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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai)
, INDIA
36Yrs Exp. in the feld of Organic Chemistry,Working for AFRICURE PHARMA as ADVISOR earlier with GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google,
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FDA Approves Investigational MS Trial
The stem cell research division of the Tisch MS Research Center of New York announced that the U.S. Food and Drug Administration (FDA) approved autologous, mesenchymal stem cell-derived neural progenitor cells (MSC-NPs) as an Investigational New Drug (IND) for an open label, phase 1 clinical trial in the treatment of multiple sclerosis.
FDA approves GlaxoSmithKline’s Tivicay, for the treatment of AIDS
August 14, 2013 | By Márcio Barra
GSK announced yesterday that the FDA has given green light for ViiV Healthcare’s Tivicay(dolutegravir) 50-mg tablets, an integrase inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 in adults and children aged 12 years and older weighing at least 40 kg (approx. 88 lbs). It can be used to treat infected adults who have been treated with other drugs or are new to treatment.
Integrase inhibitors are a new class of antiretroviral agents that block HIV replication in the body by preventing the viral DNA from integrating into the genetic material of human immune cells (T-cells). In short, they stop the virus from entering cells.
View original post 157 more words
Biocon Launches Psoriasis Drug In India; To File IND Application With US FDA This Fiscal
India’s Biocon on Saturday launched ALZUMAb, a novel biologic for the treatment of psoriasis, in India. Sreeja/IB Times
KIRAN MAZUMDAR SHAW, CHAIRMAN BIOCON
itolizumab is other name
| Jan 13: Biocon has received marketing approval in India. The company plans to file an investigational new drug application with the FDA seeking authorization for further human trials which will support regualtory approval in the US. | |
| Biocon is to seek pre-IND advice from the US FDA . | |
| On completing proof-of-concept PIII trials, Biocon will seek a licensing partner for itolizumab. The company has stated it expects to initiate licensing discussions during the 2010/2011 financial year |
Bangalore, India-based Biocon (NSE:BIOCON) announced Saturday the launch of its first biologic drug for the treatment of chronic psoriasis in India, and said it would file an investigational new drug, or IND, application with the U.S. Food and Drug Administration, or FDA, by the end of this fiscal year.
read all at
The drug, Alzumab, is the second biologic — a medicine created through a biological process and not through a chemical process — launched by the company, and is expected to serve about 1 percent to 2 percent of India’s population estimated to suffer from the ailment.
Itolizumab (INN, trade name Alzumab) is a ‘first in class’ humanized IgG1 monoclonal antibody developed by Biocon. It selectively targets CD6, a pan T cell marker involved in co-stimulation, adhesion and maturation of T cells. Itolizumab, by binding to CD6, down regulates T cell activation, causes reduction in synthesis of pro-inflammatory cytokines and possibly plays an important role by reducing T cell infiltration at sites of inflammation. A double blind, placebo controlled, phase III treat –Plaq study of itolizumab successfully met the pre-specified primary end-point of significant improvement in PASI-75 (Psoriasis Area and Severity Index) score after 12 weeks of treatment in patients with moderate to severe psoriasis compared to placebo.[2] Biocon has received marketing authorization for the drug from the Drugs Controller General of India (DCGI).
J and J gets green light for front-line Velcade in EU
Bortezomib
Johnson & Johnson’s multiple myeloma treatment Velcade has been cleared as a first-line therapy in the EU, boosting the number of patients eligible for treatment with the drug.
The European Commission gave the go-ahead for Velcade (bortezomib) as induction therapy in combination with dexamethasone and thalidomide in previously-untreated multiple myeloma patients who are eligible for high-dose chemotherapy and a stem cell transplant.
http://www.pharmatimes.com/Article/13-08-09/J_J_gets_green_light_for_front-line_Velcade_in_EU.aspx
Bortezomib bound to the core particle in a yeast proteasome. The bortezomib molecule is in the center colored by atom type (boron = pink, carbon = cyan, nitrogen = blue, oxygen = red), surrounded by the local protein surface. The blue patch is catalyticthreonine residue whose activity is blocked by the presence of bortezomib.
Bortezomib (INN, originally codenamed PS-341; marketed as Velcade by Millennium Pharmaceuticals and Bortecad by Cadila Healthcare) is the first therapeutic proteasome inhibitor to be tested in humans. It is approved in the U.S. for treating relapsedmultiple myeloma and mantle cell lymphoma. In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease.
Bortezomib was originally synthesized in 1995 (MG-341) at a company called Myogenics, which soon changed its name to ProScript. After promising preclinical results, the drug (PS-341) was tested in a small Phase I clinical trial on patients with multiple myeloma cancer. ProScript ran out of money and was bought by Leukosite in May 1999. Leukosite in turn was bought byMillennium Pharmaceuticals in October 1999. At this point in time, the project had low priority amongst other projects at the company. This changed significantly when one of the first volunteers to receive the drug in the clinical trial achieved a complete response and were still alive four years later. At the time this was a remarkable result. Later clinical experimentation indicates the possibility of a complete response in 15% of patients in a similar condition, when treated with bortezomib.
In May 2003, seven years after the initial synthesis, bortezomib (Velcade) was approved in the United States by the Food and Drug Administration (FDA) for use in multiple myeloma, based on the results from the SUMMIT Phase II trial.
Another commercially available bortezomib product – Bortenat (Natco Pharma, India), reportedly contains substantially more active entity than declared, potentially and even more resulting in increase toxicity. Moreover, Bortenat has some other chemical and formulation deviations from the registered ethic product Velcade (Millennium Pharmaceuticals and Janssen-Cilag), with unclear clinical impact
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In my practice this product
Ixchelsis, a start-up company that has come out of Pfizer’s former R D site at Sandwich, UK, is progressing a treatment for premature ejaculation boosted by the backing of Eli Lilly.
Lilly, through its venture fund set up with TVM Capital Life Science, has
invested in Ixchelsis, made up of former Pfizer scientists and headed by Gary
Muirhead. The company is based on an oxytocin receptor antagonist called IX-01
originally discovered at Sandwich which the investors say “has the potential to
be the best-in-class pharmacological approach for the treatment of
PE”.
Ixchelsis, which is based at the Sandwich site, now called Discovery
Park, will collaborate with the autonomous early phase virtual drug discovery
arm of Lilly, known as Chorus. Dr Muirhead told PharmaTimes that the
TVM model will fund through to the agreed exit point, which is completion of
proof-of-concept and this requires about $14 million.
read all at
http://www.pharmatimes.com/Article/13-08-08/Lilly_backs_Ixchelsis_a_start-up_born_at_Pfizer.aspx
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British drugmaker GlaxoSmithKline (GSK) has submitted a marketing authorisation application (MAA) to the European Medicines Agency (EMA) for its cervical cancer vaccine, Cervarix [Human papillomavirus bivalent (types 16 and 18) vaccine, recombinant].
The application in the EU is to allow administration of the vaccine in a two dosing schedule (0, 6 months) in 9-14 year old girls.
Intended to serve as an alternative dosing schedule, the two-dose schedule will help prevent premalignant genital (cervical, vulvar and vaginal) lesions and cervical cancer causally related to certain oncogenic Human Papillomavirus (HPV) types. It does not seek to replace the three-dose schedule.
read all at
Cervarix is a vaccine against certain types of cancer-causing human papillomavirus (HPV).
Cervarix is designed to prevent infection from HPV types 16 and 18, that cause about 70% of cervical cancer cases. These types also cause most HPV-induced genital and head and neck cancers. Additionally, some cross-reactive protection against virus strains 45 and 31 were shown in clinical trials. Cervarix also contains AS04, a proprietary adjuvant that has been found to boost the immune system response for a longer period of time.
Cervarix is manufactured by GlaxoSmithKline. An alternative product, from Merck & Co., is known as Gardasil.
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Oral Anti-Cancer Therapy Pomalidomide Now Approved by European Commission as Treatment for Patients with Relapsed/Refractory Multiple Myeloma – a Rare Form of Blood Cancer
POMALIDOMIDE
4-amino-2-(2,6-dixopiperidin-3- yl)isoindoline-l,3-dione; 3-(4-amino-l,3-dioxo-l,3-dihydro-isoindol-2-yl)-piperidine- 2,6-dione; 3-(4-amino-l ,3-dioxoisoindolin-2-yl)piperidine-2,6-dione; 1 ,3-dioxo-2-(2,6- dioxopiperidin-3-yl)-4-aminoisoindoline; 3-(l,3-dioxo-4-aminoisoindolin-2-yl)- piperidine-2,6-dione;
BOUDRY, Switzerland–(BUSINESS WIRE)–Aug. 9, 2013–Celgene International Sàrl, a wholly-owned subsidiary of Celgene Corporation (NASDAQ: CELG) today announced that the European Commission (EC) has granted approval for Pomalidomide Celgene®▼(pomalidomide),
in combination with dexamethasone, for the treatment of relapsed and refractory multiple myeloma (rrMM) in adult patients who have received at least two prior therapies including both lenalidomide and bortezomib and have demonstrated disease progression on the last therapy.1 Celgene intends to launch Pomalidomide Celgene in the EU under the trade name “IMNOVID®”, following submission of a regulatory notification to the European Medicines Agency (EMA) to change the trade name.
READ ALL AT
http://www.pharmalive.com/ec-approves-celgene-blood-cancer-drug
CAS 19171-19-8
Pomalidomide, an analogue of thalidomide, is an immunomodulatory antineoplastic agent. FDA approved on February 8, 2013.
Pomalidomide is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy.
Pomalidomide (INN, originally CC-4047 or 3-amino-thalidomide, trade name Pomalyst[1] in the US) is a derivative of thalidomidemarketed by Celgene. It is anti-angiogenic and also acts as an immunomodulator. Pomalidomide was approved in February 2013 by the U.S. Food and Drug Administration (FDA) as a treatment for relapsed and refractory multiple myeloma.[2] It received a similar approval from the European Commission in August 2013, and is expected to be marketed in Europe under the brand nameImnovid.[3]
Origin and development
The parent compound of pomalidomide, thalidomide, was originally discovered to inhibit angiogenesis in 1994.[4] Based upon this discovery, thalidomide was taken into clinical trials for cancer, leading to its ultimate FDA approval for multiple myeloma.[5] Further structure activity studies done in Dr. Robert D’Amato’s lab at Boston Children’s Hospital led to the first claim in 1995 that amino-thalidomide had antitumor activity.[6] Interestingly, the pronounced anti-tumor activity is due to its ability to directly inhibit both the tumor cell and vascular compartments of myeloma cancers.[7] This dual activity of pomalidomide makes it more efficacious than thalidomide in vitro and in vivo.[8]
Clinical trials
Phase I trial results showed tolerable side effects.[9]
Phase II clinical trials for multiple myeloma and myelofibrosis reported ‘promising results’.[10][11]
Phase III results were reported at ASH in 2012 and showed significant extension of progression-free survival (median 3.6 months vs. 1.8 months; P < 0.001), and overall survival in patients taking pomalidomide and dexamethasone v. dexamethasone alone.[12]
Mechanism
Pomalidomide directly inhibits angiogenesis and myeloma cell growth. This dual effect is central to its activity in myeloma, rather than other pathways such as TNF alpha inhibition, since potent TNF alpha inhibitors including rolipram and pentoxifylline do not inhibit myeloma cell growth nor angiogenesis.[7] Up regulation of Interferon gamma, IL-2 and IL-10 as well as down regulation of IL-6 have been reported for pomalidomide. These changes may contribute to pomalidomide’s anti-angiogenic and anti-myeloma activities.
Pregnancy and sexual contact warnings
Because Pomalyst can cause harm to unborn babies when administered during pregnancy, women taking Pomalyst must not become pregnant. Women must produce two negative pregnancy tests and use contraception methods before beginning Pomalyst. Women must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with Pomalyst, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of Pomalyst therapy. Pomalyst is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing Pomalyst, even if they have undergone a successful vasectomy. Male patients taking Pomalyst must not donate sperm.
Pomalidomide simple structure, synthesis is relatively easy. The glutamine ( 1 ), the compound 2 protected amino, thionyl chloride to ring palladium on carbon hydrogenation later deprotected to give compound 3 , 3 , and 4 direct condensation Pomalidomide.
PATENTS
| US PATENT No | Patent ExpirY | patent use code |
|---|---|---|
| 5635517 | Jul 24, 2016 | U-1359 |
| 6045501 | Aug 28, 2018 | U-1361 |
| 6315720 | Oct 23, 2020 | U-1361 |
| 6316471 | Aug 10, 2016 | U-1360 |
| 6476052 | Jul 24, 2016 | U-1360 |
| 6561976 | Aug 28, 2018 | U-1361 |
| 6561977 | Oct 23, 2020 | U-1361 |
| 6755784 | Oct 23, 2020 | U-1361 |
| 6908432 | Aug 28, 2018 | U-1361 |
| 8158653 | Aug 10, 2016 | |
| 8198262 | Oct 19, 2024 | U-1360 |
| 8204763 | Aug 28, 2018 | U-1361 |
| 8315886 | Oct 23, 2020 | U-1361 |
| Exclusivity Code | Exclusivity Date |
|---|---|
| ODE | Feb 8, 2020 |
| NCE | Feb 8, 2018 |
| Country | Patent Number | Approved | Expires (estimated) |
|---|---|---|---|
| United States | 8198262 | 2013-02-08 | 2024-10-19 |
| United States | 8204763 | 2013-02-08 | 2018-08-28 |
| United States | 8315886 | 2013-02-08 | 2020-10-23 |
| Country | Patent Number | Approved | Expires (estimated) |
|---|---|---|---|
| United States | 5635517 | 2013-02-08 | 2016-07-24 |
| United States | 6045501 | 2013-02-08 | 2018-08-28 |
| United States | 6315720 | 2013-02-08 | 2020-10-23 |
| United States | 6316471 | 2013-02-08 | 2016-08-10 |
| United States | 6476052 | 2013-02-08 | 2016-07-24 |
| United States | 6561976 | 2013-02-08 | 2018-08-28 |
| United States | 6561977 | 2013-02-08 | 2020-10-23 |
| United States | 6755784 | 2013-02-08 | 2020-10-23 |
| United States | 6908432 | 2013-02-08 | 2018-08-28 |
| United States | 8158653 | 2013-02-08 | 2016-08-10 |
Pomalidomide-2013, FDA approved anticancer drugs. Pomalidomide isthalidomide (thalidomide) derivative, for the treatment of multiple myeloma. Trade name Pomalyst, developed by Celgene.
Pomalidomide simple structure, synthesis is relatively easy. (From glutamine 1 ), the compound 2 is protected amino, thionyl chloride off ring after deprotection to obtain a compound with palladium on carbon hydrogenation of 3 , 3 and 4 the direct condensation Pomalidomide.
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http://www.google.com/patents/WO2012177678A2?cl=en
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Figure 1: Chronological view of the history of thalidomide and its analogs
 |
|
| Systematic (IUPAC) name | |
|---|---|
| 4-Amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione | |
| Clinical data | |
| Trade names | Imnovid, Pomalyst |
| Licence data | EMA:Link, US FDA:link |
| Pregnancy cat. |
|
| Legal status | |
| Routes | Oral |
| Pharmacokinetic data | |
| Protein binding | 12–44% |
| Metabolism | Hepatic (mostly CYP1A2 andCYP3A4 mediated; some minor contributions by CYP2C19 andCYP2D6) |
| Half-life | 7.5 hours |
| Excretion | Urine (73%), faeces (15%) |
| Identifiers | |
| CAS number | 19171-19-8  |
| ATC code | L04AX06 |
| PubChem | CID 134780 |
| Chemical data | |
| Formula | C13H11N3O4 |
| Mol. mass | 273.24 g/mol |
Figure 2: The mechanism of TLP in multiple myeloma. TLP refers to thalidomide, lenalidomide and pomalidomide.
CLIP
HONORED
Celgene’s George Muller (left) and Roger Shen-Chu Chen celebrate at the Heroes of Chemistry banquet.
Credit: Linda Wang/C&EN
The satisfaction of helping patients is what drives George Muller as an industrial scientist. Muller is coinventor of Celgene’s Polamyst for multiple myeloma.
“It’s wonderful to be able to think that the work one did in the lab ended up helping patients,” he says. “Over my career, I’ve met patients who were taking drugs on which I had worked. It’s always amazing to see the positive effects on the lives of these patients. Some of them get their lives back.”
Muller says that during the course of developing Pomalyst, they made hundreds of compounds. “We worked on the project for probably 15-plus years,” he says. The drug was approved in 2014.
References
- “Pomalyst (Pomalidomide) Official Website”. Celgene Corporation. Retrieved 2013-08-10.
- “Pomalyst (Pomalidomide) Approved By FDA For Relapsed And Refractory Multiple Myeloma”. The Myeloma Beacon. Retrieved 2013-08-10.
- “Pomalidomide Approved In Europe For Relapsed And Refractory Multiple Myeloma”. The Myeloma Beacon. Retrieved 2013-08-10.
- D’Amato, Robert J.; Loughnan, Michael S.; Flynn, Evelyn; Folkman, Judah (1994). “Thalidomide is an inhibitor of angiogenesis”. Proceedings of the National Academy of Sciences of the United States of America 91 (9): 4082–5. Bibcode:1994PNAS…91.4082D. doi:10.1073/pnas.91.9.4082. JSTOR 2364596. PMC 43727. PMID 7513432.
- http://vectorblog.org/2013/04/from-thalidomide-to-pomalyst-better-living-through-chemistry/
- http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=5,712,291.PN.&OS=PN/5,712,291&RS=PN/5,712,291
- D’Amato, R; Lentzsch, S; Anderson, KC; Rogers, MS (2001). “Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma”. Seminars in Oncology 28 (6): 597–601. doi:10.1016/S0093-7754(01)90031-4. PMID 11740816.
- Lentzsch, S; Rogers, MS; Leblanc, R; Birsner, AE; Shah, JH; Treston, AM; Anderson, KC; D’Amato, RJ (2002). “S-3-Amino-phthalimido-glutarimide inhibits angiogenesis and growth of B-cell neoplasias in mice”. Cancer Research 62 (8): 2300–5. PMID 11956087.
- Streetly, Matthew J.; Gyertson, Kylie; Daniel, Yvonne; Zeldis, Jerome B.; Kazmi, Majid; Schey, Stephen A. (2008). “Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation”. British Journal of Haematology 141 (1): 41–51. doi:10.1111/j.1365-2141.2008.07013.x. PMID 18324965.
- Jump up^ “Promising Results From 2 Trials Highlighting Pomalidomide Presented At ASH” (Press release). Celgene. December 11, 2008. Retrieved October 28, 2012.
- Jump up^ Tefferi, Ayalew (December 8, 2008). “Pomalidomide Therapy in Anemic Patients with Myelofibrosis: Results from a Phase-2 Randomized Multicenter Study”. 50th ASH Annual Meeting and Exposition. San Francisco. Retrieved October 28, 2012.
- Jump up^ “Phase III Study (MM-003) of Pomalidomide Plus Low-Dose Dexamethasone Demonstrates Significant Progression-Free and Overall Survival Improvement for Patients with Relapsed or Refractory Multiple Myeloma.”. 11 Dec 2012.
External links
POMALYST is an immunomodulatory antineoplastic agent. The chemical name is (RS)-4-Amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline-1,3dione and it has the following chemical structure:
 |
The empirical formula for pomalidomide is C13H11N3O4 and the gram molecular weight is 273.24.
Pomalidomide is a yellow solid powder. It has limited to low solubility into organic solvents and it has low solubility in all pH solutions (about 0.01 mg/mL). Pomalidomide has a chiral carbon atom which exists as a racemic mixture of the R(+) and S(-) enantiomers.
POMALYST is available in 1 mg, 2 mg, 3 mg and 4 mg capsules for oral administration. Each capsule contains pomalidomide as the active ingredient and the following inactive ingredients: mannitol, pregelatinized starch and sodium stearyl fumarate. The 1 mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, white ink and black ink. The 2 mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, FD&C red 3 and white ink. The 3 mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide and white ink. The 4 mg capsule shell contains gelatin, titanium dioxide, FD&C blue 1, FD&C blue 2 and white ink.
NDA 204026
APPR..2013-02-08
Dosages/Routes/Forms
Celgene
| Strength | Form/Route | Marketing Status | RLD | TE Code |
|---|---|---|---|---|
| 1MG | CAPSULE;ORAL | 1 | 0 | |
| 2MG | CAPSULE;ORAL | 1 | 0 | |
| 3MG | CAPSULE;ORAL | 1 | 0 | |
| 4MG | CAPSULE;ORAL | 1 | 1 |
Approval History
2013-10-03
001
Manufacturing Change or Addition
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
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