary patient advocacy organizations and represents a new frontier in which groups such as JDRF and Fast Forward ally to lessen the risk of drug discovery and accelerate the development of new therapies that can impact multi-disorders.  ”We are pleased to partner with Axxam and JDRF to advance the development of new treatments for T1D and MS,” said Dr. Timothy Coetzee, President of Fast Forward.  Adds Dr. Coetzee, “People with MS and T1D need more treatment options and the approach taken by Axxam holds great promise for both diseases.”

“Our partnership with Fast Forward and Axxam opens exciting new avenues for JDRF to speed the translation of basic research into drugs and treatments for type 1 diabetes,” said Alan J. Lewis, PhD, President and Chief Executive Officer of JDRF.  “Research into the Kv1.3 ion channel has the potential to negate the autoimmune process causing type 1 diabetes and multiple sclerosis, which must be addressed to cure these diseases.”

“It’s rewarding for Axxam to be working with two world class non-profits dedicated to speeding new therapies to their constituencies,” said  Dr. Stefan Lohmer, Ph.D., Chairman and Chief Executive Officer of Axxam. “This collaboration recognizes the quality of our research in the challenging ion channels field and we hope to be on the cusp for developing potential new therapies for both type 1 diabetes and multiple sclerosis.”

About JDRF:

JDRF is the worldwide leader for research to cure type 1 diabetes.  It sets the global agenda for diabetes research, and is the largest charitable funder and advocate of diabetes science worldwide.

The mission of JDRF is to find a cure for diabetes and its complications through the support of research.  Type 1 diabetes is an autoimmune disease that strikes children and adults suddenly, and can be fatal.  Until a cure is found, people with type 1 diabetes have to test their blood sugar and give themselves insulin injections multiple times or use a pump — each day, every day of their lives.  And even with that intensive care, insulin is not a cure for diabetes, nor does it prevent its eventual and devastating complications, which may include kidney failure, blindness, heart disease, stroke, and amputation.

Since its founding in 1970 by parents of children with type 1 diabetes, JDRF has awarded more than $1.4 billion to diabetes research, including $101 million in FY2009.  In FY2009, JDRF funded research projects in 22 countries throughout the world, including more than 40 human clinical trials.

About Fast Forward, LLC

Fast Forward, LLC is a nonprofit organization and critical initiative established by the National Multiple Sclerosis Society in order to accelerate the development of treatments for MS. Fast Forward will accomplish its mission by connecting university-based MS research with private-sector drug development and by funding small biotechnology/pharmaceutical companies to develop innovative new MS therapies and repurpose FDA-approved drugs as new treatments for MS. For more information visit: www.fastforward.org

About MS and the National Multiple Sclerosis Society

MS is a chronic, unpredictable neurological disease that affects the central nervous system. It is thought to be an autoimmune disorder, meaning the immune system incorrectly attacks healthy tissue. Symptoms may be mild, such as numbness in the limbs, or severe, such as paralysis or loss of vision. These problems may be permanent or may come and go. The National MS Society addresses the challenges of each person affected by MS by funding cutting-edge research, driving change through advocacy, facilitating professional education, collaborating with MS organizations around the world, and providing programs and services designed to help people with MS and their families move their lives forward. The Society is dedicated to achieving a world free of MS. Join the movement at  www.nationalMSsociety.org

About Axxam SpA

Axxam is a discovery company focused on research programs for different applications in the life science industry.  They are a privately owned biotech firm based at the San Raffaele Biomedical Science Park in Milan (Italy), with a team of about 60 highly skilled qualified people. Axxam began operations as an independent and privately owned company in November 2001, but its roots are built upon years of experience as part of the Bayer HealthCare, Research and Development organization.  The company performs a wide range of activities including assay development, high-throughput screening, compound profiling and hits to leads testing. In addition, Axxam conducts several discovery programs for selected targets which are carried out in partnership with other companies or non-profit organizations. For more information, please visit  www.axxam.com.

SOURCE Juvenile Diabetes Research Foundation

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Compounds that help protect nerve cells discovered by Duke team

Last Updated on Thursday, 6 May 2010 02:45 Written by Editor Thursday, 6 May 2010 02:45

DURHAM, N.C. – Scientists at Duke University Medical Center have found some compounds that improve a cell’s ability to properly “fold” proteins and could lead to promising drugs for degenerative nerve diseases, including Huntington’s disease, Alzheimer’s disease and Parkinson’s disease.

Misfolded proteins in nerve cells (neurons) are a common factor in all of these diseases. The Duke team has identified many new chemicals that activate a master regulator to increase the supply of “protein chaperone” molecules that help fold proteins properly.

The scientists further explored one of the candidate molecules to activate the master regulator of chaperone gene expression, Heat Shock Factor 1 (HSF1), to learn whether it would work in model systems of Huntington’s disease, a devastating neurodegenerative disease of protein misfolding.

They were able to show that the molecule stimulated protein chaperones in cells and in an animal system. The damage to early-state rat neurons was much lower in cells pre-treated with the HSF1 activator, and damage to the neurons of fruit flies that had a Huntington’s-like disorder was also greatly reduced.

Previous studies suggested that elevating the abundance of protein chaperones is effective in treating cell and animal models of Huntington’s and Parkinson’s diseases. This work provides a new approach to address the root cause of these diseases — protein misfolding. Earlier attempts had used heat shock and other approaches that stress a nerve cell in order to produce more chaperone molecules, but at a cost of damaging the cell to save it.

“The advantage of our screen is that it identifies molecules that can elevate the levels of chaperones without inducing cellular stress and that don’t inhibit a key protein chaperone called Hsp90 that is needed for cells to function normally,” said senior author Dennis J. Thiele, Ph.D., Professor of Pharmacology and Cancer Biology. “We found a creative way to identify new molecules that can activate the body’s natural protein folding machinery.”

The research was published in the Jan. 19 online issue of PLoS Biology.

Lead author Daniel Neef, Ph.D., says they used genetically altered yeast to find compounds that might aid chaperone development. The scientists took yeast with a deleted HSF1 (master regulator) gene and inserted the related human HSF1 gene. These yeast, however, still weren’t able to activate human HSF1 on their own, and in effect, died. They needed an additional molecule to make human HSF1 become active.

The team put these “humanized yeasts” into wells and started testing compounds that would provide the missing link. In several of the wells, if the compound worked, the yeast started multiplying. “Out of over 12,000 compounds tested from chemical libraries, about 50 compounds worked,” Neef said. The team decided to explore one of these compounds (HSF1A) in further experiments.

“The humanized yeast-based screening results in our study provide a way to identify new classes of small molecules, small enough to penetrate the blood-brain barrier to work in neurons, in flies as well as in humans,” Thiele said. “These small molecules may be effective therapies in neurodegenerative diseases caused by protein conformational disorders such as Huntington’s, Alzheimer’s and Parkinson’s disease.”

The scientists found that HSF1A could stimulate more protein chaperones and reduce the protein misfolding. They showed that adding a small amount of HSF1A to the developing rat neurons kept the proteins dissolved throughout the cell, rather than clumping visibly as speckled areas (as seen under microscopes).

“We enhanced the cells’ viability by four or five times by pre-treating them with this molecule,” Neef said. “Otherwise, the cells would have died.”

They used fruit flies with Huntington’s disease for experiments to prove that the principle would work in an animal. Adding HSF1A to the fly’s food produced more chaperone molecules in their neurons. This suggests that the molecule could travel from the fly’s stomach into its circulation and cross a barrier to the fly brain.

In the key experiment, the Huntington’s disease flies received either their usual food or food plus HSF1A. Those with untreated food developed eyes with dying photoreceptor neurons and lacking the normal red color. Those that ate HSF1A went on to have normal-colored eyes, indicating a repair had taken place, just by eating food laced with the promising compound.

source: eurekalert.org

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Open access drug discovery database launches with half a million compounds

Last Updated on Thursday, 6 May 2010 01:48 Written by Editor Thursday, 6 May 2010 01:48

Drug delivery capsules

ChEMBLdb, a vast online database of information on the properties and activities of drugs and drug-like small molecules and their targets, launches today with information on over half a million compounds. The data lie at the heart of translating information from the human genome into successful new drugs in the clinic.

The database is hosted by the European Molecular Biology Laboratory’s European Bioinformatics Institute (EMBL-EBI). It was transferred from biotech firm Galapagos NV in July 2008 through a £4.7 million Strategic Award from the Wellcome Trust.

ChEMBLdb is a unique resource because of its focus on drug discovery and its size: information on an additional 100 000 compounds has been added to the database for its launch, taking the number of small molecules to over 520 000, and it now contains over 2.4 million records of their effects on biological systems. The data include information about how small molecules bind to their targets, how these compounds affect cells and whole organisms, and information on the molecules’ absorption, distribution, metabolism, excretion and toxicity.

Dr John Overington, leader of the ChEMBL team at EMBL-EBI, said: “We hope ChEMBLdb will assist the translation of genomic-based insights into innovative drug therapies. We are pleased that there has already been big demand for ChEMBLdb data – not only from large pharmaceutical companies but also from academic institutions and small companies who will particularly benefit from free access to the data.”

The human genome sequence provided a molecular ‘parts list’ for a human being, comprising all the genes and proteins that are encoded by our genetic blueprint. In order to develop new medicines, it is important to catalogue how each of these ‘parts’ interacts with drugs and drug-like molecules. ChEMBLdb brings together information from the interface of the genome with chemistry into a set of ‘chemogenomic’ databases that can be used to help determine whether a particular molecule has the right properties to make an effective drug.

Professor Janet Thornton, Director of EMBL-EBI, said: “We are delighted to augment the biological data archived and served from EMBL-EBI with the ChEMBLdb resource. The database adds an important new capability to address the needs of the pharmaceutical and biotechnology industries, and provide the academic chemical biology communities with previously inaccessible data.”

Dr Alan Schafer, Director of Science Funding at the Wellcome Trust, said: “This unprecedented transfer of pharmaceutical data resources from the private sector to the public domain should have the greatest impact on researchers in academia and in small companies on limited budgets. ChEMBLdb will be a major resource of information for driving forward medicinal chemistry and drug development in the UK and internationally.”

The launch of ChEMBLdb is accompanied by the release of Kinase SARfari, an integrated resource of sequence, compound and screening data from a variety of sources for the protein kinases, a key family for drug discovery.

Image: Drug delivery capsules. Credit: Anna Tanczos, Wellcome Images

Contact

Craig Brierley
Senior Media Officer
Wellcome Trust
T +44 (0)20 7611 7329
E c.brierley@wellcome.ac.uk

Louisa Wright
Outreach Programme Project Leader
EMBL-EBI
T +44 (0)1223 494665
E louisa@ebi.ac.uk

Katrina Pavelin
Scientific Outreach Officer
EMBL-EBI
T +44 (0)1223 494452
E katrina@ebi.ac.uk

source; wellcome.ac.uk

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Kansas studies plants’ medicinal values

Last Updated on Thursday, 6 May 2010 11:55 Written by Editor Thursday, 6 May 2010 11:55

The snow on the ground keeps Lauren Ashman inside entering data about native plant species instead of out in the field. This is the dirty work of the $5 million Native Medicinal Plant Research Program.

Along with data entry, Ashman, junior from St. Louis, Mo., works on drying and putting the 10- to 20-pound bags of plant species in alphabetical order. Only then are they ready to go to the High Throughput Screening Lab at the Structural Biology Center on West Campus.

The project started Nov. 11, 2009, when two faculty members at the University received money from Heartland Plant Innovations, Inc., to study plants in the Kansas area. The Heartland Plant Innovations, Inc., branches from the Kansas Bioscience Authority, a center aimed at advancing Kansas’ leadership in bioscience.

Barbara Timmermann, a university distinguished professor in the Medicinal Chemistry Department, and Kelly Kindscher, associate scientist at the Kansas Biological Survey, will lead the research during the next five years.

In that time, the goal of the research is to gain credible findings and data on the local plants so various food and drug industries can understand the plants’ capabilities.

“There is a big interest in bringing business to Kansas,” Kindscher said. “The findings of this project could bring in herbal product to cosmetic or pet food companies.”

Hayley Kilroy, graduate student from Cleveland, Ohio, said Native Americans and pioneers once used the native plants for medicinal purposes. Now that the University is looking at the plants for those uses again, it will help conserve the biodiversity of Kansas.

“Conservation is important,” Kilroy said, “but when you can make money through conserving, there is a lot more incentive for it.”

The researchers face a long process of identifying, collecting and studying the plants for their medicinal uses and effectiveness. Kindscher and Timmermann said they were looking at hiring up to 12 new employees to handle maps, data and research.

Kindscher and students collected plants this summer from Douglas County and several areas of Western Kansas. The plants now sit in a lab waiting to be dried and cataloged.

“We go out in teams and gather all our plant material,” Kindscher said. “I love the field work.”

In previous years, Kindscher and others collected plants for the main purpose of researching and replanting native prairie. But the grant has narrowed their focus to the medicinal uses of specific plants.

Quinn Long, doctoral student from Franklin County, Mo., said the team would collect multiple samples from different areas for each species. Then they can study how differences in location change what chemical compounds are present in a plant. Long said different stresses, such as drought, could increase medicinal compound.

Because the program started in late fall, Timmermann’s lab doesn’t have as many samples to study. However, that will change as spring arrives and more plants can be collected.

“It would be great if we found the next best cure,” Kindscher said. “But we are not directly focusing on that or the money.”

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Sleep with the Fishes Zebrafish larvae are a surprisingly compatible stand-in for humans as researchers test the next generation of insomnia drugs.

Last Updated on Thursday, 6 May 2010 11:44 Written by Editor Thursday, 6 May 2010 11:44

There’s a new guinea pig in the search for sleep-related drugs: the zebrafish. Researchers at Harvard University have developed a screening tool that tests the effects of thousands of compounds on zebrafish behavior in an effort to discover new pathways that govern sleep. The research, published this week in the journal Science, may result in new drugs to treat insomnia and other sleep-related disorders.

Sleepy head: Harvard scientists are using zebrafish as a model to find drug candidates for insomnia and other sleep disorders. Pictured above is the head portion of a zebrafish larva. The zebrafish brain is labeled in green.
Credit: Albert Pan and Alexander Schier

Alexander Schier and his colleagues at Harvard developed an automated system to assess 60,000 distinct sleep-related behaviors in zebrafish, a tropical fish often used in scientific research. After screening 5,600 small molecules on the larvae, the team discovered 463 significant sleep-altering compounds, many of which have been known to have similar effects in humans.

“We didn’t expect as much conservation of the effects of drugs between humans and zebrafish,” says Schier, professor of molecular and cellular biology. “This was a proof of principle that many of the pathways found in humans are conserved in fish.”

Schier says such behavioral similarities may make zebrafish an ideal model for studying how and why humans sleep, mysteries that are largely unsolved. It’s still unclear what molecular mechanisms control sleep and wakefulness. Pinpointing these pathways, and finding drugs to block or promote them, is a major focus for many pharmaceutical companies–sleep drugs generate $7 billion in annual profits in the United States. However, the drug development process is tedious and expensive. Schier believes that testing drug candidates in zebrafish could be a cheap and straightforward alternative to conventional drug screening.

Typically, to test a drug, researchers first study its effects in cultured cells, looking to see if the drug binds successfully to a target receptor or molecule. They then advance the drug to animal experiments, testing behavioral effects in live subjects. But drugs that have certain effects in cultured cells often have unexpected side effects–or no effect–in a live animal.

“The advantage of zebrafish is that you can keep large numbers of animals in a very small space, and raise many, many animals relatively cheaply,” says Schier. Unlike flies and worms, which are often used in the early stages of pharmaceutical research, fish are vertebrates. “Much can be found in zebrafish that is relevant to mammals,” he says.
To screen the drugs, researchers pipetted single zebrafish larvae into a tiny well of a 96-well tray. Each well was injected with a drug, with one drug tested on 10 different larvae. They placed the tray in a recording chamber with infrared and white LED lights and a camera connected to computer software. After lining the tray up with a corresponding grid on the computer screen, researchers programmed the timing of light to simulate day and night. The camera recorded each fish’s activity over two days, and video tracking software plotted out each fish’s movements per second.

Z’s for zebrafish: Zebrafish larvae (above) are naturally transparent. Scientists hope to one day study the effects of sleep drugs on the brain and spinal cord, which can be seen in the image above as a long white structure stretching left to right.
Credit: Albert Pan and Alexander Schier

Using clustering algorithms, Schier and his colleagues grouped fish into 60,000 distinct behavioral profiles, depending on various constraints. “When you turn off the light, how often are they active? When they are inactive, how long? That’s what we observe in the fish,” says Schier. “You can measure many different parameters, and that allows you to profile different drugs.”

Anti-inflammatories, such as cytokines, nonsteroidal anti-inflammatory drugs, and cyclosporine, had a surprising effect. Normally, these drugs induce sleep when taken to combat infection such as the flu. However, Schier found that when given to normal, healthy zebrafish, these compounds, or immunomodulators, made fish more active during the day.

“In disease, immunomodulators have been implicated in sleep,” says Schier. “We propose that maybe there’s some baseline function for these immunomodulators during normal sleep and wake cycles.”

Such findings could help researchers identify new molecular players involved in sleep and wakefulness. Irina Zhdanova, associate professor of anatomy and neurobiology at Boston University Medical School, studies the physiological mechanisms of circadian rhythms and sleep in zebrafish. Zhdanova says there are many sleep-related drugs on the market with substantial side effects; these effects might be avoided with better screening tools.

“The huge scope of drugs tested [by Schier's group] shows that zebrafish-based tests can be effectively used to at least prescreen multiple classes of existing drugs and new candidate substances,” says Zhdanova. “[That is] certainly very helpful.”

In the future, Schier says, zebrafish could also be used as a model for testing drugs for human psychiatric diseases like schizophrenia and autism. The idea is to identify genes associated with the human disease, and try to engineer the same genetic defect in zebrafish. Researchers could then look for certain behavioral changes as a result, such as a fish’s sensitivity to touch, or its reaction to visual cues.

“Hopefully there would be a connection between the gene affected, and change in behavior, and one would try to correct the change in behavior by adding particular drugs,” says Schier. “That’s a bit science fiction at the moment, but it is possible.”

source:technologyreview.com

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Hunt for Dioxin Substitutes to Fight Autoimmune Diseases

Last Updated on Thursday, 6 May 2010 11:41 Written by Editor Thursday, 6 May 2010 11:41

(HealthNewsDigest.com) – CORVALLIS, Ore. – Scientists at Oregon State University are hunting for substitute chemicals for a toxic dioxin to fight diseases that are triggered by haywire immune systems attacking the body.

The dioxin, known as TCDD, has been shown to suppress the immune system in animals and prevent type 1 diabetes in mice. OSU researchers hypothesize that it could do the same in people. But they aren’t considering it as a treatment because it has produced bad side effects in animals and can cause chloracne, a disfiguring skin disease in humans.

Instead, they’re looking for safer alternatives that would function like TCDD, which is perhaps best-known for its presence in the jungle-decimating Agent Orange herbicide used during the Vietnam War.

If successful, the chemicals might be able to prevent and treat autoimmune diseases like rheumatoid arthritis, multiple sclerosis, psoriasis and type 1 diabetes.

“Immunosuppressive drugs are already used to treat these diseases, but they can create their own problems,” said Nancy Kerkvliet, an OSU immunotoxicologist who is helping conduct the research. “Consequently, the new way of thinking is to use a mixture of drugs at lower doses to reduce the side effects caused by higher dosages of individual drugs. Through our research, we’re hoping to discover new drugs that will expand the choices of drugs that can be used.”

To help with that effort, the American Recovery and Reinvestment Act of 2009 provided Kerkvliet and her team with $1.8 million.

Kerkvliet has been studying dioxins for three decades. She published a paper last year in the journal Immunotherapy that showed that in mice TCDD can prevent type 1 diabetes, which occurs when the immune system attacks the pancreas and kills the cells that produce insulin. The mice used in the study develop type 1 diabetes spontaneously because of genetic defects in their immune system. However, of the 12 mice that were treated with TCDD, none developed the disease. Eight of the 11 mice that weren’t treated with it developed diabetes by 28 weeks of age.

Kerkvliet said that TCDD’s effect on the immune system of mice works like this: First, it binds to a protein called the aryl hydrocarbon receptor (AhR) found inside a cell. The united TCDD and AhR then pass into the nucleus, latch onto DNA and turn certain genes on or off. Kerkvliet’s research suggests that this process produces regulatory T cells, which then shut down the immune system’s response. This then suppresses the development of diabetes, she said.

To help her find alternatives for TCDD, cancer biologist Siva Kolluri and his crew are screening 50,000 chemical compounds in search of ones that will bind to AhR and induce regulatory T cells. So far, they’ve tested about 5,000 in cell-based assays for their ability to activate AhR, Kolluri said.

“There have been some promising hits,” he said. “We need to make sure that they work only through this receptor. We also have to make sure they’re not toxic. We don’t want them to have any of the bad effects that TCDD has.”

Later, Kerkvliet and her team will test the compounds in mice to see if they prevent type 1 diabetes. If they do, Kerkvliet believes that it would be likely that they would also fight other autoimmune diseases because most of these diseases are also controlled by regulatory T cells. Of course, any chemicals that are successful in treating laboratory animals would eventually have to be studied in humans to see if the effects are the same.

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Science & Health > Chemistry > Zebrafish point the way Screening method finds new roles for drugs in sleeping, waking

Last Updated on Thursday, 6 May 2010 11:33 Written by Editor Thursday, 6 May 2010 11:33

A robust new technique for screening drugs’ effects on zebrafish behavior is pointing Harvard University scientists toward unexpected compounds and pathways that may govern sleep and wakefulness in humans.Among the scientists’ more intriguing findings, described in the journal Science, are that various anti-inflammatory agents in the immune system, long known to induce sleep during infection, may also shape normal sleep/wake cycles.

The new research identifies several compounds with surprising effects on sleep and wakefulness in zebrafish. But it also suggests that despite the evolutionary gap between zebrafish and mammals, they may be strikingly similar in the neurochemistry underlying their rest/wake cycles, meaning that these same compounds may prove effective in people.

“Many current drug discovery efforts rely on screening conducted outside the body,” said Alexander F. Schier, professor of molecular and cellular biology at Harvard. “Although such screens can be successful, they cannot recreate the complex neuroscience of entire organisms. These limitations are particularly acute for behavior-altering drugs, because brain activity cannot be modeled in a Petri dish or test tube.”

Together with postdoctoral fellows Jason Rihel and David Prober, Schier and other collaborators used their automated screening technique to monitor sleep and wakefulness in zebrafish for two days following administration of 5,600 compounds, creating more than 60,000 distinct behavioral profiles. By applying clustering algorithms to organize the molecules, the researchers identified 463 drug candidates that significantly altered rest and wakefulness, many of which had not previously been known to have such effects.

“For instance, we found that a diverse set of anti-inflammatory compounds increased wakefulness during the day, with much less effect at night,” Schier said. “Although these compounds have long been known to promote sleep during infection, this is an indication that the molecules that regulate the immune system may also play a role in setting normal daytime activity levels.”

Anti-inflammatory agents found to affect sleep/wake cycles included cytokines, nonsteroidal anti-inflammatory drugs, and the immunosuppressant cyclosporine. Schier and colleagues also found calcium channel inhibitors that increased rest with minimal effects on waking behavior and a class of potassium channel blockers found in a wide variety of drugs — including antimalarials, antipsychotics, and antihistamines — that selectively increased wakefulness at night without affecting total rest.

“Behavioral profiling reveals nuanced relationships between drugs and their targets,” Schier said. “It can characterize large classes of compounds and reveal differences in effectiveness, potential side effects, and combinatorial properties that might not otherwise be detected.”

Schier and his colleagues plan to expand their zebrafish screening to include many more uncharacterized compounds and to assay behaviors that, in humans, are associated with psychiatric disorders.

Schier’s co-authors on the Science paper are Jason Rihel, David A. Prober, Anthony Arvanites, Kelvin Lam, Steven Zimmerman, Sumin Jang, and Lee L. Rubin, all at Harvard; Stephen J. Haggerty of the Broad Institute of Harvard and MIT and Massachusetts General Hospital (MGH); David Kokel of MGH; and Randall T. Peterson of the Broad Institute, MGH, and Harvard Medical School.

The work was funded by the Life Sciences Research Foundation, the Helen Hay Whitney Foundation, the National Institutes of Health, the Stanley Medical Research Institute, the Harvard Stem Cell Institute, and the McKnight Endowment Fund for Neuroscience.

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Scripps Researchers Identify Novel Hepatitis C Inhibitors Drug Discovery & Development – December 21, 2009

Last Updated on Wednesday, 5 May 2010 12:49 Written by Editor Wednesday, 5 May 2010 12:49

Scientists from the Scripps Florida campus of The Scripps Research Institute and their colleagues at Boston University have described their discovery of several novel drug-like inhibitors of the hepatitis C virus (HCV). These new inhibitors have the potential to substantially widen the current options to treat HCV infection.

The research, from the laboratory of Professor Donny Strosberg, Ph.D., of Scripps Florida, supported by members of the Scripps Florida Lead Discovery Division directed by Peter Hodder, Ph.D., and colleagues from Boston University, was published in the December 2009 edition of the journal ASSAY and Drug Development Technologies and appears in the December 15, 2009 print edition of the journal Bioorganic & Medicinal Chemistry Letters.

With more than 130 million people infected worldwide by HCV, new therapeutic strategies are urgently needed for this blood-borne disease, which is the main cause, with hepatitis B, of liver cancer, according to the National Cancer Institute.

Using a new fluorescence-based assay, the scientists were able to identify four small-molecule inhibitors of dimerization of the viral core protein. In this process, which is essential to the survival of the virus, the core protein binds to itself and related proteins to form the viral capsid, the outer lipid-encapsulated protein shell that protects the virus’s genetic material like an eggshell protects its yolk sack.

“The fact that is so exciting is that no one has really considered the core protein as a viable target in HCV—in HIV, yes, but not HCV,” said Strosberg. “With this study, there is now no good reason why researchers shouldn’t go after the HCV core protein.”

One of the problems in developing drugs for HCV is that it mutates at such prodigious rates; mutations in viral enzymes tend to lead to increased drug resistance.

By targeting the interactions of the core protein with itself and with other proteins, Strosberg and his colleagues have sought to reduce the problem of rapid mutation—because the core protein mutates much less than the other HCV proteins, and because mutations that affect the interface between core and itself or other proteins would be more likely to deactivate the virus anyway. Core proteins orchestrate the assembly and release of the infectious virus, as well as the disassembly of viral particles upon entering host cells.

Significantly, the new compounds not only inhibited dimerization of the core but also inhibited propagation of HCV in isolated hepatoma cells.

The New Assay
In a study that appeared in the Journal of General Virology earlier this year, Strosberg and his colleague described how peptides (molecules of two or more amino acids that are the building blocks of proteins) derived from the HCV core protein also inhibited its dimerization. Peptides however, are difficult to administer orally, unstable in the blood circulation, and are therefore difficult to use therapeutically.

The new assay goes one step further, allowing Strosberg and his colleagues to identify the three times smaller molecules with potential to interfere with the core protein function in the virus.

“While there is no similarity structurally between these new small molecule inhibitors and the peptides, functionally they behave precisely the same way,” Strosberg said. “We developed an assay to screen small molecules that is robust and capable of revealing useful compounds that block protein-protein interactions and production of the virus.”

Protein-protein interactions, which involve such key physiological actions as signal transduction and protein assembly, are highly desirable drug discovery targets, not only for HCV, but also for other viral infections because inhibitors of these protein associations have been shown to lack many clinical complications, such as the adverse side effects of recombinant therapeutic proteins. However, designing small molecules that inhibit protein-protein interaction remains problematic for a number of reasons, primarily because proteins are so large—interactions are thought to often take place over a wide area and conformation/site-selectivity is difficult to engineer.

“We always look for the simplest solution,” Strosberg said. “We knew from our peptide study that we could split the core protein and use only one part that we knew still allowed the dimerization process. That simplified the process because the core protein is sometimes difficult to work with.”

Next, Strosberg and his team uncovered a domain on the core protein—what they call “a hot spot”—that was essential for the interaction that creates the capsid and allows the virus to function.

“Since we had already established a proof-of-concept that certain peptides could disrupt capsid formation, we left the peptide world and moved into the small-molecule world,” he said. “We developed the high-throughput version of the assay. That’s what the industry always wants to know first—can you move from a peptide to a small-molecule and can you find inhibitors among screen large collections?”

From there, the team screened small-molecule compounds that could potentially disrupt the protein-protein gears that create the viral capsid, using the protein library and high-throughput screening technology available at Scripps Florida. For initial screening, Strosberg and his colleagues used a relatively small library containing nearly 2,250 indoline alkaloid-type compounds, produced by their colleagues at Boston University.

These studies revealed the four promising compounds described in the study.

“These new compounds definitely put us closer to the ‘El Dorado’ of finding viable protein-protein inhibitors for HCV,” said Strosberg.

The small molecule inhibitor study made clear that three of the newly discovered inhibitors are relatively non-toxic compounds that could be the basis for the development of new anti-HCV drugs or could be used in combination with other compounds such as interferon on HCV targets other than the virus’s core protein.

“These small-molecule candidates are quite promising,” Strosberg said. “We continue to study the binding of these compounds with the HCV core protein and hope to design even more potent inhibitors based on their structures.”

The first author of the ASSAY and Drug Development Technologies study, “A Time-Resolved Fluorescence-Resonance Energy Transfer Assay for Identifying Inhibitors of Hepatitis C Virus Core Dimerization,” is Smitha Kota of The Scripps Research Institute. In addition to Strosberg, others authors include, Louis Scampavia, Timothy Spicer, Virginia Takahashi, and Peter Hodder of The Scripps Research Institute, and Aaron Beeler, John Snyder and John Porco of The Center for Chemical Methodology and Library Development, Boston University. See http://www.liebertonline.com/adt.

Date: December 16, 2009
Source: The Scripps Research Institute

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Ambit Biosciences and Astellas Enter Strategic Partnership to Research, Develop and Commercialize FLT3 Kinase Inhibitors in Multiple Indications

Last Updated on Wednesday, 5 May 2010 11:46 Written by Editor Wednesday, 5 May 2010 11:46

Ambit to Receive a US$40 Million Upfront Cash Payment; Up to US$350 Million in Pre-Commercialization Milestones, Double-Digit Royalties with Option to Co-promote and Share Profits in U.S.

SAN DIEGO and TOKYO, December 18 – Ambit Biosciences Corporation and Astellas Pharma Inc. today announced
that they have entered into a worldwide agreement to jointly develop and
commercialize FLT3 kinase inhibitors in oncology and non-oncology
indications. This partnership includes AC220, Ambit’s lead clinical-stage
investigational drug that entered into a Phase 2 clinical trial earlier this
month in relapsed/refractory acute myeloid leukemia (AML), and other
undisclosed FLT3 kinase inhibitors. AC220 is a novel, orally available,
potent and highly selective small molecule that was specifically designed as
a second generation FMS-like tyrosine kinase-3 (FLT3) inhibitor using Ambit’s
proprietary drug discovery engine, KINOMEscan(TM).

The companies will collaborate to develop AC220 for AML and other
indications. The parties will also collaborate on a research and development
program for a series of novel FLT3 inhibitors for a variety of oncology and
non-oncology indications. The companies will share equally in the
responsibilities and expenses for the development of AC220 and any additional
products in the U.S. and Europe, while Astellas will have sole responsibility
to fund development in all other territories. Under the terms of the
agreement, Ambit will receive an up-front cash payment of US$40 million and
will be eligible to receive pre-commercialization payments of up to US$350
million.

Astellas will have sole responsibility for funding and implementing the
commercialization of all products, and Ambit will be entitled to
post-approval milestone payments upon the achievement of certain sales
thresholds, as well as tiered double-digit royalties on net sales. In the
U.S., Ambit will also have the option to co-promote AC220 and other products
under a profit sharing arrangement where Astellas and Ambit share equally in
profits and losses generated from U.S. sales.

“We are pleased to have entered into a great partnership with Ambit,”
stated Masafumi Nogimori, president and chief executive officer of Astellas.
“We believe that AC220, as the most selective and advanced FLT3 kinase
inhibitor, has the potential to provide a new treatment option for AML where
high unmet medical needs exist. Astellas is strongly committed to focus on
oncology and this partnership is a significant milestone to establish our
franchise in oncology.”

“With their strategic commitment to the development and commercialization
of innovative oncology products, Astellas is an ideal partner for Ambit,”
said Scott Salka, Chief Executive Officer of Ambit Biosciences. “This
collaboration establishes a comprehensive and global leadership position in
the discovery and development of FLT3 kinase inhibitors, and we look forward
to working closely with Astellas to explore the clinical utility of AC220 in
AML and other indications.”

About AC220

AC220, Ambit’s lead product candidate, is being developed in
collaboration with Astellas Pharma Inc. and is a novel, potent, highly
selective, orally bioavailable second-generation FLT3 inhibitor. AC220 is
currently under evaluation in a Phase 2 clinical trial designed to support
potential registration of AC220 as monotherapy treatment in adult and elderly
patients with relapsed/refractory AML that have the internal tandem
duplication (ITD) mutation in the FLT3 kinase. AML is one of the most common
types of blood cancers in adults, and the FLT3 kinase is mutated and
constitutively activated in 25-40 percent of such patients. FLT3 ITD
mutations predict poor prognosis and decreased response to existing
treatments, including chemotherapy and hematopoietic stem cell transplant.
Ambit leveraged KINOMEscan(TM), the company’s proprietary, high-throughput
method for screening small molecule compounds against a large number of human
kinases, to advance AC220 from initial chemistry to clinical candidate
selection for IND-enabling studies in only 18 months.

About Acute Myeloid Leukemia (AML)

Acute myeloid leukemia is a form of blood cancer. According to the
American Cancer Society, approximately 13,000 new cases of AML will be
diagnosed in the United States in 2008. The median age of a patient with AML
is about 67 years. Standard treatment for patients 60 years or older with AML
includes systemic combination chemotherapy. The median survival for patients
receiving induction chemotherapy, which is associated with high mortality, is
6-11 months, with shorter survival for patients over the age of 60 years. The
five-year survival rate for AML is less than 15 percent. According to a
report from Decision Resources, the U.S. AML market is expected to more than
double by 2015.

About Ambit Biosciences

Ambit Biosciences is a privately-held biopharmaceutical company engaged
in the discovery and development of small molecule kinase inhibitors for the
treatment of cancer, inflammatory disease, and other indications. Ambit
employs a novel and proprietary kinase profiling technology, KINOMEscan(TM),
to screen compounds against 442 human kinases.

Ambit’s lead compound, AC220, is in clinical development for the
treatment of AML and other indications. Ambit has initiated a Phase 2 pivotal
trial in patients with relapsed or refractory AML and plans to commence
several other clinical studies with AC220 in 2010. Ambit’s clinical pipeline
also includes AC480, an oral pan-HER inhibitor that was in-licensed from BMS.
Ambit is conducting Phase 2 studies with AC480 in patients with solid tumor
cancers. Additionally, Ambit has an advancing pool of preclinical candidates
targeting BRAF (in collaboration with Cephalon), JAK2, Aurora, and CSF1R.
Through its KINOMEscan Division, Ambit markets its technology as a profiling
service. For more information, visit www.ambitbio.com.

About Astellas

Astellas Pharma Inc., located in Tokyo, Japan, is a pharmaceutical
company dedicated to improving the health of people around the world through
the provision of innovative and reliable pharmaceuticals. Astellas has
approximately 15,000 employees worldwide. The organization is committed to
becoming a global category leader in urology, immunology & infectious
diseases, neuroscience, DM complications & metabolic diseases and oncology.
For more information on Astellas Pharma Inc., please visit our website at
www.astellas.com/en.

Contact:
--------
Ambit Biosciences:                       Astellas Pharma:
------------------                       ----------------
M. Scott Salka                           Corporate Communications
+1-858-334-2101                          +81-(0)3-3244-3201
www.astellas.com/en/
Christopher Morl (business development)
+1-858-334-2134

Scott Lerman (media)
The Ruth Group
+1-646-536-7013
slerman@theruthgroup.com

Sara Pellegrino (investors)
The Ruth Group
+1-646-536-7002
spellegrino@theruthgroup.com
Source: blog.taragana.com

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Cellular Dynamics Announces Commercial Launch of iCell(TM) Cardiomyocytes for Drug Candidate Toxicity Screening

Last Updated on Wednesday, 5 May 2010 10:36 Written by Editor Wednesday, 5 May 2010 10:36

Human iCell Cardiomyocytes Provide Alternative to Non-human, Tumor-derived, and Cadaveric Cellular Model Systems to Better Predict Cardiac Toxicity

MADISON, Wis., Dec. 16 /PRNewswire/ — Cellular Dynamics International (CDI) today announced the commercial launch of iCell(TM) Cardiomyocytes for use in testing of new drug candidates by the pharmaceutical industry. These human heart cells are designed to aid drug discovery and improve the predictability of drug compound efficacy and toxicity screens, weeding out ineffective and potentially toxic compounds early in the pharmaceutical pipeline process before significant time and resources have been invested.

iCell Cardiomyocytes are derived from induced pluripotent stem (iPS) cells, spontaneously beat in vitro and exhibit the electrophysiological and biochemical properties of normal human heart cells. Thus, iCell Cardiomyocytes provide significant advances over non-human cell models, which may exhibit a different response than human tissue; tumor-derived cell models, which are genetically different than normal cells; and cadaveric cells, which exhibit batch-to-batch variability, de-differentiate under in vitro conditions, and exhibit non-cardiomyocyte behaviour.

iCell Cardiomyocytes are the first product ever developed from iPS cells, discovered by CDI senior research fellow Junying Yu, Ph.D., then a postdoctoral research associate in the University of Wisconsin-Madison laboratory of James Thomson, V.M.D., Ph.D., in 2007. iCell Cardiomyocytes are produced in-house by CDI from a master cell bank of iPS cells expanded from a single clonal population reprogrammed from fully mature human cells using Dr. Thomson’s patented technology. Based on strong intellectual property and exclusively licensed patents from several universities, CDI has developed a proprietary process to industrialize iCell Cardiomyocytes production so that the cardiomyocytes are manufactured at the high quantity, quality and purity required by pharmaceutical companies. CDI has successfully engaged in pre-launch validation testing with several pharmaceutical customers.

“Drug toxicity testing is an important part of early-stage drug development, said Chris Parker, chief commercial officer of CDI. “The problem our pharmaceutical customers face today is that current cell models to test drugs are inadequate, because they are either non-human, cadaveric, or tumor-derived cells. They miss toxicities that might have manifested themselves in a human cell model. With the launch of iCell Cardiomyocytes, we hope to improve the efficiency and effectiveness of preclinical research studies, so that our pharmaceutical customers are more assured of the safety and efficacy of their drug candidates and a better return on their research investment.”

Robert Palay, chief executive officer of CDI, continued, “Launching iCell Cardiomyocytes to the pharmaceutical industry is an important step for Cellular Dynamics. We have shown that we can manufacture and provide validated human iPS cell-derived terminally differentiated cardiomyocytes in the quantity and quality needed by our customers. We look forward to growing this product with our pharmaceutical customers and developing line extensions of iCell Cardiomyocytes, including panels with multiple iPS starting materials, as well as launching other iPS cell-derived iCell products.”

James Thomson, chief scientific officer of CDI, said, “Rapid application of stem cell technology has been a goal both of my laboratory at the University of Wisconsin and CDI. Utilizing human iPS cells for new drug toxicity testing should improve the drug discovery process in a timeframe that has an effect on human healthcare now, not 10 years from now. Ultimately applications of stem cell technology in drug discovery will provide great utility and enable movement toward a long-term goal of cellular-based therapeutics and personalized medicine.”

About Cellular Dynamics International, Inc.

Cellular Dynamics International, Inc. (CDI) is a leading developer of next-generation stem cell technologies for drug development and personalized medicine applications. CDI harnesses the power of pluripotent stem cells and their ability to differentiate into any cell type for world-class drug development tools. In addition, it is the leader in iPS technology, the production of pluripotent stem cell lines from adult tissue. CDI was founded in 2004 by James Thomson, a pioneer in human embryonic stem cell research at the University of Wisconsin-Madison, and Tactics II Ventures, a Wisconsin-based venture capital fund. CDI’s facilities are located in Madison, Wisconsin. See www.cellulardynamics.com.

SOURCE Cellular Dynamics International (CDI)

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Focus on collagen: in vitro systems to study fibrogenesis and antifibrosis — state of the art

Last Updated on Wednesday, 5 May 2010 10:25 Written by Editor Wednesday, 5 May 2010 10:25

Fibrosis represents a major global disease burden, yet a potent antifibrotic compound is still not in sight. Part of the explanation for this situation is the difficulties that both academic laboratories and research and development departments in the pharmaceutical industry have been facing in re-enacting the fibrotic process in vitro for screening procedures prior to animal testing.

Effective in vitro characterization of antifibrotic compounds has been hampered by cell culture settings that are lacking crucial cofactors or are not holistic representations of the biosynthetic and depositional pathway leading to the formation of an insoluble pericellular collagen matrix. In order to appreciate the task which in vitro screening of antifibrotics is up against, we will first review the fibrotic process by categorizing it into events that are upstream of collagen biosynthesis and the actual biosynthetic and depositional cascade of collagen I.

We point out oversights such as the omission of vitamin C, a vital cofactor for the production of stable procollagen molecules, as well as the little known in vitro tardy procollagen processing by collagen C-proteinase/BMP-1, another reason for minimal collagen deposition in cell culture. We review current methods of cell culture and collagen quantitation vis-a-vis the high content options and requirements for normalization against cell number for meaningful data retrieval.

Only when collagen has formed a fibrillar matrix that becomes cross-linked, invested with ligands, and can be remodelled and resorbed, the complete picture of fibrogenesis can be reflected in vitro. We show here how this can be achieved.

A well thought-out in vitro fibrogenesis system represents the missing link between brute force chemical library screens and rational animal experimentation, thus providing both cost-effectiveness and streamlined procedures towards the development of better antifibrotic drugs.

Author: Clarice ChenMichael Raghunath
Credits/Source: Fibrogenesis &Tissue Repair 2009, 2:7

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Formulation strategies for improving drug solubility using solid dispersions

Last Updated on Wednesday, 5 May 2010 10:23 Written by Editor Wednesday, 5 May 2010 10:23

Abstract:

The solubility behavior of drugs remains one of the most challenging aspects in formulation development. Solid dispersions have been employed to enhance the dissolution rates of poorly water – soluble drugs. This article reports various solubility enhancement strategies in solid dispersion. The approaches described are fusion (melting), solvent evaporation, lyophilization (freeze drying), melt agglomeration process, extruding method, spray drying technology, use of surfactant, electro static spinning method and super critical fluid technology. The paper also highlights the potential applications and limitations of these approaches in solid dispersions.

Keywords: micronization, lyophilization, melt agglomeration, extruding, amorphous state, bioavailability, solubility, dissolution

Introduction:

Drug substances are seldom administered alone, but rather as part of a formulation in combination with one or more non-medicinal agents that serve varied and specialized pharmaceutical function. The proper design and formulation of a dosage form requires consideration of the physical, chemical and biological characteristics of all the drug substances and pharmaceutical ingredients to be used in fabricating the product. An important physical-chemical property of a drug substance is solubility, especially aqueous system solubility. Solubility is a predetermined and rate limiting step for absorption. Drugs must have to enter in to the systemic circulation to exert a therapeutic effect1. In recent technologies, innovation of combinatorial chemistry and high throughput screening can effectively discover the seeds of new drugs which exhibit good pharmacological activities however 35-40 % of these new drugs discovered by those technologies suffer from poor aqueous solubility2-3. Consideration of the modifed Noyes-Whitney equation 4, 5 provide some hints regarding how the dissolution rate of very poorly soluble compounds improved to minimize the limitations to oral bioavailability:

dC /dt = AD(Cs – C) / h

where dC/dt is the rate of dissolution, A is the surface are available for dissolution, D is the diffusion coefficient of the compound, Cs is the solubility of the compound in the dissolution medium, C is the concentration of drug in the medium at time t and h is the thickness of the diffusion boundary layer adjacent to the surface of the dissolving compound. To increase the dissolution rate from equation the following approaches are available.

a) To increases the surface area available for dissolution by:

b)Decreasing the particle size of drug.

c)Optimizing the wetting characteristics of compound surface.

d)To decrease the boundary layer thickness

e)Ensure sink condition for dissolution

f)Improve apparent solubility of drug under physiologically relevant conditions. Drug administered in fed state is a way to improve the dissolution rate6.  The solubility/dissolution behavior of a drug is key determinant to its oral bioavailability, the latest frequency being the rate-limiting step to absorption of drugs from the gastrointestinal tract7-8. Consequently poor solubility results in low bioavailability, increase in the dosage, large inters and intra-subject variation and large variations in blood drug concentrations under fed versus fasted conditions. Improvement of oral bioavailability of poor water-soluble drugs remains one of the most challenging aspects of drug development. The techniques/ approaches that have commonly been used to overcome drawbacks associated with poorly water-soluble drugs, in general includes micronization, salt formation, use of surfactant and use of pro- drug 7-8 however all these techniques have certain limitations.  Micronization has several disadvantages, the main one being the limited opportunity to control important characters of the final particle such as size, shape, morphology, surface properties and electrostatic charges. In addition micronization is a high-energy process, which causes disruptions in the drug s crystal lattice, resulting in the presence of disordered or amorphous regions in the final product. The amorphous regions are thermodynamically unstable and are therefore susceptible to recrystallization upon storage, particularly in hot and humid conditions9, 10, 11 . All poorly water-soluble drugs are not suitable for improving their solubility by salt formation. The dissolution rate of a particular salt is usually different form that of parent compound. However sodium and potassium salts of weak acids dissolve more rapidly than the free salts. Potential disadvantages of salt forms include high reactivity with atmospheric carbon dioxide and water resulting in precipitation of poorly water-soluble drug, epigastric distress due to high alkalinity. Use of co-solvents or surfactants to improve dissolution rate pose problems, such as patient compliance and commercialization. Even though particle size reduction increases the dissolution rate, the formed fine powders showing poor wettability and flow properties. Solid dispersion technique has come into existence to eliminate all these problems 12-13. Solid dispersion (SD) technique has been widely used to improve the dissolution rate, solubility and oral absorption of poorly water-soluble drugs14-15. In solid dispersion the drugs are dispersed in a biologically inert matrix for the intention of enhancing oral bioavailability. Chiou and Riegelman defined these systems as the dispersion of one or more active ingredient in an inert carrier matrix at solid state prepared by the melting (fusion), solvent or melting-solvent method.16 However, the most attractive option for increasing the release rate is improvement of the solubility through formulation approaches.

Table 1 summarizes the various approaches that can be taken to improve the solubility or to increase the available surface area for dissolution. Review articles have already been published on the use of polymorphs 17, the amorphous form of the drug 18 and complexation 19, 20.

Solubility enhancement strategies in solid dispersions:

Various strategies investigated by several investigators include fusion (melting), solvent evaporation, lyophilization (freeze drying), melt agglomeration process, extruding method, spray drying technology, use of surfactant, electro static spinning method and super critical fluid technology.

Fusion method:

The fusion process is technically the less difficult method of preparing dispersions provided the drug and carrier are miscible in the molten state. This process employs melting of the mixture of the drug and carrier in metallic vessel heated in an oil bath, immediately after fusion, the sample are poured onto a metallic plate which is kept at ice bath. A modification of the process involves

Spray congealing from a modified spray drier onto cold metal surface. Decomposition should be avoided and is affected by fusion time and rate of cooling21-22. Another modification of the above method, wherein SD(s) of troglitazone- polyvinyl pyrrolidone (PVP) k 30 have been prepared by closed melting point method. This method involves controlled mixing of water content to physical mixtures of troglitazone PVP k30 by storing at various equilibrium relative humidity levels (adsorption method) or by adding water directly (charging method) and then mixer is heated. This method is reported to produce SD with 0% apparent crystallinity23. On the other hand, the fusion process does not require an organic solvent but since the melting of sparingly water-soluble drug and water-soluble polymer entails a cooling step and solid pulverizing step, a time consuming multiple stage operation is required. To overcome this problem Nakano et al 24 have described a method conceptualizing the formation of a SD as the solid-to-solid interaction between a sparingly water soluble drug, nilvadipine and water soluble polymer which, unlike conventional production method, comprises mixing a sparingly water soluble drug and water soluble polymer together under no more than the usual agitation force with heating within the temperature region not melting them, instead of heating the system to the extent that the two materials are melted , the sparingly water soluble drug can be made amorphous to have never been achieved by any dry process heretofore known.

Solvent evaporation method:

The solvent-based process uses organic solvent to dissolve and intimately disperse the drug and carrier molecule. Large volumes of solvents are generally required which can give rise to toxicological problems 25-26. Many investigators studied SD of meloxicam, naproxen27-28, rofecoxib29, felodipine30, atenolol 31, and nimesulide32 using solvent evaporation technique. These findings suggest that the above-mentioned technique can be employed successfully for improvement and stability of solid dispersions of poor water drugs. Suhagic et al. 33 prepared SD of etoricoxib using PEG and PVP as a carriers by solvent evaporation method where carriers along with drug were dissolved in 2-propanol to get a clear solution followed by solvent evaporation and finally dispersion was collected. The prepared SD(s) exhibited improved dissolution attributed to decreased crystallinity, improved wetting and improved bioavailability.

Lyophillization technique:

Freeze-drying involves transfer of heat and mass to and from the product under preparation34. Lyophillization has been thought of a molecular mixing technique where the drug and carrier are co dissolved in a common solvent, frozen and sublimed to obtain a lyophilized molecular dispersion. Betageri et al. 35, Topalogh et al. 36, Badry et al. 37 and Fathy et al.38 have successfully investigated the potential applications of lyophilization in manufacturing of SD(s). Drooge et al39 suggested spray freeze-drying as a potential alternative to the above-mentioned process to produces 9- tetrahydrocannabino containing inulinbased solid dispersions with improved incorporation of – tetrahydrocannabino in inulin.

Melt agglomeration process:

This technique has been used to prepare SD where the binder acts as a carrier. Binder (carrier), drug and excipients are heated to temperature above the melting point of the binder (melt- in procedure) or by spraying a dispersion of drug in molten binder on the heated excipient (spray-on procedure) by using a high shear mixer40. The rotary processor might be preferable to the high melt agglomeration because it is easier to control the temperature and because a higher binder content can be incorporated in the agglomerates41. Larger particles results in densification of agglomerates while fine particle cause complete adhesion to the mass to bowl shortly after melting attributed to distribution and coalescence of the fine particles41-43.

Extruding method:

The extruding method was originally designed as an extraction / casting method for polymer alloys in plastic industry, is now used to process cereals and functionalize food materials, such as tissue products from animal proteins44. Hot melt extrusion approach represent the advantageous mean of preparation of SD(s) by using the twin screw hot melt extruder where only thermo stable components are relevant45. The extruder consists of a hooper, barrel, a die, a kneading screw and heaters. The physical mixture is introduced into the hopper that is forwarded by feed screw and finally is extruded from the die44. The effect of screw revolution speed and water content on the preparation of SD(s) should be investigated, since these parameters have profound impact on the quality of SD(s). Nakamichi et al 46, studied that presence of kneading paddle element of screw results in super saturation on dissolution testing while slow revolution rate of screw and addition of the suitable amount of water increased rate of dissolution although no super saturation occurred. In addition, high screw speed high feed rate processes in comparison with low screw speed low feed rate processes caused an increase in extrudate radius and porosity and decrease in mechanical strength and drug release rate from the matrix attributed to the expansion promoted under certain extrusion conditions47. To reduce the melt viscosity in the extrudate and to be able to decrease temperature settings, a plasticizer can be added to the formulation. Typically, conventional plasticizer such as triacetin or polyethylene glycol is used in concentration range of 5-30 % weight of the extrudate that lowers the processing temperature. Carbon dioxide can act as temporary plasticizer. During extrusion carbon dioxide is transformed in gaseous phase. As a consequence carbon dioxide escapes from extrudate and does not appear in final product48. The role of methylparaben49 and sorbitol50 has also been investigated as plasticizer in preparation of SD(s) in extrusion method. This method has already been used successfully to prepare SD(s) of i traconazole and hydroxypropylmethylecellulose (HPMC) 51, indomethacin/lacidipine/nefidipine/ piroxicam/ tobutamide and polyvinylpyrrolidone (PVP) 52, itraconazole53 and HPMC 2910/ Eudragit e 100 or a mixture of Eudragit E 100-PVP vinyl acetate 64 to improve solubility and dissolution rate of poor water soluble drugs.

Spray drying:

The manufacture of milk powder was one of the first applications of spray drying when the method was developed in 1920. Today, spray drying finds great utility in pharmaceutical industry because of the rapid drying and specific characteristics such as particle size and shape of the final product. In addition, it is simple and cost effective, as it is 30-50 times less expensive than freeze-drying. It is an established method that is initiated by atomizing suspensions or solutions into fine droplets followed by a drying process, resulting solid particles. The process allows production of fine, dust free powder as well as agglomerated one to precise specifications. The operating conditions and dryer design depends upon the drying characteristics of the product and require powder specifications 54-56. Rankell et al. prepared SD(s) of loperamide with PEG 6000 by this technique wherein solutions containing different concentrations of PEG 6000 and constant amount of loperamide were spray dried. After spray drying, the dispersions were dried at 400C under vacuum until constant weight. Solvent used was dichloromethane. The prepared SD(s) exhibited higher dissolution rates than that of pure crystalline loperamide57. Chouhan et al 58 studied the suitability of this technique for preparation of SD(s) of glibenclamide polyglcolized glycerides. This study revealed the improvement in solubility and dissolution rates, also improvement in the therapeutics efficacy of amorphous glibenclamide in SD(s) was observed. Some other investigators 59-60 also reported improvement in solubility and dissolution rate. The frequent use of the organic solvent in spray drying pose problems such as residues in products, environmental pollution and operational safety as well as corporate problems such as capital investment. Tanno et al61described a process for producing the SD(s) of poorly water-soluble drugs using water-soluble polymer dispersion and/ or water-soluble polymer solution and the plasticizer solution by using 4-nozzle spray gun. The spray drying technique is a useful method to obtain spherical particle and narrow distribution. The role of porous materials such as calcium silicate, controlled pore glass and porous cellulose is appreciated to formulate solid dosages forms because they confer special characteristics such as decrease of melting point and a decrease in the crystallinity of drug entrapped in pores. In addition, porous materials control polymorphs and stabilizes meta-stable crystals in SD(s) under sever storage conditions. Moreover, porous silica has been reported to improve solubility and dissolution rates of indomethacin and tolbutamide 62-63.

The use of surfactant:

The utility of the surfactant systems in solubilization is well known. Surfactant reduces hydrophobicity of drug by reducing interfacial or surface tension because of these unique property surfactants have attracted the attention of investigators for preparation of solid dispersions64- 65. Recently a new class of surfactant known as Gelucires are introduced which identify by melting points and HLB values. Gelucire is a widely use in the formulation of semi solid dispersions. Gelucire is a saturated polyglycolized glyceride consisting of mono-, di- and triglycerides and of mono- and di- fatty acid esters of polyethylene glycol (PEG) derived from natural vegetable fatty acids and having amphiphilic character. Gelucires with low HLB can be employed to decrease the dissolution rate of drugs and higher HLB ones for fast release. Gelucire 44/14 and gelucire 50/13 are two examples of this synthetic group where 44 and 50 represent melting point, while 14 and 313 represent HLB values of gelucire respectively 66-67. Solid dispersions of antiviral agent uc-781-polyethylene glycol 6000- gelucire 44/14 and UC-781- PEG 6000-gelucire 44/14- PVP k 30 were studied. Improvement in solubility, dissolution and stability was observed 68-69. Labrasol, of same chemical nature as gelucire, is a clear liquid surfactant with a HLB of 14. Solid dispersions of piroxicam with labrasol have also resulted in improved solubility and dissolution when compared with pure drug 66-67. The amphiphilic poly (ethylene oxide)-poly (propylene oxide)- poly (ethylene oxide) (PEO-PPO-PEO) block polymers, known as poloxamer or pluronics represent another class of surfactants. These are available in various molecular weights and PEO/PPO ratios, and hence offer a large variety of physico-chemical properties 70. These block polymers are extensively used in the pharmaceutical industry as defoaming agents, gelling agents, detergents, dispersing agents, emulsifying agents and solubilizing agents71. When used in relatively high quantities, poloxamer imparts sustained-release properties to solid dosage forms, by forming a lipid matrix72. Solid dispersions using pluronic F-68 (a type of poloxamer) as a carrier were studied for improving the dissolution and bioavailability of ABT-963, a poorly water- soluble compound. Results showed that the solid dispersion substantially increased the in vitro-dissolution rate of ABT-963. A significant increase of oral bioavailability compared with conventional capsule formulation was also reported73. The presence of water and polar water-miscible solvent, a partially water-miscible solvent, a non- ionic surfactant, an anionic surfactant and cationic surfactant affect domain of the PEO-PPO-PEO block copolymer selfassembly74. Therefore, organic solvents and surfactants should be used with great care for preparation solid dispersion while using in combination with poloxamer. Inutec SPI, a derivative of inulin prepared by the reaction between isocyanates and the polyfructose backbone in the presence of a basic catalyst such as a tertiary amine or lewis acid, has also been evaluated as carrier in formulation of solid dispersions for a poorly water- soluble drug. Inutec SPI has low viscosity and stability effect on emulsion and suspension. Dissolution properties of SD(s) made up of itraconazole and Inutec SPI were improved in comparison to pure itraconazole or physical mixtures with Inutec SPI4. Hemant et al 75 and Sheen et al 76 studied that polysorbate 80, a commonly used surfactant, results in improvement of dissolution and bioavailability of poorly watersoluble drug attributed to solubilization effect of surface active agent. Polysorbate 80 also ensues complete release of drug in metastable finely dispersed state having large surface area.

Super critical fluid (scf) technology:

This technology has been introduced in the late 1980s and early 1990s, and experimental proofs of concept are abundant in the scientific literature for a plethora of model compounds from very different areas such as drugs and pharmaceutical compounds, polymers and biopolymers, explosives and energy materials, superconductors and catalyst precursors dyes and biomolecules such as proteins and peptides. Since the first experiences of Hannay et al in 1879, a number of techniques have been developed and patented in the field of SCF-assisted particle design. These methods use. SCFs either as solvent: rapid expansion from supercritical solution (RESS) or anti-solvent: gas antisolvent (GAS), supercritical antisolvent (SAS), solution enhanced dispersion by supercritical fluids (SEDS) and/or dispersing fluid: GAS, SEDS, particles from gas-saturated solution (PGSS). Conventional methods, i.e. Spray drying, solvent evaporation and hot melt method often result in low yield, high residual solvent content or thermal degradation of the active substance79. Solution enhanced dispersion by supercritical fluids (SEDS), aerosol solvent extraction system (ASES), supercritical anti-solvent (SAS), gas anti-solvent (GAS) and precipitation with a compressed fluid anti-solvent (PCA) are process of micronization. The SAS process involves the spraying of the solution composed of the solute and of the organic solvent into a continuous supercritical phase flowing cocurrently80. The use of supercritical carbon dioxide is advantageous as it is much easier to remove from the polymeric materials when the process is complete, even though a small amount of carbon dioxide remains trapped inside the polymer; it poses no danger to the patient. In addition the ability of carbon dioxide to plasticize and swell polymers can also be exploited and the process can be carried out near room temperature81. Supercritical fluids used to lower the temperature of melt dispersion process by reducing the melting temperature of dispersed active agent. The reason for this depression is the solubility of the lighter component (dense gas) in the forming phase (heavier component) 82. Wong et al compared the SD(s) of felodipine prepared by conventional solvent evaporation (CSE) and supercritical antisolvent precipitation (SAS) methods. The particle sizes of the SD(s) from CSE process increased at 1h after dispersed in distilled water. However the particle sizes of the SD(s) from SAS process were maintained for 6 h due to the increased solubility of felodipine. Moreover, SD(s) form the SAS process showed a high dissolution rate of over 90% within 2 h showing the potential applications of SCE technology in preparation of SD(s) 83.

Summary And Future Potential:

The solubility of drugs in aqueous media is a key factor highly influencing their dissolution rate and bioavailability following oral administration resulting in low bioavailability. Solubility enhancement of these drugs remains one of the most challenging aspects of drug development. A variety of devices have been developed over the years to enhance the drug solubility and dissolution of the drugs. The solid dispersion method is one of the effective approaches to achieve the goal of solubility enhancement of poorly water-soluble drugs. Various techniques, described in this review, are successfully used for the preparation of SD(s) in the bench and lab scale and can be used at industrial scale also. Solid dispersions came into limelight in pharmaceutical development due to the increasing number of drug candidates which are poorly soluble and the substantial improvements in the manufacturing methods for solid dispersions that have been made in the last few years. Although there are some hurdles like scale up and manufacturing cost to overcome, there lies a great promise that solid dispersion technology will hasten the drug release profile of poorly water soluble drugs.

Acknowledgements:

I am very much thankful to my research guide and co- guide, Dr.N.M.Patel and Dr.M.M.Patel respectively for their constant encouragement and help to write this review.

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Table 1: Approaches to improve the solubility or to increase the available surface area for dissolution

I. Physical modifications
Particle size
Micronization
Nanosuspensions
Modifications of the crystal habit
Polymorphs
Pseudopolymorphs (including solvates)
Complexation/solubilization
Use of surfactants
Use of cyclodextrines
Drug dispersion in carriers
Eutectic mixtures
Solid dispersions (non-molecular)
Solid solutions
II. Chemical modification
Soluble prodrugs
Salts

Table 2:Methods for the characterization of solid dispersions

Dissolution testing
Thermoanalytical methods: differential thermoanalysis and hot stage
Microscopy
Calorimetric analysis of the solution or melting enthalpy for calculation of
Entropy change
X-Ray diffraction
Spectroscopic methods, e.g. IR spectroscopy
Microscopic methods including polarization microscopy and scanning
Electron microscopy

Table 3: Marketed formulation of solid dispersion

Drug Name

Brand Name

Company name

Nelfinavir mesylate

Viracept®

Agouron Pharmaceuticals

Ritonavir

Norvir®

Abbott Laboratories

Amprenavir

agenerase

Glaxosmithkline

Calcitriol

Rocaltrol

Roche

Cyclosporine

A/I neoral

Novaritis

Indomethacin

Indomethacin

Eisai Co

About Authors:

Rajnikant C.Patel , Saiyad Masnoon, Madhabhai M. Patel, and Natvarlal M. Patel

Rajnikant C.Patel

Rajnikant C.Patel currently working as a lecturer and pursuing part time Ph.D. in the Department of Pharmaceutics at Kalol Institute of Pharmacy, Kalol- 38 27 21

Saiyad Masnoon

Saiyad Masnoon studying in third year B.pharm at Kalol Institute of Pharmacy, Kalol- 38 27 21

Dr.Madhabhai M. Patel

Dr. Madhabhai M. Patel is a Principal in Kalol Institute of Pharmacy, Kalol- 38 27 21

Dr.Natvarlal M. Patel

Dr. Natvarlal M. Patel is a Principal in Shri B.M.Shah College of Pharmaceutical Education and Research, Modasa

Source: pharmainfo.net

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