Antioxidant in the vegetables for treating Cystic Fibrosis.....

I did mention in my earlier blogs, about the importance of eating broccoli and how it helps to prevent cancer and the authors claimed that the key ingredient that is responsible for this activity (claimed by the authors) is sulforaphane.

Now researchers from the University of Pennsylvania, have found an interesting fact that the antioxidant thiocyanate normally existing in the body protects lung cells from injuries caused by accumulations of hydrogen peroxide and hypochlorite, the active ingredient in household bleach. These potentially harmful chemicals are made by the body as a reaction to infection and injury. In addition, thiocyanate also protects cells from hypochlorite produced in reactions involving MPO, an enzyme released from germ-fighting white blood cells during inflammation.

The research team demonstrated that in three additional cell types used to extend their ideas to other inflammation-related conditions - cardiovascular disease, neurodegeneration, and diabetes - thiocyanate at blood concentrations of at least 100 micromolar (micromoles per liter) greatly reduces the toxicity of MPO in cells, including those lining blood vessels. Humans naturally derive thiocyanate from some vegetables and blood levels of thiocyanate in the general population vary from 10 to 140 micromolar.

So without an adequate dietary supply of thiocyanate (from broccoli & Cauliflower), hypochlorite produced by the body during inflammation would cause additional collateral damage to cells, thus worsening inflammatory diseases, and predisposing humans to diseases linked to MPO activity, including atherosclerosis. Thus the authors claim that delivering thiocyanate directly to the digestive and respiratory systems might be a therapy for CF disease.

Ref :
http://www.pnas.org/content/early/2009/11/11/0911412106.full.pdf+html?sid=2078aa5c-20d6-4a74-b98a-2a5ef6df93d4

Bacterially produced antifungal on skin of amphibians may protect against lethal fungus

Bacterially produced antifungal on skin of amphibians may protect against lethal fungus

Adding one single gene to yeast dramatically improves bioethanol production from agricultural waste

Adding one single gene to yeast dramatically improves bioethanol production from agricultural waste

Picoplatin a better drug than oxaliplatin for colorectal cancer !

In one of my earlier blog, I did mention about the Cisplatin (Cisplatin doubles lung cancer survival time in mice !).

About Cis-platin & other drivatives:

Cisplatin, cisplatinum, or cis-diamminedichloroplatinum(II) is a platinum-based chemotherapy drug used to treat various types of cancers, (sarcomas, some carcinomas (small cell lung cancer, and ovarian cancer), lymphomas, and germ cell tumors. It was the first member of a class of anti-cancer drugs which now also includes carboplatin and oxaliplatin. These platinum complexes react in vivo, binding to and causing crosslinking of DNA which ultimately triggers apoptosis (programmed cell death).

Now its the turn of Picoplatin [see structure , Amminedichloro(2-methylpyridine)platinium)], Poniard Pharmaceuticals, Inc. has come up with some interesting results from its Phase 2 trial of picoplatin in patients with metastatic colorectal cancer (CRC). Picoplatin, given once every four weeks in combination with 5-fluorouracil and leucovorin in the FOLPI regimen, has comparable efficacy to oxaliplatin, given in combination with 5-fluorouracil and leucovorin in the modified FOLFOX-6 regimen, as a first-line therapy for CRC, as assessed by one-year survival rate, progression-free survival (PFS) and disease control. The company claims that, (from the updated proof-of-concept Phase 2 safety and efficacy results) picoplatin could be superior to oxaliplatin as a neuropathy-sparing alternative when used in combination as a first-line treatment for metastatic colorectal cancer.

Source : http://investor.poniard.com/ReleaseDetail.cfm?ReleaseID=424813.

Positive results from mipomersen- a new hope for FH sufferers...

About Familial hypercholesterolemia :

Familial hypercholesterolemia (also spelled familial hypercholesterolaemia) is a genetic disorder characterized by high cholesterol levels, specifically very high low-density lipoprotein (LDL, "bad cholesterol") levels, in the blood and early cardiovascular disease. Many patients have mutations in the LDLR gene that encodes the LDL receptor protein, which normally removes LDL from the circulation, or apolipoprotein B (ApoB), which is the part of LDL that binds with the receptor; mutations in other genes are rare. Patients who have one abnormal copy (are heterozygous) of the LDLR gene may have premature cardiovascular disease at the age of 30 to 40. Having two abnormal copies (being homozygous) may cause severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disorder, occurring in 1:500 people in most countries; homozygous FH is much rarer, occurring in 1 in a million births.

Heterozygous (FH) is normally treated with statins, bile acid sequestrants or other hypolipidemic agents that lower cholesterol levels. New cases are generally offered genetic counseling. Homozygous FH often does not respond to medical therapy and may require other treatments, including LDL apheresis (removal of LDL in a method similar to dialysis) and occasionally liver transplantation.

Recently, Genzyme Corp. and Isis Pharmaceuticals Inc have come up with some intresting results from the drug mipomersen [mipomersen - is an antisense oligonucleotide, with phosphorothioate linkage at 5'- postion and 2'-O-methoxymethyl moety] ( phase 3). As per the claim by the companies, the study met its primary endpoint in an intent-to-treat analysis, with a 25 percent reduction in LDL-cholesterol after 26 weeks of treatment, vs. 3 percent for placebo (p<0.001)>.

The trial met all of its secondary and tertiary endpoints, suggesting that mipomersen may offer potential benefits to patients beyond LDL-C reduction. Patients treated with mipomersen experienced a 27 percent reduction in apolipoprotein B vs. 3 percent for placebo; a 21 percent reduction in total cholesterol vs. 2 percent for placebo; and a 25 percent reduction in non-HDL cholesterol vs. 3 percent for placebo (all p<0.001).>Mipomersen patients’ HDL-C levels increased 15 percent (p=0.035 vs. placebo), which combined with the LDL-C reductions observed, resulted in improved LDL/HDL ratios, a ratio considered an important measure of cardiovascular risk. Mipomersen patients’ LDL/HDL ratios decreased by 34% (p<0.001>Mipomersen a representative of Isis’ leadership in the field of RNA targeted therapeutics will bring a sigh of relief to the sufferers of FH, in the days to come.

I had an opportunity to work with ISIS (as contract R & D, Innovasynth Technologies Limited, Khopoli) and really excited to see the results..

Ref : http://ir.isispharm.com/phoenix.zhtml?c=222170&p=irol-newsArticle&ID=1356364&highlight=

Tranexamic acid for menorrhagia.....

Tranexamic acid (marketed as Cyklokapron in the U.S. and as Transamin in Asia, and Espercil in South America) is often prescribed for excessive bleeding. It is an antifibrinolytic that competitively inhibits the activation of plasminogen to plasmin, a molecule responsible for the degradation of fibrin. Fibrin is the basic framework for the formation of a blood clot in hemostasis. It has roughly 8 times the antifibrinolytic activity of an older analogue, ε-aminocaproic acid.

The U.S. Food and Drug Administration on 16th Nov., 2009 approved Lysteda tablets (tranexamic acid), the first non-hormonal product cleared to treat heavy menstrual bleeding (menorrhagia). Lysteda works by stabilizing a protein that helps blood to clot. Tranexamic acid was first approved by the FDA in 1986 as an injection, under the brand name Cyklokapron, and is used to reduce or prevent bleeding during and following tooth extraction in patients with hemophilia, a hereditary bleeding disorder caused by the lack of a blood clotting factor.

Source : http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm190551.htm

World's first intra-arterial cerebral infusion of Avastin directly into a patient's malignant brain tumor

World's first intra-arterial cerebral infusion of Avastin directly into a patient's malignant brain tumor

Capecitabine combination therapy reduces early breast cancer recurrence...

Capecitabine, is an orally-administered chemo therapeutic agent used in the treatment of metastatic breast and colorectal cancers.

Mode of action :

Capecitabine is a prodrug, that is enzymatically converted to 5-fluorouracil in the tumor, where it inhibits DNA synthesis and slows growth of tumor tissue. The activation of capecitabine follows a pathway with three enzymatic steps and two intermediary metabolites, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR), to form 5-fluorouracil. Its being used (& FDA approved) in the treatment of adjuvant in colorectal cancer, metastatic colorectal cancer and Metastatic breast cancer - used in combination with docetaxel, after failure of anthracycline-based treatment. Also as monotherapy, if the patient has failed paclitaxel-based treatment, and if anthracycline-based treatment has either failed or cannot be continued for other reasons.

Recently, Finnish Breast Cancer Group and published in The Lancet Oncology shows women at intermediate to high-risk of early breast cancer recurrence who received capecitabine as part of their chemotherapy regimen had a 34% reduction in the risk of the disease returning or death, compared with those taking the chemotherapy combination regimen without capecitabin. The pre-planned three-year interim analysis of a randomised, prospective trial compared adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for the treatment of early breast cancer with the standard, non-capecitabine regimen (docetaxel, epirubicin, cyclophosphamide and fluorouracil). The analysis also found that patients taking the capecitabine-containing regimen were significantly less likely to have their cancer spread (distant metastasis) to another part of the body (a 36% reduction in risk was observed). This is the first phase III randomised trial to report efficacy of capecitabine combination therapy in the adjuvant treatment of early breast cancer.

Though capecitabine, has already been shown to be effective in patients with advanced breast cancer, but the most important conclusion the researchers have arrived is "capecitabine-containing regimen in the early stages of breast cancer may offer survival benefits for women".....

Source :http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970307-9/fulltext

Geron publish data on the stem cell research.....

In my earlier blog (Geron plans to advance clinical program for spinal cord injury), I did mention about the clinical program. Now Geron has come up with positive results. As per the claim by the company oligodendrocyte progenitor cells (OPCs) derived from human embryonic stem cells (hESCs), when transplanted into a rodent model of cervical spinal cord injury, reduced tissue damage within the lesion and improved recovery of locomotor function. These data provide preclinical proof-of-concept for the use of GRNOPC1, Geron's hESC-derived oligodendrocyte progenitor product, in patients with cervical spinal cord injuries.

Oligodendrocytes have two main functions in the spinal cord; they produce the myelin that wraps around nerve fibers to enable electrical impulse conduction and they produce other molecules (neurotrophic factors) that help to maintain nerve cells. In spinal cord injury oligodendrocytes are lost, resulting in the loss of myelin and death of nerve cells that can cause paralysis below the injury. The present study, conducted in a cervical model of spinal cord injury, adds to previous work in a thoracic model, which has demonstrated that injection of hESC-derived OPCs into the site of injury improved locomotor function with evidence of remyelination of nerve fibers.

Source : http://www.geron.com/media/pressview.aspx?id=1196

Capsaicin for Postherpetic neuralgia....

About Capsaicin :

Capsaicin,(8-methyl-N-vanillyl-6-nonenamide, (CH₃)₂CHCH=CH(CH₂)₄CONHCH₂C₆H₃-4-(OH)-3-(OCH₃)) is the active component of chili peppers, which are plants belonging to the genus Capsicum. It is an irritant for mammals, including humans, and produces a sensation of burning in any tissue with which it comes into contact. Capsaicin and several related compounds are called capsaicinoids and are produced as a secondary metabolite by chili peppers, probably as deterrents against certain herbivores and fungi. Pure capsaicin is a hydrophobic, colorless, odorless, crystalline to waxy compound.

We know that many pain killer gels are using this and even some companies are trying to establish the anti cancer activity (prostate cancer).

Mode of action :

The burning and painful sensations associated with capsaicin result from its chemical interaction with sensory neurons. Capsaicin, as a member of the vanilloid family, binds to a receptor called the vanilloid receptor subtype 1 (VR1). The resulting depolarization of the neuron stimulates it to signal the brain. By binding to the VR1 receptor, the capsaicin molecule produces the same sensation that excessive heat or abrasive damage would cause, explaining why the spiciness of capsaicin is described as a burning sensation.

Now FDA has approved the Qutenza(TM) (capsaicin) 8% patch, the first and only product containing prescription strength capsaicin, for the management of neuropathic pain due to postherpetic neuralgia (PHN). As per the claim by the company, Qutenza works by targeting certain pain nerves in the area of skin where pain is being experienced. The Qutenza patch is applied by a physician or a healthcare professional. Clinical studies have shown that PHN pain can be reduced for up to 12 weeks following a single one-hour treatment. Up to four patches may be used and patches may be cut to conform to the size and shape of the painful area.

Source : http://ngsx.client.shareholder.com/releasedetail.cfm?ReleaseID=424559

Memantine for Huntington's disease ?

Memantine is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system by blocking NMDA glutamate receptors. Memantine is marketed under the brands Axura and Akatinol by Merz, Namenda by Forest, Ebixa and Abixa by Lundbeck and Memox by Unipharm.

Now researchers from Burnham & University of California have found that, Memantine, which is approved to treat Alzheimer's disease, successfully treated Huntington's disease in a mouse model by preserving normal synaptic electrical activity and suppressing excessive extrasynaptic electrical activity.

Huntington's disease is a hereditary condition caused by a mutated huntingtin gene that creates a misfolded, and therefore dysfunctional, protein. The new research shows that normal synaptic receptor activity makes nerve cells more resistant to the mutant proteins. However, excessive extrasynaptic activity contributed to increased nerve cell death. The research team found that low doses of Memantine reduce extrasynaptic activity without impairing protective synaptic activity.

This finding is of great importance because of the fact that chronic neurodegenerative diseases like Huntington's, Alzheimer's and Parkinson's are all related to protein misfolding and the researchers have shown for the first time that that electrical activity controls protein folding, and if one has a drug that can adjust the electrical activity to the correct levels, one can protect against misfolding and also the research verifies that appropriate electrical activity is protective. They also found that normal synaptic activity was protective. Subsequently, they treated Huntington's disease model mice with both high and low doses of Memantine and found that the low doses were protective by blocking pathological extrasynaptic activity, while high-dose Memantine encouraged disease progression because it also blocked the protective synaptic NMDA receptor activity. Its really good achievement congratulations. After having small clinical trials, larger, international clinical trials are now being planned....


Source : http://www.eurekalert.org/pub_releases/2009-11/bi-rfp111309.php.

Pentamidine for muscle-wasting-disease.....

Pentamidine (salt of isethionate) is an antimicrobial medication primarily given for prevention and treatment of Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii, also formerly known as Pneumocystis carinii pneumonia (PCP), a severe interstitial type of pneumonia often seen in patients with HIV infection. PCP is considered an 'opportunistic infection', endangering only immunodeficient patients such as those with HIV/AIDS. Pentamidine is also used as a prophylactic in patients receiving chemotherapy, as they also have a depressed immune system as a direct side-effect of the drugs used. The mortality of untreated PCP is very high. Additionally, pentamidine has good clinical activity in treating leishmaniasis, sleeping sickness caused by different strains of Trypanosoma, and yeast infections caused by the organism Candida albicans. Pentamidine is also used as a prophylactic antibiotic for children undergoing treatment for leukemia.

Apart from these diverse applications Pentamidine, has been recently found to become a new therapy for an inherited muscular wasting disease, according to researchers at the University of Oregon and the University of Rochester School of Medicine and Dentistry in New
York.

Pentamidine, when tested in genetically altered mice, counters genetic splicing defects in RNA that lead to type 1 myotonic dystrophy - one of nine types of muscular dystrophy -- also known as DM1 and Steinart's disease. Researchers found that pentamidine disrupted the complexes formed by the expanded repeats and the MBNL protein that becomes stuck to them, allowing the protein to return to its proper location in the cell. The compound also inhibited interactions of MBNL with the cytosine-uracil-guanine repeats and partially rescued two splicing errors in the mice. Though further study like testing with patients suffering from DM1 is still to be established, its a good achievement.

Source : http://uonews.uoregon.edu/archive/news-release/2009/11/possible-help-fight-against-muscle-wasting-disease

Statins as anticancer and anti diabetic agents ?

We know that statins are widely used as cholesterol lowering drugs. They act by inhibiting HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway that leads to the synthesis of farnesyl pyrophosphate, a precursor for cholesterol synthesis and the source of lipid moieties for protein prenylation. But researchers from University of Gothenburg, have found that statins might be useful as anticancer and antidiabetic too.

Statins lower cholesterol by blocking certain enzymes involved in our metabolism. However, they have also been shown to affect other important lipids in the body, such as the lipids that help proteins to attach to the cell membrane (known as lipid modification). Because many of the proteins that are lipid-modified cause cancer, there are now hopes that it will be possible to use statins in the treatment of cancer.

Studies show that statins can have a dramatic inhibitory effect on growth and development. As the researchers managed to identify the enzyme involved, they can also explain how the effect arises at molecular level. Not least that they can prevent the growth of cancer cells caused by lipid-modified proteins, but also that they can be effective in the treatment of diabetes and neurological disorders such as Parkinson's. In one of my earlier blog, I have mentioned about the simvastin (Simvastatin prevents progression of Parkinson's Disease ?).

So in the days to come statins may be useful as anticancer, anti diabetic and even to treat Parkinsons disaese....


Source : http://www.science.gu.se/english/News/News_detail/Cholesterol-lowering_medicines_may_be_effective_against_cancer.cid898016

A tetracycline derivative for the treatment of Spinal Muscular Atrophy .....

A chemical cousin of the common antibiotic tetracycline (PTK-SMA1) might be useful in treating spinal muscular atrophy (SMA), a currently incurable disease that is the leading genetic cause of death in infants. This is the finding of a research collaboration involving Adrian Krainer, Ph.D., of Cold Spring Harbor Laboratory (CSHL) and scientists from Paratek Pharmaceuticals and Rosalind Franklin University of Medicine and Science.

About SMA :

SMA is caused by mutations in a gene called Survival of Motor Neuron 1 (SMN1), resulting in a decrease in the levels of SMN protein in the motor neurons of the spinal cord -- the cells that control muscle activity. Without the protein, these neurons degenerate, and infants born with the mutations progressively lose the ability to move, swallow, and breathe. There are no approved therapies for the treatment of SMA.

Mode of action of PTK-SMA1 :

The new molecule boosts the levels of SMN protein in cells by fixing a mistake in a cellular processing mechanism called RNA splicing. The drug candidate targets the splicing of a gene called SMN2, which is essentially a back-up copy to the SMN1 gene that’s mutated beyond repair in SMA patients. SMN2 doesn’t compensate for the loss of SMN1, however, because it produces too little functional protein. Most of the protein that is produced is missing a single important piece, without which the protein rapidly degrades. The significance of this finding is in the fact that “PTK-SMA1 is the only small molecule known to specifically alter RNA splicing by directly and solely targeting the splicing reaction” . Other molecules that affect splicing also affect other cellular processes, thus diluting their potency, and potentially increasing the risk of side effects. PTK-SMA1 has the added advantage of being a derivative of tetracyclines, which are nontoxic and have demonstrated safety in humans...

Source : http://stm.sciencemag.org/content/1/5/5ra12.abstract.

Embryonic Stem Cell Therapy Restores Walking Ability In Rats With Neck Injuries..

The first human embryonic stem cell treatment approved by the FDA for human testing has been shown to restore limb function in rats with neck spinal cord injuries -- a finding that could expand the clinical trial to include people with cervical damage.

More....Embryonic Stem Cell Therapy Restores Walking Ability In Rats With Neck Injuries