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By Nicky Blackburn, www.Israel21c.com

For Prof. Beka Solomon it was obvious. If it isn’t possible to send drugs to the brain to treat Alzheimer’s disease the normal way because of the blood-brain barrier that prevents drugs from moving from the blood stream into the brain, then send them through the nose instead.

Solomon, of the Molecular Microbiology and Biotechnology Department at Tel Aviv University, has been working in this field for the last 13 years after years of research in immunotherapy, and found in mouse trials that filamentous phages, a harmless bacterial virus found almost everywhere from the depths of the ocean to the lining of the stomach, can be an effective treatment against Alzheimer’s disease when carried to the brain through the nose.

Alzheimer’s is a debilitating disease that leads to progressive loss of memory and cognitive functions, and a great deal of suffering for both the person afflicted and their loved ones. In the U.S. alone, there are now more than five million people living with Alzheimer’s, but there is currently no drug on the market that can cure or effectively stop the progression of this disease.

The cause of this disease and other neurological diseases like amyotrophic lateral sclerosis (ALS) is widely concluded to be plaque formation, which causes inflammation in the brain. Up to now, scientists working on a cure for the disease have focused on dissolving and preventing plaque formation, but most have come up against two problems: firstly, the difficulty in developing drugs that pass through the highly selective blood-brain barrier; and secondly, unwanted side-effects of inflammation and hemorrhaging.

In her research, Solomon shows that by administering non-lytic filamentous phages in small doses through the nasal passages, the phages have a direct and rapid route to the brain. There they lock onto the extracellular plaques associated with Alzheimer’s and dissolve them, reducing inflammation in the brain without any side effects. The body then gets rid of the waste naturally.

“The filamentous phages have a nanotubular appearance which is very similar in shape to amyloid fibrils, the main component of amyloid plaque, which is the plaque linked to Alzheimer’s,” explains Solomon, who recently presented her findings at a meeting of the American Society for Microbiology in Canada.

Solomon first began thinking about sending phages through the nasal passages because the plaque that causes Alzheimer’s first appears in the olfactory bulb. As a result, one of the early symptoms of this devastating disease is loss of smell.

To test her hypothesis, Solomon and her colleagues treated 150 mice with the phage intranasally for 12 months. They found the mice that had exhibited the symptoms of Alzheimer’s regained their sense of smell and also showed memory and cognitive improvement. After one year of treatment, they had 80 percent fewer plaques than untreated mice.

The phages were eliminated from the brain and secreted from the body in urine and feces. The researchers saw no adverse effects in the peripheral organs — the kidneys, liver, lungs, and spleen biology were all normal.

“The mice showed very nice recovery of their cognitive function,” says Solomon, who emigrated with her family from Romania to Israel about 40 years ago. “We saw a reduction in the amyloid plaque and a reduction in brain inflammation. Afterward the phages were eliminated naturally from the body through the kidneys without any adverse side-effects.”

“This is a potential breakthrough, but it needs to be proved further,” Solomon told ISRAEL21c. “Bateriophages are one of the most numerous life forms on earth and mammalian organisms are very frequently exposed to interactions with them. We know for instance that they are a very important part of the natural flora of the gut and research groups all over the world have developed classic phage therapy as an alternative to antibiotics. We are used to living with them, it’s not unusual, but to take them to the brain in unusual. This is the first attempt to use phages as a treatment for Alzheimer’s.”

Ramot, the commercial arm of Tel Aviv University is now planning to commercialize Solomon’s research and has licensed the technology to a startup company.

“Beka is a real pioneer in developing an immunotherapeutic approach for the treatment of Alzheimer’s disease,” says Irit Ben-Chlouch, director of business development, life sciences at Ramot. “She was the first to show the disease can be treated using antibodies and, as the main focus of her lab, has developed several different breakthrough approaches.”

In the meantime, Solomon plans to continue with her research, which she regards as a platform technology. She and fellow researchers at the university are now exploring whether this intranasal administration of filamentous phages can also be used to help patients suffering from Parkinson’s disease and Huntingdon’s disease.

She is also exploring the possibility of adding medicines, such as anti-inflammation agents to the phages, to bring the brain additional therapeutic medicines.

By Tim Johnson, McClatchy Newspapers

BEIJING — The medicine cabinet in the average U.S. home is filling with drugs made in China , and some experts say that could be a prescription for trouble.

China’s booming pharmaceutical industry has doubled exports to the United States in the past five years, undercutting competitors and making American consumers reliant on the safety of Chinese factories and captive to any disruptions in Sino-U.S. commerce.

It might seem like merely a trade issue. But industry experts in Europe and the United States say national-security concerns are edging into the debate.

Consider this scenario:
If a major anthrax attack were to occur in the United States — larger than the one in 2001, when five people died— pharmaceutical companies that make the two antibiotics most suitable for treatment, Cipro and doxycycline, would have no choice but to rely on China or India for key ingredients once American stockpiles were exhausted. Those ingredients no longer are made in the West.

A Portuguese company that ramped up doxycycline production in 2001 at Washington’s request said China now controls the flow of its crucial drug component.

“If we were asked to do this again, we would be dependent on China providing us with key starting materials that are unavailable in the rest of the world,” said Guy Villax, the chief executive of Hovione, a Lisbon -based fine chemicals company.

The spectacular growth of China’s pharmaceutical industry coincides with some equally huge problems. A kickback scandal ensnared China’s State Food and Drug Administration and its chief in charges that they gave approval for bogus drugs, including a counterfeit antibiotic that left 13 people dead. Wary of rising public anger, the state issued a Draconian sanction: It executed the agency chief in July.

Cases of tainted toothpaste, toys, and pet food that have made global consumers wary of the “Made in China ” label added urgency to a high-profile drug agency purge.

Even so, China’s $65 billion pharmaceutical industry is galloping at an annual growth rate of 24 percent in the first eight months of this year. Competitors say China’s drug companies not only have low-cost advantages, but also get a nearly free pass from U.S. drug regulators, who hold the screws to American companies— raising their costs significantly— but rarely inspect in China .

China says it’s a reliable source of safe medicine for its own citizens and export markets. At a news conference in early December, the deputy drug agency chief, Wu Zhen, called on countries to work together to ensure a safe global supply chain of medicines.

“To solve the drug safety problems, we need international cooperation,” Wu said. “We hope to have . . . more cooperation, and less finger-pointing.”

China dominates more than just antibiotics. U.S. regulators license 714 plants in China to produce ingredients for over-the-counter, generic, and prescription drugs for Americans. China has snagged a major share of the global sales of many vitamins, antibiotics, enzymes, and painkillers. It makes a third of the world’s acetaminophen, an over-the-counter pain medication. Acetaminophen is sold under many brand names, the best known of which is Tylenol, though Tylenol itself isn’t made in China .

This brings up another possible scenario:
“Just suppose you are taking some cholesterol drug, and its intermediates or active ingredients are made in China . Then there’s some conflict with Taiwan. Will your drug still be available?” asked Joe Acker , the president of the Synthetic Organic Chemical Manufacturers’ Association , a trade group in Washington. “The whole drug supply could be in jeopardy in these kinds of situations.”

Acker noted that he thinks that the United States could rebound from disruptions in the increasingly globalized supply chain for drug components, in which materials are bought from a number of low-cost countries.

“I’m not a Chicken Little type of person,” Acker said. “However, if there were to be a major problem, and we could not source material from China, we would have to gear up production very quickly.”

The anthrax scare jolted the United States just a week after the terrorist attacks of Sept. 11, 2001. Letters containing anthrax spores were mailed to news organizations in Florida and New York and to the offices of two U.S. senators. Authorities don’t know the source of the letters, and no arrests have been made.

Because of the attacks, the Health and Human Services Department increased stockpiles of antibiotics and vaccines against anthrax.

“We have enough antibiotics . . . to treat 40 million Americans,” Bill Hall, a spokesman for the department, said in an e-mail, adding that the government also has 28.75 million doses of anthrax vaccine.

Bayer, the German health-care giant, held patent protection until 2004 over the antibiotic known as ciprofloxacin, which it marketed as Cipro. That antibiotic now is mass-produced by generic firms, which get a key ingredient, dichloro fluorobenzene, from one of four Chinese companies or two Indian firms.

The Chinese and Indian companies are all but exempt from oversight by the U.S. Food and Drug Administration.

“Only 13 inspections were conducted in China in 2007,” Rep. John Dingell, a Michigan Democrat who chairs the House Committee on Energy and Commerce, said at a hearing Nov. 1. “At this rate, it would take the FDA 55 years just to clear this backlog.”

By giving China a virtual pass on FDA inspections, Acker said, Chinese firms get a cost savings of about 25 percent above American companies, which face unannounced on-site inspections at any time.

Since European pharmaceutical companies also face tougher standards, they too have stopped producing some basic drug ingredients, ceding production to Chinese and Indian companies that face less scrutiny and have lower costs.

On both sides of the Atlantic, manufacturers say they fret over the national-security implications of the massive off-shoring of production to Asia.

“If there is a peak in demand triggered by a pandemic or a terrorist event, there will be little domestic production capacity to meet public health needs,” said an August 2006 white paper by the U.S. chemicals trade group in conjunction with the European Fine Chemicals Group, its counterpart.

Chinese chemical companies that sell ingredients used by foreign pharmaceutical firms also shield themselves from the news media.

Sun Dongliang, the deputy chief of the chemical industry chamber under the powerful China Council for the Promotion of International Trade, refused a request for an interview.

“He thinks that your interview has nothing to do with the chemical industry. It’s about pharmaceutical things,” said an assistant who gave only her surname as Guo.

All four Chinese companies that manufacture the key ingredient for ciprofloxacin declined requests for interviews.

China offered foreign journalists a tour of two model pharmaceutical plants in Hangzhou on Nov. 23. The plants were spotless. Workers in facemasks toiled in jumpsuits on assembly lines. Polished machinery gleamed. One factory made Chinese medicines to treat prostate ailments. The other made herbal remedies.

Outsiders say Chinese drug plants run the gamut from First to Third World.

“You will see some companies where you can eat off the floor. They are state-of-the-art,” said Acker, the U.S. trade group chief. “I hear other stories of places where people are making chemicals while wearing flip-flops.”

Despite multiple requests over a two-week period, McClatchy was unable to gain access to any drug ingredient-manufacturing facilities other than the model firms presented by the Chinese government.

Although Chinese authorities warn against foreign finger-pointing, the government’s own reaction to the scandal over bogus and substandard drugs earlier this year was extremely harsh.

After drug chief Zheng Xiaoyu’s execution, the state began a vast housecleaning. This week, it said it had shut down 300 drug and medical-device makers, convicted 279 people of irregularities and prompted drug companies to withdraw 7,300 applications for drug approval, indicating more rigor in the approval process.

Such actions left doubt whether consumers ought to be reassured by the factories shut down or alarmed at the state of the industry. Wu, the deputy drug chief, said he hoped to restore faith in Chinese drugs after the kickback scandal.

“The corruption case . . . has tarnished our image,” he said. “One of the targets of this campaign is to clean up the legacy caused by this corruption case.”

Still unclear is whether increased self-policing is sufficient given the magnitude of China’s production and its rising share of global medicine chests.

Villax, the Portuguese executive who’s a board member of the European Fine Chemicals Group, said some Chinese pharmaceutical manufacturers were cutting corners and that unless enforcement tightened “people will die.”

“It’s not low-cost labor that concerns us,” Villax said. “What we’re saying is there are a lot of people not playing by the rules, and not getting caught.”

A sign of the troubles that can occur in the pharmaceutical industry came at a plant that was manufacturing a key ingredient used in ciprofloxacin.

A deafening blast ripped through the Fuyuan Chemical Co. plant in Jiangsu province on July 28, 2006. Once the smoke cleared, 22 people lay dead and another 29 were injured. China’s State Administration of Work Safety later issued a report charging the plant with ignoring safety rules, adopting low construction standards and operating without permits.

By Karin Kloosterman, www.Israel21c.com

For most of his professional life, Tel Aviv University professor Michael Ovadia focused on snakes and the medicinal properties of their venom. But seven years ago, after meditating on a biblical passage, Ovadia’s career focus began to take a twist… a cinnamon twist to be exact.

Today the spiritual scientist from TAU’s Department of Zoology is commercializing a unique cinnamon extract that is touted to quell viral infections from HIV to the Avian flu.

A research and license deal on his patent-pending cinnamon extract was signed last week between TAU’s technology transfer company Ramot and Frutarom, a multinational nutraceutical company based in Israel. Frutarom is expected to use the extract in a whole host of applications from disinfecting the air as a spray against Avian flu in airports; to a daily supplement that protects people against the common flu.

Those researching in the field of natural medicine know that snake venom, especially the notorious poisonous kind, has unique anti-viral and analgesic properties that can help fight human illness and disease. For the past 40 years, Ovadia had been working with natural antidotes and found that certain kinds of venom can deactivate Parainfluenza (Sendai) virus — a virus similar to the human flu.

Work was going well. Papers were published, patents had been developed, and his reputation in the field was established. But Ovadia was still waiting for the breakthrough that every scientist dreams about.

That breakthrough would come to him one morning in the synagogue while listening to a reading from the Old Testament.

“There is a passage that explains how the High Priests — the Kohens — would prepare a holy oil used on their bodies before they made a ritual animal sacrifice,” recalls Ovadia. “I had a hunch that this oil, which was prepared with cinnamon and other spices, played a role in preventing the spread of infectious agents to people.”

Taking his hunch to the laboratory bench, Ovadia’s initial experiments proved to be true — his savory cinnamon extract was able to quickly and effectively immunize chicken embryos from the Newcastle disease virus — one which costs the poultry industry in the US millions of dollars a year.

Further studies on Avian Flu H9, Sendai virus, the HIV virus, and Herpes Simplex 1 also achieved positive results. Not only was the extract able to neutralize the viruses, it also showed for selected viruses that it has the potential to immunize against them as well.

Michael Ovadia mulls the effects of a cinnamon stick: I had a hunch that this oil [described in the Bible], which was prepared with cinnamon and other spices, played a role in preventing the spread of infectious agents to people.

Now before people start dropping cinnamon sticks in their hot chocolate and sprinkling it all over their lattes — take note that the cinnamon extract developed by Ovadia has special properties that won’t be found at coffee shops or in the kitchen cupboard. First of all, it comes from a special variety of cinnamon; coumarin and cinnamon aldehyde, which are by-products of cinnamon ‘juice’. These are actually damaging to the liver in high quantities, and must be removed.

“You cannot take high doses from the natural form of cinnamon,” Ovadia told ISRAEL21c. “If you used it several times a day to protect you from the flu, it would be toxic.”

During seasonal epidemics, around 10-20% of the world is infected with the influenza virus and the elderly and young are particularly at risk. In America alone, the U.S. Centers for Disease Control and Prevention estimates that 35-50 million Americans are infected with the flu every season. Despite the use of vaccines, the influenza virus is still associated with significant mortality worldwide — especially now that people travel regularly and work together in offices and closed spaces.

Moreover, the global circulation of the deadly Bird Flu H5 (with more than 50% mortality in infected humans) may cause a sudden worldwide pandemic within two to three months. Until a vaccine is invented, antivirals will be the only medical intervention for use in such a pandemic, says Ovadia.

“What we know is that this technology is capable of neutralizing viruses very fast and that it is applicable to various applications,” said Dr. Nissim Chen, the business development manager of Ramot who managed the commercialization process which ending up with the licensing to Frutarom. “For example, it can be used in air conditioning systems in hospitals and prevent infections spreading from one person to the other in closed spaces.”

There is a growing tendency for researchers and clinicians to explore natural compounds against disease, agrees Chen, adding that Ovadia is well-known for his work in natural inhibitors of snake venom.

“This work with cinnamon is really an extension of his research. And at Tel Aviv University in general, there are several groups working on biological and chemicals structure of natural inhibitors,” he said.

Besides the human application, Ovadia sees that cinnamon fills an important niche in the agriculture industry where chicks need to be immunized by hand against the deadly Newcastle disease virus.

“If someone needs to immunize 1,000 chicks through drops in the chick’s eye, then we know they are not doing this accurately — it is also an issue of animal welfare,” says Ovadia.

Instead, he believes, “we will be able to administer this cinnamon extract through a tiny pin prick in the shell before the chick hatches.” Such an immunization gives the chickens protection against the Newcastle virus, Ovadia assures.

Applying this research to the global scale could only be done with the help of a large company — which is where Frutarom comes in. The Israeli-based flavor and food additive company has grown in the last 10-15 years from $10 million a year to a projected $350 million by the end of 2007.

“We’re going to take this know how from a food supplement to protect people from illness to neutraceuticals in drugs; it can also be used in agriculture against Bird flu — certainly it represents a very diversified product line,” said Frutarom’s CEO Ori Yehudai.

According to the company, Ovadia will continue to lead research into the development of the extract, and Frutarom estimates that the new cinnamon product will be launched in about a year. Hopefully just before flu season.

By Nicky Blackburn, www.Israel21c.com

The best thing to do if you suffer peripheral arterial disease (PAD), a chronic condition that happens when a plaque blockage occurs in a peripheral artery in the legs or pelvis, is to walk. Walk, and walk, and walk. The act of walking enlarges and expands the small blood vessels around the artery, ensuring that you receive a steady flow of blood to the lower extremities despite the plaque blockage.

For some patients with PAD, however, walking just isn’t possible. Perhaps they have an injury or swelling, perhaps they are elderly or diabetic. The upshot is that oxygen-rich blood does not reach the lower limbs. This causes pain, changes in skin color, ulcers and difficulty in walking. But if the plaque blockage — made of fats and cholesterol — grows large enough to completely block the artery or ruptures to form a blood clot, the result is a total loss of circulation to the legs and feet, which can cause gangrene and amputation.

Nearly 12 million Americans now suffer from PAD, and experts predict this number will rise to 19 million. While there are existing treatments including angioplasty, atherectomy, or bypass for some of these people, for the 750,000 patients whose condition has deteriorated into critical limb ischemia (CLI), there is no existing therapy. These ‘no-option’ patients are not candidates for conventional treatments, have an alarming mortality rate, and face imminent amputation. Every year in America some 187,000 no-option patients undergo amputation of a lower limb.

Now Israeli start-up PerAssist has developed a new treatment that may give these no-option patients a chance to save their limbs. The company’s innovative peri-arterial booster device called PeriBoost improves blood flow to the lower limbs of PAD patients in much the same way that walking does.

A PeriBoost sleeve is fitted around a major, intact, healthy blood vessel — usually the femoral or iliac arteries — near the diseased peripheral region using a minimally invasive laparoscopic procedure. A balloon is then inserted between the artery and the sleeve, and is held in place by the sleeve. The balloon is inflated and deflated in synchronization with the patient’s heart beat. An external control device includes an ECG.

The PeriBoost enlarges and expands the small blood vessels around the artery, ensuring that you receive a steady flow of blood to the lower extremities despite the plaque blockage.

This pumping action squeezes the blood downstream, ensuring that blood flow in the artery is maximized. By doing this it enlarges the small arteries around the blockage, bringing more blood down to the lower limbs.

“We aren’t treating the block,” says Roni Bibi, the CEO of PerAssist, “We are bringing more blood downstream, enlarging the velocity and flow to the small arteries by about 90 percent, to recover the leg and avoid amputation.”

The treatment, which has not yet undergone clinical trials and is designed for the legs only, is designed to be carried out daily for three hours over three months. It is not painful, according to Bibi, and the patient can function normally throughout the procedure.

“The blood vessel is not like a muscle, it has no sensors or nerves. All we are doing is pushing it and this does not cause any pain,” Bibi tells ISRAEL21c. “The patient can eat, sleep, read – whatever they want. They won’t feel a thing.”

PeriBoost compares well to existing treatments. For example, it does not require arteries to be incised or perforated, and therefore does not damage artery walls. In one treatment, a doctor will drill inside the artery, remove the blockage and clean the artery from the inside. This is major invasive surgery, can only be carried out in the upper leg, and often ends up as nothing more than temporary relief as the same area becomes quickly blocked again. Stents and bypass surgery are also significant surgical events, and very problematic for the elderly or diabetic.

PeriBoost is likely to be much cheaper than any of these existing treatments, and it can be left in place for future use if peripheral vessels become re-occluded. The only main drawback to PeriBoost is that treatment is slow — three months, rather than a few days of recovery after one surgery.

The idea for PeriBoost came from Dr. Aaron Hoffman, the company’s chief medical officer and director of the department of vascular surgery and transplantation at Rambam Medical Center in Haifa, and a friend of his, water engineer, Gaby Weizman. Hoffman, who is also an associate professor at the faculty of medicine at the Technion-Israel Institute of Technology and has been involved in cutting-edge vascular medicine for over 20 years, recognized the problems in this field for no-option patients and turned to his friend to see if they could come up with a joint solution. In 2005 PerAssist was set up at the Misgav Venture Accelerator. Bibi joined the company as its CEO.

In the last two years the company has taken its device through successful animal trials. “It was the first medical device proven to increase the Ankle Brachial Index [ABI the golden standard for PAD diagnosis] on a large animal model,” says Bibi.

The company now plans to raise an additional investment of $1.5 million to fund it through clinical trials, which are expected to be held in Switzerland, Germany and Italy. The company aims to receive CE approval in the first stage, and afterwards look for FDA approval. If all goes according to plan, the product could be out in the European market by the end of next year, and in the US in 2009.

“This is a good project and it can help a lot of people,” says Bibi. “For so many patients there is no solution today except amputation. We are holding out the promise of an alternative.”