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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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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 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
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Nemorexant


Nemorexant.svg

Nemorexant.png

ChemSpider 2D Image | LMQ24G57E9 | C23H23ClN6O2

Nemorexant

ACT-541468, UNII LMQ24G57E9

[(2S)-2-(5-Chloro-4-methyl-1H-benzimidazol-2-yl)-2-methyl-1-pyrrolidinyl][5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone
1505484-82-1 [RN]
LMQ24G57E9
Methanone, [(2S)-2-(5-chloro-4-methyl-1H-benzimidazol-2-yl)-2-methyl-1-pyrrolidinyl][5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]-
  • Originator Actelion Pharmaceuticals
  • Developer Idorsia Pharmaceuticals
  • Class Sleep disorder therapies
  • Mechanism of Action Orexin receptor type 1 antagonists; Orexin receptor type 2 antagonists
  • Phase III Insomnia
  • 19 Oct 2018 Idorsia Pharmaceuticals plans a phase I trial for Liver disorders (Hepatic impairment) in November 2018 (PO) (NCT03713242)
  • 09 Oct 2018 Idorsia Pharmaceuticals completes a phase I trial in Insomnia (In volunteers) in Netherlands (PO) (NCT03609775)
  • 27 Sep 2018 Idorsia Pharmaceuticals plans a phase I trial for Hepatic impairment in November 2018 , (NCT03686995)

Nemorexant (developmental code name ACT-541468) is a dual orexin receptor antagonist (DORA) which was originated by Actelion Pharmaceuticals and is under development by Idorsia Pharmaceuticals for the treatment of insomnia.[1][2] It acts as a selective dual antagonist of the orexin receptors OX1 and OX2.[1][2] As of June 2018, nemorexant is in phase III clinical trials for the treatment of insomnia.[1]

Idorsia is developing nemorexant, a dual orexin receptor antagonist (DORA), for the oral treatment of insomnia and investigating the program for the treatment of COPD. In May 2018, a phase III study was initiated in subjects with insomnia disorder and in September 2018, a phase I trial was initiated in COPD.

PATENT

WO2013182972 ,

PATENT

WO2015083094 ,

Patent

WO 2015083070

Synthesis of nemorexant, using 2-methyl-L-proline hydrochloride as the starting material

N-Protection of 2-methyl-L-proline hydrochloride with Boc2O gives N-Boc-2-methyl-L-proline,

Which upon condensation with 4-chloro-3-methylbenzene-1,2-diamine using HATU and DIEA in CH2Cl2 affords the corresponding amide.

Cyclization of diamine in the presence of AcOH at 100 °C provides imidazole derivative,

Whose Boc moiety is removed by means of HCl in dioxane to yield 5-chloro-4-methyl-2-[2(S)-methylpyrrolidin-2-yl]benzimidazole hydrochloride.

N-Acylation of pyrrolidine derivative with 5-methoxy-2-(1,2,3-triazol-2-yl)benzoic acid  using HATU and DIEA in CH2Cl2 produces Nemorexant

5-methoxy-2-(1,2,3-triazol-2-yl)benzoic acid (prepared by the coupling of 2-iodo-5-methoxybenzoic acid with 1,2,3-triazole using CuI and Cs2CO3 in DMF)

PATENT

WO 2016020403

PATENT

WO 2015083071

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=E3DE4EDE68FD728AEE93D43C4BCBF8DA.wapp2nC?docId=WO2015083071&tab=PCTDESCRIPTION&maxRec=1000

Reference Example 1

1) Synthesis of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid

2-lodo-5-methoxy benzoic acid (15.0 g; 53.9 mmol) is dissolved in anhydrous DMF (45 ml) followed by the addition of 1 H-1 ,2,3-triazole (7.452 g; 108 mmol) and cesium carbonate (35.155 g; 108 mmol). By the addition of cesium carbonate the temperature of the reaction mixture increases to 40°C and gas evolved from the reaction mixture. Copper(l)iodide (514 mg; 2.7 mmol) is added. This triggers a strongly exothermic reaction and the temperature of the reaction mixture reaches 70°C within a few seconds. Stirring is continued for 30 minutes. Then the DMF is evaporated under reduced pressure followed by the addition of water (170 ml) and EtOAc (90 ml). The mixture is vigorously stirred and by the addition of citric acid monohydrate the pH is adjusted to 3-4. The precipitate is filtered off and washed with water and EtOAc and discarded. The filtrate is poured into a separation funnel and the phases are separated. The water phase is extracted again with EtOAc. The combined organic layers are dried over MgS04, filtered and the solvent is evaporated to give 7.1 g of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid as a white powder of 94% purity (6 % impurity is the regioisomerically N1-linked triazolo-derivative); tR [min] = 0.60; [M+H]+ = 220.21

2) Synthesis of (S)-1 -(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid

2-Methyl-L-proline hydrochloride (99.7 g; 602 mmol) is dissolved in a 1/1-mixture of MeCN and water (800 ml) and triethylamine (254 ml; 1810 mmol) is added. The temperature of the reaction mixture slightly rises. The reaction mixture is cooled to 10°C to 15°C followed by careful addition of a solution of Boc20 (145 g; 662 mmol) in MeCN (200 ml) over 10 minutes.

Stirring at RT is continued for 2 hours. The MeCN is evaporated under reduced pressure and aq. NaOH solution (2M; 250 ml) is added to the residual aq. part of the reaction mixture. The water layer is washed with Et20 (2x 300 ml) then cooled to 0°C followed by slow and careful addition of aq. HCI (25%) to adjust the pH to 2. During this procedure a suspension forms.

The precipitate is filtered off and dried at HV to give 1 10.9 g of the title compound as a beige powder; tR [min] = 0.68; [M+H]+ = 230.14

3) Synthesis of (S)-tert-butyl 2-((2-amino-4-chloro-3-methylphenyl)carbamoyl)-2-

(S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (60 g; 262 mmol) and HATU (100 g; 264 mmol) is suspended in DCM (600 ml) followed by the addition of DIPEA (84.6 g; 654 mmol) and 6-chloro-2,3-diaminotoluene (41 g; 262 mmol). The reaction mixture is stirred at rt for 14 hours then concentrated under reduced pressure and to the residue is added water followed by the extraction of the product with EtOAc (3x). The combined organic layers are washed with brine, dried over MgS04, filtered and the solvent is evaporated under

reduced pressure to give 185 g of the title compound as a dark brownish oil, which is used in the next step without further purification; tR [min] = 0.89; [M+H]+ = 368.01

4) Synthesis of (S)-tert-butyl 2-(5-chloro-4-methyl-1 H-benzo[d]imidazol-2-yl)-2-methylpyrrolidine-1 -carboxylate

(S)-tert-butyl 2-((2-amino-4-chloro-3-methylphenyl)carbamoyl)-2-methylpyrrolidine-1-carboxylate (185 g; 427 mmol) are dissolved in AcOH (100%; 611 ml), heated to 100°C and stirring continued for 90 minutes. The AcOH is evaporated under reduced pressure and the residue is dissolved in DCM followed by careful addition of saturated sodium bicarbonate solution. The phases are separated, the aq. phase is extracted once more with DCM, the combined aq. phases are dried over MgS04, filtered and the solvent is evaporated under reduced pressure to give 142.92 g of the title compound as a dark brown oil which is used in the next step without further purification; tR [min] = 0.69; [M+H]+ = 350.04

5) Synthesis of (S)-5-chloro-4-methyl-2-(2-methylpyrrolidin-2-yl)-1 H-benzo[d]imidazole hydrochloride

(S)-tert-butyl 2-(5-chloro-4-methyl-1 H-benzo[d]imidazol-2-yl)-2-methylpyrrolidine-1-carboxylate (355.53 g; 1.02 mol) are dissolved in dioxane (750 ml) followed by careful addition of HCI solution in dioxane (4M; 750 ml; 3.05 mol). The reaction mixture is stirred for 3 hours followed by the addition of Et20 (800 ml) which triggered precipitation of the product. The solid is filtered off and dried at high vacuum to give 298.84 g of the title compound as a redish powder; tR [min] = 0.59; [M+H]+ = 250.23

6) Synthesis of [(S)-2-(5-chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-pyrrolidin-1- -(5-methoxy-2-[1,2,3]triazol-2-yl-phenyl)-methanone

(S)-5-chloro-4-methyl-2-(2-methylpyrrolidin-2-yl)-1 H-benzo[d]imidazole hydrochloride (62.8 g; 121 mmol) is dissolved in DCM (750 ml) followed by the addition of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (62.8 g; 121 mmol) and DIPEA (103 ml; 603 mmol). Stirring is continued for 10 minutes followed by the addition of HATU (47 g; 124 mmol). The reaction mixture is stirred for 16 hours at RT. The solvents are evaporated under reduced pressure and the residue is dissolved in EtOAc (1000 ml) and washed with water (3x 750 ml). The organic phase is dried over MgS04, filtered and the solvent is evaporated under reduced pressure. The residue is purified by CC with EtOAc / hexane = 2 / 1to give 36.68 g of the title compound as an amorphous white powder. tR [min] = 0.73; [M+H]+ = 450.96

Table 1 : Characterisation data for COMPOUND as free base in amorphous form

II. Preparation of crystalline forms of COMPOUND

Example 1 :

Preparation of seeding material of COMPOUND hydrochloride in crystalline Form 1

10 mg COMPOUND is mixed with 0.2 mL 0.1 M aq. HCI and 0.8 mL EtOH. The solvent is fully evaporated and 0.05 mL isopropanol is added. Alternatively 0.05 mL methyl-isobutylketone can be added. The sample is stored closed at room temperature for 4 days and crystalline material of COMPOUND hydrochloride in crystalline Form 1 is obtained. This material can be used as seeding material for further crystallization of COMPOUND hydrochloride in crystalline Form 1.

Example 2: Preparation and characterization of COMPOUND hydrochloride in crystalline form 1

5g COMPOUND is mixed with 0.9 mL 1 M aq. HCI and 20 mL EtOH. The solvent is evaporated and 25 mL isopropanol is added. Seeds of COMPOUND hydrochloride are added and the sample is allowed to stand at room temperature. After about 2 days the suspension is filtered and the solid residue is dried at reduced pressure (2 mbar for 1 hour) and allowed to equilibrate open for 2 hours at 24°C/46% relative humidity. The obtained solid is COMPOUND hydrochloride in crystalline Form 1

Table 2: Characterisation data for COMPOUND hydrochloride in crystalline form 1

PATENT

WO-2018202689

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018202689&tab=PCTDESCRIPTION&maxRec=1000

Process for the preparation of a crystalline potassium salt of a 2-(2H-[1,2,3]triazol-2-yl)-benzoic acid derivatives is claimed. Compound is disclosed to be useful for the preparation of pharmaceuticals, especially certain orexin receptor antagonists such as nemorexant .

References

  1. Jump up to:a b c https://adisinsight.springer.com/drugs/800044843
  2. Jump up to:a b Equihua-Benítez AC, Guzmán-Vásquez K, Drucker-Colín R (July 2017). “Understanding sleep-wake mechanisms and drug discovery”. Expert Opin Drug Discov12 (7): 643–657. doi:10.1080/17460441.2017.1329818PMID 28511597.
  3. Muehlan, C.; Heuberger, J.; Juif, P.E.; Croft, M.; van Gerven, J.; Dingemanse, J.
    Accelerated development of the dual orexin receptor antagonist ACT-541468: Integration of a microtracer in a first-in-human study
    Clin Pharmacol Ther 2018, 104(5): 1022
  4. A Study to Evaluate the Pharmacokinetics of ACT-541468 in Subjects With Mild, Moderate and Severe Hepatic Impairment (NCT03713242)
    ClinicalTrials.gov Web Site 2018, October 24
  5. Boof, M.-.L.; Ufer, M.; Halabi, A.; Dingemanse, J.
    Impact of the dual orexin receptor antagonist ACT-541468 on the pharmacokinetics of the CYP3A4 probe drug midazolam and assessment of the effect of food on ACT-541468
    119th Annu Meet Am Soc Clin Pharmacol Ther (ASCPT) (March 21-24, Orlando) 2018, Abst PI-043 
  6. Muehlan, C.; Brooks, S.; Zuiker, R.; van Gerven, J.; Dingemanse, J.
    Night-time administration of ACT-541468, a novel dual orexin receptor antagonist: Characterization of its pharmacokinetics, next-day residual effects, safety, and tolerability
    32nd Annu Meet Assoc Sleep Soc (SLEEP) (June 2-6, Baltimore) 2018, Abst 0008 
  7. Proposed international nonproprietary names (Prop. INN): List 118
    WHO Drug Inf 2017, 31(4): 635

External links

Patent ID

Title

Submitted Date

Granted Date

US9790208 CRYSTALLINE SALT FORM OF (S)-(2-(6-CHLORO-7-METHYL-1H-BENZO[D]IMIDAZOL-2-YL)-2-METHYLPYRROLIDIN-1-YL)(5-METHOXY-2-(2H-1, 2, 3-TRIAZOL-2-YL)PHENYL)METHANONE AS OREXIN RECEPTOR ANTAGONIST
2014-12-02
US2016368901 CRYSTALLINE FORM OF (S)-(2-(6-CHLORO-7-METHYL-1H-BENZO[D]IMIDAZOL-2-YL)-2-METHYLPYRROLIDIN-1 -YL)(5-METHOXY-2-(2H-1, 2, 3-TRIAZOL-2-YL)PHENYL)METHANONE AND ITS USE AS OREXIN RECEPTOR ANTAGONISTS
2014-12-02
Nemorexant
Nemorexant.svg
Clinical data
Synonyms ACT-541468
Routes of
administration
By mouth
Drug class Orexin antagonist
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C23H23ClN6O2
Molar mass 450.927 g/mol
3D model (JSmol)

///////////////Nemorexant, ACT-541468, Phase III,  Insomnia

Eflornithine, эфлорнитин , إيفلورنيثين , 依氟鸟氨酸 , エフロルニチン


Figure

Eflornithine.svg

ChemSpider 2D Image | Eflornithine | C6H12F2N2O2

Eflornithine

DFMO, RMI-71782ATC:P01CX03, BRN 2250529 / HSDB 7923 / MDL 71782 / RFI 7178 / RMI 71782

Ornithine, 2-(difluoromethyl)-
UNII:ZQN1G5V6SR
ZQN1G5V6SR
эфлорнитин [Russian] [INN]
إيفلورنيثين [Arabic] [INN]
依氟鸟氨酸 [Chinese] [INN]
エフロルニチン
5551
67037-37-0 [RN]
70052-12-9 CAS
a-Difluoromethylornithine
(RS)-2,5-diamino-2-(difluoromethyl)pentanoic acid
  • Use:hirsutism treatment inhibitor of ornithine decarboxylase
  • Chemical name:2-(difluoromethyl)-dl-ornithine
  • Formula:C6H12F2N2O2, MW:182.17 g/mol
  • CAS-RN:67037-37-0
  • LD50:>3000 mg/kg (M, i.p.); >5000 mg/kg (M, p.o.);
    1364 μg/kg (R, intracerebral)

Eflornithine, also known as α-difluoromethylornithine (DFMO), is an Active Pharmaceutical Ingredient (API) on the World Health Organization’s list of essential medicines. DFMO is used to treat the second stage of African trypanosomiasis (sleeping sickness). In addition, DFMO is also used to treat opportunistic infections with Pneumocystis carinii pneumonia, a form of pneumonia found in people with a weak immune system suffering from conditions such as acquired immunodeficiency syndrome (AIDS) It has also been explored as chemopreventive agent in cancer therapy with minor success. Today, its main use is to treat excessive facial hair growth on women (hirsutism). The topical cream (Vaniqa) significantly reduces the psychological burden of those affected.\

Eflornithine is a prescription drug indicated in the treatment of facial hirsutism (excessive hair growth). Eflornithine hydrochloride cream for topical application is intended for use in women suffering from facial hirsutism and is sold by Allergan, Inc. under the brand name Vaniqa. Besides being a non-mechanical and non-cosmetic treatment, eflornithine is the only non-hormonal and non-systemic prescription option available for women who suffer from facial hirsutism. Eflornithine for injection against sleeping sickness was manufactured by Sanofi Aventis and sold under the brand name Ornidyl in the USA. It is now discontinued. Eflornithine is on the World Health Organization’s List of Essential Medicines.

Derivatives

Monohydrochloride

  • Formula:C6H12F2N2O2 • HCl
  • MW:218.63 g/mol
  • CAS-RN:68278-23-9
  • EINECS:269-532-0

Monohydrochloride monohydrate

  • Formula:C6H12F2N2O2 • HCl • H2O
  • MW:236.65 g/mol
  • CAS-RN:96020-91-6

Eflornithine, sold under the brand name Vaniqa among others, is a medication used to treat African trypanosomiasis (sleeping sickness) and excessive hair growth on the face in women.[1][2] Specifically it is used for the 2nd stage of sleeping sickness caused by T. b. gambiense and may be used with nifurtimox.[1][3] It is used by injection or applied to the skin.[1][2]

Common side effects when applied as a cream include rash, redness, and burning.[2] Side effects of the injectable form include bone marrow suppression, vomiting, and seizures.[3] It is unclear if it is safe to use during pregnancy or breastfeeding.[3] It is recommended typically for children over the age of 12.[3]

Eflornithine was developed in the 1970s and came into medical use in 1990.[4] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[5] There is no generic version as of 2015 in the United States.[6] In the United States the injectable form can be obtained from the Centers for Disease Control and Prevention.[3] In the 1990s the cost of a course of treatment in Africa was 210 USD.[7] In regions of the world where the disease is common eflornithine is provided for free by the World Health Organization.[8]

https://www.google.com/patents/US4330559

Medical uses

Sleeping sickness

Sleeping sickness, or trypanosomiasis, is treated with pentamidine or suramin (depending on subspecies of parasite) delivered by intramuscular injection in the first phase of the disease, and with melarsoprol and eflornithine intravenous injection in the second phase of the disease. Efornithine is commonly given in combination with nifurtimox, which reduces the treatment time to 7 days of eflornithine infusions plus 10 days of oral nifurtimox tablets.[9]

Eflornithine is also effective in combination with other drugs, such as melarsoprol and nifurtimox. A study in 2005 compared the safety of eflornithine alone to melarsoprol and found eflornithine to be more effective and safe in treating second-stage sleeping sickness Trypanosoma brucei gambiense.[10] Eflornithine is not effective in the treatment of Trypanosoma brucei rhodesiense due to the parasite’s low sensitivity to the drug. Instead, melarsoprol is used to treat Trypanosoma brucei rhodesiense.[11] Another randomized control trial in Uganda compared the efficacy of various combinations of these drugs and found that the nifurtimox-eflornithine combination was the most promising first-line theory regimen.[12]

A randomized control trial was conducted in Congo, Côte d’Ivoire, the Democratic Republic of the Congo, and Uganda to determine if a 7-day intravenous regimen was as efficient as the standard 14-day regimen for new and relapsing cases. The results showed that the shortened regimen was efficacious in relapse cases, but was inferior to the standard regimen for new cases of the disease.[13]

Nifurtimox-eflornithine combination treatment (NECT) is an effective regimen for the treatment of second stage gambiense African trypanosomiasis.[14][15]

Trypanosome resistance

After its introduction to the market in the 1980s, eflornithine has replaced melarsoprol as the first line medication against Human African trypanosomiasis (HAT) due to its reduced toxicity to the host.[13] Trypanosoma brucei resistant to eflornithine has been reported as early as the mid-1980s.[13]

The gene TbAAT6, conserved in the genome of Trypanosomes, is believed to be responsible for the transmembrane transporter that brings eflornithine into the cell.[16] The loss of this gene due to specific mutations causes resistance to eflornithine in several trypanosomes.[17] If eflornithine is prescribed to a patient with Human African trypanosomiasis caused by a trypanosome that contains a mutated or ineffective TbAAT6 gene, then the medication will be ineffective against the disease. Resistance to eflornithine has increased the use of melarsoprol despite its toxicity, which has been linked to the deaths of 5% of recipient HAT patients.[13]

Excess facial hair in women

The topical cream is indicated for treatment of facial hirsutism in women.[18] It is the only topical prescription treatment that slows the growth of facial hair.[19] It is applied in a thin layer twice daily, a minimum of eight hours between applications. In clinical studies with Vaniqa, 81% percent of women showed clinical improvement after twelve months of treatment.[20] Positive results were seen after eight weeks.[21] However, discontinuation of the cream caused regrowth of hair back to baseline levels within 8 weeks.[22]

Vaniqa treatment significantly reduces the psychological burden of facial hirsutism.[23]

Chemo preventative therapy

It has been noted that ornithine decarboxylase (ODC) exhibits high activity in tumor cells, promoting cell growth and division, while absence of ODC activity leads to depletion of putrescine, causing impairment of RNA and DNA synthesis. Typically, drugs that inhibit cell growth are considered candidates for cancer therapy, so eflornithine was naturally believed to have potential utility as an anti-cancer agent. By inhibiting ODC, eflornithine inhibits cell growth and division of both cancerous and noncancerous cells.

However, several clinical trials demonstrated minor results.[24] It was found that inhibition of ODC by eflornithine does not kill proliferating cells, making eflornithine ineffective as a chemotherapeutic agent. The inhibition of the formation of polyamines by ODC activity can be ameliorated by dietary and bacterial means because high concentrations are found in cheese, red meat, and some intestinal bacteria, providing reserves if ODC is inhibited.[25] Although the role of polyamines in carcinogenesis is still unclear, polyamine synthesis has been supported to be more of a causative agent rather than an associative effect in cancer.[24]

Other studies have suggested that eflornithine can still aid in some chemoprevention by lowering polyamine levels in colorectal mucosa, with additional strong preclinical evidence available for application of eflornithine in colorectal and skin carcinogenesis.[24][25] This has made eflornithine a supported chemopreventive therapy specifically for colon cancer in combination with other medications. Several additional studies have found that eflornithine in combination with other compounds decreases the carcinogen concentrations of ethylnitrosourea, dimethylhydrazine, azoxymethane, methylnitrosourea, and hydroxybutylnitrosamine in the brain, spinal cord, intestine, mammary gland, and urinary bladder.[25]

Contraindications

Topical

Topical use is contraindicated in people hypersensitive to eflornithine or to any of the excipients.[26]

Throughout clinical trials, data from a limited number of exposed pregnancies indicate that there is no clinical evidence that treatment with Vaniqa adversely affects pregnant women or fetuses.[26]

By mouth

When taken by mouth the risk-benefit should be assessed in people with impaired renal function or pre-existing hematologic abnormalities, as well as those with eighth-cranial-nerve impairment.[27] Adequate and well-controlled studies with eflornithine have not been performed regarding pregnancy in humans. Eflornithine should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus. However, since African trypanosomiasis has a high mortality rate if left untreated, treatment with eflornithine may justify any potential risk to the fetus.[27]

Side effects

Eflornithine is not genotoxic; no tumour-inducing effects have been observed in carcinogenicity studies, including one photocarcinogenicity study.[28] No teratogenic effects have been detected.[29]

Topical

The topical form of elflornithine is sold under the brand name Vaniqa . The most frequently reported side effect is acne (7–14%). Other side effects commonly (> 1%) reported are skin problems, such as skin reactions from in-growing hair, hair loss, burning, stinging or tingling sensations, dry skin, itching, redness or rash.[30]

Intravenous

The intravenous dosage form of eflornithine is sold under the brand name Ornidyl. Most side effects related to systemic use through injection are transient and reversible by discontinuing the drug or decreasing the dose. Hematologic abnormalities occur frequently, ranging from 10–55%. These abnormalities are dose-related and are usually reversible. Thrombocytopenia is thought to be due to a production defect rather than to peripheral destruction. Seizures were seen in approximately 8% of patients, but may be related to the disease state rather than the drug. Reversible hearing loss has occurred in 30–70% of patients receiving long-term therapy (more than 4–8 weeks of therapy or a total dose of >300 grams); high-frequency hearing is lost first, followed by middle- and low-frequency hearing. Because treatment for African trypanosomiasis is short-term, patients are unlikely to experience hearing loss.[30]

Interactions

Topical

No interaction studies with the topical form have been performed.[26]

Mechanism of action

Figure 1
(A) 3D structure of L-Ornithine
(B) 3D structure of Eflornithine. This molecule is similar to the structure of L-Ornithine, but its alpha-difluoromethyl group allows interaction with Cys-360 in the active site

Eflornithine ODC Reaction Mechanism

Description

Eflornithine is a “suicide inhibitor,” irreversibly binding to ornithine decarboxylase (ODC) and preventing the natural substrate ornithine from accessing the active site (Figure 1). Within the active site of ODC, eflornithine undergoes decarboxylation with the aid of cofactor pyridoxal 5’-phosphate (PLP). Because of its additional difluoromethyl group in comparison to ornithine, eflornithine is able to bind to a neighboring Cys-360 residue, permanently remaining fixated within the active site.[29]

During the reaction, eflornithine’s decarboxylation mechanism is analogous to that of ornithine in the active site, where transamination occurs with PLP followed by decarboxylation. During the event of decarboxylation, the fluoride atoms attached to the additional methyl group pull the resulting negative charge from the release of carbon dioxide, causing a fluoride ion to be released. In the natural substrate of ODC, the ring of PLP accepts the electrons that result from the release of CO2.

The remaining fluoride atom that resides attached to the additional methyl group creates an electrophilic carbon that is attacked by the nearby thiol group of Cys-360, allowing eflornithine to remain permanently attached to the enzyme following the release of the second fluoride atom and transimination.

Evidence

Figure 2
Experimental Evidence for Eflornithine End Product[31]

The reaction mechanism of Trypanosoma brucei‘s ODC with ornithine was characterized by UV-VIS spectroscopy in order to identify unique intermediates that occurred during the reaction. The specific method of multiwavelength stopped-flow spectroscopy utilized monochromatic light and fluorescence to identify five specific intermediates due to changes in absorbance measurements.[32] The steady-state turnover number, kcat, of ODC was calculated to be 0.5 s-1 at 4 °C.[32] From this characterization, the rate-limiting step was determined to be the release of the product putrescine from ODC’s reaction with ornithine. In studying the hypothetical reaction mechanism for eflornithine, information collected from radioactive peptide and eflornithine mapping, high pressure liquid chromatography, and gas phase peptide sequencing suggested that Lys-69 and Cys-360 are covalently bound to eflornithine in T. brucei ODC’s active site.[31] Utilizing fast-atom bombardment mass spectrometry (FAB-MS), the structural conformation of eflornithine following its interaction with ODC was determined to be S-((2-(1-pyrroline-methyl) cysteine, a cyclic imine adduct. Presence of this particular product was supported by the possibility to further reduce the end product to S-((2-pyrrole) methyl) cysteine in the presence of NaBH4 and oxidize the end product to S-((2-pyrrolidine) methyl) cysteine (Figure 2).[31]

Active site

Figure 3
Active Site of ODC Formed by Homodimerization (Green and White Surface Structures)
(A) Ornithine in the Active Site of ODC, Cys-360 highlighted in yellow
(B) Product of Eflornithine Decarboxylation bound to Cys 360 (highlighted in yellow). The pyrroline ring blocks ornithine from entering the active site
Derived from Grishin, Nick V., et al. “X-ray structure of ornithine decarboxylase from Trypanosoma brucei: the native structure and the structure in complex with α-difluoromethylornithine.” Biochemistry 38.46 (1999): 15174-15184. PDB ID: 2TOD

Eflornithine’s suicide inhibition of ODC physically blocks the natural substrate ornithine from accessing the active site of the enzyme (Figure 3).[29] There are two distinct active sites formed by the homodimerization of ornithine decarboxylase. The size of the opening to the active site is approximately 13.6 Å. When these openings to the active site are blocked, there are no other ways through which ornithine can enter the active site. During the intermediate stage of eflornithine with PLP, its position near Cys-360 allows an interaction to occur. As the phosphate of PLP is stabilized by Arg 277 and a Gly-rich loop (235-237), the difluoromethyl group of eflornithine is able to interact and remain fixated to both Cys-360 and PLP prior to transimination. As shown in the figure, the pyrroline ring interferes with ornithine’s entry (Figure 4). Eflornithine will remain permanently bound in this position to Cys-360. As ODC has two active sites, two eflornithine molecules are required to completely inhibit ODC from ornithine decarboxylation.

History

Eflornithine was initially developed for cancer treatment at Merrell Dow Research Institute in the late 1970s, but was found to be ineffective in treating malignancies. However, it was discovered to be highly effective in reducing hair growth,[33] as well as in the treatment of African trypanosomiasis (sleeping sickness),[34] especially the West African form (Trypanosoma brucei gambiense).

Hirsutism[]

In the 1980s, Gillette was awarded a patent for the discovery that topical application of eflornithine HCl cream inhibits hair growth. In the 1990s, Gillette conducted dose-ranging studies with eflornithine in hirsute women that demonstrated that the drug slows the rate of facial hair growth. Gillette then filed a patent for the formulation of eflornithine cream. In July 2000, the U.S. Food and Drug Administration (FDA) granted a New Drug Application for Vaniqa. The following year, the European Commission issued its Marketing Authorisation.

Sleeping sickness treatment

The drug was registered for the treatment of gambiense sleeping sickness on November 28, 1990.[35] However, in 1995 Aventis (now Sanofi-Aventis) stopped producing the drug, whose main market was African countries, because it did not make a profit.[36]

In 2001, Aventis and the WHO formed a five-year partnership, during which more than 320,000 vials of pentamidine, over 420,000 vials of melarsoprol, and over 200,000 bottles of eflornithine were produced by Aventis, to be given to the WHO and distributed by the association Médecins sans Frontières (also known as Doctors Without Borders)[37][38] in countries where sleeping sickness is endemic.

According to Médecins sans Frontières, this only happened after “years of international pressure,” and coinciding with the period when media attention was generated because of the launch of another eflornithine-based product (Vaniqa, for the prevention of facial-hair in women),[36]while its life-saving formulation (for sleeping sickness) was not being produced.

From 2001 (when production was restarted) through 2006, 14 million diagnoses were made. This greatly contributed to stemming the spread of sleeping sickness, and to saving nearly 110,000 lives.

Society and culture

Available forms

Vaniqa is a cream, which is white to off-white in colour. It is supplied in tubes of 30 g and 60 g in Europe.[30] Vaniqa contains 15% w/w eflornithine hydrochloride monohydrate, corresponding to 11.5% w/w anhydrous eflornithine (EU), respectively 13.9% w/w anhydrous eflornithine hydrochloride (U.S.), in a cream for topical administration.

Ornidyl, intended for injection, was supplied in the strength of 200 mg eflornithine hydrochloride per ml.[39]

Cost

In 2000, the cost for the 14-day regimen was US $500; a price that many in countries where the disease is common cannot afford.[13]

Market

Vaniqa, granted marketing approval by the US FDA, as well as by the European Commission[40] among others, is currently the only topical prescription treatment that slows the growth of facial hair.[19] Besides being a non-mechanical and non-cosmetic treatment, it is the only non-hormonal and non-systemic prescription option available for women who suffer from facial hirsutism.[18] Vaniqa is marketed by Almirall in Europe, SkinMedica in the USA, Triton in Canada, Medison in Israel, and Menarini in Australia.[40]

Ornidyl, the injectable form of eflornithine hydrochloride, is licensed by Sanofi-Aventis, but is currently discontinued in the US.[41]

Clip

Scalable Continuous Flow Process for the Synthesis of Eflornithine Using Fluoroform as Difluoromethyl Source

 Center for Continuous Flow Synthesis and Processing (CC FLOW)Research Center Pharmaceutical Engineering GmbH (RCPE)Inffeldgasse 13, 8010 Graz, Austria
 Institute of ChemistryUniversity of Graz, NAWI GrazHeinrichstrasse 28, A-8010 Graz, Austria
§ Microreactor Technology, Lonza AG, CH-3930 Visp, Switzerland
 Institute of Inorganic ChemistryGraz University of TechnologyStremayrgasse 9, 8010 Graz, Austria
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00318
Abstract Image

The development of a scalable telescoped continuous flow procedure for difluoromethylation of a protected amino acid with fluoroform (CHF3, R-23) gas and subsequent high temperature deprotection to provide eflornithine, an important Active Pharmaceutical Ingredient (API), is described. Eflornithine is used for the treatment of sleeping sickness and hirsutism, and it is on the World Health Organization’s list of essential medicines. Fluoroform is produced in large quantities as a side product in the manufacture of polytetrafluoroethylene (PTFE, Teflon). Fluoroform is an ozone-benign and nontoxic gas, but its release into the environment is forbidden under the Kyoto protocol owing to its high global warming potential. The existing manufacturing route to eflornithine uses chlorodifluoromethane (CHClF2, R-22) which will be phased out under the Montreal protocol; therefore, the use of the fluoroform presents a viable cost-effective and more sustainable alternative. The process parameters and equipment setup were optimized on laboratory scale for the two reaction steps to improve product yield and scalability. The telescoped flow process utilizing fluoroform gas was operated for 4 h to afford the target molecule in 86% isolated yield over two steps with a throughput of 24 mmol/h.

1hydrochloride monohydrate as colorless powder. (17.05 g, 72.3 mmol, 86% yield). Mp. 228 °C;

1H NMR (300.36 MHz, D2O): δ = 6.46 (t, 2JHF = 52.8 Hz, 1H), 3.05 (t,3JHH = 7.6 Hz, 2H), 2.25–1.97 (m, 2H), 1.96–1.79 (m, 1H), 1.76–1.59 (m, 1H) ppm.

13C NMR (75 MHz, D2O): δ = 167.8 (d, 3JCF = 6.4 Hz), 114.0 (dd, 1JCF = 249.7 Hz, 1JCF = 247.0 Hz), 64.5 (dd, 2JCF = 20.4 Hz, 2JCF = 18.7 Hz), 38.8 (d, 3JCF = 7.3 Hz), 31.6 (d, 4JCF = 3.2 Hz), 20.8 ppm.

19F NMR (282 MHz, D2O): δ = −126.28 (dd, 2JFF = 283.5 Hz, 2JHF = 52.4 Hz), – 131.76 (dd, 2JFF = 283.5 Hz, 2JHF = 52.4 Hz) ppm.

str1 str2 str3

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External links

References

    • Bey, P. et al.: J. Org. Chem. (JOCEAH) 44, 2732 (1979).
    • Metcalf, B.W. et al.: J. Am. Chem. Soc. (JACSAT) 100, 2551 (1978).
    • US 4 413 141 (Merrell-Toraude; 1.11.1983; appl. 17.9.1982; prior. 11.7.1977, 2.7.1979).
    • US 4 330 559 (Merrell-Toraude; 18.5.1982; appl. 3.2.1981; prior. 11.7.1977, 10.4.1979).
  • synthesis of (–)-isomer:

    • EP 357 029 (Merrell Dow; appl. 30.8.1989; USA-prior. 31.8.1988).
  • pharmaceutical composition:

    • BE 881 209 (Merrell-Toraude; appl. 16.5.1980; USA-prior. 10.4.1979).
  • combination with interferon:

    • US 4 499 072 (Merrell Dow; 12.2.1985; appl. 24.1.1983; prior. 29.11.1982).
Eflornithine
Eflornithine.svg
Eflornithine-3D-vdW.png
Clinical data
Trade names Vaniqa, others
Synonyms α-difluoromethylornithine or DFMO
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • C
Routes of
administration
intravenous, topical
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 100% (Intravenous)
Negligible (Dermal)
Metabolism Not metabolised
Elimination half-life hours
Excretion Kidneys
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C6H12F2N2O2
Molar mass 182.17 g·mol−1
3D model (JSmol)

/////////////ZQN1G5V6SR, эфлорнитин إيفلورنيثين 依氟鸟氨酸 , Eflornithine, エフロルニチン

FDA permits marketing of two devices that detect parathyroid tissue in real-time during surgery


DRUG REGULATORY AFFAIRS INTERNATIONAL

FDA permits marketing of two devices that detect parathyroid tissue in real-time during surgery
Today, the U.S. Food and Drug Administration permitted marketing of two devices that provide real-time location of parathyroid tissue during surgical procedures such as thyroidectomy (surgery to remove all or part of the thyroid) and parathyroidectomy (surgery to remove one or more parathyroid glands).
“For some patients with parathyroid disease, treatment may mean a surgical procedure,” said Binita Ashar, M.D., director of the Division of Surgical Devices in the FDA’s Center for Devices and Radiological Health.  “Real-time identification of parathyroid tissue during surgery can provide surgeons… Continue reading.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624982.htm?utm_campaign=11022018_PR_FDA%20authorizes%20devices%20to%20detect%20parathyroid%20tissue%20in%20during%20surgery&utm_medium=email&utm_source=Eloqua

November 2, 2018

Release

Today, the U.S. Food and Drug Administration permitted marketing of two devices that provide real-time location of parathyroid tissue during surgical procedures such as thyroidectomy (surgery to remove all or part of the thyroid) and parathyroidectomy (surgery to remove one or…

View original post 556 more words

Statement from FDA Commissioner Scott Gottlieb, M.D., on findings from the romaine lettuce E. coli O157:H7 outbreak investigation and FDA’s efforts to prevent future outbreaks


DRUG REGULATORY AFFAIRS INTERNATIONAL

tatement from FDA Commissioner Scott Gottlieb, M.D., on findings from the romaine lettuce E. coli O157:H7 outbreak investigation and FDA’s efforts to prevent future outbreaks

Earlier this year, we experienced the largest E. coli O157:H7 outbreak the country has seen in the last decade, leaving hundreds sick and claiming the lives of five people who consumed contaminated romaine lettuce.
We’re committed to taking necessary actions to prevent future outbreaks like this and to improving the safety of leafy greens available in the marketplace. Since the next romaine growing season for the Yuma region is underway, it’s critical for all of us to understand what happened so we can identify the changes that can prevent future outbreaks and reduce the scope of any problems that could arise.
Since the first signs of the outbreak appeared…Continue reading

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624867.htm?utm_campaign=11012018_Statement_findings%20from%20the%20romaine%20lettuce%20E.%20coli%20O157%3AH7&utm_medium=email&utm_source=Eloqua

November 1, 2018

Statement

Earlier this year, we experienced the largest E. coli

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FDA warns patients and doctors about risk of inaccurate results from home-use device to monitor blood thinner warfarin


DRUG REGULATORY AFFAIRS INTERNATIONAL

FDA warns patients and doctors about risk of inaccurate results from home-use device to monitor blood thinner warfarin

The U.S. Food and Drug Administration today is warning patients and doctors, who use at-home or in-the-office medical devices to monitor levels of the blood thinner, warfarin, that certain test strips used with the devices may provide inaccurate results and should not be relied upon to adjust the drug dosage. Roche Diagnostics issued a voluntary recall of certain test strip lots used with its CoaguChek test meter devices. The recall involves more than 1.1 million packages of CoaguChek XS PT Test Strips that were distributed nationwide from Jan. 12, 2018 to Oct. 29, 2018. Today, the FDA announced this action as…Continue reading 

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624904.htm?utm_campaign=11012018_PR_FDA%20warns%20of%20inaccurate%20test%20results%20for%20device%20to%20monitor%20warfarin&utm_medium=email&utm_source=Eloqua

November 1, 2018

Release

The U.S. Food and Drug Administration today is warning patients and doctors, who use at-home or in-the-office medical devices to monitor levels of…

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