7,8-Dihydroxyflavone (a selective TrkB agonist) as new class of brain protecting drugs ?

In recent days, I have seen many groups working on the diverse activities of  flavonoid family of chemicals. In my earlier blog, have mentioned about Quercetin   (quercetin a flavonoid has been reported for diverse activities). Now interestingly  investigators at Emory University School of Medicine,  have reported that '7,8-Dihydroxyflavone' (see structure - also a  member of the flavonoid family of chemicals, abundant in fruits and vegetables-cherries to soybeans)   can partially prevent the death of neurons in experimental models of three neurological diseases" and  this  selective effect suggest that it could be  a new class of brain-protecting drugs.

Investigators at Emory University School of Medicine, led by Dr. Keqiang Ye, (Associate professor of pathology and laboratory medicine), were searching for a way to mimic a protein found in the brain called BDNF (brain-derived neurotrophic factor).

BDNF has been studied extensively for its ability to protect neurons vulnerable to degeneration in several diseases, such as ALS, Parkinson's and Alzheimer's disease,  Ye, one of the authors says, "the trouble with BDNF is one of delivery. It's a protein, so it can't cross the blood-brain barrier and degrades quickly". 

Researchers tried a a library of chemicals to find those that could stimulate one of the proteins on the surfaces of neurons that BDNF binds to. They could show that, 7,8-dihydroxyflavone sends survival signals to brain cells by pulling together two TrkB receiver-dish molecules, just like BDNF does. Interesting part of this research is that, 7,8-Dihydroxyflavone is active in the brain when injected into the body cavity (meaning that it can cross the blood-brain barrier). As claimed by the co-author Ye, many experimental "neuroprotectant" drugs have been unsuccessful in clinical trials for diseases such as stroke and Parkinson's over the last decade and 7,8-Dihydroxyflavone is the first molecule that specifically triggers TrkB. To show the effects of 7,8-dihydroxyflavone depended on TrkB,  authors used mice with a modified TrkB gene and were successful in doing so. Detailed animal studies to substantiate the claim  are essential , still  in my opinion its a good achievement... (details...)

FDAs approval of Lapatinib in combination with Letrozole to treat breast cancer...

In my earlier blog, I mentioned about the combination of Lapatinib and Trastuzumab for breast cancer treatment. Now FDA has  approved Lapatinib in combination with Letrozole (see structure ; Letrozole trade name Femara, an oral non-steroidal aromatase inhibitor for the treatment of hormonally-responsive breast cancer after surgery)  to treat hormone positive and HER2-positive advanced breast cancer in postmenopausal women for whom hormonal therapy is indicated. This drug combination of  Lapatinib  & Letrozole provides women being treated for advanced breast cancer with an important treatment option. 

The entirely oral treatment regimen works by targeting both HER2 and the hormone receptors, thereby slowing the cancer cells' ability to grow or spread. As per the claim by  Dr. Richard Pazdur, (Director, Office of Oncology Drug Products, FDA's Center for Drug Evaluation and Research) women with HER2-positive disease receiving the Lapatinib plus Letrozole combination more than doubled the time they lived without the cancer progressing compared with those receiving Letrozole alone (35 weeks vs. 13 weeks).

Lapatinib, was initially approved in combination with a chemotherapy drug, Xeloda (capecitabine) in 2007. This combination was used to treat women with advanced breast cancer tumors with the HER2 protein who had received prior treatment with chemotherapy drugs, including an anthracycline and a taxane, and Herceptin (trastuzumab), an anti-cancer antibody used to treat HER2-positive advanced breast cancer. Safety information from this study was consistent with previous Lapatinib clinical studies in advanced breast cancer. The most commonly reported side effects of the combination were diarrhea, rash, nausea and fatigue. Still clinical trials are to be carried out, in my opinion its a good achievement...

Ref : http://www.prnewswire.com/news-releases/fda-expands-use-of-approved-breast-cancer-drug-83072502.html

Green tea might help to treat Uterine Fibroids....

In continuation of my update on green tea   (pic : source : greenteatruth.org ).......  

We have seen many research groups  trying to explore the  usefulness of  green tea for reduction in heart disease (bad cholesterol),  increase in metabolic rate (fat oxidization) prevention  of Alzheimer’s or Parkinson’s diseases, lowering incidence of cancers and  weight reduction.

 Now researchers from Meharry Medical College in Nashville, Tenn lead  Dr. Ayman Al-Hendy ,   have found that green tea extract shows promise as a treatment for uterine fibroids. The key ingredient responsible for this activity is  "epigallocatechin gallate (EGCG)". The researchers investigated  the effect of epigallocatechin gallate  on rat leiomyoma (ELT3) cells in vitro and in a nude mice model. ELT3 cells were treated with various concentrations of EGCG. Cell proliferation, proliferation cell nuclear antigen (PCNA), and cyclin-dependent kinase 4 (Cdk4) protein levels were evaluated. As per the claim by the researchers, EGCG significantly decreased PCNA and Cdk4 protein levels. The authotrs conclude that EGCG effectively inhibits proliferation and induces apoptosis in rat ELT3 uterine leiomyoma cells in vitro and in vivo.

Ref : http://www.ajog.org/article/S0002-9378%2809%2902102-4/fulltext

Pomegranate extract (β-Sitosterol) stimulates uterine contractions.........

In continuation of my update on pomegranate and its importance in the diet, I found this info interesting to share with...

Earlier studies have suggested that the pomegranate’s antioxidant and anti-inflammatory properties have a positive impact on health. Scientists at the University of Liverpool   and the Suranaree University of Technology, Thailand, wanted to understand its effect on uterine contractions to explore new ways of treating women who may experience difficult labours.  Currently the only available drug to treat women with a poorly contracting uterus is oxytocin, a hormone which only works approximately 50% of the time,  so there is need of a good  drug.

The team identified   β-Sitosterol,   which inhibit the absorption of cholesterol in the intestine  (as the main constituent of pomegranate seed extract) could be used as a natural stimulant to encourage the uterus to contract during  labour.

        I would say this activity (stimulation of  uterine contractions) is an interesting out come from the research group, because β-Sitosterol has been (earlier) reported ;

a) in treatment of hypercholesterolemia;
b) to possess  anticancer activity (prostate & breast);
c) in a small study, it shows a positive effect on male hair loss in combination with Saw palmetto.

Researchers,  also found that β-Sitosterol concentration  is more in the  pomegranate seed extract  rather  than pomegranate juice itself  and by adding this seed extract to the uterus tissue samples from animals they found that the muscle cells increased their activity. 

The reason for this activity,  (as claimed by the researchers) is due to a rise in calcium, which is necessary in order for any muscle to contract (which is usually affected by hormones, nerve impulses and some drug treatments) . So further studies  like how β-Sitosterol  in pomegranate extract could increase calcium are essential and might lead to  an interesting step towards identifying new ways of treating dysfunctional labour ..more..

Pazopanib for the treatment of advanced renal cell carcinoma.......

In continuation of my update on Pazopanib, I found this interesting info. In my earlier blog , I mentioned that lots of research groups are trying the same drug for other forms of cancer.  Dr. Cora Sternberg and co authors (Chief of the medical oncology department at the San Camillo and Forlanini Hospital in Rome, Italy), have come up with interesting results from a phase 3 study included 233 patients with previously untreated kidney cancer (also known as renal cell carcinoma) that was locally advanced or had spread, and 202 patients with renal cell carcinoma who had previously been treated with cytokine therapy (interferon or interleukin). The patients were randomly assigned to take pazopanib tablets (290 patients) or a placebo drug (145 patients).

As per the claim by the authors, in the pazopanib group, it took an average 9.2 months for the cancer to progress, vs. an average 4.2 months in the placebo group. The difference was greatest in previously untreated patients (11.1 months for the pazopanib group and 2.8 months for the placebo group), but also was found among patients previously treated with cytokines (7.4 months in the pazopanib group vs. 4.2 months in placebo group). 

Common side effects of pazopanib treatment included diarrhea (52 percent), high blood pressure (40 percent), hair color changes (38 percent), nausea (26 percent), weight loss (22 percent) and vomiting (21 percent).

Ref : http://jco.ascopubs.org/cgi/content/abstract/JCO.2009.23.9764v1 

FDA approves Liraglutide for Type 2 Diabetes, with a warning.....

Liraglutide, marketed under the brand name Victoza, is a long-acting glucagon-like peptide-1 (GLP-1) analog that has been developed by Novo Nordisk for the treatment of type 2 diabetes. The product was approved by the European Medicines Agency (EMEA) on July 3, 2009, Now the same drug has been approved  by the FDA.

The interesting part of this approval lies in the fact that, Liraglutide was reviewed by an FDA advisory panel which expressed serious concerns that the drug may cause thyroid tumors. Whereas based on the studies and consistent with the relevant literature it is obvious that the rodent C-cell tumors induced by dosing of liraglutide were caused by a non-genotoxic, specific receptormediated mechanism to which rodents are particularly sensitive whereas non-human primates and humans are not. Liraglutide improves control of blood glucose.  It reduces meal-related hyperglycaemia (for 12 hours after administration) by increasing insulin secretion, delaying gastric emptying, and suppressing prandial glucagon secretion.

As per the claim by the company, the advantages are:

a) acts in a glucose-dependent manner, and  stimulate insulin secretion only when blood glucose levels are

    higher than normal. Consequently, it shows negligible risk of hypoglycemia;

b) has the potential for inhibiting apoptosis and stimulating regeneration of beta cells;

c) decreases appetite and maintains body weight, as shown in a head-to-head study versus glimepiride;

d) lowers blood triglyceride levels and only mild and transient side effects, mainly gastrointestinal &
e) has a half-life after subcutaneous injection of 11–15 hours and hence once-daily GLP-1 derivative.

But the FDA, warned that the once-daily injection shouldn't be used as an initial (first-line) treatment until additional studies are completed, since the drug may cause thyroid tumors or a rare disease called medullary thyroid cancer. People at risk for this type of cancer shouldn't use the drug, the FDA stressed. Hope the further studies will rule out the possibility of the drug causing thyroid tumors..

For details, one can read the press release....

Levoleucovorin's supplemental New Drug Application (sNDA) for colorectal cancer...

We know that  Levoleucovorin (see structure; source : chemspider) is  used to treat or prevent toxic effects of methotrexate in people who have received methotrexate to treat bone cancer.

Recently, Spectrum Pharmaceuticals announced that it has met with the FDA regarding it’s supplemental New Drug Application (sNDA) for FUSILEV^® (levoleucovorin) for injection for the treatment of patients with advanced metastatic colorectal cancer. The company is expected to  to submit in the third quarter of 2010. The FDA did not request any additional efficacy studies. Hope the FDA will  approve the drug  for advanced metastatic colorectal cancer...

Ref  : http://investor.spectrumpharm.com/releasedetail.cfm?ReleaseID=439605

Rapamycin as a potential treatment for kidney disease (ADPKD).........

I did  mention about the use of Rapamycin (see structure)  to improve the  efficacy of tuberculosis vaccine in my earlier blog. This drug has been already  used as an immunosuppressant drug to prevent rejection in organ transplantation,  especially useful in kidney transplants.

 Rapamycin, was originally developed as an antifungal agent. However, this was abandoned when it was discovered that it had potent immunosuppressive and antiproliferative properties. Some researchers have  also reported that  the drug prolong the life of mice and might also be useful in the treatment of certain cancers.

Researchers from UC Santa Barbara  earlier claimed that, rapamycin has  a potential to treat  kidney disease,  however  concluded  that the  mice had different genes affected than human patients. Interestingly, the same researchers recently found that  "rapamycin is also highly effective in a new mouse model in which the same gene is affected as in most human patients".

As claimed by the lead researcher, Thomas Weimbs currently, no treatment exists to prevent or slow cyst formation and most ADPKD patients require kidney transplants or lifelong dialysis for survival. I think this will boost the confidence of the several international groups,  who are undertaking the  clinical trials  to test the safety and efficacy of rapamycin and related drugs in polycystic kidney disease. Though the  researchers are hopeful of positive results  they caution that,  it will be critical to balance any benefits against the expected side effects to judge whether these drugs should be recommended for the treatment of polycystic kidney disease. Let us be optimistic.....

Ref : http://www.ia.ucsb.edu/pa/display.aspx?pkey=2164

Positive results from Phase 2 trial of picoplatin for colorectal cancer...

In continuation of my update on picoplatin,.......

Poniard Pharmaceuticals, Inc,  claims that Phase 2 trial  study met its primary objective, that is picoplatin in combination with 5-fluorouracil and leucovorin (FOLPI regimen) was associated with a statistically significant reduction in neurotoxicity (p <0.004) compared to oxaliplatin given in combination with 5-fluorouracil and leucovorin (FOLFOX regimen). More...

FDAs approval of fampridine-SR for multiple sclerosis...

In continuation of my  update on MS, I found this info useful to share with. Multiple sclerosis (MS, also also known as disseminated sclerosis or encephalomyelitis disseminata) is a disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms. Disease onset usually occurs in young adults, and it is more common in females. MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other. Nerve cells communicate by sending electrical signals called action potentials down long fibers called axons, which are wrapped in an insulating substance called myelin.

In MS, the body's own immune system attacks and damages the myelin. When myelin is lost, the axons can no longer effectively conduct signals. The name multiple sclerosis refers to scars (scleroses, better known as plaques or lesions) in the white matter of the brain and spinal cord, which is mainly composed of myelin. (see, picture, source : URMC).

Now FDA has approved fampridine-SR (see structure, source : chemspider),  for the treatment of multiple sclerosis. Most interesting part of the research lies in the fact that Researchers at the University of Rochester Medical Center (URMC) have been evaluating the effects of the drug in MS for more than 10 years- it is the first medication shown to enhance some neurological functions in people with the disease and I think their efforts helped pave the way for action by the FDA.

Researchers at URMC helped develop the study protocols and lead the clinical trials  that demonstrated consistently improved mobility - timed walking speed- in more than a third of patients with MS. This is the first instance in which a drug for multiple sclerosis was found to improve function lost as a result of the disease. Goodman and his colleagues published the results of a Phase 3 clinical trial of the drug in the journal Lancet. Fampridine-SR is being developed by Acorda Therapeutics and marketed under the name Ampyra. The company submitted a new drug application to the FDA in February 2009. An expert advisory panel recommended approval of the drug in October and that recommendation was adopted by the FDA on 23. January 2010.

As per the claim by the researchers, fampridine improves the transmission of signals in the central nervous system of some multiple sclerosis patients by blocking potassium ion channels in nerve cells and restoring signal conduction( have covered an article in the same lines).

The authors claim that, 35% of patients taking the drug were responders who consistently improved their walking speed by an average of about 25%. While walking was the primary measure, patients also reported that they could walk farther distances, climb stairs better, and stay on their feet longer. Except for the mild seizure, at the FDA approved dosage, the drug is safe. Hope, people with MS will have some sort of relief......

Ref : http://www.urmc.rochester.edu/news/story/index.cfm?id=2744