Methotrexate & Ocrelizumab combination a new hope for RA patients....

In recent days, I have seen many researchers are trying the combination of existing drugs in combination with a monoclonal antibodies for many diseases like cancer, rheumatoid arthritis and are successful too. As synthetic chemist I was interested in knowing about these monoclonal antibodies and found some interesting info, which I am sharing herewith...

About monoclonal antibodies :

monoclonal antibodies (mAb or moAb) are monospecific antibodies that are identical because they are produced by one type of immune cell that are all clones of a single parent cell. Given almost any substance, it is possible to create monoclonal antibodies that specifically bind to that substance; they can then serve to detect or purify that substance. This has become an important tool in biochemistry, molecular biology and medicine. When used as medications, the non-proprietary drug name ends in -mab.

The invention is generally accredited to Georges Köhler, César Milstein, and Niels Kaj Jerne in 1975; who shared the Nobel Prize in Physiology or Medicine in 1984 for the discovery. The key idea was to use a line of myeloma cells that had lost their ability to secrete antibodies, come up with a technique to fuse these cells with healthy antibody-producing B-cells, and be able to select for the successfully fused cells. In 1988 Greg Winter (Nat Rev Cancer 2001;1:118-129) and his team pioneered the techniques to humanize monoclonal antibodies, removing the reactions that many monoclonal antibodies caused in some patients. Interestingly, many monoclinical antibodies have been tried for rheumatoid arthritis, chrohn's disease and as anticancer agents.

Many monoclonal antibodies like infliximab, etanercept and adalimumab were tried for the rheumatoid arthritis now its interseting to note that Genentech and Biogen Idec reported positive outcome from ocrelizumab ( humanized anti-CD20) -MTX (Methotrexate - see the structure : this drug is a part of DMARD treatment meant for RA patients) combination study in RA. The results are significant because they are the first data from a large Phase III trial to show that a humanized antibody targeted at B-cells improves the signs and symptoms of rheumatoid arthritis. Hope patients suffering from RA and those are not responding will breathe a sigh of relief in the days to come...

Ref : http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=12487

Bisphosphonates play a role in reducing recurrent breast cancer....

We know that bisphosphonates (also called diphosphonates) are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases. Bone has constant turnover, and is kept in balance (homeostasis) by osteoblasts creating bone and osteoclasts digesting bone. Bisphosphonates inhibit the digestion of bone by osteoclasts. Osteoclasts also have constant turnover and normally destroy themselves by a process called cell suicide (apoptosis). Bisphosphonates encourage osteoclasts to undergo apoptosis. Though other uses like in he treatments of osteoporosis, osteitis deformans, bone metastasis, primary multiple myeloma,hyperparathyroidism and osteogenesis imperfecta were known. A new data suggests that these agents may play a role in reducing recurrent breast cancer as well. Zoledronic acid (see the structure) is both safe and effective in preventing bone loss in postmenopausal women with breast cancer who are treated with aromatase inhibitors, according to data presented at the CTRC-AACR San Antonio Breast Cancer Symposium. Women who take aromatase inhibitors need some sort of bone protection, and this five-year data show that zoledronic acid is a viable option.

As per the claim by the researchers lead by Dr. Adam Brufsky , women who are on Medicare tend to go with tamoxifen because the cost of anastrozole puts them squarely in the donut hole of Medicare Part D, but once the cost barrier is removed there will likely be a mass switch to the aromatase inhibitor, which will necessitate the need for bone protection. More interestingly, in the same conference a research group lead by Rowan Chlebowski presented a study wherein "women who used bisphosphonates, had significantly fewer invasive breast cancers than women who did not use bisphosphonates. .......

http://www.upci.upmc.edu/news/upci_news/121009_study.cfm

Xanthohumol may help in preventing prostate cancer....

We know that Xanthohumol is a Xanthone (phenylated chalcone or Phenylflavonoid). Xanthohumol was initially detected in an extract(series of Humulones) from Hops (Humulus lupulus) and is present in beer. This prenylated flavonoid has been shown to be a potent bioactive compound. Xanthohumol has been shown to have antiproliferative and cytotoxic effects in human cancer cell lines. It has also been displayed to inhibit diacyl glycerol acetyl transferase (DGAT) and human P450 enzymes. Xanthohumol inhibits the expression of HIF-1a and VEGF under hyposic conditions.

Higher antioxidant activity is reported for prenylchalcones than for prenyl flavanones in the Cu2+- mediated oxidation of LDL, suggesting a relation between structure and function. Also, many chalcones suppress tumor promotion more effectively than flavonoids themselves.

Quantities of xanthohumol found in Hop are to small to have any biological effects under normal consumption amounts. Some of the researchers also claims that it has got anti-HIV-1 activity too.

Now researchers from German Cancer Research Center, in Heidelberg, Germany, have come up with more interesting result, i.e., Xanthohumol may aid in preventing prostate cancer. As per the claim by the authors, the compound blocks the effects of the male hormone testosterone.

Studies to date have shown that xanthohumol blocks the action of estrogen by binding to its receptor, which may lead to prevention of breast cancer. Since testosterone receptors act similarly to that of estrogen — by binding, then stimulating hormone-dependent effects, such as gene expression and cell growth — the researchers examined whether xanthohumol might not only block the effects of estrogen, but also of the male hormone androgen. Xanthohumol prevented the receptor from translocating to the cell nucleus, thus inhibiting its potential to stimulate the secretion of PSA and other hormone-dependent effects.

The interesting part of their research is the molecular modeling results, which showed that xanthohumol directly binds to the androgen receptor structure. The researchers suggest that this compound may have beneficial effects in animals — when they measured the anti-androgenic potential of xanthohumol in a rat model, they found that although xanthohumol was not able to prevent an increase in prostate weight after testosterone treatment, it could reduce testosterone-increased seminal vesicle weight.

As per the claim by the researchers the prostate weights were not changed, xanthohumol still reduced the effects of hormone signaling, such as gene expression, measured in the prostate tissue...

Ref : http://mct.aacrjournals.org/content/1/11/959.full

Carfilzomib for multiple myeloma ?

The proteasome has emerged as an important target for cancer therapy with the approval of bortezomib, a first-in-class, reversible proteasome inhibitor, for relapsed/refractory multiple myeloma (MM). However, many patients have disease that does not respond to bortezomib, whereas others develop resistance, suggesting the need for other inhibitors with enhanced activity. Therefore the researchers evaluated a novel, irreversible, epoxomicin-related proteasome inhibitor - Carfilzomib.

The second-generation proteasome inhibitor carfilzomib is showing noteworthy response rates and low levels of adverse side effects among multiple myeloma patients in a phase II clinical trial.

The updated data from the 17-site study focuses on patients with relapsed or resistant multiple myeloma who have received one to three prior therapies, but not the drug bortezomib, the original proteasome inhibitor. The results are of grat importance because of the fact that multiple myeloma is an incurable, challenging disease with devastating consequences. While new agents are extending life expectancies, they often have adverse side effects, including severe neuropathy. Carfilzomib is showing good response rates, with an improved side effects, except for minor, included fatigue, nausea and anemia.

Ref : http://bloodjournal.hematologylibrary.org/cgi/content/full/110/9/3281/F1

MSRA can be stopped before it becomes dangerous ....

In continuation of my update on MRSA (methicillin-resistant Staphylococcus aureus), I found the following info interesting.

C. Jeffrey Brinker research group has determined that the very first stage of staph infection, when bacteria switch from a harmless to a virulent form, occurs in a single cell and that this individual process can be stopped by the application of a simple protein (as against the belief that, staph infections are caused by many bacterial cells that signal each other to emit toxins. The signaling process is called quorum sensing). The most significant results from the researchers are :

1. isolation of Staphylococcus aureus bacteria in individual (isolation of an individual bacterium
previously had been achieved only computationally);

2. demonstration of release of signaling peptides from a single cell, not a quorum &

3. introduction of an inexpensive, very low-density lipoprotein (VLDL) to bind to the
messenger peptide, they stopped the single cell from reprogramming itself.

One aspect of experimental rigor was the team's ability to organize living cells into a nanostructured matrix. The researchers has already done it with yeast, and just extended the process to bacteria. Researchers are optimistic about finding a mechanism to locate bacteria reprogramming in the body so that the antidote can be delivered in time. If they achieve what they are optimistic, so there will selectivity of targeting the bacteria (human gastro-intestinal system contains many useful bacteria) which in my opinion will be a remarkable feat....

Ref : http://www.nature.com/nchembio/journal/vaop/ncurrent/full/nchembio.264.html

Anticancer & Antiinflammatory properties of Lunasin (Soy Peptide) established ?...

We know that many researchers have tried to establish the anticancer activity of the peptide lunasin (which has been already accepted as neutraceutical agent). Now researchers from University of Illinois have come up with more interesting facts, Soy peptide often discarded in the waste streams of soy-processing plants, may have important health benefits that include fighting leukemia and blocking the inflammation that accompanies such chronic health conditions as diabetes, heart disease, and stroke.

The researchers confirmed lunasin's bioavailability in the human body by doing a third study in which men consumed 50 grams of soy protein--one soy milk shake and a serving of soy chili daily-for five days. Significant levels of the peptide in the participants' blood give us confidence that lunasin-rich soy foods can be important in providing these health benefits.

In the cancer study, de Mejia's group identified a key sequence of amino acids- arginine, glycine, and aspartic acid, (the RGD motif)--that triggered the death of leukemia cells by activating a protein called caspase-3. The scientists also verified lunasin's ability to inhibit topoisomerase 2, an enzyme that marks the development of cancer, and they were able to quantify the number of leukemia cells that were killed after treatment with lunasin in laboratory experiments.

More interesting out come of their study is lunasin's potential anti-inflammatory activity, (first time) they showed that lunasin blocked or reduced the activation of an important marker called NF-kappa-B, a link in the chain of biochemical events that cause inflammation. They also found statistically significant reductions in interleukin-1 and interleukin-6, both important players in the inflammatory process (the reduction in interleukin-6 was particularly strong). As per the claim by the group, although the high cost of obtaining lunasin from soy waste limits its use for nutritional interventions, soy flour does contain high concentrations of the peptide (depending on some genotype soy).

Its good see the diverse activities associated with Soy......

Source : http://pubs.acs.org/doi/abs/10.1021/jf803303k?prevSearch=Elvira%2Bde%2BMejia&searchHistoryKey=

Discovery Of Novel New Class of Antimicrobial Agents... ......

We know that most of the bacteria are getting resistant to the present drugs and there is an urgent need to find a solution for resistant bacteria. Inn this global fight against resistant bacteria many companies are trying different ways and now Chaperone Technologies, Inc has come up with something innovative and interesting way, i.e., the company is trying to develop antimicrobial compounds that work by inhibiting bacterial hsp70 proteins (an entirely new mechanism of action).

Chaperone’s antimicrobial program focuses on development of peptide as well as small molecule hsp70 inhibitor drugs that block the effect of this important class of molecular “chaperones” whose role is to help mediate or respond to toxic misfolded proteins within bacteria. Inhibition of this critical bacterial protein has been proven to kill bacterial pathogens. Besides antimicrobials, the inhibition of hsp70 molecular chaperone proteins present in other cell-types has a range of therapeutic applications that are being investigated by the company.

Using sophisticated computerized molecular modeling techniques, proprietary high-throughput screening tools developed by Chaperone and other approaches, the company has significantly expanded its library of novel hsp70 inhibitor compounds including CHP-267 and CHP-281, just two of the many promising drug candidates from this highly promising family of small molecule inhibitors discovered by the Company. Chaperone is looking at hsp70 inhibitors as stand alone antimicrobial agents as well as in combination with other antimicrobials (e.g., Finafloxacin.HCl : see the structure -which is under phase II clinical trials). The company recently received a US Patent covering a method of significantly amplifying the effectiveness of other antimicrobials by combining their use with that of an hsp70 inhibitor. Combining a bacterial hsp70 inhibitor with another antimicrobial yields increased bacterial killing of clinically important pathogens and the potential for combination therapy.

Chaperone’s drug candidates have been proven effective against dangerous bacteria such as MRSA, acinetobacter, and vancomycin resistant enterococci. When combined with other antibiotics, Chaperone’s compounds stimulate powerful antibiotic synergy, providing superior efficacy even while using significantly lower doses of the combined agents.

Source : http://www.biospace.com/news_story.aspx?NewsEntityId=118501

Combination of EGCG & DAPH-12 - a treatment for brain disorders ?

Amyloid plaques are tightly packed sheets of proteins that infiltrate the brain. These plaques, which are stable and seemingly impenetrable, fill nerve cells or wrap around brain tissues and eventually (as in the case of Alzheimer's) suffocate vital neurons or brain cells, causing loss of memory, language, motor function and eventually premature death.

To date, researchers have had no success in destroying plaques in the human brain and only minimal success in the laboratory. One reason for these difficulties in finding compounds that can dissolve amyloids is their immense stability and their complex composition.

Yet, Dr. Duennwald ( Boston Biomedical Research Institute , BBRI) and co workers from Pennsylvania School of Medicine, experienced success in previous studies when he exposed amyloids in living yeast cells to EGCG (see the above structure). Furthermore, he and his collaborators also found before that DAPH-12, (see below structure) too, inhibits amyloid production in yeast.

About EGCG :

Epigallocatechin gallate, also known as Epigallocatechin 3-gallate, is the ester of epigallocatechin and gallic acid and a type of catechin. EGCG is the most abundant catechin in most notably tea, among other plants, and is also a potent antioxidant and that may have therapeutic properties for many disorders including cancer. It is found in green tea, but not black tea, as EGCG is converted into thearubigins in black teas. EGCG can be found in many supplements.

These findings are significant because it is the first time a combination of specific chemicals (EGCG & DAPH-12) has successfully destroyed diverse forms of amyloids at the same time.

Though the detailed mechanism is still to be established, its a good achievement and hope this combinatorial therapy will help those sufferings from Alzheimer's and other degenerative diseases (Huntington's, and Parkinson's) in the days to come.....

Ref : http://www.nature.com/nchembio/journal/v5/n12/pdf/nchembio.246.pdf

Nizatidine as an Oral Solution.....

About Nizatidine :

Nizatidine is a histamine H₂-receptor antagonist that inhibits stomach acid production, and commonly used in the treatment of peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD). It was developed by Eli Lilly and is marketed under the trade names Tazac and Axid.


Recently FDA approved the Nizatidine Oral Solution in the 15 mg/mL strength. Nizatidine Oral Solution is the first available generic in oral solution form and marks Amneal’s fourth liquid approval. It represents the company’s first exclusive generic – Amneal has 180-day exclusivity to market the product beginning from the date of first shipment......

Source : http://www.amneal.com/headlines/archive/Nizatidine_Oral_Solution_12-04-09.pdf

Statins may protect against GVHD complications

Statins may protect against GVHD complications

First live targeting of tumors with RNA-based technology

Researchers at Duke University Medical Center have devised a way they might deliver the right therapy directly to tumors using special molecules, called aptamers, (Aptamers are oligonucleotides or peptide molecules that bind to a specific target molecule) which specifically bind to living tumor tissue.......

More....First live targeting of tumors with RNA-based technology

CASD-NMR a boon to structure validation....

CASD-NMR(Critical Assessment of Automated Structure Determination) of Proteins is a rolling community-wide experiment involving developers of software tools / protocols for the automated calculation of protein structures from NMR data. The goal of CASD-NMR is to help advance the relevant methodology in order to reach the level of quality and reliability required for direct structure deposition in the PDB. CASD-NMR will also produce extensive data sets that will be useful to develop better methods for NMR structure validation. The more significance of this project is : In the future, automation in NMR will allow 'unsupervised' results to be accepted by the community as being correct and viable, ready for inclusion in the Protein Data Bank (PDB) straight away. The PDB is a database that stores macromolecular structural data that is freely and publicly available for further research.

Ref : http://www.e-nmr.eu/CASD-NMR

New target for diabtes type 2 treatment ?

Mitochondria provide energy for cellular activity. Mitochondrial damage causes people with type 2 diabetes to lose insulin-producing cells, a finding that could lead to new treatments, researchers say.

The researchers (Dr. E. Dale Abel, chief of the endocrinology and metabolism division at the University of Utah School of Medicine in Salt Lake City) found that when insulin-producing beta cells in the pancreas can't respond to circulating insulin, it triggers a "molecular cascade" that damages the normal action of a certain molecular receptor on the surface of the mitochondria. The damaged mitochondria then begin to destroy adenosine triphosphate, the prime fuel for cellular activity. As a result, the beta cells die.

The study provides novel insights into the role of insulin signaling in the regulation of the BAD/GK complex, glycolytic enzyme activity and mitochondrial metabolism in pancreatic β-cells. Ser112-BAD_S and its upstream kinases may be potential targets for the maintenance of the BAD/GK complex that is necessary for normal mitochondrial function and the regulation of β-cell survival....

Source : http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0007983

CCII capsules offer safe and effective treatment for rheumatoid arthritis

Chicken collagen can provide relief from rheumatoid arthritis (RA) symptoms. A randomised, controlled trial, published in BioMed Central's open access journal Arthritis Research & Therapy, has found that Chicken type II collagen (CCII), a protein extracted from the cartilage of chicken breast, is a safe and effective treatment for RA.

More....CCII capsules offer safe and effective treatment for rheumatoid arthritis

Positive data from rose bengal disodium for psoriasis & atopic dermatitis....

Acid Red 94, (Rose Bengal sodium salt), 3,4,5,6-tetrachloro-2-(2,4,5,7-tetraiodo-6-oxido-3-oxoxanthen-9-yl)benzoate :

Provectus Pharmaceuticals, Inc announced preliminary data for the company’s PH-10 Phase 2 clinical trial for Psoriasis as well as for its Phase 2 clinical trial for Atopic Dermatitis. As per the claim by the company, in its Phase 2 trial of PH-10 (0.001% Rose Bengal) for psoriasis, preliminary data shows that 79% of 29 subjects in the clinical trial demonstrated improvement in the Psoriasis Scoring Index (PSI) during four weeks of daily treatment with PH-10. In addition, 83% of the subjects reported no or only mild pruritus (itching) by week four of the trial, with no significant safety issues noted. The 30^th and final subject will complete final evaluation in early December.

In its Phase 2 trial of PH-10 for atopic dermatitis (“eczema”), preliminary data from the first 18 subjects indicated that 94% of subjects had improvement in the Eczema Area Severity Index (EASI) during four weeks of treatment. Subjects applied PH-10 daily for up to four weeks to skin areas affected by atopic dermatitis, with response observed weekly throughout this treatment phase and for one month after the end of this period. As in the psoriasis study, the treatments were generally well tolerated with no significant safety issues identified. Hope a sigh of relief for those suffering from psoriasis and atopic dermatitis....

Ref : http://www.pvct.com/pressrelease.html?article=20091201