Saturday, June 6, 2009

Glutamine for stomach ulcer ?

We know that Glutamine is the most abundant naturally occurring, non essential amino acid in the human body and one of the few amino acids which directly crosses the blood brain barrier. In the body it is found circulating in the blood as well as stored in the skeletal muscles. It becomes conditionally essential (requiring intake from food or supplements) in states of illness or injury.

Dietary sources of L-glutamine include beef, chicken, fish, eggs, milk, dairy products, wheat, cabbage, beets, beans, spinach, and parsley. Small amounts of free L-glutamine are also found in vegetable juices and fermented foods, such as miso.

In one of my earlier blog, I did mention that broccoli, has been found useful against the H. pylori infection, now its the turn of Glutamine-that has been found useful against the infection. Dr. Susan Hagen, Associate Director of Research in the Department of Surgery at BIDMC and Associate Professor of Surgery at Harvard Medical School and group has found that extra glutamine in the diet could protect against gastric damage caused by H. pylori.

Gastric damage develops when the bacteria weakens the stomach's protective mucous coating, damages cells and elicits a robust immune response that is ineffective at ridding the infection. Eventually, she notes, years of infection result in a combination of persistent gastritis, cell damage and an environment conducive to cancer development. Dr. Hagen and her co-authors had previously shown that glutamine protects against cell death from H. pylori-produced ammonia. And further studies revealed that, the damaging effects of ammonia on gastric cells could be reversed completely by the administration of L-glutamine," explains Hagen. "The amino acid stimulated ammonia detoxification in the stomach - as it does in the liver - so that the effective concentration of ammonia was reduced, thereby blocking cell damage', which encouraged the group to hypothesize that a similar mechanism might be at work in the intact stomach infected with H. pylori.

The results are encouraging and are of great importance, because of the fact that the animals exhibited increased expression of three cytokines - interleukin 4, interleukin 10 and transforming growth factor-alpha mRNA. According to the authors these all play an important role in the stomach's ability to protect against damaging effects resulting from other responses to H. pylori infection. And more interestingly-glutamine supplementation may be an alternative therapy for reducing the severity of infection. Thus ptoviding a relief to the patients suffering from H.Pylori. H. pylori bacteria infect more than half of the world's population and were recently identified as a Group 1 carcinogen by the WHO. Hope this inexpensive, easy-to-use treatment could be used to modify the damaging effects of H. pylori infection inthe near future.
Congrats Dr. Susuan and group. ....

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Friday, June 5, 2009

Antiinflammatory activity of H2S gas !

Its something interesting, we knew that a gas which everybody hates and even lethal has been found to possess antiinflammatory activity by Dr. Matt Whiteman from the Peninsula Medical School. The research team investigated the role of H2S in endotoxic shock, which causes a fatal loss of blood pressure and extensive tissue inflammation.

They discovered that when H2S is delivered in a slow and sustained manner, a potent anti-inflammatory effect is produced. Cell signalling molecules that drive inflammation, such as TNFα, IL-1, IL-6 and prostaglandins, were reduced while levels of the body's own anti-inflammatory molecules (i.e. IL-10) were increased. We know the side effects of NSAIds and even the so called nonulcerogenic NSAIds have side effects (except for those with selectice inhibitors of 5-LO and CO), most of them have side effects. Hope the outcome of this research will lead to compounds which can overcome the side effects. Thus generating H2S in a controlled and sustained manner offers the potential for the development of a new group of anti-inflammatory drugs or lead to the modification of existing drugs so they also release H2S and hopefully come with less gastrointestinal side-effects.

Hope, using H2S donating molecules to control H2S delivery in the body could pave the way for the development of novel approaches to the treatment of inflammatory disorders. Congrats Dr. Matt Whiteman and his group for this interesting finding...

Wednesday, June 3, 2009

Mechanism of Antibiotic Resistance Explained !

We all know that the introduction of antibiotics as drugs in the treatment of bacterial infections in the post-WWII years was a revolutionized medicine, and dramatically improved the health condition on a global scale. 60 years later now, the growing antibiotic resistance among pathogens has heavily depleted the arsenal of entailed effective antibiotic drugs and especially in the case of TB, combination of 4 drugs is being used and don't know what happens ?. Now thanx to Prof. Måns Ehrenberg for his novel discovery i.e., inhibiting the "drug efflux pumps" in bacteria, which function as their defence mechanisms against antibiotics, can mask the effect of mutations that have led to resistance in the form of low-affinity drug binding to target molecules in the cell. This is shown by researchers at Uppsala University in a new study that can provide clues to how the development of resistance to antibiotics in bacteria can be delayed.

This new study, experimentally and theoretically explained how the inhibition of these drug efflux pumps can completely mask the resistance effect of mutations that reduce the affinity of antibiotics to their target molecules in the bacteria cell. The effect of the mutations is entirely hidden when the pumps are unable to remove the antibiotic sufficiently quickly in relation to the dilution of the antibiotic through cell growth and cell division.

A new way for drug discovery....

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Tuesday, June 2, 2009

Auranofin an arthritis drug as new antibiotic?

Traces of mineral selenium is found in a number of proteins in both bacterial cells and human cells called selenoproteins. Associate Professor William Self's research shows that interrupting the way selenoproteins are made can halt the growth of the super bug Clostridium difficile and Treponema denticola, a major contributor to gum disease.

Infections of Clostridium difficile (C-diff) lead to a wide range of illnesses ranging from severe diarrhea to colitis, which can cause death. It's a life-threatening problem in hospitals and nursing homes worldwide, and the number of cases is on the rise. There are an estimated 500,000 cases per year in the US alone. Between 15,000 to 20,000 people die each year while infected with this superbug. Treponema denticola is one of leading causes of gum disease and costs individuals thousands of dollars in dental care each year.

The significance of the research lies in the fact that, the gold drug Auranofin used to treat arthritis, impacted selenium's metabolism process. The chemical reaction changes the selenium, which prevents bacteria from using it to grow. Auranofin is an FDA-approved gold salt compound that is used to control inflammation and is already known to inhibit the activity of certain selenoproteins. Since certain bacteria, such as C. difficile, require selenoproteins for energy metabolism, the drug acts as a potent antimicrobial halting the growth of the bacteria. The initial studies with C. difficile led to studies with T. denticola, known for several years to require selenium for growth. While testing the gold salt, Self's group also uncovered another surprise; the stannous salts found in many antimicrobial toothpastes in the form of stannous fluoride also inhibited the synthesis of selenoproteins. Previous independent research had already established that stannous salts are more effective at preventing tooth decay and inhibiting growth of T. denticola, but the mechanism of this inhibition of growth was not yet known. These findings could lead to new approaches to preventing gum disease. The out come of the research is really interesting because no one in the earlier days thought of this innovative idea, i.e., to block the metabolism of selenium before as a therapeutic approach. And also this may through some light how "gold salt works for arthritis". Congrats Prof. Self and co workers...

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Tuesday, May 26, 2009

Aerosol delivery of antibiotics via nanoparticles !

These days we are hearing lots of news about "nano", I would say anything and everything is nano, now its the turn of drug delivery that too as "aerosol" form!. Though there were lots of research groups trying to do the nanoway, I think this is something really interesting. Carolyn L. Cannon, M.D., Ph.D. from Washington University School of Medicine, and colleagues from the Center for Silver Therapeutics Research at the University of Akron in OH investigated the efficacy of nanoparticle-encapsulated silver-based antibiotics for treating pulmonary infections in a mouse model of pneumonia.

Treatment with antibiotic-laden nanoparticles effectively eliminated respiratory infections in mice that had been inoculated with Pseudomona aeroginosa, a common bacterial species that often infects the respiratory tract in humans, particularly immunocompromised patients, ventilated patients or those with cystic fibrosis. Infected mice that inhaled aerosolized nanoparticles encapsulating silver carbene complexes (SCCs), a novel class of silver-based antimicrobials with broad-spectrum activity, showed a significant survival advantage over the control mice that received nanoparticles without the SCCs. The results are really interesting and even the half the dose is sufficient. Toxicity results are still to be done, however this is a good beginning and hope they will come up with interesting results in the near future...

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Monday, May 25, 2009

Tuberculosis can evade immune response !

As I have mentioned in my earlier blog, more than two million people worldwide die from tuberculosis infection every year. Due in part to inappropriate antibiotic usage, there are a rising number (0.5 million in 2007) of cases of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) tuberculosis. New therapies are needed to treat these dangerous infections. We are aware that immune responses to tuberculosis rarely result in complete eradication of the infection. Instead, TB-infected immune cells promote the generation of chronic inflammation and the formation of granulomas, which are areas where the bacteria are contained but not destroyed. These are the facts that encoucouraged Dr. Susanna Grundstrom Brighenti at the Karolinska Institutet in Stockholm, Sweden, to examine the immune response in patients infected with tuberculosis. And this research is of great significance, since it is the first of its kind. The findings are really interesting and justify why the bacterium is getting resistance to the drugs. Following are the important conclusions by the researchers:

The immune cells responsible for killing the tuberculosis bacteria surrounded the granuloma, these cells had low levels of the molecules necessary to kill the TB. Instead, granulomas had high numbers of regulatory immune cells. These regulatory cells suppress the immune response, resulting in the survival of the tuberculosis bacteria and perhaps contributing to persistent long-term infection. Compartmentalization of the immune response in human TB could be part of the reason why infection is never completely eradicated but instead develops into a chronic disease. Congrats for the interesting findings and wish them further success in their future research...

Sunday, May 24, 2009

New Vaccine for TB...!

We are aware that TB has become one of the most dangerous disease (more than two billion people are infected with tuberculosis – approximately one out of every three people on the planet – and 1.8 million die annually from the disease). And also the strain is getting resistance to the single drug and a combination of Rifampicin, Ethumbutol, Isoniazid and Streptomycin a combo of 4 drugs is being used as treatment. And as per the saying "Prevention is better than Cure", a new vaccine is urgently needed, as BCG is currently the only available vaccine against TB, and provides only variable protection against pulmonary tuberculosis, which accounts for most of the worldwide disease burden. Now thanx to Dr Helen McShane, a Wellcome Trust Senior Clinical Research Fellow, working with Dr Sarah Gilbert, a Reader in Vaccinology, and Professor Adrian Hill, a Wellcome Trust Principal Research Fellow- who together achieved a milestone in developing the vaccine and it has entered Phase IIb proof-of-concept clinical trials, making it the first TB candidate vaccine for more than 80 years to get to this advanced stage of clinical trials in infants. There is still a long road ahead, but this marks an important milestone toward the goal of a more effective TB vaccine. First I congratulate for this milestone and wish them all the success in their attempt.

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Sunday, May 17, 2009

Ginseng as antiinflammatory medicine?

We did know about many uses of Ginseng, (like rejuvenating, aphrodisiac, CNS-stimulant & even diabetes mellitus type 2), but this is something new, ginseng as antiinflammatory medicine !. Allan Lau and co workers from University of Hong Kong, have come up with some interesting claims. The researchers have identified seven ginseng constituents, ginsenosides, which showed immune-suppressive effects. The anti-inflammatory role of ginseng may be due to the combined effects of these ginsenosides, targeting different levels of immunological activity, and so contributing to the diverse actions of ginseng in humans. Of the nine ginsenosides they identified, seven could selectively inhibit expression of the inflammatory gene CXCL-10. To substantiate the claim though, detailed studies are needed (to examine the potential beneficial effects of ginsenosides in the management of acute and chronic inflammatory diseases in humans) , its a good beginning..

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LXR Proteins- New target for antitubercular activity?

As we are aware that TB, has become a major threat to the world and a recent study also reports an estimated one-third of the world population is latently infected with Mycobacterium tuberculosis. And also I did mention (earlier blog) that the strain has got resistance for drugs Rifampicin and hence comibination of drugs (Rifampicin, Isoniazid, Euthumbutol) is being used. The most worst part of this is for those who are already infected with HIV. Not only these are the facts of concern, the worst part of this bacterium is "M. tuberculosis has the ability to adapt and survive for long periods of time within the host macrophage in a state of clinical dormancy". The researchers attribute the reason for this as the switching to lipids as their main carbon source of the nutrient-deficient macrophage phagosome. A recent report implicated that mycobacterial persistence is critically linked to its ability to acquire and catabolize cholesterol from the host. Cholesterol, besides being used as an energy or carbon source, is also essential for the phagocytosis of the bacterium by the macrophage and for the inhibition of phagosome maturation. Recently, liver X receptors (LXRs), LXRα and LXRβ, have emerged as master regulators of macrophage transcriptional programs involved in cholesterol, fatty acid, and glucose homeostasis. All these facts encouraged Kris Huygen and colleagues of Scientific Institute of Public Health, Belgium to identify the role of LXR proteins in the mouse immune response to airway infection with Mycobacterium tuberculosis.

In the study, when compared with normal mice, mice lacking both forms of LXR (LXR-alpha and LXR-beta) were more susceptible to airway infection with Mycobacterium tuberculosis and developed more severe disease. Further analysis revealed that these mice did not mount an effective immune response in the airways. There was no accumulation of immune cells (neutrophils) in the lungs and little evidence of Th1 and Th17 immune responses. Importantly, the marked protection from infection seen in normal mice treated with molecules that target LXRs was accompanied by increased Th1 and Th17 immune responses.

Congrats Kris for this achievement. More...

Sunday, May 10, 2009

RNA interference approach for prevention and treatment of STDs ?

In my earlier blogDiverse use of Nucleic acids”, did mention that there is much interest in the medical uses of nucleic acids. For example, antisense, ribozymes, aptamer and RNA interference (RNAi) technologies are all being developed for potential therapeutic applications. Lots of research is being done in each specified fields and in fact there are already few drugs in “antisense category” and this time something really interesting has been reported by a Post Doc., Dr. Kim Woodrow in the field of RNA interference category. The following lines briefly summerise, what actually RNAis..

RNA interference (RNAi) is a system within living cells that helps to control which genes are active and how active they are. Two types of small RNA molecules – microRNA (miRNA) and small interfering RNA (siRNA) – are central to RNA interference. RNAs are the direct products of genes, and these small RNAs can bind to specific other RNAs and either increase or decrease their activity, for example by preventing a messenger RNA from producing a protein. RNA interference has an important role in defending cells against parasitic genes, viruses and transposons – but also in directing development as well as gene expression in general

The RNAi pathway is found in many eukaryotes including animals and is initiated by the enzyme Dicer, which cleaves long double-stranded RNA (dsRNA) molecules into short fragments of ~20 nucleotides. One of the two strands of each fragment, known as the guide strand, is then incorporated into the RNA-induced silencing complex (RISC). The most well-studied outcome is post-transcriptional gene silencing, which occurs when the guide strand base pairs with a complementary sequence of a messenger RNA molecule and induces cleavage by Argonaute, the catalytic component of the RISC complex. This process is known to spread systemically throughout the organism despite initially limited molar concentrations of siRNA. The importance of the siRNA lies in the fact that “RNAi is selective on gene expression” and hence can be used in the similar fashion like the antisense drugs (already a few drugs by ISIS, Serono and others). I did work on a few oligonucleotides (phosparothiamidates), while working in Innovasynth Technologies Limited Khopoli and know how difficult is to get the precursors of the antisense drugs. In 2006, Andrew Fire and Craig C. Mello shared the Nobel Prize in Physiology or Medicine for their work on RNA interference in the nematode worm C. elegans.

Gene interference therapy is moving rapidly from basic research to application. The PLGA packaging these researchers chose is already approved as safe and non-toxic by the FDA, speeding the path to clinical trials for infectious agents such as HPV and HIV.

Congrats Dr.Kim and co workers for this achievement. The significance of this research is the fact that “a safe and effective administration of potential antiviral drugs - small interfering RNA (siRNA) molecules using densely-loaded nanoparticles made of a biodegradable polymer known as PLGA. The researchers created a stable "time release" vehicle for delivery of siRNAs to sensitive mucosal tissue like that of the female reproductive system.

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Thursday, May 7, 2009

FDA's approval of Iloperidone for schizophrenia....


We did know about the "azepines" for treatment of schizophrenia, but this is a benzisoxazole derivative something interesting. Iloperidone, 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone. The advantage, the researcher claims is that, Iloperidone acts on both dopamine and serotonin receptors, making it a favorable choice against competing drugs clozapine and olanzapine. Clinical studies have shown that some patients treated with iloperidone show reduced extrapyramidal symptoms and weight gain. Phase II testing has shown that effectiveness in humans is possible with as low as 8mg per day, and is tolerable up to 32mg per day. The common side effects with this drug are dizziness, dry mouth, fatigue, nasal congestion, sudden fall in blood pressure causing light-headedness upon standing (orthostatic hypotension), drowsiness, rapid heart rate (tachycardia) and weight increase.

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Safinamide for advanced Parkinson's disease.!

We knew thatSafinamide is a candidate drug against Alzheimer's disease. In 2007, a Phase III clinical trial, was started by Merck-Serono for Safinamide as add-on to dopamine agonist for early idiopathic Parkinson's disease. Now thanx to the same companies for having second phase III trial of Safinamide in advanced Parkinson's disease. Interestingly the same compound has been tested for restless legs syndrome (RLS) and epilepsy As of 2008[update], they are in Phase II.

Safinamide is believed to have a novel dual mechanism of action based on the enhancement of the dopaminergic function (through reversible inhibition of monoamine oxidase-B [MAO-B] and dopamine uptake) and reduction of glutamatergic activity by inhibiting glutamate release.
The earlier trials revealed that safinamide significantly improved motor function in patients with advanced Parkinson's disease. And also the results are encouraging and suggest that safinamide could have benefits beyond motor symptoms. The earlier results not only substantiates the claims but also established something interesting factors like ability of safinamide to improve depressive symptoms are important aspects of PD in addition to the other benefits. Hope after few days safinamide as an add-on therapy to levodopa will come in the market as a boon to those who are mid-to late-stage idiopathic Parkinson's disease (more than five years of disease duration).....
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Sunday, May 3, 2009

Explanation for the side effect of COX-2 inhibitors !....

When I read this article, went back to my research days (1993-1998). We did prepare some triazoles, oxadiazoles, thiadiazoles and their derivatives. The parent triazoles and oxadiazoles were tested for thier antiinflammatory activity by Carrageenan induced rat paw edema, Cotton pellet induced granuloma tissue formation methods and the results were encouraging and were even better tolerated than the standards (Diclofenac and Ibuprofen). We had many research papers that time claiming that, the selective inhibitors of COX-2 and 5-LO are the best NSAIDs. After few years there were three COX-2 inhibitors in the market (namely-Vioxx (rofecoxib), Bextra (valdecoxib) and Celebrex (celecoxib) and we were happy that atleast the ulcerogenecity of NSAIDS has been taken care of. But the days were countable and the first two drugs were withdrawn from the market, because of the cardiovascular toxicity and only celecoxib is available in the market. Now thanx to Dr. Andrew J. Dannenberg (Director of the Weill Cornell Cancer Center) and group, who have come up with a novel explanation for the cardiovascular toxicity of the COX-2 inhibitors. I would say one more "serendipity" to the drug discovery, because the trial was originally designed to identify biomarkers in urine which could indicate the presence of incipient, smoking-related lung disease. The researchers had hypothesized that early-stage lung injury could "turn on" the COX-2 gene, increasing levels of the major prostaglandin metabolite PGE-M in the urine. In addition to determining PGE-M levels, the investigators also looked at levels of the biomarker leukotriene E4 (LTE4), formed by the 5-lipoxygenase (5-LO) pathway. Both biomarkers, representing these two different pathways, are synthesized from arachidonic acid. The 5-LO pathway has also been implicated in inflammation, cancer and cardiovascular problems. The authors found that Celebrex treatment led to increases in urinary LTE4 levels, primarily among individuals who had started out with high PGE-M levels, which indicated that Celebrex 'shunted' or redirected arachidonic acid into the 5-LO pathway from the COX pathway. When one went down, the other went up." This is important because other studies have suggested an important role for the 5-LO pathway in atherosclerosis, heart attacks and stroke. And it is this increased shunting of arachidonic acid into the 5-LO pathway that may help explain why COX-2 inhibitors contribute to cardiovascular problems, the researchers say. Though further studies are essential to substantiate the claims, is a good beginning and hope with selective inhibitors of both COX-2 (cyclooxygenase) and 5-LO (lipoxygenase) are the need of today's world (I did mention in the beginning about that..)...


A best way to deal with flu pandemic......

We are aware most of the virus and baterii are getting resistance to most of the drugs. I have mentioned in my earlier blog how the virus change their structure (mutation) and become resistant to the drugs being used to treat. Scientists are scared, because many countries have started using Oseltamivir (Tamiflu) for global influenza pandemic. As per a report Tamiflu (oseltamivir) has been stockpiled by many countries anxious to be prepared should a flu pandemic strike, but the problem according to an international team of researchers, is that influenza viruses can become resistant to antiviral drugs, and the widespread use of a single drug is likely to increase the risk that a resistant strain will emerge.

The concern is that if such a strain were to spread widely, the effectiveness of antiviral drugs such as Tamiflu in treating infected patients, as well as their ability to slow the spread of a pandemic, would be greatly reduced. A research group lead by Joseph Wu (University of Hong Kong), claims that they have developed a mathematical model to arrive at a conclusion. The team found that treating just the first 1% of the population in a local epidemic with a secondary drug, rather than with oseltamivir, could substantially delay the development of resistance to oseltamivir and this reduction in resistance was predicted to benefit not only local populations, but also those in distant parts of the world where the pandemic would subsequently spread through air travel and more interesting out come of the research is "in the current emerging swine flu situation, the secondary drug could be Relenza (zanamivir), the only other approved drug to which the new H1N1 strain has been found to be susceptible". This strategy say the researchers could be as effective because it delays use of the primary stockpiled drug until a certain proportion of the local population (about 1.5% according to the model) has been infected with virus that remains susceptible to the primary drug - with drug-sensitive virus in the majority as people recover from infection and develop immunity, only a minority of further infections are likely to be resistant to the primary drug.

The researchers say technically, such a delay could be achieved by postponing the launch of any antiviral intervention, but because even a short delay would mean denying antiviral drugs to people who would benefit from them, the researchers instead propose the deployment of a small stockpile of a secondary antiviral during the early phase of the local epidemic. More.....

Friday, May 1, 2009

Pregabalin for restless legs syndrome?

We know that Pregabalin (S)-3-(aminomethyl)-5-methylhexanoic acid), is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It has also been found effective for generalized anxiety disorder and is approved for this use in Europe) and the same compound has been reported as effective treatment of chronic pain in disorders such as fibromyalgia and spinal cord injury

But something new property of this product is being presented in the American Academy of Neurology's 61st Annual Meeting in Seattle (April 25 - May 2, 2009). i.e., the drug can be used as an effective treatment for restless legs syndrome (RLS) and also helps people with the disorder get a better night's sleep.

The 12 week study involved 58 people with RLS. Of the group, 30 people received the drug pregabalin and the rest received placebo. Sleep studies were performed at the beginning and end of the research. Researchers found nearly two-thirds of the people who took pregabalin had no RLS symptoms while taking the drug. For people who still had symptoms, those symptoms had improved by 66 percent while taking the drug, compared to the placebo group where symptoms worsened by 29 percent.

Sleep also improved for those taking pregabalin. The study showed the group spent more time in slow wave sleep, otherwise known as Stage 3 or deep sleep, and they spent less time in the lighter sleep stages known as Stage 1 or Stage 2 sleep compared to those taking placebo. Congrats Dr. Diego Garcia-Borreguero (Director of the Sleep Research Institute in Madrid, Spain) for this achievement. The significance of the research lies in the fact that “compared to all the drugs that are being used to treat RLS , Pregabalin is superior over the others in helping people to get more deep sleep- a main problem with RLS…