DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India, in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA as ADVISOR earlier GLENMARK LS Research centre as consultant,Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now sSanofi, Searle India ltd, now Rpg lifesciences, etc. he is now helping millions, has million hits on google on all organic chemistry websites. His New Drug Approvals, Green Chemistry International, Eurekamoments in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide . He gas good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, polymorphism etc He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has one lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463, [email protected]

Auraptene has shown a remarkable effect in the prevention of degenerative diseases.

Uncategorized Comments Off

Oct 282013

Auraptene is a natural bioactive monoterpene coumarin ether. It was first isolated from members of the genus Citrus.

Auraptene has shown a remarkable effect in the prevention of degenerative diseases. Many studies have reported the effect of auraptene as a chemopreventative agent against cancers of liver, skin, tongue, esophagus, and colon in rodent models.^[1] The effect in humans is not yet known.

7-((E)-3, 7-Dimethylocta-2, 6-dienyloxy)-2H-chromen-2-one
Other names Aurapten 7-Geranyloxycoumarin

Curini, M., Carvotto, G., Epifano, F. and Giannone, G. “Chemistry and Biological Activity of Natural and Synthetic Prenyloxycoumarins”(2006). Current Medicinal Chemistry, 13, 199-222.

http://www.sciencedirect.com/science/article/pii/S0731708511002706

Guillian Barre Syndrome Symptoms and Treatment

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Oct 262013

Guillain Barre Syndrome

Fever is one of the most common problems and there is not a single person who does not suffer from this in his life at least once. But in some people symptoms such as tingling sensation, temporary paralysis of legs and arms may appear after an attack of fever. These are the symptoms of Guillian Barre syndrome.

Brain and backbone are very important for the movement of the body. Nerves that control the movements are also very important as they carry the signals from brain to the muscles. Muscles move according to the signals brought by the muscles. If the nerves get damaged due to some problems, symptoms such as paralysis of legs and arms, tingling sensation, losing muscles movements etc are seen. Nerve disorders are usually found in diabetic patients and alcoholics. But these may sometime appear in people after a viral infection.

When symptoms of Guillian Barre syndrome appear, the patient should be taken to the Neurologist immediately. NCS test is prescribed for the patient and depending on the test results, Guillian Barre syndrome can be confirmed. Some other test may also be required to rule out other diseases that have the same symptoms.

Treatment for Guillian Barre syndrome

If nerve damage due to Guillian Barre is only minor, the condition can be improved with few injections and physiotherapy. Improvement can be observed in two to three months. But if the severity is more and if the patient finds breathing also difficult, he should be admitted into the ICU. The patient is given treatment with medicines for five days. Treatment for Guillian Barre syndrome is expensive. The dosage of the medicine is decided depending on the body weight of the patient. Medicines may cost between Rs. 2 lakhs to 3 lakhs.

There is alternative treatment for Guillian Barre syndrome for those who cannot bear the expense of medicines. It is called the Plasmapheresis procedure. This helps in preventing the condition of the patient from deteriorating further. In this procedure, patient’s blood is taken out and plasma is separated. Blood without plasma is again transfused into the patient’s body. If necessary, healthy plasma taken from donors is also given to the patient. But this treatment should begin immediately after Guillian Barre syndrome is confirmed for effective results. This treatment costs nearly Rs. 1 lakh and the patient should be given physiotherapy treatment for muscle movement.

Guillain barre syndrome from Praveen Nagula

BAYER 2013 AND BEYOND

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Oct 252013

http://www.bayer.com/

Bayer

With 11 treatments in Phase I trials, 8 in Phase II, and 13 in Phase III, Bayer has a strong pipeline.

By far the most interest currently, given that the latest reports came out October 21st, is riociguat (BAY 63-2521),

which has had good news from its ongoing Phase III clinical trials of the treatment for pulmonary arterial hypertension, also known as PAH. PAH is a progressive condition that overburdens the heart.

Trials indicate subjects had improved heart function and could better tolerate physical exercise. Patients on riociguat improved their walking distance by 36 meters on average, while those on placebo showed no improvement.

Professor Hossein Ardeschir Ghofrani of University Hospital Giessen, the principal investigator, was quite pleased with the results and explained the value of the measurement. “The six-minute walk distance test is a well-validated clinical measure in patients with PAH, and therefore, the results of the PATENT-1 trial are encouraging. . .These data from the PATENT study suggest that riociguat may be a potential treatment option both for patients who have never been treated for PAH as well as for those who have received prior treatment.”

Hossein A. Ghofrani
Associate Professor of Internal Medicine,
MD (University of Giessen) 1995 Research interests: pulmonary hypertension, ischaemia-reperfusion, experimental therapeutics, clinical trials

http://www.uni-giessen.de/cms/fbz/fb11/forschung/graduierte/mbml/faculty

Although Bayer put forth no sales estimate for the treatment, analysts predicted 2017 sales from riociguat of $480 million.

BAYER PIPELINE AS ON OCT 25 2013

phase 1

Project	Indication
CDK-Inhibitor (BAY 1000394)	Cancer
Mesothelin-ADC (BAY 94-9343)	Cancer
PSMA Bi TE Antibody (BAY 2010112)	Cancer
PI3K-Inhibitor (BAY 1082439)	Cancer
FGFR2 Antibody (BAY 1179470)	Cancer
HIF-PH (BAY 85-3934)	Anemia
Partial Adenosine A1 Agonist(BAY 1067197)	Heart Failure
Vasopressin Receptor Antagonist(BAY 86-8050)	Heart Failure
sGC Stimulator (BAY 1021189)	Heart Failure
S-PRAnt (BAY 1002670)	Symptomatic uterine fibroids
BAY 1026153	Endometriosis

phase2

Project	Indication
PI3K-Inhibitor (BAY 80-6946)	Cancer
Regorafenib	Cancer
Refametinib (MEK-Inhibitor)	Cancer
Radium-223-Dichloride	Cancer
Sorafenib	Additional Indications
MR-Antagonist (BAY 94-8862)	Congestive Heart Failure (CHF)
MR-Antagonist (BAY 94-8862)	Diabetic Nephopathy
Riociguat (sGC Stimulator)	Pulmonary Hypertension
Neutrophil Elastase Inhibitor(BAY 85-8501)	Bronchiectasis

phase 3

Project	Indication
Sorafenib	Breast Cancer
Sorafenib	Adjuvant HCC
Sorafenib	Adjuvant RCC
Regorafenib	HCC 2nd line
Rivaroxaban	Major Adverse Cardiac Events
Rivaroxaban	CHF and CAD
peg rFVIII(BAY 94-9027)	Hemophilia
Aflibercept	Myopic choroidal neovascularization (mCNV)
Aflibercept	Diabetic Macular Edema (DME)
LCS 16	Contraception
Vaginorm	Vulvovaginal atrophy (VVA)
Sodium Deoxycholate	Submental fat removal
Cipro DPI	Lung infection
Tedizolid	Skin and Lung Infections
Amikacin Inhale	Gram-negative pneumonia

Information for Download from bayer

From molecules to medicine – A journey through research and development (PDF, 3 MB)

Sorafenib tosylate

http://newdrugapprovals.wordpress.com/2013/07/16/nexavar-sorafenib/

TEDIZOLID PHOSPHATE

http://newdrugapprovals.wordpress.com/2013/10/24/cubist-pharmaceuticals-inc-announced-that-it-has-submitted-a-nda-to-the-u-s-fda-for-approval-of-its-investigational-antibiotic-tedizolid-phosphate-tr-701/

Bayer Accelerates Clinical Development of Promising New Drug Candidates

Five new molecular entities projected to enter Phase III by 2015 / Addressing unmet medical needs in the areas of oncology, cardiology, and women’s health / Initiation of further studies with recently launched products planned to add new treatment options

Leverkusen, October 8, 2013 – Following the recent commercial introduction of five new drugs to address the medical needs of patients with various diseases, Bayer is now accelerating the development of further five promising drug candidates which are currently undergoing phase I and II clinical studies. The company today announced that it plans to progress these five new highly innovative drug candidates in the areas of oncology, cardiology, and women’s health into phase III clinical studies by 2015.

“Our Pharma research and development has done a tremendous job of bringing five new products to the market offering physicians and patients new treatment alternatives for serious diseases”, said Bayer CEO Dr. Marijn Dekkers. “Following our mission statement ‘Science For A Better Life’, the five chosen further drug candidates all have the potential to impact the way diseases are treated for the benefit of patients.”

Bayer CEO Dr. Marijn Dekkers
“Our research and development activities are strongly focused on areas where treatment options are not available today or where true breakthrough innovations are missing”, said Prof. Andreas Busch, member of the Bayer HealthCare Executive Committee and Head of Global Drug Discovery at Bayer HealthCare. “Our drug development pipeline holds a number of promising candidates which we want to bring to patients who need them urgently”, said Kemal Malik, member of the Bayer HealthCare Executive Committee, Chief Medical Officer and Head of Pharmaceutical Development at Bayer HealthCare. “Furthermore we are continuing to expand the range of indications for all our recently launched products Xarelto, Stivarga, Xofigo, Riociguat as well as Eylea and further refine the profile of these drugs in specific patient populations.”

Cl 223Ra Cl

Xofigo

http://newdrugapprovals.wordpress.com/2013/09/21/xofigo-injection-recommended-for-approval-in-eu/

The five mid-stage candidates have been selected for accelerated development based on positive “proof-of-concept” data from early clinical studies. Three of them are development compounds in the area of cardiology or the cardio-renal syndrome: Finerenone (BAY 94-8862) is a next generation oral, non-steroidal Mineralocorticoid Receptor antagonist which blocks the deleterious effects of aldosterone. Currently available steroidal MR antagonists have proven to be effective in reducing cardiovascular mortality in patients with heart failure but have significant side effects that limit their utilization. Finerenone is currently in clinical Phase IIb development for the treatment of worsening chronic heart failure, as well as diabetic nephropathy.

Finerenone (BAY 94-8862)

http://newdrugapprovals.wordpress.com/2013/10/09/finerenone-bay-94-8862-bayers-next-generation-oral-non-steroidal-mineralocorticoid-receptor-antagonist-which-blocks-the-deleterious-effects-of-aldosterone/

The second drug candidate in the area of cardiology is an oral soluble guanylate cyclase (sGC) stimulator (BAY 1021189). The start of a Phase IIb study in patients with worsening chronic heart failure is expected later this year.

For the cardio-renal syndrome, a Phase IIb program with the investigational new drug Molidustat (BAY 85-3934) is under initiation in patients with anemia associated with chronic kidney disease and/or end-stage renal disease. Molidustat is a novel inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) which stimulates erythropoietin (EPO) production and the formation of red blood cells. Phase I data have shown that inhibition of HIF-PH by Molidustat results in an increase in endogenous production of EPO.

Molidustat (BAY 85-3934)

http://newdrugapprovals.wordpress.com/2013/10/09/molidustat-bay-85-3934-bayers-drug-under-initiation-in-patients-with-anemia-associated-with-chronic-kidney-disease-andor-end-stage-renal-disease/

In oncology, Copanlisib (BAY 80-6946), a novel, oral phosphatidylinositol-3 kinases (PI3K) inhibitor, was selected for accelerated development. Copanlisib demonstrated a broad anti-tumor spectrum in preclinical tumor models and promising early clinical signals in a Phase I study in patients with follicular lymphoma. A Phase II study in patients with Non-Hodgkin’s lymphoma is currently ongoing.

Bayer has also made good progress in the development of new treatment options for patients with gynecological diseases: sPRM (BAY 1002670) is a novel oral progesterone receptor modulator that holds the promises of long-term treatment of patients with symptomatic uterine fibroids. Based on promising early clinical data the initiation of a Phase III study is planned for mid-2014.

Initiation of further studies with recently launched products
Bayer has successfully launched five new pharmaceutical products, namely Xarelto™, Stivarga™, Xofigo™, Eylea™, and Riociguat, which has very recently been approved in Canada under the trade name Adempas™.

http://newdrugapprovals.wordpress.com/2013/05/27/xarelto-approved-for-secondary-prevention-in-acute-coronary-syndrome-patients-in-europe/

Regorafenib, stivarga

http://newdrugapprovals.wordpress.com/2013/08/31/bayers-stivarga-regorafenib-tablets-approved-in-europe/

Bayer’s Eylea (aflibercept),

http://newdrugapprovals.wordpress.com/2013/06/01/lucentis-rival-one-step-away-from-nhs-approval/

Xarelto has been approved globally for five indications across seven distinct areas of use, allowing doctors to treat patients in a greater variety of venous and arterial thromboembolic conditions than any other novel oral anticoagulant. The company continues to study the use of Xarelto for the treatment of further cardiovascular diseases. Ongoing clinical Phase III studies include COMPASS and COMMANDER-HF. The COMPASS study will assess the potential use of Xarelto in combination with aspirin, or as a single treatment to prevent major adverse cardiac events (MACE) in nearly 20,000 patients with atherosclerosis related to coronary or peripheral artery disease. The COMMANDER-HF study will evaluate the potential added benefit of Xarelto in combination with single or dual-antiplatelet therapy to help reduce the risk of death, heart attack and stroke in approximately 5,000 patients with chronic heart failure and coronary artery disease, following hospitalization for exacerbation of their heart failure.
In order to answer medically relevant questions for specific patient populations Bayer has initiated a range of additional Xarelto studies in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention with stent placement (PIONEER-AF-PCI), cardioversion (X-VERT) or an AF ablation procedure (VENTURE-AF).
As an extension to the Xarelto clinical trial programme, a number of real-world studies are designed to observe and further evaluate Xarelto in everyday clinical practice. These include the XAMOS study of more than 17,000 orthopaedic surgery patients, which confirmed the clinical value of oral, once-daily Xarelto in routine clinical practice in adults following orthopaedic surgery of the hip or knee. XANTUS is designed to collate data on real-world protection with Xarelto in over 6,000 adult patients in Europe with non-valvular AF at risk of stroke while XANAP is designed to collate data on real-world protection with Xarelto in over 5,000 adult patients in Europe and Asia with non-valvular AF at risk of stroke. XALIA will generate information from over 4,800 patients treated for an acute DVT with either Xarelto or standard of care.

In the area of oncology, Stivarga has been approved in 42 countries for use against metastatic colorectal cancer that is refractory to standard therapies, and additionally for gastrointestinal stromal tumor (GIST) in the US and Japan. Bayer is now planning to assess Stivarga in earlier stages of colorectal cancer as well as other cancer types. A Phase III trial in patients with colorectal cancer after resection of liver metastases is currently under initiation. Based on early clinical data Bayer has also initiated a Phase III study in liver cancer in patients who have progressed on sorafenib treatment.

Furthermore, the anti-cancer drug Xofigo (radium 223 dichloride) is a first-in-class alpha-pharmaceutical which is designed for use in prostate cancer patients with ‘bone metastases’ (secondary cancers in the bone) to treat the cancer in the bone and to help extend their lives. Xofigo is approved in the US for the treatment of patients with advanced castrate-resistant prostate cancer with symptomatic bone metastases. In addition, the European CHMP recently gave a positive opinion for radium 223 dichloride for the same use. The decision of the European Commission on the approval is expected in the fourth quarter of 2013.
Based on the excellent Phase III results for Xofigo in patients with castration resistant prostate cancer and symptomatic bone metastases Bayer is looking to expand the use of Xofigo to earlier stages of the disease, and plans to initiate a Phase III study in combination with the novel anti-hormonal agent abiraterone. In addition, early stage signal-generating studies in other cancer forms where bone metastases are important causes of morbidity and mortality are planned.

In the area of pulmonary hypertension Adempas (Riociguat) is the first member of a novel class of compounds – so-called ‘soluble guanylate cyclase (sGC) stimulators’ – being investigated as a new and specific approach to treating different types of pulmonary hypertension (PH). Adempas has the potential to overcome a number of limitations of currently approved treatments for pulmonary arterial hypertension (PAH) and addresses the unmet medical need in patients with chronic thromboembolic pulmonary hypertension (CTEPH). It was approved for the treatment of CTEPH in Canada in September 2013, making it the world’s first drug approved in this deadly disease.
Riociguat has already shown promise as a potential treatment option beyond these two PH indications. An early clinical study was conducted in PH-ILD (interstitial lung disease), a disease characterized by lung tissue scarring (fibrosis) or lung inflammation which can lead to pulmonary hypertension, and, based on positive data, the decision was taken to initiate Phase IIb studies in PH-IIP (idiopathic pulmonary fibrosis), a subgroup of PH-ILD. Moreover, scientific evidence was demonstrated in preclinical models that the activity may even go beyond vascular relaxation. To prove the hypothesis Bayer is initiating clinical studies in the indication of systemic sclerosis (SSc), an orphan chronic autoimmune disease of the connective tissue affecting several organs and associated with high morbidity and mortality. If successful, Riociguat has the potential to become the first approved treatment for this devastating disease.

In the area of ophthalmology, Eylea (aflibercept solution for injection) is already approved in Europe and several additional countries for the treatment of neovascular (wet) age-related macular degeneration and for macular edema following central retinal vein occlusion. In September, Bayer HealthCare and Regeneron Pharmaceuticals presented data of the two phase III clinical trials VIVID-DME and VISTA-DME of VEGF Trap-Eye for the treatment of diabetic macular edema (DME) at the annual meeting of the Retina Society in Los Angeles and at the EURetina Congress in Hamburg, Germany. Both trials achieved the primary endpoint of significantly greater improvements in best-corrected visual acuity from baseline compared to laser photocoagulation at 52 weeks. Bayer plans to submit an application for marketing approval for the treatment of DME in Europe in 2013.

About Bayer HealthCare
The Bayer Group is a global enterprise with core competencies in the fields of health care, agriculture and high-tech materials. Bayer HealthCare, a subgroup of Bayer AG with annual sales of EUR 18.6 billion (2012), is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Medical Care and Pharmaceuticals divisions. Bayer HealthCare’s aim is to discover, develop, manufacture and market products that will improve human and animal health worldwide. Bayer HealthCare has a global workforce of 54,900 employees (Dec 31, 2012) and is represented in more than 100 countries. More information at www.healthcare.bayer.com.

Pfizer 2013 and beyond

companies Comments Off

Oct 252013

Pfizer

Pfizer gets a lot of coverage in the financial papers–even if some of it turns out to be misguided.

For example, Pfizer got the media coverage all drug companies desire on May 4 from Seeking Alpha, http://seekingalpha.com/article/560531-pfizer-alzheimers-drugs-will-carry-stock-to-new-highs-in-2013

a stock market blog that provides free stock market analysis. A piece entitled “Pfizer: Alzheimer’s Drugs Will Carry Stock To New Highs In 2013” had a subheading “strong pipeline.”

Turns out that was too optimistic, as Pfizer’s Alzheimer’s drug–along with Johnson and Johnson’s–both failed to produce. But many stock analysts still hold hope that Pfizer has a new ‘cash cow’ coming down the pipeline.

Daily Finance http://www.dailyfinance.com/2012/09/07/a-peek-at-pfizers-pipeline/

notes that Pfizer currently has 87 drugs in its pipeline. While its true that most are in the early stages, 11 are ready to be reviewed by the FDA.

That number puts it ahead of most of its rivals, with Eli Lilly, a close second, having 63 drugs in Phases 1-3, plus one currently being reviewed. Bristol-Myers Squibb has 46 drugs in development, 7 under review, Merck has 35 drugs in Phase 2 or 3 with two under review, and Johnson and Johnson has 18 drugs that are already in Phase 3 clinical trials or up for FDA approval.

But, of course, as the journal points out, “Quality trumps quantity. . . . One or two blockbusters can be better than several lower-revenue drugs.”

So what does Pfizer have up its sleeve that might begin to fill the very big shoes of Lipitor?

Well, the company has diversified the therapeutic areas under research, with 26% of R&D efforts going toward oncology treatments, 20% to neuroscience and pain, 17% to cardiovascular and metabolic diseases, 14% to inflammation and immunology, 5% to vaccines, and 18% toward ‘other.’

Pfizer has several medicines for diabetes alone coming up, in Phase I and Phase II trials, almost all meant to treat type 2 diabetes.

But, notes Seeking Alpha,http://seekingalpha.com/article/560531-pfizer-alzheimer-s-drugs-will-carry-stock-to-new-highs-in-2013

its blockbuster potential in this area is limited by the existing treatments of Merck and Sanofi. 10% of Sanofi’s total sales come from Lantus,

a diabetes drug useful for both types 1 and 2, and Merck made $1.3 billion off its Januvia

franchise in the first quarter of this year alone.

So hopes are pinned on Pfizer’s tofacitinib, currently under FDA review, as the treatment with the potential to earn $1 billion or more in sales, easing the gaping wound left by Lipitor. Tofacitinib prompts such high hopes because it might possibly treat rheumatoid arthritis, psoriasis, and irritable bowel syndrome. Some analysts have pinned this as the cash cow Pfizer so badly needs to replace treatments lost to the patent cliff.

Tofacitinib

http://seekingalpha.com/article/812981-pfizers-success-with-its-jak-inhibitor

If it gets approved, Tofacitinib would be first treatment for rheumatoid arthritis (RA) in a new class of medicines (known as Jenus kinase, or JAK, inhibitors), and the first JAK inhibitor approved for rheumatoid arthritis.

Tofacitinib showed statistically significant improvement compared to placebo in decreasing the symptoms of RA (as measured by 20% improvement in the American College of Rheumatology scale), in improving physical function (as measured by mean change in Health Assessment Questionnaire-Disability Index), and in leading to remission (as measured by Disease Activity Score 28 ESR).

Joel Kremer, MD, chief of medicine at Albany Medical College in N.Y., after analyzing the data, commented, “Tofacitinib appears to reduce the signs and symptoms of rheumatoid arthritis very quickly. We hope that after carefully considering the benefit/risk equation, this compound will provide an additional valuable treatment option for patients who have experienced inadequate response to prior treatments.”

Pfizer also believes its blood thinner Eliquis, which it is developing with Bristol-Myers Squibb (see below) could be a big money-maker.

apixaban, eliquis

Alzheimer’s Image Problem Solved

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Oct 252013

Copper-based radiopharmaceuticals for diagnostic imaging can target the amyloid-β plaques implicated in Alzheimer’s disease

http://www.chemistryviews.org/details/news/5384281/Alzheimers_Image_Problem_Solved.html

Alzheimer’s Image Problem Solved

ViiV Healthcare files new drug application for three-drug HIV pill with US FDA

NDA Comments Off

Oct 242013

ViiV Healthcare, a joint venture involving GlaxoSmithKline (GSK), Pfizer and Shionogi, has submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) for its investigational single-tablet regimen (STR) combining dolutegravir, abacavir and lamivudine for treatment of HIV-1 patients.

click hereViiV Healthcare files new drug application for three-drug HIV pill with US FDA

Ranbaxy obtains approval to market malaria drug in India

INDIA Comments Off

Oct 232013

Ranbaxy Laboratories has secured approval from India’s Central Drugs Standard Control Organisation (CDSCO) to produce and market its Synriam drug in the country to treat malaria caused by the Plasmodium vivax parasite in adults.

Ranbaxy obtains approval to market malaria drug in India CLICK HERE

http://www.pharmaceutical-technology.com/news/newsranbaxy-obtains-approval-market-malaria-drug-india?WT.mc_id=DN_News

AltheRx obtains US patent for solabegron combination therapy for OAB treatment

phase 2, Uncategorized Comments Off

Oct 212013

solabegron

AltheRx Pharmaceuticals has received a notice of allowance for its patent application from the US Patent and Trademark Office (USPTO) for the use of solabegron, a beta 3-adrenergic receptor agonist, in combination with antimuscarinics at both therapeutic and sub-therapeutic doses, for the treatment of overactive bladder (OAB).

AltheRx obtains US patent for solabegron combination therapy for OAB treatment

http://www.pharmaceutical-technology.com/news/newsaltherx-obtains-us-patent-for-solabegron-combination-therapy-for-oab-treatment?WT.mc_id=DN_News

Solabegron (GW-427,353) is a drug which acts as a selective agonist for the β3 adrenergic receptor. It is being developed for the treatment of overactive bladder andirritable bowel syndrome.^[1]^[2]^[3] It has been shown to produce visceral analgesia by releasing somatostatin from adipocytes.,^[4]^[5]

Solabegron was discovered by GlaxoSmithKline and acquired by AltheRx in March 2011. Solabegron relaxes the bladder smooth muscle by stimulating beta-3 adrenoceptors, a novel mechanism compared to older established drug treatments for overactive bladder syndrome such as the anticholinergic agents. Astellas Pharma have developed the first commercially available β3 adrenergic receptor, mirabegron, which is now licensed in Japan^[6] and the US^[7] for overactive bladder. Mirabegron is not licensed for irritable bowel syndrome.

A Phase II study of Solabegron for overactive bladder (OAB) looked at 258 patients with moderate to severe incontinence experiencing an average of 4.5 wet episodes per day. Results demonstrated a statistically significant improvement with Solabegron as compared to placebo, as measured by the percent reduction of the number of wet episodes and the absolute number of daily voids.

A Phase II study for irritable bowel syndrome (IBS) evaluated 102 patients with IBS. Solabegron demonstrated significant reduction in pain associated with the disorder and a trend for greater improvement in the quality of life, compared to placebo.

Both Phase II studies indicated a tolerability profile for Solabegron that was similar to placebo. The OAB patients did not suffer from dry mouth, constipation, increase in heart rate or cognitive issues.

AltheRx is currently preparing to advance Solabegron into a large clinical study in OAB.

Synthesis

Hicks A, McCafferty GP, Riedel E, Aiyar N, Pullen M, Evans C, Luce TD, Coatney RW, Rivera GC, Westfall TD, Hieble JP. GW427353 (solabegron), a novel, selective beta3-adrenergic receptor agonist, evokes bladder relaxation and increases micturition reflex threshold in the dog. Journal of Pharmacology and Experimental Therapeutics. 2007 Oct;323(1):202-9.doi:10.1124/jpet.107.125757 PMID 17626794
Grudell AB, Camilleri M, Jensen KL, Foxx-Orenstein AE, Burton DD, Ryks MD, Baxter KL, Cox DS, Dukes GE, Kelleher DL, Zinsmeister AR. Dose-response effect of a beta3-adrenergic receptor agonist, solabegron, on gastrointestinal transit, bowel function, and somatostatin levels in health.American Journal of Physiology. Gastrointestinal and Liver Physiology. 2008 May;294(5):G1114-9. PMID 18372395
Kelleher DL, Hicks KJ, Cox DS, et al. Randomized, double-blind, placebo (PLA)-controlled, crossover study to evaluate efficacy and safety of the beta 3-adrenergic receptor agonist solabegron (SOL) in patients with irritable bowel syndrome (IBS). Neurogastroenterol Motil 2008;20 (Suppl 2):131.
Cellek S, Thangiah R, Bassil AK, Campbell CA, Gray KM, Stretton JL, Lalude O, Vivekanandan S, Wheeldon A, Winchester WJ, Sanger GJ, Schemann M, Lee K. Demonstration of functional neuronal beta3-adrenoceptors within the enteric nervous system. Gastroenterology. 2007 Jul;133(1):175-83.
Schemann M, Hafsi N, Michel K, Kober OI, Wollmann J, Li Q, Zeller F, Langer R, Lee K, Cellek S. The beta3-adrenoceptor agonist GW427353 (solabegron) decreases excitability of human enteric neurons via release of somatostatin.Gastroenterology 2009 Sep 25. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/22384458
http://chembl.blogspot.co.uk/2012/07/new-drug-approvals-2012-pt-xiv.html

CHLAMYDIA

Uncategorized Comments Off

Oct 202013

Chlamydia from Kamran Afzal

MONOCLONAL ANTIBODIES

MONOCLONAL ANTIBODIES Comments Off

Oct 172013

PPT from many87

Production of MAb

Fig.1 Production of MAb

Large Scale Production Of MAbs:

Commercially, on large scale, MAbs are produced by two methods.

(a) Ascites production in mice

(b) In-vitro fermentation

The production method is summarized in Fig.no.2a & 2b.

a) Ascites Production In Mice:

The first monoclonal antibodies approved by FDA for therapeutic use OKTS, is produced by ascitic technology¹⁹.

In this method hybridoma cells are injected into peritoneal cavity of histocompatible mice. The mice are pretreated by i.p. injection of Pristane to irritate the peritoneal cavity which facilitates the growth of ascitic tumor. The fluid produced may contain the high concentration of secreted MAbs, 2 to 20 μg / ml and 2 to 6 ml or more can be harvested per mouse. Comparison of different MAb production^22,23 methods is shown inTable 1.

Drawbacks of this method are:

1. It is very costly, very difficult and not reliable.

2. Product may get contaminated with mouse immunoglobulins and also with other mouse proteins.

3. Viruses can be introduced as contaminants.

4. Antibody yield is often less as compared to other methods.

b) In-Vitro Fermentation:

In this method, the cells are grown and gradually moved to larger and larger culture ensuring exponential growth. Typical antibody levels in the culture supernatant ranges from 5-50 μg/ml depending on the individual clone and on cell density. When more production of antibody is required 1-litre cultures in roller bottles are used. Required cells are removed from rest of media by centrifugation or filtration, generally followed by ultra filtration step for concentrating the filtrate by up to 20 folds.

Advantages of this method are:

(1) As serum required in culture media is reduced, it is cost effective.

(2) There will not be any contamination with mouse immunoglobulin.

But the major drawback is that of contamination of final product with serum or protein based growth factors.

Table 1: Comparison of different MAb production methods.

Production system	Scale	Volume (ml)	Concentration (mg/ml)	Production time (weeks)	Quality
Ascites (in vivo)	20-250 mg	5-10	< 20	2-3	Low
Stir growth	—	100-2500	0.01-0.1	2-3	High
Dialysis membrane	< 50 mg	10-25	0.1-1.5	2-5	High
Roller bottles	< 2 gm	100-2000	0.01-0.2	2-6	High
Hollow fiber	0.15-30 gm	25-1000	0.2-0.3	3-12	High
Fermentor	2-100 gm	< 2000 lit	0.05-0.5	2-12	High

MAb Production

Fig. 2a: MAb Production (Flowchart)

Freeze Dried MAb Production

Fig. 2b: Freeze Dried MAb Production (Flowchart)

i) Purification:

Contamination, during production process, such as protein, nucleic acid, endotoxins, immunoglobulin and adventitious agent can be removed by purification method. The purification methods such as precipitation with ammonium sulphate, zone electrophoresis, ion exchange chromatography, hydrophobic interaction chromatography, gel filtration and affinity chromatography are used¹⁹.

· Affinity chromatography is often used for initial purification.

· Ion exchange chromatography is used for removing endotoxins and DNA.

· Gel filtration chromatography can remove both high and low molecular form of monoclonal antibodies and it is usually used as the final polishing step.

j) Characterization:

The final determination of monoclonality requires biochemical and biophysical characterization of the immunoglobulin. It is also characterized immunochemically to define its affinity for antigen, its immunoglobulin subclass, the epitopes for which it is specific and the effective number of binding site that it possesses¹⁹.

k) Final Processing:

Depending upon the intended application, the antibody may be conjugated to specific radionuclide or toxin. Then the stabilizing agent is added, and the product is filled into final container under inert gas or other specialized conditions. Lyophillization is frequently applied to get freeze dried product.

Antigenicity Of Murine MAb:

The main problem for mouse MAb is that, human body recognizes it as a foreign agent and produces antibodies against such mouse MAb. The induced human anti-mouse antibodies (HAMA) quickly reduce the effectiveness of mouse MAb and also their interaction may lead to allergic reactions.

To overcome the problem, Human MAbs can be used. Though difficult, this is possible by fusion of EBV (Epstein Barr Virus) transformed human B-lymphocyte with appropriate fusion partners²¹. EBV is a lymphotrophic DNA herpes virus which is capable of converting normal B-lymphocytes of human and/or mouse into cancer cell having proliferating capacity in vitro. But the presence of EBV as contaminant can pose a problem of producing cancer²⁴.

Even the human-human hybridomas producing MAbs have been produced ^25,26. Olsson and Kaplan in the year 1980 produced first human-human myeloma (SKO-007), against the hapten 2, 4-dinitrophenyl (DNP)¹⁹.

The routine production of human MAbs is prevented due to following reason:-

Sources of antibody producing cells²⁷.
Reliable methods for lymphocytes immortalization.
Stability²⁸ and antibody producing capacity.
Administration of some antigens to humans could endanger their health²⁹.
Recovery of B-lymphocytes from the spleen of human is impracticable.
The fusion of human lymphocytes with human lymphoblastoid cell lines is a very inefficient process.
Low production yield of human monoclonal antibody.

Hence, other alternatives methods come forth.

Advantages Of MAbs:

Pure one molecular species with high specificity for a particular antigenic target.
Anti-serum titer values are high.
Antibodies with high avaidity can be produced.
In vitro and in vivo production is possible.
Radiolabelling and fluorescent conjugation of monoclonal antibody are easy.

Disadvantages Of MAbs:

Initial cost involved in the technique is high. However, continuous production is somewhat economical.
Methods are time consuming.
Antigenicity of Murine MAb.
MAbs have comparatively less complement fixing ability than that of convectional antiserum.
MAbs are highly selective for a particular single antigenic determinant. This renders them incapable of distinguish between different molecules, cells bearing the chemical structure or determinants except one against which it is targeted.
The high antibody avidity (energy of binding to an antigen) of MAbs is advantageous for immunoassay but some property is undesirable for purification process.