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Tuesday, 14 April 2009

Drugs special-cool new stuff in medicine, 03.2009


  1. Technique tricks bacteria into generating their own vaccine
  2. Antibiotic combination defeats extensively drug-resistant TB
  3. AIDS: Microbicide gel 'highly encouraging' in lab tests
  4. Small molecules block cancer gene
  5. Vaccine to prevent colon cancer being tested in patients

Technique tricks bacteria into generating their own vaccine

February 23rd, 2009

Scientists have developed a way to manipulate bacteria so they will grow mutant sugar molecules on their cell surfaces that could be used against them as the key component in potent vaccines.

Any resulting vaccines, if proven safe, could be developed more quickly, easily and cheaply than many currently available vaccines used to prevent bacterial illnesses.

Most vaccines against bacteria are created with polysaccharides, or long strings of sugars found on the surface of bacterial cells. The most common way to develop these vaccines is to remove sugars from the cell surface and link them to proteins to give them more power to kill bacteria.

Polysaccharides alone typically do not generate a strong enough antibody response needed to kill bacteria. But this new technique would provide an easy approach to make a small alteration to the sugar structure and produce the polysaccharide by simple fermentation.

Peng George Wang, Ohio Eminent Scholar and professor of biochemistry and chemistry at Ohio State University and senior author of the study said: "All we need to do is ferment the bacteria, and then the polysaccharides that grow on the surface of the cell already incorporate the modification."

In vaccines, polysaccharides linked with carrier proteins are injected into the body. That sets off a process that causes the release of antibodies that recognize the sugars as an unwanted foreign body. The antibodies then remain dormant but ready to attack if they ever see the same polysaccharides again - which would be a signal that bacteria have infected the body.

Escherichia coli was used as a model for the study. Wang and colleagues used one of the existing monosaccharides present on the E. coli cell surface polysaccharides, called fucose, to generate this new modification. They manipulated the structure of the fucose to create 10 different analogs, or forms of the sugar in which just one small component is changed.

The scientists then manually introduced these altered forms of fucose to a solution in which bacterial cells were growing, and the bacterial cells absorbed the altered fucose as they would normal forms of the sugar. The presence of these altered forms of fucose then altered the properties of the polysaccharides that grew on the surface of the cells.

"This way, we don't have to do anything to modify the polysaccharides. We let bacteria do it for us," Wang said.

Wang said the approach is likely to be applicable to many different kinds of bacteria. But each type of pathogen must be tested individually with the alteration of sugars unique to its surface.

"If you want to prevent one type of bacteria, you have to find something very unique for this bacteria because different microbes have different characteristics," he said. "You have to find the oddest thing on the cell surface. It has to be on surface because what the body sees first is the surface."source

My comment:Not too much to say here. I hate bacterial infections enough to be happy of any new way to produce vaccines. And this new method is quite exciting! I wish them much luck.

Antibiotic combination defeats extensively drug-resistant TB

February 26th, 2009

A combination of two FDA-approved drugs, already approved for fighting other bacterial infections, shows potential for treating extensively drug resistant tuberculosis (XDR-TB), the most deadly form of the infection.

TB is caused by the bacterium Mycobacterium tuberculosis (Mtb). An estimated one-third of the world's population is infected with TB. Active disease develops in approximately 10 percent of infected people over a lifetime ─ particularly those with weak immune systems such as infants, the elderly, and people infected with HIV. Globally, cases of active TB have increased significantly since the 1980s due to the AIDS pandemic and the emergence of Mtb strains resistant to standard antibiotic treatment.

In the Science paper, Einstein researchers and collaborators at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, describe a two-drug combination that inhibited both the growth of susceptible laboratory strains and 13 XDR-TB strains isolated from TB patients in laboratory culture medium. The drugs truly work in tandem: one of them (clavulanate) inhibits a bacterial enzyme, β-lactamase, which normally shields TB bacteria from the other antibiotic (meropenem, a member of the β-lactam class of antibiotics).

The idea of inhibiting β-lactamase to make β-lactam antibiotics effective isn't new ─ which is why β-lactamase inhibitors, such as clavulanate, already exist. The strategy finally proved effective against XDR-TB because Einstein researchers conducted a detailed, methodical investigation of the β-lactamase enzyme to find the ideal combination of β-lactamase inhibitor and β-lactam antibiotic. β-lactam antibiotics include penicillin, the first antibiotic discovered and one of the safest.

Amoxicillin/clavulanic acid and meropenem have excellent safety profiles and are FDA-approved for adult and pediatric use.

In parts of Asia, 70 percent of new TB cases are multi-drug resistant, meaning they don't respond to the two antibiotics most commonly used against TB. Recently, an even greater health threat has emerged: extensively drug-resistant (XDR) bacteria that resist at least four of the drugs used to treat TB and can prove deadly. The cure rate for patients infected with XDR-TB ranges from 12 percent to 60 percent.

XDR-TB is still rare in the United States ─ 83 cases were documented by the Centers for Disease Control and Prevention between 1993 and 2007. However, worldwide, the figures are much larger and on the rise. In 2004, the World Health Organization (WHO) estimated a half-million people were infected with multi-drug resistant TB, and in some countries the percentage of XDR-TB cases is growing. In the only global TB study to date, the WHO reported in 2008 that 15 percent of multi-drug resistant TB cases in Ukraine, for example, were XDR-TB.

Current TB therapy requires four antibiotics that must be taken for at least six months.

Currently, clavulanate is not commercially available, except in combination with β-lactam antibiotics, such as amoxicillin. This combination of clavulanate and amoxicillin has been used against other types of bacteria to inhibit β-lactamase activity and make β-lactams more effective. But it has rarely been used against TB, which is why the β-lactamase inhibitor/β-lactam approach had not been comprehensively analyzed until now.

Additionally, as part of a joint collaboration between Montefiore Medical Center, The University Hospital and Academic Medical Center for Albert Einstein College of Medicine, and the Nelson Mandela School of Medicine in Durban, South Africa, a separate trial slated for 2009 will test the potency of the drug combination in a smaller number of TB patients. If the results are successful and funding is available, a trial involving a larger number of XDR-TB patients will be conducted. Montefiore researchers chose South Africa for the clinical studies because of its disproportionately high number of XDR-TB cases. In some areas of South Africa, one in four TB cases is extensively drug resistant. source

My comment: This news is of course wonderful. What makes me kind of curious is the high rite of XDR-TB in Africa. Because people often claim the resistance of bacteria to antibiotics is due to the increased use of antibiotics. Well, that certainly cannot be the case in Africa where medicaments are still not vastly used. Then how will they explain this mutation! (As for Ukraine-it's quite obvious why the big number-Chernobil!)

AIDS: Microbicide gel 'highly encouraging' in lab tests

March 4th, 2009

The dogged search for a vaginal gel to thwart the AIDS virus earned some good news on Wednesday as scientists announced that a cheap, commonly-used compound shielded monkeys from a lethal cousin of HIV.

They cautioned that a long road lies ahead before the microbicide can be verified as safe and effective for humans but hailed the outcome as a tremendous boost.

A cream that blocks or kills the human immunodeficiency virus (HIV) is a cornerstone of efforts in the fight against AIDS. It would be especially useful for women in sub-Saharan Africa, at risk from coercive sex from HIV-infected partners.

But the quest has suffered many blows. They include two trials that, dismayingly, found women who used a prototype gel ran a greater risk of HIV than those who used a dummy lookalike.

In a study published in Nature, researchers at the University of Minnesota tested a compound called glycerol monolaurate (GML).

GML exists naturally in the human body but is already licensed as an antimicrobial and anti-inflammatory agent in cosmetics and toiletries and as an emulsifier in foods.

Their hunch was that GML interferes with signalling processes in the immune system, thus blocking HIV's rampage at a key stage. When the virus enters the body, defence systems unleash a cascade of orders, dispatching so-called T immune cells to the site of the infection. It is these cells that are then hijacked by HIV and turned into virus-making mini-factories, enabling the agent to proliferate throughout the bloodstream.

"Even though it sounds counter-intuitive, halting the body's natural defence system might actually prevent transmission and and rapid spread of the infection," said chief investigator Ashley Haase.

The team gave a vaginal application of GML gel to five rhesus macaque monkeys and exposed them and a comparison group of five other animals to two large doses of simian immunodeficiency virus (SIV) -- the monkey equivalent of HIV.

Over the next two weeks, four of the control group contracted SIV. But none of the GML-treated group showed any acute infection, even though they were given up to two further shots of the virus.

GML, said the paper, breaks a "vicious cycle" of immune-system signalling and inflammatory response in the cervix and vagina.

Each dose of GML used in the experiment cost less than one US cent (0.75 of a euro cent).

He added that the compound had been repeatedly tested as safe and had no effect on beneficial vaginal bacteria.

Last month, scientists reported the first positive trial of a microbicide, a formula called PRO 2000, but said it reduced the risk of infection only by around 30 percent.

This is only half of the minimum benchmark for success. Availability of a microbicide that is 60 percent effective would avert two and a half million infections over three years, according to a 2003 mathematical study. source

My comment: This would be, of course, cool, but let's not get over enthusiastic, because most of the rapes occur without previous warning, so the woman cannot know when she'll have sex in order to put some gel prior to the intercourse. And obviously she can put the gel all day all year, because even the cost of .75$ is still quite much for Africa. But still, it sounds great.

Small molecules block cancer gene

March 10th, 2009

Finding molecules that block the activity of the oncogene Stat 3 (signal transducer and activator of transcription) required screening literally millions of compounds, using computers that compared the structure of the cancer-causing gene to those of the small molecules, said a Baylor College of Medicine researcher in a report that appears in the current online issue of the journal PLoS One .

It was worth the effort, said Dr. David J. Tweardy, professor of medicine and molecular and cellular biology and chief of the division of infectious diseases at BCM, because it could point the way to better treatment of breast and other cancers, as well as , asthma, and inflammatory bowel disease.

In other words, Tweardy and his colleagues identified an area on the Stat3 molecule that was important to its activity. Stat3 actually is critical in keeping malignant cells alive in the majority of cancers.

Once Tweardy and his colleagues had identified a critical "pocket" on Stat3, they used the computer to look for that would fit in that pocket and block the ability of Stat3 to maintain the cancer cell. That screen of nearly 1 million small molecules identified three likely compounds.

Assays of these compounds showed that they did halt the activity of Stat3 in the laboratory. With that information, Tweardy and his colleagues then screened another 2.47 million compounds for similarity to the original three.

They found another three. While five of the six had some activity in stopping Stat3, one - called 188 - was most effective. Three of the six worked to induce programmed cell death or apoptosis in breast cancer cell lines.

"It induced death in those that depend for their survival on Stat3," said Tweardy.

Tweardy and his colleagues are now looking at second generation compounds that promise to be even more effective against Stat3. source

My comment: Quite cool, right! This one is really exciting, because it really offers a way to kill cancer. And it's all based on something so simple. I like it a lot :)

Vaccine to prevent colon cancer being tested in patients

March 19th, 2009

Researchers at the University of Pittsburgh School of Medicine have begun testing a vaccine that might be able to prevent colon cancer in people at high risk for developing the disease. If shown to be effective, it might spare patients the risk and inconvenience of repeated invasive surveillance tests, such as colonoscopy, that are now necessary to spot and remove precancerous polyps.

Colon takes years to develop and typically starts with a polyp, which is a benign but abnormal growth in the intestinal lining, explained principal investigator Robert E. Schoen, M.D., M.P.H. Polyps that could become cancerous are called adenomas.

In a novel approach for , the Pitt vaccine is directed against an abnormal variant of a self-made cell protein called MUC1, which is altered and produced in excess in advanced adenomas and cancer. Vaccines currently in use to prevent cancer work via a different mechanism, specifically by blocking infection with viruses that are linked with cancer.

"By stimulating an against the MUC1 protein in these , we may be able to draw the immune system's fire to attack and destroy the ," Dr. Schoen said. "That might not only prevent progression to cancer, but even polyp recurrence."

According to co-investigator Olivera Finn, Ph.D., professor and chair of the Department of Immunology at Pitt's School of Medicine, MUC1 vaccines have been tested for safety and in patients with late-stage and pancreatic cancer.

"Patients were able to generate an immune response despite their cancer-weakened immune systems," she noted. "Patients with advanced adenomas are otherwise healthy and so they would be expected to generate a stronger immune response. That may be able to stop precancerous lesions from transforming into malignant tumors."

About a dozen people have received the experimental vaccine so far, and the researchers intend to enroll another 50 or so into the study.

People who develop advanced adenomas undergo regular surveillance with colonoscopy so that recurrent polyps, which are common, can be removed before matters get worse, Dr. Schoen said.

"Immunotherapy might be a good alternative to colonoscopy because it is noninvasive and nontoxic," he noted. "And, it could provide long-term protection."source

My comment: Now, that's also very cool. Although I generally hate unnecessary vaccines, this one is quite cool, because it can be applied only to people with hight risk factor and it can spare them the colonoscopy that is quite unpleasant and some people even say it's dangerous.

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