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Newzealand’s PHARMAC is seeking feedback on a proposal to list pegfilgrastim (Neulastim) and tocilizumab (Actemra) , from 1 July 2013, with Roche Products (NZ) Limited.

April 13, 2013 5:43 am / 2 Comments on Newzealand’s PHARMAC is seeking feedback on a proposal to list pegfilgrastim (Neulastim) and tocilizumab (Actemra) , from 1 July 2013, with Roche Products (NZ) Limited.

http://www.pharmac.health.nz/news/item/tocilizumab-and-pegfilgrastim

Tocilizumab (INN, or atlizumab, developed by Hoffmann–La Roche and Chugai and sold under the trade names Actemra and RoActemra) is an immunosuppressive drug, mainly for the treatment of rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis, a severe form of RA in children. It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer.

Pegfilgrastim is a PEGylated form of the recombinant human granulocyte colony-stimulating factor (GCSF) analog filgrastim. It serves to stimulate the level of white blood cells (neutrophils).

Amgen manufactures pegfilgrastim under the brand name Neulasta Which was mainly worked on by Martine Allard, and Roche under the name Neulastim. In India it is also marketed by Abbott Healthcare under the brand name Imupeg. The drug is prepared by coupling a 20 kDa polyethylene glycol (PEG) molecule to the N-terminus of the filgrastim protein. Pegfilgrastim has a human half-life of 15 to 80 hours, much longer than the parent filgrastim (3–4 hours).

Pegfilgrastim treatment can be used to stimulate the bone marrow to produce more neutrophils to fight infection in patients undergoing chemotherapy.

AYURVEDA-Jyotishmati / Malkangani – Staff-tree (Celastrus paniculatus)

April 13, 2013 3:46 am / 6 Comments on AYURVEDA-Jyotishmati / Malkangani – Staff-tree (Celastrus paniculatus)

Jyotishmati / Malkangani -Staff-tree, (Celastrus paniculatus)

Excellent pain reliever

Relieves pain: Apply staff-tree oil on the affected area.

Celastrus paniculatus

Scientific classification
Kingdom:	Plantae
(unranked):	Angiosperms
(unranked):	Eudicots
(unranked):	Rosids
Order:	Celastrales
Family:	Celastraceae
Genus:	Celastrus
Species:	C. paniculatus
Binomial name
*Celastrus paniculatus* Willd.
Synonyms
Celastrus dependens Wall.

Celastrus paniculatus seeds

Celastrus paniculatus is a woody liana commonly known as black oil plant, climbing staff tree, and intellect tree (Sanskrit: jyotishmati ज्योतीष्मती, Hindi: Mal-kangani माल-कांगनी, Chinese: deng you teng 灯油藤).^[1]^[2]^[3] The plant grows throughout India at elevations up to 1800 m.^[1]^[4] Oil from the seeds is used as a traditional medicine in Indian Unani and Ayurvedic medicine.^[1]^[5]

C. paniculatus is a deciduous vine with stems up to 10 centimeters in diameter and 6 meters long with rough, pale brown exfoliating bark covered densely with small, elongated lenticles. The leaves are simple, broad, and oval, obovate or elliptic in shape, with toothed margins.^[1]^[2] The Intellect tree, or Celastrus paniculatus, is a climbing shrub, also known as malkangani, found throughout India. The seeds contain fatty acids and alkaloids, and have sedative and antidepressant actions. Botanist M. Daniel states that the seeds are used to sharpen the memory, and Ayurvedic practitioners also use the seed oil as a brain tonic and as a treatment for memory loss. A study published in the August 2004 issue of the “Journal of Ethnopharmacology” found that intellect tree’s ability to improve memory loss may be due to its neuroprotective actions. A study of rats suggested the aqueous extract of Celastrus paniculatus seed has dose-dependent cholinergic activity, thereby improving memory performance.^[6]

Premila, M. S. (2006). Ayurvedic Herbs: A Clinical Guide to the Healing Plants of Traditional Indian Medicine. New York: Haworth Press. ISBN 0-7890-1768-7.
H. F. Macmillan (1989). Handbook of Tropical Plants. Columbia, Mo: South Asia Books. ISBN 81-7041-177-7.
Putz, Francis E.; Mooney, Harold A. (1991). The Biology of vines. Cambridge, UK: Cambridge University Press. ISBN 0-521-39250-0.
Zhixiang Zhang, Michele Funston: Celastrus, in Flora of China, Vol. 11
Chopra, R. N. Indigenous Drugs of india. Kolkata: Academic Publishers. ISBN 978-81-85086-80-4.
Bhanumathy M. Harish MS. Shivaprasad HN. Sushma G.”Nootropic activity of Celastrus paniculatus seed.Pharmaceutical Biology. 48(3):324-7, 2010 Mar.

Caldecott, Todd (2006). Ayurveda: The Divine Science of Life. Elsevier/Mosby. ISBN 0-7234-3410-7. Contains a detailed monograph on Celastrus paniculatus (Jyotishmati) as well as a discussion of health benefits and usage in clinical practice. Available online at http://www.toddcaldecott.com/index.php/herbs/learning-herbs/351-jyotishmati

Native to: India, China, Sri Lanka, and south-east Asia

Celastrus paniculatus is a shrub used in Ayurdevic medicine in India. Various properties are attributed to the aerial parts of the plant, but we will deal here primarily with the seeds and the oil expressed from them. Celastrus paniculatus oil is cold-pressed raw herbal oil expressed from the Malkangni/Intellect Tree seeds of Celastrus panuculatis, a shrub native to India. While Celastrus oil has been used in India for centuries it is only within the past few years that it has started to become known outside of Ayurvedic medicine, the traditional medicinal practice of India.

1. The oil is used to increase memory and facilitate learning.

2. It induces a feeling of well-being and has reported aphrodisiac effects.

The oil in its raw state has a shelf life of 2 years if kept in a cool and dark place such as a refrigerator. When put into softgels the shelf life can be expected to be much longer, on the order of four years if kept in a dark and refrigerated state.

Oil Chemical Composition:

The oil contains protein, carbohydrates (less than 1 calorie per dose), fats (saturated fats: .022 of 1%, polyunsaturated fats: .035 of 1%, monounsaturated fats: .032 of 1%) Vitamin C, Sodium, Potassium, ash, Calcium, Iron, and Sesqiterpene polyesters.

Uses of Malkangni:

1. Celastrus paniculata is a treasured medicinal herb that is revered for its effects on the brain and has been used for centuries in Ayurveda for sharpening the memory, increasing intellect, and improving concentration.

2. The seed oil is used for massage with great benefit, especially in vata diseases like sciatica, lumbago, paralysis, arthritis and facial palsy.

3. The seed oil is useful to hasten the healing in nonhealing wounds and ulcers.

4. Essential for acne, boils, eczema and hair loss.

5. Excellent pain reliever Relieves pain

The seed oil is extremely beneficial as a sirovirecana cleansing nasal therapy, wherein the drops instilled into nostrils, ward off mucous secretions in colds and cough.

Habitat:

It grows almost all over India, up to attitude of 1,800 meter Specially Punjab, Kashmir etc. hilly state. It is also found SriLanka, Malaya deep and Philippines. Globally the species occurs in the tropical and subtropical regions of India, Myanmar (earlier Burma), China, Malaysia, SriLanka and Philippines and also in North America. Within India, it occurs in Andhra Pradesh, Karnataka, Goa, Maharashtra, Gujarat, Madhya Pradesh, Uttar Pradesh, Arunachal Pradesh, Punjab and Himachal Pradesh.

The leaf and seed of Jyotismati is used in the form of powder and oil to treat udara roga, wound, sidhma, drowsiness in fever and amenorrhoea and many Skin diseases.

Morphology Description:

Malkagni is a large, woody, climbing shrub. The leaves are ovate oblong-elliptic, the flowers are unisexual, small greenish white or yellowish green, the capsules are globose, yellow 1-6 seeded and transversely wrinkled, the seeds are ellipsoid or ovoid, yellowish or reddish-brown in color enclosed in scarlet aril, which stains yellowish orange.

Chemical Composition:

The seeds yield brownish yellow oil 52.2% with an unpleasant taste. This oil is reported to contain acetic acids & benzoic acids in addition to the higher amount of the fatty acids.

Application:

The oil of Malkagini locally act as a good analgesic, anti-inflammatory it overcome pain and inflammation in case of paralysis, facial paralysis, joint pains, sciatica, lumber pain etc.

Ayurveda recognizes its seeds as an effective nervine tonic. Its use is recommended in chronic debilitating diseases of nervous system. The seeds possess emetic, diaphoretic, febrifugal and Nervine properties and are used for sharpening the memory & learning abilities.

Effect on Doshas – Pacifies Vata & Kapha, Promotes Pitta.

Launch of semi-synthetic artemisinin a milestone for malaria, synthetic biology

April 13, 2013 1:40 am / 3 Comments on Launch of semi-synthetic artemisinin a milestone for malaria, synthetic biology

Apr 11th, 2013
Launch of semi-synthetic artemisinin a milestone for malaria, synthetic biology
(Nanowerk News) Twelve years after a breakthrough discovery in his University of California, Berkeley, laboratory, professor of chemical engineering Jay Keasling is seeing his dream come true.
On April 11, the pharmaceutical company Sanofi will launch the large-scale production of a partially synthetic version of artemisinin, a chemical critical to making today’s front-line antimalaria drug, based on Keasling’s discovery.read more at nanowerk http://www.nanowerk.com/news2/biotech/newsid=29955.php The “semi-synthetic” artemisinin is chemically modified to an active drug, such as artesunate, and combined in ACT with another antimalarial drug to lessen the chance that the malaria parasite will develop resistance to artemisinin. Sanofi plans to produce 35 tons of artemisinin in 2013 and, on average, 50 to 60 tons a year by 2014, which will translate to between 80 and 150 million ACT treatments. Sweet wormwood was used in ancient Chinese therapy to treat various illnesses, including fevers typical of malaria. In the 1970s, Chinese scientists rediscovered it and identified its active ingredient, artemisinin, and artemisinin is now extracted from sweet wormwood grown commercially in China, Southeast Asia and Africa. The quality, supply and cost have been unpredictable and inconsistent, however. Keasling’s goal was to create a synthetic version with a stable and ideally lower price that could be produced in sufficient quantity to treat the 300-500 million cases of malaria that arise each year. Sanofi and OneWorld Health, the not-for-profit drug development affiliate of the Program for Appropriate Technology in Health (PATH), have launched a commercial-scale production line for semisynthetic artemisinin, a move they say is “a pivotal milestone in the fight against malaria”. Global demand for artemisinin is the most effective malaria treatment available but the existing botanical supply – which is derived from the sweet wormwood plant – is inconsistent. Therefore, Sanofi says that having “multiple sources of high-quality artemisinin will strengthen the artemisinin supply chain, contribute to a more stable price and ultimately ensure greater availability of treatment”. The company notes that the production line at its facility in Garessio, Italy, will be able to produce enough artemisinin, using technology developed by US firm Amyris, for around 80-150 million artemisinin-based combination therapies by 2014.

Otsuka’s New Drug Application for Tolvaptan, the Investigational Compound for Autosomal Dominant Polycystic Kidney Disease (ADPKD), Accepted for Review by the US Food and Drug Administration (FDA)

April 12, 2013 12:31 pm / Leave a comment

Otsuka Pharmaceutical Co., Ltd. announced today that the U.S. Food and Drug Administration (FDA) has accepted for priority review the company’s new drug application (NDA) for the potential use of tolvaptan for the treatment of autosomal dominant polycystic kidney disease (ADPKD). Phase III clinical trial results………..read more at financial post

http://www.financialpost.com/markets/news/Otsuka+Drug+Application+Tolvaptan+Investigational+Compound+Autosomal/8231579/story.html

Tolvaptan

and enantiomer
Systematic (IUPAC) name
N-(4-{[(5R)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl}-3-methylphenyl)-2-methylbenzamide

	Tolvaptan (INN), also known as OPC-41061, is a selective, competitive vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca and in India is manufactured & sold by MSN laboratories Ltd. under the trade name Tolvat & Tolsama.

Merck seeks approval for pill form of antifungal,noxafil

April 12, 2013 10:19 am / 3 Comments on Merck seeks approval for pill form of antifungal,noxafil

Posaconazole is a triazole antifungal drug marketed in the United States, the European Union, and in other countries by Schering-Plough under the trade name Noxafil. In Canada, posaconazole is marketed by Schering-Plough under the trade name Posanol.

11 april2013

Merck & Co says that a New Drug Application for a tablet formulation of the company’s antifungal Noxafil has been accepted for review by the US Food and Drug Administration.

Merck currently markets Noxafil (posaconazole) in liquid form for invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being “severely immunocompromised”. This covers patients who have received haematopoietic stem cell transplants and have graft-versus-host disease, or patients with cancers of the blood who are experiencing prolonged low white blood cell counts as a result of chemotherapy.

Specifically, Merck is seeking FDA approval of Noxafil tablets for once-daily administration, following a twice-a-day loading dose on the first day of therapy. The pill has already been filed with the European Medicines Agency and the drug giant plans to seek regulatory approval for the tablet formulation in other countries around the world.

Robin Isaacs, head of infectious disease clinical research at Merck Research Laboratories, said the filing for a Noxafil pill “is an example of Merck’s ongoing commitment to developing new therapy options for patients in the hospital setting”. He added that “invasive fungal infections are a significant cause of illness and death among severely immunocompromised patients”.

ACADIA Pharmaceuticals announced , it no longer needs to conduct additional Phase III trials for its pimavanserin drug for the treatment of Parkinson’s disease psychosis

April 12, 2013 10:06 am / 3 Comments on ACADIA Pharmaceuticals announced , it no longer needs to conduct additional Phase III trials for its pimavanserin drug for the treatment of Parkinson’s disease psychosis

	cas no 706779-91-1 706782-28-7 (tartrate)

11, april 2013

ACADIA Pharmaceuticals announced following its FDA meeting, it no longer needs to conduct additional Phase III trials for its pimavanserin drug for the treatment of Parkinson’s disease psychosis. The company plans to seek early approval for the drug.

ACADIA Pharmaceuticals Inc. announced that the FDA has agreed that the data from the pivotal Phase III -020 study, together with supportive data from other studies with pimavanserin, are sufficient to support the filing of a New Drug Application, or NDA, for the treatment of Parkinson’s disease psychosis, or PDP. ACADIA will no longer conduct the Phase III -021 study that was planned as a confirmatory trial. ACADIA believes FDA decision will reduce substantially both the time and cost of the company’s PDP development program.

ACADIA is currently focused on completing the remaining elements of its pimavanserin PDP development program that are needed for submission of an NDA. ACADIA is currently targeting an NDA submission near the end of 2014.

Pimavanserin (ACP-103) is a drug developed by Acadia Pharmaceuticals which acts as an inverse agonist on the serotonin receptor subtype 5-HT_2A, with 10x selectivity over 5-HT_2C, and no significant affinity or activity at 5-HT_2B or dopamine receptors.^[1] As of September 3 2009, pimavanserin has not met expectations for Phase III clinical trials for the treatment of Parkinson’s disease psychosis,^[2] and is in Phase II trials for adjunctive treatment of schizophrenia alongside an antipsychotic medication.^[3] It is expected to improve the effectiveness and side effect profile of antipsychotics.^[4]^[5]^[6]

Vanover KE, Weiner DM, Makhay M, Veinbergs I, Gardell LR, Lameh J, Del Tredici AL, Piu F, Schiffer HH, Ott TR, Burstein ES, Uldam AK, Thygesen MB, Schlienger N, Andersson CM, Son TY, Harvey SC, Powell SB, Geyer MA, Tolf BR, Brann MR, Davis RE (May 2006). “Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine_2A receptor inverse agonist”. J Pharmacol Exp Ther 317 (2): 910–8. doi:10.1124/jpet.105.097006. PMID 16469866.
ACADIA Pharmaceuticals. “Treating Parkinson’s Disease – Clinical Trial Pimavanserin – ACADIA”. Retrieved 2009-04-11.^{[dead link]}
“ACADIA Announces Positive Results From ACP-103 Phase II Schizophrenia Co-Therapy Trial” (Press release). ACADIA Pharmaceuticals. 2007-03-19. Retrieved 2009-04-11.
Gardell LR, Vanover KE, Pounds L, Johnson RW, Barido R, Anderson GT, Veinbergs I, Dyssegaard A, Brunmark P, Tabatabaei A, Davis RE, Brann MR, Hacksell U, Bonhaus DW (August 2007). “ACP-103, a 5-hydroxytryptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models”. J Pharmacol Exp Ther 322 (2): 862–70. doi:10.1124/jpet.107.121715. PMID 17519387.
Vanover KE, Betz AJ, Weber SM, Bibbiani F, Kielaite A, Weiner DM, Davis RE, Chase TN, Salamone JD (October 2008). “A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model”. Pharmacol Biochem Behav 90 (4): 540–4. doi:10.1016/j.pbb.2008.04.010. PMC 2806670. PMID 18534670.
Abbas A, Roth BL (December 2008). “Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders”. Expert Opin Pharmacother 9 (18): 3251–9. doi:10.1517/14656560802532707. PMID 19040345.

Phase 3-AMG 145 for hyperlipidaemia and mixed dyslipidaemia

April 12, 2013 3:43 am / 2 Comments on Phase 3-AMG 145 for hyperlipidaemia and mixed dyslipidaemia

AMG 145

Amgen Limited.

AMG 145 is a fully-human monoclonal antibody which targets proprotein convertase subtilisin/kexin type 9 (PCSK9).

It is intended for use in the reduction of elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo-B), non-high density lipoprotein cholesterol (non-HDL-C) and lipoprotein A (Lp(a)) in patients with primary hyperlipidaemia and mixed dyslipidaemia.

It is also intended for use as an adjunct to other lipid lowering therapies in patients with primary Ho-FH.

Dyslipidaemias include a wide range of lipid abnormalities and disturbances in lipid metabolism that lead to changes in plasma lipoprotein function and/or levels. Along with other cardiovascular risk factors, this may lead to the development of atherosclerosis. TC and LDL-C levels constitute the primary targets of therapy as evidence showing that reducing TC and LDL-C can prevent cardiovascular disease (CVD) is strong and compelling(1). However, other dyslipidaemias also predispose to premature CVD. The atherogenic lipid triad consisting of increased very low density lipoprotein (VLDL) remnants manifested as mildly elevated triglycerides (TG), increased small dense low-density lipoprotein (LDL) particles, and reduced high-density lipoprotein-cholesterol (HDL-C) levels is a common pattern found in premature CVD.

Hypercholesterolaemia is defined as the presence of high concentrations of cholesterol in the blood(2). Blood cholesterol has a log-linear relationship to the risk of CVD and is a key modifiable risk factor. In high-income countries, blood cholesterol levels >3.8mmol/L(b) are estimated to be responsible for more than 50% of CVD associated events(3). Primary hypercholesterolaemia is associated with an underlying genetic cause. This may be a specific genetic defect, as in familial hypercholesterolaemia (FH), or the interaction of multiple genes with dietary and other risk factors (non-familial hypercholesterolaemia).

FH is often transmitted as a codominant trait, with two principle forms described: homozygous-FH (Ho-FH) and heterozygous-FH (He-FH) in which either both or one of the pair of LDL-C receptor genes is defective or mutated with reduced activity. FH results in markedly elevated LDL-C levels, with other forms of cholesterol remaining normal. He-FH is often clinically silent and may be diagnosed at any age following a complete lipid analysis. Untreated, He-FH typically leads to symptomatic CVD by the fourth or fifth decade of life(2,4). The more severe homozygous form may be manifest from an early age, and is characterised by extravascular cholesterol deposits, cutaneous or tendon xanthomas, LDL-C levels >3.3 g/L(b) and arteriopathy.

Paragazole Excels as Breast Cancer Treatment

April 12, 2013 3:34 am / 2 Comments on Paragazole Excels as Breast Cancer Treatment

April 2013

Breast cancers that lack estrogen receptors are more difficult to treat than ER+ cancers. Research presented at the AACR Annual Meeting 2013 demonstrates an investigational drug, Paragazole, that makes triple-negative breast cancer cells express estrogen receptors, and that increases the sensitivity of these cells to chemotherapy.

“Basically what we’re trying to do is use triple-negative breast cancer models to develop targeted drugs for treatment. Paragazole is an especially exciting candidate,” said Jennifer Diamond, MD, investigator at the University of Colorado Cancer Center and medical oncologist at the University of Colorado Hospital.

Paragazole is a novel histone deacetylase (HDAC) inhibitor developed at CU Boulder in the laboratories of Xuedong Liu and Andy Phillips, being tested at the CU Cancer Center. In this study, Diamond and colleagues tested the drug against a range of breast cancer cell lines with and without combination with chemotherapies paclitaxel, gemcitabine or carboplatin. Interestingly, it was specifically the cell lines that didn’t express estrogen– the aggressive, triple-negative cells– that were most affected by paragazole. Sure enough, the researchers saw increased expression of CARM1 mediated estrogen receptors in these especially sensitive cells.

It was as if paragazole set up these triple negative cells so that chemotherapy could be more effective.

“This really is a case in which the result was greater than the sum of its parts. Paragazole with chemotherapy was more effective than the combined effects of both drugs, alone,” Diamond said.

Studies with the drug are continuing with the eventual goal of moving the therapy from the lab to the clinic in selected patients.

PFIZER’S Palbociclib Granted Breakthrough Label by the Food and Drug Administration

April 12, 2013 3:14 am / 1 Comment on PFIZER’S Palbociclib Granted Breakthrough Label by the Food and Drug Administration

CHEMICAL NAMES
1. Pyrido[2,3-d]pyrimidin-7(8H)-one, 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-
piperazinyl)-2-pyridinyl]amino]-
2. 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-
yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one
MOLECULAR FORMULA C24H29N7O2
MOLECULAR WEIGHT 447.5
TRADEMARK None as yet
SPONSOR Pfizer Inc.
CODE DESIGNATION PD-0332991
CAS#: 571190-30-2 (PD0332991); 827022-32-2 (PD0332991 HCl salt)

http://www.ama-assn.org/resources/doc/usan/palbociclib.pdf FOR STRUCTURE AND DETAILS

Palbociclib, also known as PD0332991, is an orally available pyridopyrimidine-derived cyclin-dependent kinase (CDK) inhibitor with potential antineoplastic activity. PD-0332991 selectively inhibits cyclin-dependent kinases (particularly Cdk4/cyclin D1 kinase), which may inhibit retinoblastoma (Rb) protein phosphorylation; inhibition of Rb phosphorylation prevents Rb-positive tumor cells from entering the S phase of the cell cycle (arrest in the G1 phase), resulting in suppression of DNA replication and decreased tumor cell proliferation. PD 0332991 is a highly specific inhibitor of cyclin-dependent kinase 4 (Cdk4) (IC50 = 0.011 μmol/L) and Cdk6 (IC50 = 0.016 μmol/L), having no activity against a panel of 36 additional protein kinases. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

Date: April 10, 2013

Pfizer Inc. said that its experimental pill for advanced, often deadly breast cancer has been designated as a breakthrough therapy by the Food and Drug Administration.

The breakthrough designation, created under legislation enacted last summer to fund and improve operations of the FDA, is meant to speed up development and review of experimental treatments that are seen as big advances over existing therapies for serious diseases. Pfizer is working with the agency to determine exactly what research results it will need to apply for approval of the drug.

Palbociclib is being evaluated as an initial treatment for the biggest subgroup of postmenopausal women whose breast cancer is locally advanced or has spread elsewhere in the body. About 60% of women with such advanced breast cancer have tumors classified as ER+, or estrogen-receptor positive, but HER2-, or lacking an excess of the growth-promoting protein HER2.

Estrogen-receptor positive tumors have proteins inside and on the surface of their cells to which the estrogen hormone can attach and then fuel growth of cells. These tumors tend to grow slowly and can be fought with drugs that block estrogen’s effects.

Meanwhile, about 80% of breast cancer tumor cells are HER2 negative. That means that unlike HER2 positive tumors, they don’t produce too much of the HER2 protein, which makes tumors grow and spread more aggressively than in other breast cancer types.

New York-based Pfizer is currently running a late-stage study of palbociclib at multiple centers, comparing its effects when used in combination with letrozole with the effects of letrozole alone.

Letrozole, sold under the brand name Femara for about the past 15 years, is a pill that works by inhibiting aromatase. That’s an enzyme in the adrenal glands that makes estrogen.

According to Pfizer, palbociclib targets enzymes called cyclin dependent kinases 4 and 6. By inhibiting those enzymes, the drug has been shown in laboratory studies to block cell growth and suppress copying of the DNA of the cancer cells.

Pfizer, which has made research on cancer medicines a priority in recent years, also is testing palbociclib as a treatment for other cancers.

Highlight of recent study using PD-0332991

Phase I study of PD-0332991: Forty-one patients were enrolled. DLTs were observed in five patients (12%) overall; at the 75, 125, and 150 mg once daily dose levels. The MTD and recommended phase II dose of PD 0332991 was 125 mg once daily. Neutropenia was the only dose-limiting effect. After cycle 1, grade 3 neutropenia, anemia, and leukopenia occurred in five (12%), three (7%), and one (2%) patient(s), respectively. The most common non-hematologic adverse events included fatigue, nausea, and diarrhea. Thirty-seven patients were evaluable for tumor response; 10 (27%) had stable disease for ≥4 cycles of whom six derived prolonged benefit (≥10 cycles). PD 0332991 was slowly absorbed (median T(max), 5.5 hours), and slowly eliminated (mean half-life was 25.9 hours) with a large volume of distribution (mean, 2,793 L). The area under the concentration-time curve increased linearly with dose. Using an E(max) model, neutropenia was shown to be proportional to exposure. CONCLUSIONS:
PD 0332991 warrants phase II testing at 125 mg once daily, at which dose neutropenia was the sole significant toxicity. (Source: Clin Cancer Res; 18(2); 568-76.)

Phase I study of PD-0332991 in 3-week cycles (Schedule 2/1): Six patients had DLTs (18%; four receiving 200 mg QD; two receiving 225 mg QD); the MTD was 200 mg QD. Treatment-related, non-haematological adverse events occurred in 29 patients (88%) during cycle 1 and 27 patients (82%) thereafter. Adverse events were generally mild-moderate. Of 31 evaluable patients, one with testicular cancer achieved a partial response; nine had stable disease (≥10 cycles in three cases). PD 0332991 was slowly absorbed (mean T(max) 4.2 h) and eliminated (mean half-life 26.7 h). Volume of distribution was large (mean 3241 l) with dose-proportional exposure. Using a maximum effective concentration model, neutropenia was proportional to exposure. CONCLUSION: PD 0332991 was generally well tolerated, with DLTs related mainly to myelosuppression. The MTD, 200 mg QD, is recommended for phase II study. (source: Br J Cancer. 2011 Jun 7;104(12):1862-8)

References

1: Flaherty KT, Lorusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS, Shaik MN, Wilner KD, O’Dwyer PJ, Schwartz GK. Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res. 2012 Jan 15;18(2):568-76. doi: 10.1158/1078-0432.CCR-11-0509. Epub 2011 Nov 16. PubMed PMID: 22090362.

2: Smith D, Tella M, Rahavendran SV, Shen Z. Quantitative analysis of PD 0332991 in mouse plasma using automated micro-sample processing and microbore liquid chromatography coupled with tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Oct 1;879(27):2860-5. doi: 10.1016/j.jchromb.2011.08.009. Epub 2011 Aug 16. PubMed PMID: 21889427.

3: Katsumi Y, Iehara T, Miyachi M, Yagyu S, Tsubai-Shimizu S, Kikuchi K, Tamura S, Kuwahara Y, Tsuchiya K, Kuroda H, Sugimoto T, Houghton PJ, Hosoi H. Sensitivity of malignant rhabdoid tumor cell lines to PD 0332991 is inversely correlated with p16 expression. Biochem Biophys Res Commun. 2011 Sep 16;413(1):62-8. doi: 10.1016/j.bbrc.2011.08.047. Epub 2011 Aug 17. PubMed PMID: 21871868; PubMed Central PMCID: PMC3214763.

4: Schwartz GK, LoRusso PM, Dickson MA, Randolph SS, Shaik MN, Wilner KD, Courtney R, O’Dwyer PJ. Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1). Br J Cancer. 2011 Jun 7;104(12):1862-8. doi: 10.1038/bjc.2011.177. Epub 2011 May 24. PubMed PMID: 21610706; PubMed Central PMCID: PMC3111206.

5: Nguyen L, Zhong WZ, Painter CL, Zhang C, Rahavendran SV, Shen Z. Quantitative analysis of PD 0332991 in xenograft mouse tumor tissue by a 96-well supported liquid extraction format and liquid chromatography/mass spectrometry. J Pharm Biomed Anal. 2010 Nov 2;53(3):228-34. doi: 10.1016/j.jpba.2010.02.031. Epub 2010 Feb 26. PubMed PMID: 20236782.

6: Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, Los G, Slamon DJ. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):R77. doi: 10.1186/bcr2419. PubMed PMID: 19874578; PubMed Central PMCID: PMC2790859.

7: Menu E, Garcia J, Huang X, Di Liberto M, Toogood PL, Chen I, Vanderkerken K, Chen-Kiang S. A novel therapeutic combination using PD 0332991 and bortezomib: study in the 5T33MM myeloma model. Cancer Res. 2008 Jul 15;68(14):5519-23. doi: 10.1158/0008-5472.CAN-07-6404. PubMed PMID: 18632601.

8: Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004 Nov;3(11):1427-38. PubMed PMID: 15542782.

AYURVEDA–Manjishta, Rubia cordifolia

April 11, 2013 1:25 pm / 15 Comments on AYURVEDA–Manjishta, Rubia cordifolia

Rubia cordifolia

Rubia cordifolia
Scientific classification
Kingdom:	Plantae
(unranked):	Angiosperms
(unranked):	Eudicots
(unranked):	Asterids
Order:	Gentianales
Family:	Rubiaceae
Tribe:	Rubieae
Genus:	Rubia
Species:	R. cordifolia
Binomial name
*Rubia cordifolia* L.

Rubia cordifolia, often known as Common Madder or Indian Madder, is a species of flowering plant in the coffee family, Rubiaceae. It has been cultivated for a red pigment derived from roots.

Common names of this plant include Manjistha in Sanskrit, Marathi, Kannada and Bengali, Majith in Hindi and Gujarati, Tamaralli in Telugu, Manditti in Tamil.

Description

It can grow to 1.5 m in height. The evergreen leaves are 5–10 cm long and 2–3 cm broad, produced in whorls of 4-7 starlike around the central stem. It climbs with tiny hooks at the leaves and stems. The flowers are small (3–5 mm across), with five pale yellow petals, in dense racemes, and appear from June to August, followed by small (4–6 mm diameter) red to black berries. The roots can be over 1 m long, up to 12 mm thick. It prefers loamy soils with a constant level of moisture. Madders are used as food plants for the larvae of some Lepidoptera species including Hummingbird hawk moth.

Uses

Rubia cordifolia was an economically important source of a red pigment in many regions of Asia, Europe and Africa. It was extensively cultivated from antiquity until the mid nineteenth century. The plant’s roots contain an organic compound called Alizarin, that gives its red colour to a textile dye known as Rose madder. It was also used as a colourant, especially for paint, that is referred to as Madder lake. The substance was also derived other species; Rubia tinctorum, also widely cultivated, and the Asiatic species Rubia argyi (H. Léveillé & Vaniot) H. Hara ex Lauener (synonym = Rubia akane Nakai,^[1] based on the Japanese Aka (アカ or あか) = red, and ne (ネ or ね) = root). The invention of a synthesized duplicate, an anthracene compound called alizarin, greatly reduced demand for the natural derivative.^[2]

The roots of Rubia cordifolia are also the source of a medicine used in Ayurveda, this is commonly known in Ayurvedic Sanskrit as Manjistha (or Manjista or Manjishta) and the commercial product in Hindi as Manjith.^[3]

It is known as btsod (Tibetan: བཙོད་) in Traditional Tibetan Medicine where it is used to treat blood disorders; spread heat (Tibetan: འགྲམས་ཚད་), excess heat in the lungs, kidneys, and intestines; reduce swelling; and is a component of the three reds (Tibetan: དམར་གསུམ་), a subcompound included in many Tibetan preparations in order to remove excess heat in the blood.^[4]

In Traditional Chinese Medicine it is known as qiàn cǎo gēn (茜草根).

The following properties were described in various cellular and animal models:

anti-inflammatory^[5]

urolithiasis ^[6]

Iwatsuki, K., T. Yamazaki, D. E. Boufford and H. Ohba. 1993. Flora of Japan IIIa: 232.
“Material Name: madder”. material record. Museum of Fine Arts, Boston. November 2007. Retrieved 2009-01-01.
R. Daman, S. Bhandari, B. Singh and Brij Lal; S. Pathania (2006). “Comparative Studies of Rubia cordifolia L. and its Commercial Samples”. Ethnobotanical Leaflets (11): 179–188.
Gyatso, Thinley; Hakim, Chris (2010). Essentials of Tibetan traditional medicine. Berkeley, Calif.: North Atlantic Books. p. 167. ISBN 978-1-55643-867-7.
Joshan Rani S., Nagarauk R., Anuradha P. “Antibacterial properties of extracts of Indian medicinal plants: Syzygium alternifolium, phyllanthus niruri and rubia cordifolia” Biomedical and Pharmacology Journal 2010 3:1 (123-128)
Divakar K., Pawar A.T., Chandrasekhar S.B., Dighe S.B., Divakar G.”Protective effect of the hydro-alcoholic extract of Rubia cordifolia roots against ethylene glycol induced urolithiasis in rats” Food and Chemical Toxicology 2010 48:4 (1013-1018)

Caldecott, Todd (2006). Ayurveda: The Divine Science of Life. Elsevier/Mosby. ISBN 0-7234-3410-7. Contains a detailed monograph on Rubia cordifolia (Manjishta) as well as a discussion of health benefits and usage in clinical practice. Available online at http://www.toddcaldecott.com/index.php/herbs/learning-herbs/306-manjishta

Manjishta, considered to be the best all around herbal blood purifier according to Ayurvedic Text, Manjishta Rasayana cools and helps detoxify the blood. Manjishta relieves pain caused by inflammation such as a tooth ache, helps stop bleeding, and helps remove obstructions in the blood stream, liver, and kidneys. It can assist all inflammatory conditions of the blood and female reproductive system. It can help dissolve abnormal growths in the tissues. Manjishta can improve blood flow and promote healing of broken bones and tissue damaged by injury or infection. It may help with sexually transmitted diseases.

Ayurveda is a holistic healing science which comprises of two words, Ayu and Veda. Ayu means life and Veda means knowledge or science. So the literal meaning of the word Ayurveda is the science of life. Ayurveda is a science dealing not only with treatment of some diseases but is a complete way of life. Ayurveda is the ancient Indian medical science, the origin of which can be traced back to the Vedas, which are the oldest available classics of the world. Vedas are the ancient books of knowledge, or science, from India.

They contain practical and scientific information on various subjects beneficial to the humanity like health, philosophy, engineering, astrology etc. Ayurveda combines physical, psychological and spiritual therapies in an approach to health, that has addressed itself to the fundamental principles of good health and longevity. It has developed a tradition of medicine and a system of treatment based on the inherent ability of the human body to rejuvenate, to heal and to restore its natural balance.

Ayurveda is based on a system of Tridosha or Three Humours which classifies all individual constitutions of people, diseases, herbs and other non-herbal remedies and therapies according to whether they are Vata (air or nerve oriented), Kapha (water or mucoid type) or Pitta (fire type) [5] .
Herbs that have pungent, sour and salty flavors stimulate fire; herbs that are astringent (drying) and bitter stimulate vata-air, or the nerve centered humour; herbs that are sweet, salty and sour stimulate or increase Kapha-water, or the mucoid humour.

In contrast, herbs that are sweet, sour and salty flavored ameliorate Vata-air, which means that they have a particular affinity for the nervous system. Herbs that are astringent, sweet and bitter ameliorate Pitta-fire, meaning that they are soothing and anti-inflammatory.

Finally herbs that are pungent, bitter and astringent ameliorate Kapha-water, which means they tend to increase digestive fire, expel and dry excessive fluid build up in the system, including clearing excessive fat from the body, and the accumulation of cholesterol and other fatty deposits in the veins and arteries of the body.
This Indian system of medicine has laid down principles and methods of treatment for various diseases including chronic illnesses where there is no definite curative treatment, and symptomatic relief is the only existing treatment option.

Origin

Ayurvedic medicine originated in the early civilizations of India some 3,000-5,000 years ago. It is mentioned in the Vedas, the ancient religious and philosophical texts that are the oldest surviving literature in the world, which makes Ayurvedic medicine the oldest surviving healing system.

According to the texts, Ayurveda was conceived by enlightened wise men as a system of living harmoniously and maintaining the body so that mental and spiritual awareness could be possible. Medical historians believe that Ayurvedic ideas were transported from ancient India to China and were instrumental in the development of Chinese medicine.

Ayurveda is a science based on ancient Indian philosophy. The Vedas encompass the whole knowledge of the Universe. There are four Vedas, namely, Rigveda, Yajurveda, Samaveda and Atharvaveda. Amongst these, the Atharvaveda mainly deals with different facets of health.

The main body of Ayurveda is found in the fourth Veda – the Artharvaveda. Ayurveda is an offspring of the Atharvaveda and is also considered as the fifth Veda. Ayurveda is recognized as an upa or supplementary Veda in its own right. It contains the description of various diseases and their aetiology, and recommends the correct diet and behaviour regimen to counter those diseases.

Mythology has it that Brahma, the creator, imparted the knowledge of Ayurveda to Prajapati Daksha who, in turn, passed it on to the Ashwinikumara twins who were the physicians to the gods. The Ashwinikumaras then offered this knowledge to Lord Indra. Lord Indra instructed Dhanwantari to spread this invaluable science of longevity on the earth. Sushruta, a renowned surgeon and student of Dhanwantari, wrote his famous compendium on surgery – the Sushruta Samhita. The credit for the famous treatise on general medicine, the Charaka Samhita, goes to Charaka who probably lived sometime between the second century B.C. and the second century A.D.. Sushruta Samhita and Charaka Samhita are the two ancient treatises on which Ayurveda is based.

Ayurvedic philosophy provides a link between the living and non-living matters of the universe and indicates the origin of human and plant life from the five basic elements which are earth, water, fire, air and ether.

Principles of Ayurveda

Ayurveda is bestowed upon us by our ancestors, who were eminent and wiser and having insight into our being. Basically Ayurveda is Health promotive – preventive – curative and nutritive – all self contained.

The two principle objectives of Ayurveda are :

(a.) “Swasthyas swasthya rakshanam” – To prolong life and promote perfect health ( add years to life and life to years )

(b.) “Aturasya vikar prashamanamcha” – To completely eradicate the disease and dysfunction of the body.

Ayurveda takes the individual as whole and seeks to re-establish harmony between all the constituents in the body. Perfect balance of the tripod – Mind, Body and Spirit means perfect health.

To understand Ayurvedic treatment, it is necessary to have an idea how the Ayurvedic system views the body. The basic life force in the body is prana, which is also found in the elements and is similar to the Chinese notion of chi.

In Ayurveda, there are five basic elements that contain prana: earth, water, fire, air, and ether. These elements interact and are further organized in the human body as three main categories or basic physiological principles in the body that govern all bodily functions known as the doshas. The three doshas are vata, pitta, and kapha. Each person has a unique blend of the three doshas, known as the person’s prakriti, which is why Ayurvedic treatment is always individualized. In Ayurveda, disease is viewed as a state of imbalance in one or more of a person’s doshas, and an Ayurvedic physician strives to adjust and balance them, using a variety of techniques.

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AYURVEDA–Manjishta, Rubia cordifolia

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