Positive phase III efficacy clinical trial for Fentanyl sublingual spray .....

INSYS Therapeutics, Inc. announced positive results from the pivotal phase III efficacy  trial for patients utilizing the Fentanyl Sublingual Spray (SL Spray) technology to treat breakthrough cancer pain.  The company claims that all primary and secondary endpoints were achieved in the study, and the drug is the first product to ever show statistically significant pain relief when measuring the summary of pain intensity difference at five minutes (SPID(5)) in a phase III breakthrough cancer pain trial using Fentanyl.

Dr. Richard Rauck, a principal investigator in the Phase III study observed,  the sublingual spray demonstrated very rapid, effective pain relief. Patients began to experience meaningful pain relief within five minutes. This observation was supported by the clinical research findings.  As claimed by the researchers, to date, no other transmucosal Fentanyl  (see the general structure) product has produced pain relief this quickly. This  finding is supported with continued pain relief at all subsequent time intervals. 

Hope this easy-to-use oral spray that can produce effective, potent and very rapid pain relief will be a tremendous advantage for the  patients who experience moderate to severe cancer breakthrough pain.....

Ref : http://www.insysrx.com/news.htm

Japanese patent for Archexin (a novel anti-cancer drug)....

Rexahn Pharmaceuticals, Inc., a clinical stage pharmaceutical company commercializing potential best in class oncology and CNS therapeutics, announced that the Japanese Patent Office has issued a patent for its novel anti-cancer compound, Archexin. As per the claim by the company,  Archexin is a first in class, potent inhibitor of Akt protein kinase in the treatment of cancer. 

The AKT pathway is an important therapeutic target for cancer drug discovery as it functions as a main point for transducing extracellular and intracellular oncogenic signals. Moreover, alternations of the AKT pathway have been found in a wide range of cancers. Akt regulates signal processes of cell proliferation and survival, angiogenesis, and drug resistance in cancer. Archexin is being developed to treat solid tumors and has FDA Orphan drug designation for RCC, pancreatic, stomach, glioblastoma, and ovarian cancers. Archexin is in Phase II clinical development for pancreatic cancer as lead indication.

Archexin(R) was fromerly named as RX-0201, is  an oligonucleotide compound that  inhibits the expression of human Akt-1. I am really happy for this approval because, in my opinion this will boost the new field of drugs (ologonucleotides/antisense). I have covered some developments in this field, those interested can read earlier articles...

Combination therapy (Dutasteride & Tamsulosin) more effective for enlarged prostate...

Researchers from UT Southwestern Medical Center, lead by  Dr. Claus Roehrborn have come out with something interesting finding, i.e., two drugs  (Dutasteride, see left structure)  and Tamsulosin (see below structure) commonly prescribed for enlarged prostate yielded better results than either of the medicines alone.

The study, which included more than 4,800 men, is one of the first to compare single and combo medication regimens in such a large group.

 The first group of study participants received the drug dutasteride; the  second group received tamsulosin; and the third received a combination of the two medicines. Researchers found that, the combination therapy to be superior at reducing risk of BPH   progression   (25 % reduction in prostate volume). Interestingly, patients who received the combination therapy also showed a 50 percent reduction of prostate-specific antigen (PSA), a protein produced by both cancerous and noncancerous prostate tissue. 

Compared with tamsulosin alone, the combination of drugs reduced the incidence of acute urinary retention by 67 percent and reduced the need for BPH-related surgery by 70 percent.  They also  found  a 65 percent decrease in the relative risk of acute urinary retention or BPH-related surgery compared with tamsulosin alone and just over a 19 percent reduction compared with dutasteride alone.

Researchers conclude that  this research should provide physicians better information when they decide on a course of treatment for patients with BPH.....

Ref :  http://www.utsouthwestern.edu/utsw/cda/dept353744/files/578603.html

Presentations on Geron's Telomerase Inhibitor at AACR Special Conference

In continuation of my update on Geron's Telomerase Inhibitor..... Geron Corporation, announced several presentations at the American Association for Cancer Research (AACR) Special Conference on The Role of Telomeres and Telomerase in Cancer Research held in Fort Worth, TX between February 27th and March 1st. The conference comprised ten scientific sessions with over fifty oral presentations.

Geron scientists and collaborators presented recent data on the company's telomerase inhibitor, imetelstat sodium (GRN163L), And highlighted the drug's activity against cancer stem cells. As per the claim by the CMO & EVP, Stephen M. Kelsey,   the telomerase inhibitor is showing anti-cancer stem cell activity in a range of preclinical models. In Phase II trials of imetelstat starting this year Greron is targeting malignancies that are thought to be driven, at least in part, by cancer stem cells ....

Ref: http://www.geron.com/media/pressview.aspx?id=1213

Maple Syrup and Maple water contain abscisic acid.....

It has recently been reported that maple syrup contains polyphenols  and shows ORAC (Oxygen Radical Absorbance Capacity, a unit of measurement for antioxidants developed by the NIH)  values which compare to commonly eaten fruits and vegetables such as broccoli. Now, further research on maple syrup and its original form, maple water, conducted by Dr Yves Desjardins and his colleagues (at  Institut des neutraceutiques et des aliments fonctionnels), has revealed that both products contain equally important quantities of terpenes, and in particular, abscisic acid (see structure), a phytohormone whose health benefits have only recently been discovered. 

Vegetable physiologists and botanical researchers have known about the physiological properties of abscisic acid in the vegetable kingdom for a long time, but its health benefits for humans has only recently come to light. Along with other effects, it is known to stimulate insulin release through pancreatic cells and to increase sensitivity of fat cells to insulin, which makes it a potent weapon against  metabolic syndrome and diabetes. So its good to see that maple products contain a whole host of complementary active elements. The sugar molecules which provide the energy and sweetness in maple products are inherently complemented by abscisic acid molecules because they encourage insulin homeostasis. 

The authors conclude that, further studies are obviously needed before one can more accurately understand how eating maple products affects insulin behavior......

Ref : Dr Yves Desjardins et.al., (Emerging Topics in Health Effects of Fruits and Vegetables symposium which forms part of the 28th International Horticultural Congress in Portugal, August 22-27, 2010.)

Oldest epilepsy drug (Ethosuximide) best for Children with "Petit Mal"....

Ethosuximide ( see structure)  is a succinimide anticonvulsant, used mainly in absence seizures. Ethosuximide is considered the first choice drug for treating absence seizures in part because it lacks the idiosyncratic hepatotoxicity of the alternative anti-absence drug Valproic acid. There is some controversy over the exact mechanism by which ethosuximide prevents absence seizures. While the view that ethosuximide is a T-type calcium channel blocker gained widespread support following its proposal, attempts to replicate the initial finding were inconsistent.

Now researchers, lead by Dr. Tracy A. Glauser, Director of Comprehensive Epilepsy Center at Cincinnati Children's Hospital Medical Center, have come up with an interesting finding, i.e., ethosuximide (Zarontin), one of the oldest anti-seizure medications  is most effective at controlling what is called absence or "petit mal" epilepsy, with the fewest side effects. Valproic acid (Valproate, Depakote) came second, and the newest drug, lamotrigine (Lamictal), was third.

The study included children aged 2.5 to 13 years, newly diagnosed with epilepsy and free of other problems, such as autism. They were randomly assigned to one of the three drugs. The study measured primarily whether they were free of seizures without intolerable side effects after 16 weeks, with a few children continuing for as long as 20 weeks. The study also measured how the drugs affected the children's ability to pay attention.

Ethosuximide prevented seizures in 53 percent of the children, slightly less than the 58 percent freedom-from-failure rate of valproic acid but significantly better than the 29 percent for lamotrigine. But only 33 percent of those taking the older drug had significant attention problems, compared to 49 percent of those taking valproic acid, the researchers found. 

Researchers conclude that, it was somewhat unexpected that the oldest of the drugs had as good an effect as the other and better side effects &  the study highlights the importance of looking not only at seizure control but also how the child does otherwise.......

Ref : http://www.cincinnatichildrens.org/about/news/release/2010/epilepsy-trial-3-4-2010.htm

Cabazitaxel improves survival in patients with metastatic hormone-refractory prostate cancer....

Cabazitaxel (see structure), is an orally bioavailable semi-synthetic  derivative of the natural taxoid 10-deacetylbaccatin III with potential antineoplastic activity. Cabazitaxel binds to and stabilizes tubulin, resulting in the inhibition of microtubule depolymerization and cell division, cell cycle arrest in the G2/M phase, and the inhibition of tumor cell proliferation. Unlike other taxane compounds, this agent is a poor substrate for the membrane-associated, multidrug resistance (MDR), P-glycoprotein (P-gp) efflux pump and may be useful for treating multidrug-resistant tumors. In addition, cabazitaxel penetrates the blood-brain barrier (BBB).

Sanofi-aventis recently announced results from a Phase 3 trial which demonstrated cabazitaxel plus prednisone/prednisolone significantly improved overall survival and progression-free survival in patients with metastatic (advanced) hormone-refractory prostate cancer whose disease progressed following treatment with docetaxel-based chemotherapy. 

TROPIC (trial) was designed to assess patients with metastatic hormone-refractory prostate cancer whose disease had progressed following treatment with docetaxel-based chemotherapy. Results showed that the combination of cabazitaxel and prednisone/prednisolone significantly reduced the risk of death by 30%.

Researchers are  happy with these compelling results  and  hope that these results will provide new options and hope for patients with serious diseases, such as metastatic hormone-refractory prostate cancer.....

Ref : http://en.sanofi-aventis.com/binaries/20100304_Asco_GU_en_tcm28-27547.pdf

Pycnogenol counteracts kidney damage due to hyprtension...

Pycnogenol® is the patented trade name for a water extract of the bark of the French maritime pine (Pinus pinaster ssp. atlantica), which is grown in coastal southwest France.  Pycnogenol® contains oligomeric proanthocyanidins (OPCs) as well as several other bioflavonoids (catechin, epicatechin), phenolic fruit acids (such as ferulic acid and caffeic acid), and taxifolin. Procyanidins are oligometric catechins found at high concentrations in red wine, grapes, cocoa, cranberries, apples, and some supplements such as Pycnogenol.

Scientific evidence on its antioxidative capacity and protective action on the vascular system have been published in the most renowned scientific journals. Additional published findings have demonstrated Pycnogenol’s beneficial effects in cardiovascular health (reduces LDL), skincare (e.g., Melasma, erythema, Chronic venous insufficiency), cognitive function, diabetes health, inflammation, sports nutrition, asthma and allergy relief and menstrual disorders, among others.

Earlier research suggested that, supplementation of Pycnogenol® with  conventional diabetes treatment may lower glucose levels and improve endothelial function and may improve symptoms associated with diabetic microangiopathy.

Now researchers lead by Dr. Gianni Belcaro, have come up with an interesting finding.i.e.,  Pycnogenol®  counteracts kidney damage caused by hypertension, lowering urinary proteins and improving blood flow to the kidneys.

The randomized, controlled study conducted by the G D'Annunzio University in Italy investigated 55 hypertensive patients who showed early signs of impaired kidney function, as judged by elevated amounts of proteins found in their urine.  The patients were divided into two groups.  Both groups were treated with anti-hypertensive medication Ramipril and one group of 29 patients took Pycnogenol in addition to the Ramipril.

After six months of treatment with Ramipril, average protein levels decreased to 64 mg per 24-hour period, remaining well above an acceptable level.  Conversely, the group taking Pycnogenol® as an adjunct to Ramipril had an average of only 39 mg per 24-hour period, a decrease of nearly double compared with anti-hypertensive medication taken alone.

The study also found a statistically significant decrease in patients' blood pressure when taking Pycnogenol® in conjunction with Ramipril.  As per the clam by the researchers, the addition of Pycnogenol® decreased both systolic and diastolic pressures by an additional three to six percent.  Pycnogenol® was also found to lower the patients' elevated levels of inflammatory marker CRP, a blood protein associated with the risk for acute cardiovascular events such as heart attack, reducing values to a healthy level.

Researchers conclude that, Pycnogenol® as an adjunct to the medication produced significantly greater results, particularly for kidney function restoration  and Pycnogenol® continues to demonstrate its abilities as a natural solution for the complete cardiovascular system....

Ref :  Dr. Gianni Belcaro et.al., March 2010, Journal of Cardiovascular Pharmacology...

Novel compound found effective against avian influenza virus (H5N1)....

Currently, two neuraminidase (NA) inhibitors, oseltamivir and zanamivir, which must be administrated twice daily for 5 days for maximum therapeutic effect, are licensed for the treatment of influenza. However, oseltamivir-resistant mutants of seasonal H1N1 and highly pathogenic H5N1 avian influenza A viruses have emerged. Therefore, alternative antiviral agents are needed.

Now  researchers from Japan,  lead by Yoshihiro Kawaoka,  have come up with a new neuraminidase inhibitor, R-125489, and its prodrug, CS-8958.  CS-8958 functions as a long-acting NA inhibitor in vivo (mice) and is efficacious against seasonal influenza strains following a single intranasal dose.

As per the claim by the researchers, R-125489 interferes with the NA activity of H5N1 viruses, including oseltamivir-resistant and different clade strains. A single dose of CS-8958 (1,500 µg/kg) given to mice 2 h post-infection with H5N1 influenza viruses produced a higher survival rate than did continuous five-day administration of oseltamivir (50 mg/kg twice daily).

Researchers conclude that, CS-8958 is a promising candidate for a new neuraminidase inhibitor to prevent and treat influenza patients infected with H5N1 and other subtype viruses... 

Ref : Yoshihiro Kawaoka et. al., PLoS Pathogens Feb., 2010

Baked rhubarb may help fight cancer....

Rhubarb (herbaceous perennial plants growing from short, thick rhizomes) is a  group of plants that belong to the genus Rheum in the family Polygonaceae.  They have large leaves that are somewhat triangular shaped with long fleshy petioles and small flowers. While the leaves are toxic, the plants have medicinal uses, but most commonly the plant's stalks (see picture, source : Wikipedia) are cooked and used in pies and other foods for their tart flavour.  A number of varieties have been domesticated for human consumption, most of which are recognised as Rheum x hybridum by the Royal Horticultural Society.

Rhubarb (stem & roots) has been used as a strong laxative (the two  - anthraquinones emodin and rhein are responsible). Rubarb has been used in traditional Chinese medicine & medieval Arabic and European prescriptions. The rhizomes ('roots') contain stilbene compounds (including rhaponticin) which seem to lower blood glucose levels in diabetic mice.

Now,  researchers from Biomedical Research Center at Sheffield Hallam University, lead by Dr. Nikki Jordan-Mahy, have come up with new findings. Researchers found that baking British garden rhubarb for 20 minutes dramatically boosted levels of anti-cancer chemicals called polyphenols. Previous research has shown that polyphenols selectively kill or prevent the growth of cancer cells.

This is the first study to examine the benefits of British rhubarb, specifically a variety grown in South Yorkshire. Earlier research has studied Oriental medicinal rhubarb, which has been used in traditional Chinese medicine for thousands of years. 

Baking and slow stewing offered the best maintenance of colour through preservation of anthocyanin and the highest antioxidant capacity. Baking for 20 min provided well-cooked rhubarb with the highest antioxidant capacity and the highest anthocyanin content, which is important for the aesthetic quality of the dish.  

As per the claim by the researchers, LC–MS analysis putatively identified over 40 polyphenol components in raw rhubarb (including anthraquinone, stilbene, anthocyanin and flavonol derivatives.) Baking caused selective effects on the stability of the different polyphenol components. Initially, the yield of all components increased but there was a drastic decline in the relative stability of anthraquinone aglycones with increasing cooking time and initial evidence for the turnover of other anthraquinone derivatives was obtained. Researchers now plan to study the effect of rhubarb's polyphenols on leukemia.....

Ref : Dr. Nikki Jordan-Mahy, et. al., Food Chemistry, Vol. 119, Issue 2, 15 March 2010, Pages 758-764

Avosentan lower doses for Overt Diabetic Nephropathy ?

Avosentan (see structure) is a potent, selective endothelin A  receptor blocker and there is convincing evidence that the endothelin system contributes to diabetic nephropathy and cardiovascular disease. Many groups are working with this drug.  Now researchers from Schwabing General Hospital and KfH Kidney Centre, in Munchen, Germany have come out with interesting results, as per claim by the lead researcher, Dr.Johannes Mann, the drug avosentan substantially reduces urinary protein loss in people with type 2 diabetes and kidney disease, but the drug causes serious side effects.

Avosentan at either dose (25 & 50 mg) lowered patients' urinary protein excretion by 40%-50% (compared with less than 10% in patients taking placebo), individuals taking the drug experienced a high incidence of serious, sometimes life-threatening side effects. These included complications of fluid overload such as pulmonary edema, as well as congestive heart failure. In addition, there were more deaths in the groups taking avosentan (21 and 17) than in the group taking placebo. 

Dr. Mann noted that the findings from the ASCEND trial highlight the risks and potential benefits of endothelin antagonists in kidney disease patients with proteinuria and will help investigators design future studies to test the drugs' potential. Specifically, lower doses of avosentan may generate more positive results....

Ref : Mann J.F., et. al., J Am Soc Nephrol. 2010 Feb 18.

Serotonin-Specific Reuptake Inhibitor (SSRIs) as antiinflammatory agents?

We know that Selective serotonin reuptake inhibitors or serotonin-specific reuptake inhibitor (SSRIs) are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. They are also typically effective and used in treating premature ejaculation problems as well as some cases of insomnia.  Now researchers from Brighton and Sussex Medical School (BSMS) in the UK, lead by Dr. Sandra Sacre have come up with an interesting findings, i.e., two SSRIs fluoxetine &  citalopram significantly inhibited disease progression of collagen-induced arthritis (CIA) in mice. As per the claim by the researchers both SSRIs exhibited antiinflammatory effects and may provide drug development opportunities for arthritic conditions such as rheumatoid arthritis (RA).

Prior studies (of SSRIs)  have shown that patients with depression,  who respond to treatment with SSRIs display a reduction in cytokine levels (signals that can induce inflammation), suggesting a connection between SSRIs and the immune system. 

In the current study, researchers used a CIA mouse model due to the similarities to human RA, including synovitis, bone erosion and pannus formation. At the onset of arthritis, mice were treated daily for 7 days with a dose of 10 or 25 mg/kg of fluoxetine and 25 mg/kg of citalopram. At the lower dose of fluoxetine the mice showed a small reduction in the clinical score (a combined measure of redness, swelling and joint mobility/deformity) and a slower increase in paw swelling. At a dose of 25 mg/kg, fluoxetine halted disease progression and no further elevation was noted in the clinical score or paw swelling.

Researchers observed reduced inflammation, reduced cartilage and bone erosion, and a preservation of the joint structure in the mice treated with a higher dose of fluoxetine.  Citalopram was not as effective as fluoxetine at inhibiting disease progression in this model. 

They  also observed a decrease in cytokine production from cultures of human RA synovial joint tissues that were treated with SSRIs.  Toll-like receptors (TLRs) are strong activators of immune cells leading to the production of cytokines that can induce inflammation. Fluoxetine was found to inhibit the activation of TLRs more effectively than citalopram. 

Researchers conclude that SSRIs effectively target TLRs contributing to inflammation and could provide therapeutic benefit in RA, they are not ideal candidates to progress into clinical trials (from the data, the  effective inhibition of RA requires levels of the drugs higher than the safe therapeutic dosages.) The authors suggest further study of the role of TLRs in chronic inflammation may uncover drugs that offer an effective treatment of RA in the future..... 

Ref : http://www3.interscience.wiley.com/journal/123235497/abstract

Bitter melon (gourd) extract inhibits breast cancer cell proliferation.....

Momordica charantia (picture, source : wikipedia) is a tropical  and subtropical vine of the family Cucurbitaceae, widely grown for edible fruit, which is among the most bitter of all vegetables. English names for the plant and its fruit include bitter melon or bitter gourd.  Extract of this vegetable is being popularized as a dietary supplement in Western Countries, since it is known to contain additional glycosides such as mormordin, vitamin C, carotenoids, flavanoids and polyphenols.

Momordica charantia has a non-nitrogenous neutral principle charantin (see structure  an insulin-like chemical that can lower blood sugar and cholesterol), and on hydrolysis gives glucose and a sterol.

Now researchers from Saint Louis University, have come up with an in interesting finding, i.e., bitter melon extract, a common dietary supplement, exerts a significant effect against breast cancer cell growth and may eventually become a chemopreventive agent against this form of cancer.

Previous research has shown Momordica charantia, to have hypoglycemic and hypolipidemic effects. Because of these effects, the extract is commonly used in folk medicines as a remedy for diabetes in locales such as India, China and Central America, as per  the claim by  researchers.

Using human breast cancer cells and primary human mammary epithelial cells in vitro, Dr. Ratna  Ray (Professor in the Department of Pathology at Saint Louis University) and colleagues found the bitter melon extract significantly decreased proliferation, of cell growth and division, and induced death in breast cancer cells. These early results offer an encouraging path for research into breast cancer. Researchers claim that, "this study may provide us with one more agent as an extract that could be used against breast cancer if additional studies hold true". 

Ray and colleagues are currently conducting follow-up studies using a number of cancer cell lines to examine the anti proliferative effect of the extract. They are also planning a preclinical trial to evaluate its chemopreventive efficacy by oral administration. Hope they come up with positive results.......

Ref : Dr. Ratna Ray et.al., Cancer Research, 10.1158/0008-5472, February 23, 2010.

Closantel for treating river blindness ?

Closantel (see structure) is a broad-spectrum salicylanilide  anthelmintic used as antitrematode, antinematodes and antiarthropods in combination with benzimidazole anthelmintic such as mebendazole.  Closantel is used also as an acaricide.

Now  scientists  at the  Scripps  Research  Institute,  lead   by  Dr. Christian Gloeckner have discovered a potential new use for the drug closantel, i.e., the drug may be useful in combating river blindness, a tropical disease that is the world's second leading infectious cause of blindness for humans. 

River blindness is caused by thread-like filarial nematode worms, Onchocerca volvulus, which are transmitted among humans through the bite of a black fly. The nematodes then multiply and spread throughout the body. When they die, they cause a strong immune system response that can destroy surrounding tissue, including that of the eye. Currently, the only drug available for mass treatment of river blindness is ivermectin  and it now appears that resistance to that drug is emerging.

Chitin is the protective outer covering that forms part of O. volvulus's outer cuticle. While knowledge of chitin biosynthesis in nematodes is limited, scientists do know that two classes of enzymes are critical for maintenance of the pathway chitin synthases and chitinases, digestive enzymes that break down glycosidic bonds in chitin. The dynamic synthesis and degradation of chitin by these enzymes is a prerequisite for the organism's development and therefore a potential drug target. Therefore, researchers focused on these enzymes. 

In this method,  chitinase's enzymatic activity was monitored by a fluorescent signal  (when a huge decrease in the signal was observed the enzyme was essentially  knocked-out). Researchers  tried in vivo method (Closantel,  completely prevented molting from the L3 to L4 stage) also. As per the claim by the researchers, out of levfloxacin, lomefloxacin, dexketoprofen, and closantel (tried), only closantel was found to exhibit potent enough inhibition to warrant further investigation. 

Researchers conclude that based on its specificity, potency, and ease of synthesis, closantel or one its analogues might represent a promising alternative or adjunct therapy in combination with ivermectin for the treatment of onchocerciasis....

Ref : Christian Gloeckner et. al., Proceedings of the National Academy of Sciences (PNAS)

New evidence that green tea may help fight glaucoma and other eye diseases

In continuation of my update on green tea and its usefulness, I am sharing herewith this interesting article, where in the researchers claim that there is a possibility that green tea may protect against glaucoma and other common eye diseases.....

New evidence that green tea may help fight glaucoma and other eye diseases