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...

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....

Ref : http://www.pnas.org/content/early/2009/04/30/0811514106.abstract?sid=4175ffe7-b04b-4fc3-9270-af9a9bd5d953

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...

Ref :http://www.springerlink.com/content/g6725k414863446q/?p=1f9d7cac7a4e4867af336327382c16bd&pi=4

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...

Ref :http://www.thoracic.org/sections/publications/press-releases/conference/articles/2009/abstracts-and-press-releases/cannon.pdf

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...

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.

Ref : http://www.ox.ac.uk/media/news_stories/2009/090423.html

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..

Ref : http://www.translational-medicine.com/content/pdf/1479-5876-7-34.pdf

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...

RNA interference approach for prevention and treatment of STDs ?

In my earlier blog “Diverse 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.

Ref : http://www.nature.com/nmat/journal/vaop/ncurrent/abs/nmat2444.html

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

Iloperidone

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.

Ref :http://www.fda.gov/bbs/topics/NEWS/2009/NEW02009.html