DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Health Canada approves NEUPRO (Rotigotine) patch for treatment of Parkinson’s disease and Restless Legs Syndrome
Rotigotine
Novel dosage form represents new treatment for Parkinson’s with efficacy in motor symptoms of the disease
April 2,2013
UCB Canada Inc. announced today that Health Canada has approved NEUPRO® (rotigotine), the first and only non-ergolinic dopamine agonist available in a patch, to treat the signs and symptoms of idiopathic Parkinson’s disease (PD) and moderate-to-severe idiopathic restless legs syndrome (RLS), also known as Willis-Ekbom disease, in adults.
NEUPRO® is the first new treatment for Parkinson’s disease approved by Health Canada in five years and provides 24-hour delivery of rotigotine through the skin into the blood stream. NEUPRO® has demonstrated efficacy in managing motor symptoms associated with Parkinson’s disease.
“The ability to ensure a steady 24-hour delivery of medication with NEUPRO® may help to reduce debilitating on and off symptoms which many patients experience with Parkinson’s treatments,” says Dr. David Grimes, Director, Parkinson’s Disease and Movement Disorders Clinic at the Ottawa Hospital. “The impact of sustained symptom control in the morning and in the evening can have a substantial effect on a patient’s quality of life.”
UCB Canada Inc. is undertaking all measures required to supply the Canadian market with NEUPRO.
“Parkinson Society Canada is pleased to learn that Canadians living with Parkinson’s now have another treatment option to help manage the symptoms of this chronic disease,” says Joyce Gordon, President and CEO, Parkinson Society Canada. “With innovative therapies such as NEUPRO® and ongoing research into the causes of this disease, we will help to ensure a brighter future and better quality of life for Canadians living with Parkinson’s.”
Although the precise mechanisms of action of NEUPRO® as treatment for PD and RLS are unknown, as a PD treatment, the mechanism of action is thought to be related to increasing the activities of the dopamine receptors within the caudate-putamen, the region of the brain that regulates movement. Similarly, in RLS, the mechanism of action of NEUPRO® is thought to be related to its ability to stimulate dopamine receptors.
Data Demonstrated Significant Symptom Improvement for PD and RLS
The effectiveness of NEUPRO® (rotigotine) in the treatment of Parkinson’s disease was evaluated in a multinational drug development program consisting of four randomized, double-blind placebo-controlled phase 3 trials. A total of seven Canadian trial sites were involved in the international studies. In all trials, patients underwent a weekly titration of NEUPRO® in 2 mg/24 hour increments to the assigned or optimal dose.
In two trials, statistically significant improvements in the combined scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) were observed in early-stage PD patients receiving NEUPRO® compared to patients receiving placebo. The UPDRS is a validated multi-item rating scale intended to evaluate mentation (mental activity), activities of daily living (ADL), motor performance, and complications of therapy. The two trials measured only the ADL and motor performance sections of the UPDRS. The UPDRS contains 13 questions relating to ADL, such as speech, dressing, and cutting food with utensils, and 27 questions related to the cardinal motor symptoms in PD patients—i.e., tremor, rigidity, bradykinesia, and postural instability.
Two trials of NEUPRO® in patients with advanced-stage PD examined change from baseline in “off” time, periods when the effectiveness of medication wears off and PD symptoms return. Statistically significant changes in off-times were observed in advanced-stage PD patients receiving NEUPRO® compared with those who received placebo.
The effectiveness of NEUPRO® in the treatment of Restless Legs Syndrome (RLS) was evaluated in two fixed-dose, randomized, double-blind, placebo-controlled phase 3 trials with maintenance periods of 6 months duration. Patients received NEUPRO® doses ranging from 0.5 mg/24 hours to 3 mg/24 hours, or placebo, once daily. Statistically significant improvements in sum scores on the International RLS Rating Scale (IRLS Scale) and the Clinical Global Impression – Improvement (CGI-I) assessment were observed in RLS patients receiving NEUPRO® compared with those receiving placebo. The IRLS Scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The CGI-I is designed to clinically assess RLS symptoms on a 7-point scale.
In clinical trials, treatment emergent adverse events reported in more than 10% of patients treated with NEUPRO® for Parkinson’s disease included nausea, vomiting, dizziness, somnolence, application site reactions and headache. Treatment emergent adverse events reported in more than 10% of patients treated with NEUPRO® for Restless Legs Syndrome, included nausea, application site reactions, fatigue and headache.
About Parkinson’s disease
Parkinson’s disease (PD) is a chronic, degenerative neurological disease which affects approximately 100,000 Canadians. PD develops with the loss of nerve cells in the brain that produce a chemical called dopamine. The symptoms of PD can have an impact on many dimensions of patients’ lives. As dopamine levels fall, movement (motor) symptoms—tremors (uncontrollable shaking), rigidity (stiffness or muscle tensing) and bradykinesia (slowness and loss of spontaneous movement) — can progress, along with the underlying symptoms of PD, which are less well recognized and may be under-treated.
About Restless Legs Syndrome
Restless Legs Syndrome (RLS) is a neurological disorder characterized by unpleasant sensations in the legs and an uncontrollable urge to move to gain relief. Over 80% of people with RLS also have periodic limb movement disorder (PLMD), which causes rhythmic limb movements during sleep. RLS affects between three and 10 per cent of the population to some extent. Some estimates are much higher because RLS is thought to be underdiagnosed, and in some cases, misdiagnosed. Most people with RLS have difficulty falling asleep and staying asleep. Daytime symptoms of RLS, such as inability to sit still and involuntary leg jerks, are increasingly recognized. While the underlying pathophysiology of RLS is not fully understood, it is thought to involve central dopamine systems. Recent neuroimaging data suggest that RLS patients may carry an abnormality in dopamine transport that can be visualized both day and night. RLS can cause exhaustion and daytime fatigue, and may affect work and personal relationships. Patients with moderate-to-severe RLS are often unable to concentrate, have impaired memory, or fail to accomplish daily tasks. These patients may require long-term treatment for their RLS symptoms.
About UCB Canada Inc.
Inspired by patients and driven by science, UCB Canada Inc. is a biopharmaceutical company focused on the discovery and development of innovative medicines and solutions to transform the lives of people living with severe auto-immune and central nervous system diseases. For more information, please consult www.ucb.com/worldwide/canada.
Rotigotine (Neupro) is a dopamine agonist of the non-ergoline class of medications indicated for the treatment of Parkinson’s disease (PD) and restless legs syndrome (RLS) in Europe and the United States. It is formulated as a once-daily transdermal patchwhich provides a slow and constant supply of the drug over the course of 24 hours.
Like other dopamine agonists, rotigotine has been shown to possess antidepressanteffects and may be useful in the treatment of depression as well.
Rotigotine was developed by Aderis Pharmaceuticals. In 1998, Aderis licensed worldwide development and commercialization rights for rotigotine to the German pharmaceutical company Schwarz Pharma (today a subsidiary of the Belgian company UCB S.A.).
The drug has been approved by the EMEA for use in Europe in 2006 and is today being sold in several European countries. In 2007, the Neupro patch was approved by the Food and Drug Administration (FDA) as the first transdermal treatment of Parkinson’s disease in the United States. However, as of 2008, Schwarz Pharma has recalled all Neupro patches in the United States and some in Europe because of problems with the delivery mechanism. The patch was reformulated, and was reintroduced in the United States in 2012.
Rotigotine has been authorized as a treatment for restless legs syndrome since August 2008.
Rotigotine is analogous to 7-OH-DPAT and UH-232, all three of which are aminotetralinderivatives. These compounds are similar in structure to dopamine, likely underlying theirpharmacology.
Cusack, N. J.; Peck, J. V.; Drugs Future 1993, 18, 1005.
FDA Approves Tris Pharma’s New Drug Application for Karbinal ER
Carbinoxamine Maleate
2-[p-Chloro-a-[2-(dimethylamino)ethoxy]benzyl]pyridine maleate (1:1) [3505-38-2].
April 3, 2013
Tris Pharma, a specialty pharmaceutical company focused on developing innovative drug delivery technologies, today announced that the U.S. Food and Drug Administration (FDA) has approved its New Drug Application (NDA) for Karbinal ER (carbinoxamine maleate) Extended-release Oral Suspension 4mg/5mL, the first sustained-release histamine receptor blocking agent indicated for the treatment of seasonal and perennial allergic rhinitis in children ages 2 and up.
“Karbinal ER is dosed only once every 12 hours, making it an attractive treatment option for the millions of allergy sufferers who don’t respond to second-generation antihistamines and aren’t satisfied with the cumbersome dosing schedules associated with the first-generation antihistamines,” said Ketan Mehta, founder, President, and CEO of Tris Pharma. “The approval of Karbinal ER marks our fourth liquid extended-release NDA approval based upon our proprietary OralXR+ technology. We are in the process of finalizing our marketing partner and plan to launch later this year in anticipation of the fall allergy season.”
Based on physician interviews approximately 30 percent of patients don’t get adequate relief from the non-sedating antihistamines. Carbinoxamine is a mildly-sedating antihistamine with years of proven safety and efficacy. Prior to 2006, carbinoxamine was widely used, with dozens of carbinoxamine-containing combination products including extended-release solid-dose products. However, nearly all of these were older products that hadn’t gone through the FDA’s rigorous approval process. Following the Drug Efficacy Study Implementation (DESI) review, the FDA removed all unapproved products with the exception of two immediate-release formulations, creating a void for patients and doctors who valued the benefits associated with an extended-release formulation.
Dr. Laura Garabedian, a New York-based pediatrician, said, “While I’ve always found carbinoxamine to be an effective option for treating the symptoms of allergies in children, the existing immediate-release formulations of carbinoxamine require dosing multiple times a day. This is especially inconvenient for children who are in school. Now, with the approval of Karbinal ER, I look forward to having an effective and great-tasting extended-release liquid formulation to offer patients as young as two years old.”
Karbinal ER Extended-release Oral Suspension is an H1 receptor antagonist indicated for the symptomatic treatment of:
- Seasonal and perennial allergic rhinitis
- Vasomotor rhinitis
- Allergic conjunctivitis due to inhalant allergens and foods
- Mild, uncomplicated allergic skin manifestations of urticaria and angioedema
- Dermatographism
- As therapy for anaphylactic reactions adjunctive to epinephrine and other standard measures after the acute manifestations have been controlled
- Amelioration of the severity of allergic reactions to blood or plasma
Tris Pharma is a specialty pharmaceutical company focused on the research and development of technologies-driven products. Tris has pioneered the delivery of sustained release in the liquid, chewable/ODT and strip dosage forms so patients do not have to swallow a pill. Tris’ Nobuse™ technology provides abuse deterrence for opioids and other abuse-prone drugs. Tris’ R&D and manufacturing facilities are located in Monmouth Junction, New Jersey, U.S.A. For more information, please visit http://www.trispharma.com.
Genmab: Daratumumab Granted Fast Track Designation By FDA
Monoclonal antibody
2/4/2013
Genmab A/S announced that the US Food and Drug Administration has granted Fast Track designation for daratumumab. This designation covers patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or are double refractory to a PI and an IMiD.
In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop and commercialize daratumumab.
A general representation of the method used to produce monoclonal antibodies.
Daratumumab is an investigational anti-cancer drug. It binds to CD38.[1] Daratumumab was originally developed by Genmab, but it is now being jointly developed by Genmab along with the Johnson & Johnson subsidiary Janssen Biotech, which acquired worldwide commercialization rights to the drug from Genmab.[2]
Encouraging preliminary results were reported in June 2012 from a Phase 1/2 clinical trial in relapsed multiple myeloma patients.[3] Updated trial results presented in December 2012 indicate daratumumab is continuing to show promising single-agent anti-myeloma activity.[4]
- World Health Organization (2009). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 101” (PDF). WHO Drug Information 23 (2).
- “‘Janssen Biotech Announces Global License and Development Agreement for Investigational Anti-Cancer Agent Daratumumab'”. Janssen Biotech. Retrieved 2013-01-31.
- “ASCO: Drug Shows Promise in Myeloma”. MedPage Today.
- “‘Daratumumab Continues To Show Promise For Relapsed/Refractory Myeloma Patients (ASH 2012)'”. The Myeloma Beacon. Retrieved 2013-01-31.
AYURVEDA SPOTLIGHT- ASHWAGANDHA, THE STRESS BUSTER
Withania somnifera, also known as ashwagandha, Indian ginseng, poison gooseberry, or winter cherry, is a plant in the Solanaceae or nightshade family. Several other species in the genus Withania are morphologically similar. It is used as a herb inAyurvedic medicine.
| Ashwagandha root is known as “Indian Ginseng”. In Ayurvedic medicine it is considered an adaptogen that facilitates learning and memory. |
It grows as a short shrub (35–75 cm) with a central stem from which branches extend radially in a star pattern (stellate) and covered with a dense matte of wooly hairs (tomentose). The flowers are small and green, while the ripe fruit is orange-red and has milk-coagulating properties. The plant’s long, brown, tuberous roots are used for medicinal purposes.
Ashwagandha in Sanskrit means “horse’s smell” (ashwa– horse, gandha– smell), probably originating from the odour of its root which resembles that of a sweaty horse.
The species name somnifera means “sleep-inducing” in Latin
Cultivation
Ashwagandha plant with berries
Withania somnifera is cultivated in many of the drier regions of India, such as Mandsaur Districtof Madhya Pradesh, Punjab, Sindh, Gujarat,and Rajasthan.It is also found in Nepal
Withania somnifera is grown as late rainy-season (kharif) crop. Semitropical areas receiving 500 to 750 mm rainfall are suitable for its cultivation as a rainfed crop. If one or two winter rains are received, then root development improves.
The crop requires a relatively dry season during its growing period. It can tolerate a temperature range of 20 to 38°C and as low a temperature as 10°C. The plant grows from sea level to an altitude of 1500 meters.
Ashvagandha plant at Talkatora Gardens, Delhi
Withania somnifera is prone to several pests and diseases. Leaf spot disease caused byAlternaria alternata is the most prevalent disease, which is most severe in the plains ofPunjab, Haryana, and Himachal Pradesh. Biodeterioration of its pharmaceutically active components during leaf spot disease has been reported. The Choanephora cucurbitarumcauses a stem and leaf rot of Withania somnifera Oxyrachis tarandus (atreehopper/cowbug species) feeds on the apical portions of the stem, making them rough and woody in appearance and brown in colour. The apical leaves are shed and the plant gradually dies away. Carmine red spider mite (Tetranychus urticae) is the most prevalent pest of Withania somnifera in India.
The berries can be used as a substitute for rennet, to coagulate milk in cheese-making
The main chemical constituents are alkaloids and steroidal lactones. These include tropineand cuscohygrine. The leaves contain the steroidal lactones, withanolides, notably withaferin A, which was the first withanolide to be isolated from W. somnifera.
Traditional medicinal uses
In Ayurveda, the berries and leaves of W. somnifera are locally applied to tumors, tubercular glands, carbuncles, and ulcers.[5] The roots of W. somnifera are used to prepare the herbal remedy ashwagandha, which has been traditionally used to treat various symptoms and conditions.
Side effects
In two published clinical trials of W. somnifera, the side effects were not significantly different from those experienced by placebo-treated individuals.
Ashwagandha Scientific Research
Ashwagandha contains many useful medicinal chemicals, including withanolides, (steroidal lactones), alkaloids, choline, fatty acids, amino acids, and a variety of sugars. While the leaves and fruit have valuable therapeutic properties, the root of the ashwagandha plant is the part most commonly used in Western herbal remedies.
Medical researchers have been studying ashwagandha with great interest and as of this date have carried out 216 studies of its healing benefits, summarized below:
- confers immune system protection
- combats the effects of stress
- improves learning, memory, and reaction time
- reduces anxiety and depression without causing drowsiness
- stabilizes blood sugar
- lowers cholesterol
- reduces brain-cell degeneration
- contains anti-malarial properties
- offers anti-inflammatory benefits
Some studies have also found that ashwagandha inhibits the growth of cancer cells in small animals, but further research is needed to determine whether the herb prevents the development of tumors in human beings.
Ashwagandha in particular is known for its ability to calm, and some research indicates this herb can be used to promote sleep. In Texas, researchers noted the similarities in the sleep-inducing properties of ashwagandha and the calming effects of the well-known amino acid GABA. Likewise, ashwagandha has also been shown to ease anxiety or restlessness, as well as to reduce the symptoms of drug withdrawal. Its ability to stabilize moods and encourage adrenal recovery is highly valued by many herbalists.
But the benefits of ashwagandha extend far beyond mood. In India it is also used to help older patients with mental agility, cognitive ability, and memory. It is also known for its ability to fight off cold and cough symptoms. Preliminary studies give researchers reason to feel that ashwagandha also has the potential ability to decrease cancer cells without adversely affecting healthy cells.
Ashwagandha Practical and Precautions
The usual recommended dose is 600 to 1000 mg, twice daily. For people who suffer from insomnia and anxiety, having a cup of hot milk that contains a teaspoon of powdered ashwagandha before bedtime is beneficial. In extremely large doses, ashwagandha has been reported to induce abortions in animals. Although no similar studies have been carried out on humans, women should avoid the herb during pregnancy.You should consult your ayurvedic doctor or other health care professional before starting on any ayurveda treatment.
Other Name:
Ajagandha, Amangura, Amukkirag, Asan, Asana, Asgand, Asgandh, Asgandha, Ashagandha, Ashvagandha, Ashwaganda, Ashwanga, Asoda, Asundha, Asvagandha, Aswagandha, Avarada, Ayurvedic Ginseng, Cerise d’Hiver, Clustered Wintercherry, Ghoda Asoda, Ginseng Ayurvédique, Ginseng Indien, Hayahvaya, Indian Ginseng, Kanaje Hindi, Kuthmithi, Orovale, Peyette, Physalis somnifera, Samm Al Ferakh, Samm Al Rerakh, Sogade-Beru, Strychnos, Turangi-Ghanda, Vajigandha, Winter Cherry, Withania, Withania somnifera.
Drug spotlight-Raloxifene
Raloxifene
Raloxifene: The FDA approved Raloxifene to reduce the risk of invasive breast cancer in postmenopausal women in 2007. It was initially developed to treat osteoporosis.
| Identifiers | |
|---|---|
| CAS number | 84449-90-1 |
Raloxifene (marketed as Evista by Eli Lilly and Company) is an oral selective estrogen receptor modulator (SERM) that has estrogenic actions on bone and anti-estrogenic actions on the uterus and breast. It is used in the prevention of osteoporosis in postmenopausal women.
In 2006, the National Cancer Institute announced that raloxifene was as effective astamoxifen in reducing the incidence of breast cancer in postmenopausal women at increased risk. A major adverse effect of tamoxifen is uterine cancer; raloxifene had fewer uterine cancers. Tamoxifen increased the risk of cataracts, but raloxifene did not. Both groups had more blood clots in veins and the lungs, but that side effect was more common with tamoxifen than raloxifene.[2][3][4] On September 14, 2007, the U.S. Food and Drug Administration announced approval of raloxifene for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer.[5]
An editorial in Lancet Oncology criticized the way that information about the drug was released.[6]
Raloxifene hydrochloride (HCl) has the empirical formula C28H27NO4S•HCl, which corresponds to a molecular weight of 510.05 g/mol. Raloxifene HCl is an off-white to pale-yellow solid that is slightly soluble in water.
SERMs mimic estrogen in some tissues and have anti-estrogen activity in others. Other SERMs, such as Pfizer’s lasofoxifene and Wyeth’s bazedoxifene are in the later development phases.
Raloxifene is indicated for the treatment and prevention of osteoporosis in postmenopausalwomen, for reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis. For either osteoporosis treatment or prevention, supplemental calciumand/or vitamin D should be added to the diet if daily intake is inadequate.
Raloxifene is contraindicated in lactating women or women who are or may becomepregnant, in women with active or past history of venous thromboembolic events, includingdeep vein thrombosis, pulmonary embolism, and retinal vein thrombosis and in women known to be hypersensitive to raloxifene.
Common adverse events considered to be drug-related were hot flashes and leg cramps.
Raloxifene may infrequently cause serious blood clots to form in the legs, lungs, or eyes. Other reactions experienced include leg swelling/pain, trouble breathing, chest pain, vision changes. Raloxifene is a teratogenic drug, i.e., can cause developmental abnormalities such as birth defects.
In a 2006 study published in New England Journal of Medicine, raloxifene produced significantly more strokes and blood clots than the placebo.[7]
A report in September 2009 from Health and Human Services’ Agency for Healthcare Research and Quality suggests that tamoxifen and raloxifene, used to treat breast cancer significantly reduce invasive breast cancer in midlife and older women, but also increase the risk of adverse side effects.[8]
As cancer drug
Bottle of Raloxifene
Raloxifene reduces the risk of hormone-positive breast cancer and vertebral fractures “without a shadow of a doubt,” but its effects on cardiovascular disease remain less certain, according to the results of the “Raloxifene for Use of the Heart” (RUTH) study published in the July 13, 2006 issue of the New England Journal of Medicine by Dr. Elizabeth Barrett-Connor (University of California at San Diego) and colleagues.[9]
In the trial, in women with coronary heart disease (CHD) or multiple risk factors for CHD, raloxifene had no significant effect on the primary end point, coronary events, but it did significantly increase the risk of venous thromboembolism (VTE). And although the drug had no effect on stroke, there was a seemingly paradoxical significant increase in death from stroke.[10]
On September 14, 2007, Steven K. Galson, the director of the United States Food and Drug Administration’s Center for Drug Evaluation and Research announced authorization of the sale of raloxifene to prevent invasive breast cancer in post-menopausal women.[11]
Chemical synthesis
Jones, Charles D.; Jevnikar, Mary G.; Pike, Andrew J.; Peters, Mary K.; Black, Larry J.; Thompson, Allen R.; Falcone, Julie F.; Clemens, James A. (1984). “Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride (LY 156758), a remarkably effective estrogen antagonist with only minimal intrinsic estrogenicity”. Journal of Medicinal Chemistry 27 (8): 1057–66.doi:10.1021/jm00374a021. PMID 6431104.
- Jeong, Eun Ju; Liu, Yong; Lin, Huimin; Hu, Ming (2005-03-15). “Species- and Disposition Model-Dependent Metabolism of Raloxifene in Gut and Liver: Role of UGT1A10”. Drug Metabolism and Disposition ( ASPET) 33 (6): 785–794. doi:10.1124/dmd.104.001883.PMID 15769887. Retrieved 2010-10-20.
- Study of Tamoxifen and Raloxifene (STAR) Trial Cancer.gov
- Results of the Study of Tamoxifen and Raloxifene (STAR) Released: Osteoporosis Drug Raloxifene Shown to be as Effective as Tamoxifen in Preventing Invasive Breast Cancer (Press Release) 06/21/2006
- Vogel, Victor; Joseph Constantino, Lawrence Wickerman et al. (2006-06-21). “Effects of Tamoxifen vs. Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes”. The Journal of the American Medical Association 295 (23): 2727–2741. doi:10.1001/jama.295.23.joc60074. PMID 16754727.
- “FDA Approves New Uses for Evista” (Press release). U.S. Food and Drug Administration. 2007-09-14. Retrieved 2007-09-15.
- Thelancetoncology, (2006). “A STARring role for raloxifene?”. Lancet Oncol 7 (6): 443. doi:10.1016/S1470-2045(06)70701-X.PMID 16750489.
- 355:125-137 July 13, 2006, Effects of Raloxifene on Cardiovascular Events and Breast Cancer in Postmenopausal Women Elizabeth Barrett-Connor, Lori Mosca, Peter Collins, et al. for the Raloxifene Use for The Heart (RUTH) Trial Investigators [Free full text]
- OncoGenetics.Org (September 2009). “Medications Effective in Reducing Risk of Breast Cancer But Increase Risk of Adverse Effects”. OncoGenetics.Org. Retrieved 2009-09-14.[dead link]
- Lisa Nainggolan (July 12, 2006). A balancing act: The pro and cons of raloxefene.
- Barrett-Connor E, Mosca L, Collins P, et al. (2006-07-13). “Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women”. New England Journal of Medicine 355 (2): 125–137. doi:10.1056/NEJMoa062462. PMID 16837676.
- AFP.google.com, US approves Lilly’s Evista for breast cancer prevention
- STAR: a head-to-head comparison of tamoxifen and raloxifene as breast-cancer preventatives
- Full Prescribing Information
- Position paper of the National Women’s Health Network
- Heringa M (2003). “Review on raloxifene: profile of a selective estrogen receptor modulator”. Int J Clin Pharmacol Ther 41 (8): 331–45. PMID 12940590.
- Barrett-Connor E (2001). “Raloxifene: risks and benefits”. Ann N Y Acad Sci 949: 295–303. doi:10.1111/j.1749-6632.2001.tb04036.x. PMID 11795366.
- Raloxifene bound to proteins in the PDB
Dr. Reddy’s launches Zenatane (Isotretinoin Capsules USP) in US
Isotretinoin
1 APRIL, 2013
India-based Dr. Reddy’s Laboratories has announced the launch of Zenatane (Isotretinoin Capsules USP) in 20mg and 40mg strengths in the US.
The launch follows the FDA approval of the company’s ANDA for Zenatane 10mg, 20mg and 40mg.
Zenatane (Isotretinoin Capsules USP) is a generic version, therapeutically equivalent to Accutane (Isotretinoin Capsules USP).
Isotretinoin is indicated for the treatment of severe recalcitrant nodular acne.
The company is making the product available in 10mg, 20mg, and 40mg strengths in boxes of 30 as unit dose blisters.
Isotretinoin, first marketed as Accutane byHoffmann-La Roche, is a medication used mostly for cystic acne. It is also achemotherapy treatment used in brain, pancreatic and other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. Its effects are systemic and nonselective. It is a retinoid, meaning it is related to vitamin A, and is found in small quantities naturally in the body.
Isotretinoin’s best-known and most dangerous side effect is birth defects due to in utero exposure. This is because of the molecule’s close resemblance to retinoic acid, a natural vitamin A derivative which controls normal embryonic development. In the United States a special procedure is required to obtain the pharmaceutical (see below).
In 2009, Roche decided to pull Accutane off the US market after juries had awarded millions of dollars in damages to former Accutane users over inflammatory bowel disease claims. Among others, actor James Marshall sued Roche over Accutane-related disease that resulted in removal of his colon.
The most common brands are Roaccutane (Hoffman-La Roche, known as Accutane in the United States before July 2009), Amnesteem (Mylan), Claravis (Barr), Isotroin(Cipla) or Sotret (Ranbaxy).
FOUNDER
LATE DR ANJI REDDY
BioMarin Submits Vimizim BLA to the U.S. FDA for the Treatment of MPS IVA
Elosulfase alfa, BMN-110
STRUCTURAL FORMULA
Monomer
APQPPNILLL LMDDMGWGDL GVYGEPSRET PNLDRMAAEG LLFPNFYSAN 50
PLCSPSRAAL LTGRLPIRNG FYTTNAHARN AYTPQEIVGG IPDSEQLLPE 100
LLKKAGYVSK IVGKWHLGHR PQFHPLKHGF DEWFGSPNCH FGPYDNKARP 150
NIPVYRDWEM VGRYYEEFPI NLKTGEANLT QIYLQEALDF IKRQARHHPF 200
FLYWAVDATH APVYASKPFL GTSQRGRYGD AVREIDDSIG KILELLQDLH 250
VADNTFVFFT SDNGAALISA PEQGGSNGPF LCGKQTTFEG GMREPALAWW 300
PGHVTAGQVS HQLGSIMDLF TTSLALAGLT PPSDRAIDGL NLLPTLLQGR 350
LMDRPIFYYR GDTLMAATLG QHKAHFWTWT NSWENFRQGI DFCPGQNVSG 400
VTTHNLEDHT KLPLIFHLGR DPGERFPLSF ASAEYQEALS RITSVVQQHQ 450
EALVPAQPQL NVCNWAVMNW APPGCEKLGK CLTPPESIPK KCLWSH 496
Disulfide bridges
139-139′ 282-393 282′-393′ 463-492 463′-492′ 475-481 475′-481′
Sulfatase, chondroitin,
structure
http://www.ama-assn.org/resources/doc/usan/elosulfase-alfa.pdf
1 APRIL, 2013
BioMarin Pharmaceutical Inc. has submitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for Vimizim (elosulfase alfa), an enzyme replacement therapy under evaluation for the treatment of patients with the rare lysosomal storage disorder mucopolysaccharidosis type IVA (MPS IVA), also called Morquio A syndrome. The company intends to submit an application for registration in the European Union (EU) by the end of April 2013.
“Based on the positive results from our Phase 3 pivotal study, we believe that Vimizim offers a substantial benefit to patients with MPS IVA, a severely debilitating and progressive disease for which there is no current treatment,” said Hank Fuchs, M.D., Chief Medical Officer of BioMarin. “The submission of the BLA represents a significant milestone for BioMarin and is the result of the strong, collaborative effort of many hard working employees, investigators, patients, and their families. With this application, BioMarin continues in its long-standing tradition of developing important therapies for those who are most in need. We look forward to working with the U.S. regulatory authorities to bring this treatment to patients.”
About MPS IVA
Mucopolysaccharidosis IVA (MPS IVA, also known as Morquio A Syndrome) is a disease characterized by deficient activity of N-acetylgalactosamine-6-sulfatase (GALNS) causing excessive lysosomal storage of glycosaminoglycans such as keratan sulfate and chondroitin sulfate. This excessive storage causes a systemic skeletal dysplasia, short stature, and joint abnormalities, which limit mobility and endurance. Malformation of the chest impairs respiratory function, and looseness of joints in the neck cause spinal instability and potentially spinal cord compression. Other symptoms may include hearing loss, corneal clouding, and heart disease. Initial symptoms often become evident in the first five years of life. The disease substantially limits both the quality and length of life of those affected.
The rate of incidence of MPS IVA is as yet unconfirmed and varies among different populations but estimates vary between 1 in 200,000 live births and 1 in 250,000 live births. The estimated prevalence is between 1,000 and 1,500 patients in the U.S., EU and Japan and between 1,500 to 2,000 patients in the rest of the world for a total of 2,500 to 3,000 patients.
About BioMarin
BioMarin develops and commercializes innovative biopharmaceuticals for serious diseases and medical conditions. The company’s product portfolio comprises four approved products and multiple clinical and pre-clinical product candidates. Approved products include Naglazyme® (galsulfase) for mucopolysaccharidosis VI (MPS VI), a product wholly developed and commercialized by BioMarin; Aldurazyme® (laronidase) for mucopolysaccharidosis I (MPS I), a product which BioMarin developed through a 50/50 joint venture with Genzyme Corporation; Kuvan® (sapropterin dihydrochloride) Tablets, for phenylketonuria (PKU), developed in partnership with Merck Serono, a division of Merck KGaA of Darmstadt, Germany; and Firdapse™ (amifampridine), which has been approved by the European Commission for the treatment of Lambert Eaton Myasthenic Syndrome (LEMS). Product candidates include BMN-110 (elosulfase alfa), formally referred to as GALNS, which successfully completed Phase III clinical development for the treatment of MPS IVA, PEG-PAL (PEGylated recombinant phenylalanine ammonia lyase), which is currently in Phase II clinical development for the treatment of PKU, BMN-701, a novel fusion protein of insulin-like growth factor 2 and acid alpha glucosidase (IGF2-GAA), which is currently in Phase I/II clinical development for the treatment of Pompe disease, BMN-673, a poly ADP-ribose polymerase (PARP) inhibitor, which is currently in Phase I/II clinical development for the treatment of genetically-defined cancers, and BMN-111, a modified C-natriuretic peptide, which is currently in Phase I clinical development for the treatment of achondroplasia. For additional information, please visit www.BMRN.com. Information on BioMarin’s website is not incorporated by reference into this press release.
DRUG SPOTLIGHT-IMATINIB
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| ImatinibCAS No:- [152459-95-5]IUPAC Name:- 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamideM. P.:- 211-213 °CMW: 493.60 | |
| 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamideImatinib (originally STI571) is a drug used to treat certain cancers. It is marketed byNovartis as Gleevec (USA) or Glivec (Europe/Australia/Latin America) as its mesylatesalt, imatinib mesilate (INN).Imatinib is the first of a new class of drugs that act by specifically inhibiting a certainenzyme – a receptor tyrosine kinase – that is characteristic of a particular cancer cell, rather than non-specifically inhibiting and killing all rapidly dividing cells. Imatinib was a model for other targeted therapies that inhibited this class of enzymes.It is used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors(GISTs) and some other diseases. By 2011, Gleevec has been FDA approved to treat ten different cancers.In CML, the tyrosine kinase enzyme ABL in white blood cells is locked in its activated form. This causes the excessive proliferation and high white blood cell count which is characteristic of CML. Imatinib binds to the site of tyrosine kinase activity, and prevents its activity, causing tumor cell death (apoptosis). |
bcr-abl kinase (green), which causes CML, inhibited by imatinib (red; small molecule).
Chronic myelogenous leukemia
The U.S. Food and Drug Administration (FDA) has approved imatinib as first-line treatment for Philadelphia chromosome (Ph)-positive CML, both in adults and children. The drug is approved in multiple Ph-positive cases CML, including after stem cell transplant, in blast crisis, and newly diagnosed
Legal challenge to generics
In 2007, imatinib became a test case through which Novartis challenged India’s patent laws. A win for Novartis would make it harder for Indian companies to produce generic versions of drugs still manufactured under patent elsewhere in the world. Doctors Without Borders argues a change in law would make it impossible for Indian companies to produce cheap generic antiretrovirals (anti-HIV medication), thus making it impossible for Third World countries to buy these essential medicines.[43] On 6 August 2007, the Madras High Court dismissed the writ petition filed by Novartis challenging the constitutionality of Section 3(d) of Indian Patent Act, and deferred to the World Trade Organization (WTO) forum to resolve the TRIPS compliance question. As of 2009 India has refused to grant patent exclusivity..
On April 01, 2013 Supreme Court of India dismissed the plea of Novartis for the grant of patent.
in germany
synthesis
i. Cyanamide, nitric acid, ethanol, reflux, 25 h,
ii. 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one, sodium hydroxide, isopropanol, reflux, 12 h,
iii. 10% palladium on carbon, hydrogen gas, ethyl acetate, room temperature, 6.5 h,
iv. 4-(4-methylpiperazinomethyl)-benzoyl chloride, pyridine, room temperature, 23 h
Anticancer drug imatinib mesylate (Imatinib Mesylate). Tradename Gleevec (Gleevec). Manufacturer Novartis. The FDA in May 2001 approved the listing for the treatment of Philadelphia chromosome (Bcr-Abl)-positive chronic myeloid leukemia (Chronic Myelogenous Leukemia, CML) and gastrointestinal stromal tumor (gastrointestinal stromal tumor, GIST) and other illnesses.
Imatinib is a tyrosine kinase inhibitor. In the early high-throughput screening, found two – phenylamino-pyrimidine (2-phenylaminopyrimidine) compounds of the Philadelphia chromosome mutant Bcr-Abl protein have a good inhibition, improvement of its structure obtained after imatinib.
Inverse synthetic analysis will be divided into four imatinib into fragment A has 1,3 – parents electrical, fragment B are 1,3 – parent nuclear, fragments A and B constitute a pyrimidine ring.
Compound 4 can be obtained in two ways, benzyl bromide 1 and secondary amines 2 by SN2 reaction, or the aldehyde 3 with a secondary amine 2 by reductive amination. Sodium cyanoborohydride electron withdrawing effect of the cyano group, thereby reducing the activity of the negative hydrogen, it may be present in acidic solution. Also in the acidic conditions of aldehydes and secondary amines imine positive ions, which is higher than the activity of aldehyde reduction.This is why the reductive amination reagent with inert negative and hydrogen under acidic conditions. 4 hydrolyzed ester with thionyl chloride into the acid chloride 5 . The reaction of aniline and cyanamide dinucleophile guanidine 7 . Compound 8 and DMF-DMA reaction electrophilic reagent parents 9 , 7 , and 9 ring closure under alkaline conditions to generate 10 . Finally, reduction, amidation, and a salt of imatinib mesylate generated.
Medicine for Blood Cancer
‘Imitinef Mercilet’ is a medicine which cures blood cancer.
Its available free of cost at “Adyar Cancer Institute in Chennai”.
Create Awareness. It might help someone.Cancer Institute in Adyar, Chennai
‘Imitinef Mercilet’ is apparently an alternative spelling of the drug Imatinib mesylate which is used in the treatment of some forms of leukemia along with other types of cancer. Imatinib, often referred to a “Gleevec”, has proved to be an effective treatment for some forms of cancers. However, “blood cancer” is a generalized term for cancers that affect the blood, lymphatic system or bone marrow. The three types of blood cancer are listed as leukemia, lymphoma, and multiple myeloma. These three malignancies require quite different kinds of treatments. While drugs (including Imatinib), along with other treatments such as radiation can help to slow or even stop the progress of these cancers, there is currently no single drug treatment that can be said to actually cure all such cancers.
Category: Cancer
Address: East Canal Bank Road , Gandhi Nagar
Adyar, Chennai -600020
Landmark: Near Michael School
Phone: 044-24910754 044-24910754 ,
044-24911526 044-24911526 , 044-22350241
Imatinib is a small molecule selectively inhibiting specific tyrosine kinases that has emerged recently as a valuable treatment for patients with advanced GIST. The use of imatinib as monotherapy for the treatment of GIST has been described in PCT publication WO 02/34727, which is here incorporated by reference. However, it has been reported that primary resistance to imatinib is present in a population of patients, for example 13.7% of patients in one study. In addition, a number of patients acquire resistance to treatment with imatinib. More generally this resistance is partial with progression in some lesions, but continuing disease control in other lesions. Hence, these patients remain on imatinib treatment but with a clear need for additional or alternative therapy.
Imatinib is 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide having the formula I
The preparation of imatinib and the use thereof, especially as an anti-tumour agent, are described in Example 21 of European patent application EP-A-0 564 409, which was published on 6 Oct. 1993, and in equivalent applications and patents in numerous other countries, e.g. in U.S. Pat. No. 5,521,184 and in Japanese patent 2706682
Anthera Initiates CHABLIS-SC1 Phase 3 Clinical Study in Lupus with Blisibimod
STRUCTURAL FORMULA
Monomer sequence
GCKWDLLIKQ WVCDPLGSGS ATGGSGSTAS SGSGSATHML PGCKWDLLIK 50
QWVCDPLGGG GGVDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP 100
EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRVVSVLT 150
VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 200
LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY 250
SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK 290
Disulfide bridges
2-13 2′-13′ 43-54 43′-54′ 69-69′ 72-72′ 104-164 104′-164′ 210-268 210′-268′
Protein (synthetic cytokine BAFF-binding domain fragment) fusion protein with
immunoglobulin G1 (human Fc fragment), dimer
http://www.ama-assn.org/resources/doc/usan/blisibimod.pdf SEE MORE
March 27, 2013 /
Anthera Pharmaceuticals, Inc. , a biopharmaceutical company developing drugs to treat serious diseases associated with inflammation and autoimmune disorders, today announced it has initiated the CHABLIS-SC1 Phase 3 study of blisibimod, a novel inhibitor of B-Cell Activating Factor (BAFF) for the treatment of systemic lupus erythematosus (lupus). Lupus is a chronic autoimmune disease, which often leads to severe skin rash, fatigue, joint pain and major organ complications.
The Phase 3 CHABLIS-SC1 study is a multicenter, placebo-controlled, randomized, double-blind study designed to evaluate the efficacy, safety, tolerability and immunogenicity of blisibimod in patients with clinically active SLE (SELENA-SLEDAI > 10) who have not achieved optimal resolution of their disease with corticosteroid use. The study will enroll patients from Latin America, Asia Pacific and Commonwealth of Independent States who will be randomized to receive blisibimod or placebo for 52 weeks after which they will have the option to receive blisibimod therapy in an open-label, long-term, follow-up safety study. The study will enroll approximately 400 patients and the primary endpoint will be a Systemic Lupus Erythematosus Response Index-8 (SRI-8). An SRI-8 responder is defined as a patient who has achieved a reduction in SELENA-SLEDAI equal to or greater than 8 points, and no new BILAG A or two B organ domain scores, and no increase in Physician’s Global Assessment (PGA) of greater than 0.3 on a three point scale. As part of the CHABLIS-SC1 clinical study an independent statistician will conduct interim analyses to validate key study assumptions. A summary of these analyses will be published later in 2013.
Blisibimod (also known as A-623, formerly AMG 623) is a selective antagonist of B-cell activating factor (BAFF, also known as B-lymphocyte stimulator or BLyS), being developed by Anthera Pharmaceuticals as a treatment for systemic lupus erythematosus.[1] It is currently under active investigation in clinical trials.[2]
- “A-623: BAFF Peptibody for the Treatment of Lupus”. Anthera Pharmaceuticals, Inc. Retrieved 2011-07-08.
- “Anthera Initiates Expanded and Extended PEARL-SC Phase 2b Clinical Study in Lupus With A-623 – A Subcutaneous Dual Inhibitor of Membrane and Soluble B-Cell Activating Factor (BAFF or BLyS)” (Press release). Anthera Pharmaceuticals, Inc.. 29 July 2010.
New Drug Approvals 