EIDD-2801 works similarly to Gilead Sciences’ remdesivir, an unapproved drug that was developed for the Ebola virus and is being studied in five Phase III trials against COVID-19. Both molecules are nucleoside analogs that metabolize into an active form that blocks RNA polymerase, an essential component of viral replication.
ATI 7505 / ATI-7505
860174-12-5 (free base) 860169-57-9 (HCl)
Naronapride (free base), also known as ATI-7505, is a highly selective, high-affinity 5-HT(4) receptor agonist for gastrointestinal motility disorders. ATI-7505 accelerates overall colonic transit and tends to accelerate GE and AC emptying and loosen stool consistency.
Investigated for use/treatment in gastroesophageal reflux disease (GERD) and gastroparesis.
Renexxion , presumed to have been spun-out from Armetheon , under license from ARYx Therapeutics is developing naronapride (ATI-7505; phase 2 clinical in February 2020), an analog of the gastroprokinetic 5-HT 4 agonist cisapride identified using ARYx’s RetroMetabolic platform technology (ARM), for the oral treatment of upper GI disorders. In September 2018, this was still the case . PATENT
Process for preparing trihydrate salt of naronapride hydrochloride as 5-HT 4 receptor agonist useful for treating gastrointestinal disorders such as dyspepsia, gastroparesis, constipation, post-operative ileus. Appears to be the first filing from the assignee and the inventors on this compound,
In some aspects, provided herein is a method of making a trihydrate form of (3S, 4R, 3’R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-l-yl]-hexanoic acid l-azabicyclo[2.2.2]oct-3’-yl ester di-hydrochloride salt, which has the following formula:
Example 5: NMR Characterization of the Trihydrate
 ^-Nuclear Magnetic Resonance Spectroscopy (‘H-NMR) : Approximately 6 mg of the trihydrate was dissolved in in 1 g of deuterated solvent (dimethylsulfoxide (DMSO)-C45 99.9% d, with 0.05% v/v tetramethyl silane (TMS)). A Varian Gemini 300 MHz FT-NMR spectrometer was used to obtain the ¾-NMK spectrum. A list of the peaks is provided in Table 1 below. A representative ‘H-NMR spectrum is provided in FIG. 6.
Table 1. ‘H-NMR peak list for trihydrate
 13 C-Nuclear Magnetic Resonance Spectroscopy ( 13C-NMR ): Approximately 46 mg of the trihydrate was dissolved in 1 mL of deuterated solvent (deuterium oxide, Aldrich, 99.9% D, TPAS 0.75%). The 13C-NMR spectrum was obtained using a Varian Gemini 300 MHz FT-NMR spectrometer. A list of the peaks is provided in Table 2 below. A representative 13C-NMR spectrum is provided in FIG. 7.
Table 2. 13C-NMR peak list for trihydrate
US10570127 claiming composition (eg tablet) comprising a trihydrate form of naronapride.
1: Jiang C, Xu Q, Wen X, Sun H. Current developments in pharmacological therapeutics for chronic constipation. Acta Pharm Sin B. 2015 Jul;5(4):300-9. doi: 10.1016/j.apsb.2015.05.006. Epub 2015 Jun 6. Review. PubMed PMID: 26579459; PubMed Central PMCID: PMC4629408.
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////////////NARONAPRIDE, ATI 7505, ATI 7505,PHASE 2
- Molecular FormulaC63H111N11O12
- Average mass1214.622 Da
Aurinia Pharmaceuticals (following its merger with Isotechnika ), in collaboration with licensee Paladin Labs (a subsidiary of Endo International plc ), 3SBio ,and ILJIN , is developing a capsule formulation of the immunosuppressant calcineurin inhibitor peptide voclosporin for the treatment of psoriasis, the prevention of organ rejection after transplantation, autoimmune disease including systemic lupus erythematosus and lupus nephritis, and nephrotic syndrome including focal segmental glomerulosclerosis;
Voclosporin is an experimental immunosuppressant drug being developed by Aurinia Pharmaceuticals. It is being studied as a potential treatment for lupus nephritis (LN) and uveitis. It is an analog of ciclosporin that has enhanced action against calcineurin and greater metabolic stability. Voclosporin was discovered by Robert T. Foster and his team at Isotechnika in the mid 1990s. Isotechnika was founded in 1993 and merged with Aurinia Pharmaceuticals in 2013.
Initially, voclosporin was a mixture of equal proporations of cis and trans geometric isomers of amino acid-1 modified cyclosporin. Later, in collaboration with Roche in Basel, Switzerland, voclosporin’s manufacturing was changed to yield the predominantly trans isomer which possesses most of the beneficial effect of the drug (immunosuppression) in the treatment of organ transplantation and autoimmune diseases.
Novel crystalline forms of voclosporin which is a structural analog of cyclosporine A as calcineurin signal-transduction pathway inhibitor useful for treating lupus nephritis.
Voclosporin is a structural analog of cyclosporine A, with an additional single carbon extension that has a double-bond on one side chain. Voclosporin has the chemical name (3S,6S,9S,l2R,l5S,l8S,2lS,24S,30S,33S)-30-Ethyl-33-[(lR,2R,4E)-l-hydroxy-2-methyl-4,6-heptadien-l-yl]-6,9,l8,24-tetraisobutyl-3,2l-diisopropyl-l,4,7,l0,l2,l5,l9,25,28-nonamethyl-l,4,7,l0,l3,l6,l9,22,25,28,3 l-undecaazacyclotritriacontane-2,5,8,l l,l4,l7,20,23,26,29,32-undecone and the following chemical structure:
Voclosporin is reported to be a semisynthetic structural analogue of cyclosporine that exerts its immunosuppressant effects by inhibition of the calcineurin signal-transduction pathway and is in Phase 3 Clinical Development for Lupus Nephritis.
 Voclosporin and process for preparation thereof are known from International Patent Application No. WO 1999/18120.
 Certain mixtures of cis and trans-isomers of cyclosporin A analogs referred to as
ISATX247 in different ratios are known from U.S. Patent No. 6,998,385, U.S. Patent No. 7,332,472 and U.S. Patent No. 9,765,119.
 Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Voclosporin, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis – “TGA”, or differential scanning calorimetry – “DSC”), powder X-ray diffraction (PXRD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state (13C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
 Different salts and solid state forms (including solvated forms) of an active
pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.
 Discovering new salts, solid state forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other salts or polymorphic forms. New salts, polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life.
 For at least these reasons, there is a need for solid state forms (including solvated forms) of Voclosporin and salts thereof.
Column: Zorbax SB C18, 1.8 pm, 100×2.1 mm
Mobile phase: A: 38 ACN : 7 TBME : 55 voda : 0.02 H3P04 (V/V/V/V)
B: 70 ACN : 7 TBME : 23 voda : 0.02 H P04 (V/V/V/V)
Flow rate: 0.5 mL/min
Analysis time: 26 minutes + 3 minutes equilibration
Injection volume: 3.0 pL
Column temperature: 90 °C
Detection: UV, 210 nm
 The starting material Voclosporin crude may be obtained according to ET.S. Patent No. 6,998,385 ETnless otherwise indicated, the purity is determined by HPLC (area percent). The crude product contained according to HPLC analysis 42.6 % trans-Voclosporin (further only Voclosporin), 40.2 % cis-Voclosporin and 2.9 % Cyclosporin A. The crude Voclosporin was purified by column chromatography on silica gel using a mixture of toluene and acetone 82 : 18 (v/v) as mobile phase. The fractions were monitored by HPLC. The appropriate fractions were joined and evaporated, obtaining purified Voclosporin as a white foam. According to HPLC analysis it contained 85.7 % Voclosporin, 3.6 % cis-Voclosporin and 2.6 % Cyclosporin A (further only purified Voclosporin).
 The Voclosporin crude (containing about 42.6 % of Voclosporin) was used for further optimization of the chromatographic separation of cis-Voclosporin and Voclosporin and the effort resulted in improved process for chromatographic separation which includes purification by column chromatography on silica gel using a mixture of toluene and methylisobutylketone 38 : 62 as mobile phase. The fractions were monitored by HPLC. The appropriate fractions were joined and evaporated to a dry residue, weighing 31.0 grams. This residue was not analyzed. The material was dissolved in 25 ml of acetone and then 50 ml of water was added and the solution was let to crystallize for 2 hours in the refrigerator. Then the crystalline product was separated by filtration and dried in vacuum dryer (40 °C, 50 mbar, 12 hours), obtaining 29.6 g of dry product containing 90.6 % of Voclosporin, 0.4 % cis-Voclosporin and 3.7 % Cyclosporin A (further mentioned as final Voclosporin).
Example 1: Preparation of Voclosporin Form A
4.1 grams of Purified Voclosporin was dissolved in acetone and the solution was evaporated to 8.0 grams and the concentrate was diluted by 6 ml of water. The solution was let to crystallize in refrigerator at about 2 °C for 12 hours. The crystalline product was filtered off, washed by a mixture of acetone and water 1 : 1 (v/v) and dried on open air obtaining 2.6 grams of crystalline product Form A. Voclosporin form A was confirmed by PXRD as presented in Figure 1.
Example 2: Preparation of Voclosporin Form B
 1.0 gram of Purified Voclosporin was dissolved in a mixture of 1.5 ml acetone and 3.0 ml n-hexane. The solution was let to crystallize in refrigerator at about 2 °C for 12 hours. The crystalline product was filtered off, washed by a mixture of acetone and hexane 1 : 2 (v/v) and dried on open air obtaining 0.5 grams of crystalline product Form B. Voclosporin form B was confirmed by PXRD as presented in Figure 2.
Example 3: Preparation of Amorphous Voclosporin
 2.0 grams of Purified Voclosporin was dissolved in 40 ml of hot cyclohexane and the solution was stirred for 12 hours at room temperature. Then the crystalline product was filtered off and washed with 5 ml of cyclohexane and dried on open air, obtaining 1.3 grams of amorphous powder. Amorphous Voclosporin was confirmed by PXRD as presented in Figure 3
Example 4: Preparation of Voclosporin Form C
 Final Voclosporin (2 grams) was dissolved in acetonitrile (20 ml) at 50 °C, water (6 ml) was added with stirring, and the clear solution was allowed to crystallize 5 days at 20 °C. Colorless needle crystals were directly mounted to the goniometer head in order to define the crystal structure. Voclosporin form C was confirmed by X-ray crystal structure determination.
VCS, ISA247, Luveniq
3D model (JSmol)
|Molar mass||1214.646 g·mol−1|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
methanol; potassium carbonate;
Reactants can be synthesized in 7 steps.
Synthesis, vol. 44, 1, (2012), p. 63 – 68
sulfuric acid; tetrahydrofuran;
ISOTECHNIKA INC., WO2004/89960, A2, (2004) 20 ml of THF were added and the reaction mixture was cooled to 0 °C. 2.7 ML (48.69 mmol, 3 equiv. ) of concentrated sulfuric acid were added. The temperature was raised to RT. After completion of the reaction (ca 1 hour), 100 ml of water were added. The organic phase was separated and washed 2 times with 50 ml water. The water phases were re-extracted sequentially with 50 ml dichloromethane. The c ombined organic phases were dried over NA2SO4, filtered and concentrated under reduced pressure at 3 0°C. The resulting white foam was re-dissolved in 250 ml MTBE and after a few minutes, the crystalli zation started. After stirring 15 min. at RT and 2 hours at 0-2 C, THE SUSPENSION WAS FILTERED. THE crystals were washed with 50 ml cold MTBE (-20 °C) and dried at 40-50 °C under reduced pressure to p rovide 19.2 g of (E) -acetyl-ISA247 as white powder in >98percent isomeric purity (400MHZ LH NMR). (E)-ACETYL-ISA247 can be RECRYSTALLIZED by dissolving the solid in dichloromethane at room temperatur e and exchanging the solvent to MTBE (by adding MTBE, concentrating the solution to half its volume under reduced pressure at 40°C and repeating these operation 2 to three times). The solution is cool ed to room temperature and the crystallization then starts within a few minutes. The suspension is s tirred at room temperature for 2h and 30min at 0°C. The crystals of (E) -acetyl-ISA247 are isolated after filtration, washing with MTBE and drying under reduced pressure at 40°C.iii) Peterson eliminat ion The CRUDE-TRIMETHYLSILYALCOHOL diastereomers mixture (11 g, maximum 4.056 mmol) was dissolved in 25 ml THF. 0.679 ml (12.16 mmol, 3 equiv.) concentrated sulfuric were added dropwise maintaining th e temperature between 20 °C and 25 °C. After 2 hours at RT, 50 ml half saturated aqueous NaCl soluti on were added. The resulting mixture was extracted twice with 50 ML MTBE. The organic phases were washed with 50ML of a half saturated aqueous NACL solution, combined, dried over NA2SO4 and concentrat ed under reduce pressure at 40°C. The resulting crude E-acetyl-ISA247 was re-dissolved in 20 ml dich loromethane and concentrated under reduced pressure. The crude product was dissolved in 60 ml MTBE. The crystallization started within 10 min. The suspension was stirred for an additional 15 min. at R T and 2 hours AT-10 °C. The crystals were isolated by filtration, washed with 20 ml cold MTBE (-20 ° C) and dried under reduced pressure to provide 3. 6 G of (E)-ACETYL-ISA247 in ca 98percent isomeric purity by NMR.iii) Peterson elimination After overnight reaction, the organic layer was separated an d the water phase was discarded. 50 ML THF were added to the organic phase. The solution was concent rated under reduced pressure at 30 °C to half its volume. 100 ML THP were added and the solution was concentrated to 80 ML. The volume was adjusted to 100 ml with THF and the solution was cooled to 0- 2 °C. 1. 812 ML (32. 46 MMOL, 2 equiv.) concentrated sulfuric acid were added dropwise over 5 min., maintaining the temperature below 5 °C. After addition, the reaction cooling bath was removed and th e temperature was raised to RT. After 4 hours reaction, 40 ML water were added followed by 20 ml MTB E. The aqueous layer was separated and discarded. The organic phase was washed with 40 ml NAHCO3 Q, 20 ML saturated NACLAQ, 40 ml saturated NaClaq, dried over Na2SO4, filtered and concentrated at 40 ° C under reduced pressure. The crude E-acetyl-ISA247 was RE-DISSOLVED in 200 ml MTBE and crystallizat ion started within a few minutes. After 15 min. at RT and 2.5 hours at 0 °C, the suspension was filt ered, the crystals were washed with 50 ML MTBE and dried at 50 °C under reduced pressure to give 18. 45 g of (E) -acetyl-ISA247 as a white powder (>98percent isomeric purity by NMR).iii) Peterson elim ination 5 ml THF were added to the organic phase and the solution was cooled to 0- 2 °C. 181 UL (3.2 46, 2 equiv. ) concentrated sulfuric acid were added. The reaction mixture was warmed up to RT. Afte r stirring overnight, 20 ml water were added. The aqueous layer was separated and discarded. The organic phase was washed with 20 ml of 5percent aqueous NAHCO3 solution, dried over MGS04, filtered and concentrated under reduced pressure at 40 °C to give 2 g of (E) -acetyl-ISA247 as a white foam in > 98percent double bond isomeric purity (by NMR).ii) Peterson elimination The crude product was dissol ved in 11.15 ML THF and 268 P1 concentrated sulfuric acid were added. The reaction mixture was heate d at 33 °C for 1.5 hour and then cooled to RT. 22 ml water were added and the reaction mixture was e xtracted with 22 ml MTBE. The aqueous phase was RE-EXTRACTED with 11 ml MTBE. The organic layer were washed with 11 ml water, combined, dried over NA2SO4, filtered and concentrated at 40 °C under redu ced pressure to give 1.89 g of crude (E) -acetyl-ISA247 as a beige powder. The crude product was re-dissolved in 20 ml MTBE at RT. The crystallization started within a few minutes. The suspension was stirred 30 min. at RT, 45 min. at-10 °C and was filtered. The solid was washed with cold MTBE and dr ied at 40 °C under reduced pressure to give 1.02 g of (E)-acetylISA247 as a white powder in ca 98per cent double bond isomeric purity (NMR). ii) Peterson elimination The crude product was dissolved in 8 ML THF at RT. The solution was cooled to 0-5 °C and 200 UL of concentrated sulfuric acid were adde d dropwise. The temperature was raised to RT and the reaction mixture was stirred 10 hours. 40 ml MTBE and 15 ml of water were added. The water phase was separated and discarded. The organic phase was washed 15 ml of a 5percent aqueous NAHCO3 solution, 15 ml of a half saturated aqueous NACL solution, dried over NA2SO4, filtered and concentrated under reduced pressure to give 1. 8 g of crude E-acet yl- ISA247. The crude diene was dissolved in 20 ml dichloromethane. 20 ML MTBE were added, and the s olution was concentrated at 40 °C under reduced pressure to half its volume. The last two operations was repeated three times to in order to exchange the solvent from dichloromethane to MTBE. The solution was cooled to RT and the crystallization started within a few minutes. The suspension was stirr ed 2 hours at RT and 30 min. at 0 °C. The suspension was filtered. The solid was washed with 15 ml M TBE and dried under reduced pressure at 40 °C to give 1.1 g OF E-ACETYL-ISA247 in >95percent double bond isomeric purity (NMR), as a white powder.ii) Peterson elimination The crude product was dissolv ed in 10 ml THF at RT. The solution was cooled to 0-5 °C and 200 UL of concentrated sulfuric acid we re added dropwise. The temperature was raised to RT and the reaction mixture was stirred overnight. 40 ml MTBE and 15 ML of water were added. The water phase was separated and discarded. The organic p hase was washed with 15 ml water, 15 ml of a 5percent aqueous NAHCO3 solution, 15 ml of a half saturated aqueous NaCl solution, filtered and concentrated under reduced pressure to give 1.8 g of crude E-ACETYL-ISA247. The crude diene was redissolved in 35 ml of MTBE. The crystallization started withi n a few minutes. The suspension was stirred 2 hours at RT and 30 min. at 0 °C. The suspension was fi ltered. The solid was washed with 15 ml MTBE and dried under reduced pressure at 40 °C to gi ve 1 g of E-acetyl-ISA247 in >95percent double bond isomeric purity (NMR), as a white powder.
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19: Kunynetz R, Carey W, Thomas R, Toth D, Trafford T, Vender R. Quality of life in plaque psoriasis patients treated with voclosporin: a Canadian phase III, randomized, multicenter, double-blind, placebo-controlled study. Eur J Dermatol. 2011 Jan-Feb;21(1):89-94. doi: 10.1684/ejd.2010.1185. PubMed PMID: 21227890.
20: Deuter CM. [Systemic voclosporin for uveitis treatment]. Ophthalmologe. 2010 Jul;107(7):672-5. doi: 10.1007/s00347-010-2217-5. German. PubMed PMID: 20571806.
//////////VOCLOSPORIN, Voclosporin, ISA247, ISAtx 247, ISAtx-247, ISAtx247, Luveniq, LX211,
Azithromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes middle ear infections, strep throat, pneumonia, traveler’s diarrhea, and certain other intestinal infections. It can also be used for a number of sexually transmitted infections, including chlamydia and gonorrhea infections. Along with other medications, it may also be used for malaria. It can be taken by mouth or intravenously with doses once per day.
Common side effects include nausea, vomiting, diarrhea and upset stomach. An allergic reaction, such as anaphylaxis, QT prolongation, or a type of diarrhea caused by Clostridium difficile is possible. No harm has been found with its use during pregnancy. Its safety during breastfeeding is not confirmed, but it is likely safe. Azithromycin is an azalide, a type of macrolide antibiotic. It works by decreasing the production of protein, thereby stopping bacterial growth.
Azithromycin was discovered 1980 by Pliva, and approved for medical use in 1988. It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system. The World Health Organization classifies it as critically important for human medicine. It is available as a generic medication and is sold under many trade names worldwide. The wholesale cost in the developing world is about US$0.18 to US$2.98 per dose. In the United States, it is about US$4 for a course of treatment as of 2018. In 2016, it was the 49th most prescribed medication in the United States with more than 15 million prescriptions.
Azithromycin is used to treat many different infections, including:
- Prevention and treatment of acute bacterial exacerbations of chronic obstructive pulmonary disease due to H. influenzae, M. catarrhalis, or S. pneumoniae. The benefits of long-term prophylaxis must be weighed on a patient-by-patient basis against the risk of cardiovascular and other adverse effects.
- Community-acquired pneumonia due to C. pneumoniae, H. influenzae, M. pneumoniae, or S. pneumoniae
- Uncomplicated skin infections due to S. aureus, S. pyogenes, or S. agalactiae
- Urethritis and cervicitis due to C. trachomatis or N. gonorrhoeae. In combination with ceftriaxone, azithromycin is part of the United States Centers for Disease Control-recommended regimen for the treatment of gonorrhea. Azithromycin is active as monotherapy in most cases, but the combination with ceftriaxone is recommended based on the relatively low barrier to resistance development in gonococci and due to frequent co-infection with C. trachomatis and N. gonorrhoeae.
- Trachoma due to C. trachomatis
- Genital ulcer disease (chancroid) in men due to H. ducrey
- Acute bacterial sinusitis due to H. influenzae, M. catarrhalis, or S. pneumoniae. Other agents, such as amoxicillin/clavulanate are generally preferred, however.
- Acute otitis media caused by H. influenzae, M. catarrhalis or S. pneumoniae. Azithromycin is not, however, a first-line agent for this condition. Amoxicillin or another beta lactam antibiotic is generally preferred.
- Pharyngitis or tonsillitis caused by S. pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy
Azithromycin has relatively broad but shallow antibacterial activity. It inhibits some Gram-positive bacteria, some Gram-negative bacteria, and many atypical bacteria.
A strain of gonorrhea reported to be highly resistant to azithromycin was found in the population in 2015. Neisseria gonorrhoeae is normally susceptible to azithromycin, but the drug is not widely used as monotherapy due to a low barrier to resistance development. Extensive use of azithromycin has resulted in growing Streptococcus pneumoniae resistance.
Aerobic and facultative Gram-positive microorganisms
- Staphylococcus aureus (Methicillin-sensitive only)
- Streptococcus agalactiae
- Streptococcus pneumoniae
- Streptococcus pyogenes
Aerobic and facultative Gram-negative microorganisms
- Haemophilus ducreyi
- Haemophilus influenzae
- Moraxella catarrhalis
- Neisseria gonorrhoeae
- Bordetella pertussis
- Legionella pneumophila
- Chlamydophila pneumoniae
- Chlamydia trachomatis
- Mycoplasma genitalium
- Mycoplasma pneumoniae
- Ureaplasma urealyticum
Pregnancy and breastfeeding[edit source]
Safety of the medication during breastfeeding is unclear. It was reported that because only low levels are found in breast milk and the medication has also been used in young children, it is unlikely that breastfed infants would suffer adverse effects. Nevertheless, it is recommended that the drug be used with caution during breastfeeding.
Azithromycin appears to be effective in the treatment of COPD through its suppression of inflammatory processes. And potentially useful in asthma and sinusitis via this mechanism. Azithromycin is believed to produce its effects through suppressing certain immune responses that may contribute to inflammation of the airways.
Most common adverse effects are diarrhea (5%), nausea (3%), abdominal pain (3%), and vomiting. Fewer than 1% of people stop taking the drug due to side effects. Nervousness, skin reactions, and anaphylaxis have been reported. Clostridium difficile infection has been reported with use of azithromycin. Azithromycin does not affect the efficacy of birth control unlike some other antibiotics such as rifampin. Hearing loss has been reported.
In 2013 the FDA issued a warning that azithromycin “can cause abnormal changes in the electrical activity of the heart that may lead to a potentially fatal irregular heart rhythm.” The FDA noted in the warning a 2012 study that found the drug may increase the risk of death, especially in those with heart problems, compared with those on other antibiotics such as amoxicillin or no antibiotic. The warning indicated people with preexisting conditions are at particular risk, such as those with QT interval prolongation, low blood levels of potassium or magnesium, a slower than normal heart rate, or those who use certain drugs to treat abnormal heart rhythms.
Mechanism of action
Azithromycin prevents bacteria from growing by interfering with their protein synthesis. It binds to the 50S subunit of the bacterial ribosome, thus inhibiting translation of mRNA. Nucleic acid synthesis is not affected.
Azithromycin is an acid-stable antibiotic, so it can be taken orally with no need of protection from gastric acids. It is readily absorbed, but absorption is greater on an empty stomach. Time to peak concentration (Tmax) in adults is 2.1 to 3.2 hours for oral dosage forms. Due to its high concentration in phagocytes, azithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations are released. The concentration of azithromycin in the tissues can be over 50 times higher than in plasma due to ion trapping and its high lipid solubility. Azithromycin’s half-life allows a large single dose to be administered and yet maintain bacteriostatic levels in the infected tissue for several days.
Following a single dose of 500 mg, the apparent terminal elimination half-life of azithromycin is 68 hours. Biliary excretion of azithromycin, predominantly unchanged, is a major route of elimination. Over the course of a week, about 6% of the administered dose appears as unchanged drug in urine.
A team of researchers at the pharmaceutical company Pliva in Zagreb, SR Croatia, Yugoslavia, — Gabrijela Kobrehel, Gorjana Radobolja-Lazarevski, and Zrinka Tamburašev, led by Dr. Slobodan Đokić — discovered azithromycin in 1980. It was patented in 1981. In 1986, Pliva and Pfizer signed a licensing agreement, which gave Pfizer exclusive rights for the sale of azithromycin in Western Europe and the United States. Pliva put its azithromycin on the market in Central and Eastern Europe under the brand name Sumamed in 1988. Pfizer launched azithromycin under Pliva’s license in other markets under the brand name Zithromax in 1991. Patent protection ended in 2005.
It is available as a generic medication. The wholesale cost is about US$0.18 to US$2.98 per dose. In the United States it is about US$4 for a course of treatment as of 2018. In India, it is about US$1.70 for a course of treatment.
In 2010, azithromycin was the most prescribed antibiotic for outpatients in the US, whereas in Sweden, where outpatient antibiotic use is a third as prevalent, macrolides are only on 3% of prescriptions.
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Keywords: Antibacterial (Antibiotics); Macrolides.
- “Azithromycin”. Drug Information Portal. U.S. National Library of Medicine.
|Trade names||Zithromax, Azithrocin, others|
|Other names||9-deoxy-9α-aza-9α-methyl-9α-homoerythromycin A|
|By mouth (capsule, tablet or suspension), intravenous, eye drop|
|Drug class||Macrolide antibiotic|
|Bioavailability||38% for 250 mg capsules|
|Elimination half-life||11–14 h (single dose) 68 h (multiple dosing)|
|Excretion||Biliary, kidney (4.5%)|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||748.984 g·mol−1 g·mol−1|
|3D model (JSmol)|
/////////AZITHROMYCIN, Antibacterial, Antibiotics, Macrolides, CORONA VIRUS, COVID 19, アジスロマイシン ,
|Molecular Weight:||329.31 g/mol|
Electron microscope image of SARS virus in a tissue culture isolate, courtesy of CDC Public Health Image Library.
The drug EIDD-1931 was effective against SARS and MERS viruses in the laboratory, and a modified version (EIDD-2801) could potentially be valuable against 2019-nCoV.
Emory, collaborators testing antiviral drug as potential treatment for coronaviruses
An antiviral compound discovered at Emory University could potentially be used to treat the new coronavirus associated with the outbreak in China and spreading around the globe. Drug Innovation Ventures at Emory (DRIVE), a non-profit LLC wholly owned by Emory, is developing the compound, designated EIDD-2801.
In testing with collaborators at the University of North Carolina at Chapel Hill and Vanderbilt University Medical Center, the active form of EIDD-2801, which is called EIDD-1931, has shown efficacy against the related coronaviruses SARS (Severe Acute Respiratory Syndrome)- and MERS-CoV (Middle East Respiratory Syndrome Coronavirus). Some of the data was recently published in Journal of Virology.
EIDD-2801 is an oral ribonucleoside analog that inhibits the replication of multiple RNA viruses, including respiratory syncytial virus, influenza, chikungunya, Ebola, Venezuelan equine encephalitis virus, and Eastern equine encephalitis viruses.
“We have been planning to enter human clinical tests of EIDD-2801 for the treatment of influenza, and recognized that it has potential activity against the current novel coronavirus,” says George Painter, PhD, director of the Emory Institute for Drug Development (EIDD) and CEO of DRIVE. “Based on the drug’s broad-spectrum activity against viruses including influenza, Ebola and SARS-CoV/MERS-CoV, we believe it will be an excellent candidate.”
“Our studies in the Journal of Virology show potent activity of the EIDD-2801 parent compound against multiple coronaviruses including SARS and MERS,” says Mark Denison, MD, the Stahlman Professor of Pediatrics and director of pediatric infectious diseases at Vanderbilt University School of Medicine. “It also has a strong genetic barrier to development of viral resistance, and its oral bioavailability makes it a candidate for use during an outbreak.”
“Generally speaking, seasonal flu is still a much more common threat than this coronavirus, however, novel emerging coronaviruses represent a considerable threat to global health as evidenced by the new 2019-nCoV,” said Ralph Baric, PhD, an epidemiology professor at the University of North Carolina’s Gillings School of Global Public Health. “But the reason the new coronavirus is so concerning is that it’s much more likely to be deadly than the flu – fatal for about one in 25 people versus one in 1,000 for the flu.”
The development of EIDD-2801 has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), under contract numbers HHSN272201500008C and 75N93019C00058, and from the Defense Threat Reduction Agency (DTRA), under contract numbers HDTRA1-13-C-0072 and HDTRA1-15-C-0075, for the treatment of Influenza, coronavirus, chikungunya, and Venezuelan equine encephalitis virus.
About DRIVE: DRIVE is a non-profit LLC wholly owned by Emory started as an innovative approach to drug development. Operating like an early stage biotechnology company, DRIVE applies focus and industry development expertise to efficiently translate discoveries to address viruses of global concern. Learn more at: http://driveinnovations.org/
Emory-discovered antiviral is poised for COVID-19 clinical trials
The nucleoside inhibitor has advantages over Gilead’s remdesivir but has yet to be tested in humans
Asmall-molecule antiviral discovered by Emory University chemists could soon start human testing against COVID-19, the respiratory disease caused by the novel coronavirus. That’s the plan of Ridgeback Biotherapeutics, which licensed the compound, EIDD-2801, from an Emory nonprofit.
But remdesivir can only be given intravenously, meaning it would be difficult to deploy widely. In contrast, EIDD-2801 can be taken in pill form, says Mark Denison, a coronavirus expert and director of the infectious diseases division at Vanderbilt Medical School. Denison partnered with Emory and researchers at the University of North Carolina to test the compound against coronaviruses.
EIDD-2801 has other promising features. Many antivirals work by introducing errors into the viral genome, but, unlike other viruses, coronaviruses can fix some mistakes. In lab experiments, EIDD-2801 “was able to overcome the coronavirus proofreading function,” Denison says.
He also notes that while remdesivir and EIDD-2801 both block RNA polymerase, they appear to do it in different ways, meaning they could be complementary.
Unlike remdesivir, EIDD-2801 lacks human safety data. Ridgeback founder and CEO Wendy Holman says she expects the US Food and Drug Administration to give the green light for a Phase I study in COVID-19 infections within “weeks, not months.”
////////EIDD 2801, EMORY, CORONA VIRUS, COVID 19,
Chloroquine is a medication used primarily to prevent and to treat malaria in areas where that parasitic disease is known to remain sensitive to its effects. A benefit of its use in therapy, when situations allow, is that it can be taken by mouth (versus by injection). Controlled studies of cases involving human pregnancy are lacking, but the drug may be safe for use for such patients.[verification needed] However, the agent is not without the possibility of serious side effects at standard doses, and complicated cases, including infections of certain types or caused by resistant strains, typically require different or additional medication. Chloroquine is also used as a medication for rheumatoid arthritis, lupus erythematosus, and other parasitic infections (e.g., amebiasis occurring outside of the intestines). Beginning in 2020, studies have proceeded on its use as a coronavirus antiviral, in possible treatment of COVID-19.
Chloroquine, otherwise known as chloroquine phosphate, is in the 4-aminoquinoline class of drugs. As an antimalarial, it works against the asexual form of the malaria parasite in the stage of its life cycle within the red blood cell. In its use against rheumatoid arthritis and lupus erythematosus, its activity as a mild immunosuppressive underlies its mechanism. Antiviral activities, established and putative, are attributed to chloroquines inhibition of glycosylation pathways (of host receptor sialylation or virus protein post-translational modification), or to inhibition of virus endocytosis (e.g., via alkalisation of endosomes), or other possible mechanisms. Common side effects resulting from these therapeutic uses, at common doses, include muscle problems,[clarification needed] loss of appetite, diarrhea, and skin rash.[clarification needed] Serious side effects include problems with vision (retinopathy), muscle damage, seizures, and certain anemias.
Chloroquine was discovered in 1934 by Hans Andersag. It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system. It is available as a generic medication. The wholesale cost in the developing world is about US$0.04. In the United States, it costs about US$5.30 per dose.
Chloroquine has been used in the treatment and prevention of malaria from Plasmodium vivax, P. ovale, and P. malariae. It is generally not used for Plasmodium falciparum as there is widespread resistance to it.
Chloroquine has been extensively used in mass drug administrations, which may have contributed to the emergence and spread of resistance. It is recommended to check if chloroquine is still effective in the region prior to using it. In areas where resistance is present, other antimalarials, such as mefloquine or atovaquone, may be used instead. The Centers for Disease Control and Prevention recommend against treatment of malaria with chloroquine alone due to more effective combinations.
In treatment of amoebic liver abscess, chloroquine may be used instead of or in addition to other medications in the event of failure of improvement with metronidazole or another nitroimidazole within 5 days or intolerance to metronidazole or a nitroimidazole.
Side effects include blurred vision, nausea, vomiting, abdominal cramps, headache, diarrhea, swelling legs/ankles, shortness of breath, pale lips/nails/skin, muscle weakness, easy bruising/bleeding, hearing and mental problems.
- Unwanted/uncontrolled movements (including tongue and face twitching) 
- Deafness or tinnitus.
- Nausea, vomiting, diarrhea, abdominal cramps
- Mental/mood changes (such as confusion, personality changes, unusual thoughts/behavior, depression, feeling being watched, hallucinating)
- Signs of serious infection (such as high fever, severe chills, persistent sore throat)
- Skin itchiness, skin color changes, hair loss, and skin rashes.
- Chloroquine-induced itching is very common among black Africans (70%), but much less common in other races. It increases with age, and is so severe as to stop compliance with drug therapy. It is increased during malaria fever; its severity is correlated to the malaria parasite load in blood. Some evidence indicates it has a genetic basis and is related to chloroquine action with opiate receptors centrally or peripherally.
- Unpleasant metallic taste
- This could be avoided by “taste-masked and controlled release” formulations such as multiple emulsions.
- Chloroquine retinopathy
- Electrocardiographic changes
- This manifests itself as either conduction disturbances (bundle-branch block, atrioventricular block) or Cardiomyopathy – often with hypertrophy, restrictive physiology, and congestive heart failure. The changes may be irreversible. Only two cases have been reported requiring heart transplantation, suggesting this particular risk is very low. Electron microscopy of cardiac biopsies show pathognomonic cytoplasmic inclusion bodies.
- Pancytopenia, aplastic anemia, reversible agranulocytosis, low blood platelets, neutropenia.
Chloroquine has not been shown to have any harmful effects on the fetus when used for malarial prophylaxis. Small amounts of chloroquine are excreted in the breast milk of lactating women. However, this drug can be safely prescribed to infants, the effects are not harmful. Studies with mice show that radioactively tagged chloroquine passed through the placenta rapidly and accumulated in the fetal eyes which remained present five months after the drug was cleared from the rest of the body. Women who are pregnant or planning on getting pregnant are still advised against traveling to malaria-risk regions.
There is not enough evidence to determine whether chloroquine is safe to be given to people aged 65 and older. Since it is cleared by the kidneys, toxicity should be monitored carefully in people with poor kidney functions.
- Ampicillin– levels may be reduced by chloroquine;
- Antacids– may reduce absorption of chloroquine;
- Cimetidine– may inhibit metabolism of chloroquine; increasing levels of chloroquine in the body;
- Cyclosporine– levels may be increased by chloroquine; and
- Mefloquine– may increase risk of convulsions.
Chloroquine is very dangerous in overdose. It is rapidly absorbed from the gut. In 1961, a published compilation of case reports contained accounts of three children who took overdoses and died within 2.5 hours of taking the drug. While the amount of the overdose was not stated, the therapeutic index for chloroquine is known to be small. One of the children died after taking 0.75 or 1 gram, or twice a single therapeutic amount for children. Symptoms of overdose include headache, drowsiness, visual disturbances, nausea and vomiting, cardiovascular collapse, seizures, and sudden respiratory and cardiac arrest.
An analog of chloroquine – hydroxychloroquine – has a long half-life (32–56 days) in blood and a large volume of distribution (580–815 L/kg). The therapeutic, toxic and lethal ranges are usually considered to be 0.03 to 15 mg/l, 3.0 to 26 mg/l and 20 to 104 mg/l, respectively. However, nontoxic cases have been reported up to 39 mg/l, suggesting individual tolerance to this agent may be more variable than previously recognised.
Chloroquine’s absorption of the drug is rapid. It is widely distributed in body tissues. It’s protein binding is 55%.[ It’s metabolism is partially hepatic, giving rise to its main metabolite, desethylchloroquine. It’s excretion os ≥50% as unchanged drug in urine, where acidification of urine increases its elimination It has a very high volume of distribution, as it diffuses into the body’s adipose tissue.
Accumulation of the drug may result in deposits that can lead to blurred vision and blindness. It and related quinines have been associated with cases of retinal toxicity, particularly when provided at higher doses for longer times. With long-term doses, routine visits to an ophthalmologist are recommended.
Chloroquine is also a lysosomotropic agent, meaning it accumulates preferentially in the lysosomes of cells in the body. The pKa for the quinoline nitrogen of chloroquine is 8.5, meaning—in simplified terms, considering only this basic site—it is about 10% deprotonated at physiological pH (per the Henderson-Hasselbalch equation) This decreases to about 0.2% at a lysosomal pH of 4.6.Because the deprotonated form is more membrane-permeable than the protonated form, a quantitative “trapping” of the compound in lysosomes results.
Mechanism of action
The lysosomotropic character of chloroquine is believed to account for much of its antimalarial activity; the drug concentrates in the acidic food vacuole of the parasite and interferes with essential processes. Its lysosomotropic properties further allow for its use for in vitro experiments pertaining to intracellular lipid related diseases, autophagy, and apoptosis.
Inside red blood cells, the malarial parasite, which is then in its asexual lifecycle stage, must degrade hemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. Digestion is carried out in a vacuole of the parasitic cell.
Hemoglobin is composed of a protein unit (digested by the parasite) and a heme unit (not used by the parasite). During this process, the parasite releases the toxic and soluble molecule heme. The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite biocrystallizes heme to form hemozoin, a nontoxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals.
Chloroquine enters the red blood cell by simple diffusion, inhibiting the parasite cell and digestive vacuole. Chloroquine then becomes protonated (to CQ2+), as the digestive vacuole is known to be acidic (pH 4.7); chloroquine then cannot leave by diffusion. Chloroquine caps hemozoin molecules to prevent further biocrystallization of heme, thus leading to heme buildup. Chloroquine binds to heme (or FP) to form the FP-chloroquine complex; this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion.  Parasites that do not form hemozoin are therefore resistant to chloroquine.
Resistance in malaria[edit source]
Since the first documentation of P. falciparum chloroquine resistance in the 1950s, resistant strains have appeared throughout East and West Africa, Southeast Asia, and South America. The effectiveness of chloroquine against P. falciparum has declined as resistant strains of the parasite evolved. They effectively neutralize the drug via a mechanism that drains chloroquine away from the digestive vacuole. Chloroquine-resistant cells efflux chloroquine at 40 times the rate of chloroquine-sensitive cells; the related mutations trace back to transmembrane proteins of the digestive vacuole, including sets of critical mutations in the P. falciparum chloroquine resistance transporter (PfCRT) gene. The mutated protein, but not the wild-type transporter, transports chloroquine when expressed in Xenopus oocytes (frog’s eggs) and is thought to mediate chloroquine leak from its site of action in the digestive vacuole. Resistant parasites also frequently have mutated products of the ABC transporter P. falciparum multidrug resistance (PfMDR1) gene, although these mutations are thought to be of secondary importance compared to Pfcrt. Verapamil, a Ca2+ channel blocker, has been found to restore both the chloroquine concentration ability and sensitivity to this drug. Recently, an altered chloroquine-transporter protein CG2 of the parasite has been related to chloroquine resistance, but other mechanisms of resistance also appear to be involved. Research on the mechanism of chloroquine and how the parasite has acquired chloroquine resistance is still ongoing, as other mechanisms of resistance are likely.
Chloroquine has antiviral effects. It increases late endosomal or lysosomal pH, resulting in impaired release of the virus from the endosome or lysosome – release requires a low pH. The virus is therefore unable to release its genetic material into the cell and replicate.
Against rheumatoid arthritis, it operates by inhibiting lymphocyte proliferation, phospholipase A2, antigen presentation in dendritic cells, release of enzymes from lysosomes, release of reactive oxygen species from macrophages, and production of IL-1.
In Peru the indigenous people extracted the bark of the Cinchona plant trees and used the extract (Chinchona officinalis) to fight chills and fever in the seventeenth century. In 1633 this herbal medicine was introduced in Europe, where it was given the same use and also began to be used against malaria. The quinoline antimalarial drug quinine was isolated from the extract in 1820, and chloroquine is an analogue of this.
Chloroquine was discovered in 1934, by Hans Andersag and coworkers at the Bayer laboratories, who named it “Resochin”. It was ignored for a decade, because it was considered too toxic for human use. During World War II, United States government-sponsored clinical trials for antimalarial drug development showed unequivocally that chloroquine has a significant therapeutic value as an antimalarial drug. It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria.
Chloroquine comes in tablet form as the phosphate, sulfate, and hydrochloride salts. Chloroquine is usually dispensed as the phosphate.
Brand names include Chloroquine FNA, Resochin, Dawaquin, and Lariago.
In late January 2020 during the 2019–20 coronavirus outbreak, Chinese medical researchers stated that exploratory research into chloroquine and two other medications, remdesivir and lopinavir/ritonavir, seemed to have “fairly good inhibitory effects” on the SARS-CoV-2 virus, which is the virus that causes COVID-19. Requests to start clinical testing were submitted. Chloroquine had been also proposed as a treatment for SARS, with in vitro tests inhibiting the SARS-CoV virus.
Chloroquine has been recommended by Chinese, South Korean and Italian health authorities for the treatment of COVID-19. These agencies noted contraindications for people with heart disease or diabetes. Both chloroquine and hydroxychloroquine were shown to inhibit SARS-CoV-2 in vitro, but a further study concluded that hydroxychloroquine was more potent than chloroquine, with a more tolerable safety profile. Preliminary results from a trial suggested that chloroquine is effective and safe in COVID-19 pneumonia, “improving lung imaging findings, promoting a virus-negative conversion, and shortening the disease course.” Self-medication with chloroquine has caused one known fatality.
In October 2004, a group of researchers at the Rega Institute for Medical Research published a report on chloroquine, stating that chloroquine acts as an effective inhibitor of the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro.
The radiosensitizing and chemosensitizing properties of chloroquine are beginning to be exploited in anticancer strategies in humans. In biomedicinal science, chloroquine is used for in vitro experiments to inhibit lysosomal degradation of protein products.
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|Trade names||Aralen, other|
|Other names||Chloroquine phosphate|
|Elimination half-life||1-2 months|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||319.872 g·mol−1|
|3D model (JSmol)|
//////////////CHLOROQUINE,, クロロキン, ANTIMALARIAL, COVID 19, CORONA VIRUS, Хлорохин , クロロキン , كلوروكين
CAS Registry Number: 50-65-7
Niclosamide, sold under the brand name Niclocide among others, is a medication used to treat tapeworm infestations. This includes diphyllobothriasis, hymenolepiasis, and taeniasis. It is not effective against other worms such as pinworms or roundworms. It is taken by mouth.
Side effects include nausea, vomiting, abdominal pain, and itchiness. It may be used during pregnancy and appears to be safe for the baby. Niclosamide is in the anthelmintic family of medications. It works by blocking the uptake of sugar by the worm.
Niclosamide was discovered in 1958. It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system. The wholesale cost in the developing world is about 0.24 USD for a course of treatment. It is not commercially available in the United States. It is effective in a number of other animals.
Side effects include nausea, vomiting, abdominal pain, constipation, and itchiness. Rarely, dizziness, skin rash, drowsiness, perianal itching, or an unpleasant taste occur. For some of these reasons, praziquantel is a preferable and equally effective treatment for tapeworm infestation.
Mechanism of action
Niclosamide’s metabolic effects are relevant to wide ranges of organisms, and accordingly it has been applied as a control measure to organisms other than tapeworms. For example, it is an active ingredient in some formulations such as Bayluscide for killing lamprey larvae, as a molluscide, and as a general purpose piscicide in aquaculture. Niclosamide has a short half-life in water in field conditions; this makes it valuable in ridding commercial fish ponds of unwanted fish; it loses its activity soon enough to permit re-stocking within a few days of eradicating the previous population. Researchers have found that niclosamide is effective in killing invasive zebra mussels in cool waters.
Niclosamide is being studied in a number of types of cancer. Niclosamide along with oxyclozanide, another anti-tapeworm drug, was found in a 2015 study to display “strong in vivo and in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA)”.
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|Trade names||Niclocide, Fenasal, Phenasal, others|
|AHFS/Drugs.com||Micromedex Detailed Consumer Information|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||327.119 g/mol g·mol−1|
|3D model (JSmol)|
|Melting point||225 to 230 °C (437 to 446 °F)|
//////////Niclosamide ニクロサミド , никлосамид , نيكلوساميد , 氯硝柳胺 , covid 19, corona virus
Nitazoxanide is a broad-spectrum antiparasitic and broad-spectrum antiviral drug that is used in medicine for the treatment of various helminthic, protozoal, and viral infections. It is indicated for the treatment of infection by Cryptosporidium parvum and Giardia lamblia in immunocompetent individuals and has been repurposed for the treatment of influenza. Nitazoxanide has also been shown to have in vitro antiparasitic activity and clinical treatment efficacy for infections caused by other protozoa and helminths; emerging evidence suggests that it possesses efficacy in treating a number of viral infections as well.
Chemically, nitazoxanide is the prototype member of the thiazolides, a class of drugs which are synthetic nitrothiazolyl-salicylamide derivatives with antiparasitic and antiviral activity. Tizoxanide, an active metabolite of nitazoxanide in humans, is also an antiparasitic drug of the thiazolide class.
Nitazoxanide is an effective first-line treatment for infection by Blastocystis species and is indicated for the treatment of infection by Cryptosporidium parvum or Giardia lamblia in immunocompetent adults and children. It is also an effective treatment option for infections caused by other protozoa and helminths (e.g., Entamoeba histolytica, Hymenolepis nana, Ascaris lumbricoides, and Cyclospora cayetanensis).
As of September 2015, it is in phase 3 clinical trials for the treatment influenza due to its inhibitory effect on a broad range of influenza virus subtypes and efficacy against influenza viruses that are resistant to neuraminidase inhibitors like oseltamivir. Nitazoxanide is also being researched as a potential treatment for chronic hepatitis B, chronic hepatitis C, rotavirus and norovirus gastroenteritis.
Chronic hepatitis B
Nitazoxanide alone has shown preliminary evidence of efficacy in the treatment of chronic hepatitis B over a one-year course of therapy. Nitazoxanide 500 mg twice daily resulted in a decrease in serum HBV DNA in all of 4 HBeAg-positive patients, with undetectable HBV DNA in 2 of 4 patients, loss of HBeAg in 3 patients, and loss of HBsAg in one patient. Seven of 8 HBeAg-negative patients treated with nitazoxanide 500 mg twice daily had undetectable HBV DNA and 2 had loss of HBsAg. Additionally, nitazoxanide monotherapy in one case and nitazoxanide plus adefovir in another case resulted in undetectable HBV DNA, loss of HBeAg and loss of HBsAg. These preliminary studies showed a higher rate of HBsAg loss than any currently licensed therapy for chronic hepatitis B. The similar mechanism of action of interferon and nitazoxanide suggest that stand-alone nitazoxanide therapy or nitazoxanide in concert with nucleos(t)ide analogs have the potential to increase loss of HBsAg, which is the ultimate end-point of therapy. A formal phase Ⅱ study is being planned for 2009.
Chronic hepatitis C
Romark initially decided to focus on the possibility of treating chronic hepatitis C with nitazoxanide. The drug garnered interest from the hepatology community after three phase II clinical trials involving the treatment of hepatitis C with nitazoxanide produced positive results for treatment efficacy and similar tolerability to placebo without any signs of toxicity. A meta-analysis from 2014 concluded that the previous held trials were of low-quality and with held with a risk of bias. The authors concluded that more randomized trials with low risk of bias are needed to give any determine if Nitazoxanide can be used as an effective treatment for chronic hepatitis C patients.
Nitazoxanide has gone through Phase II clinical trials for the treatment of hepatitis C, in combination with peginterferon alfa-2a and ribavirin.Romark Laboratories has announced encouraging results from international Phase I and II clinical trials evaluating a controlled release version of nitazoxanide in the treatment of chronic hepatitis C virus infection. The company used 675 mg and 1,350 mg twice daily doses of controlled release nitazoxanide showed favorable safety and tolerability throughout the course of the study, with mild to moderate adverse events. Primarily GI-related adverse events were reported.
A randomised double-blind placebo-controlled study published in 2006, with a group of 38 young children (Lancet, vol 368, page 124-129) concluded that a 3-day course of nitazoxanide significantly reduced the duration of rotavirus disease in hospitalized pediatric patients. Dose given was “7.5 mg/kg twice daily” and the time of resolution was “31 hours for those given nitazoxanide compared with 75 hours for those in the placebo group.” Rotavirus is the most common infectious agent associated with diarrhea in the pediatric age group worldwide.
Teran et al.. conducted a study at the Pediatric Center Albina Patinö, a reference hospital in the city of Cochabamba, Bolivia, from August 2007 to February 2008. The study compared nitazoxanide and probiotics in the treatment of acute rotavirus diarrhea. They found Small differences in favor of nitazoxanide in comparison with probiotics and concluded that nitazoxanide is an important treatment option for rotavirus diarrhea.
Lateef et al.. conducted a study in India that evaluated the effectiveness of nitazoxanide in the treatment of beef tapeworm (Taenia saginata) infection. They concluded that nitazoxanide is a safe, effective, inexpensive, and well-tolerated drug for the treatment of niclosamide- and praziquantel-resistant beef tapeworm (Taenia saginata) infection.
A retrospective review of charts of patients treated with nitazoxanide for trichomoniasis by Michael Dan and Jack D. Sobel demonstrated negative result. They reported three case studies; two of which with metronidazole-resistant infections. In Case 3, they reported the patient to be cured with high divided dose tinidazole therapy. They used a high dosage of the drug (total dose, 14–56 g) than the recommended standard dosage (total dose, 3 g) and observed a significant adverse reaction (poorly tolerated nausea) only with the very high dose (total dose, 56 g). While confirming the safety of the drug, they showed nitazoxanide is ineffective for the treatment of trichomoniasis.
The side effects of nitazoxanide do not significantly differ from a placebo treatment for giardiasis; these symptoms include stomach pain, headache, upset stomach, vomiting, discolored urine, excessive urinating, skin rash, itching, fever, flu syndrome, and others. Nitazoxanide does not appear to cause any significant adverse effects when taken by healthy adults.
Information on nitazoxanide overdose is limited. Oral doses of 4 grams in healthy adults do not appear to cause any significant adverse effects. In various animals, the oral LD50 is higher than 10 g/kg.
Due to the exceptionally high plasma protein binding (>99.9%) of nitazoxanide’s metabolite, tizoxanide, the concurrent use of nitazoxanide with other highly plasma protein-bound drugs with narrow therapeutic indices (e.g., warfarin) increases the risk of drug toxicity. In vitro evidence suggests that nitazoxanide does not affect the CYP450 system.
The anti-protozoal activity of nitazoxanide is believed to be due to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reaction which is essential to anaerobic energy metabolism. PFOR inhibition may also contribute to its activity against anaerobic bacteria.
It has also been shown to have activity against influenza A virus in vitro. The mechanism appears to be by selectively blocking the maturation of the viral hemagglutinin at a stage preceding resistance to endoglycosidase H digestion. This impairs hemagglutinin intracellular trafficking and insertion of the protein into the host plasma membrane.
Nitazoxanide modulates a variety of other pathways in vitro, including glutathione-S-transferase and glutamate-gated chloride ion channels in nematodes, respiration and other pathways in bacteria and cancer cells, and viral and host transcriptional factors.
Following oral administration, nitazoxanide is rapidly hydrolyzed to the pharmacologically active metabolite, tizoxanide, which is 99% protein bound. Tizoxanide is then glucuronide conjugated into the active metabolite, tizoxanide glucuronide. Peak plasma concentrations of the metabolites tizoxanide and tizoxanide glucuronide are observed 1–4 hours after oral administration of nitazoxanide, whereas nitazoxanide itself is not detected in blood plasma.
Roughly 2⁄3 of an oral dose of nitazoxanide is excreted as its metabolites in feces, while the remainder of the dose excreted in urine. Tizoxanide is excreted in the urine, bile and feces. Tizoxanide glucuronide is excreted in urine and bile.
Nitazoxanide is the prototype member of the thiazolides, which is a drug class of structurally-related broad-spectrum antiparasitic compounds. Nitazoxanide is a light yellow crystalline powder. It is poorly soluble in ethanol and practically insoluble in water.
Nitazoxanide was originally discovered in the 1980s by Jean-François Rossignol at the Pasteur Institute. Initial studies demonstrated activity versus tapeworms. In vitro studies demonstrated much broader activity. Dr. Rossignol co-founded Romark Laboratories, with the goal of bringing nitazoxanide to market as an anti-parasitic drug. Initial studies in the USA were conducted in collaboration with Unimed Pharmaceuticals, Inc. (Marietta, GA) and focused on development of the drug for treatment of cryptosporidiosis in AIDS. Controlled trials began shortly after the advent of effective anti-retroviral therapies. The trials were abandoned due to poor enrollment and the FDA rejected an application based on uncontrolled studies.
Subsequently, Romark launched a series of controlled trials. A placebo-controlled study of nitazoxanide in cryptosporidiosis demonstrated significant clinical improvement in adults and children with mild illness. Among malnourished children in Zambia with chronic cryptosporidiosis, a three-day course of therapy led to clinical and parasitologic improvement and improved survival. In Zambia and in a study conducted in Mexico, nitazoxanide was not successful in the treatment of cryptosporidiosis in advanced infection with human immunodeficiency virus at the doses used. However, it was effective in patients with higher CD4 counts. In treatment of giardiasis, nitazoxanide was superior to placebo and comparable to metronidazole. Nitazoxanide was successful in the treatment of metronidazole-resistant giardiasis. Studies have suggested efficacy in the treatment of cyclosporiasis, isosporiasis, and amebiasis. Recent studies have also found it to be effective against beef tapeworm(Taenia saginata).
Nitazoxanide is sold under the brand names Adonid, Alinia, Allpar, Annita, Celectan, Colufase, Daxon, Dexidex, Diatazox, Kidonax, Mitafar, Nanazoxid, Parazoxanide, Netazox, Niazid, Nitamax, Nitax, Nitaxide, Nitaz, Nizonide, NT-TOX, Pacovanton, Paramix, Toza, and Zox.
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Nitazoxanide [NTZ: 2-acetyloxy-N-(5-nitro-2-thiazolyl)benzamide] is a thiazolide antiparasitic agent with excellent activity against a wide variety of protozoa and helminths. … Nitazoxanide (NTZ) is a main compound of a class of broad-spectrum anti-parasitic compounds named thiazolides. It is composed of a nitrothiazole-ring and a salicylic acid moiety which are linked together by an amide bond … NTZ is generally well tolerated, and no significant adverse events have been noted in human trials . … In vitro, NTZ and tizoxanide function against a wide range of organisms, including the protozoal species Blastocystis hominis, C. parvum, Entamoeba histolytica, G. lamblia and Trichomonas vaginalis 
- White CA (2004). “Nitazoxanide: a new broad spectrum antiparasitic agent”. Expert Rev Anti Infect Ther. 2 (1): 43–9. doi:10.1586/14787184.108.40.206. PMID 15482170.
- Anderson, V. R.; Curran, M. P. (2007). “Nitazoxanide: A review of its use in the treatment of gastrointestinal infections”. Drugs. 67(13): 1947–1967. doi:10.2165/00003495-200767130-00015. PMID 17722965.
Nitazoxanide is effective in the treatment of protozoal and helminthic infections … Nitazoxanide is a first-line choice for the treatment of illness caused by C. parvum or G. lamblia infection in immunocompetent adults and children, and is an option to be considered in the treatment of illnesses caused by other protozoa and/or helminths.
- Sisson G1, Goodwin A, Raudonikiene A, Hughes NJ, Mukhopadhyay AK, Berg DE, Hoffman PS. (July 2002). “Enzymes associated with reductive activation and action of nitazoxanide, nitrofurans, and metronidazole in Helicobacter pylori”. Antimicrob. Agents Chemother. 46 (7): 2116–23. doi:10.1128/aac.46.7.2116-2123.2002. PMC 127316. PMID 12069963.
Nitazoxanide (NTZ) is a redox-active nitrothiazolyl-salicylamide
- Korba BE, Montero AB, Farrar K, et al. (January 2008). “Nitazoxanide, tizoxanide and other thiazolides are potent inhibitors of hepatitis B virus and hepatitis C virus replication”. Antiviral Res. 77 (1): 56–63. doi:10.1016/j.antiviral.2007.08.005. PMID 17888524.
- “Blastocystis: Resources for Health Professionals”. United States Centers for Disease Control and Prevention. 2017-05-02. Retrieved 4 January 2016.
- Roberts T, Stark D, Harkness J, Ellis J (May 2014). “Update on the pathogenic potential and treatment options for Blastocystis sp”. Gut Pathog. 6: 17. doi:10.1186/1757-4749-6-17. PMC 4039988. PMID 24883113.
Blastocystis is one of the most common intestinal protists of humans. … A recent study showed that 100% of people from low socio-economic villages in Senegal were infected with Blastocystis sp. suggesting that transmission was increased due to poor hygiene sanitation, close contact with domestic animals and livestock, and water supply directly from well and river . …
Table 2: Summary of treatments and efficacy for Blastocystis infection
- Muñoz P, Valerio M, Eworo A, Bouza E (2011). “Parasitic infections in solid-organ transplant recipients”. Curr Opin Organ Transplant. 16 (6): 565–575. doi:10.1097/MOT.0b013e32834cdbb0. PMID 22027588. Retrieved 7 January 2016.
Nitazoxanide: intestinal amoebiasis: 500 mg po bid x 3 days
- “Hymenolepiasis: Resources for Health Professionals”. United States Centers for Disease Control and Prevention. 2017-05-02. Retrieved 4 January 2016.
- Hagel I, Giusti T (October 2010). “Ascaris lumbricoides: an overview of therapeutic targets”. Infectious Disorders – Drug Targets. 10 (5): 349–67. doi:10.2174/187152610793180876. PMID 20701574.
new anthelmintic alternatives such as tribendimidine and Nitazoxanide have proved to be safe and effective against A. lumbricoides and other soil-transmitted helminthiases in human trials.
- Shoff WH (5 October 2015). Chandrasekar PH, Talavera F, King JW (eds.). “Cyclospora Medication”. Medscape. WebMD. Retrieved 11 January 2016.
Nitazoxanide, a 5-nitrothiazole derivative with broad-spectrum activity against helminths and protozoans, has been shown to be effective against C cayetanensis, with an efficacy 87% by the third dose (first, 71%; second 75%). Three percent of patients had minor side effects.
- Li TC, Chan MC, Lee N (September 2015). “Clinical Implications of Antiviral Resistance in Influenza”. Viruses. 7 (9): 4929–4944. doi:10.3390/v7092850. PMC 4584294. PMID 26389935.
Oral nitazoxanide is an available, approved antiparasitic agent (e.g., against cryptosporidium, giardia) with established safety profiles. Recently, it has been shown (together with its active metabolite tizoxanide) to possess anti-influenza activity by blocking haemagglutinin maturation/trafficking, and acting as an interferon-inducer . … A large, multicenter, Phase 3 randomized-controlled trial comparing nitazoxanide, oseltamivir, and their combination in uncomplicated influenza is currently underway (NCT01610245).
Figure 1: Molecular targets and potential antiviral treatments against influenza virus infection
- Teran, C. G.; Teran-Escalera, C. N.; Villarroel, P. (2009). “Nitazoxanide vs. Probiotics for the treatment of acute rotavirus diarrhea in children: A randomized, single-blind, controlled trial in Bolivian children”. International Journal of Infectious Diseases. 13(4): 518–523. doi:10.1016/j.ijid.2008.09.014. PMID 19070525.
- Lateef, M.; Zargar, S. A.; Khan, A. R.; Nazir, M.; Shoukat, A. (2008). “Successful treatment of niclosamide- and praziquantel-resistant beef tapeworm infection with nitazoxanide”. International Journal of Infectious Diseases. 12 (1): 80–82. doi:10.1016/j.ijid.2007.04.017. PMID 17962058.
- World Journal of Gastroenterology 2009 April 21, Emmet B Keeffe MD, Professor, Jean-François Rossignol The Romark Institute for Medical Research, Tampa
- Keeffe, E. B.; Rossignol, J. F. (2009). “Treatment of chronic viral hepatitis with nitazoxanide and second generation thiazolides”. World Journal of Gastroenterology. 15 (15): 1805–1808. doi:10.3748/wjg.15.1805. PMC 2670405. PMID 19370775.
- Nikolova, Kristiana; Gluud, Christian; Grevstad, Berit; Jakobsen, Janus C (2014). “Nitazoxanide for chronic hepatitis C”. Cochrane Database of Systematic Reviews (4): CD009182. doi:10.1002/14651858.CD009182.pub2. ISSN 1465-1858. PMID 24706397.
- “Romark Initiates Clinical Trial Of Alinia For Chronic Hepatitis C In The United States” (Press release). Medical News Today. August 16, 2007. Retrieved 2007-10-11.
- Franciscus, Alan (October 2, 2007). “Hepatitis C Treatments in Current Clinical Development”. HCV Advocate. Archived from the original on September 6, 2003. Retrieved 2007-10-11.
- Rossignol, Jean-François; Abu-Zekry, Mona; Hussein, Abeer; Santoro, M Gabriella (2006). “Effect of nitazoxanide for treatment of severe rotavirus diarrhoea: randomised double-blind placebo-controlled trial”. The Lancet. 368 (9530): 124–9. CiteSeerX 10.1.1.458.1597. doi:10.1016/S0140-6736(06)68852-1. PMID 16829296.
- Dan, M.; Sobel, J. D. (2007). “Failure of Nitazoxanide to Cure Trichomoniasis in Three Women”. Sexually Transmitted Diseases. 34 (10): 813–4. doi:10.1097/NMD.0b013e31802f5d9a. PMID 17551415.
- “Nitazoxanide”. MedlinePlus. Retrieved 9 April 2014.
- Shakya, A; Bhat, HR; Ghosh, SK (2018). “Update on Nitazoxanide: A Multifunctional Chemotherapeutic Agent”. Current Drug Discovery Technologies. 15 (3): 201–213. doi:10.2174/1570163814666170727130003. PMID 28748751.
- Rossignol, J. F.; La Frazia, S.; Chiappa, L.; Ciucci, A.; Santoro, M. G. (2009). “Thiazolides, a New Class of Anti-influenza Molecules Targeting Viral Hemagglutinin at the Post-translational Level”. Journal of Biological Chemistry. 284 (43): 29798–29808. doi:10.1074/jbc.M109.029470. PMC 2785610. PMID 19638339.
- White Jr, AC (2003). “Nitazoxanide: An important advance in anti-parasitic therapy”. Am. J. Trop. Med. Hyg. 68 (4): 382–383. doi:10.4269/ajtmh.2003.68.382. PMID 12875283.
- Lateef, M.; Zargar, S. A.; Khan, A. R.; Nazir, M.; Shoukat, A. (2008). “Successful treatment of niclosamide- and praziquantel-resistant beef tapeworm infection with nitazoxanide”. International Journal of Infectious Diseases. 12 (1): 80–2. doi:10.1016/j.ijid.2007.04.017. PMID 17962058.
- Cynthia Liu, Qiongqiong Zhou, Yingzhu Li, Linda V. Garner, Steve P. Watkins, Linda J. Carter, Jeffrey Smoot, Anne C. Gregg, Angela D. Daniels, Susan Jervey, Dana Albaiu. Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases. ACS Central Science 2020; doi:10.1021/acscentsci.0c00272
- “Nitazoxanide”. MedlinePlus Drug Information. U.S. National Library of Medicine. 28 July 2010. Retrieved 2010-08-19.
- “Parasitic infections”. Am J Transplant. 4 (Suppl 10): 142–55. 2004. doi:10.1111/j.1600-6135.2004.00677.x. PMID 15504227.
|Trade names||Alinia, Nizonide, and others|
|Protein binding||Nitazoxanide: ?
Tizoxanide: over 99%
|Metabolism||Rapidly hydrolyzed to tizoxanide|
|Elimination half-life||3.5 hours|
|Excretion||Renal, biliary, and fecal|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||307.283 g/mol g·mol−1|
|3D model (JSmol)|
//////////////nitazoxanide, corona virus, covid 19
- Molecular FormulaC11H15N5O3
- Average mass265.268 Da
222631-44-9, BCX-4430 (HCL salt form of galidesivir)
Galidesivir (BCX4430, Immucillin-A) is an antiviral drug, an adenosine analog (a type of nucleoside analog). It is developed by BioCryst Pharmaceuticals with funding from NIAID, originally intended as a treatment for hepatitis C, but subsequently developed as a potential treatment for deadly filovirus infections such as Ebola virus disease and Marburg virus disease.
It also shows broad-spectrum antiviral effectiveness against a range of other RNA virus families, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses, flaviviruses and phleboviruses. BCX4430 has been demonstrated to protect against both Ebola and Marburg viruses in both rodents and monkeys, even when administered up to 48 hours after infection, and development for use in humans was then being fast-tracked due to concerns about the lack of treatment options for the 2013-2016 Ebola virus epidemic in West Africa.
When any new virus emerges, drug and vaccine developers spring into action, searching for products to stop it in its tracks. Drug discovery campaigns launch, vaccine development efforts ramp up, and everyone mobilizes to get it all into the clinic as quickly as possible.
The current pandemic, driven by a coronavirus known as SARS-CoV-2, is no different. Already, a Phase I study of an mRNA-based vaccine developed by Moderna has begun, and major pharma companies and small biotechs are working on other types of vaccines. But even if they work, the most optimistic timelines put a vaccine a year to 18 months away.
The more immediate approach to an outbreak is to scour the medicine cabinet for existing molecules that could be repurposed against a new virus. The most advanced potential treatment is Gilead Sciences’ remdesivir, an antiviral discovered during the 2014 Ebola epidemic. The compound is already being tested in four, Phase III trials—two in China and two in the US—against the respiratory disease COVID-19. Gilead expects the first dataset from those studies to come out in April.
A new paper from CAS explored remdesivir and other possible options the cabinet might contain (ACS Cent. Sci. 2020, DOI: 10.1021/acscentsci.0c00272). CAS, a division of the American Chemical Society, which publishes C&EN, looked at the landscape of patent and journal articles covering small molecules, antibodies, and other therapeutic classes to identify therapies with potential activity against COVID-19.
SARS-CoV-2, belongs to the same family as two coronaviruses responsible for earlier outbreaks, Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). Because all three feature structurally similar proteins that allow entry into and replication inside host cells, CAS searched for patent data related to those more well-studied coronaviruses.
C&EN has assembled the relevant small molecules identified by CAS, which can be explored by the stage in the viral life cycle they aim to disrupt.
|Patent ID||Title||Submitted Date||Granted Date|
|US7390890||Inhibitors of nucleoside metabolism||2007-08-23||2008-06-24|
|US7211653||Inhibitors of nucleoside metabolism||2005-02-03||2007-05-01|
|US6803455||Inhibitors of nucleoside metabolism||2003-05-22||2004-10-12|
|US6492347||Inhibitors of nucleoside metabolism||2002-05-23||2002-12-10|
|US6228847||Inhibitors of nucleoside metabolism||2001-05-08|
|Patent ID||Title||Submitted Date||Granted Date|
|EP1023308||INHIBITORS OF NUCLEOSIDE METABOLISM||2000-08-02||2005-09-07|
|US6066722||Inhibitors of nucleoside metabolism||2000-05-23|
- Warren TK, Wells J, Panchal RG, Stuthman KS, Garza NL, Van Tongeren SA, et al. (April 2014). “Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430” (PDF). Nature. 508 (7496): 402–5. Bibcode:2014Natur.508..402W. doi:10.1038/nature13027. PMID 24590073.
- Kamat SS, Burgos ES, Raushel FM (October 2013). “Potent inhibition of the C-P lyase nucleosidase PhnI by Immucillin-A triphosphate”. Biochemistry. 52 (42): 7366–8. doi:10.1021/bi4013287. PMC 3838859. PMID 24111876.
- Westover JB, et al. Galidesivir limits Rift Valley fever virus infection and disease in Syrian golden hamsters. Antiviral Res. 2018 Aug;156:38-45. Westover, J. B.; Mathis, A.; Taylor, R.; Wandersee, L.; Bailey, K. W.; Sefing, E. J.; Hickerson, B. T.; Jung, K. H.; Sheridan, W. P.; Gowen, B. B. (2018). “Galidesivir limits Rift Valley fever virus infection and disease in Syrian golden hamsters”. Antiviral Research. 156: 38–45. doi:10.1016/j.antiviral.2018.05.013. PMC 6035881. PMID 29864447.
- Rodgers P (8 April 2014). “BioWar Lab Helping To Develop Treatment For Ebola”. Forbes Magazine.
- Julander JG, Siddharthan V, Evans J, Taylor R, Tolbert K, Apuli C, et al. (January 2017). “Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model”. Antiviral Research. 137: 14–22. doi:10.1016/j.antiviral.2016.11.003. PMC 5215849. PMID 27838352.
- Praveen Duddu. Coronavirus outbreak: Vaccines/drugs in the pipeline for Covid-19. clinicaltrialsarena.com 19 February 2020.
|Chemical and physical data|
|Molar mass||265.268 g·mol−1|
|3D model (JSmol)|
//////////////Galidesivir, Immucillin-A, OLF97F86A7, UNII:OLF97F86A7, галидесивир , غاليديسيفير , 加利司韦 , BCX4430, BCX 4430, CORONAVIRUS, COVID 19
Hydroxychloroquine (HCQ), sold under the brand name Plaquenil among others, is a medication used for the prevention and treatment of certain types of malaria. Specifically it is used for chloroquine-sensitive malaria. Other uses include treatment of rheumatoid arthritis, lupus, and porphyria cutanea tarda. It is taken by mouth. It is also being used as an experimental treatment for coronavirus disease 2019 (COVID-19).
Common side effects include vomiting, headache, changes in vision and muscle weakness. Severe side effects may include allergic reactions. Although all risk cannot be excluded it remains a treatment for rheumatic disease during pregnancy. Hydroxychloroquine is in the antimalarial and 4-aminoquinoline families of medication.
Hydroxychloroquine was approved for medical use in the United States in 1955. It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system. The wholesale cost in the developing world is about US$4.65 per month as of 2015, when used for rheumatoid arthritis or lupus. In the United States the wholesale cost of a month of treatment is about US$25 as of 2020. In the United Kingdom this dose costs the NHS about £ 5.15. In 2017, it was the 128th most prescribed medication in the United States with more than five million prescriptions.
Hydroxychloroquine is widely used in the treatment of post-Lyme arthritis. It may have both an anti-spirochaete activity and an anti-inflammatory activity, similar to the treatment of rheumatoid arthritis.
The drug label advises that hydroxychloroquine should not be prescribed to individuals with known hypersensitivity to 4-Aminoquinoline compounds. There are a range of other contraindications  and caution is required if patients have certain heart conditions, diabetes, psoriasis etc.
The most common adverse effects are a mild nausea and occasional stomach cramps with mild diarrhea. The most serious adverse effects affect the eye, with dose-related retinopathy as a concern even after hydroxychloroquine use is discontinued. For short-term treatment of acute malaria, adverse effects can include abdominal cramps, diarrhea, heart problems, reduced appetite, headache, nausea and vomiting.
For prolonged treatment of lupus or rheumatoid arthritis, adverse effects include the acute symptoms, plus altered eye pigmentation, acne, anemia, bleaching of hair, blisters in mouth and eyes, blood disorders, convulsions, vision difficulties, diminished reflexes, emotional changes, excessive coloring of the skin, hearing loss, hives, itching, liver problems or liver failure, loss of hair, muscle paralysis, weakness or atrophy, nightmares, psoriasis, reading difficulties, tinnitus, skin inflammation and scaling, skin rash, vertigo, weight loss, and occasionally urinary incontinence. Hydroxychloroquine can worsen existing cases of both psoriasis and porphyria.
Children may be especially vulnerable to developing adverse effects from hydroxychloroquine.
One of the most serious side effects is retinopathy (generally with chronic use). People taking 400 mg of hydroxychloroquine or less per day generally have a negligible risk of macular toxicity, whereas the risk begins to go up when a person takes the medication over 5 years or has a cumulative dose of more than 1000 grams. The daily safe maximum dose for eye toxicity can be computed from one’s height and weight using this calculator. Cumulative doses can also be calculated from this calculator. Macular toxicity is related to the total cumulative dose rather than the daily dose. Regular eye screening, even in the absence of visual symptoms, is recommended to begin when either of these risk factors occurs.
Toxicity from hydroxychloroquine may be seen in two distinct areas of the eye: the cornea and the macula. The cornea may become affected (relatively commonly) by an innocuous cornea verticillata or vortex keratopathy and is characterized by whorl-like corneal epithelial deposits. These changes bear no relationship to dosage and are usually reversible on cessation of hydroxychloroquine.
The macular changes are potentially serious. Advanced retinopathy is characterized by reduction of visual acuity and a “bull’s eye” macular lesion which is absent in early involvement.
Due to rapid absorption, symptoms of overdose can occur within a half an hour after ingestion. Overdose symptoms include convulsions, drowsiness, headache, heart problems or heart failure, difficulty breathing and vision problems.
Hydroxychloroquine overdoses are rarely reported, with 7 previous cases found in the English medical literature. In one such case, a 16-year-old girl who had ingested a handful of hydroxychloroquine 200mg presented with tachycardia (heart rate 110 beats/min), hypotension (systolic blood pressure 63 mm Hg), central nervous system depression, conduction defects (ORS = 0.14 msec), and hypokalemia (K = 2.1 meq/L). Treatment consisted of fluid boluses and dopamine, oxygen, and potassium supplementation. The presence of hydroxychloroquine was confirmed through toxicologic tests. The patient’s hypotension resolved within 4.5 hours, serum potassium stabilized in 24 hours, and tachycardia gradually decreased over 3 days.
Care should be taken if combined with medication altering liver function as well as aurothioglucose (Solganal), cimetidine (Tagamet) or digoxin (Lanoxin). HCQ can increase plasma concentrations of penicillamine which may contribute to the development of severe side effects. It enhances hypoglycemic effects of insulin and oral hypoglycemic agents. Dose altering is recommended to prevent profound hypoglycemia. Antacids may decrease the absorption of HCQ. Both neostigmine and pyridostigmine antagonize the action of hydroxychloroquine.
Specifically, the FDA drug label for hydroxychloroquine lists the following drug interactions :
- Digoxin (wherein it may result in increased serum digoxin levels)
- Insulin or antidiabetic drugs (wherein it may enhance the effects of a hypoglycemic treatment)
- Drugs that prolong QT interval and other arrhythmogenic drugs (as Hydroxychloroquine prolongs the QT interval and may increase the risk of inducing ventricular arrhythmias if used concurrently)
- Mefloquine and other drugs known to lower the convulsive threshold (co-administration with other antimalarials known to lower the convulsion threshold may increase risk of convulsions)
- Antiepileptics (concurrent use may impair the antiepileptic activity)
- Methotrexate (combined use is unstudied and may increase the frequency of side effects)
- Cyclosporin (wherein an increased plasma cylcosporin level was reported when used together).
Hydroxychloroquine has similar pharmacokinetics to chloroquine, with rapid gastrointestinal absorption and elimination by the kidneys. Cytochrome P450 enzymes (CYP2D6, 2C8, 3A4 and 3A5) metabolize hydroxychloroquine to N-desethylhydroxychloroquine.
Antimalarials are lipophilic weak bases and easily pass plasma membranes. The free base form accumulates in lysosomes (acidic cytoplasmic vesicles) and is then protonated, resulting in concentrations within lysosomes up to 1000 times higher than in culture media. This increases the pH of the lysosome from 4 to 6. Alteration in pH causes inhibition of lysosomal acidic proteases causing a diminished proteolysis effect. Higher pH within lysosomes causes decreased intracellular processing, glycosylation and secretion of proteins with many immunologic and nonimmunologic consequences. These effects are believed to be the cause of a decreased immune cell functioning such as chemotaxis, phagocytosis and superoxide production by neutrophils. HCQ is a weak diprotic base that can pass through the lipid cell membrane and preferentially concentrate in acidic cytoplasmic vesicles. The higher pH of these vesicles in macrophages or other antigen-presenting cells limits the association of autoantigenic (any) peptides with class II MHC molecules in the compartment for peptide loading and/or the subsequent processing and transport of the peptide-MHC complex to the cell membrane.
Mechanism of action
Hydroxychloroquine increases lysosomal pH in antigen-presenting cells. In inflammatory conditions, it blocks toll-like receptors on plasmacytoid dendritic cells (PDCs). Hydroxychloroquine, by decreasing TLR signaling, reduces the activation of dendritic cells and the inflammatory process. Toll-like receptor 9 (TLR 9) recognizes DNA-containing immune complexes and leads to the production of interferon and causes the dendritic cells to mature and present antigen to T cells, therefore reducing anti-DNA auto-inflammatory process.
In 2003, a novel mechanism was described wherein hydroxychloroquine inhibits stimulation of the toll-like receptor (TLR) 9 family receptors. TLRs are cellular receptors for microbial products that induce inflammatory responses through activation of the innate immune system.
As with other quinoline antimalarial drugs, the mechanism of action of quinine has not been fully resolved. The most accepted model is based on hydrochloroquinine and involves the inhibition of hemozoin biocrystallization, which facilitates the aggregation of cytotoxic heme. Free cytotoxic heme accumulates in the parasites, causing their deaths.
Brand names of hydroxychloroquine include Plaquenil, Hydroquin, Axemal (in India), Dolquine, Quensyl, Quinoric.
Hydroxychloroquine and chloroquine have been recommended by Chinese and South Korean health authorities for the experimental treatment of COVID-19. In vitro studies in cell cultures demonstrated that hydroxychloroquine was more potent than chloroquine against SARS-CoV-2.
On 17 March 2020, the AIFA Scientific Technical Commission of the Italian Medicines Agency expressed a favorable opinion on including the off-label use of chloroquine and hydroxychloroquine for the treatment of SARS-CoV-2 infection.
white solid (0.263 g, 78%). 1H NMR
(600 MHz, CDCl3
) δ 8.48 (d, J = 5.4 Hz, 1H), 7.93 (d, J = 5.4 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.34 (dd, J = 8.8, 7.3 Hz, 1H), 6.39 (d, J = 5.4 Hz, 1H), 4.96 (d, J = 7.5 Hz, 1H), 3.70 (sx,J = 6.8 Hz, 1H), 3.55 (m, 2H), 2.57 (m, 5H), 2.49 (m, 2H),
1.74–1.62 (m, 1H), 1.65–1.53 (m, 3H), 1.31 (d, J = 6.9 Hz, 3H),
1.24 (d, J = 7.2 Hz, 2H);
13C NMR (125 MHz, CDCl3) δ 152.2,
149.5, 149.2, 135.0, 129.0, 125.4, 121.2, 117.4, 99.4, 58.6, 54.9,
53.18, 48.5, 47.9, 34.5, 24.1, 20.6, 11.9. Spectra were obtained
in accordance with those previously reported [38,39].
38. Cornish, C. A.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1985,
39. Münstedt, R.; Wannagat, U.; Wrobel, D. J. Organomet. Chem. 1984,
264, 135–148. doi:10.1016/0022-328X(84)85139-6
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Typical dose is 600mg per day. Costs 0.28157 per dose. Month has about 30 days.
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- Marmor, MF; Kellner, U; Lai, TYY; Lyons, JS; Mieler, WF (February 2011). “Revised Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy”. Ophthalmology. 118 (2): 415–22. doi:10.1016/j.ophtha.2010.11.017. PMID 21292109.
- Marquardt, Kathy; Albertson, Timothy E. (1 September 2001). “Treatment of hydroxychloroquine overdose”. The American Journal of Emergency Medicine. 19 (5): 420–424. doi:10.1053/ajem.2001.25774. ISSN 0735-6757. PMID 11555803.
- “Russian Register of Medicines: Plaquenil (hydroxychloroquine) Film-coated Tablets for Oral Use. Prescribing Information” (in Russian). Sanofi-Synthelabo. Archived from the original on 16 August 2016. Retrieved 14 July 2016.
- Mohammad, Samya; Clowse, Megan E. B.; Eudy, Amanda M.; Criscione-Schreiber, Lisa G. (March 2018). “Examination of Hydroxychloroquine Use and Hemolytic Anemia in G6PDH-Deficient Patients”. Arthritis Care & Research. 70 (3): 481–485. doi:10.1002/acr.23296. ISSN 2151-4658. PMID 28556555.
- Kalia, S; Dutz, JP (2007). “New Concepts in Antimalarial Use and Mode of Action in Dermatology”. Dermatologic Therapy. 20 (4): 160–74. doi:10.1111/j.1529-8019.2007.00131.x. PMID 17970883.
- Kaufmann, AM; Krise, JP (2007). “Lysosomal Sequestration of Amine-containing Drugs: Analysis and Therapeutic Implications”. Journal of Pharmaceutical Sciences. 96 (4): 729–46. doi:10.1002/jps.20792. PMID 17117426.
- Ohkuma, S; Poole, B (1978). “Fluorescence Probe Measurement of the Intralysosomal pH in Living Cells and the Perturbation of pH by Various Agents”. Proceedings of the National Academy of Sciences of the United States of America. 75 (7): 3327–31. doi:10.1073/pnas.75.7.3327. PMC 392768. PMID 28524.
- Ohkuma, S; Chudzik, J; Poole, B (1986). “The Effects of Basic Substances and Acidic Ionophores on the Digestion of Exogenous and Endogenous Proteins in Mouse Peritoneal Macrophages”. The Journal of Cell Biology. 102 (3): 959–66. doi:10.1083/jcb.102.3.959. PMC 2114118. PMID 3949884.
- Oda, K; Koriyama, Y; Yamada, E; Ikehara, Y (1986). “Effects of Weakly Basic Amines on Proteolytic Processing and Terminal Glycosylation of Secretory Proteins in Cultured Rat Hepatocytes”. The Biochemical Journal. 240 (3): 739–45. doi:10.1042/bj2400739. PMC 1147481. PMID 3493770.
- Hurst, NP; French, JK; Gorjatschko, L; Betts, WH (1988). “Chloroquine and Hydroxychloroquine Inhibit Multiple Sites in Metabolic Pathways Leading to Neutrophil Superoxide Release”. The Journal of Rheumatology. 15 (1): 23–27. PMID 2832600.
- Fox, R (1996). “Anti-malarial Drugs: Possible Mechanisms of Action in Autoimmune Disease and Prospects for Drug Development”. Lupus. 5: S4–10. doi:10.1177/096120339600500103. PMID 8803903.
- Waller; et al. Medical Pharmacology and Therapeutics (2nd ed.). p. 370.
- Takeda, K; Kaisho, T; Akira, S (2003). “Toll-Like Receptors”. Annual Review of Immunology. 21: 335–76. doi:10.1146/annurev.immunol.21.120601.141126. PMID 12524386.
- “Hydroxychloroquine trade names”. Drugs-About.com. Retrieved 18 June 2019.
- “Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia”. China Law Translate. 3 March 2020. Retrieved 18 March 2020.
- “Physicians work out treatment guidelines for coronavirus”. Korea Biomedical Review. 13 February 2020. Retrieved 18 March2020.
- Yao, Xueting; Ye, Fei; Zhang, Miao; Cui, Cheng; Huang, Baoying; Niu, Peihua; Liu, Xu; Zhao, Li; Dong, Erdan; Song, Chunli; Zhan, Siyan (9 March 2020). “In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)”. Clinical Infectious Diseases. doi:10.1093/cid/ciaa237. ISSN 1537-6591. PMID 32150618.
- “Azioni intraprese per favorire la ricerca e l’accesso ai nuovi farmaci per il trattamento del COVID-19”. Italian Medicines Agency (AIFA) (in Italian). 17 March 2020. Retrieved 18 March2020.
- “Hydroxychloroquine”. Drug Information Portal. U.S. National Library of Medicine.
Hydroxychloroquine freebase molecule
|Trade names||Plaquenil, others|
|Other names||Hydroxychloroquine sulfate|
|By mouth (tablets)|
|Bioavailability||Variable (74% on average); Tmax = 2–4.5 hours|
|Elimination half-life||32–50 days|
|Excretion||Mostly Kidney (23–25% as unchanged drug), also biliary (<10%)|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||335.872 g/mol g·mol−1|
|3D model (JSmol)|
///////////Hydroxychloroquine, Hydroxy chloroquine, HCQ, ヒドロキシクロロキン , covid 19, coronavirus, antimalarial, гидроксихлорохин , هيدروكسيكلوروكين , 羟氯喹 , Oxychlorochin, Plaquenil , Plaquenil®,
- Molecular FormulaC22H25BrN2O3S
- Average mass477.414 Da
Umifenovir (trade names Arbidol Russian: Арбидол, Chinese: 阿比朵尔) is an antiviral treatment for influenza infection used in Russia and China. The drug is manufactured by Pharmstandard (Russian: Фармстандарт). Although some Russian studies have shown it to be effective, it is not approved for use in other countries. It is not approved by FDA for the treatment or prevention of influenza. Chemically, umifenovir features an indole core, functionalized at all but one positions with different substituents. The drug is claimed to inhibit viral entry into target cells and stimulate the immune response. Interest in the drug has been renewed as a result of the SARS-CoV-2 outbreak.
Testing of umifenovir’s efficacy has mainly occurred in China and Russia, and it is well known in these two countries. Some of the Russian tests showed the drug to be effective and a direct comparison with Tamiflu showed similar efficiency in vitro and in a clinical setting. In 2007, Arbidol (umifenovir) had the highest sales in Russia among all over-the-counter drugs.
Mode of action
Umifenovir inhibits membrane fusion. Umifenovir prevents contact between the virus and target host cells. Fusion between the viral envelope (surrounding the viral capsid) and the cell membrane of the target cell is inhibited. This prevents viral entry to the target cell, and therefore protects it from infection.
As well as specific antiviral action against both influenza A and influenza B viruses, umifenovir exhibits modulatory effects on the immune system. The drug stimulates a humoral immune response, induces interferon-production, and stimulates the phagocytic function of macrophages.
More recent studies indicate that umifenovir also has in vitro effectiveness at preventing entry of Ebolavirus Zaïre Kikwit, Tacaribe arenavirus and human herpes virus 8 in mammalian cell cultures, while confirming umifenovir’s suppressive effect in vitro on Hepatitis B and poliovirus infection of mammalian cells when introduced either in advance of viral infection or during infection.
In February 2020, Li Lanjuan, an expert of the National Health Commission of China, proposed using Arbidol (umifenovir) together with darunavir as a potential treatment during the 2019–20 coronavirus pandemic. Chinese experts claim that preliminary tests had shown that arbidol and darunavir could inhibit replication of the virus. So far without additional effect if added on top of recombinant human interferon α2b spray.
Side effects in children include sensitization to the drug. No known overdose cases have been reported and allergic reactions are limited to people with hypersensitivity. The LD50 is more than 4 g/kg.
In 2007, the Russian Academy of Medical Sciences stated that the effects of Arbidol (umifenovir) are not scientifically proven.
Russian media criticized lobbying attempts by Tatyana Golikova (then-Minister of Healthcare) to promote umifenovir, and the unproven claim that Arbidol can speed up recovery from flu or cold by 1.3-2.3 days. They also debunked claims that the efficacy of umifenovir is supported by peer-reviewed studies.
1,2-Dimethyl-5-hydroxyindole-3-acetic acid ethyl ester (I) is acetylated with acetic anhydride affording the O-acyl derivative (II) , which is brominated to the corresponding dibromide compound (III) . The reaction of (III) with thiophenol in KOH yields (IV) , which is then submitted to a conventional Mannich condensation with formaldehyde and dimethylamine in acetic acid, giving the free base of arbidol (V), which is treated with aqueous hydrochloric acid .
- “Full Prescribing Information: Arbidol® (umifenovir) film-coated tablets 50 and 100 mg: Corrections and Additions”. State Register of Medicines (in Russian). Open joint-stock company “Pharmstandard-Tomskchempharm”. Retrieved 3 June 2015.
- Recommended INN: List 65., WHO Drug Information, Vol. 25, No. 1, 2011, page 91
- Leneva IA, Russell RJ, Boriskin YS, Hay AJ (February 2009). “Characteristics of arbidol-resistant mutants of influenza virus: implications for the mechanism of anti-influenza action of arbidol”. Antiviral Research. 81 (2): 132–40. doi:10.1016/j.antiviral.2008.10.009. PMID 19028526.
- “FDA Approved Drugs for Influenza”. U.S. Food and Drug Administration.
- Leneva IA, Fediakina IT, Gus’kova TA, Glushkov RG (2005). “[Sensitivity of various influenza virus strains to arbidol. Influence of arbidol combination with different antiviral drugs on reproduction of influenza virus A]”. Terapevticheskii Arkhiv (Russian translation). ИЗДАТЕЛЬСТВО “МЕДИЦИНА”. 77 (8): 84–8. PMID 16206613.
- Wang MZ, Cai BQ, Li LY, Lin JT, Su N, Yu HX, Gao H, Zhao JZ, Liu L (June 2004). “[Efficacy and safety of arbidol in treatment of naturally acquired influenza]”. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae. 26 (3): 289–93. PMID 15266832.
- Boriskin YS, Leneva IA, Pécheur EI, Polyak SJ (2008). “Arbidol: a broad-spectrum antiviral compound that blocks viral fusion”. Current Medicinal Chemistry. 15 (10): 997–1005. doi:10.2174/092986708784049658. PMID 18393857.
- Leneva IA, Burtseva EI, Yatsyshina SB, Fedyakina IT, Kirillova ES, Selkova EP, Osipova E, Maleev VV (February 2016). “Virus susceptibility and clinical effectiveness of anti-influenza drugs during the 2010-2011 influenza season in Russia”. International Journal of Infectious Diseases. 43: 77–84. doi:10.1016/j.ijid.2016.01.001. PMID 26775570.
- Boriskin YS, Pécheur EI, Polyak SJ (July 2006). “Arbidol: a broad-spectrum antiviral that inhibits acute and chronic HCV infection”. Virology Journal. 3: 56. doi:10.1186/1743-422X-3-56. PMC 1559594. PMID 16854226.
- Shi L, Xiong H, He J, Deng H, Li Q, Zhong Q, Hou W, Cheng L, Xiao H, Yang Z (2007). “Antiviral activity of arbidol against influenza A virus, respiratory syncytial virus, rhinovirus, coxsackie virus and adenovirus in vitro and in vivo”. Archives of Virology. 152 (8): 1447–55. doi:10.1007/s00705-007-0974-5. PMID 17497238.
- Glushkov RG, Gus’kova TA, Krylova LIu, Nikolaeva IS (1999). “[Mechanisms of arbidole’s immunomodulating action]”. Vestnik Rossiiskoi Akademii Meditsinskikh Nauk (in Russian) (3): 36–40. PMID 10222830.
- Pécheur EI, Lavillette D, Alcaras F, Molle J, Boriskin YS, Roberts M, Cosset FL, Polyak SJ (May 2007). “Biochemical mechanism of hepatitis C virus inhibition by the broad-spectrum antiviral arbidol”. Biochemistry. 46 (20): 6050–9. doi:10.1021/bi700181j. PMC 2532706. PMID 17455911.
- Pécheur EI, Borisevich V, Halfmann P, Morrey JD, Smee DF, Prichard M, Mire CE, Kawaoka Y, Geisbert TW, Polyak SJ (January 2016). “The Synthetic Antiviral Drug Arbidol Inhibits Globally Prevalent Pathogenic Viruses”. Journal of Virology. 90 (6): 3086–92. doi:10.1128/JVI.02077-15. PMC 4810626. PMID 26739045.
- Hulseberg CE, Fénéant L, Szymańska-de Wijs KM, Kessler NP, Nelson EA, Shoemaker CJ, Schmaljohn CS, Polyak SJ, White JM. Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses. J Virol. 2019 Apr 3;93(8). pii: e02185-18. doi:10.1128/JVI.02185-18 PMID 30700611
- Ng E (4 February 2020). “Coronavirus: are cocktail therapies for flu and HIV the magic cure?”. South China Morning Post.
Bangkok and Hangzhou hospitals put combination remedies to the test.
- Zheng W, Lau M (4 February 2020). “China’s health officials say priority is to stop mild coronavirus cases from getting worse”. South China Morning Post.
- Lu H (January 2020). “Drug treatment options for the 2019-new coronavirus (2019-nCoV)”. Bioscience Trends. doi:10.5582/bst.2020.01020. PMID 31996494.
- “Efficacies of lopinavir/ritonavir and abidol in the treatment of novel coronavirus pneumonia”. 4 February 2020. Retrieved 24 February 2020.
- “АРБИДОЛ® (ARBIDOL)”. Vidal. Archived from the originalon 4 February 2009.
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- (in Russian) Arbidol
- English published clinical studies and translations for Arbidol 1973–2016
|Oral (hard capsules, tablets)|
|Elimination half-life||17–21 hours|
|Excretion||40% excrete as unchanged umifenovir in feces (38.9%) and urine (0.12%)|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||477.41 g/mol g·mol−1|
|3D model (JSmol)|
Umifenovir is an indole-based, hydrophobic, dual-acting direct antiviral/host-targeting agent used for the treatment and prophylaxis of influenza and other respiratory infections.13 It has been in use in Russia for approximately 25 years and in China since 2006. Its invention is credited to a collaboration between Russian scientists from several research institutes 40-50 years ago, and reports of its chemical synthesis date back to 1993.13 Umifenovir’s ability to exert antiviral effects through multiple pathways has resulted in considerable investigation into its use for a variety of enveloped and non-enveloped RNA and DNA viruses, including Flavivirus,2 Zika virus,3 foot-and-mouth disease,4 Lassa virus,6 Ebola virus,6 herpes simplex,8, hepatitis B and C viruses, chikungunya virus, reovirus, Hantaan virus, and coxsackie virus B5.13,9 This dual activity may also confer additional protection against viral resistance, as the development of resistance to umifenovir does not appear to be significant.13
Umifenovir is currently being investigated as a potential treatment and prophylactic agent for COVID-19 caused by SARS-CoV2 infections in combination with both currently available and investigational HIV therapies.1,16,17
Umifenovir is currently licensed in China and Russia for the prophylaxis and treatment of influenza and other respiratory viral infections.13 It has demonstrated activity against a number of viruses and has been investigated in the treatment of Flavivirus,2 Zika virus,3 foot-and-mouth disease,4 Lassa virus,6 Ebola virus,6 and herpes simplex.8 In addition, it has shown in vitro activity against hepatitis B and C viruses, chikungunya virus, reovirus, Hantaan virus, and coxsackie virus B5.13,9
Umifenovir exerts its antiviral effects via both direct-acting virucidal activity and by inhibiting one (or several) stage(s) of the viral life cycle.13 Its broad-spectrum of activity covers both enveloped and non-enveloped RNA and DNA viruses. It is relatively well-tolerated and possesses a large therapeutic window – weight-based doses up to 100-fold greater than those used in humans failed to produce any pathological changes in test animals.13
Umifenovir does not appear to result in significant viral resistance. Instances of umifenovir-resistant influenza virus demonstrated a single mutation in the HA2 subunit of influenza hemagglutinin, suggesting resistance is conferred by prevention of umifenovir’s activity related to membrane fusion. The mechanism through which other viruses may become resistant to umifenovir requires further study.13
Mechanism of action
Umifenovir is considered both a direct-acting antiviral (DAA) due to direct virucidal effects and a host-targeting agent (HTA) due to effects on one or multiple stages of viral life cycle (e.g. attachment, internalization), and its broad-spectrum antiviral activity is thought to be due to this dual activity.13 It is a hydrophobic molecule capable of forming aromatic stacking interactions with certain amino acid residues (e.g. tyrosine, tryptophan), which contributes to its ability to directly act against viruses. Antiviral activity may also be due to interactions with aromatic residues within the viral glycoproteins involved in fusion and cellular recognition,5,7 with the plasma membrane to interfere with clathrin-mediated exocytosis and intracellular trafficking,10 or directly with the viral lipid envelope itself (in enveloped viruses).13,12 Interactions at the plasma membrane may also serve to stabilize it and prevent viral entry (e.g. stabilizing influenza hemagglutinin inhibits the fusion step necessary for viral entry).13
Due to umifenovir’s ability to interact with both viral proteins and lipids, it may also interfere with later stages of the viral life cycle. Some virus families, such as Flaviviridae, replicate in a subcellular compartment called the membranous web – this web requires lipid-protein interactions that may be hindered by umifenovir. Similarly, viral assembly of hepatitis C viruses is contingent upon the assembly of lipoproteins, presenting another potential target.13
Umifenovir is rapidly absorbed following oral administration, with an estimated Tmax between 0.65-1.8 hours.14,15,13 The Cmax has been estimated as 415 – 467 ng/mL and appears to increase linearly with dose,14,15 and the AUC0-inf following oral administration has been estimated to be approximately 2200 ng/mL/h.14,15
Volume of distribution
Data regarding the volume of distribution of umifenovir are currently unavailable.
Data regarding protein-binding of umifenovir are currently unavailable.
Umifenovir is highly metabolized in the body, primarily in hepatic and intestinal microsomess, with approximately 33 metabolites having been observed in human plasma, urine, and feces.14 The principal phase I metabolic pathways include sulfoxidation, N-demethylation, and hydroxylation, followed by phase II sulfate and glucuronide conjugation. In the urine, the major metabolites were sulfate and glucuronide conjugates, while the major species in the feces was unchanged parent drug (~40%) and the M10 metabolite (~3.0%). In the plasma, the principal metabolites are M6-1, M5, and M8 – of these, M6-1 appears of most importance given its high plasma exposure and long elimination half-life (~25h), making it a potentially important player in the safety and efficacy of umifenovir.14
Enzymes involved in the metabolism of umifenovir include members of the cytochrome P450 family (primarily CYP3A4), flavin-containing monooxygenase (FMO) family, and UDP-glucuronosyltransferase (UGT) family (specifically UGT1A9 and UGT2B7).14,11
- Lu H: Drug treatment options for the 2019-new coronavirus (2019-nCoV). Biosci Trends. 2020 Jan 28. doi: 10.5582/bst.2020.01020. [PubMed:31996494]
- Haviernik J, Stefanik M, Fojtikova M, Kali S, Tordo N, Rudolf I, Hubalek Z, Eyer L, Ruzek D: Arbidol (Umifenovir): A Broad-Spectrum Antiviral Drug That Inhibits Medically Important Arthropod-Borne Flaviviruses. Viruses. 2018 Apr 10;10(4). pii: v10040184. doi: 10.3390/v10040184. [PubMed:29642580]
- Fink SL, Vojtech L, Wagoner J, Slivinski NSJ, Jackson KJ, Wang R, Khadka S, Luthra P, Basler CF, Polyak SJ: The Antiviral Drug Arbidol Inhibits Zika Virus. Sci Rep. 2018 Jun 12;8(1):8989. doi: 10.1038/s41598-018-27224-4. [PubMed:29895962]
- Herod MR, Adeyemi OO, Ward J, Bentley K, Harris M, Stonehouse NJ, Polyak SJ: The broad-spectrum antiviral drug arbidol inhibits foot-and-mouth disease virus genome replication. J Gen Virol. 2019 Sep;100(9):1293-1302. doi: 10.1099/jgv.0.001283. Epub 2019 Jun 4. [PubMed:31162013]
- Kadam RU, Wilson IA: Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol. Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):206-214. doi: 10.1073/pnas.1617020114. Epub 2016 Dec 21. [PubMed:28003465]
- Hulseberg CE, Feneant L, Szymanska-de Wijs KM, Kessler NP, Nelson EA, Shoemaker CJ, Schmaljohn CS, Polyak SJ, White JM: Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses. J Virol. 2019 Apr 3;93(8). pii: JVI.02185-18. doi: 10.1128/JVI.02185-18. Print 2019 Apr 15. [PubMed:30700611]
- Zeng LY, Yang J, Liu S: Investigational hemagglutinin-targeted influenza virus inhibitors. Expert Opin Investig Drugs. 2017 Jan;26(1):63-73. doi: 10.1080/13543784.2017.1269170. Epub 2016 Dec 14. [PubMed:27918208]
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/////////////////Arbidol, umifenovir, covid 19, corona virus, Арбидол , 阿比朵尔 ,