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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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FDA approves first treatment Ruzurgi (amifampridine) for children with Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder


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FDA approves first treatment Ruzurgi (amifampridine)  for children with Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder

The U.S. Food and Drug Administration today approved Ruzurgi (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in patients 6 to less than 17 years of age. This is the first FDA approval of a treatment specifically for pediatric patients with LEMS. The only other treatment approved for LEMS is only approved for use in adults.

“We continue to be committed to facilitating the development and approval of treatments for rare diseases, particularly those in children,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This approval will provide a much-needed treatment option for pediatric patients with LEMS who have significant weakness and fatigue that can often cause great difficulties with daily activities.”

LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. In people with LEMS, the body’s own immune system attacks the neuromuscular junction (the connection between nerves and muscles) and disrupts the ability of nerve cells to send signals to muscle cells. LEMS may be associated with …

May 06, 2019

The U.S. Food and Drug Administration today approved Ruzurgi (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in patients 6 to less than 17 years of age. This is the first FDA approval of a treatment specifically for pediatric patients with LEMS. The only other treatment approved for LEMS is only approved for use in adults.

“We continue to be committed to facilitating the development and approval of treatments for rare diseases, particularly those in children,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This approval will provide a much-needed treatment option for pediatric patients with LEMS who have significant weakness and fatigue that can often cause great difficulties with daily activities.”

LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. In people with LEMS, the body’s own immune system attacks the neuromuscular junction (the connection between nerves and muscles) and disrupts the ability of nerve cells to send signals to muscle cells. LEMS may be associated with other autoimmune diseases, but more commonly occurs in patients with cancer such as small cell lung cancer, where its onset precedes or coincides with the diagnosis of cancer. LEMS can occur at any age. The prevalence of LEMS specifically in pediatric patients is not known, but the overall prevalence of LEMS is estimated to be three per million individuals worldwide.

Use of Ruzurgi in patients 6 to less than 17 years of age is supported by evidence from adequate and well-controlled studies of the drug in adults with LEMS, pharmacokinetic data in adult patients, pharmacokinetic modeling and simulation to identify the dosing regimen in pediatric patients and safety data from pediatric patients 6 to less than 17 years of age.

The effectiveness of Ruzurgi for the treatment of LEMS was established by a randomized, double-blind, placebo-controlled withdrawal study of 32 adult patients in which patients were taking Ruzurgi for at least three months prior to entering the study. The study compared patients continuing on Ruzurgi to patients switched to placebo. Effectiveness was measured by the degree of change in a test that assessed the time it took the patient to rise from a chair, walk three meters, and return to the chair for three consecutive laps without pause. The patients that continued on Ruzurgi experienced less impairment than those on placebo. Effectiveness was also measured with a self-assessment scale for LEMS-related weakness that evaluated the feeling of weakening or strengthening. The scores indicated greater perceived weakening in the patients switched to placebo.

The most common side effects experienced by pediatric and adult patients taking Ruzurgi were burning or prickling sensation (paresthesia), abdominal pain, indigestion, dizziness and nausea. Side effects reported in pediatric patients were similar to those seen in adult patients. Seizures have been observed in patients without a history of seizures. Patients should inform their health care professional immediately if they have signs of hypersensitivity reactions such as rash, hives, itching, fever, swelling or trouble breathing.

The FDA granted this application Priority Review and Fast Track designations. Ruzurgi also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Ruzurgi to Jacobus Pharmaceutical Company, Inc.

https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-children-lambert-eaton-myasthenic-syndrome-rare-autoimmune-disorder?utm_campaign=050619_PR_FDA%20approves%20first%20treatment%20for%20children%20with%20LEMS&utm_medium=email&utm_source=Eloqua

/////////////////FDA 2019, Ruzurgi, amifampridine,  Lambert-Eaton myasthenic syndrome, LEMS,  RARE DISEASES, CHILDREN, Jacobus Pharmaceutical Company, Priority Review,  Fast Track designations, Orphan Drug designation

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First FDA-approved vaccine Dengvaxia for the prevention of dengue disease in endemic regions


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First FDA-approved vaccine for the prevention of dengue disease in endemic regions

May 01, 2019

The U.S. Food and Drug Administration announced today the approval of Dengvaxia, the first vaccine approved for the prevention of dengue disease caused by all dengue virus serotypes (1, 2, 3 and 4) in people ages 9 through 16 who have laboratory-confirmed previous dengue infection and who live in endemic areas. Dengue is endemic in the U.S. territories of American Samoa, Guam, Puerto Rico and the U.S. Virgin Islands.

“Dengue disease is the most common mosquito-borne viral disease in the world and global incidence has increased in recent decades,” said Anna Abram, FDA deputy commissioner for policy, legislation, and international affairs. “The FDA is committed to working proactively with our partners at the U.S. Centers for Disease Control and Prevention, as well as international partners, including the World Health Organization, to combat public health threats, including through facilitating the development and availability of medical products to address emerging infectious diseases. While there is no cure for dengue disease, today’s approval is an important step toward helping to reduce the impact of this virus in endemic regions of the United States.”

The CDC estimates more than one-third of the world’s population is living in areas at risk for infection by dengue virus which causes dengue fever, a leading cause of illness among people living in the tropics and subtropics. The first infection with dengue virus typically results in either no symptoms or a mild illness that can be mistaken for the flu or another viral infection. A subsequent infection can lead to severe dengue, including dengue hemorrhagic fever (DHF), a more severe form of the disease that can be fatal. Symptoms may include stomach pain, persistent vomiting, bleeding, confusion and difficulty breathing. Approximately 95 percent of all severe/hospitalized cases of dengue are associated with second dengue virus infection. Because there are no specific drugs approved for the treatment of dengue disease, care is limited to the management of symptoms.

Each year, an estimated 400 million dengue virus infections occur globally according to the CDC. Of these, approximately 500,000 cases develop into DHF, which contributes to about 20,000 deaths, primarily among children. Although dengue cases are rare in the continental U.S., the disease is regularly found in American Samoa, Puerto Rico, Guam, the U.S. Virgin Islands, as well as Latin America, Southeast Asia and the Pacific islands.

“Infection by one type of dengue virus usually provides immunity against that specific serotype, but a subsequent infection by any of the other three serotypes of the virus increases the risk of developing severe dengue disease, which may lead to hospitalization or even death,” said Peter Marks, M.D., director of the FDA’s Center for Biologics Evaluation and Research. “As the second infection with dengue is often much more severe than the first, the FDA’s approval of this vaccine will help protect people previously infected with dengue virus from subsequent development of dengue disease.”

The safety and effectiveness of the vaccine was determined in three randomized, placebo-controlled studies involving approximately 35,000 individuals in dengue-endemic areas, including Puerto Rico, Latin America and the Asia Pacific region. The vaccine was determined to be approximately 76 percent effective in preventing symptomatic, laboratory-confirmed dengue disease in individuals 9 through 16 years of age who previously had laboratory-confirmed dengue disease. Dengvaxia has already been approved in 19 countries and the European Union.

The most commonly reported side effects by those who received Dengvaxia were headache, muscle pain, joint pain, fatigue, injection site pain and low-grade fever. The frequency of side effects was similar across Dengvaxia and placebo recipients and tended to decrease after each subsequent dose of the vaccine.

Dengvaxia is not approved for use in individuals not previously infected by any dengue virus serotype or for whom this information is unknown. This is because in people who have not been infected with dengue virus, Dengvaxia appears to act like a first dengue infection – without actually infecting the person with wild-type dengue virus – such that a subsequent infection can result in severe dengue disease.Therefore, health care professionals should evaluate individuals for prior dengue infection to avoid vaccinating individuals who have not been previously infected by dengue virus. This can be assessed through a medical record of a previous laboratory-confirmed dengue infection or through serological testing (tests using blood samples from the patient) prior to vaccination.

Dengvaxia is a live, attenuated vaccine that is administered as three separate injections, with the initial dose followed by two additional shots given six and twelve months later.

The FDA granted this application Priority Review and a Tropical Disease Priority Review Voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of certain tropical diseases. The approval was granted to Sanofi Pasteur.

https://www.fda.gov/news-events/press-announcements/first-fda-approved-vaccine-prevention-dengue-disease-endemic-regions?utm_campaign=050119_PR_First%20FDA-approved%20vaccine%20for%20prevention%20of%20dengue%20in%20endemic%20areas&utm_medium=email&utm_source=Eloqua

//////////fda 2019, Priority Review, Tropical Disease Priority Review Voucher , Sanofi Pasteur,  Dengvaxia, vaccine, dengue

FDA approves first treatment for pediatric patients with lupus


The U.S. Food and Drug Administration today approved Benlysta (belimumab) intravenous (IV) infusion for treatment of children with systemic lupus erythematosus (SLE) – often referred to as simply “lupus” – a serious chronic disease that causes inflammation and damage to various body tissues and organs. This is the first time that the FDA has approved a treatment for pediatric patients with SLE. Benlysta has been approved for use in adult patients since 2011.
“The agency expedited the review and approval of this application because Benlysta IV fulfils an unmet need for therapies, specifically in pediatric patients with SLE. While there is no cure for lupus, treatment can help our youngest patients control their disease with the hope of …

April 26, 2019

Release

The U.S. Food and Drug Administration today approved Benlysta (belimumab) intravenous (IV) infusion for treatment of children with systemic lupus erythematosus (SLE) – often referred to as simply “lupus” – a serious chronic disease that causes inflammation and damage to various body tissues and organs. This is the first time that the FDA has approved a treatment for pediatric patients with SLE. Benlysta has been approved for use in adult patients since 2011.

“The agency expedited the review and approval of this application because Benlysta IV fulfils an unmet need for therapies, specifically in pediatric patients with SLE. While there is no cure for lupus, treatment can help our youngest patients control their disease with the hope of improving their quality of life and lowering their risk of long-term organ damage and disability,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research.

While childhood-onset SLE is rare, when diagnosed, it is generally more active in children and adolescents than adult patients, particularly in how it impacts organs such as the kidneys and central nervous system. As a result of the disease starting early in life, pediatric patients with SLE are at a higher risk for developing increased organ damage and complications from the disease as well as adverse events from the life-long treatments usually required.

The efficacy of Benlysta IV for the treatment of SLE in pediatric patients was studied over 52 weeks in 93 pediatric patients with SLE. The proportion of pediatric patients achieving the composite primary endpoint, the SLE response index (SRI-4), was higher in pediatric patients receiving Benlysta IV plus standard therapy compared to placebo plus standard therapy. Pediatric patients who received Benlysta IV plus standard therapy also had a lower risk of experiencing a severe flare, as well as longer duration of time until a severe flare (160 days versus 82 days). The drug’s safety and pharmacokinetic profiles in pediatric patients were consistent with those in adults with SLE.

Benlysta’s doctor and patient information includes a warning for mortality, serious infections, hypersensitivity and depression, based on data from the clinical studies in adults with SLE. The drug should not be administered with live vaccines. The manufacturer is required to provide a Medication Guide to inform patients of the risks associated with Benlysta.

The most common side effects in patients included nausea, diarrhea and fever. Patients also commonly experienced infusion reactions, so healthcare professionals are advised to pre-treat patients with an antihistamine.

The FDA granted this application a Priority Review designation. The FDA granted the approval of Benlysta to GlaxoSmithKline.

////////////Benlysta, belimumab, fda 2019, Priority Review, GlaxoSmithKline

ブレキサノロン , Brexanolone, Allopregnanolone


Allopregnanolone.png

ChemSpider 2D Image | Allopregnanolone | C21H34O2

Image result for Brexanolone

Brexanolone

318.501 g/mol, C21H34O2

CAS: 516-54-1

ブレキサノロン

MFCD00003677
Pregnan-20-one, 3-hydroxy-, (3α,5α)-
Pregnan-20-one, 3-hydroxy-, (3α,5α)- [ACD/Index Name]
S39XZ5QV8Y
TU4383000
UNII:S39XZ5QV8Y
(1S,2S,7S,11S,14S,15S,5R,10R)-14-acetyl-5-hydroxy-2,15-dimethyltetracyclo[8.7.0.0<2,7>.0<11,15>]heptadecane
(+)-3a-Hydroxy-5a-pregnan-20-one
(+)-3α-Hydroxy-5α-pregnan-20-one
(3α,5α)-3-Hydroxypregnan-20-one [ACD/IUPAC Name]
10446
3211363 [Beilstein]
3a-Hydroxy-5a-pregnan-20-one

The U.S. Food and Drug Administration today approved Zulresso (brexanolone) injection for intravenous (IV) use for the treatment of postpartum depression (PPD) in adult women. This is the first drug approved by the FDA specifically for PPD. 

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm633919.htm?utm_campaign=031919_PR_FDA%20approves%20new%20drug%20for%20post-partum%20depression&utm_medium=email&utm_source=Eloqua

March 19, 2019

Release

The U.S. Food and Drug Administration today approved Zulresso (brexanolone) injection for intravenous (IV) use for the treatment of postpartum depression (PPD) in adult women. This is the first drug approved by the FDA specifically for PPD.

“Postpartum depression is a serious condition that, when severe, can be life-threatening. Women may experience thoughts about harming themselves or harming their child. Postpartum depression can also interfere with the maternal-infant bond. This approval marks the first time a drug has been specifically approved to treat postpartum depression, providing an important new treatment option,” said Tiffany Farchione, M.D., acting director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research. “Because of concerns about serious risks, including excessive sedation or sudden loss of consciousness during administration, Zulresso has been approved with a Risk Evaluation and Mitigation Strategy (REMS) and is only available to patients through a restricted distribution program at certified health care facilities where the health care provider can carefully monitor the patient.”

PPD is a major depressive episode that occurs following childbirth, although symptoms can start during pregnancy. As with other forms of depression, it is characterized by sadness and/or loss of interest in activities that one used to enjoy and a decreased ability to feel pleasure (anhedonia) and may present with symptoms such as cognitive impairment, feelings of worthlessness or guilt, or suicidal ideation.

Zulresso will be available only through a restricted program called the Zulresso REMS Program that requires the drug be administered by a health care provider in a certified health care facility. The REMS requires that patients be enrolled in the program prior to administration of the drug. Zulresso is administered as a continuous IV infusion over a total of 60 hours (2.5 days). Because of the risk of serious harm due to the sudden loss of consciousness, patients must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring (monitors oxygen levels in the blood). While receiving the infusion, patients must be accompanied during interactions with their child(ren). The need for these steps is addressed in a Boxed Warning in the drug’s prescribing information. Patients will be counseled on the risks of Zulresso treatment and instructed that they must be monitored for these effects at a health care facility for the entire 60 hours of infusion. Patients should not drive, operate machinery, or do other dangerous activities until feelings of sleepiness from the treatment have completely gone away.

The efficacy of Zulresso was shown in two clinical studies in participants who received a 60-hour continuous intravenous infusion of Zulresso or placebo and were then followed for four weeks. One study included patients with severe PPD and the other included patients with moderate PPD. The primary measure in the study was the mean change from baseline in depressive symptoms as measured by a depression rating scale. In both placebo controlled studies, Zulresso demonstrated superiority to placebo in improvement of depressive symptoms at the end of the first infusion. The improvement in depression was also observed at the end of the 30-day follow-up period.

The most common adverse reactions reported by patients treated with Zulresso in clinical trials include sleepiness, dry mouth, loss of consciousness and flushing. Health care providers should consider changing the therapeutic regimen, including discontinuing Zulresso in patients whose PPD becomes worse or who experience emergent suicidal thoughts and behaviors.

The FDA granted this application Priority Review and Breakthrough Therapydesignation.

Approval of Zulresso was granted to Sage Therapeutics, Inc.

Allopregnanolone, also known as 5α-pregnan-3α-ol-20-one or 3α,5α-tetrahydroprogesterone (3α,5α-THP), as well as brexanolone (USAN),[1] is an endogenous inhibitory pregnane neurosteroid[2] which has been approved by the FDA as a treatment for post-partum depression. It is synthesized from progesterone, and is a potent positive allosteric modulator of the action of γ-aminobutyric acid (GABA) at GABAA receptor.[2] Allopregnanolone has effects similar to those of other positive allosteric modulators of the GABA action at GABAA receptor such as the benzodiazepines, including anxiolyticsedative, and anticonvulsant activity.[2][3][4] Endogenously produced allopregnanolone exerts a pivotal neurophysiological role by fine-tuning of GABAA receptor and modulating the action of several positive allosteric modulators and agonists at GABAA receptor.[5] The 21-hydroxylated derivative of this compound, tetrahydrodeoxycorticosterone (THDOC), is an endogenous inhibitory neurosteroid with similar properties to those of allopregnanolone, and the 3β-methyl analogue of allopregnanolone, ganaxolone, is under development to treat epilepsy and other conditions, including post-traumatic stress disorder (PTSD).[2]

Biochemistry

Biosynthesis

The biosynthesis of allopregnanolone in the brain starts with the conversion of progesterone into 5α-dihydroprogesterone by 5α-reductase type I. After that, 3α-hydroxysteroid dehydrogenase converts this intermediate into allopregnanolone.[2] Allopregnanolone in the brain is produced by cortical and hippocampus pyramidal neurons and pyramidal-like neurons of the basolateral amygdala.[6]

Biological activity

Allopregnanolone acts as a highly potent positive allosteric modulator of the GABAA receptor.[2] While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABAA receptor isoforms, those isoforms containing δ subunitsexhibit the greatest potentiation.[7] Allopregnanolone has also been found to act as a positive allosteric modulator of the GABAA-ρ receptor, though the implications of this action are unclear.[8][9] In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be a negative allosteric modulator of nACh receptors,[10] and also appears to act as a negative allosteric modulator of the 5-HT3 receptor.[11] Along with the other inhibitory neurosteroids, allopregnanolone appears to have little or no action at other ligand-gated ion channels, including the NMDAAMPAkainate, and glycine receptors.[12]

Unlike progesterone, allopregnanolone is inactive at the nuclear progesterone receptor (nPR).[12] However, allopregnanolone can be intracellularly oxidized into 5α-dihydroprogesterone, which is an agonist of the nPR, and thus/in accordance, allopregnanolone does appear to have indirect nPR-mediated progestogenic effects.[13] In addition, allopregnanolone has recently been found to be an agonist of the newly discovered membrane progesterone receptors (mPR), including mPRδmPRα, and mPRβ, with its activity at these receptors about a magnitude more potent than at the GABAA receptor.[14][15] The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective and antigonadotropic properties.[14][16] Also like progesterone, recent evidence has shown that allopregnanolone is an activator of the pregnane X receptor.[12][17]

Similarly to many other GABAA receptor positive allosteric modulators, allopregnanolone has been found to act as an inhibitor of L-type voltage-gated calcium channels (L-VGCCs),[18] including α1 subtypes Cav1.2 and Cav1.3.[19] However, the threshold concentration of allopregnanolone to inhibit L-VGCCs was determined to be 3 μM (3,000 nM), which is far greater than the concentration of 5 nM that has been estimated to be naturally produced in the human brain.[19] Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone.[19] Also, allopregnanolone, along with several other neurosteroids, has been found to activate the G protein-coupled bile acid receptor (GPBAR1, or TGR5).[20] However, it is only able to do so at micromolar concentrations, which, similarly to the case of the L-VGCCs, are far greater than the low nanomolar concentrations of allopregnanolone estimated to be present in the brain.[20]

Biological function

Allopregnanolone possesses a wide variety of effects, including, in no particular order, antidepressantanxiolyticstress-reducingrewarding,[21] prosocial,[22] antiaggressive,[23]prosexual,[22] sedativepro-sleep,[24] cognitivememory-impairmentanalgesic,[25] anestheticanticonvulsantneuroprotective, and neurogenic effects.[2] Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of moodanxietypremenstrual syndromecatamenial epilepsy, and various other neuropsychiatric conditions.[26][27][28]

Increased levels of allopregnanolone can produce paradoxical effects, including negative moodanxietyirritability, and aggression.[29][30][31] This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABAA receptor – moderate level increases (in the range of 1.5–2 nM/L total allopregnanolone, which are approximately equivalent to luteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it.[29][30] This seems to be a common effect of many GABAA receptor positive allosteric modulators.[26][31] In accordance, acute administration of low doses of micronized progesterone (which reliably elevates allopregnanolone levels) has been found to have negative effects on mood, while higher doses have a neutral effect.[32]

During pregnancy, allopregnanolone and pregnanolone are involved in sedation and anesthesia of the fetus.[33][34]

Chemistry

Allopregnanolone is a pregnane (C21) steroid and is also known as 5α-pregnan-3α-ol-20-one, 3α-hydroxy-5α-pregnan-20-one, or 3α,5α-tetrahydroprogesterone (3α,5α-THP). It is very closely related structurally to 5-pregnenolone (pregn-5-en-3β-ol-20-dione), progesterone (pregn-4-ene-3,20-dione), the isomers of pregnanedione (5-dihydroprogesterone; 5-pregnane-3,20-dione), the isomers of 4-pregnenolone (3-dihydroprogesterone; pregn-4-en-3-ol-20-one), and the isomers of pregnanediol (5-pregnane-3,20-diol). In addition, allopregnanolone is one of four isomers of pregnanolone (3,5-tetrahydroprogesterone), with the other three isomers being pregnanolone (5β-pregnan-3α-ol-20-one), isopregnanolone(5α-pregnan-3β-ol-20-one), and epipregnanolone (5β-pregnan-3β-ol-20-one).

Derivatives

A variety of synthetic derivatives and analogues of allopregnanolone with similar activity and effects exist, including alfadolone (3α,21-dihydroxy-5α-pregnane-11,20-dione), alfaxolone (3α-hydroxy-5α-pregnane-11,20-dione), ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), hydroxydione (21-hydroxy-5β-pregnane-3,20-dione), minaxolone (11α-(dimethylamino)-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one), Org 20599 (21-chloro-3α-hydroxy-2β-morpholin-4-yl-5β-pregnan-20-one), Org 21465 (2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-yl methanesulfonate), and renanolone (3α-hydroxy-5β-pregnan-11,20-dione).

Research

Allopregnanolone and the other endogenous inhibitory neurosteroids have short terminal half-lives and poor oral bioavailability, and for these reason, have not been pursued for clinical use as oral therapies, although development as a parenteral therapy for multiple indications has been carried out. However, synthetic analogs with improved pharmacokineticprofiles have been synthesized and are being investigated as potential oral therapeutic agents.

In other studies of compounds related to allopregnanolone, exogenous progesterone, such as oral micronized progesterone (OMP), elevates allopregnanolone levels in the body with good dose-to-serum level correlations.[35] Due to this, it has been suggested that OMP could be described as a prodrug of sorts for allopregnanolone.[35] As a result, there has been some interest in using OMP to treat catamenial epilepsy,[36] as well as other menstrual cycle-related and neurosteroid-associated conditions. In addition to OMP, oral pregnenolonehas also been found to act as a prodrug of allopregnanolone,[37][38][39] though also of pregnenolone sulfate.[40]

Allopregnanolone has been under development by Sage Therapeutics as an intravenously administered drug for the treatment of super-refractory status epilepticuspostpartum depression, and essential tremor.[41] As of 19 March 2019 the FDA has approved allopregnanolone for postpartum depression.

References

  1. ^ “ChemIDplus – 516-54-1 – AURFZBICLPNKBZ-SYBPFIFISA-N – Brexanolone [USAN] – Similar structures search, synonyms, formulas, resource links, and other chemical information”. NIH Toxnet. Retrieved 26 December 2017.
  2. Jump up to:a b c d e f g Reddy DS (2010). Neurosteroids: endogenous role in the human brain and therapeutic potentialsProg. Brain Res. Progress in Brain Research. 186. pp. 113–37. doi:10.1016/B978-0-444-53630-3.00008-7ISBN 9780444536303PMC 3139029PMID 21094889.
  3. ^ Reddy DS, Rogawski MA (2012). “Neurosteroids — Endogenous Regulators of Seizure Susceptibility and Role in the Treatment of Epilepsy”Jasper’s Basic Mechanisms of the Epilepsies, 4th Edition: 984–1002. doi:10.1093/med/9780199746545.003.0077ISBN 9780199746545.
  4. ^ T. G. Kokate, B. E. Svensson & M. A. Rogawski (September 1994). “Anticonvulsant activity of neurosteroids: correlation with γ-aminobutyric acid-evoked chloride current potentiation”. The Journal of Pharmacology and Experimental Therapeutics270 (3): 1223–1229. PMID 7932175.
  5. ^ Pinna, G; Uzunova, V; Matsumoto, K; Puia, G; Mienville, J. -M; Costa, E; Guidotti, A (2000-03-01). “Brain allopregnanolone regulates the potency of the GABAA receptor agonist muscimol”Neuropharmacology39 (3): 440–448. doi:10.1016/S0028-3908(99)00149-5PMID 10698010.
  6. ^ Agís-Balboa, Roberto C.; Pinna, Graziano; Zhubi, Adrian; Maloku, Ekrem; Veldic, Marin; Costa, Erminio; Guidotti, Alessandro (2006-09-26). “Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis”Proceedings of the National Academy of Sciences103 (39): 14602–14607. doi:10.1073/pnas.0606544103ISSN 0027-8424PMC 1600006PMID 16984997.
  7. ^ Mousavi Nik A, Pressly B, Singh V, Antrobus S, Hulsizer S, Rogawski MA, Wulff H, Pessah IN (2017). “Rapid Throughput Analysis of GABAA Receptor Subtype Modulators and Blockers Using DiSBAC1(3) Membrane Potential Red Dye”Mol. Pharmacol92 (1): 88–99. doi:10.1124/mol.117.108563PMC 5452057PMID 28428226.
  8. ^ Morris KD, Moorefield CN, Amin J (October 1999). “Differential modulation of the gamma-aminobutyric acid type C receptor by neuroactive steroids”. Mol. Pharmacol56 (4): 752–9. PMID 10496958.
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  10. ^ Bullock AE, Clark AL, Grady SR, et al. (June 1997). “Neurosteroids modulate nicotinic receptor function in mouse striatal and thalamic synaptosomes”. J. Neurochem68 (6): 2412–23. doi:10.1046/j.1471-4159.1997.68062412.xPMID 9166735.
  11. ^ Wetzel CH, Hermann B, Behl C, et al. (September 1998). “Functional antagonism of gonadal steroids at the 5-hydroxytryptamine type 3 receptor”. Mol. Endocrinol12 (9): 1441–51. doi:10.1210/mend.12.9.0163PMID 9731711.
  12. Jump up to:a b c Mellon SH (October 2007). “Neurosteroid regulation of central nervous system development”Pharmacol. Ther116 (1): 107–24. doi:10.1016/j.pharmthera.2007.04.011PMC 2386997PMID 17651807.
  13. ^ Rupprecht R, Reul JM, Trapp T, et al. (September 1993). “Progesterone receptor-mediated effects of neuroactive steroids”. Neuron11 (3): 523–30. doi:10.1016/0896-6273(93)90156-lPMID 8398145.
  14. Jump up to:a b Thomas P, Pang Y (2012). “Membrane progesterone receptors: evidence for neuroprotective, neurosteroid signaling and neuroendocrine functions in neuronal cells”Neuroendocrinology96 (2): 162–71. doi:10.1159/000339822PMC 3489003PMID 22687885.
  15. ^ Pang Y, Dong J, Thomas P (January 2013). “Characterization, neurosteroid binding and brain distribution of human membrane progesterone receptors δ and {epsilon} (mPRδ and mPR{epsilon}) and mPRδ involvement in neurosteroid inhibition of apoptosis”Endocrinology154 (1): 283–95. doi:10.1210/en.2012-1772PMC 3529379PMID 23161870.
  16. ^ Sleiter N, Pang Y, Park C, et al. (August 2009). “Progesterone receptor A (PRA) and PRB-independent effects of progesterone on gonadotropin-releasing hormone release”Endocrinology150 (8): 3833–44. doi:10.1210/en.2008-0774PMC 2717864PMID 19423765.
  17. ^ Lamba V, Yasuda K, Lamba JK, et al. (September 2004). “PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators”. Toxicol. Appl. Pharmacol199 (3): 251–65. doi:10.1016/j.taap.2003.12.027PMID 15364541.
  18. ^ Hu AQ, Wang ZM, Lan DM, et al. (July 2007). “Inhibition of evoked glutamate release by neurosteroid allopregnanolone via inhibition of L-type calcium channels in rat medial prefrontal cortex”. Neuropsychopharmacology32 (7): 1477–89. doi:10.1038/sj.npp.1301261PMID 17151597.
  19. Jump up to:a b c Earl DE, Tietz EI (April 2011). “Inhibition of recombinant L-type voltage-gated calcium channels by positive allosteric modulators of GABAA receptors”J. Pharmacol. Exp. Ther337 (1): 301–11. doi:10.1124/jpet.110.178244PMC 3063747PMID 21262851.
  20. Jump up to:a b Keitel V, Görg B, Bidmon HJ, et al. (November 2010). “The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain”. Glia58 (15): 1794–805. doi:10.1002/glia.21049PMID 20665558.
  21. ^ Rougé-Pont F, Mayo W, Marinelli M, Gingras M, Le Moal M, Piazza PV (July 2002). “The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens”. Eur. J. Neurosci16 (1): 169–73. doi:10.1046/j.1460-9568.2002.02084.xPMID 12153544.
  22. Jump up to:a b Frye CA (December 2009). “Neurosteroids’ effects and mechanisms for social, cognitive, emotional, and physical functions”Psychoneuroendocrinology. 34 Suppl 1: S143–61. doi:10.1016/j.psyneuen.2009.07.005PMC 2898141PMID 19656632.
  23. ^ Pinna G, Costa E, Guidotti A (February 2005). “Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior”Proc. Natl. Acad. Sci. U.S.A102 (6): 2135–40. doi:10.1073/pnas.0409643102PMC 548579PMID 15677716.
  24. ^ Terán-Pérez G, Arana-Lechuga Y, Esqueda-León E, Santana-Miranda R, Rojas-Zamorano JÁ, Velázquez Moctezuma J (October 2012). “Steroid hormones and sleep regulation”Mini Rev Med Chem12 (11): 1040–8. doi:10.2174/138955712802762167PMID 23092405.
  25. ^ Patte-Mensah C, Meyer L, Taleb O, Mensah-Nyagan AG (February 2014). “Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain”. Prog. Neurobiol113: 70–8. doi:10.1016/j.pneurobio.2013.07.004PMID 23948490.
  26. Jump up to:a b Bäckström T, Andersson A, Andreé L, et al. (December 2003). “Pathogenesis in menstrual cycle-linked CNS disorders”. Ann. N. Y. Acad. Sci1007: 42–53. doi:10.1196/annals.1286.005PMID 14993039.
  27. ^ Guille C, Spencer S, Cavus I, Epperson CN (July 2008). “The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: implications for diagnosis and treatment”Epilepsy Behav13 (1): 12–24. doi:10.1016/j.yebeh.2008.02.004PMC 4112568PMID 18346939.
  28. ^ Finocchi C, Ferrari M (May 2011). “Female reproductive steroids and neuronal excitability”. Neurol. Sci. 32 Suppl 1: S31–5. doi:10.1007/s10072-011-0532-5PMID 21533709.
  29. Jump up to:a b Bäckström T, Haage D, Löfgren M, et al. (September 2011). “Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons”. Neuroscience191: 46–54. doi:10.1016/j.neuroscience.2011.03.061PMID 21600269.
  30. Jump up to:a b Andréen L, Nyberg S, Turkmen S, van Wingen G, Fernández G, Bäckström T (September 2009). “Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators”. Psychoneuroendocrinology34 (8): 1121–32. doi:10.1016/j.psyneuen.2009.02.003PMID 19272715.
  31. Jump up to:a b Bäckström T, Bixo M, Johansson M, et al. (February 2014). “Allopregnanolone and mood disorders”. Prog. Neurobiol113: 88–94. doi:10.1016/j.pneurobio.2013.07.005PMID 23978486.
  32. ^ Andréen L, Sundström-Poromaa I, Bixo M, Nyberg S, Bäckström T (August 2006). “Allopregnanolone concentration and mood–a bimodal association in postmenopausal women treated with oral progesterone”. Psychopharmacology187 (2): 209–21. doi:10.1007/s00213-006-0417-0PMID 16724185.
  33. ^ Mellor DJ, Diesch TJ, Gunn AJ, Bennet L (2005). “The importance of ‘awareness’ for understanding fetal pain”. Brain Res. Brain Res. Rev49 (3): 455–71. doi:10.1016/j.brainresrev.2005.01.006PMID 16269314.
  34. ^ Lagercrantz H, Changeux JP (2009). “The emergence of human consciousness: from fetal to neonatal life”Pediatr. Res65 (3): 255–60. doi:10.1203/PDR.0b013e3181973b0dPMID 19092726[…] the fetus is sedated by the low oxygen tension of the fetal blood and the neurosteroid anesthetics pregnanolone and the sleep-inducing prostaglandin D2 provided by the placenta (36).
  35. Jump up to:a b Andréen L, Spigset O, Andersson A, Nyberg S, Bäckström T (June 2006). “Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone”. Maturitas54 (3): 238–44. doi:10.1016/j.maturitas.2005.11.005PMID 16406399.
  36. ^ Orrin Devinsky; Steven Schachter; Steven Pacia (1 January 2005). Complementary and Alternative Therapies for Epilepsy. Demos Medical Publishing. pp. 378–. ISBN 978-1-934559-08-6.
  37. ^ Saudan C, Desmarchelier A, Sottas PE, Mangin P, Saugy M (2005). “Urinary marker of oral pregnenolone administration”. Steroids70 (3): 179–83. doi:10.1016/j.steroids.2004.12.007PMID 15763596.
  38. ^ Piper T, Schlug C, Mareck U, Schänzer W (2011). “Investigations on changes in ¹³C/¹²C ratios of endogenous urinary steroids after pregnenolone administration”. Drug Test Anal3(5): 283–90. doi:10.1002/dta.281PMID 21538944.
  39. ^ Sripada RK, Marx CE, King AP, Rampton JC, Ho SS, Liberzon I (2013). “Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits”Biol. Psychiatry73 (11): 1045–53. doi:10.1016/j.biopsych.2012.12.008PMC 3648625PMID 23348009.
  40. ^ Ducharme N, Banks WA, Morley JE, Robinson SM, Niehoff ML, Mattern C, Farr SA (2010). “Brain distribution and behavioral effects of progesterone and pregnenolone after intranasal or intravenous administration”Eur. J. Pharmacol641 (2–3): 128–34. doi:10.1016/j.ejphar.2010.05.033PMC 3008321PMID 20570588.
  41. ^ “Brexanolone – Sage Therapeutics”. AdisInsight.

Further reading

Allopregnanolone
Skeletal formula of allopregnanolone
Ball-and-stick model of the allopregnanolone molecule
Names
IUPAC name

1-(3-Hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone
Other names

ALLO; Allo; ALLOP; AlloP; Brexanolone; 5α-Pregnan-3α-ol-20-one; 3α-Hydroxy-5α-pregnan-20-one; 3α,5α-Tetrahydroprogesterone; 3α,5α-THP; Zulresso
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
UNII
Properties
C21H34O2
Molar mass 318.501 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

//////////Brexanolone, Priority Review, Breakthrough Therapy designation, Zulresso, Sage Therapeutics Inc, FDA 2019, ブレキサノロン , Brexanolone, Allopregnanolone

CC(=O)C1CCC2C1(CCC3C2CCC4C3(CCC(C4)O)C)C

Caplacizumab-yhdp, カプラシズマブ


FDA approves first therapy Cablivi (caplacizumab-yhdp) カプラシズマブ  , for the treatment of adult patients with a rare blood clotting disorder

FDA

February 6, 2019

The U.S. Food and Drug Administration today approved Cablivi (caplacizumab-yhdp) injection, the first therapy specifically indicated, in combination with plasma exchange and immunosuppressive therapy, for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), a rare and life-threatening disorder that causes blood clotting.

“Patients with aTTP endure hours of treatment with daily plasma exchange, which requires being attached to a machine that takes blood out of the body and mixes it with donated plasma and then returns it to the body. Even after days or weeks of this treatment, as well as taking drugs that suppress the immune system, many patients will have a recurrence of aTTP,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Cablivi is the first targeted treatment that inhibits the formation of blood clots. It provides a new treatment option for patients that may reduce recurrences.”

Patients with aTTP develop extensive blood clots in the small blood vessels throughout the body. These clots can cut off oxygen and blood supply to the major organs and cause strokes and heart attacks that may lead to brain damage or death. Patients can develop aTTP because of conditions such as cancer, HIV, pregnancy, lupus or infections, or after having surgery, bone marrow transplantation or chemotherapy.

The efficacy of Cablivi was studied in a clinical trial of 145 patients who were randomized to receive either Cablivi or a placebo. Patients in both groups received the current standard of care of plasma exchange and immunosuppressive therapy. The results of the trial demonstrated that platelet counts improved faster among patients treated with Cablivi, compared to placebo. Treatment with Cablivi also resulted in a lower total number of patients with either aTTP-related death and recurrence of aTTP during the treatment period, or at least one treatment-emergent major thrombotic event (where blood clots form inside a blood vessel and may then break free to travel throughout the body).The proportion of patients with a recurrence of aTTP in the overall study period (the drug treatment period plus a 28-day follow-up period after discontinuation of drug treatment) was lower in the Cablivi group (13 percent) compared to the placebo group (38 percent), a finding that was statistically significant.

Common side effects of Cablivi reported by patients in clinical trials were bleeding of the nose or gums and headache. The prescribing information for Cablivi includes a warning to advise health care providers and patients about the risk of severe bleeding.

Health care providers are advised to monitor patients closely for bleeding when administering Cablivi to patients who currently take anticoagulants.

The FDA granted this application Priority Review designation. Cablivi also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Cablivi to Ablynx.

 EU

Cablivi is the first therapeutic approved in Europe, for the treatment of a rare blood-clotting disorder

On September 03, 2018, the European Commission has granted marketing authorization for Cablivi™ (caplacizumab) for the treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), a rare blood-clotting disorder. Cablivi is the first therapeutic specifically indicated for the treatment of aTTP   1. Cablivi was designated an ‘orphan medicine’ (a medicine used in rare diseases) on April 30, 2009. The approval of Cablivi in the EU is based on the Phase II TITAN and Phase III HERCULES studies in 220 adult patients with aTTP. The efficacy and safety of caplacizumab in addition to standard-of-care treatment, daily PEX and immunosuppression, were demonstrated in these studies. In the HERCULES study, treatment with caplacizumab in addition to standard-of-care resulted in a significantly shorter time to platelet count response (p<0.01), the study’s primary endpoint; a significant reduction in aTTP-related death, recurrence of aTTP, or at least one major thromboembolic event during study drug treatment (p<0.0001); and a significantly lower number of aTTP recurrences in the overall study period (p<0.001). Importantly, treatment with caplacizumab resulted in a clinically meaningful reduction in the use of PEX and length of stay in the intensive care unit (ICU) and the hospital, compared to the placebo group. Cablivi was developed by Ablynx, a Sanofi company. Sanofi Genzyme, the specialty care global business unit of Sanofi, will work with relevant local authorities to make Cablivi available to patients in need in countries across Europe.

About aTTP aTTP is a life-threatening, autoimmune blood clotting disorder characterized by extensive clot formation in small blood vessels throughout the body, leading to severe thrombocytopenia (very low platelet count), microangiopathic hemolytic anemia (loss of red blood cells through destruction), ischemia (restricted blood supply to parts of the body) and widespread organ damage especially in the brain and heart. About Cablivi Caplacizumab blocks the interaction of ultra-large von Willebrand Factor (vWF) multimers with platelets and, therefore, has an immediate effect on platelet adhesion and the ensuing formation and accumulation of the micro-clots that cause the severe thrombocytopenia, tissue ischemia and organ dysfunction in aTTP   2.

Note – Caplacizumab is a bivalent anti-vWF Nanobody that received Orphan Drug Designation in Europe and the United States in 2009, in Switzerland in 2017 and in Japan in 2018. The U.S. Food and Drug Administration (FDA) has accepted for priority review the Biologics License Application for caplacizumab for treatment of adults experiencing an episode of aTTP. The target action date for the FDA decision is February 6, 2019

http://hugin.info/152918/R/2213684/863478.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/004426/WC500255075.pdf

Image result for Caplacizumab

More………….

EVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA ISRTGGSTYY
PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAG VRAEDGRVRT LPSEYTFWGQ
GTQVTVSSAA AEVQLVESGG GLVQPGGSLR LSCAASGRTF SYNPMGWFRQ APGKGRELVA
AISRTGGSTY YPDSVEGRFT ISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR
TLPSEYTFWG QGTQVTVSS
(disulfide bridge: 22-96, 153-227)

Sequence:

1EVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA
51ISRTGGSTYY PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAG
101VRAEDGRVRT LPSEYTFWGQ GTQVTVSSAA AEVQLVESGG GLVQPGGSLR
151LSCAASGRTF SYNPMGWFRQ APGKGRELVA AISRTGGSTY YPDSVEGRFT
201ISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR TLPSEYTFWG
251QGTQVTVSS

EU 2018/8/31 APPROVED, Cablivi

Treatment of thrombotic thrombocytopenic purpura, thrombosis

Immunoglobulin, anti-(human von Willebrand’s blood-coagulation factor VIII domain A1) (human-Lama glama dimeric heavy chain fragment PMP12A2h1)

Other Names

  • 1: PN: WO2011067160 SEQID: 1 claimed protein
  • 98: PN: WO2006122825 SEQID: 98 claimed protein
  • ALX 0081
  • ALX 0681
  • Caplacizumab
FORMULA
C1213H1891N357O380S10
CAS
915810-67-2
MOL WEIGHT
27875.8075

Caplacizumab (ALX-0081) (INN) is a bivalent VHH designed for the treatment of thrombotic thrombocytopenic purpura and thrombosis.[1][2]

This drug was developed by Ablynx NV.[3] On 31 August 2018 it was approved in the European Union for the “treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), in conjunction with plasma exchange and immunosuppression”.[4]

It is an anti-von Willebrand factor humanized immunoglobulin.[5] It acts by blocking platelet aggregation to reduce organ injury due to ischemia.[5] Results of the phase II TITAN trial have been reported.[5]

In February 2019, caplacizumab-yhdp (CABLIVI, Ablynx NV) has been approved by the Food and Drug Administration for treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP). The drug is used in combination with plasma exchange and immunosuppressive therapy. [6]

PATENTS

WO 2006122825

WO 2009115614

WO 2011067160

WO 2011098518

WO 2011162831

WO 2013013228

WO 2014109927

WO 2016012285

WO 2016138034

WO 2016176089

WO 2017180587

WO 2017186928

WO 2018067987

Image result for Caplacizumab

Caplacizumab
Monoclonal antibody
Type Single domain antibody
Source Humanized
Target VWF
Clinical data
Synonyms ALX-0081
ATC code
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C1213H1891N357O380S10
Molar mass 27.88 kg/mol

CLIP

https://www.tandfonline.com/doi/full/10.1080/19420862.2016.1269580

Caplacizumab (ALX-0081) is a humanized single-variable-domain immunoglobulin (Nanobody) that targets von Willebrand factor, and thereby inhibits the interaction between von Willebrand factor multimers and platelets. In a Phase 2 study (NCT01151423) of 75 patients with acquired thrombotic thrombocytopenic purpura who received SC caplacizumab (10 mg daily) or placebo during plasma exchange and for 30 d afterward, the time to a response was significantly reduced with caplacizumab compared with placebo (39% reduction in median time, P = 0.005).39Peyvandi FScully MKremer Hovinga JACataland SKnöbl PWu HArtoni AWestwood JPMansouri Taleghani MJilma B, et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med 2016; 374(6):51122; PMID:26863353; http://dx.doi.org/10.1056/NEJMoa1505533[Crossref][PubMed][Web of Science ®][Google Scholar] The double-blind, placebo-controlled, randomized Phase 3 HERCULES study (NCT02553317) study will evaluate the efficacy and safety of caplacizumab treatment in more rapidly curtailing ongoing microvascular thrombosis when administered in addition to standard of care treatment in subjects with an acute episode of acquired thrombotic thrombocytopenic purpura. Patients will receive an initial IV dose of either caplacizumab or placebo followed by daily SC injections for a maximum period of 6 months. The primary outcome measure is the time to platelet count response. The estimated enrollment is 92 patients, and the estimated primary completion date of the study is October 2017. A Phase 3 follow-up study (NCT02878603) for patients who completed the HERCULES study is planned.

References

///////////////caplacizumab, Cablivi,  Ablynx, Priority Review, Orphan Drug designation,  fda 2019, eu 2018, Caplacizumab, nti-vWF Nanobody, Orphan Drug Designation, aTTP, Cablivi, Ablynx, Sanofi , ALX-0081, カプラシズマブ  , PEPTIDE, ALX 0081

FDA approves first treatment Firdapse (amifampridine) for Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder


 

FDA approves first treatment Firdapse (amifampridine) for Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder

The U.S. Food and Drug Administration today approved Firdapse (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults. LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. This is the first FDA approval of a treatment for LEMS.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/UCM627093.htm?utm_campaign=11282018_PR_FDA%20approves%20treatment%20for%20LEMS&utm_medium=email&utm_source=Eloqua

 

November 28, 2018

Release

The U.S. Food and Drug Administration today approved Firdapse (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults. LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. This is the first FDA approval of a treatment for LEMS.

“There has been a long-standing need for a treatment for this rare disorder,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “Patients with LEMS have significant weakness and fatigue that can often cause great difficulties with daily activities.”

In people with LEMS, the body’s own immune system attacks the neuromuscular junction (the connection between nerves and muscles) and disrupts the ability of nerve cells to send signals to muscle cells. LEMS may be associated with other autoimmune diseases, but more commonly occurs in patients with cancer such as small cell lung cancer, where its onset precedes or coincides with the diagnosis of cancer. The prevalence of LEMS is estimated to be three per million individuals worldwide.

The efficacy of Firdapse was studied in two clinical trials that together included 64 adult patients who received Firdapse or placebo. The studies measured the Quantitative Myasthenia Gravis score (a 13-item physician-rated categorical scale assessing muscle weakness) and the Subject Global Impression (a seven-point scale on which patients rated their overall impression of the effects of the study treatment on their physical well-being). For both measures, the patients receiving Firdapse experienced a greater benefit than those on placebo.

The most common side effects experienced by patients in the clinical trials were burning or prickling sensation (paresthesia), upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, elevated liver enzymes, back pain, hypertension and muscle spasms. Seizures have been observed in patients without a history of seizures. Patients should inform their health care provider immediately if they have signs of hypersensitivity reactions such as rash, hives, itching, fever, swelling or trouble breathing.

The FDA granted this application Priority Review and Breakthrough Therapydesignations. Firdapse also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Firdapse to Catalyst Pharmaceuticals, Inc.

///////////Priority Review,  Breakthrough Therapy,  Firdapse,  Orphan Drug designation, fda 2018, amifampridine

FDA approves new treatment for patients with acute myeloid leukemia


FDA approves new treatment Daurismo (glasdegib) for patients with acute myeloid leukemia 
The U.S. Food and Drug Administration today approved Daurismo (glasdegib) tablets to be used in combination with low-dose cytarabine (LDAC), a type of chemotherapy, for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are 75 years of age or older or who have other chronic health conditions or diseases (comorbidities) that may preclude the use of intensive chemotherapy.
“Intensive chemotherapy is usually used to control AML, but many adults with AML are unable to have intensive chemotherapy because of its toxicities. Today’s approval gives health care providers another tool to use in the treatment of AML patients with various, unique needs. Clinical trials showed that  ..

November 21, 2018

Release

The U.S. Food and Drug Administration today approved Daurismo (glasdegib) tablets to be used in combination with low-dose cytarabine (LDAC), a type of chemotherapy, for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are 75 years of age or older or who have other chronic health conditions or diseases (comorbidities) that may preclude the use of intensive chemotherapy.

“Intensive chemotherapy is usually used to control AML, but many adults with AML are unable to have intensive chemotherapy because of its toxicities. Today’s approval gives health care providers another tool to use in the treatment of AML patients with various, unique needs. Clinical trials showed that overall survival was improved using Daurismo in combination with LDAC compared to LDAC alone for patients who would not tolerate intensive chemotherapy,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of abnormal white blood cells in the bloodstream and bone marrow. The National Cancer Institute at the National Institutes of Health estimates that in 2018, approximately 19,520 people will be diagnosed with AML and approximately 10,670 patients with AML will die of the disease. Almost half of the adults diagnosed with AML are not treated with intensive chemotherapy because of comorbidities and chemotherapy related toxicities.

The efficacy of Daurismo was studied in a randomized clinical trial in which 111 adult patients with newly diagnosed AML were treated with either Daurismo in combination with LDAC or LDAC alone. The trial measured overall survival (OS) from the date of randomization to death from any cause. Results demonstrated a significant improvement in OS in patients treated with Daurismo. The median OS was 8.3 months for patients treated with Daurismo plus LDAC compared with 4.3 months for patients treated with LDAC only.

Common side effects reported by patients receiving Daurismo in clinical trials include low red blood cell count (anemia), tiredness (fatigue), bleeding (hemorrhage), fever with low white blood cell count (febrile neutropenia), muscle pain, nausea, swelling of the arms or legs (edema), low platelet counts (thrombocytopenia), shortness of breath (dyspnea), decreased appetite, distorted taste (dysgeusia), pain or sores in the mouth or throat (mucositis), constipation and rash.

The prescribing information for Daurismo includes a Boxed Warning to advise health care professionals and patients about the risk of embryo-fetal death or severe birth defects. Daurismo should not be used during pregnancy or while breastfeeding. Pregnancy testing should be conducted in females of reproductive age prior to initiation of Daurismo treatment and effective contraception should be used during treatment and for at least 30 days after the last dose. The Boxed Warning also advises male patients of the potential risk of drug exposure through semen and to use condoms with a pregnant partner or a female partner that could become pregnant both during treatment and for at least 30 days after the last dose. Daurismo must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. Patients should also be advised not to donate blood or blood products during treatment. Health care providers should also monitor patients for changes in the electrical activity of the heart, called QT prolongation.

The FDA granted this application Priority Review designation. Daurismo also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Daurismo to Pfizer.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm626443.htm?utm_campaign=112118_PR_FDA%20approves%20new%20treatment%20for%20patients%20with%20acute%20myeloid%20leukemia&utm_medium=email&utm_source=Eloqua

//////////////Daurismo, glasdegib, fda 2018, Priority Review, Orphan Drug 

FDA approves new drug Aemcolo (rifamycin), to treat travelers’ diarrhea


FDA approves new drug to treat travelers’ diarrhea
The U.S. Food and Drug Administration today approved Aemcolo (rifamycin), an antibacterial drug indicated for the treatment of adult patients with travelers’ diarrhea caused by noninvasive strains of Escherichia coli (E. coli), not complicated by fever or blood in the stool.
“Travelers’ diarrhea affects millions of people each year and having treatment options for this condition can help reduce symptoms of the condition,” said Edward Cox, M.D., M.P.H., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.
Travelers’ diarrhea is the most common travel-related illness, affecting an estimated 10 to 40 percent of travelers worldwide each year. Travelers’ diarrhea is defined by …

November 16, 2018

Release

The U.S. Food and Drug Administration today approved Aemcolo (rifamycin), an antibacterial drug indicated for the treatment of adult patients with travelers’ diarrhea caused by noninvasive strains of Escherichia coli (E. coli), not complicated by fever or blood in the stool.

“Travelers’ diarrhea affects millions of people each year and having treatment options for this condition can help reduce symptoms of the condition,” said Edward Cox, M.D., M.P.H., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Travelers’ diarrhea is the most common travel-related illness, affecting an estimated 10 to 40 percent of travelers worldwide each year. Travelers’ diarrhea is defined by having three or more unformed stools in 24 hours, in a person who is traveling. It is caused by a variety of pathogens, but most commonly bacteria found in food and water. The highest-risk destinations are in most of Asia as well as the Middle East, Africa, Mexico, and Central and South America.

The efficacy of Aemcolo was demonstrated in a randomized, placebo-controlled clinical trial in 264 adults with travelers’ diarrhea in Guatemala and Mexico. It showed that Aemcolo significantly reduced symptoms of travelers’ diarrhea compared to the placebo.

The safety of Aemcolo, taken orally over three or four days, was evaluated in 619 adults with travelers’ diarrhea in two controlled clinical trials. The most common adverse reactions with Aemcolo were headache and constipation.

Aemcolo was not shown to be effective in patients with diarrhea complicated by fever and/or bloody stool or diarrhea due to pathogens other than noninvasive strains of E. coli and is not recommended for use in such patients. Aemcolo should not be used in patients with a known hypersensitivity to rifamycin, any of the other rifamycin class antimicrobial agents (e.g. rifaximin), or any of the components in Aemcolo.

The FDA granted Aemcolo a Qualified Infectious Disease Product (QIDP)designation. QIDP designation is given to antibacterial and antifungal drug products that treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. As part of QIDP designation, the Aemcolo marketing application was granted Priority Review under which the FDA’s goal is to take action on an application within an expedited time frame.

The FDA granted approval of Aemcolo to Cosmo Technologies, Ltd.

///////////////// Aemcolo, rifamycin, fda 2018, qidp, priority review

USFDA approval to Lumoxiti (moxetumomab pasudotoxtdfk) a new treatment for hairy cell leukemia


Image result for moxetumomab pasudotox tdfk

USFDA approval to Lumoxiti is a new treatment for hairy cell leukemia

On September 13, 2018, the U.S. Food and Drug Administration approved Lumoxiti (moxetumomab pasudotoxtdfk) injection for intravenous use for the treatment of adult patients with relapsed or refractory Hairy Cell Leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog 1. Lumoxiti is a CD22-directed cytotoxin and is the first of this type of treatment for patients with HCL. The efficacy of Lumoxiti was studied in a single-arm, open-label clinical trial of 80 patients who had received prior treatment for HCL with at least two systemic therapies, including a purine nucleoside analog. The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR. Thirty percent of patients in the trial achieved durable CR, and the overall response rate (number of patients with partial or complete response to therapy) was 75 percent. The FDA granted this application Fast Track and Priority Review designations. Lumoxiti also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The FDA granted the approval of Lumoxiti to AstraZeneca Pharmaceuticals. About Hairy Cell Leukemia HCL is a rare, slow-growing cancer of the blood in which the bone marrow makes too many B cells (lymphocytes), a type of white blood cells that fight infection. HCL is named after these extra B cells which look “hairy” when viewed under a microscope. As the number of leukemia cells increases, fewer healthy white blood cells, red blood cells and platelets are produced.

About Lumoxiti2 Lumoxiti (moxetumomab pasudotox) is a CD22-directed cytotoxin and a first-in-class treatment in the US for adult patients with relapsed or refractory hairy cell leukaemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Lumoxiti is not recommended in patients with severe renal impairment (CrCl ≤ 29 mL/min). It comprises the CD22 binding portion of an antibody fused to a truncated bacterial toxin; the toxin inhibits protein synthesis and ultimately triggers apoptotic cell death.

September 13, 2018

Release

The U.S. Food and Drug Administration today approved Lumoxiti (moxetumomab pasudotox-tdfk) injection for intravenous use for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Lumoxiti is a CD22-directed cytotoxin and is the first of this type of treatment for patients with HCL.

“Lumoxiti fills an unmet need for patients with hairy cell leukemia whose disease has progressed after trying other FDA-approved therapies,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This therapy is the result of important research conducted by the National Cancer Institute that led to the development and clinical trials of this new type of treatment for patients with this rare blood cancer.”

HCL is a rare, slow-growing cancer of the blood in which the bone marrow makes too many B cells (lymphocytes), a type of white blood cell that fights infection. HCL is named after these extra B cells which look “hairy” when viewed under a microscope. As the number of leukemia cells increases, fewer healthy white blood cells, red blood cells and platelets are produced.

The efficacy of Lumoxiti was studied in a single-arm, open-label clinical trial of 80 patients who had received prior treatment for HCL with at least two systemic therapies, including a purine nucleoside analog. The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR. Thirty percent of patients in the trial achieved durable CR, and the overall response rate (number of patients with partial or complete response to therapy) was 75 percent.

Common side effects of Lumoxiti include infusion-related reactions, swelling caused by excess fluid in body tissue (edema), nausea, fatigue, headache, fever (pyrexia), constipation, anemia and diarrhea.

The prescribing information for Lumoxiti includes a Boxed Warning to advise health care professionals and patients about the risk of developing capillary leak syndrome, a condition in which fluid and proteins leak out of tiny blood vessels into surrounding tissues. Symptoms of capillary leak syndrome include difficulty breathing, weight gain, hypotension, or swelling of arms, legs and/or face. The Boxed Warning also notes the risk of hemolytic uremic syndrome, a condition caused by the abnormal destruction of red blood cells. Patients should be made aware of the importance of maintaining adequate fluid intake, and blood chemistry values should be monitored frequently. Other serious warnings include: decreased renal function, infusion-related reactions and electrolyte abnormalities. Women who are breastfeeding should not be given Lumoxiti.

The FDA granted this application Fast Track and Priority Review designations. Lumoxiti also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Lumoxiti to AstraZeneca Pharmaceuticals.

1 https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm620448.htm

2 https://www.astrazeneca.com/media-centre/press-releases/2018/us-fda-approves-lumoxiti-moxetumomab-pasudotox-tdfk-for-certain-patientswith-relapsed-or-refractory-hairy-cell-leukaemia.html

/////////// Lumoxiti, moxetumomab pasudotoxtdfk, FDA 2018, Fast Track,  Priority Review ,  Orphan Drug, AstraZeneca

FDA approves first treatment Libtayo (cemiplimab-rwlc) for advanced form of the second most common skin cancer


FDA approves first treatment for advanced form of the second most common skin cancer

New drug targets PD-1 pathway

The U.S. Food and Drug Administration today approved Libtayo (cemiplimab-rwlc) injection for intravenous use for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. This is the first FDA approval of a drug specifically for advanced CSCC.

September 28, 2018

Release

The U.S. Food and Drug Administration today approved Libtayo (cemiplimab-rwlc) injection for intravenous use for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. This is the first FDA approval of a drug specifically for advanced CSCC.

Libtayo works by targeting the cellular pathway known as PD-1 (protein found on the body’s immune cells and some cancer cells). By blocking this pathway, the drug may help the body’s immune system fight the cancer cells.

“We’re continuing to see a shift in oncology toward identifying and developing drugs aimed at a specific molecular target. With the Libtayo approval, the FDA has approved six immune checkpoint inhibitors targeting the the PD-1 / PD-L1 pathway for treating a variety of tumors, from bladder to head and neck cancer, and now advanced CSCC,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This type of cancer can be difficult to treat effectively when it is advanced and it is important that we continue to bring new treatment options to patients.”

CSCC is the second most common human cancer in the United States with an estimated annual incidence of approximately 700,000 cases. The most common form of skin cancer is basal cell cancer. Squamous cells are thin, flat cells that look like fish scales and are found in the tissue that forms the surface of the skin. CSCC usually develops in skin areas that have been regularly exposed to the sun or other forms of ultraviolet radiation. While the majority of patients with CSCC are cured with surgical resection, a small percentage of patients will develop advanced disease that no longer responds to local treatments including surgery and radiation. Advanced CSCC may cause disfigurement at the site of the tumor and local complications such as bleeding or infection, or it may spread (metastasize) to local lymph nodes, distant tissues and organs and become life-threatening.

The safety and efficacy of Libtayo was studied in two open label clinical trials. A total of 108 patients (75 with metastatic disease and 33 with locally-advanced disease) were included in the efficacy evaluation. The study’s primary endpoint was objective response rate, or the percentage of patients who experienced partial shrinkage or complete disappearance of their tumor(s) after treatment. Results showed that 47.2 percent of all patients treated with Libtayo had their tumors shrink or disappear. The majority of these patients had ongoing responses at the time of data analysis.

Common side effects of Libtayo include fatigue, rash and diarrhea. Libtayo must be dispensed with a patient Medication Guide that describes uses of the drug and its serious warnings. Libtayo can cause the immune system to attack normal organs and tissues in any area of the body and can affect the way they work. These reactions can sometimes become severe or life-threatening and can lead to death. These reactions include the risk of immune-mediated adverse reactions including lung problems (pneumonitis), intestinal problems (colitis), liver problems (hepatitis), hormone gland problems (endocrinopathies), skin (dermatologic) problems and kidney problems. Patients should also be monitored for infusion-related reactions.

Libtayo can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception.

The FDA granted this application Breakthrough Therapy and Priority Reviewdesignations.

The FDA granted the approval of Libtayo to Regeneron Pharmaceuticals, Inc.

////////////Libtayo, cemiplimab-rwlc, FDA 2018,  Breakthrough Therapy,  Priority Review
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