Posted on February 1, 2013 by DR ANTHONY MELVIN CRASTO Ph.D

Pancreatic Cancer A Preclinical Evaluation of Minnelide as a Therapeutic Agent Against Pancreatic Cancer

• Rohit Chugh,et al

Sci Transl Med 17 October 2012 4:156ra139. DOI:10.1126/scitranslmed.3004334

1. Leuenroth, Stephanie (2007). “Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease”. PNAS104 (11): 4389-4394. doi:10.1073/pnas.0700499104. Retrieved 18 October 2012.
2. Chugh, Rohit (2012). “A Preclinical Evaluation of Minnelide as a Therapeutic Agent Against Pancreatic Cancer”. Science Translational Medicine4 (156): 156ra139. doi:10.1126/scitranslmed.3004334. Retrieved 18 October 2012.

Triptolide (1) is a structurally unique diterpene triepoxide isolated from a traditional Chinese medicinal plant with anti-inflammatory, immunosuppressive, contraceptive and antitumor activities. Its molecular mechanism of action, however, has remained largely elusive to date. We report that triptolide covalently binds to human XPB (also known as ERCC3), a subunit of the transcription factor TFIIH, and inhibits its DNA-dependent ATPase activity, which leads to the inhibition of RNA polymerase II–mediated transcription and likely nucleotide excision repair. The identification of XPB as the target of triptolide accounts for the majority of the known biological activities of triptolide. These findings also suggest that triptolide can serve as a new molecular probe for studying transcription and, potentially, as a new type of anticancer agent through inhibition of the ATPase activity of XPB.

‘If you liked this post, say thanks by sharing it or mail me amcrasto@gmail.com, all content is academic.

Monoclonal antibody

Genzyme’s LEMTRADA™ (alemtuzumab) Application for MS Accepted for Review by the FDA

January 28, 2013

Genzyme, a Sanofi Company (EURONEXT: SAN and NYSE: SNY), announced that the U.S. Food and Drug Administration (FDA) has accepted for review the company’s supplemental Biologics License Application (sBLA) file seeking approval of LEMTRADA (alemtuzumab) for the treatment of relapsing multiple sclerosis (RMS). The company also reported key highlights from the U.S. launch of once-daily, oral AUBAGIO (teriflunomide).

LEMTRADA sBLA Accepted by FDA

The FDA has accepted for standard review the company’s sBLA file seeking approval of LEMTRADA. Genzyme expects FDA action on the application in the second half of 2013. Genzyme has already submitted its marketing authorization application for LEMTRADA to the European Medicines Agency (EMA) and the review process is underway. The Committee for Medicinal Products for Human Use (CHMP) opinion for LEMTRADA is expected in Q2 2013.

The LEMTRADA clinical development program includes CARE-MS I and CARE-MS II (Comparison of Alemtuzumab and Rebif^® Efficacy in Multiple Sclerosis), randomized Phase III studies comparing LEMTRADA to a standard of care MS treatment, Rebif,in patients with relapsing-remitting MS who were naïve to prior treatment or who had relapsed while on prior therapy, respectively. Genzyme announced publication of results of these studies in The Lancet in November 2012.

AUBAGIO Early Launch Indicators in the U.S.

Since its launch in October, once-daily, oral AUBAGIO has shown very encouraging early launch indicators among U.S. prescribers.¹ Key highlights from the launch include:

• More than 80 percent of MS specialists in the U.S. have prescribed AUBAGIO;
• Approximately 1 in 5 patients prescribed AUBAGIO were treatment-naïve;
• More than 50 percent of AUBAGIO patients were most recently on Copaxone^® or Avonex^®

“Genzyme is making a difference for people living with MS and realizing its vision of being leaders in MS,” said Genzyme President and CEO, David Meeker, M.D. “The initial uptake of AUBAGIO by U.S. prescribers shows the importance of a once-daily oral option in MS. In addition, the acceptance of the LEMTRADA file in the U.S. marks another important milestone in bringing this potentially transformative therapy to MS patients. We look forward to a series of product launches in 2013 in Europe and other major markets.”

AUBAGIO is approved for use in both the U.S. and Australia.

About Alemtuzumab/LEMTRADA™

Alemtuzumab is a monoclonal antibody that selectively targets CD52, a protein abundant on T and B cells. Treatment with alemtuzumab results in the depletion of circulating T and B cells thought to be responsible for the damaging inflammatory process in MS. Alemtuzumab has minimal impact on other immune cells. The acute anti-inflammatory effect of alemtuzumab is immediately followed by the onset of a distinctive pattern of T and B cell repopulation that continues over time, rebalancing the immune system in a way that potentially reduces MS disease activity.

Alemtuzumab (marketed as Campath, MabCampath or Campath-1H and currently under further development as Lemtrada) is a monoclonal antibody used in the treatment of chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL) and T-cell lymphoma. It is also used in some conditioning regimens for bone marrow transplantation, kidney transplantation and Islet cell transplantation.

Alemtuzumab binds to CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived. After treatment with alemtuzumab, these CD52-bearing lymphocytes are targeted for destruction.

Alemtuzumab is used as second-line therapy for CLL. It was approved by the US Food and Drug Administration for CLL patients who have been treated with alkylating agents and who have failed fludarabine therapy. It has been approved by Health Canada for the same indication, and additionally for CLL patients who have not had any previous therapies.

It is also used under clinical trial protocols for treatment of some autoimmune diseases, such as multiple sclerosis, in which it shows promise.^[1][2] Alemtuzumab was withdrawn from the markets in the US and Europe in 2012 to prepare for a higher-priced relaunch aimed at multiple sclerosis.^[3]

A complication of therapy with alemtuzumab is that it significantly increases the risk for opportunistic infections, in particular, reactivation of cytomegalovirus.

1. Drug may reverse MS brain damage”. 22 Oct 2008.
2. “Sanofi and Genzyme Report New Positive Data from First Phase III Study with MS Drug”. 24 Oct 2011.
3. “Sanofi withdraws Campath in US and EU”. Pharma Times Online. August 21, 2012.

DR ANTHONY CRASTO, PhD, ICT Organic chemistry, Currently working with GLENMARK GENERICS LTD research centre as Principal Scientist, process research (bulk actives) at Mahape, Navi Mumbai, India, helping millions, million hits on google on all organic chemistry websites, Hands on experience in developing novel routes for drug molecules and implementation on commercial scale. several international patents published.pushing boundaries, one lakh connections on all networking sites

Jan. 28, 2013

Jan. 28, 2013

(Z)-5-Tetradecen-1-ol, mw 212.37, formula C14H20O CAS 40642-42-0

Odorant receptors, present on nasal sensory neurons, perceive volatile compounds and regulate animal behavior such as reproduction. The nature of the ligands interacting with these receptors is, however, largely unknown.
Keiichi Yoshikawa and colleagues, University of Tokyo, Japan, shed new light on this issue. The researchers demonstrated that, in mice, preputial gland cells generate and secrete into the urine the unsaturated aliphatic alcohol (Z)-5-tetradecen-1-ol (pictured). This compound is regulated by the male hormone testosterone and acts as a natural agonist of the mouse odorant receptor Olfr288, affecting attractiveness to female mice. The urine of males lacking (Z)-5-tetradecen-1-ol, in fact, failed to attract females.

By identifying a novel receptor-ligand interaction in the mouse olfactory system, this study offers new insights into the complex chemistry regulating reproductive behavior.

• An unsaturated aliphatic alcohol as a natural ligand for a mouse odorant receptor,
  K. Yoshikawa, H. Nakagawa, N. Mori, H. Watanabe, K. Touhara,
  Nature Chem. Biol. 2013.
  DOI: 10.1038/nchembio.1164
• Ohloff, G. et al. 1977. Helv. Chim. Acta. 60:1161-1174.
• http://www.cas-msds.com/40642-42-0

• Bestmann, H.J., Brosche, T., Koschatzky, K.H., Michaelis, K., Platz, H., Vostrowsky, O., and Knauf, W. 1980. Pheromone XXX. Identifizierung eines neuartigen pheromonkomplexes aus der graseule Scotia exclamationis. Tetrahedron Lett. 21:747-750.

  Kelkar, S.V., Reddy, G.B., and Kulkarni, G.H. 1989. Indian J. Chem. Sect. B. 28:980-981.

  Ohloff, G., Vial, C., Näf, F., and Pawlak, M. 1977. Stereoselective syntheses of the isomeric 5, 10-pentadecadienals. Helv. Chim. Acta. 60:1161-1174.

  DR ANTHONY MELVIN CRASTO Ph.Damcrasto@gmail.com MOBILE-+91 9323115463 GLENMARK SCIENTIST , NAVIMUMBAI, INDIA DR ANTHONY CRASTO, PhD, ICT Organic chemistry, Currently working with GLENMARK GENERICS LTD research centre as Principal Scientist, process research (bulk actives) at Mahape, Navi Mumbai, India, helping millions, million hits on google on all organic chemistry websites, Hands on experience in developing novel routes for drug molecules and implementation on commercial scale. several international patents published.pushing boundaries, one lakh connections on all networking sites

Jan. 25, 2013

Celsion Corporation a leading oncology drug development company, and Zhejiang Hisun Pharmaceutical Company Ltd. a leading Chinese pharmaceutical company, today announced that they have entered into a technology development agreement for ThermoDox® for the greater China territory.

ThermoDox® is a proprietary heat-activated liposomal encapsulation of doxorubicin, an approved and frequently used oncology drug for the treatment of a wide range of cancers. For primary liver cancer, ThermoDox® is being evaluated in a 700 patient global Phase III study at 79 clinical sites under an FDA Special Protocol Assessment.

Cartoon diagram of two doxorubicin molecules intercalating DNA, from PDB1D12.

1. Laginha, K.M. “Determination of Doxorubicin Levels in Whole Tumor and Tumor Nuclei in Murine Breast Cancer Tumors.”Clinical Cancer Research. October 1, 2005. Vol. 11 (19). Retrieved on April 19, 2007.
2. “Doxorubicin (Systemic).” Mayo Clinic. Last updated on: June 15, 1999. Retrieved on April 19, 2007. Archived April 3, 2007 at the Wayback Machine
3. Weiss RB (December 1992). “The anthracyclines: will we ever find a better doxorubicin?”. Seminars in Oncology 19 (6): 670–86. PMID 1462166.
4. Tan C, Tasaka H, Yu KP, Murphy ML, Karnofsky DA (March 1967). “Daunomycin, an antitumor antibiotic, in the treatment of neoplastic disease. Clinical evaluation with special reference to childhood leukemia”. Cancer 20 (3): 333–53. doi:10.1002/1097-0142(1967)20:3<333::AID-CNCR2820200302>3.0.CO;2-K.PMID 4290058.
5. Arcamone F, Cassinelli G, Fantini G, et al. (1969). “Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius“. Biotechnol Bioeng 11 (6): 1101–10. doi:10.1002/bit.260110607. PMID 5365804.
6. Di Marco A, Gaetani M, Scarpinato B (February 1969). “Adriamycin (NSC-123,127): a new antibiotic with antitumor activity”. Cancer Chemother Rep 53 (1): 33–7. PMID 5772652.
7. “DOXIL Product Information.” Ortho Biotech Products, L.P. Retrieved on April 19, 2007. Archived September 21, 2007 at the Wayback Machine

DRUG BEING RELEASED FROM HEAT ACTIVATED LIPOSOME

.

.

.

.

ABRAXANE. Celgene’s Abraxane shows promise in pancreatic…

ABRAXANE, a microtubule inhibitor, is an albumin-bound form of paclitaxel with a mean particle size of approximately 130 nanometers. Paclitaxel exists in the particles in a non-crystalline, amorphous state. ABRAXANE is supplied as a white to yellow, sterile, lyophilized powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each single-use vial contains 100 mg of paclitaxel (bound to human albumin) and approximately 900 mg of human albumin (containing sodium caprylate and sodium acetyltryptophanate). Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel. ABRAXANE is free of solvents.

The active agent in ABRAXANE is paclitaxel.

The chemical name for paclitaxel is 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.

Paclitaxel is a white to off-white crystalline powder with the empirical formula C₄₇H₅₁NO₁₄ and a molecular weight of 853.91. It is highly lipophilic, insoluble in water, and melts at approximately 216°C to 217°C.

 

A drug that Celgene acquired in its $2.9 billion acquisition of abraxis bioscience in 2010 is showing promise against the notoriously hard-to-treat pancreatic cancer.

The disease kills 38,000 Americans each year, nearly as many as those who die from breast cancer and a much larger percentage rate of those diagnosed. So observers see promise from the results of a new study that showed Celgene’s Abraxane plus gemcitabine, the standard drug for pancreatic cancer, led to a median survival rate of 8.5 months, compared with 6.7 months for those who received gemcitabine alone. It also improved survival rates after one and two years, the company reported today.

The results were pretty much in line with what investors were expecting, according to The New York Times. Analysts saw potential when Celgene added Abraxane to its portfolio because it is a “platform drug” used to treat several forms of cancer. It was approved in the U.S. in October for treating lung cancer and is approved in the U.S. and many other countries for treating breast cancer.

The drug had sales of $320 million in the first 9 months of last year. The global market for pancreatic cancer treatments is only about $700 million, according to industry research firm Decision Resources. The firm estimates the U.S. market will grow to $829 million in the U.S. by 2019. Celgene said it would apply for approval in the the first half of the year for Abraxane the new indication, according to The New York Times.

But Abraxane is not the only investigational drug showing promise for treating pancreatic cancer. As the newspaper points out, a trial of Folfirinox, a combination of four generic cancer drugs showed a median survival of 11.1 months compared with 6.8 months for those getting gemcitabine. On the other hand, patients have to wear an infusion pump to take Folfirinox and it can be hard to tolerate.

“The simplicity of Abraxane plus gemcitabine may be attractive to physicians and patients,” Dr. Neal J. Meropol of the University Hospitals and Case Western Reserve University in Cleveland tells The New York Times.

.

/

/

.