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|A vial of Convidecia vaccine|
|Vaccine type||Viral vector|
|Legal status||Full and Emergency authorizations|
Recombinant vaccine (adenovirus type 5 vector)
Recombinant Novel Coronavirus Vaccine (Adenovirus Type 5 Vector)
CanSino Biologics, china
AD5-nCOV, trade-named Convidecia, is a single-dose viral vector vaccine for COVID-19 developed by CanSino Biologics. It conducted its Phase III trials in Argentina, Chile, Mexico, Pakistan, Russia, and Saudi Arabia with 40,000 participants.
In February 2021, global data from Phase III trials and 101 COVID cases showed that the vaccine had a 65.7% efficacy in preventing moderate symptoms of COVID-19, and 91% efficacy in preventing severe disease. It has similar efficacy to Johnson & Johnson’s Ad26.COV2.S, another one-shot adenovirus vector vaccine with 66% efficacy in a global trial. Convidecia is similar to other viral vector vaccines like AZD1222, Gam-COVID-Vac, and Ad26.COV2.S. Its single-dose regimen and normal refrigerator storage requirement (2°to 8 °C) could make it a favorable vaccine option for many countries.
Convidecia is approved for use by some countries in Asia, Europe, and Latin America. Production capacity for Ad5-NCov should reach 500 million doses in 2021. Manufacturing will take place in China, Malaysia, Mexico, and Pakistan.
Ad5-nCoV is a recombinant adenovirus type-5 vector (Ad5) vaccine currently being investigated for prophylaxis against SARS-CoV-2.1,2 It is being developed by CanSino Biologics Inc., in partnership with the Beijing Institute of Biotechnology, who in March 2020 announced the approval of a phase I clinical trial (ChiCTR2000030906)1 with an expected completion in December 2020. The study will evaluate antibody response in healthy patients between the ages of 18 and 60 who will receive one of three study doses, with follow-up taking place at weeks 2 and 4 and months 3 and 6 post-vaccination.2
- Chinese Clinical Trial Register: A phase I clinical trial for recombinant novel coronavirus (2019-COV) vaccine (adenoviral vector) [Link]
- Antibody Society: COVID-19 Archives [Link]
In February 2021, data released from an interim analysis of Phase III trials with 30,000 participants and 101 COVID cases showed that globally, the vaccine had an efficacy of 65.7% at preventing moderate cases of COVID-19 and 90.98% efficacy at preventing severe cases. In the Pakistan trial subset, the vaccine had an efficacy of 74.8% at preventing symptomatic cases 100% for preventing severe disease.
While the efficacy rates were lower than the Pfizer–BioNTech and Moderna vaccines, its single-dose regimen and normal refrigerator storage requirement (2 to 8 °C) could make it a favorable option for many countries. It has similar efficacy to Johnson & Johnson’s Ad26.COV2.S, another one-shot adenovirus vaccine found to be 66% effective in a global trial.
In early 2020, Chen Wei led a joint team of the Institute of Biotechnology, the Academy of Military Medical Sciences and CanSino Biologics to develop AD5-nCOV. According to the Chinese state media, the team registered an experimental COVID-19 vaccine for Phase I trial in China on 17 March 2020 to test its safety. The trial was conducted on 108 healthy adults aged 18 to 60 in two medical facilities in Wuhan, Hubei province.
In April, Ad5-nCoV became the first COVID-19 vaccine candidate in the world to begin Phase II trials. The Phase II trial results were published in the peer-reviewed journal The Lancet in August 2020, and noted neutralizing antibody and T cell responses based on statistical analyses of data involving 508 eligible participants. In September, Zeng Guang, chief scientist of the Chinese Center for Disease Control and Prevention said the amount of COVID-19 antibodies in subjects from the Phase I trials remained high six months after the first shot. Zeng said the high levels of antibodies suggested the shots may provide immunity for an extended period of time, although Phase III results were still required. On September 24, CanSino began Phase IIb trials on 481 participants to evaluate the safety and immunogenicity of Ad5-nCoV for children ages 6–17 and elderly individuals ages 56 and above.
On 16 May 2020, Canadian Prime Minister Justin Trudeau announced Health Canada had approved Phase II trials to be conducted by the Canadian Center for Vaccinology (CCfV) on the COVID-19 vaccine produced by CanSino. Scott Halperin, director of the CCfV said the vaccine would not be the only one going into clinical trials in Canada, and any potential vaccine would not be publicly available until after Phase 3 is complete. If the vaccine trials were successful, then the National Research Council would work with CanSino to produce and distribute the vaccine in Canada. In August 2020, the National Research Council disclosed the vaccine had not been approved by Chinese customs to ship to Canada, after which the collaboration between CanSino and the Canadian Center for Vaccinology was abandoned.
Nasal spray trials
In September, CanSino began a Phase I trial in China with 144 adults to determine the safety and immunogenicity of the vaccine to be administered as a nasal spray, in contrast with most COVID-19 vaccine candidates which require intramuscular injection. On June 3, 2021, Chen Wei announced the expansion of clinical trials was approved by the NMPA, in the meantime, they are applying for Emergency Use Listing for the nasal spray.
In April 2021, a new trial was registered in Jiangsu involving one dose of Convidecia followed by a dose of ZF2001 28 or 56 days later using different technologies as a way to further boost efficacy.
In February, Chen Wei who lead the development of the vaccine, said annual production capacity for Ad5-NCov could reach 500 million doses in 2021.
In Malaysia, final filling and packaging of the vaccine for distribution would be completed by Solution Biologics.
In May, Pakistan began filling and finishing 3 million doses a month at the National Institute of Health, which would be branded as PakVac for domestic distribution.
If the vaccine is approved in Russia, Petrovax said it would produce 10 million doses per month in 2021.
Marketing and deployment
In February, Malaysia‘s Solution Biologics agreed to supply 3.5 million doses to the government. The doses would be delivered starting in April with 500,000 complete doses, with the rest in bulk to be finished by Solution Biologics.
In December 2020, Mexico‘s Foreign Minister Marcelo Ebrard signed an agreement for 35 million doses. In February, Mexico approved the vaccine for emergency use. Mexico received active ingredients for 2 million doses with a total of 6 million doses expected to arrive in February.
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/////////Convidicea, Ad5-nCoV, Recombinant vaccine, adenovirus type 5 vector, CanSino Biologics, china, SARS-CoV-2, corona virus, vaccine, covid 19
NEW DRUG APPROVALS
Origin of EpiVacCorona antigenes
- MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAATGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIAYPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTWPLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYSIAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSAGINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRIAATMENAQKGEIMPNIPQMSAFWYAVRTAVINAASGRQTVDEALKDAQTNSSSNNNNNNNNNNLGDNGPQNQRNAPRITFGGPSDSTGSNQNGERSGARSKQRRPQGLPNNTASWFTALTQHGKEDLKFPRGQGVPINTNSSPDDQIGYYRRATRRIRGGDGKMKDLSPRWYFYYLGTGPEAGLPYGANKDGIIWVATEGALNTPKDHIGTRNPANNAAIVLQLPQGTTLPKGFYAEGSRGGSQASSRSSSRSRNSSRNSTPGSSRGTSPARMAGNGGDAALALLLLDRLNQLESKMSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKAYNVTQAFGRRGPEQTQGNFGDQELIRQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFPPTEPKKDKKKKADETQALPQRQKKQQTVTLLPAADLDDLSKQLQQSMSSADSTQA. “Carrier protein sequence”.
Federal Budgetary Research Institution State Research Center of Virology and Biotechnology
PATENT https://www.fips.ru/registers-doc-view/fips_servlet?DB=RUPAT&DocNumber=2743594&TypeFile=htmlRU 2 743 594 RU 2 743 593RU 2 743 595 RU 2 738 081 Science (Washington, DC, United States) (2021), 372(6538), 116-117.
EpiVacCorona (Russian: ЭпиВакКорона, tr. EpiVakKorona) is a peptide-based vaccine against COVID-19 developed by the VECTOR center of Virology. It consists of three chemically synthesized peptides (short fragments of a viral spike protein) that are conjugated to a large carrier protein. This protein is a fusion product of a viral nucleocapsid protein and a bacterial MBP protein.The third phase of a clinical trial, which should show whether the vaccine is able to protect people from COVID-19 or not, was launched in November 2020 with more than three thousand participants. It is assumed it will be completed in August 2021. According to the vaccine developers, the peptides and the viral part of the chimeric protein should immunize people who received this vaccine against SARS-CoV-2 and trigger the production of protective antibodies. However, some experts in the field have expressed concerns about the selection of peptides for use as vaccine antigens. In addition, there are also serious concerns about the vaccine immunogenicity data, which have fueled independent civic research efforts and criticism by some experts. Meanwhile, the EpiVacCorona has received vaccine emergency authorization in a form of government registration and is available for vaccination outside the clinical trials. The vaccine delivered via intramuscular route and aluminum hydroxide serves as an immunological adjuvant.
Origin of EpiVacCorona antigenes
The vaccine includes three chemically synthesized short fragments of the viral spike protein – peptides, which, according to the developers of EpiVacCorona represent the protein regions containing B-cell epitopes that should be recognized by the human immune system.
These peptides are represented by following amino acid sequences:
In the vaccine all peptides are conjugated to a carrier protein, which is an expression product of the chimeric gene. This chimeric gene was created by fusion of two genes originating from different organisms, namely a gene encoding a viral nucleocapsid protein and a gene encoding a bacterial maltose-binding protein (MBP). The fusion chimeric gene expressed in Escherichia coli. The sequence of the chimeric protein is available from the patent. The genetic construct of the chimeric gene also includes a short genetic fragment encoding a polyhistidine-tag, which is used to purify the chimeric protein from E. coli lysate. After the purification, the protein is conjugated with three peptides in a way that only one variant of the peptide molecule is attached to each protein molecule. As a result, three types of conjugated molecules are created: chimeric protein with attached peptide number 1, the same protein with peptide number 2, and finally the same protein with peptide number 3. All three types of conjugated molecules are included in the vaccine.
EpiVacCorona: antigens origin and composition
Vaccine antigens and antibodies
According to the developers’ publications, vaccine antigens are three peptides of the spike protein and a chimeric protein consisting of two parts (viral nucleocapsid protein and bacterial maltose-binding protein). In addition, the polyhistidine-tag – a short peptide that is introduced into a vaccine composition to purify a chimeric protein from a bacterial lysate – is also a vaccine antigen against which antibodies can form in those who have received the vaccine. A person vaccinated with EpiVacCorona can develop antibodies not only to the peptides of the spike protein, but also to other antigens present in the vaccine. According to Anna Popova who is a head of the Federal Service for Supervision of Consumer Rights Protection and Human Welfare, it takes 42 days for those vaccinated with EpiVacCorona to develop immunity.
Immunogenic peptide screening in rabbits for EpiVacCorona design
The primary screening of peptides for the search for the most immunogenic ones was carried out in animals. The level of antibodies that was triggered by each tested peptide after administration to rabbits was measured. In the test, hemocyanin protein was used as a carrier protein for the studied peptides. Further, on six species of animals (mice, rats, rabbits, African green monkeys, rhesus monkeys, guinea pigs), the vaccine was shown to be harmless in terms of such parameters as general toxicity, allergic properties, and mutagenic activity. In four species of animals (hamsters, ferrets, African green monkeys, rhesus monkeys), specific activity was shown: immunogenicity and protective properties against SARS-CoV-2. The main results of preclinical studies are published in the “Bulletin of the Russian Academy of Medical Sciences”.
The trial “Study of the Safety, Reactogenicity and Immunogenicity of “EpiVacCorona” Vaccine for the Prevention of COVID-19 (EpiVacCorona)” was registered in clinical trial database with ClinicalTrials.gov identifier: NCT04780035. Another trial with the same title was registered with ClinicalTrials.gov Identifier: NCT04527575. Results of the trial that included data on 86 participants were published in Russian Journal of Infection and Immunity, indicating preliminary evidence of safety and an immune response. The publication reports preliminary results of the first two phases of clinical trials of the vaccine in volunteers, of which 14 people aged 18-30 years participated in the first phase, and 86 volunteers aged 18-60 years in the second phase. It is claimed that antibodies were formed in 100% of the volunteers, and the vaccine is also claimed to be safe.
EpiVacCorona Vaccine Development Timeline
The third phase of a clinical trial, which should show whether the vaccine is able to protect people from COVID-19 or not, was launched in November 2020 with more than three thousand participants planned. It is expected to be completed in September 2021. In the clinical trials database the phase III trial etitled “Study of the Tolerability, Safety, Immunogenicity and Preventive Efficacy of the EpiVacCorona Vaccine for the Prevention of COVID-19” was registered only in March 2021 with ClinicalTrials.gov Identifier: NCT04780035. Phase 3-4 trial was registered in Russia at 18.11.2020 with 4991 participants planned.
The following patents of the Russian Federation for invention have been published, which protect the EpiVacCorona vaccine:
“Peptide immunogens and vaccine composition against coronavirus infection COVID-19 using peptide immunogens” (No. 2738081). There are 7 peptides in patented vaccine compositions.
“Peptide immunogens and vaccine composition against coronavirus infection COVID-19 using peptide immunogens” (No. 2743593). The patented vaccine composition contains 2 peptides.
“Peptide immunogens used as a component of a vaccine composition against coronavirus infection COVID-19″ (No. 2743594). The patented vaccine composition contains 3 peptides.
“Vaccine composition against coronavirus infection COVID-19″ (No. 2743595). The patented vaccine composition contains 3 peptides.
In all of these patents, the carrier protein is referred to as a chimeric fusion protein with an amino acid sequence derived from two parts, a bacterial maltose binding protein and a viral nucleocapsid protein.
EpiVacCorona vaccine registration certificate
Full authorization Emergency authorization
The VECTOR has received vaccine emergency authorization in a form of government registration in October 2020.
In Russia phase III clinical study is called post-registration study. Therefore, government registration of the vaccine means permission to perform phase III clinical research and public vaccination outside of clinical trials as well. Since December 2020, the vaccine has been released for public vaccination in Russia.
Russia’s Chief Health Officer Anna Popova said: “In December 2020 the EpiVacCorona documents were presented to the World Health Organization, and we are expecting a decision from WHO.” However, Deutsche Welle reports “As of March 1, the WHO had yet to receive an Expression of Interest (EOI) from EpiVacCorona’s developers, “VECTOR,” to enable WHO experts to evaluate their vaccine.”
The Deputy Director-General of the World Health Organization (WHO) Dr. Soumya Swaminathan during news conference in Geneva that took place in October 2020, told: “We will only be able to have a position on a vaccine when we see results of the phase III clinical trials.” According to the center’s director Rinat Maksyutov, many government and non-government organizations want to test or be involved in the production of the vaccine. As of March 30, Venezuela obtained 1000 doses of the Russian EpiVacCorona vaccine for a trial. Venezuela also has reached a deal to purchase doses of the vaccine, as well as manufacture it locally, Vice President Delcy Rodriguez provided this information on June 4, 2021. Turkmenistan expects to receive EpiVacCorona, as the vaccine has already been approved for use in that country.
Independent study of clinical trial participants
Ministry of Health’s response to a request from trial participants to perform independent antibody screening tests
English translation of Ministry of Health’s response to a request from trial participants to perform independent antibody screening tests.
At the start of the Phase III, trial participants and those vaccinated outside the trial began to form a community through the Telegram messenger network. On January 18, 2021, the members of the community turned to the Ministry of Health of the Russian Federation with an open letter, in which they stated that the production of antibodies after vaccination among them is much lower than declared by vaccine developers. Study participants claimed that antibodies were not found in more than 50% of those who documented their participation in the study, although only 25% of the participants should have had a placebo according to the study design. The trial participants also claimed that negative results were obtained using the a special ELISA test developed and recommended by VECTOR for EpiVacCorona detection. More questions about the quality and protectiveness of antibodies induced by EpiVacCorona appeared along with the first results of a special antibody VECTOR’s test, when, with a positive special test, negative results of all other commercially available tests were otained: LIAISON SARS-CoV-2 S1 / S2 IgG – DiaSorin, IgM / IgG – Mindray, SARS-CoV-2 IgG – Abbott Architect, Anti-SARS-CoV-2 ELISA (IgG) – Euroimmun, Access SARS-CoV-2 IgG (RBD) – Beckman Coulter, “SARS-CoV-2-IgG-ELISA -BEST “-” Vector-Best “,” Anti-RBD IgG “- Gamaleya Research Center. Clinical trial participants conducted their own antibody mini-study that was performed in independent Russian laboratory. The study participants asked Dr. Alexander Chepurnov, the former head of the infectious diseases department at VECTOR, who now works at another medical institute, to check neutralizing antibodies presence in their serum samples. They also sent to Dr. Chepurnov control serum samples from former COVID-19 patients or people vaccinated with another Russian vaccine, Sputnik V, which is known to trigger the production of neutralizing antibodies. All serum samples were blinded before antibody tests. On 23 March 2021, the participants reported the results of their mini-study in an open letter to the Ministry of Health of the Russian Federation. According to the letter, even with the help of the VECTOR antibody detection system, antibodies were detected only in 70-75% of those vaccinated with EpiVacCorona. However, the level of antibodies was very low. Moreover, according to the letter, virus-neutralizing antibodies were not detected in the independent research Dr. Alexander Chepurnov laboratory at all. The trial participants asked Ministry of Health in their open letter to perform independent study for the verification of their findings. In addition, the letter reports 18 cases of COVID-19 cases as of March 22, 2021 among those who received the vaccine and became ill (sometimes severe) three weeks or later after the second dose of EpiVacCorona. April 20, 2021 the study participants got a reply, with refusal of performing any additional verification antibody tests or investigation of sever COVID-19 cases among vaccinated individuals. The reply include the following text: “Considering that the listed immunobiological preparations (vaccines) for the prevention of COVID-19 are registered in the prescribed manner, their effectiveness and safety have been confirmed.”
Vaccine criticism by independent experts
Some independent experts criticized the vaccine design and clinical data presentation in the publication. The experts are saying that peptide selection is “crucial” for the innovative peptide approach, which VECTOR uses for EpiVacCorona design. However, some researchers are not convinced that the viral spike protein peptides selected for the vaccine are actually “visible” by human immune system. They stated that these peptides do not overlap with peptides that have been shown in several publications to contain human linear B cell epitopes in spike protein of SARS-CoV-2. Moreover, the study was criticized for the lack of positive control of convalescent plasma samples in reports related to neutralizing antibody titers in vaccinated individuals. The same study was also criticized for presence of detectable antibodies in negative controls samples that were not discussed by authors. In addition, vaccine developers have been criticized for aggressively advertising their vaccine efficacy prior to the completion of phase III clinical trial. The most substantial criticism came from Dr. Konstantin Chumakov, who currently serves as the Associate Director for Research at the FDA Office of Vaccines Research and Review. Dr. Chumakov said: “I would not be in a hurry to call this peptide formulation a vaccine yet, because its effectiveness has not yet been proven…For the introduction of such a vaccine, the level of evidence must be much higher, and therefore the developers of EpiVacCorona, before launching their vaccine on the market, had to conduct clinical trials and prove that their vaccine actually protects against the disease. However, such tests were not carried out, which is absolutely unacceptable.”
The title page of the “EpiVacCorona” patent with Anna’s Popova name among inventors
Conflict of interest
The vaccine design was protected by several already issued patents (see section above). In each patent one of its co-authors is a namesake of Anna Popova who is a head of the Federal Service for Supervision of Consumer Rights Protection and Human Welfare. This patent authorship represents an issue as far as Anna Popova is a head of the Russian agency that is charged with overseeing vaccine safety and efficacy. As a co-author of these patents, she might have an interest in promoting the vaccine despite its shortcomings.
- ^ Jump up to:a b c d e f Ryzhikov AB, Ryzhikov EA, Bogryantseva MP, Usova SV, Danilenko ED, Nechaeva EA, Pyankov OV, Pyankova OG, Gudymo AS, Bodnev SA, Onkhonova GS, Sleptsova ES, Kuzubov VI, Ryndyuk NN, Ginko ZI, Petrov VN, Moiseeva AA, Torzhkova PY, Pyankov SA, Tregubchak TV, Antonec DV, Gavrilova EV, Maksyutov RA (2021). “A single blind, placebo-controlled randomized study of the safety, reactogenicity and immunogenicity of the “EpiVacCorona” Vaccine for the prevention of COVID-19, in volunteers aged 18–60 years (phase I–II)”. Russian Journal of Infection and Immunity. 11 (2): 283–296. doi:10.15789/2220-7619-ASB-1699.
- ^ Jump up to:a b c d e Federal Budgetary Research Institution State Research Center of Virology and Biotechnology “Vector” (2 March 2021). “Multicenter Double-blind Placebo-controlled Comparative Randomized Study of the Tolerability, Safety, Immunogenicity and Prophylactic Efficacy of the EpiVacCorona Peptide Antigen-based Vaccine for the Prevention of COVID-19, With the Participation of 3000 Volunteers Aged 18 Years and Above (Phase III-IV)”.
- ^ Jump up to:a b c d e f g DobrovidovaApr. 6, Olga; 2021; Am, 11:05 (6 April 2021). “Russia’s COVID-19 defense may depend on mystery vaccine from former bioweapons lab—but does it work?”. Science | AAAS. Retrieved 24 April 2021.
- ^ Jump up to:a b c d e f Dobrovidova, Olga (9 April 2021). “Latest Russian vaccine comes with a big dose of mystery”. Science. 372 (6538): 116–117. doi:10.1126/science.372.6538.116. ISSN 0036-8075. PMID 33833104. S2CID 233191522.
- ^ Jump up to:a b c Staff, Reuters (26 March 2021). “Volunteers break rank to raise doubts in trial of Russia’s second COVID-19 vaccine”. Reuters. Retrieved 23 April 2021.
- ^ Jump up to:a b c d e f g “”ЭпиВакКорона” глазами участников клинических испытаний и ученых-биологов”. Троицкий вариант — Наука (in Russian). 23 March 2021. Retrieved 23 April 2021.
- ^ Jump up to:a b c d e https://epivakorona.com/openletter.htm
- ^ Jump up to:a b c “EpiVacCorona’s race to the finish line Meduza speaks to the developer and manufacturer about concerns surrounding Russia’s latest coronavirus vaccine”. meduza.io. Retrieved 23 April2021.
- ^ Jump up to:a b “Нет антител, вопросы к составу, непрозрачность данных. Что не так с вакциной “ЭпиВакКорона””. BBC News Русская служба (in Russian). Retrieved 23 April 2021.
- ^ Jump up to:a b c d “Sputnik V’s ugly cousin Clinical results for Russia’s EpiVacCorona vaccine are finally here, but developers published in an obscure local journal, raising questions and concerns”. meduza.io. Retrieved 23 April 2021.
- ^ “About 200,000 EpiVacCorona vaccine doses go into civil circulation in Russia”. TASS. Retrieved 25 April 2021.
- ^ Jump up to:a bhttps://www.researchgate.net/publication/350822775_Immunogenicity_and_protectivity_of_the_peptide_candidate_vaccine_against_SARS-CoV-2
- ^ Jump up to:a b Ryzhikov AB, Ryzhikov EA, Bogryantseva MP, Usova SV, Danilenko ED, Imatdinov IR, Nechaeva EA, Pyankov OV, Pyankova OG, Gudymo AS, Bodnev SA, Onkhonova GS, Sleptsova ES, Kuzubov VI, Ryndyuk NN, Ginko ZI, Petrov VN, Moiseeva AA, Torzhkova PY, Pyankov SA, Tregubchak TV, Antonec DV, Sleptsova ES, Gavrilova EV, Maksyutov RA (2021). “Immunogenicity and Protectivityof the Peptide Vaccine againstSARS-CoV-2”. Annals of the Russian Academy of Medical Sciences. 76 (1): 5–19. doi:10.15690/vramn1528.
- ^ Ryzhikov, A. B.; Ryzhikov, Е. А.; Bogryantseva, M. P.; Usova, S. V.; Danilenko, E. D.; Nechaeva, E. A.; Pyankov, O. V.; Pyankova, O. G.; Gudymo, A. S. (24 March 2021). “A single blind, placebo-controlled randomized study of the safety, reactogenicity and immunogenicity of the “EpiVacCorona” Vaccine for the prevention of COVID-19, in volunteers aged 18–60 years (phase I–II)”. Russian Journal of Infection and Immunity. Retrieved 23 April 2021.
- ^ “People vaccinated with Russia’s EpiVacCorona need 42 days to develop immunity – watchdog”. TASS. Retrieved 25 April 2021.
- ^ “Что ждать от “ЭпиВакКороны”. Все о пептидной вакцине против COVID-19″. РИА Новости(in Russian). 1 January 2021. Retrieved 24 April 2021.
- ^ s.r.o, Direct Impact. “AIM database substance – EpiVacCorona”. AIM. Retrieved 25 April 2021.
- ^ Jump up to:a b Federal Budgetary Research Institution State Research Center of Virology and Biotechnology “Vector” (20 February 2021). “Simple, Blind, Placebo-controlled, Randomized Study of the Safety, Reactogenicity and Immunogenicity of Vaccine Based on Peptide Antigens for the Prevention of COVID-19 (EpiVacCorona), in Volunteers Aged 18-60 Years (I-II Phase)”.
- ^ Реестр Клинических исследований COV/pept-03/20; 
- ^MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAATGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIAYPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTWPLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYSIAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSAGINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRIAATMENAQKGEIMPNIPQMSAFWYAVRTAVINAASGRQTVDEALKDAQTNSSSNNNNNNNNNNLGDNGPQNQRNAPRITFGGPSDSTGSNQNGERSGARSKQRRPQGLPNNTASWFTALTQHGKEDLKFPRGQGVPINTNSSPDDQIGYYRRATRRIRGGDGKMKDLSPRWYFYYLGTGPEAGLPYGANKDGIIWVATEGALNTPKDHIGTRNPANNAAIVLQLPQGTTLPKGFYAEGSRGGSQASSRSSSRSRNSSRNSTPGSSRGTSPARMAGNGGDAALALLLLDRLNQLESKMSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKAYNVTQAFGRRGPEQTQGNFGDQELIRQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFPPTEPKKDKKKKADETQALPQRQKKQQTVTLLPAADLDDLSKQLQQSMSSADSTQA. “Carrier protein sequence”.
- ^ Jump up to:a b “Russia begins post-registration trials of EpiVacCorona Covid-19 vaccine”. http://www.clinicaltrialsarena.com. Retrieved 25 April 2021.
- ^ “Вакцина “ЭпиВакКорона” поступила в гражданский оборот”. РИА Новости (in Russian). 11 December 2020. Retrieved 23 April 2021.
- ^ “Turkmenistan registers vaccines for the prevention of infectious diseases”. Turkmenistan Today. 29 January 2021.
- ^ “Turkmenistan: Master Berdymukhamedov goes to Moscow | Eurasianet”. eurasianet.org. Retrieved 25 April 2021.
- ^ “Russia submits EpiVacCorona vaccine documents to WHO – Rospotrebnadzor head Popova”. interfax.com. Retrieved 23 April 2021.
- ^ Welle (www.dw.com), Deutsche. “Two more Russian vaccines: What we do and don’t know | DW | 09.03.2021”. DW.COM. Retrieved 23 April 2021.
- ^ “COVID-19 vaccine: WHO in talks with Russia on its second vaccine EpiVacCorona”. mint. 16 October 2020. Retrieved 9 June 2021.
- ^ “Vector Center says has over 45 inquiries from abroad about its EpiVacCorona vaccine”. TASS. Retrieved 25 April 2021.
- ^ Foundation, Thomson Reuters. “Venezuela receives doses of Russian EpiVacCorona vaccine for trials”. news.trust.org. Retrieved 25 April 2021.
- ^ “Venezuela to purchase and manufacture Russia’s EpiVacCorona vaccine”. Reuters. 5 June 2021. Retrieved 13 June 2021.
- ^ turkmenportal. “Turkmenistan Approves Use of Russia’s EpiVacCorona Vaccine | Society”. Business Turkmenistan Information Center. Retrieved 25 April 2021.
- ^ Jones, Ian; Roy, Polly (20 February 2021). “Sputnik V COVID-19 vaccine candidate appears safe and effective”. The Lancet. 397 (10275): 642–643. doi:10.1016/S0140-6736(21)00191-4. ISSN 0140-6736. PMC 7906719. PMID 33545098.
- ^ “Участники КИ “ЭпиВакКороны” продолжают исследовать эффективность вакцины”. pcr.news. Retrieved 24 April 2021.
- ^ Li, Yang; Ma, Ming-Liang; Lei, Qing; Wang, Feng; Hong, Wei; Lai, Dan-Yun; Hou, Hongyan; Xu, Zhao-Wei; Zhang, Bo; Chen, Hong; Yu, Caizheng (30 March 2021). “Linear epitope landscape of the SARS-CoV-2 Spike protein constructed from 1,051 COVID-19 patients”. Cell Reports. 34 (13): 108915. doi:10.1016/j.celrep.2021.108915. ISSN 2211-1247. PMC 7953450. PMID 33761319.
- ^ “Вакцина “ЭпиВакКорона” в иллюстрациях”. Троицкий вариант — Наука (in Russian). 23 March 2021. Retrieved 24 April 2021.
- ^ Yi, Zhigang; Ling, Yun; Zhang, Xiaonan; Chen, Jieliang; Hu, Kongying; Wang, Yuyan; Song, Wuhui; Ying, Tianlei; Zhang, Rong; Lu, HongZhou; Yuan, Zhenghong (December 2020). “Functional mapping of B-cell linear epitopes of SARS-CoV-2 in COVID-19 convalescent population”. Emerging Microbes & Infections. 9 (1): 1988–1996. doi:10.1080/22221751.2020.1815591. ISSN 2222-1751. PMC 7534331. PMID 32844713.
- ^ Poh, Chek Meng; Carissimo, Guillaume; Wang, Bei; Amrun, Siti Naqiah; Lee, Cheryl Yi-Pin; Chee, Rhonda Sin-Ling; Fong, Siew-Wai; Yeo, Nicholas Kim-Wah; Lee, Wen-Hsin; Torres-Ruesta, Anthony; Leo, Yee-Sin (1 June 2020). “Two linear epitopes on the SARS-CoV-2 spike protein that elicit neutralising antibodies in COVID-19 patients”. Nature Communications. 11 (1): 2806. doi:10.1038/s41467-020-16638-2. ISSN 2041-1723. PMC 7264175. PMID 32483236.
- ^ Li, Yang; Lai, Dan-Yun; Zhang, Hai-Nan; Jiang, He-Wei; Tian, Xiaolong; Ma, Ming-Liang; Qi, Huan; Meng, Qing-Feng; Guo, Shu-Juan; Wu, Yanling; Wang, Wei (October 2020). “Linear epitopes of SARS-CoV-2 spike protein elicit neutralizing antibodies in COVID-19 patients”. Cellular & Molecular Immunology. 17 (10): 1095–1097. doi:10.1038/s41423-020-00523-5. ISSN 2042-0226. PMC 7475724. PMID 32895485.
- ^ Farrera-Soler, Lluc; Daguer, Jean-Pierre; Barluenga, Sofia; Vadas, Oscar; Cohen, Patrick; Pagano, Sabrina; Yerly, Sabine; Kaiser, Laurent; Vuilleumier, Nicolas; Winssinger, Nicolas (2020). “Identification of immunodominant linear epitopes from SARS-CoV-2 patient plasma”. PLOS ONE. 15 (9): e0238089. doi:10.1371/journal.pone.0238089. ISSN 1932-6203. PMC 7480855. PMID 32903266.
- ^ Shrock, Ellen; Fujimura, Eric; Kula, Tomasz; Timms, Richard T.; Lee, I.-Hsiu; Leng, Yumei; Robinson, Matthew L.; Sie, Brandon M.; Li, Mamie Z.; Chen, Yuezhou; Logue, Jennifer (27 November 2020). “Viral epitope profiling of COVID-19 patients reveals cross-reactivity and correlates of severity”. Science. 370 (6520): eabd4250. doi:10.1126/science.abd4250. ISSN 1095-9203. PMC 7857405. PMID 32994364.
- ^ “Константин Чумаков: “Даже если человек переболел COVID-19, ему все равно нужно привиться. Иммунный ответ на прививку лучше и долговечнее, чем на саму болезнь””. republic.ru (in Russian). Retrieved 24 April 2021.
- Margarita Romanenko’s Lecture about Russian Covid-vaccines
- Meduza – Interview with EpiVacCorona developers, 23 March 2021
- Infection and Immunity – Study of the safety, reactogenicity and immunogenecity of the “EpiVacCorona” vaccine (PHASE I–II)
|Vaccine type||Peptide subunit|
|Legal status||Registered in Russia on 14 October 2020 RU Registered.TU approved.Full list : List of EpiVacCorona COVID-19 vaccine authorizations|
|Part of a series on the|
|COVID-19 (disease)SARS-CoV-2 (virus)|
EpiVacCorona Vaccine, developed by the Vektor State Research Center of Virology and Biotechnology in Russia, is based on peptide-antigens that facilitate immunity to the SARS-CoV-2 virus1. It is currently being tested in Phase I/II clinical trials for safety and immunogenicity (NCT04527575)1,2.
- Precision Vaccinations: VACCINE INFO EpiVacCorona Vaccine [Link]
- The Pharma Letter: Russia’s EpiVacCorona vaccine post-registration trials started [Link]
//////EpiVacCorona, SARS-CoV-2, RUSSIA, CORONA VIRUS, COVID 19, VACCINE, PEPTIDE
NEW DRUG APPROVALS
A COVID-19 vaccine comprising a dimeric form of SARS-CoV-2 receptor-binding domain (RBD) produced in China hamster ovary (CHO) cells and adjuvanted with aluminum hydroxide (Anhui Zhifei Longcom/Institute of Microbiol. China Academy of Sciences)
Anhui Zhifei Longcom Biopharmaceutical, Institute of Microbiology of the Chinese Academy of Sciences
CHO Cells Recombinant Vaccine
- Chinese Academy of Sciences (Originator)
- Zhifei Longcom (Originator)
Human SARS-CoV-2 (Covid-19 coronavirus) vaccine consisting of recombinant dimer comprising two RBD domains (R319-K527) of the spike glycoprotein of SARS-CoV-2 fused via a disulfide link; expressed in CHO cells
ZF-2001 is a recombinant coronavirus vaccine jointly developed by the Institute of Microbiology of the Chinese Academy of Sciences and Zhifei Longcom. The vaccine became available in 2021 in Uzbekistan under an emergency use authorization for the prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19). The vaccine is currently evaluated in phase III clinical trials.
This vaccine candidate, developed in China, uses SARS-CoV-2 protein subunits that are entirely engineered, created, and secreted by Chinese Hamster Ovary (CHO) cells1. The vaccine candidate is sponsored by Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd. and is undergoing phase I clinical trials to evaluate safety and tolerability.
ZF2001, trade-named ZIFIVAX, is an adjuvanted protein subunit COVID-19 vaccine developed by Anhui Zhifei Longcom in collaboration with the Institute of Microbiology at the Chinese Academy of Sciences. As of December 2020, the vaccine candidate was in Phase III trials with 29,000 participants in China, Ecuador, Malaysia, Pakistan, and Uzbekistan.
ZF2001 was first approved for use in Uzbekistan and later China. Production capacity is expected to be one billion doses a year. Phase II results published in The Lancet on the three dose administration showed seroconversion rates of neutralizing antibodies of between 92% to 97%.
Anhui Zhifei Longcom Biopharmaceuticals began a phase 3 clinical trial for its recombinant protein vaccine candidate in December, according to the WHO. State-run China Global Television Network in November reported that a one-year trial would take place in Uzbekistan and aim to recruit 5,000 volunteers. Anhui Zhifei is a unit of private firm Chongqing Zhifei Biological Products. It is co-developing the vaccine with the Chinese Academy of Sciences, a government institution.
Emergency Use Authorization received in UZ by Zhifei Longcom for the prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19)
As described in Cell, the CoV spike receptor-binding domain (RBD) is an attractive vaccine target for coronaviruses but is constrained by limited immunogenicity, however a dimeric form of MERS-CoV RBD offers greater protection. The RBD-dimer significantly increases neutralizing antibodies compared to a conventional monomeric form and protected mice against MERS-CoV infection. CoV RBD-dimer have been produced at high yields in pilot scale production.
Rather than injecting a whole virus, subunit vaccines contains virus particles specially selected to stimulate an immune response. Because the fragments are incapable of causing disease, subunit vaccines are considered very safe. Subunit vaccines in widespread use include the Hepatitis B vaccine and Pertussis vaccine. However, as only a few viral components are included in the vaccine which does not display the full complexity of the virus, their efficacy may be limited. Subunit vaccines are delivered alongside adjuvants and booster doses may be required.
According to industry experts, production for this kind of vaccine is stable and reliable, and easier to achieve large-scale industrial production at home and overseas. However it was noted it can be very inconvenient for people to come back for a second and third dose.
ZF2001 (Anhui Zhifei Longcom Biopharmaceutical/Chinese Academy of Medical Sciences)
The latest subunit vaccine candidate to enter Phase 3 clinical studies is the adjuvanted RBD-dimeric antigen designed by Anhui Zhifei Longcom Biopharmaceutical and the Institute of Microbiology of the Chinese Academy of Medical Sciences. Phase 3 clinical study was launched on December104 and will be initially carried out in China and Uzbekistan while Indonesia, Pakistan and Ecuador will follow as study sites (Clinical Trial Identifier: NCT04646590 and Registration Number: ChiCTR2000040153). The design of the study involves recruitment of 22,000 volunteers from China and 7000 subjects outside China for a total of 29,000 volunteers. There are still no published results on this candidate, however data from its Phase 2 placebo-controlled clinical trial (Clinical Trial Identifier: NCT04466085) conducted on a total of 900 participants ranging from 18 to 59 years old suggest that a 2 or 3 dose regimen is evaluated. Each immunization will be separated by the next by 4 weeks.
Phase I and II trials and results
In July, Longcom began a randomized, double-blind, placebo-controlled Phase II trial with 900 participants aged 18–59 in Changsha, Hunan divided into low-dose, high-dose, and placebo groups. In August, an additional Phase II trial was launched with 50 participants aged 60 and above.
In Phase II results published in The Lancet, on the two-dose schedule, seroconversion rates of neutralizing antibodies after the second dose were 76% (114 of 150 participants) in a 25 μg group and 72% (108 of 150) in a 50 μg group. On the three-dose schedule, seroconversion rate of neutralizing antibodies after the third dose were 97% (143 of 148 participants) in the 25 μg group and 93% (138 of 148) in the 50 μg group. 7 to 14 days after the administration of the third dose, the GMTs of neutralizing antibodies reached levels that were significantly higher than observed in human convalescent serum of recovering COVID-19 patients, especially in the 25 μg group.
Phase III trials
In December, Longcom began enrollment of a Phase III randomized, double-blind, placebo-controlled clinical trial for 29,000 participants, including 750 participants between 18-59 and 250 participants 60 and older in China and 21,000 participants between 18-59 and 7,000 participants 60 and older outside China.
In February, Pakistan‘s Drug Regulatory Authority (DRAP) approved Phase III trials with approximately 10,000 participants to be conducted at UHS Lahore, National Defense Hospital, and Agha Khan Hospital.
In February, lab studies of twelve serum samples taken from recipients of BBIBP-CorV and ZF2001 retained neutralizing activity against the Beta variant although with weaker activity than against the original virus. For ZF-2001, geometric mean titers declined by 1.6-fold, from 106.1 to 66.6, which was less than antisera from mRNA vaccine recipients with a 6-folds decrease. Preliminary clinical data from Novavax and Johnson & Johnson also showed they were less effective in preventing COVID-19 in South Africa, where the new variant is widespread.
The company’s vaccine manufacturing facility was put into use in September. In February 2021, Pu Jiang, General Manager of Zhifei Longcom, said the company had an annual production capacity of 1 billion doses.
Marketing and deployment
Full authorization Emergency authorization
On March 1, Uzbekistan granted approval for ZF2001 (under tradename ZF-UZ-VAC 2001) after having taken part in the Phase III trials. In March, Uzbekistan received 1 million doses and started vaccinations in April. By May, a total of 3 million doses had been delivered.
On March 15, China approve of ZF2001 for emergency use after being approved by Uzbekistan earlier in the month.
- ^ Jump up to:a b “Anhui Zhifei Longcom: RBD-Dimer – COVID19 Vaccine Tracker”. covid19.trackvaccines.org. Retrieved 27 December2020.
- ^ “COVID-19 Vaccine: ZIFIVAX by Anhui Zhifei Longcom Biopharma, Institute of Microbiology Chinese Academy of Sciences”. covidvax.org. Retrieved 27 December 2020.
- ^ “Fifth Chinese Covid-19 vaccine candidate ready to enter phase 3 trials”. South China Morning Post. 20 November 2020. Retrieved 27 December 2020.
- ^ Jump up to:a b Ying TP (7 December 2020). “MYEG to conduct phase 3 clinical trial for China’s Covid-19 vaccine in Msia | New Straits Times”. NST Online. Retrieved 27 December 2020.
- ^ Zimmer C, Corum J, Wee SL (10 June 2020). “Coronavirus Vaccine Tracker”. The New York Times. ISSN 0362-4331. Retrieved 27 December 2020.
- ^ Jump up to:a b c d “China’s production bottleneck ‘could be eased with latest Covid-19 vaccine'”. South China Morning Post. 17 March 2021. Retrieved 18 March 2021.
- ^ Jump up to:a b Liu, Roxanne (15 March 2021). “China IMCAS’s COVID-19 vaccine obtained emergency use approval in China”. Reuters. Retrieved 15 March 2021.
- ^ Jump up to:a b Mamatkulov, Mukhammadsharif (1 March 2021). “Uzbekistan approves Chinese-developed COVID-19 vaccine”. Reuters. Retrieved 2 March 2021.
- ^ Jump up to:a b Yang, Shilong; Li, Yan; Dai, Lianpan; Wang, Jianfeng; He, Peng; Li, Changgui; Fang, Xin; Wang, Chenfei; Zhao, Xiang; Huang, Enqi; Wu, Changwei (24 March 2021). “Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19 in adults: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials”. The Lancet Infectious Diseases. 0. doi:10.1016/S1473-3099(21)00127-4. ISSN 1473-3099. PMC 7990482. PMID 33773111.
- ^ Dai L, Zheng T, Xu K, Han Y, Xu L, Huang E, et al. (August 2020). “A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS”. Cell. 182 (3): 722–733.e11. doi:10.1016/j.cell.2020.06.035. PMC 7321023. PMID 32645327.
- ^ Jump up to:a b “What are protein subunit vaccines and how could they be used against COVID-19?”. http://www.gavi.org. Retrieved 27 December2020.
- ^ Dong Y, Dai T, Wei Y, Zhang L, Zheng M, Zhou F (October 2020). “A systematic review of SARS-CoV-2 vaccine candidates”. Signal Transduction and Targeted Therapy. 5 (1): 237. doi:10.1038/s41392-020-00352-y. PMC 7551521. PMID 33051445.
- ^ Clinical trial number NCT04445194 for “Phase I Clinical Study of Recombinant Novel Coronavirus Vaccine” at ClinicalTrials.gov
- ^ Clinical trial number NCT04466085 for “A Randomized, Blinded, Placebo-controlled Trial to Evaluate the Immunogenicity and Safety of a Recombinant New Coronavirus Vaccine (CHO Cell) With Different Doses and Different Immunization Procedures in Healthy People Aged 18 to 59 Years” at ClinicalTrials.gov
- ^ Clinical trial number NCT04550351 for “A Randomized, Double-blind, Placebo-controlled Phase I Clinical Trial to Evaluate the Safety and Tolerability of Recombinant New Coronavirus Vaccines (CHO Cells) in Healthy People Aged 60 Years and Above” at ClinicalTrials.gov
- ^ Clinical trial number NCT04646590 for “A Phase III Randomized, Double-blind, Placebo-controlled Clinical Trial in 18 Years of Age and Above to Determine the Safety and Efficacy of ZF2001, a Recombinant Novel Coronavirus Vaccine (CHO Cell) for Prevention of COVID-19” at ClinicalTrials.gov
- ^ Jump up to:a b c “Another Chinese Covid-19 vaccine enters late-stage human trials with a plan to produce 300 million doses annually”. Business Insider. Retrieved 27 December 2020.
- ^ Reuters Staff (11 November 2020). “Uzbekistan to carry out late-stage trial of Chinese COVID-19 vaccine candidate”. Reuters. Retrieved 27 December 2020.
- ^ “Uzbekistan poised to start trials on Chinese COVID-19 vaccine | Eurasianet”. eurasianet.org. Retrieved 27 December 2020.
- ^ “Ecuador participará en ensayos de una vacuna china contra el covid-19”. CNN (in Spanish). 29 December 2020. Retrieved 23 January 2021.
- ^ “China’s third vaccine enters Pakistan”. The Nation. 15 February 2021. Retrieved 28 February 2021.
- ^ “Covid vaccine tracker: How do the leading jabs compare?”. http://www.ft.com. 23 December 2020. Retrieved 27 December 2020.
- ^ Jump up to:a b Liu, Roxanne (3 February 2021). “Sinopharm’s COVID-19 vaccine remained active against S.Africa variant, effect reduced – lab study”. Reuters. Retrieved 29 March 2021.
- ^ Huang, Baoying; Dai, Lianpan; Wang, Hui; Hu, Zhongyu; Yang, Xiaoming; Tan, Wenjie; Gao, George F. (2 February 2021). “Neutralization of SARS-CoV-2 VOC 501Y.V2 by human antisera elicited by both inactivated BBIBP-CorV and recombinant dimeric RBD ZF2001 vaccines”. bioRxiv: 2021.02.01.429069. doi:10.1101/2021.02.01.429069.
- ^ uz, Kun. “Uzbekistan receives 1 million doses of ZF-UZ-VAC 2001 vaccine”. Kun.uz. Retrieved 28 March 2021.
- ^ Romakayeva, Klavdiya (18 May 2021). “Uzbekistan receives third batch of Chinese-Uzbek COVID-19 vaccine”. Trend.Az. Retrieved 19 May 2021.
|Vaccine type||Protein subunit|
|Part of a series on the|
|COVID-19 (disease)SARS-CoV-2 (virus)|
////////ZF2001, ZIFIVAX, corona virus, covid 19, SARS-CoV-2, ZF 2001, ZF-UZ-VAC2001, Uzbekistan, approvals 2021
NEW DRUG APPROVALS
CAS Registry Number: 64-86-8CAS Name:N-[(7S)-5,6,7,9-Tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[a]heptalen-7-yl]acetamideMolecular Formula: C22H25NO6Molecular Weight: 399.44
CSIR-Laxai Life Sciences get DCGI nod for clinical trials Colchicine on Covid patients
It is an important therapeutic intervention for Covid-19 patients with cardiac co-morbidities and also for reducing proinflammatory cytokines
The Council of Scientific & Industrial Research (CSIR), and Laxai Life Sciences Pvt. Ltd. Hyderabad, have obtained approval from the Drug Controller General of India (DCGI) to undertake a two-arm phase-II clinical trial of the drug Colchicine for Covid-19 treatment.
The partner CSIR institutes in this important clinical trial are the CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad and CSIR-Indian Institute of Integrative Medicine (IIIM), Jammu.
According to Ram Vishwakarma, advisor to DG-CSIR, colchicine, in combination with standard of care, will be an important therapeutic intervention for Covid-19 patients with cardiac co-morbidities and also for reducing proinflammatory cytokines, leading to faster recovery.
A number of global studies have confirmed now that cardiac complications during the course of Covid-19 infections and post-covid syndrome are leading to the loss of many lives, and it is essential to look for new or repurposed drugs.
CHAIRMAN AND MD, LAXAI
A visionary & an entrepreneur with 17 years of experience in technology and bio-pharma industries. Founder and ex-CEO of LAXAI Pharma Ltd – a clinical data services company based in NJ, USA. Past employment: Pfizer, Wyeth Pharmaceuticals, Johnson & Johnson and Deloitte.
Vamsi provides a unique blend of operational and financial experience – along with a strong and expansive network of key influencers, industry experts and financial partners. He delivers a visionary understanding of client challenges and opportunities, and the instinctive ability to facilitate collaboration between the right people to turn strategic concepts into actionable plans – and, ultimately, into business results.
Dr S Chandrasekhar (Director CSIR-IICT, Hyderabad) and Dr. DS Reddy (Director, CSIR-IIIM, Jammu), the two partner institutes from CSIR said that they were looking forward to the outcome of this Phase II clinical efficacy trial on Colchicine, which may lead to life-saving intervention in the management of hospitalised patients.
Dr S Chandrasekhar (Director CSIR-IICT, Hyderabad)
Dr. DS Reddy (Director, CSIR-IIIM, Jammu)
India is one of the largest producers of this key drug and if successful, it will be made available to the patients at an affordable cost.
According to Ram Upadhayay, CEO, Laxai the enrollment of patients has already begun at multiple sites across India and the trial is likely to be completed in the next 8-10 weeks.
The drug can be made available to the large population of India based on the results of this trial and regulatory approval, he added.
Recent clinical studies have reported in leading medical journals about colchicine being associated with a significant reduction in the rates of recurrent pericarditis, post-pericardiotomy syndrome, and peri-procedural atrial fibrillation following cardiac surgery and atrial fibrillation ablation, according to a release.
Ram Upadhayaya, PhD
Chief Executive Officer, LAXAI
Ram Upadhayaya, CEO of Laxai Life Sciences, brings with him more than two decades of R&D experience spanning both academia and industry. A Ph. D in synthetic organic Chemistry, Ram has held key positions with leading international drug discovery organizations such as Bioimics AB Sweden, and Lupin India. Apart from his industrial background, Ram has been deeply associated with academic research. He was associated with Institute of Molecular Medicine, India as Principal Scientist as well as Uppsala University, Sweden in the capacity of Assistant Professor (Forskare). During these stints he significantly contributed to the development of novel therapeutics against infectious diseases such as AIDS and TB.
Ram has 10 international patents to his credit and has authored 25 peer reviewed publications. He is concurrently a consultant to the scientific advisory committee of the Principal Scientific Advisor, Government of India.
Raghava Reddy Kethiri, PhD, LAXAI
Chief Scientific Officer
25+ years of experience at various leadership positions in Biotech, CRO and Universities; Ex Karlsruhe Institute of Technology (KIT), Technical University of Dresden (TUD), JADO Technologies , Dresden, Germany, Jubilant Biosys, India
Delivered several leads, optimised leads and PCCs/DCs across Oncology, Pain, CNS, MD and Antibacterial therapeutics areas for global pharmaceutical companies. Co-Inventor of two clinical candidates ASN-001 ( NCT 02349139) for Metastatic Castration Resistant Prostrate Cancer & ASN-007 (NCT 03415126) for metastatic KRAS, NRAS & HRAS mutated solid tumors. Co-authored over 60 publications/patents (US/EU/Indian)
CAS Registry Number: 64-86-8
CAS Name:N-[(7S)-5,6,7,9-Tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[a]heptalen-7-yl]acetamideMolecular Formula: C22H25NO6Molecular Weight: 399.44Percent Composition: C 66.15%, H 6.31%, N 3.51%, O 24.03%
Literature References: A major alkaloid of Colchicum autumnale L., Liliaceae. Extraction procedure: Chemnitius, J. Prakt. Chem. [II] 118, 29 (1928); F. E. Hamerslag, Technology and Chemistry of Alkaloids (New York, 1950) pp 66-80. Structure: Dewar, Nature155, 141 (1945); King et al.,Acta Crystallogr.5, 437 (1952); Horowitz, Ullyot, J. Am. Chem. Soc.74, 487 (1952). Crystal structure: L. Lessinger, T. N. Margulis, Acta Crystallogr.B34, 578 (1978).
Total synthesis: Schreiber et al.,Helv. Chim. Acta44, 540 (1961); Van Tamelen et al.,Tetrahedron14, 8 (1961); Nakamura, Chem. Pharm. Bull.8, 843 (1960); Sunagawa et al.,ibid.9, 81 (1961); 10, 281 (1962); Scott et al.,Tetrahedron21, 3605 (1965); Woodward, Harvey Lectures, Ser. 59 (Academic Press, New York, 1965) p 31; Kotani et al.,Chem. Commun.1974, 300; D. A. Evans et al.,J. Am. Chem. Soc.103, 5813 (1981).
Biosynthesis: Leete, Tetrahedron Lett.1965, 333; Battersby et al.,J. Chem. Soc.1964, 4257; Hill, Unrau, Can. J. Chem.43, 709 (1965). Tubulin-binding activity: J. M. Andreu, S. N. Timasheff, Proc. Natl. Acad. Sci. USA79, 6753 (1982). Toxicity: S. J. Rosenbloom, F. C. Ferguson, Toxicol. Appl. Pharmacol.13, 50 (1968); R. P. Beliles, ibid.23, 537 (1972). Clinical evaluations in cirrhosis of the liver: M. M. Kaplan et al.,N. Engl. J. Med.315, 1448 (1986); D. Kershenobich et al.,ibid.318, 1709 (1988). Bibliography of early literature: Eigsti, Lloydia10, 65 (1947).
Monograph: O. J. Eigsti, P. Dustin, Jr., Colchicine in Agriculture, Medicine, Biology and Chemistry (Iowa State College Press, Ames, Iowa, 1955). Reviews: Fleming, Selected Organic Syntheses (John Wiley, London, 1973) pp 183-207; G. Lagrue et al.,Ann. Med. Interne132, 496-500 (1981); F. D. Malkinson, Arch. Dermatol.118, 453-457 (1982). Comprehensive description: D. K. Wyatt et al.,Anal. Profiles Drug Subs.10, 139-182 (1981).
Properties: Pale yellow scales or powder, mp 142-150°. Darkens on exposure to light. Has been crystallized from ethyl acetate, pale yellow needles, mp 157°. [a]D17 -429° (c = 1.72). [a]D17 -121° (c = 0.9 in chloroform). pK at 20°: 12.35; pH of 0.5% soln: 5.9. uv max (95% ethanol): 350.5, 243 nm (log e 4.22; 4.47). One gram dissolves in 22 ml water, 220 ml ether, 100 ml benzene; freely sol in alcohol or chloroform. Practically insol in petr ether. Forms two cryst compds with chloroform, B.CHCl3 or B.2CHCl3, which do not give up their chloroform unless heated between 60 and 70° for considerable time. LD50 in rats (mg/kg): 1.6 i.v. (Rosenbloom, Ferguson); in mice (mg/kg): 4.13 i.v. (Beliles).
Melting point: mp 142-150°; mp 157°pKa: pK at 20°: 12.35; pH of 0.5% soln: 5.9Optical Rotation: [a]D17 -429° (c = 1.72); [a]D17 -121° (c = 0.9 in chloroform)Absorption maximum: uv max (95% ethanol): 350.5, 243 nm (log e 4.22; 4.47)
Toxicity data: LD50 in rats (mg/kg): 1.6 i.v. (Rosenbloom, Ferguson); in mice (mg/kg): 4.13 i.v. (Beliles)Use: In research in plant genetics (for doubling chromosomes).Therap-Cat: Gout suppressant. Treatment of Familial Mediterranean Fever.Therap-Cat-Vet: Has been used as an antineoplastic.Keywords: Antigout.
DOI: 10.1002/hlca.19610440225 DOI: 10.1021/ja00409a032
Here, we describe a concise, enantioselective, and scalable synthesis of (−)-colchicine (9.2% overall yield, >99% ee). Moreover, we have also achieved the first syntheses of (+)-demecolcinone and metacolchicine, and determined their absolute configurations. The challenging tricyclic 6-7-7 core of colchicinoids was efficiently introduced using an intramolecular oxidopyrylium-mediated [5 + 2] cycloaddition reaction. Notably, the synthesized colchicinoid 23 exhibited potent inhibitory activity toward the cell growth of human cancer cell lines (IC50 = ∼3.0 nM), and greater inhibitory activity towards microtubule assembly than colchicine, making it a promising lead in the search for novel anticancer agents.
Enantioselective total synthesis of (−)- and (+)-colchicine
The synthesis began with the transition-metal-catalyzed C–H bond functionalization of 7 with 14 (Scheme 1). Inspired by Li’s seminal work,18 we applied the strategy to compound 7. Pleasingly, after optimization, we successfully generated the N-sulfonyl imine in situ by reaction of 7 with TsNH2 (15) in the presence of anhydrous CuSO4 in THF. Furthermore, subsequent treatment of this imine with [RhCp*Cl2]2 (1 mol%), AgSbF6 (4 mol%), NaOAc (2.0 equiv.), and 14 (2.0 equiv.) at 80 °C afforded ortho-olefinated benzaldehyde 16 in good yield (90% on a 0.5 g scale; 70% on a 5.0 g scale). This modified catalytic C–H bond activation involved a transient directing group.19
Recently one of my relatives have fallen ill and was prescribed with some colchicine. Looking at the structure of the molecule, and with nothing much to do, I decided to put my retrosynthetic skills to the test. Here is a picture of my thought process:
Is there a better way to design a synthesis for this compound using the disconnection method.
From 11b, a Birch reduction is carried out to give the qunione 10b. A rearrangement of the ketone with methanediazonium gives 9b. A dihydroxylation with a peroxy acid and subsequent addition of water gives 8b. A double dehydration reaction with sulfuric acid, coupled with the protection of the ketone with propan-1,3-diol gives the seven-membered quinone 7b. A Heck reaction (or Ullmann reaction) with 7a with a palladium catalyst yields 6. (The protection group is thereafter labelled “PG”) Friedel-Crafts acylation with ethanoyl chloride yields 5 (although on second thoughts, I should have done the acylation from 7a from the start). A Michael addition is then carried out with BuLiBuLi to lithiate the ketone to give the terminal imine 4. Since this terminal imine is unstable, a mild reducing agent converts the imine to the amine 3. The ketone is then removed by addition of dithiol and subsequently reduced by Raney nickel to form 2. Finally, a simple condensation reaction between the amine and acetic anhydride, followed by deprotection of the ketone using an acid, yields the final product colchicine, 1.
Colchicine is a medication used to treat gout and Behçet’s disease. In gout, it is less preferred to NSAIDs or steroids. Other uses for colchicine include the management of pericarditis and familial Mediterranean fever. Colchicine is taken by mouth.
Colchicine has a narrow therapeutic index and overdosing is therefore a significant risk. Common side effects of colchicine include gastrointestinal upset, particularly at high doses. Severe side effects may include low blood cells and rhabdomyolysis, and the medication can be deadly in overdose. It is not clear whether colchicine is safe for use during pregnancy, but its use during breastfeeding appears to be safe. Colchicine works by decreasing inflammation via multiple mechanisms.
Colchicine, in the form of the autumn crocus (Colchicum autumnale), has been used as early as 1500 BC to treat joint swelling. It was approved for medical use in the United States in 1961. It is available as a generic medication in the United Kingdom. In 2017, it was the 201st-most commonly prescribed medication in the United States, with more than two million prescriptions.
Colchicine is an alternative for those unable to tolerate NSAIDs in gout. At high doses, side effects (primarily gastrointestinal upset) limit its use. At lower doses, it is well tolerated. One review found low-quality evidence that low-dose colchicine (1.8 mg in one hour or 1.2 mg per day) reduced gout symptoms and pain, whereas high-dose colchicine (4.8 mg over 6 hours) was effective against pain, but caused more severe side effects, such as diarrhea, nausea or vomiting.
For treating gout symptoms, colchicine is used orally with or without food, as symptoms first appear. Subsequent doses may be needed if symptoms worsen. There is preliminary evidence that daily colchicine (0.6 mg twice daily) was effective as a long-term prophylaxis when used with allopurinol to reduce the risk of increased uric acid levels and acute gout flares, although adverse gastrointestinal effects may occur.
Colchicine is also used as an anti-inflammatory agent for long-term treatment of Behçet’s disease. It appears to have limited effect in relapsing polychondritis, as it may only be useful for the treatment of chondritis and mild skin symptoms. It is a component of therapy for several other conditions, including pericarditis, pulmonary fibrosis, biliary cirrhosis, various vasculitides, pseudogout, spondyloarthropathies, calcinosis, scleroderma, and amyloidosis. Research regarding the efficacy of colchicine in many of these diseases has not been performed. It is also used in the treatment of familial Mediterranean fever, in which it reduces attacks and the long-term risk of amyloidosis.
Colchicine is effective for prevention of atrial fibrillation after cardiac surgery. Potential applications for the anti-inflammatory effect of colchicine have been studied with regard to atherosclerosis and chronic coronary disease (e.g., stable ischemic heart disease). In people with recent myocardial infarction (recent heart attack), it has been found to reduce risk of future cardiovascular events. Its clinical use may grow to include this indication.
Long-term (prophylactic) regimens of oral colchicine are absolutely contraindicated in people with advanced kidney failure (including those on dialysis). About 10-20 percent of a colchicine dose is excreted unchanged by the kidneys; it is not removed by hemodialysis. Cumulative toxicity is a high probability in this clinical setting, and a severe neuromyopathy may result. The presentation includes a progressive onset of proximal weakness, elevated creatine kinase, and sensorimotor polyneuropathy. Colchicine toxicity can be potentiated by the concomitant use of cholesterol-lowering drugs.
Deaths – both accidental and intentional – have resulted from overdose of colchicine. Typical side effects of moderate doses may include gastrointestinal upset, diarrhea, and neutropenia. High doses can also damage bone marrow, lead to anemia, and cause hair loss. All of these side effects can result from inhibition of mitosis, which may include neuromuscular toxicity and rhabdomyolysis.
According to one review, colchicine poisoning by overdose (range of acute doses of 7 to 26 mg) begins with a gastrointestinal phase occurring 10–24 hours after ingestion, followed by multiple organ dysfunction occurring 24 hours to 7 days after ingestion, after which the affected person either declines into multi-organ failure or recovers over several weeks.
Colchicine can be toxic when ingested, inhaled, or absorbed in the eyes. Colchicine can cause a temporary clouding of the cornea and be absorbed into the body, causing systemic toxicity. Symptoms of colchicine overdose start 2 to 24 hours after the toxic dose has been ingested and include burning in the mouth and throat, fever, vomiting, diarrhea, and abdominal pain. This can cause hypovolemic shock due to extreme vascular damage and fluid loss through the gastrointestinal tract, which can be fatal.
If the affected person survives the gastrointestinal phase of toxicity, they may experience multiple organ failure and critical illness. This includes kidney damage, which causes low urine output and bloody urine; low white blood cell counts that can last for several days; anemia; muscular weakness; liver failure; hepatomegaly; bone marrow suppression; thrombocytopenia; and ascending paralysis leading to potentially fatal respiratory failure. Neurologic symptoms are also evident, including seizures, confusion, and delirium; children may experience hallucinations. Recovery may begin within six to eight days and begins with rebound leukocytosis and alopecia as organ functions return to normal.
Long-term exposure to colchicine can lead to toxicity, particularly of the bone marrow, kidney, and nerves. Effects of long-term colchicine toxicity include agranulocytosis, thrombocytopenia, low white blood cell counts, aplastic anemia, alopecia, rash, purpura, vesicular dermatitis, kidney damage, anuria, peripheral neuropathy, and myopathy.
No specific antidote for colchicine is known, but supportive care is used in cases of overdose. In the immediate period after an overdose, monitoring for gastrointestinal symptoms, cardiac dysrhythmias, and respiratory depression is appropriate, and may require gastrointestinal decontamination with activated charcoal or gastric lavage.
Mechanism of toxicity
With overdoses, colchicine becomes toxic as an extension of its cellular mechanism of action via binding to tubulin. Cells so affected undergo impaired protein assembly with reduced endocytosis, exocytosis, cellular motility, and interrupted function of heart cells, culminating in multi-organ failure.
In the United States, there are several hundred recorded cases of colchicine toxicity annually; approximately 10% of which end with serious morbidity or mortality. Many of these cases are intentional overdoses, but others were accidental; for example, if the drug was not dosed appropriately for kidney function. Most cases of colchicine toxicity occur in adults. Many of these adverse events resulted from the use of intravenous colchicine.
Colchicine interacts with the P-glycoprotein transporter, and the CYP3A4 enzyme involved in drug and toxin metabolism. Fatal drug interactions have occurred when colchicine was taken with other drugs that inhibit P-glycoprotein and CYP3A4, such as erythromycin or clarithromycin.
People taking macrolide antibiotics, ketoconazole or cyclosporine, or those who have liver or kidney disease, should not take colchicine, as these drugs and conditions may interfere with colchicine metabolism and raise its blood levels, potentially increasing its toxicity abruptly. Symptoms of toxicity include gastrointestinal upset, fever, muscle pain, low blood cell counts, and organ failure. People with HIV/AIDS taking atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir may experience colchicine toxicity. Grapefruit juice and statins can also increase colchicine concentrations.
In gout, inflammation in joints results from the precipitation of circulating uric acid, exceeding its solubility in blood and depositing as crystals of monosodium urate in and around synovial fluid and soft tissues of joints. These crystal deposits cause inflammatory arthritis, which is initiated and sustained by mechanisms involving various proinflammatory mediators, such as cytokines. Colchicine accumulates in white blood cells and affects them in a variety of ways: decreasing motility, mobilization (especially chemotaxis) and adhesion.
Under preliminary research are various mechanisms by which colchicine may interfere with gout inflammation:
- inhibits microtubule polymerization by binding to its constitutive protein, tubulin
- as availability of tubulin is essential to mitosis, colchicine may inhibit mitosis
- inhibits activation and migration of neutrophils to sites of inflammation
- interferes with the inflammasome complex found in neutrophils and monocytes that mediate interleukin-1β activation, a component of inflammation
- inhibits superoxide anion production in response to urate crystals
- interrupts mast cell and lysosome degranulation
- inhibits release of glycoproteins that promote chemotaxis from synovial cells and neutrophils
Generally, colchicine appears to inhibit multiple proinflammatory mechanisms, while enabling increased levels of anti-inflammatory mediators. Apart from inhibiting mitosis, colchicine inhibits neutrophil motility and activity, leading to a net anti-inflammatory effect, which has efficacy for inhibiting or preventing gout inflammation.
The plant source of colchicine, the autumn crocus (Colchicum autumnale), was described for treatment of rheumatism and swelling in the Ebers Papyrus (circa 1500 BC), an Egyptian medical papyrus. It is a toxic alkaloid and secondary metabolite. Colchicum extract was first described as a treatment for gout in De Materia Medica by Pedanius Dioscorides, in the first century AD. Use of the bulb-like corms of Colchicum to treat gout probably dates to around 550 AD, as the “hermodactyl” recommended by Alexander of Tralles. Colchicum corms were used by the Persian physician Avicenna, and were recommended by Ambroise Paré in the 16th century, and appeared in the London Pharmacopoeia of 1618. Colchicum use waned over time, likely due to the severe gastrointestinal side effects preparations caused. In 1763, Colchicum was recorded as a remedy for dropsy (now called edema) among other illnesses. Colchicum plants were brought to North America by Benjamin Franklin, who had gout himself and had written humorous doggerel about the disease during his stint as United States Ambassador to France.
Colchicine was first isolated in 1820 by the French chemists P. S. Pelletier and J. B.Caventou. In 1833, P. L. Geiger purified an active ingredient, which he named colchicine. It quickly became a popular remedy for gout. The determination of colchicine’s structure required decades, although in 1945, Michael Dewar made an important contribution when he suggested that, among the molecule’s three rings, two were seven-member rings. Its pain-relieving and anti-inflammatory effects for gout were linked to its ability to bind with tubulin.
An unintended consequence of the 2006 U.S. Food and Drug Administration (FDA) safety program called the Unapproved Drugs Initiative—through which the FDA sought more rigorous testing of efficacy and safety of colchicine and other unapproved drugs—was a price increase of 2000 percent  for “a gout remedy so old that the ancient Greeks knew about its effects.” Under Unapproved Drugs Initiative small companies like URL Pharma, a Philadelphia drugmaker, were rewarded with licenses for testing of medicines like colchicine. In 2009, the FDA reviewed a New Drug Application for colchicine submitted by URL Pharma. URL Pharma did the testing, gained FDA formal approval, and was granted rights over colchicine. With this monopoly pricing power, the price of colchicine increased.
In 2012 Asia’s biggest drugmaker, Takeda Pharmaceutical Co., acquired URL Pharma for $800 million including the rights to colchicine (brand name Colcrys) earning $1.2 billion in revenue by raising the price even more.
Oral colchicine had been used for many years as an unapproved drug with no FDA-approved prescribing information, dosage recommendations, or drug interaction warnings. On July 30, 2009, the FDA approved colchicine as a monotherapy for the treatment of three different indications (familial Mediterranean fever, acute gout flares, and for the prophylaxis of gout flares), and gave URL Pharma a three-year marketing exclusivity agreement in exchange for URL Pharma doing 17 new studies and investing $100 million into the product, of which $45 million went to the FDA for the application fee. URL Pharma raised the price from $0.09 per tablet to $4.85, and the FDA removed the older unapproved colchicine from the market in October 2010, both in oral and intravenous forms, but allowed pharmacies to buy up the older unapproved colchicine. Colchicine in combination with probenecid has been FDA-approved before 1982.
July 29, 2009, colchicine won FDA approval in the United States as a stand-alone drug for the treatment of acute flares of gout and familial Mediterranean fever. It had previously been approved as an ingredient in an FDA-approved combination product for gout. The approval was based on a study in which two doses (1.2 mg and 0.6 mg) an hour apart were as effective as higher doses in combating the acute flare of gout.
As a drug antedating the FDA, colchicine was sold in the United States for many years without having been reviewed by the FDA for safety and efficacy. The FDA reviewed approved colchicine for gout flares, awarding Colcrys a three-year term of market exclusivity, prohibiting generic sales, and increasing the price of the drug from $0.09 to $4.85 per tablet.
Numerous consensus guidelines, and previous randomized controlled trials, had concluded that colchicine is effective for acute flares of gouty arthritis. However, as of 2006, the drug was not formally approved by the FDA, owing to the lack of a conclusive randomized control trial (RCT). Through the Unapproved Drugs Initiative, the FDA sought more rigorous testing of the efficacy and safety of colchicine and other unapproved drugs. In exchange for paying for the costly testing, the FDA gave URL Pharma three years of market exclusivity for its Colcrys brand, under the Hatch-Waxman Act, based in part on URL-funded research in 2007, including pharmacokinetic studies and a randomized control trial with 185 patients with acute gout.
In April 2010, an editorial in the New England Journal of Medicine said that the rewards of this legislation are not calibrated to the quality or value of the information produced, that no evidence of meaningful improvement to public health was seen, and that it would be less expensive for the FDA, the National Institutes of Health or large insurers to pay for trials themselves. Furthermore, the cost burden of this subsidy falls primarily on patients or their insurers. In September 2010, the FDA ordered a halt to marketing unapproved single-ingredient oral colchicine.
Colchicine patents expire on February 10, 2029.
URL Pharma also received seven years of market exclusivity for Colcrys in the treatment of familial Mediterranean fever, under the Orphan Drug Law. URL Pharma then raised the price per tablet from $0.09 to $4.85 and sued to remove other versions from the market, increasing annual costs for the drug to U.S. state Medicaid programs from $1 million to $50 million. Medicare also paid significantly higher costs, making this a direct money-loser for the government. (In a similar case, thalidomide was approved in 1998 as an orphan drug for leprosy and in 2006 for multiple myeloma.)
It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002) and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities.
Formulations and dosing
Trade names for colchicine are Colcrys or Mitigare which are manufactured as a dark– and light-blue capsule having a dose of 0.6 mg. Colchicine is also prepared as a white, yellow, or purple pill (tablet) having a dose of 0.6 mg.
Colchicine is typically prescribed to mitigate or prevent the onset of gout, or its continuing symptoms and pain, using a low-dose prescription of 0.6 to 1.2 mg per day, or a high-dose amount of up to 4.8 mg in the first 6 hours of a gout episode. With an oral dose of 0.6 mg, peak blood levels occur within one to two hours. For treating gout, the initial effects of colchicine occur in a window of 12 to 24 hours, with a peak within 48 to 72 hours. It has a narrow therapeutic window, requiring monitoring of the subject for potential toxicity. Colchicine is not a general pain relief drug, and is not used to treat pain in other disorders.
According to laboratory research, the biosynthesis of colchicine involves the amino acids phenylalanine and tyrosine as precursors. Giving radioactive phenylalanine-2-14C to C. byzantinum, another plant of the family Colchicaceae, resulted in its incorporation into colchicine. However, the tropolone ring of colchicine resulted from the expansion of the tyrosine ring. Radioactive feeding experiments of C. autumnale revealed that colchicine can be synthesized biosynthetically from (S)-autumnaline. That biosynthesic pathway occurs primarily through a phenolic coupling reaction involving the intermediate isoandrocymbine. The resulting molecule undergoes O-methylation directed by S-adenosylmethionine. Two oxidation steps followed by the cleavage of the cyclopropane ring leads to the formation of the tropolone ring contained by N-formyldemecolcine. N-formyldemecolcine hydrolyzes then to generate the molecule demecolcine, which also goes through an oxidative demethylation that generates deacetylcolchicine. The molecule of colchicine appears finally after addition of acetyl-coenzyme A to deacetylcolchicine.
Colchicine may be purified from Colchicum autumnale (autumn crocus) or Gloriosa superba (glory lily). Concentrations of colchicine in C. autumnale peak in the summer, and range from 0.1% in the flower to 0.8% in the bulb and seeds.
Colchicine is widely used in plant breeding by inducing polyploidy in plant cells to produce new or improved varieties, strains and cultivars. When used to induce polyploidy in plants, colchicine cream is usually applied to a growth point of the plant, such as an apical tip, shoot, or sucker. Seeds can be presoaked in a colchicine solution before planting. Since chromosome segregation is driven by microtubules, colchicine alters cellular division by inhibiting chromosome segregation during meiosis; half the resulting gametes, therefore, contain no chromosomes, while the other half contains double the usual number of chromosomes (i.e., diploid instead of haploid, as gametes usually are), and lead to embryos with double the usual number of chromosomes (i.e., tetraploid instead of diploid). While this would be fatal in most higher animal cells, in plant cells it is not only usually well-tolerated, but also frequently results in larger, hardier, faster-growing, and in general more desirable plants than the normally diploid parents. For this reason, this type of genetic manipulation is frequently used in breeding plants commercially.
When such a tetraploid plant is crossed with a diploid plant, the triploid offspring are usually sterile (unable to produce fertile seeds or spores), although many triploids can be propagated vegetatively. Growers of annual triploid plants not readily propagated vegetatively cannot produce a second-generation crop from the seeds (if any) of the triploid crop and need to buy triploid seed from a supplier each year. Many sterile triploid plants, including some trees, and shrubs, are becoming increasingly valued in horticulture and landscaping because they do not become invasive species and will not drop undesirable fruit and seed litter. In certain species, colchicine-induced triploidy has been used to create “seedless” fruit, such as seedless watermelons (Citrullus lanatus). Since most triploids do not produce pollen themselves, such plants usually require cross-pollination with a diploid parent to induce seedless fruit production.
The ability of colchicine to induce polyploidy can be also exploited to render infertile hybrids fertile, for example in breeding triticale (× Triticosecale) from wheat (Triticum spp.) and rye (Secale cereale). Wheat is typically tetraploid and rye diploid, with their triploid hybrid infertile; treatment of triploid triticale with colchicine gives fertile hexaploid triticale.
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- ^ Puéchal X, Terrier B, Mouthon L, Costedoat-Chalumeau N, Guillevin L, Le Jeunne C (March 2014). “Relapsing polychondritis”. Joint Bone Spine. 81 (2): 118–24. doi:10.1016/j.jbspin.2014.01.001. PMID 24556284.
- ^ Alabed S, Cabello JB, Irving GJ, Qintar M, Burls A (August 2014). “Colchicine for pericarditis” (PDF). The Cochrane Database of Systematic Reviews. 8 (8): CD010652. doi:10.1002/14651858.CD010652.pub2. PMID 25164988.
- ^ Jump up to:a b c d e f g h i j Goldfrank’s toxicologic emergencies. Nelson, Lewis, 1963- (Eleventh ed.). New York. 2019-04-11. ISBN 978-1-259-85961-8. OCLC 1020416505.
- ^ Portincasa P (2016). “Colchicine, Biologic Agents and More for the Treatment of Familial Mediterranean Fever. The Old, the New, and the Rare”. Current Medicinal Chemistry. 23 (1): 60–86. doi:10.2174/0929867323666151117121706. PMID 26572612.
- ^ Lennerz C, Barman M, Tantawy M, Sopher M, Whittaker P (December 2017). “Colchicine for primary prevention of atrial fibrillation after open-heart surgery: Systematic review and meta-analysis” (PDF). International Journal of Cardiology. 249: 127–137. doi:10.1016/j.ijcard.2017.08.039. PMID 28918897.
- ^ Malik, Jahanzeb; Javed, Nismat; Ishaq, Uzma; Khan, Umar; Laique, Talha (17 May 2020). “Is There a Role for Colchicine in Acute Coronary Syndromes? A Literature Review”. Cureus. 12(5): e8166. doi:10.7759/cureus.8166. PMC 7296886. PMID 32550081.
- ^ Imazio M, Andreis A, Brucato A, Adler Y, De Ferrari GM (July 2020). “Colchicine for acute and chronic coronary syndromes”. Heart. 106 (20): heartjnl–2020–317108. doi:10.1136/heartjnl-2020-317108. PMID 32611559. S2CID 220305546.
- ^ Nidorf SM, Fiolet AT, Mosterd A, Eikelboom JW, Schut A, Opstal TS, et al. (August 2020). “Colchicine in Patients with Chronic Coronary Disease”. The New England Journal of Medicine. 383(19): 1838–1847. doi:10.1056/NEJMoa2021372. PMID 32865380.
- ^ Kaul S, Gupta M, Bandyopadhyay D, Hajra A, Deedwania P, Roddy E, et al. (December 2020). “Gout Pharmacotherapy in Cardiovascular Diseases: A Review of Utility and Outcomes”. American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions. doi:10.1007/s40256-020-00459-1. PMC 7768268. PMID 33369719.
- ^ Reyes, Aaron Z; Hu, Kelly A; Teperman, Jacob; Wampler Muskardin, Theresa L; Tardif, Jean-Claude; Shah, Binita; Pillinger, Michael H (2020-12-08). “Anti-inflammatory therapy for COVID-19 infection: the case for colchicine”. Annals of the Rheumatic Diseases: annrheumdis–2020–219174. doi:10.1136/annrheumdis-2020-219174. ISSN 0003-4967. PMID 33293273.
- ^ Jump up to:a b c d “CDC – The Emergency Response Safety and Health Database: Biotoxin: Cochicine”. Centers for Disease Control and Prevention, US Department of Health and Human Services. Retrieved 31 December 2015.
- ^ Jump up to:a b c d e f g h Finkelstein Y, Aks SE, Hutson JR, Juurlink DN, Nguyen P, Dubnov-Raz G, et al. (June 2010). “Colchicine poisoning: the dark side of an ancient drug”. Clinical Toxicology. 48 (5): 407–14. doi:10.3109/15563650.2010.495348. PMID 20586571. S2CID 33905426.
- ^ Jump up to:a b Matt Doogue (2014). “Colchicine – extremely toxic in overdose” (PDF). Christchurch and Canterbury District Health Board, New Zealand. Retrieved 23 August 2018.
- ^ Graham W, Roberts JB (March 1953). “Intravenous colchicine in the management of gouty arthritis”. Annals of the Rheumatic Diseases. 12 (1): 16–9. doi:10.1136/ard.12.1.16. PMC 1030428. PMID 13031443.
- ^ Jump up to:a b “Colcrys (colchicine). Summary review for regulatory action”(PDF). Center for Drug Evaluation and Research, US Food and Drug Administration. 30 July 2009. Retrieved 19 August 2018.
- ^ Hartung EF (September 1954). “History of the use of colchicum and related medicaments in gout; with suggestions for further research”. Annals of the Rheumatic Diseases. 13 (3): 190–200. doi:10.1136/ard.13.3.190. PMC 1006735. PMID 13198053.(free BMJ registration required)
- ^ Ebadi MS (2007). Pharmacodynamic basis of herbal medicine. ISBN 978-0-8493-7050-2.
- ^ Pelletier and Caventou (1820) “Examen chimique des plusieurs végétaux de la famille des colchicées, et du principe actif qu’ils renferment. [Cévadille (veratrum sabadilla); hellébore blanc (veratrum album); colchique commun (colchicum autumnale)]”(Chemical examination of several plants of the meadow saffron family, and of the active principle that they contain.) Annales de Chimie et de Physique, 14 : 69-81.
- ^ Geiger, Ph. L. (1833) “Ueber einige neue giftige organische Alkalien” (On some new poisonous organic alkalis) Annalen der Pharmacie, 7 (3) : 269-280; colchicine is discussed on pages 274-276.
- ^ Dewar MJ (February 3, 1945). “Structure of colchicine”. Letters to Editor. Nature. 155 (3927): 141–142. Bibcode:1945Natur.155..141D. doi:10.1038/155141d0. S2CID 4074312. Dewar did not prove the structure of colchicine; he merely suggested that it contained two seven-membered rings. Colchicine’s structure was determined by X-ray crystallography in 1952 King MV, de Vries JL, Pepinsky R (July 1952). “An x-ray diffraction determination of the chemical structure of colchicine”. Acta Crystallographica. 5 (4): 437–440. doi:10.1107/S0365110X52001313. Its total synthesis was first accomplished in 1959 Eschenmoser A (1959). “Synthese des Colchicins”. Angewandte Chemie. 71 (20): 637–640. doi:10.1002/ange.19590712002.
- ^ Jump up to:a b “FDA Unapproved Drugs Initiative”.
- ^ Jump up to:a b c Langreth R, Koons C (6 October 2015). “2,000% Drug Price Surge Is a Side Effect of FDA Safety Program”. Bloomberg. Retrieved 27 October 2015.
- ^ Jump up to:a b “FDA Approves Colchicine With Drug Interaction and Dose Warnings”. July 2009.
- ^ Jump up to:a b “Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations”. fda.gov.
- ^ “Questions and Answers for Patients and Healthcare Providers Regarding Single-ingredient Oral Colchicine Products”. fda.gov.
- ^ “FDA Approves Gout Treatment After Long Years of Use”. medpagetoday.com. 3 August 2009. Archived from the original on 5 August 2009. Retrieved 3 August 2009.
- ^ Cerquaglia C, Diaco M, Nucera G, La Regina M, Montalto M, Manna R (February 2005). “Pharmacological and clinical basis of treatment of Familial Mediterranean Fever (FMF) with colchicine or analogues: an update”. Current Drug Targets. Inflammation and Allergy. 4 (1): 117–24. doi:10.2174/1568010053622984. PMID 15720245. Archived from the original on 2008-12-11. Retrieved 2019-07-06.
- ^ Karst KR (21 October 2009). “California Court Denies Preliminary Injunction in Lanham Act Case Concerning Unapproved Colchicine Drugs”.
- ^ Meyer H (29 December 2009). “The High Price of FDA Approval”. The Philadelphia Inquirer – via Kaiser Health News.
- ^ Colcrys vs. Unapproved Colchicine Statement from URL Pharma
- ^ “About Colcrys”. Colcrys. URL Pharma. Retrieved 11 September 2011.
- ^ Jump up to:a b Kesselheim AS, Solomon DH (June 2010). “Incentives for drug development–the curious case of colchicine”. The New England Journal of Medicine. 362 (22): 2045–7. doi:10.1056/NEJMp1003126. PMID 20393164.
- ^ “FDA orders halt to marketing of unapproved single-ingredient oral colchicine”. 30 September 2010.
- ^ “Generic Colcrys Availability”. drugs.com.
- ^ “40 CFR Appendix A to Part 355, The List of Extremely Hazardous Substances and Their Threshold Planning Quantities”. LII / Legal Information Institute. Retrieved 2018-03-11.
- ^ Jump up to:a b “Colchicine images”. Drugs.com. 6 August 2018. Retrieved 21 August 2018.
- ^ Leete E (1963). “The biosynthesis of the alkaloids of Colchicum: The incorporation of phenylalaline-2-C14 into colchicine and demecolcine”. J. Am. Chem. Soc. 85 (22): 3666–3669. doi:10.1021/ja00905a030.
- ^ Herbert, Richard B. (2001). “The biosynthesis of plant alkaloids and nitrogenous microbial metabolites”. Nat. Prod. Rep. 18 (1): 50–65. doi:10.1039/A809393H. PMID 11245400.
- ^ Dewick PM (2009). Medicinal natural products: A biosynthetic approach. Wiley. pp. 360–362.
- ^ Jump up to:a b c Griffiths AJF, Gelbart WM, Miller JH (1999). Modern Genetic Analysis: Changes in Chromosome Number. W. H. Freeman, New York.
- ^ Derman H, Emsweller SL. “The use of colchicine in plant breeding”. archive.org. Retrieved 26 April 2016.
- Dowd, Matthew J. (April 30, 1998). “Colchicine”. Virginia Commonwealth University. Archived from the original on 2010-06-10.
- EXT LINKS
- “Colchicine”. Drug Information Portal. U.S. National Library of Medicine.
- “Colchicine : Biotoxin”. Emergency Response Safety and Health Database. 8 November 2017.
|Trade names||Colcrys, Mitigare, others|
|License data||US DailyMed: Colchicine|
|ATC code||M04AC01 (WHO)|
|Legal status||AU: S4 (Prescription only)CA: ℞-onlyUK: POM (Prescription only)US: ℞-only|
|Metabolism||Metabolism, partly by CYP3A4|
|Elimination half-life||26.6-31.2 hours|
|CompTox Dashboard (EPA)||DTXSID5024845 DTXSID20274387, DTXSID5024845|
|Chemical and physical data|
|Molar mass||399.437 g·mol−1|
|3D model (JSmol)||Interactive image|
///////////Colchicine, CSIR, Laxai Life Sciences, DCGI, clinical trials, Covid patients, covid 19, corona virus
NEW DRUG APPROVALS
BioE COVID-19, BECOV2D
Adjuvanted protein subunit vaccine
Corbevax is a “recombinant protein sub-unit” vaccine, which means it is made up of a specific part of SARS-CoV-2 — the spike protein on the virus’s surface.
The spike protein allows the virus to enter the cells in the body so that it can replicate and cause disease. However, when this protein alone is given to the body, it is not expected to be harmful as the rest of the virus is absent. The body is expected to develop an immune response against the injected spike protein. Therefore, when the real virus attempts to infect the body, it will already have an immune response ready that will make it unlikely for the person to fall severely ill.
Although this technology has been used for decades to make hepatitis B vaccines, Corbevax will be among the first Covid-19 vaccines to use this platform. Novavax has also developed a protein-based vaccine, which is still waiting for emergency use authorisation from various regulators.
How Corbevax was made
While it is indigenously produced, Corbevax’s beginnings can be traced to the Baylor College of Medicine’s National School of Tropical Medicine. The School had been working on recombinant protein vaccines for coronaviruses SARS and MERS for a decade.
“We knew all the techniques required to produce a recombinant protein (vaccine) for coronaviruses at high levels of efficiency and integrity,” said Dr Peter Hotez, Professor and Dean at the School.
When the genetic sequence for SARS-CoV-2 was made available in February 2020, researchers at the School pulled out the sequence for the gene for the spike protein, and worked on cloning and engineering it. The gene was then put into yeast, so that it could manufacture and release copies of the protein. “It’s actually similar to the production of beer. Instead of releasing alcohol, in this case, the yeast is releasing the recombinant protein,” Dr Hotez said.
After this, the protein was purified to remove any remnants of the yeast “to make it pristine”. Then, the vaccine was formulated using an adjuvant to better stimulate the immune response.
Most of these ingredients are cheap and easy to find.
In August, BCM transferred its production cell bank for this vaccine to Biological E, so that the Hyderabad-based company could take the candidate through trials. The vaccine has received approval for phase 3 trials, which the government expects will be over by July.
Biological E is also expected to scale up production for the world.
How Corbevax is different
Other Covid-19 vaccines approved so far are either mRNA vaccines (Pfizer and Moderna), viral vector vaccines (AstraZeneca-Oxford/Covishield, Johnson & Johnson and Sputnik V) or inactivated vaccines (Covaxin, Sinovac-CoronaVac and Sinopharm’s SARS-CoV-2 Vaccine–Vero Cell).
Inactivated vaccines, which include killed particles of the whole SARS-CoV-2 virus, attempt to target the entire structure of the virus. On the other hand, Corbevax, like the mRNA and viral vector Covid-19 vaccines, targets only the spike protein, but in a different way.
Viral vector and mRNA and vaccines use a code to induce our cells to make the spike proteins against which the body have to build immunity. “In this case (Corbevax), we’re actually giving the protein,” said Dr Hotez.
Like most other Covid-19 vaccines, Corbevax is administered in two doses. However, as it is made using a low-cost platform, it is also expected to be among the cheapest available in the country.
Why Corbevax matters
This is the first time the Indian government has placed an order for a vaccine that has not received emergency use authorisation, paying Rs 1,500 crore in advance to block an order that could vaccinate 15 crore Indian citizens. The Centre has provided major pre-clinical and clinical trial support towards the vaccine’s development, including a grant-in-aid of Rs 100 crore from the Department of Biotechnology.
A major reason for India placing such a big order is the difficulties it is facing in enhancing vaccine supplies. While the US, UK and the EU had made advance payments and at-risk investments into vaccines like Pfizer, AstraZeneca and Moderna, India waited until after its first two vaccines were approved before placing limited orders. Even after the government eased regulatory requirements for foreign vaccines, it did not receive a speedy response from companies like Pfizer and Moderna, their supplies already blocked through orders from other countries. India is currently in negotiations for a limited supply of Pfizer’s vaccine, and expecting to secure up to two billion doses of Covid vaccines by December this year. Given the ease with which it can be mass produced, Corbevax could make up a sizeable portion of this expected supply.
Biological E, the manufacturer of Corbevax
Biological E, headquartered in Hyderabad, was founded by Dr D V K Raju in 1953 as a biological products company that pioneered the production of heparin in India. By 1962, it forayed into the vaccines space, producing DPT vaccines on a large-scale. Today, it is among the major vaccine makers in India and, by its own claim, the “largest” tetanus vaccine producer in the world.
It has seven WHO-prequalified shots, including a five-in-one vaccine against diphtheria, tetanus, pertussis, hepatitis B and haemophilus influenza type-b infections. Its vaccines are supplied to over 100 countries and it has supplied more than two billion doses in the last 10 years alone.
Since 2013, the company has been under the management of Mahima Datla — the third generation of the founding family. During her time as managing director, the company has received WHO prequalification of its Japanese encephalitis, DTwP and Td as well as measles and rubella vaccines and also commenced commercial operations in the US.
Corbevax or BioE COVID-19, is a COVID-19 vaccine candidate developed by Indian biopharmacutical firm Biological E. Limited (BioE), the Baylor College of Medicine in Houston, United States, and Dynavax Technologies. It is a protein subunit vaccine.
Phase I and II trials
Phase III trials
In April 2021, the Drugs Controller General of India permitted the vaccine candidate to start phase III clinical trials. A total of 1,268 healthy participants between the age of 18 and 80 years to be selected from 15 sites across India for the trial and intended to be part of a larger global Phase III study.
Manufacturing and Orders
In April 2021, the U.S. International Development Finance Corporation (DFC) announced that it would fund the expansion of BioE’s manufacturing capabilities, so that it could produce at least 1 billion doses by end of 2022.
- ^ Bharadwaj, Swati (3 June 2021). “Telangana: Biological E starts at risk manufacturing of Corbevax”. The Times of India. Retrieved 3 June 2021.
- ^ “A prospective open label randomised phase-I seamlessly followed by phase-II study to assess the safety, reactogenicity and immunogenicity of Biological E’s novel Covid-19 vaccine containing Receptor Binding Domain of SARS-CoV-2 for protection against Covid-19 disease when administered intramuscularly in a two dose schedule (0, 28D) to healthy volunteers”. ctri.nic.in. Clinical Trials Registry India. 13 January 2021. CTRI/2020/11/029032. Archived from the original on 12 November 2020.
- ^ “CEPI partners with Biological E Limited to advance development and manufacture of COVID-19 vaccine candidate”. cepi.net. CEPI. Retrieved 5 March 2021.
- ^ Chui M (16 November 2020). “Biological E. Limited and Baylor COVID-19 vaccine begins clinical trial in India”. Baylor College of Medicine.
- ^ Jump up to:a b Leo L (16 November 2020). “Biological E initiates human trials of vaccine”. Mint.
- ^ “Coronavirus | Biological E gets nod to start Phase III trials of COVID-19 vaccine”. The Hindu. 24 April 2021.
- ^ Jump up to:a b Leo, Leroy (24 April 2021). “Biological E completes phase-2 covid vaccine trial, gets SEC nod for phase-3”. mint.
- ^ “A Prospective, multicentre, Phase II Seamlessly Followed by Phase III Clinical Study to Evaluate the Immunogenicity and Safety of Biological E’s CORBEVAX Vaccine for Protection Against COVID-19 Disease When Administered to COVID-19-Negative Adult Subjects”. ctri.nic.in. Clinical Trials Registry India. 5 June 2021. CTRI/2021/06/034014.
- ^ Basu, Nayanima (25 April 2021). “US assures export of raw materials to India for Covid vaccines as Doval speaks to Sullivan”. ThePrint.
- ^ “Health ministry buys 300 mn doses of Biological-E’s Covid vaccine in advance”. Hindustan Times. 3 June 2021. Retrieved 4 June 2021.
CorbevaxVaccine descriptionTargetSARS-CoV-2Vaccine typeProtein subunitClinical dataTrade namesCorbevaxOther namesBECOV2DRoutes of
- “Explained: How Corbevax is different”. The Indian Express.
|Part of a series on the|
|COVID-19 (disease)SARS-CoV-2 (virus)|
///////////Biological E, SARS-CoV-2, Baylor College, CORONA VIRUS, COVID 19, Corbevax, BioE COVID-19, BECOV2D, INDIA, Dynavax Technologies
NEW DRUG APPROVALS
Providence Therapeutics; Canadian government
bioRxiv (2021), 1-50.
Safe and effective vaccines are needed to end the COVID-19 pandemic caused by SARS-CoV-2. Here we report the preclinical development of a lipid nanoparticle (LNP) formulated SARS-CoV-2 mRNA vaccine, PTX-COVID19-B. PTX-COVID19-B was chosen among three candidates after the initial mouse vaccination results showed that it elicited the strongest neutralizing antibody response against SARS-CoV-2. Further tests in mice and hamsters indicated that PTX-COVID19-B induced robust humoral and cellular immune responses and completely protected the vaccinated animals from SARS-CoV-2 infection in the lung. Studies in hamsters also showed that PTX-COVID19-B protected the upper respiratory tract from SARS-CoV-2 infection. Mouse immune sera elicited by PTX-COVID19-B vaccination were able to neutralize SARS-CoV-2 variants of concern (VOCs), including the B.1.1.7, B.1.351 and P.1 lineages. No adverse effects were induced by PTX-COVID19-B in both mice and hamsters. These preclinical results indicate that PTX-COVID19-B is safe and effective. Based on these results, PTX-COVID19-B was authorized by Health Canada to enter clinical trials in December 2020 with a phase 1 clinical trial ongoing (ClinicalTrials.gov number: NCT04765436).
PTX-COVID19-B is a messenger RNA (mRNA)-based COVID-19 vaccine, a vaccine for the prevention of the COVID-19 disease caused by an infection of the SARS-CoV-2 coronavirus, created by Providence Therapeutics—a private Canadian drug company co-founded by Calgary, Alberta-based businessman Brad T. Sorenson and San Francisco-based Eric Marcusson. in 2013. A team of eighteen working out of Sunnybrook Research Institute in Toronto, Ontario developed PTX-COVID19-B in less than four weeks, according to the Calgary Herald. Human trials with sixty volunteers began on January 26, 2021 in Toronto.
Providence, which has no manufacturing facilities, partnered with Calgary-based Northern mRNA—the “anchor tenant” in their future manufacturing facilities pending financing.
On 30 April 2021, Sorenson announced that Providence Therapeutics would be leaving Canada and any vaccine that it developed would not be manufactured in Canada.
Providence Therapeutics Holdings Inc. was co-founded in Toronto, Ontario by Calgary, Alberta-based businessman Brad T. Sorenson and San Francisco-based Eric Marcusson Ph.D, who was also the Chief Scientific Officer.
PTX-COVID19-B is a messenger RNA (mRNA)-based COVID-19 vaccine. In an interview with CTV news, Sorenson said they were “building some of the important building blocks for the messenger RNA … that provides instructions to cells … to build proteins that may treat or prevent disease”.
As of January 2021, Northern RNA’s Calgary lab was proposed as the site where manufacturing of PTX-COVID19-B would take place. Providence Therapeutics’ partner, Northern RNA, which located at 421 7 Avenue SW in Calgary, has been described as Providence Therapeutics northern division.
A February 2021 Manitoba government press release said that the Winnipeg-based Emergent BioSolutions would be manufacturing the vaccine.
Human trials began on January 26, 2021 with 60 volunteers between the ages of 18 to 65 in Toronto. Of these, 15 would receive a placebo and 3 groups of 15 would receive different doses of the vaccine. The volunteers will be monitored for 13 months. The company said that enough data would be available in May which could result in a Phase 2 clinical testing beginning soon after that, pending regulatory approval. If the results of a subsequent larger human trial are positive, the vaccine could enter a commercialization phase in 2022. The Phase 1 clinical trial lead was Piyush Patel. At the 29 April meeting with the House of Commons, Sorenson estimated that PTX-COVID19-B could be approved by Health Canada by “January or February 2022”.:8
Shortly after the first human trials on PTX-COVID19-B began in late January, on 11 February 2021, Manitoba Premier Brian Pallister announced a “term sheet” between the province and Providence Therapeutics through which Manitoba would receive 2 million doses of PTX-COVID19-B pending its approval by Health Canada. The term sheet includes “best-price guarantee” PTX-COVID19-B. According to a provincial statement released by the Manitoba government, pending approval of the vaccine, the actual manufacturing would take place in Winnipeg by Emergent BioSolutions. Pallister said that, “Building a secure, made-in-Canada vaccine supply will put Canadians at the head of the line to get a COVID vaccine, where we belong.” The down payment would be 20% with a subsequent 40% to be paid when the vaccine was approved by Health Canada; the balance would be paid on delivery of the doses. Specifics about the contract were released in April 2021: the total cost was estimated as CAD $36 million and the agreement included a clause for a non-refundable advance payment of CAD $7.2 million. Sorenson made this comment to Global News: “Under no circumstances is Manitoba going to be on the hook for $7.2 million unless they get real value out of it”.
As part of the federal government’s “next generation manufacturing supercluster” program, Providence and Northern mRNA had also been “cleared to access up to $5 million” towards the manufacturing start up process, according to a federal government spokesperson.
The CBC report in late April 2021 also stated that “it could be eligible for a slice of $113 million in additional funding from the National Research Council of Canada Industrial Research Assistance Program”. The federal government had provided funding to some other companies in Canada that were also working to develop a COVID-19 vaccine.
Sorenson as Providence Therapeutics CEO posted an open letter to Prime Minister Justin Trudeau, in which he requested $CDN 150 million upfront to be used to pay for clinical trial and material costs.
On 29 April 2021, Sorenson appeared before the House of Commons standing committee on international trade, to ask the Minister of Procurement, Anita Anand, to consider PTX-COVID19-B as an alternative to Moderna and Pfizer for the “2022 booster vaccines”. Sorenson said that the NRC had approached Providence Therapeutics in 2020 after the company had announced their Phase I trial PTX-COVID19-B. Sorenson told the Standing Committee that, “We’ve had really good dialogue ever since phase I started. That process has gone on. That started probably [in February], as we geared up to conclude our phase I trial and release data. Although the NRC is capped at $10 million, which is certainly not sufficient to carry out phase II and phase III trials, the NRC has, through the bureaucracy, elevated us back up to the strategic innovation fund. That occurred about three weeks ago. We’re now working with the strategic innovation fund.”:7
He later said that no reply had been received from the government.
In a meeting with the federal COVID-19 vaccine task force and Sorenson, task force members expressed concerns that “Providence might not be able to scale up production fast enough”.
PTX-COVID19-B, an mRNA Humoral Vaccine, is Intended for Prevention of COVID-19 in a General Population. This Study is Designed to Evaluate Safety, Tolerability, and Immunogenicity of PTX-COVID19-B Vaccine in Healthy Seronegative Adults Aged 18-64… https://clinicaltrials.gov/ct2/show/NCT04765436
Hyderabad Drugmaker To Make Canada Firm’s mRNA Covid Vaccine In India.. https://www.ndtv.com/india-news/hyderabad-drugmaker-biological-e-to-make-canada-firms-mrna-covid-vaccine-in-india-2454000
Biological E., will run a clinical trial of Providence’s vaccine in India and seek emergency use approval for it, the company said in a statement
Hyderabad-based Biological E said on Tuesday it has entered into a licensing agreement with Providence Therapeutics Holdings to manufacture the Canadian company’s mRNA COVID-19 vaccine in India.
Biological E., which also has a separate deal to produce about 600 million doses of Johnson & Johnson’s COVID-19 shot annually, will run a clinical trial of Providence’s vaccine in India and seek emergency use approval for it, the company said in a statement.
Providence will sell up to 30 million doses of its mRNA vaccine, PTX-COVID19-B, to Biological E, and will also provide the necessary technology transfer of the shot, with a minimum production capacity of 600 million doses in 2022 and a target capacity of 1 billion doses.
Financial details of the transaction were not disclosed.
India has been struggling with a devastating second wave of the pandemic and has managed to fully vaccinate only about 3% of its population. On Monday, the Serum Institute of India said it will increase production of AstraZeneca’s shot by nearly 40% in June, a step towards bridging the shortfall in the country.
“The mRNA platform has emerged as the front runner in delivering the first vaccines for emergency use to combat the COVID-19 pandemic,” said Mahima Datla, Biological E.’s managing director.
Messenger ribonucleic acid (mRNA) vaccines prompt the body to make a protein that is part of the virus, triggering an immune response. US companies Pfizer and Moderna use mRNA technology in their COVID-19 shots.
The drug regulator has approved clinical trials of another mRNA vaccine developed by local firm Gennova Biopharmaceuticals, and the government has said it will fund the studies.
Providence Therapeutics Announces Very Favorable Interim Phase 1 Trial Data for PTX-COVID19-B, its mRNA Vaccine Against COVID-19
CALGARY, AB, May 12, 2021 / – Providence Therapeutics Holdings Inc. (“Providence”) announced today very favorable interim clinical data of PTX-COVID19-B, its vaccine candidate against SARS-CoV-2 (“COVID-19”), from its Phase 1 study entitled “PRO-CL-001, A Phase 1, First-in-Human, Observer-Blinded, Randomized, Placebo Controlled, Ascending Dose Study to Evaluate the Safety, Tolerability, and Immunogenicity of PTX-COVID19-B Vaccine in Healthy Seronegative Adults Aged 18-64” (the “Phase 1 Study”), which found that PTX-COVID19-B met Providence’s target results for safety, tolerability, and immunogenicity in the participants of the Phase 1 Study.
Highlights from Providence Therapeutics’ “Phase 1 Study”:
- PTX-COVID19-B was generally safe and well tolerated
- PTX-COVID19-B exhibited strong virus neutralization capability across the 16µg, 40µg and 100µg dose cohorts
- PTX-COVID19-B 40µg dose was selected for Phase 2 study
- PTX-COVID19-B will be evaluated in additional Phase 1 population cohorts
The Phase 1 Study was designed with dose-escalations and was performed in seronegative adult subjects without evidence of recent exposure to COVID-19. The subjects were randomized to receive either the PTX-COVID19-B vaccine or a placebo in a 3:1 ratio. A total of 60 subjects participated in the Phase 1 Study.
The overall results of the Phase 1 Study are that PTX-COVID19-B was safe and well tolerated at the three dose levels of 16µg, 40µg and 100µg. Adverse events identified in the Phase 1 Study were generally mild to moderate in severity, self-resolving and transient. There were no serious adverse events reported in the Phase 1 Study. The most common adverse event reported in the Phase 1 Study was redness and pain at the injection site. Systemic reactions reported in the Phase 1 Study were generally mild to moderate and well tolerated with headache being the most common reaction reported. The reported adverse events of the Phase 1 Study were in line with the expectations of management of Providence as they compare very favorably to the adverse events data published on other mRNA vaccines for COVID-19 that have been approved for use by various health authorities around the world.
Based on the results of the Phase 1 Study, Providence intends to use a 40µg dose for the Phase 2 study of PTX-COVID19-B that is anticipated to be initiated in June 2021. Additional Phase 1 studies in adolescent and elderly populations are also planned to be undertaken by Providence.
PTX-COVID19-B vaccination induced high anti-S IgG antibodies:
Participants in the Phase 1 Study were vaccinated on day zero and day twenty-eight. Plasma samples were collected on day 1, day 8, day 28 (prior to the participant receiving the second dose), and day 42 to determine levels of IgG anti-S protein using electrochemiluminescence (“ECL”) assays from Meso Scale Discovery (“MSD”). Study participants in all three vaccine dose cohorts of the Phase 1 Study developed a strong IgG antibody response against Spike protein that was detected by day 28 and enhanced by day 42. No antibodies against S protein were detected in participants in the Phase 1 Study injected with placebo. The highest levels of antibodies were found in the 40 and 100 µg doses. By day 42, PTX-COVID19-B vaccinated participants had more than one log higher antibody levels than convalescent subjects-plasma (indicated in the dotted line) which was evaluated in the same assay.
Based on the interim data of the Phase 1 Study, the level of antibodies produced in participants by PTX-COVID19-B compare favorably to the levels of antibodies produced by other mRNA vaccines that have been approved for use against COVID-19 based on the recently published report from Stanford University, where IgG responses in individuals vaccinated with the COVID-19 mRNA vaccine compared to COVID-19 infected patients were evaluated.
PTX-COVID19-B vaccination induced high neutralizing antibody levels:
Neutralizing activity from the Phase 1 Study participants’ plasma was evaluated by S-ACE2 MSD assay. The results indicate that the antibodies block the interaction between S protein with the ACE2 receptor and the decrease in ECL signal is used to calculate percentage inhibition of the plasma at the same dilution. All participants in the Phase 1 Study from the 16, 40 and 100 µg dose levels showed blocking activity by day 28 and all of them reached 100% blocking activity by day 42 with samples diluted 1:100 or greater. Moreover, the quantification of the antibody levels in ng/mL with a reference standard showed that all participants in the Phase 1 Study produced neutralizing antibodies by day 28 with the first immunization and increase ten-fold by day 42, two weeks after the administration of the second dose. These results indicate that PTX-COVID19-B induced a strong neutralizing antibody response which compares very favorably to the published results of other mRNA vaccines. Further studies are being conducted by Providence to determine neutralization activity using a pseudo-virus assay.
Providence intends to advance a Phase 2 clinical trial in early June 2021, with multiple trial sites in Canada. The Phase 2 clinical trial is anticipated to be structured as a comparator trial using Pfizer/BioNTech vaccine as the positive control.
About Providence Therapeutics
Providence is a leading Canadian clinical stage biotechnology company pioneering mRNA therapeutics and vaccines with operations in Calgary, Alberta and Toronto, Ontario. In response to a worldwide need for a COVID-19 vaccine, Providence expanded its focus beyond oncology therapies and devoted its energy and resources to develop a world-class mRNA vaccine for COVID-19. Providence is focused on serving the needs of Canada, and other countries that may be underserved by large pharmaceutical programs. For more information, please visit providencetherapeutics.com.
- ^ “Canadian company urges human trials after COVID-19 vaccine results in mice”. Lethbridge News Now. 5 August 2020. Retrieved 19 March 2021.
- ^ Jump up to:a b c d e f g h Tasker, John Paul (30 April 2021). “COVID-19 vaccine maker Providence says it’s leaving Canada after calls for more federal support go unanswered”. CBC News. Retrieved 1 May 2021.
- ^ Jump up to:a b c Stephenson, Amanda (26 January 2021). “Made-in-Canada COVID vaccine to be manufactured in Calgary”. Calgary Herald. Retrieved 22 March 2021.
- ^ Clinical trial number NCT04765436 for “PTX-COVID19-B, an mRNA Humoral Vaccine, is Intended for Prevention of COVID-19 in a General Population. This Study is Designed to Evaluate Safety, Tolerability, and Immunogenicity of PTX-COVID19-B Vaccine in Healthy Seronegative Adults Aged 18-64” at ClinicalTrials.gov
- ^ “Providence Therapeutics Holdings Inc: PTX-COVID19-B”. Montreal: McGill University. Retrieved 19 March 2021.
- ^ “Made-in-Canada coronavirus vaccine starts human clinical trials”. Canadian Broadcasting Corporation. 26 January 2021.
- ^ Jump up to:a b “Company Profile”. PitchBook.
- ^ Jump up to:a b “Company Profile”. DNB.
- ^ Jump up to:a b Code, Jillian (5 February 2021). “‘Do something’ Made-In-Canada vaccine CEO pleads for federal government to respond”. CTV News. Calgary, Alberta. Retrieved 22 March 2021.
- ^ Jump up to:a b Fieldberg, Alesia (26 January 2021). “Providence Therapeutics begins first clinical trials of Canadian-made COVID-19 vaccine”. CTV. Retrieved 2 May 2021.
- ^ Jump up to:a b c d “Manitoba Supports Made-In-Canada COVID-19 Vaccine to Protect Manitobans” (Press release). 11 February 2021. Retrieved 3 May 2021.
- ^ Providence Therapeutics Holdings Inc.: a Phase I, First-in-Human, Observer-Blinded, Randomized, Placebo Controlled, Ascending Dose Study to Evaluate the Safety, Tolerability, and Immunogenicity of PTX-COVID19-B Vaccine in Healthy Seronegative Adults Aged 18-64 (Report). Clinical Trials via U.S. National Library of Medicine. 19 February 2021. Retrieved 1 May2021.
- ^ Jump up to:a b c Gibson, Shane (11 February 2021). “Manitoba agrees to purchase 2M doses of Providence Therapeutics coronavirus vaccine”. Global News. Retrieved 2 May 2021.
- ^ “Providence Therapeutics begins first clinical trials of Canadian-made COVID-19 vaccine”. CTV. Retrieved 2 May 2021.
- ^ Jump up to:a b c Evidence (PDF), 43rd Parliament, 2nd Session. Standing Committee on International Trade, 29 April 2021, retrieved 2 May2021
- ^ Sorenson, Brad (5 February 2021). “An Open Letter to the Government of Canada”. Retrieved 3 May 2021.
- ^ Dyer, Steven. “‘Canada had an opportunity’, Calgary company explores taking vaccine development out of Canada”. CTV. Retrieved 2 May 2021.
|Part of a series on the|
|COVID-19 (disease)SARS-CoV-2 (virus)|
NEW DRUG APPROVALS
DNA vaccine construct encoding a spike protein antigen of SARS-CoV-2 virus (Zydus-Cadila)
bioRxiv (2021), 1-26.
ZyCoV-D is a genetically engineered DNA plasmid based vaccine encoding for the membrane proteins of the virus. The clinical trials to study the immunogenicity, and safety of the vaccine, will administer three doses at an interval of 28 days in 1048 individuals.
Phase 1/2: CTRI/2020/07/026352
|Part of a series on the|
|SARS-CoV-2 (virus)COVID-19 (disease)|
ZyCoV-D is a DNA plasmid based COVID-19 vaccine being developed by Cadila Healthcare with support from the Biotechnology Industry Research Assistance Council.
The ZYCOV-D vaccine candidate was developed by Cadila Healthcare Ltd. based in India1. The vaccine was developed using a DNA vaccine platform with a non-replicating and non-integrating plasmid carrying the gene of interest3. Once the plasmid DNA is introduced into host cells and the viral protein is translated, it elicits a strong immune response, stimulating the humoral and cellular components of the immune system3. The DNA vaccine platform offers minimal biosafety requirements, more improved vaccine stability, and lower cold chain requirements3. Phase I clinical trials of this vaccine candidate were completed in July 2020, with the company reporting successful dosing and tolerance1,2. As of August, 2020 the candidate is in Phase II clinical trials1.
NEW DRUG APPROVALS
Phase I and II trials
In February 2020, Cadila Healthcare decided to develop a DNA plasmid based COVID-19 vaccine at their Vaccine Technology Centre (VTC) in Ahmedabad. The vaccine candidate was able to pass the pre-clinical trials on animal models successfully. A report of the study was made available via bioRxiv. Thereafter, human trials for Phase I and II were approved by the regulator.
The Phase II trials of the vaccine candidate were conducted in over 1,000 volunteers as part of the adaptive Phase I/II multi-centric, dose escalation, randomised, double-blind placebo controlled method.
Phase III trials
In November 2020, the company announced it would test the vaccine candidate on 30,000 patients in Phase III trials. The vaccine would be given out in three doses at five sites across four cities of India. In January 2021, the Drugs Controller General of India (DCGI) granted permission to conduct the Phase III clinical trials for 28,216 Indian participants.
In April 2021, the company reported that they expected to have initial data for the Phase III trials by May 2021.
On 23 April 2021, production of the ZyCoV-D vaccine was started, with a yearly capacity of 240 million doses. It is expected to get emergency use authorization in May or June.
- ^ “Zydus Cadila launches a fast tracked programme to develop vaccine for the novel coronavirus, 2019-nCoV (COVID-19)”(PDF). http://www.zyduscadila.com. Cadila Healthcare.
- ^ Dey A, Rajanathan C, Chandra H, Pericherla HP, Kumar S, Choonia HS, et al. (26 January 2021). “Immunogenic Potential of DNA Vaccine candidate, ZyCoV-D against SARS-CoV-2 in Animal Models”. bioRxiv: 2021.01.26.428240. doi:10.1101/2021.01.26.428240. S2CID 231777527.
- ^ “A prospective, randomized, adaptive, phase I/II clinical study to evaluate the safety and immunogenicity of Novel Corona Virus −2019-nCov vaccine candidate of M/s Cadila Healthcare Limited by intradermal route in healthy subjects”. ctri.nic.in. Clinical Trials Registry India. 15 December 2020. CTRI/2020/07/026352. Archived from the original on 22 November 2020.
- ^ “Zydus Cadila’s ZyCov-D vaccine found to be ‘safe and immunogenic'”. @businessline. The Hindu. 24 December 2020.
- ^ Rawat K, Kumari P, Saha L (February 2021). “COVID-19 vaccine: A recent update in pipeline vaccines, their design and development strategies”. European Journal of Pharmacology. 892: 173751. doi:10.1016/j.ejphar.2020.173751. PMC 7685956. PMID 33245898.
- ^ Thacker T (7 November 2020). “Zydus Cadila to test ZyCoV-D on 30,000 patients in Phase-3 trials”. The Economic Times.
- ^ “Covid 19 vaccine in India: Zydus Cadila begins enrolment for Phase 3 trial of ZyCoV-D in 4 cities”. The Financial Express. 22 January 2021.
- ^ “DBT-BIRAC supported indigenously developed DNA Vaccine Candidate by Zydus Cadila, approved for Phase III clinical trials”. pib.gov.in. Press Information Bureau. 3 January 2021.
- ^ “Novel Corona Virus-2019-nCov vaccine by intradermal route in healthy subjects”. ctri.nic.in. Clinical Trials Registry – India. Retrieved 10 April 2021.
- ^ Das, Sohini (22 April 2021). “Cadila Healthcare testing two-shot regimen for ZyCoV-D, data likely by May”. Business Standard India.
- ^ Writer, Staff (24 April 2021). “Cadila Healthcare starts production of Covid vaccine candidate”. mint. Retrieved 27 April 2021.
Zydus Cadila Covid vaccine close to getting approved in India, says MD Sharvil Patel
In an exclusive interview with India Today TV, Managing Director of Zydus Cadila Dr Sharvil Patel said the company’s Covid vaccine candidate ZyCoV-D against the Covid-19 infection is very close to getting approved in India. They are likely to apply for emergency use authorisation this month.
Ahmedabad-based pharmaceutical company Zydus Cadila is likely to submit the application for emergency use authorisation of its Covid-19 vaccine candidate ‘ZyCoV-D’ in India this month. The company is confident that the vaccine will be approved in May itself. The company plants to produce one crore doses of its ‘painless’ Covid-19 vaccine per month.
If approved, ZyCoV-D will be the fourth vaccine to be used in India’s Covid-19 vaccination drive. Made in India, the company plans to ramp up the vaccine’s production to 3-4 crore doses per month and is already in talks with two other manufacturing companies for the same
Although the vaccine should ideally be stored between 2 and 8 degrees Celsius, it remains stable even at room temperature conditions at 25 degrees Celsius. It is easy to administer, the developers said, and will be administered via intradermal injection.
If approved for emergency use, ZyCoV-D could help India fill the vacuum of vaccine doses currently being experienced in the country’s immunisation drive.
Earlier in April, Zydus Cadila announced that its drug Virafin had received restricted emergency use approval from the Drug Controller General of India for the treatment of mild cases of Covid-19.
In an exclusive interview with India Today TV, Sharvil Patel sheds details on all aspects of the Covid-19 vaccine ZyCoV-D.
When asked the status of Covid vaccine candidate ZyCoV-D and when exactly Zydus Cadila would apply for emergency use authorisation in India, Dr Sharvil Patel said the vaccine was getting very close to getting approved in the country.
“I am very happy to say that India’s first indigenously developed DNA vaccine candidate against Covid, which is our ZyCoV-D, is getting very close to approval,” he said.
“We have almost completed all our recruitment for the clinical trials. We have, by far, recruited the largest number of patients for a Covid vaccine trial in India. The number of volunteers who have been vaccinated as a part of the trial is 28,000,” Sharvil Patel said.
Sharvil Patel also said that his company has also included children in the 12-17 age group for the vaccine trials.
He said, “The recruitment holds very important milestones in terms of cohorts because not only have we included the elderly and those with co-morbidities, but also children in the age group of 12 to 17 years.”
Sharvil Patel said as soon as the efficacy data is obtained, Sydus Cadila will file for emergency use authorisation. As soon as the approval is granted, Zydus Cadila will start production of Covid-19 vaccines from July, he said.
“We hope to see our efficacy data in the middle of May. As soon as we see strong efficacy which correlates to the vaccine’s strong immunogenicity in Phase 2, we will file for emergency use authorization. We hope to produce a good quantity of the vaccine from July onwards to make sure it is available to the people. That is the need of the hour right now,” Sharvil Patel said.
He said by May the company will be in a position to talk to the regulators about the restricted use of the Covid-19 vaccine. “The regulatory process is a rolling one. I believe the regulators look at the data in a short period of time,” Sharvil Patel said.
“We have submitted a lot of data already so that it will aid the regulators once we provide them with the efficacy results. We are, hence, expecting to get the approval in May itself,” Sharvil Patel said.
///////////ZyCoV-D, COVID 19, CORONA VIRUS, VACCINE, INDIA 2021, APPROVALS 2021, SARS-CoV-2
- Molecular FormulaC6H12O5
- Average mass164.156 Da
- 2 DG
- Ba 2758
- D-Glucose, 2-deoxy-
- NSC 15193
2-DGD-arabino-2-DesoxyhexoseD-arabino-Hexopyranose, 2-deoxy- [(4R,5S,6R)-6-(Hydroxymethyl)oxane-2,4,5-triol2-deoxyglucopyranose2-deoxymannopyranose2-dGlc
CAS Registry Number: 154-17-6
CAS Name: 2-Deoxy-D-arabino-hexose
Additional Names: D-arabino-2-desoxyhexose; 2-deoxyglucose; 2-DGManufacturers’ Codes: Ba-2758Molecular Formula: C6H12O5Molecular Weight: 164.16Percent Composition: C 43.90%, H 7.37%, O 48.73%Literature References: Antimetabolite of glucose, q.v., with antiviral activity.
Synthesis: M. Bergmann et al.,Ber.55, 158 (1922); 56, 1052 (1923); J. C. Sowden, H. O. L. Fischer, J. Am. Chem. Soc.69, 1048 (1947); H. R. Bolliger, Helv. Chim. Acta34, 989 (1954); H. R. Bolliger, M. D. Schmid, ibid. 1597, 1671; H. R. Bolliger, “2-Deoxy-D-arabino-hexose (2-Deoxy-D-glucose)” in Methods in Carbohydrate Chemistryvol. I, R. L. Whistler, M. L. Wolfrom, Eds. (Academic Press, New York, 1962) pp 186-189.
Inhibition of influenza virus multiplication: E. D. Kilbourne, Nature183, 271 (1959).
Effects on herpes simplex virus: R. J. Courtney et al.,Virology52, 447 (1973). Mechanism of action studies: M. R. Steiner et al.,Biochem. Biophys. Res. Commun.61, 745 (1974); E. K. Ray et al.,Virology58, 118 (1978). Use in human genital herpes infections: H. A. Blough, R. L. Giuntoli, J. Am. Med. Assoc.241, 2798 (1979); L. Corey, K. K. Holmes, ibid.243, 29 (1980). Effect vs respiratory syncytial viral infections in calves: S. B. Mohanty et al.,Am. J. Vet. Res.42, 336 (1981).
Properties: Cryst from acetone or butanone, mp 142-144°. [a]D17.5 +38.3° (35 min) ®+45.9° (c = 0.52 in water); +22.8° (24 hrs) ® +80.8° (c = 0.57 in pyridine).
Melting point: mp 142-144°
Optical Rotation: [a]D17.5 +38.3° (35 min) ®+45.9° (c = 0.52 in water); +22.8° (24 hrs) ® +80.8° (c = 0.57 in pyridine) Derivative Type: a-Form
Properties: Cryst from isopropanol, mp 134-136°. [a]D26 +156° ® +103° (c = 0.9 in pyridine).Melting point: mp 134-136°Optical Rotation: [a]D26 +156° ® +103° (c = 0.9 in pyridine) Use: Exptlly as an antiviral agent.
Source Temperature: 210 °C Sample Temperature: 150 °C Direct, 75 eV
14.0 2.2 15.0 11.5 17.0 3.9 18.0 19.4 19.0 13.7 26.0 2.5 27.0 12.1 28.0 21.9 29.0 31.2 30.0 4.6 31.0 41.3 32.0 12.4 39.0 5.9 40.0 2.1 41.0 10.9 42.0 12.4 43.0 46.3 44.0 31.5 45.0 34.3 46.0 2.8 47.0 4.1 53.0 1.5 54.0 2.0 55.0 14.4 56.0 35.3 57.0 55.7 58.0 11.4 59.0 2.0 60.0 100.0 61.0 31.1 62.0 2.3 68.0 4.6 69.0 12.2 70.0 3.0 71.0 34.9 72.0 7.0 73.0 25.3 74.0 46.6 75.0 5.1 81.0 1.5 82.0 2.4 83.0 1.3 84.0 1.3 85.0 18.1 86.0 55.3 87.0 4.6 89.0 1.2 91.0 1.5 97.0 3.6 98.0 2.9 99.0 1.7 100.0 3.5 102.0 1.1 103.0 19.8 104.0 1.4 111.0 1.6 115.0 25.2 116.0 3.0 117.0 2.1 120.0 3.3 128.0 1.0 129.0 2.5 133.0 1.8 147.0 2.2 1H NMR DMSO D6
1H NMR D20
IR NUJOL MULL
PAPERCollection of Czechoslovak Chemical Communications (1955), 20, 42-5. http://cccc.uochb.cas.cz/20/1/0042/
Preparation of 2-deoxy-D-glucose
By: Stanek, Jaroslav; Schwarz, Vladimir
Triacetyl-D-glucal (I) adds (BzO)2IAg and (BzO)2BrAg, to give 1-benzoyl-3,4,6-triacetyl-2-deoxy-2-iodo-α-D-glucopyranose (II) and 1-benzoyl-3,4,6-triacetyl-2-deoxy-2-bromo-α-D-glucopyranose (III), resp. Both halogen derivs. give 2-deoxy-D-glucose (IV) by reduction. Adding a C6H6 soln. of 16.7 g. iodine into a suspension of 33.6 g. dry BzOAg in 200 ml. C6H6, treating the mixt. with a soln. of 20 g. I in 200 ml. C6H6, heating the mixt. 7 hrs. on the steam bath, removing the AgI, evapg. the solvent, and crystg. the residue from EtOH gave 20.8 g. (54.7%) II, m. 129-30°, [α]21D 21.7°. Analogous procedure with 13.4 g. BzOAg, 4.6 g. Br, and 8 g. I gave 3.9 g. (33%) III, m. 139-40°, [α]17D 33.5°. The same compd. (3 g.), m. 140°, [α]18D 33.6°, was obtained by adding 3.2 g. Br to a soln. of 5.44 g. I in 50 ml. CCl4, by refluxing the mixt. 2 hrs. with 6 g. BzOAg, filtering off the AgBr, and evapg. the solvent. Reducing 8 g. II or an equiv. III in 150 ml. MeOH with 60 g. Zn activated by 1 hr. immersion in a soln. of 60 g. CuSO4 in 1500 ml. H2O, removing Zn after 8 hrs., evapg. the MeOH, and sapong. the residue with Ba(OH)2 yielded 0.42 g. (20%) IV, m. 145°, [α]18D 46.1°.
Wavlen: 589.3 nm; Temp: 18 °C, +46.1 ° ORD
https://patents.google.com/patent/WO2004058786A1/enThe present invention relates to a process for the synthesis of 2-deoxy-D-glucose. Background of the invention 2-deoxy-D-glucose is useful in control of respiratory infections and for application as an antiviral agent for treatment of human genital herpes.Prior art for preparation of 2-deoxy-D-glucose while operable, tend to be expensive and time consuming. Reference may be made to Bergmann, M., Schotte, H., Lechinsky, W., Ber, 55, 158 (1922) and Bergmann, M., Schotte, H., Lechinsky, W., Ber 56, 1052 (1923) which disclose the preparation of 2-deoxy-D-glucose in low yield by mineral acid catalyzed addition of water to D-glucal. Another method of producing 2-deoxy-D-glucose is from diethyldithioacetal derivative of D-glucose (Bolliger, H.R. Schmid, M.D., Helv. Chim. Ada 34, 989 (1951); Bolliger, H.R., Schmid, M.D., Helv. Chim. A a 34, 1597 (1951); Bolliger, H.R. Schmid, M.D., Helv. Chim. Ada 34, 1671 (1951) and from D-arabhiose by reaction with nitromethane followed by acetylation, reduction and hydrolysis (Sowden, J.C, Fisher, H.O.L., J. Am. Chem., 69, 1048 (1947). However these methods result in the formation of 2- deoxy-D-glucose in low yield and of inferior purity due to the formation of several byproducts and involve use of toxic reagents such as ethanethiol and nitromethane. As a result purification of 2-deoxy-D-glucose has to be done by recrystallisation which is tedious, time consuming and difficult.Accordingly it is important to develop a process for synthesis of 2-deoxy-D-glucose which obviates the drawbacks as detailed above and results in good yield and good purity. Objects of the inventionThe main object of the present invention is to provide a process for the synthesis of 2- deoxy-D-glucose resulting in good yield and with good purity.Another object of the invention is to provide an economical process for the synthesis of 2-deoxy-D-glucose. Summary of the inventionA process that would produce 2-deoxy-D-glucose economically and with desired purity, is a welcome contribution to the art. This invention fulfills this need efficiently.Accordingly the present invention relates to a process for the synthesis of 2-deoxy- D-glucose comprising haloalkoxylation of R-D-Glucal wherein R is selected from H and 3, 4, 6-tri-O-benzyl, to obtain alkyl 2-deoxy-2-halo-R-α/ -D-gluco/mannopyranoside, converting alkyl 2-deoxy-2-halo-R-α/β-D-gluco/mannopyranoside by reduction to alkyl 2- deoxy-α/β-D-glucopyranoside, hydrolysing alkyl 2-deoxy-α/β-D-glucopyranoside to 2- deoxy-D-glucose.In one embodiment of the invention, the alkyl 2-deoxy-α/β-D-glucopyranoside is obtained by (a) haloalkoxylating 3,4,6,-tri-O-benzyl-D-glucal to alkyl 2-deoxy-2-halo-3,4,6-tri-O- benzyl-α/β-D-gluco-/mannopyranoside; (b) subjecting alkyl 2-deoxy-2-halo-3,4,6-tri-O-benzyl-α/β-D-gluco/mannopyranoside to reductive dehalogenation and debenzylation to obtain alkyl 2-deoxy -α/β-D- glucopyranoside. In another embodiment of the invention, in step (a) haloalkoxylation of 3,4,6-tri-O- benzyl-D-glucal is carried out by reaction with a haloalkoxylating agent selected from a N- halosuccinimide and a N-haloacetamide, and alcohol.The reaction scheme for the reactions involved in the process of the invention are also given below:
in R’=CH3I R=C6H5CH2 H R=C6H5CH2, X=Br, R’=CH3 IV R=H V R=CH3, C2HSJ C6H5CH3, iPr, X=Br
Such overall synthesis may be depicted as follows where R=H, CH3, C2H5, (CH3)2CH, C6H5CH ; RX-CH3; X-CL, Br.Example 1 To a solution of 3,4,6-tri-O-benzyl-D-glucal (39 g, 0.09 mol) in dichloromethane (20ml) and methanol (100 ml) was added N-bromosuccinimide (18.7 g, 0.09 mil) during 10 min. at room temperature and stirred for 4 h. After completion of the reaction solvent was distilled off. The resultant residue extracted into carbon tetrachloride (2×100 ml) and organic phase concentrated to obtain methyl 2-bromo 2-deoxy-3,4,6-tri-O-benzyl-α/β-D-gluco- /mannopyranoside as a syrup. Quantity obtained 50 g. 1H NMR (200 MHz, CDC13) 3.40-4.00 (m, 7H, H-2,5,6,6′ and OCH3) 4.30-5.10 (m, 9H, H-1,3,4 and 3xPhCH2O), 7.10-7.60 (m, 15H, Ar-H). A solution of methyl 2-bromo-2-deoxy-3,4,6-tri-O-benzyl-α/β-D-gluco- /mannopyranoside (50 g) in methanol (300) was charged into one litre autoclave along with Raney nickel (10 ml) Et3N (135 ml) and subjected to hydrogenation at 120 psi pressure at 50°C for 8 h. After completion of the reaction the catalyst was filtered off and the residue washed with methanol (25 ml). The filtrate was concentrate to obtain methyl 2-deoxy-3,4,6- tri-O-benzyl-α/β-D-glucopyranoside as a syrup (37.9 g, 89%). 1H NMR (200 MHz, CDC13): δ 1.50-2.40 (m,2H,H-2,2′)5 3.32, 3.51 (2s, 3H, OCH3) 3.55-4.00 (m, 5H, H-3,4,5,6,6′), 4.30-5.00 (m, 7H, 3xPhCH2, H-l), 7.10-7.45 (m, 15H, Ar-H). The syrup of methyl 2-deoxy-3,4,6- tri-O-benzyl-α/β-D-glucopyranoside (37.9g) was dissolved in methanol (200 ml). 1 g of 5%Pd/C was added and hydrogenated at 150 psi pressure at room temperature. After 5 hours catalyst was filtered off and solvent evaporated. Quantity of the methyl 2-deoxy-α/β-D- glucopyranoside obtained 10.5 g (70%). [ ]D + 25.7° (c 1.0, MeOH), 1H NMR (200 MHz, D2O); δ 1.45-2.40 (m, 2H, H-2,2′) 3.20-4.80, (m 9H, H- 1,3,4,5,6,6′ – OCH3).Example 2 To a solution of D-glucal (64.6g, 0.44 mol) in methanol (325 ml) at 10°C was addedN-bromosuccinimide (78.7 g, 0.44 mol) during 40 min. maintaining the temperature between 10-15°C during the addition. The reaction mixture was stirred at room temperature. After 5 hours solvent was evaporated to obtain a residue which was refluxed in ethyl acetate (100 ml). Ethyl acetate layer was discarded to leave a residue of methyl 2-bromo-2-deoxy-α/β-D- gluco/mannopyranoside (105 g) as a syrup. [α]D + 36° (c 1.0, MeOH). 1H NMR (200 MHz, D2O): δ 3.47, 3.67 (2s, 3H, OCH3), 3.70-4.05 (m, 6h, H-23,4,5,6,6′), 4.48-5.13 (2s, 1H, H-l). The syrupy methyl 2-bromo-2-deoxy-α/β-D-gluco-/mannopyranoside was dissolved in methanol (400 ml), a slurry of 80 g Raney nickel (a 50% slurry in methanol), Et3N (30 ml) and hydrogenated in a Parr apparatus at 120 psi. After 8-9 hours, the reaction mixture was filtered through a Celite filter pad and washed with MeOH. The washings and filtrate were combined and triturated with hexane to separate and remove by filtration insoluble triethylamine hydrobromide and traces of succinimide. The filtrate was concentrated to a residue. The isolated yield of methyl 2-deoxy-α/β-D-glucopyranoside was 89%. Ethyl 2-bromo-2deoxy-α/β-D-gluco-/mannopyranoside: When solvent was ethanol instead of methanol the compound obtained was ethyl 2- bromo-2-deoxy-α/β-D-gluco-/mannopyranoside. 1HNMR (200 MHz, D2O): δ 1.10-1.32 (m, 3H, CH3), 2.80 (s, 4H, -CO(CH2)2CO-NH-), 3.40-4.10 (m, 8H, H-2,3,4,5,6,6′, CH2), 4.40, 5.20 (2s 1H, H-l α/β).Isopropyl 2-bromo-2-deoxy- /β-D-gluco-/mannopyranoside: When isopropanol instead of methanol was used as a solvent the compound obtained was isopropyl 2-bromo-2-deoxy-α/β-D-gluco/mannopyranoside. 1H NMR (200 MHz, D2O): δ 1.10-1.30 (m, 6H, 2xCH3) 2.80 (s, 4H, -CO(CH2)2CO-NH-), 3.60-4.60 (m 8H,H- 2,3,4,5,6,6′, CH2) 4.40, 5.30 (2s, 1H, H-l, α/β).Example 3 A mixture of D-glucal (64.6 g), methanol (400 ml), N-bromosuccinimide (79 g) were stirred at 15 C for 6 h. The reaction mixture was hydrogenated in a Parr apparatus in presence of 60 g of Raney nickel catalyst (a 50% slurry in methanol) and triethylamine (62 ml). After 8-9 h, the reaction mixture was filtered on a Celite filter pad. The Celite pad was washed with methanol. The washings and filtrate were combined, concentrated to a thick heavy syrup, dissolve in chloroform (500 ml), pyridine (400 ml) and acetic anhydride (251 ml) was added while stirring, maintaining the temperature between 5-10°C. After 12 hours, the reaction mixture was diluted with CHC13 (500 ml) transferred to a separating funnel and organic phase was washed with water. The organic phase was separated, dried (Na2SO4) and concentrated to obtain methyl 2-deoxy-3,4,6-tri-O-acetyl-2 deoxy-α/β-D-glucopyranoside as a syrup (163.43 g, 87%). [α]D + 65.0° (c 1.0, CHC13) 1H NMR (200 MHz, CDC13): δ 1.55-1.90 (m, 2H, H-2,2′), 2.01, 2.04,2.11, 2.15, (4s, 9H, 3xOCOCH3), 2.18,3.40 (2s, 3H, OCH3), 3.45-50 (m, 3H, H-5, 6,6′) 4.80-5.40 (m, 3H,H-1,3,4). The syrup was dissolved in methanol (600 ml) IN NaOMe in methanol (25ml) was added and left at room temperature. After 6-10 h, dry CO2 gas was passed into the reaction mixture, solvent was evaporated to obtain a syrupy residue. The residue was once again extracted into dry methanol and concentrated to obtain methyl 2-deoxy-α/β-D-glucopyranoside as syrup. Quantity obtained 81 g (92%).Example 4 A 500 ml round bottom flask equipped with magnetic stir bar was charged with a solution of D-glucal (32.3 g) in methanol (175 ml), cooled to 15°C, N-bromosucci-t imide (NBS) (39.4 g) was added and stirred for 6 hours at 15°C. The reaction mixture was concentrated to half the volume, cooled to 0°C and separated succinimide was removed by filtration. To the filtrate was added a slurry of 30 g Raney nickel (a 50% slurry in methanol) Et3N (32 ml) and hydrogenated in a Parr apparatus at 120 psi. After 7-8 hours, the reaction mixture was filtered through a Celite filter pad, and washed with MeOH. The washings and filtrate were combined and triturate with hexane to separate and remove by filtration insoluble triethylamine hydrobromide and succinimide. The filtrate was concentrated to a residue, dissolved in methanol and triturated with hexane to remove most of the triethylamine hydrobromide and succinimide. The filtrate was concentrated to obtain methyl 2-deoxy-α/β- D-glucopyranoside (85%).Example 5 To a stirred solution of methyl 3,4,6-tri-O-acetyl-2-deoxy-α/β-D-glucopyranoside (47 g) (from example 3) in acetic acid (40 ml) and acetic anhydride (110 ml) was added concentrated sulphuric acid (0.94 ml) at 0°. The reaction mixture was brought to room temperature and stirred. After 2 hours the reaction mixture was diluted with water (50 ml) and extracted into CH2C12 (3×150 ml). The organic phase was separated, washed with saturated NaHCO3 solution, H2O dried over Na2SO and concentrated to obtain 2-deoxy- 1,3,4,6-tetra-O-acetyl-α/β-D-glucopyranoside as a crystalline compound, mp. 115-118°C. Quantity obtained 44.5 g (86%). [α]D + 21.5° (c 1.0, CHC13). 1H NMR (200 MHz, CDC13): δ 1.50-2.45 (m, 14H, H-2,2′, 4xOCOCH3), 3.85-5.40, (m, 5H, H-3,4,5,6,6′), 5.75-6.20 (m, 1H, H-l,α/ β). To a heterogeneous mixture of l,3,4,6-tetra-O-acetyl-2-deoxy-α/β-D- glucopyranoside (10 g) in water (100 ml) was added acetyl chloride (10 ml) and heated to 80°C. After 6 hours the reaction mixture was cooled to room temperature, neutralised with saturated aq. Ba(OH)2, concentrated to half the volume and filtered on a Celite pad. Filtrate was concentrated on a rotary evaporator and dried over anhydrous P2O5 to obtain a residue which was dissolved in hot isopropyl alcohol and filtered on a pad of Celite to obtain a clear filtrate. The filtrate was concentrated to a residue, dissolved in hot isopropyl alcohol (50 ml), acetone (75 ml) and seeded with a few crystals of 2-deoxy-D-glucose. After 15-18 hours at 5°C crystalline title product was filtered. Quantity obtained 3.21 g (64.9%) m.p. 148-149°C.Example 6 A heterogeneous mixture of l,3,4,6-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (9 g) (from example 5), water (30 ml) and 11% aq. H2SO (0.3 ml) was stirred at 85°C for 7 h to obtain a homogenous solution. The reaction mixture was cooled, neutralised with aq. Ba(OH)2 solution and filtered. The filtrate obtained was concentrated to half the volume and solids separated were filtered. To the filtrate was added activated carbon (1 g) and filtered. The filtrate was concentrated on a rotary evaporator and dried over P2O5 to obtain 2-deoxy- D-glucose that was crystallized from methyl alcohol (27 ml) and acetone (54 ml). Quantity obtained 2.4 g. mp. 146-149°C.Example 7A heterogeneous mixture of l,3,4,6-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside(25g) (from example 5), H2O (250 ml), toluene (250 ml) and glacial acetic acid (1.25 ml) was heated to reflux for 10-12 hours, while it was connected to a Dean- Stark azeotropic distillation apparatus. An azeotropic mixture of acetic acid, toluene was collected to remove acetic acid and every one hour fresh toluene (50 ml) was introduced. After completion of the reaction, toluene was removed by distillation from the reaction mixture to obtain a residue that was dissolved in methanol, treated with charcoal and filtered. The filtrate was separated, concentrated to a residue and crystallized from isopropyl alcohol and acetone to obtain 2- deoxy-D-glucose (7.33 g, 59%). mp. 148-151°C.Example 8 A heterogeneous mixture of l,3,4,5-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (lOg) (from example 5), H2O (200 ml) cone. HC1 (0.3 ml) and glacial acetic acid (0.5 ml) was heated to 85°C. After 6 hours the reaction mixture was cooled to room temperature, neutralized with aq. Ba(OH)2 and filtered on a pad of Celite. Filtrate was separated, treated with charcoal and filtered. The filtrate was concentrated to a residue and crystallized from MeOH, acetone to obtain the product. Quantity obtained 2.75 g. mp. 147-148°C.Example 9 A heterogeneous mixture of l,3,4,5-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside(lOg) (from example 3) water (100 ml) and cone. HCI (0.5ml) was heated to 80°C. After 2-5 hours the reaction mixture was cooled to room temperature, neutralized with aq. Ba(OH)2 and filtered on a pad of Celite. The filtrate was concentrated to a residue, dissolved in ethanol, treated with charcoal and filtered. The filtrate was concentrated to a solid residue andcrystallized from methanol-acetone to obtain the title product. Quantity obtained 3.15g mp. 148-151°C.Example 10A solution of methyl 2-deoxy-α/β-D-glucopyranoside (30g) (from example 2) water(15 ml) and cone. HCI (1.5 ml) was heated to 80-85°C. After 3-5 hours the reaction mixture was cooled to room temperature, neutralized with aq. Ba(OH)2 and filtered to remove insoluble salts. The filtrate was concentrated to a residue, crystallized from MeOH, acetone and hexane to obtain 2-deoxy-D-glucose (11.77 g) mp. 149-151°C.Example 11A solution of methyl 2-deoxy-α/β-D-glucopyranoside (30g) (from example 2) water (195 ml) and cone. H2SO (5.9 ml) was heated to 80°C. After 2-3 hours the reaction mixture was cooled, neutralized with aq. Ba(OH)2 and filtered. The filtrate was separated, treated with charcoal and filtrate. The Filtrate was concentrated to a residue and crystallized from isopropyl alcohol to obtain the title product. Quantity obtained 5.2 g. mp. 152-154°C.Example 12 A mixture of methyl 2-deoxy-α/β-D-glucopyranoside (24g) (from example 2) water(125 ml) and IR 120 H+ resin (7.5 ml) was heated to 90-95°C for 2h. The reaction mixture was cooled to room temperature, filtered and the resin was washed with water (20 ml). The filtrate was concentrated to residue and crystallized from ethanol to obtain 2-deoxy-D- glucose (8.8 g), mp. 150-152°C. The main advantages of the present invention are:-1). It does not involve the use of toxic mercaptans like ethane thiol. 2). This process does not involve reaction of D-glucal with mineral acid, thereby avoiding the formation of Ferrier by-products.
2-Deoxy-d-glucose is a glucose molecule which has the 2-hydroxyl group replaced by hydrogen, so that it cannot undergo further glycolysis. As such; it acts to competitively inhibit the production of glucose-6-phosphate from glucose at the phosphoglucoisomerase level (step 2 of glycolysis). In most cells, glucose hexokinase phosphorylates 2-deoxyglucose, trapping the product 2-deoxyglucose-6-phosphate intracellularly (with exception of liver and kidney)[; thus, labelled forms of 2-deoxyglucose serve as a good marker for tissue glucose uptake and hexokinase activity. Many cancers have elevated glucose uptake and hexokinase levels. 2-Deoxyglucose labeled with tritium or carbon-14 has been a popular ligand for laboratory research in animal models, where distribution is assessed by tissue-slicing followed by autoradiography, sometimes in tandem with either conventional or electron microscopy.
2-DG is uptaken by the glucose transporters of the cell. Therefore, cells with higher glucose uptake, for example tumor cells, have also a higher uptake of 2-DG. Since 2-DG hampers cell growth, its use as a tumor therapeutic has been suggested, and in fact, 2-DG is in clinical trials.  A recent clinical trial showed 2-DG can be tolerated at a dose of 63 mg/kg/day, however the observed cardiac side-effects (prolongation of the Q-T interval) at this dose and the fact that a majority of patients’ (66%) cancer progressed casts doubt on the feasibility of this reagent for further clinical use. However, it is not completely clear how 2-DG inhibits cell growth. The fact that glycolysis is inhibited by 2-DG, seems not to be sufficient to explain why 2-DG treated cells stop growing. Because of its structural similarity to mannose, 2DG has the potential to inhibit N-glycosylation in mammalian cells and other systems, and as such induces ER stress and the Unfolded Protein Response (UPR) pathway.
Clinicians have noted that 2-DG is metabolised in the pentose phosphate pathway in red blood cells at least, although the significance of this for other cell types and for cancer treatment in general is unclear.
Work on the ketogenic diet as a treatment for epilepsy have investigated the role of glycolysis in the disease. 2-Deoxyglucose has been proposed by Garriga-Canut et al. as a mimic for the ketogenic diet, and shows great promise as a new anti-epileptic drug. The authors suggest that 2-DG works, in part, by increasing the expression of Brain-derived neurotrophic factor (BDNF), Nerve growth factor (NGF), Arc (protein) (ARC), and Basic fibroblast growth factor (FGF2). Such uses are complicated by the fact that 2-deoxyglucose does have some toxicity.
A study found that by combining the sugar 2-deoxy-D-glucose (2-DG) with fenofibrate, a compound that has been safely used in humans for more than 40 years to lower cholesterol and triglycerides, an entire tumor could effectively be targeted without the use of toxic chemotherapy.
2-DG has been used as a targeted optical imaging agent for fluorescent in vivo imaging. In clinical medical imaging (PET scanning), fluorodeoxyglucose is used, where one of the 2-hydrogens of 2-deoxy-D-glucose is replaced with the positron-emitting isotope fluorine-18, which emits paired gamma rays, allowing distribution of the tracer to be imaged by external gamma camera(s). This is increasingly done in tandem with a CT function which is part of the same PET/CT machine, to allow better localization of small-volume tissue glucose-uptake differences.
Resistance to 2-DG has been reported in HeLa cells  and in yeast; in the latter, it involves the detoxification of a metabolite derived from 2-DG (2DG-6-phosphate) by a phosphatase. Despite the existence of such a phosphatase in human (named HDHD1A) However it is unclear whether it contributes to the resistance of human cells to 2DG or affects FDG-based imaging.
Indian Pat. Appl., 2004DE02075,
STARTING MATERIAL CAS 69515-91-9
C14 H20 O9, 332.30
D-arabino-Hexopyranose, 2-deoxy-, 1,3,4,6-tetraacetate
Bioorganic & Medicinal Chemistry Letters, 22(10), 3540-3543; 2012
https://patents.google.com/patent/US6933382B2/en2-deoxy-D-glucose is useful in control of respiratory infections and for application as an antiviral agent for treatment of human genital herpes.Prior art for preparation of 2-deoxy-D-glucose while operable, tend to be expensive and time consuming. Reference may be made to Bergmann M., Schotte, H., Lechinsky, W., Ber, 55, 158 (1922) and Bergmann, M., Schotte, H., Lechinsky, W., Ber 56, 1052 (1923) which disclose the preparation of 2-deoxy-D-glucose in low yield by mineral acid catalyzed addition of water to D-glucal. Another method of producing 2-deoxy-D-glucose is from diethyldithioacetal derivative of D-glucose (Bolliger, H. R. Schmid, M. D., Helv. Chim. Acta 34, 989 (1951); Bolliger, H. R., Schmid, M. D., Helv, Chim. Acta 34, 1597 (1951); Bolliger, H. R Schmid, M. D., Helv. Chim. Acta 34, 1671 (1951) and from D-arabinose by reaction with nitromethane followed by acetylation, reduction and hydrolysis (Sowden, J. C., Fisher, H. O. L., J. Am. Chem., 69, 1048 (1947). However these methods result in the formation of 2-deoxy-D-glucose in low yield and of inferior purity due to the formation of several by-products and involve use of toxic reagents such as ethanethiol and nitromethane. As a result purification of 2-deoxy-D-glucose has to be done by recrystallisation which is tedious, time consuming and difficult.
EXAMPLE 1To a solution of 3,4,6-tri-O-benzyl-D-glucal (39 g, 0.09 mmol) in dichloromethane (20 ml) and methanol (100 ml) was added N-bromosuccinimide (18.7 g, 0.09 mil) during 10 min. at room temperature and stirred for 4 h. After completion of the reaction solvent was distilled off. The resultant residue extracted into carbon tetrachloride (2×100 ml) and organic phase concentrated to obtain methyl 2-bromo 2-deoxy-3,4,6-tri-O-benzyl-α/β-D-gluco-/mannopyranoside as a syrup. Quantity obtained 50 g. 1H NMR (200 MHz, CDCl3) 3.40-4.00 (m, 7H, H-2,5,6,6′ and OCH3) 4.30-5.10 (m, 9H, H-1,3,4 and 3×PhCH2O), 7.10-7.60 (m 15H, Ar—H). A solution of methyl 2-bromo-2-deoxy-3,4,6-tri-O-benzyl/α/β-D-gluco-/mannopyranoside (50 g) in methanol (300) was charged into one liter autoclave along with Raney nickel (10 ml) Et3N (135 ml) and subjected to hydrogenation at 120 psi pressure at 50° C. for 8 h. After completion of the reaction the catalyst was filtered off and the residue washed with methanol (25 ml). The filtrate was concentrate to obtain methyl 2-deoxy-3,4,6-tri-O-benzyl-α/β-D-glucopyranoside as a syrup (37.9 g, 89%). 1H NMR (200 MHz CDCl3): δ 1.50-2.40 (m,2H,H-2,2′), 3.32, 3.51 (2s, 3H, OCH3) 3.55-4.00 (m, 5, H-3,4,5,6,6′) 4.30-5.00 (M 7H, 3×PhCH2, H-1), 7.10-7.45 (m, 15H, Ar—H). The syrup of methyl 2-deoxy-3,4, 6-tri-O-benzyl-α/β-D-glucopyranoside (37.9 g) was dissolved in methanol (200 ml). 1 g of 5% Pd/C was added and hydrogenated at 150 psi pressure at room temperature. After 5 hours catalyst was filtered off and solvent evaporated. Quantity of the methyl 2-deoxy-α/β-D-glucopyranoside obtained 10.5 g (70%). [α]D+25.7° (c 1.0, MeOH), 1H NMR (200 MHz, D2O); δ 1.45-2.40 (m, 2H, H-2,2′) 3.20-4.80, (m 9H, H-1,3,4,5,6,6′—OCH3).EXAMPLE 2To a solution of D-glucal (64.6 g, 0.44 mmol) in methanol (325 ml) at 10° C. was added N-bromosuccinimide (78.7 g, 0.44 mol) during 40 min. maintaining the temperature between 10-15° C. during the addition. The reaction mixture was stirred at room temperature. After 5 hours solvent was evaporated to obtain a residue which was refluxed in ethyl acetate (100 ml). Ethyl acetate layer was discarded to leave a residue of methyl 2-bromo-2-deoxy-α/β-D-gluco/mannopyranoside (105 g) as a syrup. [α]D+36° (c 1.0, MeOH). 1H NMR (200 MHz, D2O): δ 3.47, 3.67 (2s, 3H, OCH3), 3.70-4.05 (m, 6h, H-2,3,4,5,6,6′), 4.48-5.13 (28, 1H, 1H, H-1). The syrupy methyl 2-bromo-2-deoxy-α/β-D-gluco-/mannopyranoside was dissolved in methanol (400 ml), a slurry of 80 g Raney nickel (a 50% slurry in methanol), Et3N (30 ml) and hydrogenated in a Parr apparatus at 120 psi. After 8-9 hours, the reaction mixture was filtered through a Celite filter pad and washed with MeOH. The washings and filtrate were combined and triturated with hexane to separate and remove by filtration insoluble triethylamine hydrobromide and traces of succinimide. The filtrate was concentrated to a residue. The isolated yield of methyl 2-deoxy-α/β-D-glucopyranoside was 89%.Ethyl 2-bromo-2deoxy-α/β-D-gluco-/mannopyranoside:When solvent was ethanol instead of methanol the compound obtained was ethyl 2-bromo-2deoxy-α/β-D-gluco-/mannopyranoside. 1H NMR (200 MHz, D2O): δ 1.10-1.32 (m, 3H, CH3), 2.80 (s, 4H, —CO(CH2)2CO—NH—), 3.40-4.10 (m, 8H, H-2,3,4,5,6,6′, CH2), 4.40, 5.20 (2s 1H, H-1, α/β).Isopropyl 2-bromo-2-deoxy-α/β-D-gluco-/mannopyranoside:When isopropanol instead of methanol was used as a solvent the compound obtained was isopropyl 2-bromo-2-deoxy-α/β-D-gluco/mannopyranoside, 1H NMR (200 MHz, D2O): δ 1.10-1.30 (m, 6H, 2×CH3) 2.80 (s, 4H, —CO(CH2)2CO—NH—), 3.60-4.60 (m 8H,H-2,3,4,5,6,6′, CH2) 4.40, 5,30 (2s, 1H, H-1, α/β.EXAMPLE 3A mixture of D-glucal (64.6 g), methanol (400 ml), N-bromosuccinimide (79 g) were stirred at 15° C. for 6 h. The reaction mixture was hydrogenated in a Parr apparatus in presence of 60 g of Raney nickel catalyst (a 50% slurry in methanol) and triethylamine (62 ml). After 8-9 h, the reaction mixture was filtered on a Celite filter pad. The Celite pad was washed with methanol. The washings and filtrate were combined, concentrated to a thick heavy syrup, dissolve in chloroform (500 ml), pyridine (400 ml) and acetic anhydride (251 ml) was added while stirring, maintaining the temperature between 5-10° C. After 12 hours, the reaction mixture was diluted with CHCl3 (500 ml) transferred to a separating funnel and organic phase was washed with water. The organic phase was separated, dried (Na2SO4) and concentrated to obtain methyl 2-deoxy-3,4,6-tri-O-acetyl-2 deoxy-α/β-D-glucopyranoside as a syrup (163.43 g, 87%). [α]D+65.0° (c 1.0, CHCl3) 1H NMR (200 MHz, CDCl3): δ 1.55-1.90 (m, 2H, H-22′), 2.01, 2.04, 2.11, 2.15, (4s, 9H, 3×OCOCH3), 2.18, 3.40 (2s, 3H, OCH3), 3.45-50 (m, 3H, H-5, 6,6′) 4.80-5.40 (m, 3H,H-1,3,4). The syrup was dissolved in methanol (600 ml) 1N NaOMe in methanol (25 ml) was added and left at room temperature. After 6-10 h, dry CO2 gas was passed into the reaction mixture, solvent was evaporated to obtain a syrupy residue. The residue was once again extracted into dry methanol and concentrated to obtain methyl 2-deoxy-α/β-D-glucopyranoside as syrup. Quantity obtained 81 g (92%).EXAMPLE 4A 500 ml round bottom flask equipped with magnetic stir bar was charged with a solution of D-glucal (323 g) in methanol (175 ml), cooled to 15° C., N-bromosuccinimide (NIBS) (39.4 g) was added and stirred or 6 hours at 15° C., The reaction mixture was concentrated to half the volume, cooled to 0° C. and separated succinimide, was removed by filtration. To the filtrate was added a slurry of 30 g Raney nickel (a 50% slurry in Methanol) Et3N (32 ml) and hydrogenated in a Parr apparatus at 120 psi. After 7-8 hours, the reaction mixture was filtered through a Celite filter pad, and washed with MeOH. The washings and filtrate were combined and triturate with hexane to separate and remove by filtration insoluble triethylamine hydrobromide and succinimide. The filtrate was concentrated to a residue, dissolved in methanol and triturated with hexane to remove most of the triethylamine hydrobromide and succinimide. The filtrate was concentrated to obtain methyl 2-deoxy-α/β-D-glucopyranoside (85%).EXAMPLE 5To a stirred solution of methyl 3,4,6-tri-O-acetyl-2-deoxy-α/β-D-glucopyranoside (47 g) (from example 3) in acetic acid (40 ml) and acetic anhydride (110 ml) was added concentrated sulphuric acid (0.94 ml) at 0°. The reaction mixture was brought to room temperature and stirred. After 2 hours the reaction mixture was diluted with water (50 ml) and extracted into CH2Cl2 (3×150 ml). The organic phase was separated, washed with saturated NaHCO3 solution H2O dried over Na2SO4 and concentrated to obtain 2-deoxy-1,3,4,6-tetra-O-acetyl-α/β-D-glucopyranoside as a crystalline compound. mp. 115-118° C. Quantity obtained 44.5 g (86%). [α]D+21.5° (c 1.0, CHCl3). 1H NMR (200 MHz, CDCl3): δ 1.50-2.45 (m, 14H, H-2,2′, 4×OCOCH3), 3.85-5.40, (m, 5H, H-3,4,5,6,6′), 5.75-6.20 (m, 1H, H-1, α/β). To a heterogeneous mixture of 1,3,4,6-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (10 g) in water (100 ml) was added acetyl chloride (10 ml) and heated to 80° C. After 6 hours the reaction mixture was cooled to room temperature, neutralised with saturated aq. Ba(OH)2, concentrated to half the volume and filtered on a Celite pad, Filtrate was concentrated on a rotary evaporator and dried over anhydrous P2O5 to obtain a residue which was dissolved in hot isopropyl alcohol and filtered on a pad of Celite to obtain a clear filtrate. The filtrate was concentrated to a residue, dissolved in hot isopropyl alcohol (50 ml), acetone (75 ml) and seeded with a few crystals of 2-deoxy-D-glucose. After 15-18 hours at 5° C. crystalline title product was filtered. Quantity obtained 3.21 g (64.9%) m.p. 148-149° C.EXAMPLE 6A heterogeneous mixture of 1,3,4,6-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (9 g) (from example 5), water (30 ml) and 11% aq. H2SO4 (0.3 ml) was stirred at 85° C. for 7 h to obtain a homogenous solution. The reaction mixture was cooled, neutralised with aq. Ba(OH)2 solution and filtered. The filtrate obtained was concentrated to half the volume and solids separated were filtered. To the filtrate was added activated carbon (1 g) and filtered. The filtrate was concentrated on a rotary evaporator and dried over P2O5 to obtain 2-deoxy-D-glucose that was crystallized from methyl alcohol (27 ml) and acetone (54 ml). Quantity obtained 2.4 g. mp. 146-149° C.,EXAMPLE 7A heterogeneous mixture of 1,3,4,tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (25 g) (from example 5), H2O (250 ml), toluene (250 ml) and glacial acetic acid (1.25 ml) was heated to reflux for 10-12 hours, while it was connected to a Dean-Stark azeotropic distillation apparatus. An azeotropic mixture of acetic acid, toluene was collected to remove acetic acid and every one hour fresh toluene (50 ml) was introduced. After completion of the reaction, toluene was removed by distillation from the reaction mixture to obtain a residue that was dissolved in methanol, treated with charcoal and filtered. Be filtrate was separated, concentrated to a residue and crystallized from isopropyl alcohol and acetone to obtain 2-deoxy-D-glucose (7.33 g, 59%). mp. 148-151° C.EXAMPLE 8A heterogeneous mixture of 1,3,4,5-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (10 g) (tom example 5), H2O (200 ml) conc. HCl (0.3 ml) and glacial acetic acid (0.5 ml) was heated to 85° C. After 6 hours the reaction mixture was cooled to room temperature, neutralized with aq. Ba(OH)2 and filtered on a pad of Celite. Filtrate was separated, treated with charcoal and filtered. The filtrate was concentrated to a residue and crystallized from MeOH, acetone to obtain the product. Quantity obtained 275 g. mp. 147-148° C.EXAMPLE 9A heterogeneous mixture of 1,3,4,5-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (10 g) (from example 3) water (100 ml) and conc. HCl (0.5 ml) was heated to 80° C. After 2-5 hours the reaction mixture was cooled to room temperature, neutralized with aq. Ba(OH)2 and filtered on a pad of Celite. The filtrate was concentrated to a residue, dissolved in ethanol, treated with charcoal and filtered. The filtrate was concentrated to a solid residue and crystallized from methanol-acetone to obtain the title product. Quantity obtained 3.15 g mp. 148-151° C.,EXAMPLE 10A solution of methyl 2-deoxy-α/β-D-glucopyranoside (30 g) (from example 2) water (15 ml) and conc. HCl (1.5 ml) was heated to 80-85° C. After 3-5 hours the reaction mixture was cooled to room temperature, neutralize with aq. Ba(OH)2 and filtered to remove insoluble salts. The filtrate was concentrated to a residue, crystallized from MeOH, acetone and hexane to obtain 2-deoxy-D-glucose (11.77 g) mp. 149-151° C.EXAMPLE 11A solution of methyl 2-deoxy-α/β-D-glucopyranoside (30 g) (form example 2) water (195 ml) and conc. H2SO4 (5.9 ml) was heated to 80° C. After 2-3 hours the reaction mixture was cooled, neutralized with aq. Ba(OH)2 and filtered. The filtrate was separated, treated with charcoal and filtrate. The Filtrate was concentrated to a residue and crystallized from isopropyl alcohol to obtain the title product. Quantity obtained 5.2 g. mp. 152-154° C.EXAMPLE 12A mixture of methyl 2-deoxy-α/β-D-glucopyranoside (24 g) (from example 2) water (125 ml) and IR 120H+resin (7.5 ml) was heated to 90-95° C. for 2 h. The reaction mixture was cooled to room temperature, filtered and the resin was washed with water (20 ml). The filtrate was concentrated to residue and crystallized from ethanol to obtain 2-deoxy-D-glucose (8.8 g), mp. 150-152° C.CLIP
- ^ Merck Index, 11th Edition, 2886.
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The Drugs Controller General of India (DCGI) has given permission for the emergency use of drug 2-deoxy-D-glucose (2-DG) as an adjunct therapy in moderate to severe Covid-19 cases, said Defence Research and Development Organisation on Saturday.
“Being a generic molecule and analogue of glucose, it can be easily produced and made available in plenty,” said the DRDO in a statement.
An adjunct therapy refers to an alternative treatment that is used together with the primary treatment. Its purpose is to assist the primary treatment.
“The drug has been developed by DRDO lab Institute of Nuclear Medicine and Allied Sciences in collaboration with Dr Reddy’s Laboratories. Clinical trial have shown that this molecule helps in faster recovery of hospitalized patients and reduces supplemental oxygen dependence,” the statement read.
According to DRDO, the patients treated with 2-DG showed faster symptomatic cure than Standard of Care (SoC) on various endpoints in the efficacy trends.
“A significantly favourable trend (2.5 days difference) was seen in terms of the median time to achieving normalization of specific vital signs parameters when compared to SOC,” it said.
The drug comes in powder form in sachets, which is taken orally by dissolving it in water.
“It accumulates in the virus-infected cells and prevents virus growth by stopping viral synthesis and energy production,” said the DRDO.
In April 2020, during the first wave of the Covid-19 pandemic, INMAS-DRDO scientists conducted laboratory experiments of 2-DG with the help of the Centre for Cellular and Molecular Biology (CCMB), Hyderabad.
They found that this molecule works effectively against the SARS-CoV-2 virus and inhibits viral growth.
Based on the results, the DCGI had in May 2020 permitted Phase-II clinical trial of 2-DG in Covid-19 patients.
In Phase-II trials (including dose-ranging) conducted from May to October 2020, the drug was found to be safe and showed significant improvement in the patients’ recovery.
“Phase IIa was conducted in 6 hospitals and Phase IIb (dose-ranging) clinical trial was conducted at 11 hospitals all over the country. Phase-II trial was conducted on 110 patients,” said the DRDO.
NEW DRUG APPROVALS
|3D model (JSmol)||Interactive image|
|Molar mass||164.16 g/mol|
|Melting point||142 to 144 °C (288 to 291 °F; 415 to 417 K)|
|Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).|
////////////2-Deoxy-D-glucose, 2 dg, 2-dg, 2 DEOXY D GLUCOSE, COVID 19, CORONA VIRUS, INDIA 2021, DCGI, DRDO, DR REDDYS