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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 AFRICURE PHARMA, ROW2TECH, CLEANCHEM LABS as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 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, 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 32 PLUS year tenure till date Feb 2023, 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 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, 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 38 lakh plus views on New Drug Approvals Blog in 227 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 He has total of 32 International and Indian awards

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FDA approves novel treatment Oxbryta (voxelotor) to target abnormality in sickle cell disease

November 26, 2019 11:00 am / Leave a comment


Today, the U.S. Food and Drug Administration granted accelerated approval to Oxbryta (voxelotor) for the treatment of sickle cell disease (SCD) in adults and pediatric patients 12 years of age and older.
“Today’s approval provides additional hope to the 100,000 people in the U.S., and the more than 20 million globally, who live with this debilitating blood disorder,” said Acting FDA Commissioner Adm. Brett P. Giroir, M.D. “Our scientific investments have brought us to a point where we have many more tools available in the battle against sickle cell disease, which presents daily challenges for those living with it. We remain committed to raising the profile of this disease as a public health priority and to approving new therapies that are proven to be safe and effective. Together with improved provider education, patient empowerment, and improved care delivery systems, these newly approved drugs have the potential to immediately impact people living with SCD.”

Sickle cell disease is a lifelong, inherited blood disorder in which red blood cells are abnormally shaped (in a crescent, or “sickle” shape), which restricts the flow in blood vessels and limits oxygen delivery to the body’s tissues, leading to severe pain and organ damage. It is also characterized by severe and chronic inflammation that worsens vaso-occlusive crises during which patients experience episodes of extreme pain and organ damage. Nonclinical studies have demonstrated that Oxbryta inhibits red blood cell sickling, improves red blood cell deformability (ability of a red blood cell to change shape) and improves the blood’s ability to flow.

“Oxbryta is an inhibitor of deoxygenated sickle hemoglobin polymerization, which is the central abnormality in sickle cell disease,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “With Oxbryta, sickle cells are less likely to bind together and form the sickle shape, which can cause low hemoglobin levels due to red blood cell destruction. This therapy provides a new treatment option for patients with this serious and life-threatening condition.”

Oxbryta’s approval was based on the results of a clinical trial with 274 patients with sickle cell disease. In the study, 90 patients received 1500 mg of Oxbryta, 92 patients received 900 mg of Oxbryta and 92 patients received a placebo. Effectiveness was based on an increase in hemoglobin response rate in patients who received 1500 mg of Oxbryta, which was 51.1% for these patients compared to 6.5% in the placebo group.

Common side effects for patients taking Oxbryta were headache, diarrhea, abdominal pain, nausea, fatigue, rash and pyrexia (fever).
Oxbryta was granted Accelerated Approval, which enables the FDA to approve drugs for serious conditions to fill an unmet medical need based on a result that is reasonably likely to predict a clinical benefit to patients. Further clinical trials are required to verify and describe Oxbryta’s clinical benefit.
The FDA granted this application Fast Track designation. Oxbryta 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 Oxbryta to Global Blood Therapeutics.

/////////fda 2019, Fast Track designation,  Oxbryta, Orphan Drug designation, voxelotor, Global Blood Therapeutics, sickle cell disease

http://s2027422842.t.en25.com/e/es?s=2027422842&e=279688&elqTrackId=376c7bc788024cd5a73d955f2e3dcbdc&elq=28d3a5d8573843f29b6ae4275802f1c8&elqaid=10429&elqat=1

FDA approves new treatment XCOPRI (cenobamate tablets) for adults with partial-onset seizures

November 22, 2019 1:26 pm / Leave a comment


The U.S. Food and Drug Administration today approved XCOPRI (cenobamate tablets) to treat partial-onset seizures in adults.
“XCOPRI is a new option to treat adults with partial-onset seizures, which is an often difficult-to-control condition that can have a significant impact on patient quality of life,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “Patients can have different responses to the various seizure medicines that are available. This approval provides an additional needed treatment option for people with this condition.”
A seizure is a usually short episode of abnormal electrical activity in the brain. Seizures can cause uncontrolled movements,  abnormal thinking or behavior, and abnormal sensations. Movements can be violent, and changes in consciousness can occur. Seizures occur when clusters of nerve cells (neurons) in the brain undergo uncontrolled activation. A partial-onset seizure begins in a limited area of the brain.
The safety and efficacy of XCOPRI to treat partial-onset seizures was established in two randomized, double-blind, placebo-controlled studies that enrolled 655 adults. In these studies, patients had partial-onset seizures with or without secondary generalization for an average of approximately 24 years and median seizure frequency of 8.5 seizures per 28 days during an 8-week baseline period. During the trials, doses of 100, 200, and 400 milligrams (mg) daily of XCOPRI reduced the percent of seizures per 28 days compared with the placebo group. The recommended maintenance dose of XCOPRI, following a titration (medication adjustment) period, is 200 mg daily; however, some patients may need an additional titration to 400 mg daily, the maximum recommended dose, based on their clinical response and tolerability.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported among patients taking XCOPRI. In the clinical trials, some patients experienced DRESS, and one patient died, when XCOPRI was titrated rapidly (weekly or faster titration). No cases of DRESS were reported in an open-label safety study of 1,339 epilepsy patients when XCOPRI was started at 12.5 mg per day and adjusted every two weeks; however, this finding does not show that the risk of DRESS is prevented by a slower titration. A higher percentage of patients who took XCOPRI also had a shortening of the QT interval (an assessment of certain electrical properties of the heart) of greater than twenty milliseconds compared to placebo. XCOPRI should not be used in patients with hypersensitivity to cenobamate or any of the inactive ingredients in XCOPRI or Familial Short QT syndrome. QT shortening can be associated with ventricular fibrillation, a serious heart rhythm problem.
Antiepileptic drugs (AEDs), including XCOPRI, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients taking an AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. XCOPRI may cause neurological adverse reactions, including somnolence (sleepiness) and fatigue, dizziness, trouble with walking and coordination, trouble with thinking, and visual changes. Patients should also be advised not to drive or operate machinery until the effect of XCOPRI is known.
The most common side effects that patients in the clinical trials reported were somnolence (sleepiness), dizziness, fatigue, diplopia (double vision), and headaches.
The FDA granted the approval of XCOPRI to SK Life Science Inc.
////////fda 2019, XCOPRI, cenobamate, SK Life Science

FDA approves first treatment Givlaari (givosiran) for inherited rare disease

November 21, 2019 10:47 am / Leave a comment


Today, the U.S. Food and Drug Administration granted approval to Givlaari (givosiran) for the treatment of adult patients with acute hepatic porphyria, a genetic disorder resulting in the buildup of toxic porphyrin molecules which are formed during the production of heme (which helps bind oxygen in the blood).
“This buildup can cause acute attacks, known as porphyria attacks, which can lead to severe pain and paralysis, respiratory failure, seizures and mental status changes. These attacks occur suddenly and can produce permanent neurological damage and death,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “Prior to today’s approval, treatment options have only provided partial relief from the intense unremitting pain that characterizes these attacks. The drug approved today can treat this disease by helping to reduce the number of attacks that disrupt the lives of patients.”
The approval of Givlaari was based on the results of a clinical trial of 94 patients with acute hepatic porphyria. Patients received a placebo or Givlaari. Givlaari’s performance was measured by the rate of porphyria attacks that required hospitalizations, urgent health care visits or intravenous infusion of hemin at home. Patients who received Givlaari experienced 70% fewer porphyria attacks compared to patients receiving a placebo.
Common side effects for patients taking Givlaari were nausea and injection site reactions. Health care professionals are advised to monitor patients for anaphylactic (allergic) reaction and renal (kidney) function. Patients should have their liver function tested before and periodically during treatment.
The FDA granted this application Breakthrough Therapy designation and Priority Review designation. Givlaari 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 Givlaari to Alnylam Pharmaceuticals.

http://s2027422842.t.en25.com/e/es?s=2027422842&e=277662&elqTrackId=376c7bc788024cd5a73d955f2e3dcbdc&elq=d02d631b3809408d94ccf3f5bec31dbd&elqaid=10358&elqat=1

///////////Givlaari, givosiran, fda 2019, Breakthrough Therapy designation,  Priority Review, Orphan Drug

Blarcamesine, ブラルカメシン ,

November 1, 2019 9:24 am / Leave a comment


Thumb

Anavex-2-73.png

Blarcamesine

ブラルカメシン;

[(2,2-diphenyloxolan-3-yl)methyl]dimethylamine

  • Anavex 2-73
  • Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanemethanamine
  • THD-DP-FM
  • AE-37 / AE37 / ANAVEX 2-73 FREE BASE
  • UNII 9T210MMZ3F
Formula
C19H23NO
Cas
195615-83-9
195615-84-0 HCL
Mol weight
281.392

Treatment of Rett syndrome, Investigated for use/treatment in breast cancer.

Anti-amnesic, Muscarinic/sigma receptor agonist

  • Originator Anavex Life Sciences
  • Developer ABX-CRO; Anavex Life Sciences; The Michael J. Fox Foundation for Parkinsons Research
  • Class Antidementias; Antidepressants; Antiepileptic drugs; Antiparkinsonians; Anxiolytics; Behavioural disorder therapies; Dimethylamines; Furans; Neuroprotectants; Neuropsychotherapeutics; Nootropics; Small molecules
  • Mechanism of Action Muscarinic receptor modulators; Sigma-1 receptor agonists
  • Orphan Drug Status Yes – Epilepsy; Rett syndrome
  • Phase II/III Alzheimer’s disease
  • Phase II Parkinson’s disease; Rett syndrome
  • Preclinical Amyotrophic lateral sclerosis; Angelman syndrome; Anxiety disorders; Autistic disorder; Fragile X syndrome; Multiple sclerosis
  • No development reported Cognition disorders; Epilepsy; Stroke
  • 28 Oct 2019 No recent reports of development identified for phase-I development in Cognition-disorders in USA
  • 09 Oct 2019 Anavex Life Sciences initiates enrolment in the long term extension ATTENTION-AD trial for Alzheimer’s disease in (country/ies)
  • 02 Oct 2019 Anavex Life Sciences has patent protection covering compositions of matter and methods of treating Alzheimer’s disease for blarcamesine in USA
  • Anavex Life Sciences is developing ANAVEX-2-73 and its active metabolite ANAVEX-19-144, for treating Alzheimer’s disease, epilepsy, stroke and Rett syndrome.

ANAVEX2-73 is an experimental drug is in Phase II trials for Alzheimer’s disease, phase I trials for epilepsy, and in preclinical trials for amyotrophic lateral sclerosis, Parkinson’s disease, Rett syndrome, stroke.[1][2] ANAVEX2-73 acts as a muscarinic receptor and a moderate sigma1 receptor agonist.[1] ANAVEX2-73 may function as a pro-drug for ANAVEX19-144 as well as a drug itself. ANAVEX19-144 is the active metabolite of ANAVEX 1-41, which is similar to ANAVEX2-73 but it is not as selective for sigma receptor.[2]

Properties and uses

ANAVEX2-73 has an inhibitory constant (ki) lower than 500 nM for all M1–M4 muscarinic acetylcholine receptor subtypes, demonstrating that it acts as a powerful antimuscarinic compound.[2] ANAVEX2-73 was originally tested in mice against the effect of the muscarinic receptor antagonist scopolamine, which induces learning impairment.[1] M1 receptor agonists are known to reverse the amnesia caused by scopolamine.[3] Scopolamine is used in the treatment of Parkinson’s disease and motion sickness by reducing the secretions of the stomach and intestines and can also decreases nerve signals to the stomach.[3] This is via competitive inhibition of muscarinic receptors.[3] Muscarinic receptors are involved in the formation of both short term and long term memories.[1] Experiments in mice have found that M1 and M3 receptor agonists inhibit the formation of amyloid-beta and target GSK-3B.[clarification needed]Furthermore, stimulation of the M1 receptor activates AF267B, which in turn blocks β-secretase, which cleaves the amyloid precursor protein to produce the amyloid-beta peptide. These amyloid-beta peptides aggregate together to form plaques. This enzyme[clarification needed] is involved in the formation of Tau plaques, which are common in Alzheimer’s disease.[clarification needed][4]Therefore. M1 receptor activation appears to decreases tau hyperphosphorylation and amyloid-beta accumulation.[4]

Sigma1 activation appears to be only involved in long-term memory processes. This partly explains why ANAVEX2-73 seems to be more effective in reversing scopolamine-induced long-term memory problems compared to short-term memory deficits.[1] The sigma-1 receptor is located on mitochondria-associated endoplasmic reticulum membranes and modulates the ER stress response and local calcium exchanges with the mitochondria. ANAVEX2-73 prevented Aβ25-35-induced increases in lipid peroxidation levels, Bax/Bcl-2ratio and cytochrome c release into the cytosol, which are indicative of elevated toxicity.[clarification needed] ANAVEX2-73 inhibits mitochondrial respiratory dysfunction and therefore prevents against oxidative stress and apoptosis. This drug prevented the appearance of oxidative stress. ANAVEX2-73 also exhibits anti-apoptotic and anti-oxidant activity. This is due in part because sigma-1 agonists stimulate the anti-apoptoic factor Bcl-2 due to reactive oxygen species dependent transcriptional activation of nuclear factor kB.[5] Results from Marice (2016) demonstrate that sigma1 compounds offer a protective potential, both alone and possibly with other agents like donepezil, an acetylcholinesterase inhibitor, or the memantine, a NMDA receptor antagonist.[6]

PATENT

WO9730983

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019200345&tab=PCTDESCRIPTION&_cid=P10-K2E5QZ-30663-1

Novel crystalline forms of A2-73 (blarcamesine hydrochloride, ANAVEX2-73, AV2-73), a mixed muscarinic receptor ligand and Sig-1 R agonist useful for treating Alzheimer’s disease.

PATENT

WO2017013498

SYN

By Foscolos, George B. et alFrom Farmaco, 51(1), 19-26; 1996

References

  1. ^ Jump up to:a b c d e “Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma” (PDF). Journal of Psychopharmacology. Archived from the original (PDF) on 2015-11-12. Retrieved 2016-05-25.
  2. ^ Jump up to:a b c “ANAVEX 2-73 – AdisInsight”. Adisinsight.springer.com. Retrieved 2016-05-25.
  3. ^ Jump up to:a b c Malviya, M; Kumar, YC; Asha, D; Chandra, JN; Subhash, MN; Rangappa, KS (2008). “Muscarinic receptor 1 agonist activity of novel N-arylthioureas substituted 3-morpholino arecoline derivatives in Alzheimer’s presenile dementia models”. Bioorg Med Chem. 16: 7095–7101. doi:10.1016/j.bmc.2008.06.053.
  4. ^ Jump up to:a b Leal, NS; Schreiner, B; Pinho, CM; Filadi, R; Wiehager, B; Karlström, H; Pizzo, P; Ankarcrona, M (2016). “Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid β-peptide production”. J Cell Mol Med. 20: 1686–1695. doi:10.1111/jcmm.12863. PMC 4988279. PMID 27203684.
  5. ^ Lahmy, V; Long, R; Morin, D; Villard, V; Maurice, T (2015-09-28). “Mitochondrial protection by the mixed muscarinic/σ1 ligand ANAVEX2-73, a tetrahydrofuran derivative, in Aβ25-35 peptide-injected mice, a nontransgenic Alzheimer’s disease model”. Front Cell Neurosci. 8: 463. doi:10.3389/fncel.2014.00463. PMC 4299448. PMID 25653589.
  6. ^ Maurice, T (2015-09-28). “Protection by sigma-1 receptor agonists is synergic with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments”. Behav. Brain Res. 296: 270–8. doi:10.1016/j.bbr.2015.09.020. PMID 26386305.

//////////Blarcamesine, ブラルカメシン , Orphan Drug Status, PHASE 2

CN(C)CC1CCOC1(C1=CC=CC=C1)C1=CC=CC=C1

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