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INDIA 2020, 14.05.2020, Centhaquine citrate bulk and Centhaquine citrate injection 1.0mg/vial, Add on resuscitative agent for hypovolemic shock
- OriginatorMidwestern University; Pharmazz
- ClassAnalgesics; Antihaemorrhagics; Antihypertensives; Cardiovascular therapies; Piperazines; Quinolines; Small molecules
- Mechanism of ActionAlpha 1 adrenergic receptor antagonists; Alpha 2 adrenergic receptor agonists
- RegisteredHaemorrhagic shock
- Phase IHeart arrest; Postoperative pain
- 20 Jul 2020Pharmazz plans to launch centhaquin for Haemorrhagic shock (Adjuvant therapy) in India by the middle of September 2020
- 20 Jul 2020Efficacy data from a phase III trial in Haemorrhagic shock released by Pharmazz
- 02 Jun 2020Centhaquine is still in phase I trials for Postoperative pain in USA (Pharmazz pipeline, June 2020)
SYNCenthaquin is a compound that produces hypotension and bradycardia in higher doses and resuscitation in lower doses. It is water insoluble, and is unsuitable for intravenous use. We prepared the citrate salt of centhaquin and evaluated its cardiovascular efficacy vs. centhaquin. Centhaquin citrate was prepared and characterized; its purity was determined by HPLC. Mean arterial pressure (MAP), heart rate (HR), pulse pressure (PP), cardiac output (CO), stroke volume (SV) and stroke work (SW) following intravenous administration of centhaquin and the citrate (0.05, 0.15 and 0.45 mg.kg(-1)) were determined in anaesthetized male Sprague-Dawley rats. Centhaquin citrate was 99.8% pure and water soluble. Centhaquin (0.05, 0.15 and 0.45 mg.kg(-1)) produced a maximal decrease in MAP of 15.6, 25.2 and 28.1%, respectively; while centhaquin citrate produced a greater (p<0.001) decrease of 35.7, 47.1 and 54.3%, respectively. The decrease in PP and HR produced by the citrate was greater than centhaquin (p<0.001). At 0.45 mg.kg(-1) centhaquin produced a maximal decrease of 20.9% (p<0.01) in CO, while centhaquin citrate produced a decrease of 42.1% (p<0.001). Reduction in SV (p<0.01) and SW (p<0.001) produced by centhaquin citrate were greater than centhaquin. Centhaquin citrate has greater cardiovascular activity compared to centhaquin.https://www.semanticscholar.org/paper/Synthesis-and-characterization-of-centhaquin-and-a-Reniguntala-Lavhale/6ca3975b114b0f23753e7a47710eff2467bc2dae
Shock due to severe hemorrhage accounts for a large proportion of posttraumatic deaths, particularly during early stages of injury (Wu, Dai et al. 2009). A majority of deaths due to hemorrhage occur within the first six hours after trauma (Shackford, Mackersie et al. 1993), but many of these deaths can be prevented (Acosta, Yang et al. 1998).
 Shock is accompanied by circulatory failure which is the primary cause of mortality and morbidity. Presently, the recommended fluid therapy uses large volumes of Lactated Ringer’s solution (LR), which is effective in restoring hemodynamic parameters, but presents logistic and physiologic limitations (Vincenzi, Cepeda et al. 2009). For example, resuscitation using a large volume of crystalloids, like LR, has been associated with secondary abdominal compartment syndrome, pulmonary edema, cardiac dysfunction, and paralytic ileus (Balogh, McKinley et al. 2003). Therefore, a need exists in the art for a resuscitation agent that improves survival time, and can be used with a small volume of resuscitation fluid, for resuscitation in hypovolemic shock.
 Centhaquin (2-[2-(4-(3-methyphenyl)-l-piperazinyl) ethyl-quinoline) is a centrally acting antihypertensive drug. The structure of centhaquin was determined (Bajpai et al., 2000) and the conformation of centhaquin was confirmed by X-ray diffraction (Carpy and Saxena, 1991).
Structure of centhaquin (2-[2-(4-(3-methyphenyl)- 1 -piperazinyl) ethyl] -quinoline) (as free base)
 Centhaquin is an active cardiovascular agent that produces a positive inotropic effect and increases ventricular contractions of isolated perfused rabbit heart (Bhatnagar, Pande et al. 1985). Centhaquin does not affect spontaneous contractions of the guinea pig right auricle, but significantly potentiates positive inotropic effect of norepinephrine (NE) (Srimal, Mason et al. 1990). The direct or indirect positive inotropic effect of centhaquin can lead to an increase in cardiac output (CO). Centhaquin produces a decrease in mean arterial pressure (MAP) and heart rate (HR) in anesthetized rats and conscious freely moving cats and rats (Srimal, Gulati et al. 1990) due to its central sympatholytic activity (Murti, Bhandari et al. 1989; Srimal, Gulati et al. 1990; Gulati, Hussain et al. 1991). When administered locally into a dog femoral artery, centhaquin (10 and 20 μg) increased blood flow, which was similar to that observed with acetylcholine and papaverine. However, the vasodilator effect of centhaquin could not be blocked by atropine or dibenamine (Srimal, Mason et al. 1990). The direct vasodilator or central sympatholytic effect of centhaquin is likely to decrease systemic vascular resistance (SVR).
 It was found that centhaquin enhances the resuscitative effect of hypertonic saline (HS) (Gulati, Lavhale et al. 2012). Centhaquin significantly decreased blood lactate and increases MAP, stroke volume, and CO compared to hypertonic saline alone. It is theorized, but not relied upon, that the cardiovascular actions of hypertonic saline and centhaquin are mediated through the ventrolateral medulla in the brain (Gulati, Hussain et al. 1991 ; Cavun and Millington 2001) and centhaquin may be augmenting the effect of hypertonic saline.
 A large volume of LR (i.e., about three times the volume of blood loss) is the most commonly used resuscitation fluid therapy (Chappell, Jacob et al. 2008), in part because LR does not exhibit the centrally mediated cardiovascular effects of hypertonic saline. Large volume resuscitation has been used by emergency medical personnel and surgeons to reverse hemorrhagic shock and to restore end-organ perfusion and tissue oxygenation. However, there has been a vigorous debate with respect to the optimal methods of resuscitation (Santry
ased on the molecular weight of centhaquin (free base) (MW-332) and centhaquin citrate (MW-523), for identical doses of centhaquin (as free base) and centhaquin citrate, centhaquin citrate provides only 63.5% of centhaquin free base compared to the dose of centhaquin free base, e.g., a 0.05 mg dose of centhaquin citrate contains a 0.0318 mg of centhaquin (as free base). Similarly, a dose of centhaquin citrate dihydrate (MW-559) provides 59.4% centhaquin (free base) of the same dose as centhaquin (as free base), i.e., a 0.0005 mg dose of centhaquin citrate dihydrate contains 0.030 mg of centhaquin (as free base). Surprisingly, and as demonstrated below, at the same mg/kg dose centhaquin citrate and centhaquin citrate dihydrate provides greater cardiovascular effects than centhaquin free base.
Synthesis of Centhaquin
 The synthesis of centhaquin was reported by Murthi and coworkers (Murthi et al U.S. Patent No. 3,983,121 ; Murti, Bhandari et al. 1989). In one procedure, reactants 1 and 2 were stirred at reflux for 15 hours. The resulting product was purified by evaporating the solvents to obtain an oil, which was heated in vacuo (100°C, 1 mm Hg). The remaining residue was recrystallized from ether-petroleum ether to obtain the final centhaquin product 3. The melting point reported for centhaquin was 76-77°C. In a subsequent publication (Murti, Bhandari et al. 1989), the reaction mixture was concentrated following 24 hours of reflux, diluted with water, and basified with aqueous NaOH. The basic mixture was extracted with ethyl acetate, and the ethyl acetate extracts were dried over anhydrous sodium sulfate and evaporated in vacuo to give centhaquin which was crystallized from hexane. The melting point of centhaquin (free base) obtained in this procedure was 82°C. The product obtained using either purification method is light tan in color, which is indicative of small amounts of impurities that were not completely removed using previously reported purification methods.
 In accordance with the present invention, an improved purification method was found. According to the improved method, reactants 1 and 2 were stirred at reflux for 24 hours. The solvents were evaporated in vacuo and the resulting mixture was diluted with water and basified (10% NaOH). The basic mixture was extracted with ethyl acetate and the combined ethyl acetate extracts are dried over anhydrous sodium sulfate and evaporated in vacuo to obtain a residue, which was further purified with column chromatography (Si02, ethyl acetate). The resulting product can be decolorized using activated charcoal or directly crystallized from hot hexane to yield pure centhaquin. The resulting product is an off-white crystalline solid having a melting point of 94-95°C (free base). The product was
characterized using proton NMR, mass spectral, and elemental analysis and indicated high purity and superior quality.
 Synthesis and characterization of centhaquin (free base): A mixture of 2- vinylquinoline (1) (5.0 g, 32.2 mmol, 98.5%) and 1 -(3-methylphenyl)piperazine (2) (5.68 g, 32.2 mmol, 99.0%) in absolute ethyl alcohol (150 ml) and glacial acetic acid (3.5 ml) was stirred at reflux for 24 hours in a round bottom flask. The reaction mixture was concentrated in vacuo, diluted with water (150 ml) and treated with 10% aqueous NaOH (150 ml). The residue was extracted with ethyl acetate (4 x 125 ml), dried with anhydrous Na2S04, and concentrated under reduced pressure to yield a crude product which was purified by column chromatography using silica gel (100-200 mesh) with ethyl acetate as an eluent. The resulting compound was recrystallized from hot hexane and filtered, to yield centhaquin as an off- white crystalline solid (7.75 g, 23.4 mmol, 73% yield); mp. 94-95°C; i? 0.30 (100% ethyl acetate); 1H NMR (300 MHz, CDC13): δ 8.07 (t, J= 7.5 Hz, 2 H), 7.78 (d, J= 7.8 Hz, 1 H), 7.70 (t, J= 7.8 Hz, 1 H), 7.50 (t, J= 7.5 Hz, 1 H), 7.36 (d, J= 8.4 Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1 H), 6.77 – 6.74 (m, 2 H), 6.69 (d, J= 7.2 Hz, 1 H), 3.26- 3.21 (m, 6 H), 2.97 – 2.92 (m, 2 H), 2.76 – 2.73 (m, 4 H), 2.32 (s, 3 H); HRMS (ESI) m/z 332.2121 [M+l]+ (calcd for C22H26N3 332.2122); Anal. (C22H25N3) C, H, N.
 Preparation of centhaquin citrate: Centhaquin (free base) (5.62 g, 16.98 mmol) was treated with citric acid (3.26 g, 16.98 mmol) in a suitable solvent and converted to the citrate salt obtained as an off-white solid (7.96 g, 15.2 mmol, 90%); m.p. 94-96°C ; Anal.
10065] Figs. 1(a) and 1(b) are high resolution mass spectral analyses of centhaquin free base (Fig 1(a)) and centhaquin citrate (Fig. 1(b)). Compound samples were analyzed following ionization using electrospray ionization (ESI).
[0066J For centhaquin free base in Fig 1(a), a base peak [M+l]+ was observed at m z 332.2141 (theory: 332.2121) consistent with the elemental composition of protonated centhaquin (C22H26N3).
 For centhaquin citrate in Fig 1(b), the mass spectrum was identical to the mass spectrum obtained for the free base. An [M+l]+base peak was observed at m z 332.2141 (theory: 332.2121), which corresponds to the elemental composition of protonated centhaquin (C22H26N3). This result is typical of salts of organic bases to yield the [M+l]+ of the free base as observed here with centhaquin citrate.
 Mass spectrometry is one of the most sensitive analytical methods, and examination of the mass spectra of Fig. 1 indicate that the samples are devoid of any extraneous peaks and are of homogeneous purity (>99.5).
////////////Centhaquine, PMZ-2010, PMZ 2010, INDIA 2020, 2020 APPROVALS
MFCD00869707 [MDL number]
- Molecular FormulaC19H27N3O5S2
- Average mass441.565 Da
N-[4-[2-[methyl[2-[4-[(methylsulfonyl)amino]phenoxy]ethyl]amino]ethyl]phenyl]-methanesulfonamideNCGC00164549-01PB0478000SMR000466333Tikosyn (TN)Research Code：UK-68798Trade Name：Tikosyn®MOA：Atrial potassium channel blockerIndication：Atrial flutter; Atrial fibrillationStatus：ApprovedCompany：Pfizer (Originator)Sales：ATC Code：C01BD04
INDIA 31/7/2020 APPROVED CDSCO
Dofetilide was first approved by the U.S. Food and Drug Administration (FDA) on Oct 1, 1999, then approved by European Medicine Agency (EMA) on Nov 29, 1999. It was developed and marketed as Tikosyn® by Pfizer.
Dofetilide is a selective blocker of delayed rectifier outward potassium current (IKr). It is indicated for the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm.
Tikosyn® is available capsule for oral use, containing 0.125, 0.25 or 0.5 mg of free Dofetilide. The recommended dose is 500 µg orally twice daily.
Dofetilide is a class III antiarrhythmic agent. It is marketed under the trade name Tikosyn by Pfizer, and is available in the United States in capsules containing 125, 250, and 500 µg of dofetilide. It is not available in Europe or Australia. In the United States it is only available by mail order or through specially trained local pharmacies.
Dofetilide is used for the maintenance of sinus rhythm in individuals prone to the occurrence of atrial fibrillation and flutter arrhythmias, and for chemical cardioversion to sinus rhythm from atrial fibrillation and flutter.
Based on the results of the Danish Investigations of Arrhythmias and Mortality on Dofetilide (“DIAMOND”) study, dofetilide does not affect mortality in the treatment of patients post-myocardial infarction with left ventricular dysfunction, however it was shown to decrease all-cause readmissions as well as CHF-related readmissions. Because of the results of the DIAMOND study, some physicians use dofetilide in the suppression of atrial fibrillation in individuals with LV dysfunction, however use appears limited: After initially receiving marketing approval in Europe in 1999, Pfizer voluntarily withdrew this approval in 2004 for commercial reasons and it is not registered in other first world countries.
It has clinical advantages over other class III antiarrhythmics in chemical cardioversion of atrial fibrillation, and maintenance of sinus rhythm, and does not have the pulmonary or hepatotoxicity of amiodarone, however atrial fibrillation is not generally considered life-threatening, and dofetilide causes an increased rate of potentially life-threatening arrhythmias in comparison to other therapies.
Prior to administration of the first dose, the corrected QT (QTc) must be determined. If the QTc is greater than 440 msec (or 500 msec in patients with ventricular conduction abnormalities), dofetilide is contraindicated. If heart rate is less than 60 bpm, the uncorrected QT interval should be used. After each subsequent dose of dofetilide, QTc should be determined and dosing should be adjusted. If at any time after the second dose of dofetilide the QTc is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), dofetilide should be discontinued. 
Torsades de pointes is the most serious side effect of dofetilide therapy. The incidence of torsades de pointes is 0.3-10.5% and is dose-related, with increased incidence associated with higher doses. The majority of episodes of torsades de pointes have occurred within the first three days of initial dosing. Patients should be hospitalized and monitored for the first three days after starting dofetilide.
The risk of inducing torsades de pointes can be decreased by taking precautions when initiating therapy, such as hospitalizing individuals for a minimum of three days for serial creatinine measurement, continuous telemetry monitoring and availability of cardiac resuscitation.
Mechanism of action
This causes the refractory period of atrial tissue to increase, hence its effectiveness in the treatment of atrial fibrillation and atrial flutter.
Dofetilide does not affect dV/dTmax (the slope of the upstroke of phase 0 depolarization), conduction velocity, or the resting membrane potential.
There is a dose-dependent increase in the QT interval and the corrected QT interval (QTc). Because of this, many practitioners will initiate dofetilide therapy only on individuals under telemetry monitoring or if serial EKG measurements of QT and QTc can be performed.
Peak plasma concentrations are seen two to three hours after oral dosing when fasting. Dofetilide is well absorbed in its oral form, with a bioavailability of >90%. Intravenous administration of dofetilide is not available in the United States. 
The elimination half-life of dofetilide is roughly 10 hours; however, this varies based on many physiologic factors (most significantly creatinine clearance), and ranges from 4.8 to 13.5 hours. Due to the significant level of renal elimination (80% unchanged, 20% metabolites), the dose of dofetilide must be adjusted to prevent toxicity due to impaired renal function.
Dofetilide is metabolized predominantly by CYP3A4 enzymes predominantly in the liver and GI tract. This means that it is likely to interact with drugs that inhibit CYP3A4, such as erythromycin, clarithromycin, or ketoconazole, resulting in higher and potentially toxic levels of dofetilide. 
A steady-state plasma level of dofetilide is achieved in 2–3 days.
In the kidneys, dofetilide is eliminated via cation exchange (secretion). Agents that interfere with the renal cation exchange system, such as verapamil, cimetidine, hydrochlorothiazide, itraconazole, ketoconazole, prochlorperazine, and trimethoprim should not be administered to individuals taking dofetilide.
About 20 percent of dofetilide is metabolized in the liver via the CYP3A4 isoenzyme of the cytochrome P450 enzyme system. Drugs that interfere with the activity of the CYP3A4 isoenzyme can increase serum dofetilide levels. If the renal cation exchange system is interfered with (as with the medications listed above), a larger percentage of dofetilide is cleared via the CYP3A4 isoenzyme system.
After its initial US FDA approval, due to the pro-arrhythmic potential it was only made available to hospitals and prescribers that had received education and undergone specific training in the risks of treatment with dofetilide; however, this restriction was subsequently removed in 2016. [15
Reference：1. US5079248A / US4959366A.
2. J. Med. Chem. 1990, 33, 1151-1155.
EP 0245997; JP 1987267250; US 4959366; US 5079248
This compound can be prepared by several related ways: 1) The condensation of N-methyl-2-(4-nitrophenyl)ethylamine (I) with 4-(2-chloroethoxy)nitrobenzene (II) by means of NaI and K2CO3 in refluxing acetonitrile gives 1-(4-nitrophenoxy)-5-(4-nitrophenyl)-3-methyl-3-azapentane (III), which is reduced with H2 over Pd/C in ethanol, yielding the corresponding diamino derivative (IV). Finally, this compound is acylated with methanesulfonyl anhydride in dichloromethane. 2) The condensation of (I) with N-[4-(2-chloroethoxy)phenyl]methanesulfonamide (V) with NaI and K2CO3 as before gives 1-[4-(methanesulfonamide)phenoxy]-3-methyl-5-(4-nitrophenyl)-3-azapentane (VI), which is reduced with H2 over Pd/C as before, yielding the corresponding amino derivative (VII). Finally, this compound is acylated with methanesulfonyl anhydride as usual. 3) The condensation of (II) with N-[4-[2-(methylamino)ethyl]phenyl]methanesulfonamide (VIII) with NaI and K2CO3 as usual gives 1-[4-(methanesulfonamido)phenyl]-3-methyl-5-(4-nitrophenoxy)-3-azapentane (IX), which is reduced with H2 and RaNi to the corresponding amino derivative (X). Finally, this compound is acylated with methanesulfonyl chloride and pyridine. 4) By condensation of N-[4-[2-(methanesulfonyloxy)ethyl]phenyl]methanesulfonamide (XI) with N-[4-[2-(methylamino)ethoxy]phenyl]methanesulfonamide (XII) in refluxing ethanol. 5) By condensation of (V) with (VIII) by means of NaHCO3.
- ^ Lenz TL; Hilleman DE (July 2000). “Dofetilide, a new class III antiarrhythmic agent”. Pharmacotherapy. 20 (7): 776–86. doi:10.1592/phco.20.9.776.35208. PMID 10907968.
- ^ Jump up to:a b Wathion, Noel (2004-04-13). “Public Statement on Tikosyn (dofetilide): Voluntary Withdrawal of the Marketing Authorisation in the European Union” (PDF). European Agency for the Evaluation of Medicinal Products.
- ^ Australian Medicines Handbook 2014
- ^ Jump up to:a b TIKOSYN® (dofetilide). Pfizer. <http://www.tikosyn.com/>.
- ^ Banchs JE; Wolbrette DL; Samii SM; et al. (November 2008). “Efficacy and safety of dofetilide in patients with atrial fibrillation and atrial flutter”. J Interv Card Electrophysiol. 23(2): 111–5. doi:10.1007/s10840-008-9290-6. PMID 18688699. S2CID 25162347.
- ^ Lenz TL; Hilleman DE (November 2000). “Dofetilide: A new antiarrhythmic agent approved for conversion and/or maintenance of atrial fibrillation/atrial flutter”. Drugs Today. 36 (11): 759–71. doi:10.1358/dot.2000.36.11.601530. PMID 12845335.
- ^ Torp-Pedersen C, Møller M, Bloch-Thomsen PE, et al. (September 1999). “Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group”. The New England Journal of Medicine. 341 (12): 857–65. doi:10.1056/NEJM199909163411201. PMID 10486417.
- ^ Torp-Pedersen C; ller M; Mø Bloch-Thomsen PE; et al. (September 1999). “Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group”. N. Engl. J. Med. 341 (12): 857–65. doi:10.1056/NEJM199909163411201. PMID 10486417.
- ^ Micromedex Drugdex drug evaluations micromedex.com
- ^ Torp-Pedersen C, Møller M, Bloch-Thomsen PE, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med 1999; 341:857.
- ^ Roukoz H; Saliba W (January 2007). “Dofetilide: a new class III antiarrhythmic agent”. Expert Rev Cardiovasc Ther. 5 (1): 9–19. doi:10.1586/14779072.5.1.9. PMID 17187453. S2CID 11255636.
- ^ 1Rasmussen HS, Allen MJ, Blackburn KJ, et al. Dofetilide, a novel class III antiarrhythmic agent. J Cardiovasc Pharmacol 1992; 20 Suppl 2:S96.
- ^ “Dofetilide.” Lexicomp. Wulters Kluwer Health, n.d. Web. <online.lexi.com>.
- ^ Walker DK, Alabaster CT, Congrave GS, et al. Significance of metabolism in the disposition and action of the antidysrhythmic drug, dofetilide. In vitro studies and correlation with in vivo data. Drug Metab Dispos 1996; 24:447.
- ^ “Information for Tikosyn (dofetilide)”. US Food and Drug Administration. 2016-03-09.
DofetilideCAS Registry Number: 115256-11-6CAS Name:N-[4-[2-[Methyl[2-[4-[(methylsulfonyl)amino]phenoxy]ethyl]amino]ethyl]phenyl]methanesulfonamideAdditional Names: 1-(4-methanesulfonamidophenoxy)-2-[N-(4-methanesulfonamidophenethyl)-N-methylamino]ethaneManufacturers’ Codes: UK-68798Trademarks: Tikosyn (Pfizer)Molecular Formula: C19H27N3O5S2Molecular Weight: 441.56Percent Composition: C 51.68%, H 6.16%, N 9.52%, O 18.12%, S 14.52%Literature References: Potassium channel blocker. Prepn: J. E. Arrowsmith et al.,EP245997; P. E. Cross et al.,US4959366 (1987, 1990 both to Pfizer); idemet al.,J. Med. Chem.33, 1151 (1990). HPLC determn in urine: D. K. Walker et al.,J. Chromatogr.568, 475 (1991). Mechanism of action study: D. Carmeliet, J. Pharmacol. Exp. Ther.262, 809 (1992). Review of pharmacology and pharmacokinetics: H. S. Rasmussen et al.,ibid.20, Suppl. 2, S96-S105 (1992). Clinical trial in atrial fibrillation and flutter: B. L. Norgaard et al.,Am. Heart J.137, 1062 (1999); in congestive heart failure: C. Torp-Pedersen et al.,N. Engl. J. Med.341, 857 (1999).Properties: Crystals from ethyl acetate/methanol (10:1), mp 147-149° (Cross); from hexane/ethyl acetate, mp 151-152° (Arrowsmith). Also reported as white crystalline solid, mp 161° (Rasmussen). pKa 7.0, 9.0, 9.6. Distribution coefficient (pH 7.4): 0.96. Sol in 0.1M NaOH, acetone, 0.1M HCl; very slightly sol in water, propan-2-ol.Melting point: mp 147-149° (Cross); mp 151-152° (Arrowsmith); mp 161° (Rasmussen)pKa: pKa 7.0, 9.0, 9.6Therap-Cat: Antiarrhythmic (class III).Keywords: Antiarrhythmic; Potassium Channel Blocker.
|ATC code||C01BD04 (WHO)|
|Protein binding||60% -70%|
|Elimination half-life||10 hours|
|CompTox Dashboard (EPA)||DTXSID5046433|
|Chemical and physical data|
|Molar mass||441.56 g·mol−1|
|3D model (JSmol)||Interactive image|
////////////DOFETILIDE, 2020 APPROVALS, INDIA 2020, UK 68798, UNII:R4Z9X1N2ND, дофетилид , دوفيتيليد ,多非利特 , TIKOSYN
- (S)-PA 824
2019/8/14 FDA 2109 APPROVED
MP 149-150 °C, Li, Xiaojin; Bioorganic & Medicinal Chemistry Letters 2008, Vol 18(7), Pg 2256-2262 and Orita, Akihiro; Advanced Synthesis & Catalysis 2007, Vol 349(13), Pg 2136-2144
Pretomanid is an antibiotic used for the treatment of multi-drug-resistant tuberculosis affecting the lungs. It is generally used together with bedaquiline and linezolid. It is taken by mouth.
Pretomanid was approved for medical use in the United States in 2019. Pretomanid was developed by TB Alliance, a not-for-profitproduct development partnership dedicated to the discovery and development of new, faster-acting and affordable medicines for tuberculosis (TB).
Global Alliance for the treatment of tuberculosis (TB).
The compound was originally developed by PathoGenesis (acquired by Chiron in 2000). In 2002, a co-development agreement took place between Chiron (acquired by Novartis in 2005) and the TB Alliance for the development of the compound. The compound was licensed to Fosunpharma by TB Alliance in China.
Pretomanid is the generic, nonproprietary name for the novel anti-bacterial drug compound formerly called PA-824. Pretomanid is referred to as “Pa” in regimen abbreviations, such as BPaL. The “preto” prefix of the compound’s name honors Pretoria, South Africa, the home of a TB Alliance clinical development office where much of the drug’s development took place. The “manid” suffix is used to group compounds with similar chemical structures. This class of drug is variously referred to as nitroimidazoles, nitroimidazooxazines or nitroimidazopyrans. Development of this compound was initiated because of the urgent need for new antibacterial drugs effective against resistant strains of tuberculosis. Also, current anti-TB drugs are mainly effective against replicating and metabolically active bacteria, creating a need for drugs effective against persisting or latent bacterial infections as often occur in patients with tuberculosis.
Discovery and pre-clinical development
Pretomanid was first identified in a series of 100 nitroimidazopyran derivatives synthesized and tested for antitubercular activity. Importantly, pretomanid has activity against static M. tuberculosis isolates that survive under anaerobic conditions, with bactericidal activity comparable to that of the existing drug metronidazole. Pretomanid requires metabolic activation by Mycobacterium for antibacterial activity. Pretomanid was not the most potent compound in the series against cultures of M. tuberculosis, but it was the most active in infected mice after oral administration. Oral pretomanid was active against tuberculosis in mice and guinea pigs at safely tolerated dosages for up to 28 days.
Limited FDA approval
FDA approved pretomanid only in combination with bedaquiline and linezolid for treatment of a limited and specific population of adult patients with extensively drug resistant, treatment-intolerant or nonresponsive multidrug resistant pulmonary tuberculosis. Pretomanid was approved under the Limited Population Pathway (LPAD pathway) for antibacterial and antifungal drugs. The LPAD Pathway was established by Congress under the 21st Century Cures Act to expedite development and approval of antibacterial and antifungal drugs to treat serious or life-threatening infections in a limited population of patients with unmet need. Pretomanid is only the third tuberculosis drug to receive FDA approval in more than 40 years.
HETERO RESEARCH FOUNDATION
- By Reddy, Bandi Parthasaradhi; Reddy, Kura Rathnakar; Reddy, Adulla Venkat Narsimha; Krishna, Bandi Vamsi
- From Indian Pat. Appl. (2018), IN 201641030408
The nitroimidazooxazine Formula I (PA-824) is a new class of bioreductive drug for tuberculosis. The recent introduction of the nitroimidazooxazine Formula I (PA-824) to clinical trial by the Global Alliance for TB Drug Development is thus of potential significance, since this compound shows good in vitro and in vivo activity against Mycobacterium tuberculosis in both its active and persistent forms. Tuberculosis (TBa) remains a leading infectious cause of death worldwide, but very few new drugs have been approved for TB treatment ifi the past 35 years, the current drug therapy for TB is long and complex, involving multidrug combinations.
The mechanism of actiém of Pretomanid is thoughrto involve reduction of the nitro group, in a‘ process dependent on the Bacterial ‘ m E Nfilw‘fieéFPEOEPEa‘e fillyeifiaasnfi (F8189); $943“; 20mm; “q Mcyarecent Swiss on mutant strains showed that a 151-amino acid (17.37 kDa) protein of unknown function, Rv3547, also, appears to be critical for this activation. Equivalent genes are present in M. boVis and MaVium.
Pretomanid and its pharmace’utically acceptable salts Were generically disclosed in US 5,668,127 A and Specifically disclosed in US 6,087,358 A. US ‘358 patent discloses a process for the preparation of Pretomanid, which is as shown below in scheme 1:
CN 104177372 A discloses a process for the preparation of Pretomanid, which is as shown below in scheme II:
Bioorganic & Medicinal Chemistry Letters 2008, Volume: 18, Issue: 7, Pages: 2256-2262 discloses a process for the preparation of Pretomanid, which is as shown below in scheme Ill:
US 7,!15,736 B2-discloses_a process fdr the preparation of 3S-Hydroxy-6-nitrQ-2H-3, 4— dihydro-[2-1b]-imidazopyran which is a key intermediate of Pretomanid, which is as shown below in scheme IV:
Journal Medicinal Chemistry 2009, Volume: 52, Pages: 637 — 645 discloses a process for the preparation of ‘Pretomanid, which is as shown below in scheme V:
Joumal Organic Chemistry 2010; Volume: 75 (2]), Pages: 7479—82 discloses a process for. the preparation of Pretomanid, which is as shown below in scheme VI:
Example 3: Preparation of Pretomanid (S) 1- -(3 (tert- -Butyldomethylsilyloxy)- -2- -(-4 -(trifluoromethoxy)-71benzyloxy2‘- propyl)- 2- -methylP AT E N4Tnitro- fi-Eimigazole (Efgm Awlas (3315;501:1691 gin! %etra%1y7drofuraen (18(150 ml) at room temperature and stirred for 5 to 10 minutes then TBAF (9516 ml) was added to the reaction mixture and stirred for 2 hours, at room temperature, afler completion of the reaction removed solvent through vacuum to obtained residue, dissolved the residue in MDC (1800 ml) and water (1800 ml) stirred, separated the layers and the organic layer washed with 10% ‘ sodium bicarbonate the obtained organic solution was concentrated under atmospheric pressure to obtained residue added MeOH (1730 ml) at room temperature and the reaction mixture was cooled to 0°C to 5°C, added KOH (24.5 gm) at the same temperaturé then cooled to room temperature and stirred for 24 hours. After completion of reaction DM Water added drop wise over 30 minutes at 10°C to 15° C and stirred for 1 hour to 1 hour 30 minutes at room’lemperature, filtrated the compound and washed with DM wa‘er (133 ml) and dried under vacuum for 10 hours at 50° C. Yield: 53 gm , Chromatographic purity: 97.69% (by HPLC):
Example 4: Purification of Pretomanid Pretomanid (53 gm) was dissolved in MDC (795 ml) at room temperatur’e and stirred for 10 to 15 minutes, added charcoal (10 gm) and stirred for 30-35 minutes, remove the charcoal and concentrated to obtained residue: Dissolved the obtained residue in IPA (795 ml) and the reaction mixture was heated to 80°C maintained for 10-15 minutes, added cyclohexane (1600ml) for 30 minutes at 80° C, then cooled to room temperature and stirred the reaction mass for overnight, filtered the solid and washed with cyclohexane (265 ml), and dried under vacuum for 10 hours at 50° C. Yield: 48 gm (Percentage of Yield: 90%) Chromatographic purity: 99.97% by HPLC).
Science (Washington, DC, United States) (2008), 322(5906), 1392-1395.
Huagong Shikan (2010), 24(4), 32-34, 51.
Xiaojin; Bioorganic & Medicinal Chemistry Letters 2008, Vol 18(7), Pg 2256-2262
aDHP = 3,4-dihydropyran; p-TsOH = p-toluenesulfonic acid; MsOH = methanesulfonic acid.
aCl3CCN = trichloroacetonitrile; TBME = tert-butylmethyl ether; TfOH = trifluoromethanesulfonic acid.
Journal of Medicinal Chemistry (2010), 53(1), 282-294.
Journal of Medicinal Chemistry (2009), 52(3), 637-645.
- “FDA approves new drug for treatment-resistant forms of tuberculosis that affects the lungs”. FDA. 14 August 2019. Retrieved 28 August 2019.
- “Compounds | TB Alliance”. http://www.tballiance.org. Retrieved 2019-04-18.
- Abutaleb Y (14 August 2019). “New antibiotic approved for drug-resistant tuberculosis”. Washington Post.
- “TB Medicine Pretomanid Enters Regulatory Review Process in the United States | TB Alliance”. http://www.tballiance.org. Retrieved 2019-04-18.
- “About TB Alliance”. TB Alliance. Retrieved 2019-04-18.
- “PA-824 has a New Generic Name: Pretomanid”. TB Alliance. Retrieved 2019-04-18.
- Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, Tompkins NM, Rose JD, Reynolds RC, Orme IM (June 2005). “Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models”. Antimicrobial Agents and Chemotherapy. 49 (6): 2294–301. doi:10.1128/AAC.49.6.2294-2301.2005. PMC 1140539. PMID 15917524.
- FDA News Release. FDA approves new drug for treatment-resistant forms of tuberculosis that affects the lungs.
|Chemical and physical data|
|Molar mass||359.261 g·mol−1|
|3D model (JSmol)|
//////////////Pretomanid, FDA 2109, プレトマニド , Antibacterial, tuberculostatic, PA-824, ANTI tuberculostatic
BBR-2778 , CTK0H5262
CTI BioPharma has obtained Israeli Ministry of Health’s approval for Pixuvri (pixantrone), as a monotherapy to treat adult patients with multiply relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma who have received up to three previous courses of treatment.
The company also announced that the Dutch Healthcare Authority and the College voor zorgverzekeringen of the Netherlands have approved funding for Pixuvri as an add-on drug for patients who need a third or fourth-line treatment option for aggressive B-cell lymphoma.
Tel Aviv University faculty of medicine Dr Abraham Avigdor said: “The approval of PIXUVRI in Israel provides patients with aggressive B-cell NHL who have failed second or third-line therapy a new approved option, where none existed before, that can effectively treat their disease with manageable side-effects.
|Jmol-3D images||Image 1|
|Molar mass||325.365 g/mol|
|Excretion||Fecal (main route of excretion) and renal (4–9%)|
|Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)|
Pixantrone dimaleate [USAN]
Benz(g)isoquinoline-5,10-dione, 6,9-bis((2-aminoethyl)amino)-, (2Z)-2-butenedioate (1:2)
On May 10, 2012, the European Commission issued a conditional marketing authorization valid throughout the European Union for pixantrone for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin’s B-cell lymphoma (NHL). Pixantrone is a cytotoxic aza-anthracenedione that directly alkylates DNA-forming stable DNA adducts and cross-strand breaks. The recommended dose of pixantrone is 50 mg/m2 administered on days 1, 8, and 15 of each 28-day cycle for up to 6 cycles. In the main study submitted for this application, a significant difference in response rate (proportion of complete responses and unconfirmed complete responses) was observed in favor of pixantrone (20.0% vs. 5.7% for pixantrone and physician’s best choice, respectively), supported by the results of secondary endpoints of median progression-free and overall survival times (increase of 2.7 and 2.6 months, respectively). The most common side effects with pixantrone were bone marrow suppression (particularly of the neutrophil lineage) nausea, vomiting, and asthenia. This article summarizes the scientific review of the application leading to approval in the European Union. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu).
Pixantrone (rINN; trade name Pixuvri) is an experimental antineoplastic (anti-cancer) drug, an analogue of mitoxantrone with fewertoxic effects on cardiac tissue. It acts as a topoisomerase II poison and intercalating agent. The code name BBR 2778 refers topixantrone dimaleate, the actual substance commonly used in clinical trials.
Anthracyclines are important chemotherapy agents. However, their use is associated with irreversible and cumulative heart damage. Investigators have attempted to design related drugs that maintain the biological activity, but do not possess the cardiotoxicity of the anthracyclines. Pixantrone was developed to reduce heart damage related to treatment while retaining efficacy.
Random screening at the US National Cancer Institute of a vast number of compounds provided by the Allied Chemical Company led to the discovery of ametantrone as having significant anti-tumor activity. Further investigation regarding the rational development of analogs of ametantrone led to the synthesis of mitoxantrone, which also exhibited marked anti-tumor activity Mitoxantrone was considered as an analog of doxorubicin with less structural complexity but with a similar mode of action. In clinical studies, mitoxantrone was shown to be effective against numerous types of tumors with less toxic side effects than those resulting from doxorubicin therapy. However, mitoxantrone was not totally free of cardiotoxicity. A number of structurally modified analogs of mitoxantrone were synthesized and structure-activity relationship studies made. BBR 2778 was originally synthesized by University of Vermont researchers Miles P. Hacker and Paul A. Krapcho and initially characterized in vitro for tumor cell cytotoxicity and mechanism of action by studies at the Boehringer Mannheim Italia Research Center, Monza, and University of Vermont, Burlington.Other studies have been completed at the University of Texas M. D. Anderson Cancer Center, Houston, the Istituto Nazionale Tumori,Milan, and the University of Padua. In the search for novel heteroanalogs of anthracenediones, it was selected as the most promising compound. Toxicological studies indicated that BBR 2778 was not cardiotoxic, and US patents are held by the University of Vermont. An additional US patent application was completed in June 1995 by Boehringer Mannheim, Italy.
Novuspharma, an Italian company, was established in 1998 following the merger of Boehringer Mannheim and Hoffmann-La Roche, and BBR 2778 was developed as Novuspharma’s leading anti-cancer drug, pixantrone. A patent application for the injectable preparation was filed in May 2003.
Pixantrone is a substance that is being studied in the treatment of cancer. It belongs to the family of drugs called antitumor antibiotics. phase III clinical trials of pixantrone have been completed. Pixantrone is being studied as an antineoplastic for different kinds of cancer, including solid tumors and hematological malignancies such as non-Hodgkin lymphomas.
Animal studies demonstrated that pixantrone does not worsen pre-existing heart muscle damage, suggesting that pixantrone may be useful in patients pretreated with anthracyclines. While only minimal cardiac changes are observed in mice given repeated cycles of pixantrone, 2 cycles of traditional anthracyclines doxorubicin or mitoxantrone result in marked or severe heart muscle degeneragion.
Clinical trials substituting pixantrone for doxorubicin in standard first-line treatment of patients with aggressive non-Hodgkin’s lymphoma, had a reduction in severe side effects when compared to patients treated with standard doxorubicin-based therapy. Despite pixantrone patients receiving more treatment cycles, a three-fold reduction in the incidence of severe heart damage was seen as well as clinically significant reductions in infections and thrombocytopenia, and a significant reduction in febrile neutropenia. These findings could have major implications for treating patients with breast cancer, lymphoma, and leukemia, where debilitating cardiac damage from doxorubicin might be prevented.Previous treatment options for multiply relapsed aggressive non-Hodgkin lymphoma had disappointing response rates.
The completed phase II RAPID trial compared the CHOP-R regimen of Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, and Rituximab to the same regimen, but substituting Doxorubicin with Pixantrone. The objective was to show that Pixantrone was not inferior to Doxorubicin and less toxic to the heart.
The pivotal phase III EXTEND (PIX301) randomized clinical trial studied pixantrone to see how well it works compared to other chemotherapy drugs in treating patients with relapsed non-Hodgkin’s lymphoma. The complete response rate in patients treated with pixantrone has been significantly higher than in those receiving other chemotherapeutic agents for treatment of relapsed/refractory aggressive non-Hodgkin lymphoma.
U.S. Food and Drug Administration
The FDA granted fast track designation for pixantrone in patients who had previously been treated two or more times for relapsed or refractory aggressive NHL. Study sponsor Cell Therapeutics announced that Pixantrone achieved the primary efficacy endpoint. The minutes of the Oncologic Drugs Advisory Committee meeting of March 22, 2010show that this had not in fact been achieved with statistical significance and this combined with major safety concerns lead to the conclusion that the trial was not sufficient to support approval. In April 2010 the FDA asked for an additional trial.
European Medicines Agency
On May 5, 2009, Pixantrone became available in Europe on a Named-Patient Basis. A named-patient program is a compassionate use drug supply program under which physicians can legally supply investigational drugs to qualifying patients. Under a named-patient program, investigational drugs can be administered to patients who are suffering from serious illnesses prior to the drug being approved by the European Medicines Evaluation Agency. “Named-patient” distribution refers to the distribution or sale of a product to a specific healthcare professional for the treatment of an individual patient. In Europe, under the named-patient program the drug is most often purchased through the national health system. In 2012 pixantrone received conditional marketing authorization in the European Union as Monotherapy to Treat Adult Patients with Multiply Relapsed or Refractory Aggressive Non-Hodgkin B-Cell Lymphomas.
Pixantrone is as potent as mitoxantrone in animal models of multiple sclerosis. Pixantrone has a similar mechanism of action as mitoxantrone on the effector function of lymphomonocyte B and T cells in experimental allergic encephalomyelitis but with lower cardiotoxicity. Pixantrone inhibits antigen specific and mitogen induced lymphomononuclear cell proliferation, as well as IFN-gamma production. Clinical trials are currently ongoing in Europe.
Pixantrone also reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats, and in vitro cell viability experiments indicated that Pixantrone significantly reduces amyloid beta (A beta(1-42)) neurotoxicity, a mechanism implicated in Alzheimer’s disease.
3,4-Pyridinedicarboxylic acid (I) was converted to the cyclic anhydride (II) upon heating with acetic anhydride. Friedel-Crafts condensation of anhydride (II) with p-difluorobenzene (III) in the presence of AlCl3 gave rise to a mixture of two regioisomeric keto acids, (IV) and (V). Cyclization of this mixture in fuming sulfuric acid at 140 C generated the benzoisoquinoline (VI) (1,2). Subsequent displacement of the fluorine atoms of (VI) with ethylenediamine ( VII) in pyridine provided the target bis (2-aminoethylamino) derivative, which was finally converted to the stable dimaleate salt. Alternatively, ethylenediamine (VII) was protected as the mono-N-Boc derivative (VIII) by treatment with Boc2O. Condensation of the difluoro compound (VI) with the protected ethylenediamine (VIII) furnished (IX). The Boc groups of (IX) were then removed by treatment with trifluoroacetic acid. After adjustment of the pH to 4.2 with KOH, treatment with maleic acid provided BBR-2778.
J Med Chem1994,37, (6): 828
- Cavalletti E, Crippa L, Mainardi P, Oggioni N, Cavagnoli R, Bellini O, Sala F. (2007). “Pixantrone (BBR 2778) has reduced cardiotoxic potential in mice pretreated with doxorubicin: comparative studies against doxorubicin and mitoxantrone”. Invest New Drugs. 25 (3): 187–95. doi:10.1007/s10637-007-9037-8. PMID 17285358.
- De Isabella P, Palumbo M, Sissi C, Capranico G, Carenini N, Menta E, Oliva A, Spinelli S, Krapcho AP, Giuliani FC, Zunino F. (1995). “Topoisomerase II DNA cleavage stimulation, DNA binding activity, cytotoxicity, and physico-chemical properties of 2-aza- and 2-aza-oxide-anthracenedione derivatives”. Mol Pharmacol. 48 (1): 30–8.PMID 7623772.
- Evison BJ, Mansour OC, Menta E, Phillips DR, Cutts SM (2007). “Pixantrone can be activated by formaldehyde to generate a potent DNA adduct forming agent”. Nucleic Acids Res. 35 (11): 3581–9. doi:10.1093/nar/gkm285. PMC 1920253.PMID 17483512.
- Krapcho AP, Petry ME, Getahun Z, Landi JJ Jr, Stallman J, Polsenberg JF, Gallagher CE, Maresch MJ, Hacker MP, Giuliani FC, Beggiolin G, Pezzoni G, Menta E, Manzotti C, Oliva A, Spinelli S, Tognella S (1994). “6,9-Bis[(aminoalkyl)amino]benzo[g]isoquinoline-5,10-diones. A novel class of chromophore-modified antitumor anthracene-9,10-diones: synthesis and antitumor evaluations”. J Med Chem. 37 (6): 828–37. doi:10.1021/jm00032a018. PMID 8145234.
- US patent 5587382, Krapcho AP, Hacker MP, Cavalletti E, Giuliani FC, “6,9-bis[(2-aminoethyl) amino]benzo [g]isoquinoline-5,10- dione dimaleate; an aza-anthracenedione with reduced cardiotoxicity”, issued 1996-12-24, assigned to Boehringer Mannheim Italia, SpA
- Zwelling LA, Mayes J, Altschuler E, Satitpunwaycha P, Tritton TR, Hacker MP. (1993). “Activity of two novel anthracene-9,10-diones against human leukemia cells containing intercalator-sensitive or -resistant forms of topoisomerase II”. Biochem Pharmacol. 46 (2): 265–71. doi:10.1016/0006-2952(93)90413-Q. PMID 8394077.
- Borchmann P, Reiser M (May 2003). “Pixantrone (Novuspharma)”. IDrugs 6 (5): 486–90. PMID 12789604.
- EP patent 1503797, Bernareggi A, Livi V, “Injectable Pharmaceutical Compositions of an Anthracenedione Derivative with Anti-Tumoral Activity”, published 2003-11-27, issued 2008-09-29, assigned to Cell Therapeutics Europe S.R.L.
- Pollack, Andrew (2003-06-17). “Company News; Cell Therapeutics Announces Plan To Buy Novuspharma”. The New York Times. Retrieved 2010-05-22.
- Mosby’s Medical Dictionary, 8th edition. © 2009, Elsevier. “definition of antineoplastic antibiotic”. Free Online Medical Dictionary, Thesaurus and Encyclopedia. Retrieved 2012-01-31.
- “NCT00088530”. BBR 2778 for Relapsed, Aggressive Non-Hodgkin’s Lymphoma (NHL). ClinicalTrials.gov. Retrieved 2012-01-31.
- “NCT00551239”. Fludarabine and Rituximab With or Without Pixantrone in Treating Patients With Relapsed or Refractory Indolent Non-Hodgkin Lymphoma. ClinicalTrials.gov. 2012-01-31. Retrieved 2012-01-31.
- “Pixantrone Combination Therapy for First-line Treatment of Aggressive Non-Hodgkin’s Lymphoma Results in Reduction in Severe Toxicities Including Heart Damage When Compared to Doxorubicin-based Therapy”. Press Release. Retrieved 2012-01-31.
- Engert A, Herbrecht R, Santoro A, Zinzani PL, Gorbatchevsky I (September 2006). “EXTEND PIX301: a phase III randomized trial of pixantrone versus other chemotherapeutic agents as third-line monotherapy in patients with relapsed, aggressive non-Hodgkin’s lymphoma”. Clin Lymphoma Myeloma 7 (2): 152–4.doi:10.3816/CLM.2006.n.055. PMID 17026830.
- “NCT00268853”. A Trial in Patients With Diffuse Large-B-cell Lymphoma Comparing Pixantrone Against Doxorubicin. ClinicalTrials.gov. Retrieved 2012-01-31.
- “NCT00101049”. BBR 2778 for Relapsed, Aggressive Non-Hodgkin’s Lymphoma (NHL). ClinicalTrials.gov. Retrieved 2012-01-31.
- Vesely N, Eckhardt SG (2010-03-22). “NDA 022-481 PIXUVRI (pixantrone dimaleate) injection” (pdf). Summary Minutes of the Oncologic Drugs Advisory Committee. United States Food and Drug Administration. Retrieved 2012-01-31.
- “Cell Therapeutics Formally Appeals FDA’s Nonapprovable Ruling for Pixantrone”. GEN News. 2010-12-03.
- “Pixantrone Now Available in Europe on a Named-Patient Basis”. Retrieved 2012-01-31.
- Gonsette RE, Dubois B (August 2004). “Pixantrone (BBR2778): a new immunosuppressant in multiple sclerosis with a low cardiotoxicity”. J. Neurol. Sci. 223(1): 81–6. doi:10.1016/j.jns.2004.04.024. PMID 15261566.
- Mazzanti B, Biagioli T, Aldinucci A, Cavaletti G, Cavalletti E, Oggioni N, Frigo M, Rota S, Tagliabue E, Ballerini C, Massacesi L, Riccio P, Lolli F (November 2005). “Effects of pixantrone on immune-cell function in the course of acute rat experimental allergic encephalomyelitis”. J. Neuroimmunol. 168 (1-2): 111–7.doi:10.1016/j.jneuroim.2005.07.010. PMID 16120465.
- Ubiali F, Nava S, Nessi V, Longhi R, Pezzoni G, Capobianco R, Mantegazza R, Antozzi C, Baggi F (February 2008). “Pixantrone (BBR2778) reduces the severity of experimental autoimmune myasthenia gravis in Lewis rats”. J. Immunol. 180 (4): 2696–703. PMID 18250482.
- Colombo R, Carotti A, Catto M, Racchi M, Lanni C, Verga L, Caccialanza G, De Lorenzi E (April 2009). “CE can identify small molecules that selectively target soluble oligomers of amyloid beta protein and display antifibrillogenic activity”. Electrophoresis 30(8): 1418–29. doi:10.1002/elps.200800377. PMID 19306269.