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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.

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

AltheRx obtains US patent for solabegron combination therapy for OAB treatment

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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

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Oct 202013

Chlamydia from Kamran Afzal

Alkermes obtains US FDA fast-track status for depression drug

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Oct 152013

STR CREDIT

http://www.med-chemist.com/

POSTED ON Tuesday, October 15, 2013 FOR ALKS 5461

Irish biotechnology firm Alkermes has received fast-track designation for its proprietary investigational medicine ALKS 5461 from the US Food and Drug Administration (FDA).

Fast-track designation was granted for the adjunctive treatment of patients with major depressive disorder (MDD) who don’t respond to standard therapies. The process intended to speed-up the review of drugs, which treat serious conditions and fill an unmet medical need.

http://www.pharmaceutical-technology.com/news/newsalkermes-obtains-us-fda-fast-track-status-for-depression-drug?WT.mc_id=DN_News

see a presentation

Ehrich ALKS 5461 Presentation

phx.corporate-ir.net/External.File?item…t=1‎

The drug, ALKS 5461, “significantly reduced” symptoms of depression in the 142-patient study, from the second of three phases of clinical trials generally required for regulatory approval, Alkermes said today in a statement. Based on the results, the company plans to request a meeting with the U.S. Food and Drug Administration and start later-stage studies.“We had been deliberately modest with folks over the last year because it’s so potentially important we thought we should be skeptical until we see a confirmatory study,” Alkermes Chief Executive Officer Richard Pops said in a telephone interview today. “The result was so clear when we un-blinded that it was self-evident that we needed to keep going.”

Patients Tested
Alkermes’s drug was tested in patients for whom other medicines, called selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, haven’t worked as well as hoped. Treatments in those classes include Eli Lilly & Co. (LLY)’s Prozac and Cymbalta. ALKS 5461 was tested on top of drugs patients were already taking as that may be the way the medicine would be used if approved, Pops said.

“This is a potentially very important positive development for Alkermes as ALKS 5461 is an oral, once-a-day drug which has a novel mechanism of action for treating MDD, which represents a very large market opportunity,” Cory Kasimov, an analyst with JPMorgan Chase & Co. (JPM), wrote in a research note today.

About 16.1 million people in the U.S. experience major depressive disorder, or MDD, each year and many don’t get enough of a benefit from the first antidepressants they try, according to Alkermes. Of about 10 million patients who receive treatment for MDD, two-thirds aren’t adequately helped and try a second therapy, Pops said.

ALKS 5461 is a combination of another compound, ALKS 33, and buprenorphine, a therapy that stimulates the opioid system and is approved for treatment of addiction to opioids such as heroin.

The company decided to test the combination based on the premise that opioids have been shown to help in treatment of depression. The problem was their addictive properties, Pops said. ALKS 33 is an opioid receptor blocker, and its use is designed to combat addictive effects.

“We wanted to know if you can decouple the addictive properties of an opioid from antidepressive properties,” Pops said. With ALKS 5461, “we’re pushing the gas and the brake at the same time.”

Alkermes is equipped to start a bigger trial on its own, and may talk with pharmaceutical companies about partnerships to sell the drug outside the U.S. if it’s approved, Pops said, noting “it’s too early” to discuss commercial plans

Sexually Transmitted diseases

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Oct 142013

Sexually Transmitted Diseases from tumalapalli venkateswara rao

Psoriasis

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Oct 112013

Psoriasis from Harshad Deshpande

CILNIDIPINE 西尼地平

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Oct 032013

cilnidipine

西尼地平

CAS 132203-70-4

(E) – (±) 1 ,4 a dihydro-2 ,6 – dimethyl-4 – (3 – nitrophenyl) -3,5 – pyridinedicarboxylic acid, 2 – methoxy- ethyl butylester 3 – phenyl – 2 – propenyl ester FRC-8653 Cinalong
More FRC 8653 1,4-Dihydro-2 ,6-dimethyl-4-(3-nitrophenyl) 3 ,5-pyridinedicarboxylic acid 2-methoxyethyl (2E)-3-phenyl-2-propenyl ester
Molecular formula:C ₂₇ H ₂₈ N ₂ O ₇
Molecular Weight:492.52

CAS Name: 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 2-methoxyethyl (2E)-3-phenyl-2-propenyl ester

Additional Names: (±)-(E)-cinnamyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate

Manufacturers’ Codes: FRC-8653

Trademarks: Atelec (Morishita); Cinalong (Fujirebio); Siscard (Boehringer, Ing.)

Molecular Formula: C27H28N2O7

Molecular Weight: 492.52

Percent Composition: C 65.84%, H 5.73%, N 5.69%, O 22.74%

Properties: Crystals from methanol, mp 115.5-116.6°. LD50 in male, female mice, rats (mg/kg): ³5000, ³5000, ³5000, 4412 orally;³5000 all species s.c.; 1845, 2353, 441, 426 i.p. (Wada).

Melting point: mp 115.5-116.6°

Toxicity data: LD50 in male, female mice, rats (mg/kg): ³5000, ³5000, ³5000, 4412 orally; ³5000 all species s.c.; 1845, 2353, 441, 426 i.p. (Wada)

Antihypertensive; Dihydropyridine Derivatives; Calcium Channel Blocker; Dihydropyridine Derivatives.

Cilnidipine (INN) is a calcium channel blocker. It is sold as Atelec in Japan, asCilaheart, Cilacar in India, and under various other trade names in East Asian countries.

Cilnidipine is a dual blocker of L-type voltage-gated calcium channels in vascular smooth muscle and N-type calcium channels in sympathetic nerve terminals that supply blood vessels. However, the clinical benefits of cilnidipine and underlying mechanisms are incompletely understood.

Clinidipine is the novel calcium antagonist accompanied with L-type and N-type calcium channel blocking function. It was jointly developed by Fuji Viscera Pharmaceutical Company, Japan and Ajinomoto, Japan and approved to come into market for the first time and used for high blood pressure treatment in 1995. in india j b chemicals & pharmaceuticals ltd and ncube pharmaceutical develope a market of cilnidipine.

Hypertension is one of the most common cardiovascular disease states, which is defined as a blood pressure greater than or equal to 140/90 mm Hg. Recently, patients with adult disease such as hypertension have rapidly increased. Particularly, since damages due to hypertension may cause acute heart disease or myocardial infarction, etc., there is continued demand for the development of more effective antihypertensive agent.

Meanwhile, antihypertensive agents developed so far can be classified into Angiotensin II Receptor Blocker (ARB), Angiotensin-Converting Enzyme Inhibitor (ACEI) or Calcium Chanel Blocker (CCB) according to the mechanism of actions. Particularly, ARB or CCB drugs manifest more excellent blood pressure lowering effect, and thus they are more frequently used.

However, these drugs have a limit in blood pressure lowering effects, and if each of these drugs is administered in an amount greater than or equal to a specific amount, various side-effects may be caused. Therefore, there have been many attempts in recent years to obtain more excellent blood pressure lowering effect by combination therapy or combined preparation which combines or mixes two or more drugs.

Particularly, since side-effect due to each drug is directly related to the amount or dose of a single drug, there have been active attempts to combine or mix two or more drugs thereby obtaining more excellent blood pressure lowering effect through synergism of the two or more drugs while reducing the amount or dose of each single drug.

For example, US 20040198789 discloses a pharmaceutical composition for lowering blood pressure combining lercanidipine, one of CCB, and valsartan, irbesartan or olmesartan, one of ARB, etc. In addition, a combined preparation composition which combines or mixes various blood pressure lowering drugs or combination therapy thereof has been disclosed.

cilnidipine Compared with other calcium antagonists, clinidipine can act on the N-type calcium-channel that existing sympathetic nerve end besides acting on L-type calcium-channel that similar to most of the calcium antagonists. Due to its N-type calcium-channel blocking properties, it has more advantages compared to conventional calcium-channel blockers. It has lower incidence of Pedal edema, one of the major adverse effects of other calcium channel blockers. Cilnidipine has similar blood pressure lowering efficacy as compared to amlodipine. One of the distinct property of cilnidipine from amlodipine is that it does not cause reflex tachycardia.

In recent years, cardiovascular disease has become common, the incidence increased year by year, about a patient of hypertension in China. 3-1. 500 million, complications caused by hypertension gradually increased, and more and more young patients with hypertension technology. In recent years, antihypertensive drugs also have great development, the main first-line diuretic drug decompression 3 – blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, ar blockers and vascular angiotensin II (Ang II) receptor antagonist.

In the anti-hypertensive drugs, calcium antagonists are following a – blockers after another rapidly developing cardiovascular drugs, has been widely used in clinical hypertension, angina and other diseases, in cardiovascular drugs in the world, ranked first.

Cilnidipine for the long duration of the calcium channel blockers, direct relaxation of vascular smooth muscle, dilation of peripheral arteries, the peripheral resistance decreased, with lower blood pressure, heart rate without causing a reflex effect.

Cilnidipine is a dihydropyridine CCB as well as an antihypertensive. Cilnidipinehas L- and N-calcium channel blocking actions. Though many of the dihydropyridine CCBs may cause an increase in heart rate while being effective for lowering blood pressure, it has been confirmed that cilnidipine does not increase the heart rate and has a stable hypotensive effect. (Takahiro Shiokoshi, “Medical Consultation & New Remedies” vol. 41, No. 6, p. 475-481)

http://www.mcyy.com.cn/e-product2.asp
Löhn M, Muzzulini U, Essin K, et al. (May 2002). “Cilnidipine is a novel slow-acting blocker of vascular L-type calcium channels that does not target protein kinase C”. J. Hypertens. 20 (5): 885–93. PMID 12011649.

Cilnidipine (CAS NO.: 132203-70-4), with its systematic name of (+-)-(E)-Cinnamyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate, could be produced through many synthetic methods.

Following is one of the synthesis routes: By cyclization of 2-(3-nitrobenzylidene)acetocetic acid cinnamyl ester (I) with 2-aminocrotonic acid 2-methoxyethyl ester (II) by heating at 120 °C.

NMR

CARBOHYDRATE POLYMERS 90 PG 1719-1724 , YR2012

Numerous peaks were found in the spectrum of cilnidipine: 2.3555 (3H, s, CH3), 2.3886(3H, s, CH3), 3.2843(CD3OD), 3.3292(3H, s, OCH3), 3.5255–3.5623(2H, m, CH3OCH2CH2 ), 4.1224–4.1597(2H, m, CH3OCH2CH2 ), 4.6695–4.7293(2H, m, CH2 CH CH ), 4.8844(D2O), 5.1576(1H, s, CH), 6.2609(1H, dt, CH2 CH CH ), 6.5518(1H, d, CH2 CH CH ), 7.2488–7.3657(6H, m, ArH), 7.7002(1H, dd, ArH), 7.9805(1H, dd, ArH), 8.1548(1H, s, ArH)

References:

Dihydropyridine calcium channel blocker. Prepn: T. Kutsuma et al., EP 161877; eidem, US 4672068(1985, 1987 both to Fujirebio).

Pharmacology: K. Ikeda et al., Oyo Yakuri 44, 433 (1992).

Mechanism of action study: M. Hosonoet al., J. Pharmacobio-Dyn. 15, 547 (1992).

LC-MS determn in plasma: K. Hatada et al., J. Chromatogr. 583, 116 (1992). Clinical study: M. Ishii, Jpn. Pharmacol. Ther. 21, 59 (1993).

Acute toxicity study: S. Wada et al., Yakuri to Chiryo 20, Suppl. 7, S1683 (1992), C.A. 118, 32711 (1992).

U.S Patent No. 4,572,909 discloses amlodipine; U.S Patent No. 4,446,325 discloses aranidipine; U.S Patent No. 4,772,596 discloses azelnidipine; U.S Patent No. 4,220,649 discloses barnidipine; U.S Patent No. 4,448,964 discloses benidipine; U.S Patent No. 5,856,346 discloses clevidipine; U.S Patent No. 4,466,972 discloses isradipine; U.S Patent No. 4,885,284 discloses efonidipine; and U.S Patent No. 4,264,61 1 discloses felodipine.

U.S Patent No. 5,399,578 discloses Valsartan; European Patent No. 0 502 314 discloses Telmisartan; U.S Patent No. 5,138,069 discloses Losartan; U.S Patent No. 5,270,317 discloses Irbesartan; U.S Patent No. 5,583,141 and 5,736,555 discloses Azilsartan; U.S Patent No. 5,196,444 discloses Candesartan; U.S Patent No. 5,616,599 discloses Olmesartan; and U.S Patent No. 5,185,351 discloses Eprosartan.

U.S Patent No. 4,374,829 discloses enalapril; U.S Patent No. 4,587,258 discloses ramipril; U.S Patent No. 4,344,949 discloses quinapril; U.S Patent No. 4,508,729 discloses perindopril; U.S Patent No. 4,374,829 discloses lisinopril; U.S Patent No. 4,410,520 discloses benazepril; U.S Patent No. 4,508,727 discloses imidapril; U.S Patent No. 4,316,906 discloses zofenopril; U.S Patent Nos. 4,046,889 and 4,105,776 discloses captopril; and U.S Patent No. 4,337,201 discloses fosinopril.

Planar chemical structures of these calcium blockers of formula (I) are shown below.
Amlodipine is 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine disclosed in USP 4,572,909, Japanese patent publication No. Sho 58-167569 and the like.
Aranidipine is 3-(2-oxopropoxycarbonyl)-2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,446,325 and the like.
Azelnidipine is 2-amino-3-(1-diphenylmethyl-3-azetidinyloxycarbonyl)-5-isopropoxycarbonyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,772,596, Japanese patent publication No. Sho 63-253082 and the like.
Barnidipine is 3-(1-benzyl-3-pyrrolidinyloxycarbonyl)-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,220,649, Japanese patent publication No. Sho 55-301 and the like.
Benidipine is 3-(1-benzyl-3-piperidinyloxycarbonyl)-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine and is described in the specifications of U.S. Patent No. 4,501,748, Japanese patent publication No. Sho 59-70667 and the like.
Cilnidipine is 2,6-dimethyl-5-(2-methoxyethoxycarbonyl)-4-(3-nitrophenyl)-3-(3-phenyl-2-propenyloxycarbonyl)-1,4-dihydropyridine disclosed in USP 4,672,068, Japanese patent publication No. Sho 60-233058 and the like.
Efonidipine is 3-[2-(N-benzyl-N-phenylamino)ethoxycarbonyl]-2,6-dimethyl-5-(5,5-dimethyl-1,3,2-dioxa-2-phosphonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,885,284, Japanese patent publication No. Sho 60-69089 and the like.
Elgodipine is 2,6-dimethyl-5-isopropoxycarbonyl-4-(2,3-methylenedioxyphenyl)-3-[2-[N-methyl-N-(4-fluorophenylmethyl)amino]ethoxycarbonyl]-1,4-dihydropyridine disclosed in USP 4,952,592, Japanese patent publication No. Hei 1-294675 and the like.
Felodipine is 3-ethoxycarbonyl-4-(2,3-dichlorophenyl)-2,6-dimethyl-5-methoxycarbonyl-1,4-dihydropyridine disclosed in USP 4,264,611, Japanese patent publication No. Sho 55-9083 and the like.
Falnidipine is 2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)-3-(2-tetrahydrofurylmethoxycarbonyl)-1,4-dihydropyridine disclosed in USP 4,656,181, Japanese patent publication (kohyo) No. Sho 60-500255 and the like.
Lemildipine is 2-carbamoyloxymethyl-4-(2,3-dichlorophenyl)-3-isopropoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine disclosed in Japanese patent publication No. Sho 59-152373 and the like.
Manidipine is 2,6-dimethyl-3-[2-(4-diphenylmethyl-1-piperazinyl)ethoxycarbonyl]-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,892,875, Japanese patent publication No. Sho 58-201765 and the like.
Nicardipine is 2,6-dimethyl-3-[2-(N-benzyl-N-methylamino)ethoxycarbonyl]-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 3,985,758, Japanese patent publication No. Sho 49-108082 and the like.
Nifedipine is 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridine disclosed in USP 3,485,847 and the like.
Nilvadipine is 2-cyano-5-isopropoxycarbonyl-3-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,338,322, Japanese patent publication No. Sho 52-5777 and the like.
Nisoldipine is 2,6-dimethyl-3-isobutoxycarbonyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 4,154,839, Japanese patent publication No. Sho 52-59161 and the like.
Nitrendipine is 3-ethoxycarbonyl-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine disclosed in USP 3,799,934, Japanese patent publication (after examination) No. Sho 55-27054 and the like.
Pranidipine is 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-3-(3-phenyl-2-propen-1 -yloxycarbonyl)-1,4-dihydropyridine disclosed in USP 5,034,395, Japanese patent publication No. Sho 60-120861 and the like.

Process for synthesis of chiral 3-substituted tetrahydroquinoline derivatives……..WO 2013140419…CSIR INDIA PATENT

drugs, Uncategorized Comments Off

Oct 012013

sumanirole

179386-43-7
179386-44-8 (maleate)

Sumanirole maleate, U-95666 (free base), U-95666E, PNU-95666E

	Process for synthesis of chiral 3-substituted tetrahydroquinoline derivatives
	Council Of Scientific & Industrial Research
	The present invention relates to novel and concise process for the construction of chiral 3-substituted tetrahydroquinoline derivatives based on proline catalyzed asymmetric α-functionalization of aldehyde, followed by in situ reductive cyclization of nitro group under catalytic hydrogenation condition with high optical purities. Further the invention relates to conversion of derived chiral 3-substituted tetrahydroquinoline derivatives into therapeutic agents namely (-)-sumanirole (96% ee) and 1-[(S)-3-(dimethylamino)-3,4-dihydro-6,7-dimethoxy-quinolin-1(2H)-yl]propanone[(S)-903] (92% ee).
	Process,sumanirole
Indications	Restless legs syndrome; Parkinsons disease
Target-based Actions	Dopamine D2 receptor agonist
Other Actions	Anxiolytic; Antiparkinsonian

Inventors	Boopathi, Senthil, Kumar; Arumugam, Sudalai; Rawat, Varun
IPC Codes	C07D 215/20; C07D 471/06; C07D 215/38

DRUG	sumanirole
Publication Date	26-Sep-2013 WO-2013140419-A1

Sumanirole (PNU-95,666) is a highly selective D₂ receptor full agonist, the first of its kind to be discovered. It was developed for the treatment of Parkinson’s disease andrestless leg syndrome. While it has never been approved for medical use it is a highly valuable tool compound for basic research to identify neurobiological mechanisms that are based on a dopamine D2-linked (vs. D1, D3, D4, and D5-linked) mechanism of action

sumanirole

OTHER INFO

D-Phenylalanine (I) was protected as the methyl carbamate (II) by acylation with methyl chloroformate under Schotten-Baumann conditions. The N-methoxy amide (III) was then prepared by coupling of (II) with O-methyl hydroxylamine in the presence of EDC. Cyclization of (III) to the N-methoxy quinolinone (IV) was accomplished by treatment with bis(trifluoroacetoxy)iodobenzene in the presence of trifluoroacetic acid. Simultaneous reduction of the N-methoxy lactam and carbamate functions of (IV) by means of borane-methyl sulfide complex provided diamine (V). The aliphatic amino group of (V) was then selectively protected as the benzyl carbamate (VI) by using N-(benzyloxycarbonyloxy)succinimide at -40 C. Reaction of (VI) with phosgene, followed by treatment of the intermediate carbamoyl chloride with O-methyl hydroxylamine gave rise to the N-methoxy urea derivative (VII). This was cyclized with bis(trifluoroacetoxy)iodobenzene to the imidazoquinolinone (VIII). The N-methoxy and N-benzyloxycarbonyl groups of (VIII) were then removed by hydrogenolysis in the presence of Pearlman’s catalyst, and the title compound was finally converted to the corresponding maleate salt.