Combination of Phentermine & Topiramate for obesity treatment......

We know that Phentermine (see structure) is  an appetite suppressant of the  amphetamine and phenethylamine class. It is approved as an appetite suppressant to help reduce weight in obese patients. Its  usually used for short-term and in combination with exercise, diet and behavioral modification. Is typically prescribed for individuals, who are at increased medical risk because of their weight and works by helping to release certain chemicals in the brain that control appetite.  

Mode of action : Phentermine, in doses clinically used, works on the hypothalamus portion of the brain to release norepinephrine, a neurotransmitter or chemical messenger that signals a fight-or-flight response, reducing hunger. Phentermine works outside the brain as well to release epinephrine or adrenaline causing fat cells to break down stored fat, but the principal basis of efficacy is hunger-reduction. At high doses, phentermine releases serotonin and dopamine as well, but such doses are never used in clinical medicine.  

Topiramate (structure below), is a known anticonvulsant agent and  also  reported  for  the  treatment   of

SSRI-  induced weight gain in anxiety disorders. However a combination   of these two drugs (Phentermine & Topiramate) has been  tried by VIVUS, Inc. and has submitted New Drug Application (NDA)   to the U.S. Food and Drug Administration (FDA) seeking approval of Qnexa (Phentermine & Topiramate combination) - its investigational drug for the treatment of obesity, including weight loss and maintenance of weight loss, in patients who are obese or overweight with co-morbidities such as hypertension, type 2 diabetes, dyslipidemia or central adiposity.

The NDA submission follows the successful completion of the phase 3 program for Qnexa, including the recently announced results from the two pivotal, year-long phase 3 studies (EQUIP and CONQUER). In these trials, patients treated with all three doses of Qnexa achieved significant percent and categorical weight loss compared to placebo and met regulatory requirements for weight loss products as defined in the current FDA Guidance for Developing Products for Weight Management. Patients treated with Qnexa also had significant dose-related improvements in a variety of secondary endpoints including reductions in cardiovascular and metabolic risk factors. Hope people with obesity, will breathe a sigh of relief in the near future....

Ref : http://ir.vivus.com/releasedetail.cfm?ReleaseID=433172

Gren tea for new type of H1N1 Flu ......

In continuatation of my update on Epigallocatechin gallate (EGCg), I find this info something different and interesting too. We are aware about the antioxidant and anticancer activities of this compound, but now researchers from Central Research Institute of ITO EN, Ltd., & School of Pharmaceutical Sciences, University of Shizuoka have found the same compound to inhibits flu infection. As per the researchers claim, the compound had an inhibitory effect against three types of influenza viruses, including the swine-origin H1N1 virus that caused pandemic flu in 2009, and that its effect did not depend on the type of virus. These findings once again suggest that green tea is effective in preventing flu.

Gargling with green tea has already proved to prevent the onset of seasonal flu. It has become clear that catechin, a major type of polyphenol in green tea, plays a major role in prevention of flu infection, and that, among different types of catechin, EGCg displays the strongest antiviral activity. More interestingly, the researchers have conducted examinations to see if EGCg also shows antiviral activity against the new type of H1N1 virus, regardless of viral subtypes.

Solutions containing three types of viruses including the H1N1 virus were mixed with EGCg extracted from green tea. The mixture was added to cultured cells, which were thus infected. The cells were incubated for a set period of time, and the number of infected cells was counted. The concentration of EGCg at which virus infection was inhibited to 50% of the level of infection without EGCg was calculated.

The experiments showed that EGCg prevented flu virus infections at lower concentrations than Amantadine (a drug used to prevent and treat flu). A typical concentration of EGCg in green tea infused from a teapot is reported as 5,000-7,000 micromoles/L. Therefore, these results indicate that green tea diluted 1,000-fold or more is effective to halve infections by three types of viruses, including H1N1.

Those interested to know the details about green tea can visit the site.

Ref : http://www.itoen.co.jp/eng/corporate_info/index.html

Bromo furanones a new class of antimicrobials.....

We know that Candida albicans is the most virulent  Candida species of medical importance, which presents a great threat to immunocompromised individuals such as HIV patients. Candida albicans is carried by about 75 percent of the public. Typically the fungus is harmless but, in individuals with HIV or otherwise compromised immune systems, it can cause candidiasis, which has a high mortality rate. The fungi can also form biofilms that attach to surfaces and are up to 1,000 times more resistant to anti-fungals.

Currently, there are only four classes of antifungal agents available for treating fungal infections: azoles (Diflucan, flucanazole), polyenes, pyrimidines, and echinocandins. The fast spread of multidrug resistant C. albicans strains has increased the demand for new antifungal drugs.

Now two Syracuse University scientists have developed new brominated furanones (see structure) that exhibit powerful anti-fungal properties.

As per the claim by the researchers, the compound exhibited more than 80 percent. Structure and activity of this class of furanones reveals that the exocyclic vinyl bromide conjugated with the carbonyl group is the most important structural element for fungal inhibition. Furthermore, gene expression analysis using DNA microarrays showed that 3 μg/mL of 4-bromo-5Z-(bromomethylene)-3-butylfuran-2-one (BF1) upregulated 32 C. albicans genes with functions of stress response, NADPH dehydrogenation, and small-molecule transport, and repressed 21 genes involved mainly in cell-wall maintenance.

Interestingly, only a small overlap is observed between the gene expression changes caused by the representative brominated furanone in this study and other antifungal drugs reported in literature. This result suggests that brominated furanones and other antifungal drugs may target different fungal proteins or genes.

The existence of such new targets provides an opportunity for developing new agents to control fungal pathogens which are resistant to currently available drugs.

The research team has also shown previously that these furanones inhibit bacterial biofilm formation; thus they may help control chronic infections where biofilms often appear, on surgical, dental and other implants. Hope broad spectrum of other potential capabilities make this class of compounds a new way to combat the microbes in the days to come...

Ref : http://springerlink.com/content/92735526v5013088/

Mitaplatin as a better anticancer agent.......

In continuation of my update on Platinum compounds as anticancer drugs, I find  this one more interesting info to share with. MIT chemists have developed a new platinum compound that is as powerful as the commonly used anticancer drug cisplatin but better able to destroy tumor cells.

As per the claim by the researchers, glycolytic metabolism of most solid tumors, known as the Warburg effect, is associated with resistance to apoptosis that enables cancer cells to survive. Dichloroacetate (DCA) is an anticancer agent that can reverse the Warburg effect by inhibiting a key enzyme in cancer cells, pyruvate dehydrogenase kinase (PDK), that is required for the process. DCA is currently not approved for cancer treatment in the USA. With this idea behind researchers have prepared the new compound by combining dichloroacetate, DCA and cisplatin. Mitaplatin, thus obtained has two DCA units which are appended to the axial positions of a six-coordinate Pt (IV) center.

As per the claim by the authors, the negative intracellular redox potential reduces the platinum to release cisplatin, a Pt (II) compound, and two equivalents of DCA. By a unique mechanism, mitaplatin thereby attacks both nuclear DNA with cisplatin and mitochondria with DCA selectively in cancer cells. The cytotoxicity of mitaplatin in a variety of cancer cell lines equals or exceeds that of all known Pt (IV) compounds and is comparable to that of cisplatin.

Mitaplatin alters the mitochondrial membrane potential gradient of cancer cells, promoting apoptosis by releasing cytochrome c and translocating apoptosis inducing factor from mitochondria to the nucleus. Cisplatin formed upon cellular reduction of mitaplatin enters the nucleus and targets DNA to form 1,2-intrastrand d(GpG) cross-links characteristic of its own potency as an anticancer drug. These properties of mitaplatin are manifest in its ability to selectively kill cancer cells cocultured with normal fibroblasts and to partially overcome cisplatin resistance. Further studies like mice transplanted with human tissues are to be substantiated, in my opinion its a good achievement...

Ref : http://www.pnas.org/content/early/2009/12/09/0912276106.abstract?related-urls=yes&legid=pnas;0912276106v1

Mode of action of Cordycepin (a drug from cordyceps mushroom) established.....

We know that Cordycepin, or 3'-deoxyadenosine (known polyadenylation inhibitor),   was initially extracted from fungi of genus Cordyceps, (Cordyceps is a strange parasitic mushroom that grows on caterpillars). 3'-Deoxy adnosine has shown to possess diverse activities such as anti-proliferative, pro-apoptotic and anti-inflammatory effects. Properties attributed to cordyceps mushroom in Chinese medicine made it interesting to investigate and it has been studied for some time. In fact, the first scientific publication on cordycepin was in 1950 . Now it can be prepared from a cultivated form and also by synthetically. The problem was that although cordycepin was a promising drug, it was quickly degraded in the body. Now researcher Dr. de Moor has come up with interesting explanation about how the drug works.

The team has observed two effects on the cells: at a low dose cordycepin inhibits the uncontrolled growth and division of the cells and at high doses it stops cells from sticking together, which also inhibits growth. Both of these effects probably have the same underlying mechanism, which is that cordycepin interferes with how cells make proteins. At low doses cordycepin interferes with the production of mRNA, the molecule that gives instructions on how to assemble a protein. And at higher doses it has a direct impact on the making of proteins. More interestingly, the team has developed a very effective method that can be used to test new, more efficient or more stable versions of the drug in the Petri dish...

Ref : http://www.bbsrc.ac.uk/media/releases/2009/091223-new-insights-mushroom-derived-drug-for-cancer.html

Trabectedin for advanced soft tissue sarcoma....

Patients with a rare form of cancer called advanced soft tissue sarcoma could now benefit from a new drug called trabectedin, after the National Institute for Health and Clinical Excellence (NICE) approved the drug for NHS use.The same drug was given orphan status for ovarian cancer & soft tissue sarcoma by USFDA. Hope patients suffering from soft tissue sarcoma will breathe a sigh of relief.

Research suggests that the drug may extend life by at least three months more than other NHS treatments and that it may therefore be beneficial for some of the 500 to 600 people in England and Wales with advanced soft tissue sarcoma.

Under the latest guidance, the drug is recommended as a treatment for people with advanced soft tissue sarcoma who have previously failed to respond to treatment with anthracyclines and ifosfamide, or who are unable to tolerate those treatments. More...

Pyramidine core- a new drug for drug resistant non small cell lung cancers

Dana-Farber investigators hypothesized current agents lose their potency because they don't bind as tightly or fully to the EGFR T790M protein as they ideally should. To improve the fit, researchers led by chemical biologist Nathanael Gray, PhD, prepared a group of inhibitors with a different structural scaffold, known as a pyrimidine core, which, it was thought, would mesh more thoroughly. They lab-tested the agents in NSCLC cells with EGFR T90M and found several that were up to 100 times more potent than quinazolines [erlotinib (Tarceva), gefitinib (Iressa), and cetuximab (Erbitux)] in restricting cell growth. As an unexpected bonus, these compounds were nearly 100 times less powerful at slowing the growth of cells with normal EGFR, suggesting they would be less likely to produce side effects than current drugs. The agent which performed the best is the pyrimidine WZ4002. Those interested, can watch the video description (Pasi Jänne).

http://www.dana-farber.org/abo/news/press/2009/research-yields-new-agent-for-some-drug-resistant-non-small-cell-lung-cancers.html

Novel nanotechnology heals abscesses caused by resistant staph bacteria

Novel nanotechnology heals abscesses caused by resistant staph bacteria

New three-drug combination for multiple myeloma ! ...

The regimen, known as RVD, combined the drugs Revlimid - (lenalidomide), Velcade - (bortezomib) and dexamethasone, which previously were found to be highly effective in multiple myeloma patients who had relapsed or no longer responded to first-line therapies.

Fifteen of the 35 newly diagnosed patients in the open-label phase 2 portion of the study subsequently underwent autologous (using their own blood-forming stem cells) transplants, a standard treatment for multiple myeloma and did very well.

For the entire group, after a median 19.3 months of follow up, the median time-to-progression (TTP) of the disease, progression-free survival (PFS), and overall survival (OS) had not yet been reached, according to the presentation. The estimated TTP and PFS at one year are 76 percent, and the estimated one-year overall survival is 100 percent, the results showed.

The more interesting part of the study is that the high response rate was not affected by the specific genetic characteristics of the patients' disease. Patients with so-called "adverse cytogenetics" are at higher risk for treatment failure and death, but in the current study the drug combination worked as well for them as it did in patients with more favorable cytogenetic features.

Except for the main adverse effect, peripheral neuropathy (numbness or pain in the extremities), which typically cleared up after dosages were lowered and the treatment was completed.

The combination has now gone into large phase 3 clinical trials, and the researchers think that this regimen has the potential to be a new standard of treatment in multiple myeloma....

http://www.dana-farber.org/abo/news/press/2009/multiple-myeloma-patients-experience-high-response-rate-with-new-three-drug-combination.html

Apremilast a new hope for severe Psoriasis...

About apremilast :

(S)-N-{2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methanesulfonyl- ethyl]- 1,3-dioxo - 2,3 -dihydro - 1H-isoindol-4-yl}acetamide.

Apremilast, is a member of a proprietary pipeline of novel small molecules with anti-inflammatory activities that inhibit the production of multiple proinflammatory mediators including, PDE-4, TNF-alpha, interleukin-2 (IL-2), interferon-gamma, leukotrienes, and nitric oxide synthase.

Now Celgene announces positive data from its apremilast Phase IIb study for plaque-type psoriasis.

As per the claim by the company, 41% of patients treated with 30mg of oral apremilast BID achieved a PASI-75 after 16 weeks (p<0.001).

Ref : :http://ir.celgene.com/phoenix.zhtml?c=111960&p=irol-newsArticle&ID=1365878&highlight=

Treprostinil as IV infusion reduces breathlessness in PAH patients...

The treatment, continuous intravenous (IV) treprostinil, (see structure, the drug has already been approved by the U.S. Food and Drug Administration for the treatment of pulmonary arterial hypertension PAH) based on its similarity to an approved treatment delivered subcutaneously (directly into the skin). Practicing physicians, had hesitated to endorse the treatment because it did not have its own placebo-controlled study. But now the researchers from University of Rochester Medical Center, have come up with interesting results.

The more interesting part of their research is that PAH patients had higher than normal blood levels of factors known to play central roles in the clogging of arteries as part of major diseases like atherosclerosis and hypertension, including angiopoietin-2 (Ang-2) and platelet derived growth factor. Treatment with treprostinil was associated with lowers levels of Ang-2.

Though the mode of action has to be established (relaxing muscles surrounding blood vessels for easier blood flow and turning off sticky ingredients that cause blood clots e.g. platelets) , its is a good achievement. Treprostinil-treated patients feel like they are breathing easier because their lung arteries, not the lungs themselves, are working more efficiently. Better understanding of the mechanisms involved may lead to refinements in drug design; for example, blocking the effects of Ang-2 to treat the disease (may be easier on patients than a continuous IV infusion). Though further studies are essential, its a good achievement and hope in the days to come people with PHT will definitely breathe a sigh of relief instead of breathlessnessssss.....

Source : http://www.urmc.rochester.edu/news/story/index.cfm?id=2711

FDA approves Olanzapine as Extended Release Injectable Suspension.....

In continuation of my update on drug development for schizophrenia , am sharing this info. The U.S. Food and Drug Administration (FDA) approved ZYPREXA RELPREVV (olanzapine) For Extended Release Injectable Suspension for the treatment of schizophrenia in adults. Different from both oral and injected short-acting formulations, long-acting formulations of antipsychotics allow for stable concentrations of the active drug to remain at a therapeutic range for an extended period of time.

The FDA approval is based on a broad clinical data package involving 2,054 patients, in which ZYPREXA RELPREVV was found to be effective in controlling symptoms of schizophrenia, including hallucinations, delusions, apathy and social withdrawal. Efficacy was shown without the need for oral supplementation. Clinical data showed that ZYPREXA RELPREVV dosages (150, 210, 300 and 405 mg) provide therapeutic olanzapine exposure for two or four weeks depending on the dose. More interesting outcome from these trials is that ZYPREXA RELPREVV was found to have a similar safety profile as oral olanzapine, with the exception of injection-related events, including post-injection delirium/sedation syndrome (PDSS).

PDSS events have occurred in < 0.1 percent of injections and approximately 2 percent of patients. The potential for onset of an event is greatest within the first hour after injection. The majority of cases have occurred within the first three hours after injection; however cases have occurred after three hours. All patients largely recovered within 72 hours.....

Ref : http://newsroom.lilly.com/releasedetail.cfm?ReleaseID=429876

Synthetic platelets halt blood-clotting time....

Lavik and co workers made platelets from polymers already used in treatments approved by FDA. They also built the parts of the synthetic platelets that bind to natural platelets from relatively short pieces of proteins (asthey're more stable than longer pieces and cheaper). To avoid formation of an artificial clot, each synthetic platelet is built with a surrounding water shield. Fluorescing compounds showed the synthetic platelets not bound in clots were flushed from the rat model's system in a day. No ill effects were seen in the following week......

More.....Synthetic platelets halt blood-clotting time

Nilotinib more efficiant over Imatinib for (Ph+ CML)....

Nilotinib (see structure) :

Nilotinib, in the form of the hydrochloride monohydrate salt, is a tyrosine kinase inhibitor, approved as Tasigna in USA and the EU for drug - resistant chronic myelogenous leukemia (June 2006), resistant to treatment with imatinib (Gleevec), another tyrosine kinase inhibitor currently used as a first-line treatment.

In a recently held large clinical trial, nilotinib demonstrated greater efficacy over the current gold standard treatment, imatinib, in adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML) in the chronic phase.

As per the claim by the researchers, in the first head-to-head study of these two oral treatments as initial therapy for this life-threatening leukaemia, nilotinib demonstrated statistically significant improvement over imatinib in key measures of effectiveness used in the trial. The trial showed that at 12 months, significantly fewer patients on nilotinib 300mg twice-daily progressed from the initial chronic phase of the disease to the later accelerated or blast crisis phases than those on imatinib 400mg once-daily. This demonstrates that nilotinib provided significantly better control of the disease compared to imatinib.

95% of patients with CML have an abnormality known as the Philadelphia chromosome. This chromosome produces a type of protein called Bcr-Abl, which is responsible for the overproduction of the cancerous white blood cells that are the main feature in Ph+ CML. Nilotinib is a potent and selective inhibitor of the Bcr-Abl protein, thereby inhibiting the production of these cancerous cells.

Ref : http://www.novartis.com/newsroom/media-releases/en/2009/1359764.shtml

Lidocaine IV injection as pain killer after ambulatory surgery ?

We know that, Lidocaine or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.

Now researchers from University of Virginia, Charlottesville, have come up with interesting info about the same drug. As per the claim by the researchers low doses of lidocaine given intravenously can help to control pain after common ambulatory surgery procedures. Intravenous lidocaine may offer a safe, inexpensive, and effective option for improving pain control after minimally invasive or minor surgery, reports the new study led by Dr Danja S. Groves of University of Virginia, Charlottesville. The results are surprising, because local anesthetics such as lidocaine are usually injected close to the nerve to numb the area for surgery. Though the anestheas (higher dose) are toxic, previous studies have found that that IV lidocaine injection is safe in small doses. Though the mode of action and anti inflammatory activity are still to be expalined, is a good achievement...

Ref : http://www.newswise.com/articles/view/559452/