WO2013020600A1 - Pharmaceutical composition comprising a drug containing at least one toxicophore function and n-acetyl-l-cysteine - Google Patents
Pharmaceutical composition comprising a drug containing at least one toxicophore function and n-acetyl-l-cysteine Download PDFInfo
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- WO2013020600A1 WO2013020600A1 PCT/EP2011/063829 EP2011063829W WO2013020600A1 WO 2013020600 A1 WO2013020600 A1 WO 2013020600A1 EP 2011063829 W EP2011063829 W EP 2011063829W WO 2013020600 A1 WO2013020600 A1 WO 2013020600A1
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- Prior art keywords
- pharmaceutical composition
- drug
- composition according
- tablet
- toxicophore
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- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 title claims abstract description 76
- 229940079593 drug Drugs 0.000 title claims abstract description 72
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- HYWYRSMBCFDLJT-UHFFFAOYSA-N nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 claims description 41
- 229960000965 nimesulide Drugs 0.000 claims description 40
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims description 35
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Classifications
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a pharmaceutical composition containing at least one drug containing at least a toxicophore function, N-acetyl-L-cysteine (NAC), at least one antioxidant agent and at least one pharmaceutically acceptable excipient, and the same for use in the prevention and/or reduction of the occurrence of idiosyncratic adverse drug reactions ( IADRs ) caused by said drug.
- a pharmaceutical composition containing at least one drug containing at least a toxicophore function, N-acetyl-L-cysteine (NAC), at least one antioxidant agent and at least one pharmaceutically acceptable excipient, and the same for use in the prevention and/or reduction of the occurrence of idiosyncratic adverse drug reactions ( IADRs ) caused by said drug.
- IADRs idiosyncratic adverse drug reactions
- Adverse drug reactions can be classified as predictable (type A reactions) or idiosyncratic (type B reactions ) .
- Type A reactions are dose-dependent and occur in a relatively consistent time frame; all individuals are susceptible.
- a typical example is acetaminophen induced hepatotoxicity (Larson AM, Poison J, et al . Acute Liver Failure Study Group. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005 Dec ; 42 ( 6 ): 1364-72 ; Amar PJ, Schiff ER. Acetaminophen safety and hepatotoxicity-where do we go from here? Expert Opin Drug Saf. 2007 Jul ; 6 ( 4 ) : 341-55. ) .
- Glutathione is an antioxidant produced within the body that is involved in detoxification processes, since it forms stable and water-soluble adducts with the reactive species originated by some drugs, removing them from circulation.
- GSH levels than constitute an important threshold that determines the toxicity of a drug able to form reactive intermediates species, as it determines the occurrence of the dose-dependent predictable adverse drug reactions (ADRs, type A reactions).
- GSH depletion may originate from the administration of high doses of drugs, due to the fact that GSH binds to the high amounts of reactive intermediate metabolites released by said drugs .
- GSH levels are mostly relevant for acute toxicit .
- IADRs idiosyncratic adverse drug reactions
- IADRs occurrence is not directly related to the administered dose of a drug, however it is obvious that higher doses, by generating higher amounts of reactive metabolites, increase the probability of IADRs.
- the final response is indeed the product of a number of factors: drug dose, amount and reactivity of electrophile metabolites, patient physiological condition and reactivity of the immunological system.
- IADRs are currently unpredictable and difficult to diagnose, and they occur at doses that do not normally cause toxicity. They typically display a variable onset time after the beginning of drug therapy and they may also occur in a later stage, far-off from the drug administration ( aplowitz N. Idiosyncratic drug hepatotoxicity . Nat Rev Drug Discov.
- IADRs Clinically apparent consequences of IADRs are, for example, hepato-toxicity , skin reactions and blood dyscrasias (Zhang X. et al. Drug Metab. Pharmacokinet . (2011), 26 (1): 47-59).
- IADRs are difficult to understand and to predict by use of current preclinical testing paradigms or during phase I clinical trials. Better prediction of idiosyncratic drug induced liver injury will require an understanding of the modes and mechanisms of the reactions.
- Said reactive species originate from drugs containing the so called toxicophores, i.e. metabolically activated functions ( enzymatically catalyzed) within a chemical structure.
- Examples of reactive species are intermediate electrophile metabolites such as quinones, quinone-imine , quinine-methide derivatives.
- Mitochondrial damage has been proven to be an important component of the mechanism of idiosyncratic drug- induced liver injury, which can lead to the death of hepatocytes. Screening for mitochondrial functionality is thus well recognized in the art for the evaluation of the safety of drug candidates (Zhang X. et al. Drug Metab. Pharmacokinet (2011), 26 (1): 47-59).
- IADRs subsides after cessation of treatment, thus posing a significant diagnostic hurdle.
- IADRs are up to now contrasted only by suspending the drug administration or by symptoms relief.
- NAC N-acetyl-L-cysteine
- NAC is therefore currently known, and actually used, for the treatment of hepatic failure of different etiology, particularly in case of acute toxicity due to abuse or overdose of drugs resulting in marked glutathione depletion.
- NAC is thus normally administered, as an antidote, after the assumption of a drug and it is administered orally or by intravenous infusion in very high dosages.
- intravenous NAC is indicated for the treatment of acetaminophen overdose. When taken in large quantities, the toxic benzoquinone imine acetaminophen metabolite accumulates, and the body glutathione reserves are not sufficient to inactivate it.
- NAC N-acetyl-L-cysteine
- Drugs containing toxicophores giving rise to reactive quinones, quinine-imine , quinine-methide derivatives cause, besides liver ISDRs, skin ISDRs, like macupapular rashes, urticaria, Steven-Johnson syndrome and toxic epidermal necrolysis and include widely used drugs such as atorvastatin , diclofenamic acid or a salt thereof, nimesulide, trazodone, amiodarone, buspirone, carbamazepine , flutamide, minocycline, phenytoin, paroxetine, tacrine, tadalafil, tamoxifen, trimethoprim, nevirapine, trovafloxacin or a mixture thereof .
- atorvastatin diclofenamic acid or a salt thereof
- trazodone amiodarone
- buspirone carbamazepine
- flutamide minocycline
- Atorvastatin is a lipid-lowering agent, able to inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, which catalyzes the conversion of HMG-CoA to mevalonate. Atorvastatin is marketed as its calcium salt. Atorvastatin metabolic pathways give rise to orto and para-hydroxy acetanilido metabolites which can be oxidized to form electrophile quinone imine intermediates that can be trapped by GSH (see scheme 1)( Jacobsen , Kuhn B, Soldner A, Kirchner G, Sewing KF, Kollman PA, Benet LZ, Christians U.
- Lactonization is the critical first step in the disposition of the 3- hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin.
- Drug Metab Dispos. 2000 Nov; 28 ( 11 ): 1369- Atorvastatin calcium tablets available on the market for oral administration contain 10, 20, 40 or 80 mg of active principle.
- Nimesulide N- ( 4-Nitro-2-phenoxyphenyl ) methane sulfonamide, is a non-selective non-steroidal antiinflammatory drug (NSAID). It is used to treat acute pain, and the symptoms of painful osteoarthritis.
- NSAID non-selective non-steroidal antiinflammatory drug
- nimesulide When first put on the market, nimesulide was used to treat a wide range of painful conditions, but concerns arising over the rare but severe idiosyncratic hepatotoxicity led to restrict its use to the maximum daily dose of 200 mg (Questions and answer on the CHMP recommendation on nimesulide containing medicines London, 21 September 2007. Doc. Ref. EMEA/430988/2007 ) . The mechanisms associated with nimesulide toxicity remain unknown. Nimesulide is rapidly absorbed and it is normally bio-transformed in the liver to metabolites which are then eliminated in the urine/feces ( Bernareggi A. Clinical pharmaco-kinetics of nimesulide. Clin.Pharmacokinet . 1998; 35: 247-274).
- Nimesulide is contained in several oral formulations as : immediate release tablets (25, 50 and 100 mg), sachets (100 mg) and syrups (50 mg/5ml).
- Diclofenamic acid or a salt thereof is a worldwide prescribed NSAID used in acute, short-term and chronic treatment regimens.
- Diclofenamic acid as its sodium (Diclofenac Na) , potassium, diethylamine or epolamine salt, is contained in several oral formulations as immediate release tablets (25, 50 and 75 mg), delayed release tablets (100 mg) sachets (25, 50 mg) and syrups (50 mg/5ml). Injectable formulation are also available (75 mg/3ml)
- Trazodone is an antidepressant chemically unrelated to tricyclic, tetracyclic, or other known anti-depressant agents.
- IADRs There are several cases of IADRs including acute and chronic hepatitis associated with trazodone use. Although the cause of this toxicity is unknown, in most cases liver biopsy specimens from dead patients revealed centrozonal necrosis consistent with a toxic aetiology initiated by electrophile imino quinone or epoxide metabolites (scheme 4) (Kalgutkar AS, Henne KR, Lame ME, Vaz AD, Collin C, Soglia JR, Zhao SX, Hop CE .
- Trazodone is supplied as trazodone HC1 for oral administration in 50 mg, 100 mg, 150 mg, and 300 mg tablets .
- the simultaneous administration, in a single pharmaceutical form, of a drug containing at least one toxicophore function with N-acetyl-L-cysteine (NAC), at least one antioxidant agent and at least one physiologically acceptable excipient can prevent and/or reduce the occurrence of idiosyncratic adverse drug reactions ( IADRs ) correlated to said drugs, by preventively avoiding the accumulation of toxic reactive intermediates.
- NAC N-acetyl-L-cysteine
- the term “drug” refers to "active ingredient” and, therefore, the term “drug containing at least one toxicophore function” refers to active ingredient containing at least one toxicophore function .
- toxicophore function refers to a feature or group within a chemical structure that is thought to be responsible for the toxic properties, either directly or thereby metabolic activation originating reactive species. Examples of reactive species are intermediate electrophile metabolites such as quinones, quinone-imine , quinine- methide derivatives .
- NAC in association with drug(s) containing at least one toxicophore function represents a significant improvement and/or a useful alternative to the GSH detoxification system, while concurrently contributing to maintain the thiol status, wherein thiol status of the invention refers to the pool of SH- containing molecules maintaining the red-ox status, and providing cysteine as a precursor for GSH synthesis.
- the administration of NAC in association with drugs containing at least one toxicophore function can be therefore usefully used to prevent and/or reduce the occurrence of IADRs in all cases in which the GSH detoxification system is depleted becoming less effective .
- the presence of at least one antioxidant agent allows to obtain an improved stability of the N-acetyl-L-cysteine by removing contaminant oxidizers and/or heavy metals possibly present.
- object of the present invention is a pharmaceutical composition
- a pharmaceutical composition comprising at least one drug containing at least one toxicophore function, N-acetyl- L-cysteine, at least one antioxidant agent and at least one physiologically acceptable excipient.
- a pharmaceutical composition comprising at least one drug containing at least one toxicophore function, N-acetyl- L-cysteine, at least one antioxidant agent and at least one physiologically acceptable excipient for use in the prevention and/or reduction of the occurrence of IADRs caused by said drug, while maintaining the therapeutic profile of the drug itself.
- the pharmaceutical composition of the invention is preferably for use in the prevention and/or reduction of the occurrence of idiosyncratic adverse drug reaction in patients undergoing a treatment with at least one drug containing at least one toxicophore function.
- Further object of the present invention is a method for preventing and/or reducing the occurrence of idiosyncratic adverse drug reactions caused by a drug containing at least one toxicophore function which comprises the simultaneous administration, in a single pharmaceutical form, of at least one drug containing at least one toxicophore function, N-acetyl-L-cysteine , at least one antioxidant agent and at least one physiologically acceptable excipient.
- said idiosyncratic adverse drug reactions are preferably skin diseases (as, for example, macupapular rashes, urticaria, Steven-Johnson syndrome, toxic epidermal necrolysis), liver diseases and/or blood dyscrasias.
- skin diseases as, for example, macupapular rashes, urticaria, Steven-Johnson syndrome, toxic epidermal necrolysis
- liver diseases and/or blood dyscrasias.
- the pharmaceutical composition is preferably administered to mammals, more preferably humans comprising adults and paediatric population wherein the term "paediatric population” refers to subject from born to 18 years old.
- the N-acetyl-L-cysteine (NAC) is contained in an amount from 1 to 10 fold higher with respect to the drug, on a molar basis.
- Preferred drugs of the present invention are those including in their structure at least one toxicophore function, able to release reactive intermediate metabolites such as, for example, the electrophile quinones, imino-quinones , quinone-methides , derivatives .
- the drug containing at least one toxicophore function is preferably selected from atorvastatin , diclofenamic acid or salts thereof (sodium, potassium, diethylamine or epolamine salt), nimesulide, trazodone, amiodarone, buspirone, carbamazepine , flutamide, minocycline, phenytoin, paroxetine, tacrine, tadalafil, tamoxifen, trimethoprim, trovafloxacin and nevirapine. More preferably, the drug is nimesulide or at least one diclofenamic acid salt. Much more preferably, the drug is nimesulide or diclofenamic sodium salt (Diclofenac Na) .
- the pharmaceutical composition contains nimesulide, diclofenamic acid sodium salt or both.
- said at least one antioxidant is preferably selected from of vitamin E, tioctic acid, sodium metabisulphite and a mixture thereof .
- said at least one antioxidant is present in an amount ranging from 2 mg to 100 mg by weight, based on the total weight of the composition, preferably from 5 mg to 50 mg by weight, more preferably ranging from 3 to 10 mg by weight for vitamin E, ranging from 10 to 50 mg by weight for tioctic acid and/or ranging from 2 to 5 mg by weight for sodium metabisulphite based on the total weight of the composition.
- a chelating agent is added to the composition of the invention, preferably the chelating agent is comprised in an amount ranging from 5 to 20 mg by weight, based on the total weight of the composition and more preferably it corresponds to Na edetate.
- the pharmaceutical composition according to the invention is preferably formulated in oral, sub-lingual, or parenteral form; more preferably the pharmaceutical composition of the invention is then formulated in tablet, capsule, sachet, dragee, bead, granule, solution or suspension; much more preferably in tablet.
- tablette refers to any kind of tablet comprising single layered(conventional tablet), multi-layered, coated- tablet, minitablet or matrix tablet;
- the multi-layered tablet of the invention can be preferably formulated as a tab-in tab, bilayered or trilayered tablet in view of the technical effect and/or advantage to be reached, and/or of the selected drug and the layers are preferably isolated one from another.
- the "tablet” according to the invention can be preferably obtained by direct compression and/or by wet granulation .
- multi-layered refers to a tablet comprising at least one layer containing:
- At least one antioxidant at least one antioxidant, and optionally at least one physiologically acceptable excipient;
- the term "tab-in-tab” refers to a tablet wherein a smaller tablet is contained, and it is intended to obtain an improved stability of the final tablet and/or of the used drug(s).
- the N-acetyl-L-cysteine and at least one antioxidant optionally with at least one physiologically acceptable excipient are preferably contained in the outer tablet, while at least one of the above listed drugs is preferably contained in the inner tablet with at least one physiologically acceptable excipient.
- the "bilayered tablet” refers to a tablet comprising two layers, superimposed, one containing the N-acetyl-L-cysteine and at least one antioxidant and optionally at least one physiologically acceptable excipient, and the other containing at least one of the above listed drugs and at least one physiologically acceptable excipient; preferably, the by-layered tablet of the invention is directed to a composition in which both layers are for immediate release .
- the "trilayered tablet” is then preferably directed to a composition containing three layers: a first layer containing N-acetyl-L-cysteine and at least one antioxidant and optionally at least one physiologically acceptable excipient, an intermediate second, inert, layer, and a third layer containing at least one of the above listed drugs and at least one physiologically acceptable excipient; the trilayered structure according to the invention is preferably intended for incompatibility of components and/or for combining different release profiles.
- inert layer refers to a layer in which only physiologically acceptable excipients are contained.
- the above at least one physiologically acceptable excipient can be selected from diluent agents, disintegrant agents, glidant agents, fillers, binding agents, solubilising agents, lubricant agents, release agents, plasticizer agents, chelating/anticoagulant agents, protecting coating agents, preservatives, aromatizer agents and a mixture thereof .
- suitable disintegrant agents can be preferably selected from crosscaramellose , crosspovidone , cellulose microcrystalline , sodium lauryl sulphate, sodium starch glycolate and a mixture thereof;
- suitable glidant agents can be preferably selected from corn starch, talc, magnesium trisilicate, colloidal silica anhydrous and a mixture thereof;
- suitable diluent agents can be preferably selected from povidoneK30/ gelucine, cellulose microcrystalline, lactose, mannitol, sorbitol, kaolin, sucrose, calcium phosphate, threalose, xylitol and corn starch;
- suitable lubricant agent can be preferably selected from talc, sodium benzoate, poloxamer and a mixture thereof;
- suitable release agent can be preferably selected from magnesium stearate, sodium stearil fumarate, Ca/Zn stearate, polyethylene glycols (>6000);
- suitable plasticizer agent can be
- Any other physiologically acceptable excipient can be used for the pharmaceutical composition of the invention .
- At least one solvent and/or diluent can be further added to the composition as, for example, water in case of injectable compositions.
- composition of the invention is thus preferably directed to oral, sub-lingual, intravenous, intramuscular or subcutaneous administration.
- the pharmaceutical composition of the invention can be preferably directed to immediate, controlled or delayed release, more preferably for immediate release.
- the pharmaceutical composition of the invention is preferably administered once daily, twice daily, thrice daily, or according to the standard dose regime foreseen for the drug(s) contained in the composition .
- the pharmaceutical composition of the invention shows the advantage of preventing and/or reducing the occurrence of idiosyncratic adverse reactions caused by those drugs containing at least one toxicophore function, by the addition of N-acetyl-L-cysteine .
- composition of the invention is demonstrated by the improved mitochondrial functionality leading to an improvement of the hepatic cell growth ( hepatocytes ) .
- human hepatocytes were exposed to concentrations of diclofenac and/or nimesulide 60 to 240 times lower than those normally used with the control acetaminophen.
- the invention also shows the advantage to provide a pharmaceutical formulation containing N-acetyl-L- cysteine with an improved stability.
- the pharmaceutical composition is formulated as an immediate release wherein the bioavailability rate of N- acetyl-L-cysteine is faster than that of the drug/s, contained in the pharmaceutical composition.
- the composition comprises at least one of the following combinations: Table 1 :
- composition according to the present invention and as above described preferably corresponds to a so-called fixed dose combination (FDC), as defined by "Guideline on clinical development of fixed combination medicinal products (CHMP) " London, 19 February 2009 doc. Ref . Chmp/ewp/240/95 rev.
- FDC fixed dose combination
- fixed combinations refers to medicinal products containing two or more active substances, which can be either well-known or not yet authorized for the intended claim, in fixed ratio of doses (see also WHO technical report series, N.929 p-no 107, 2005).
- Diclofenamic acid sodium salt (Diclofenac Na) ) ) ) ) ) , nimesulide, 4-Hydroxy-nimesulide and N- acetyl-L- cysteine were evaluated to determine the in vitro toxicity on human fresh hepatocytes.
- the endpoints performed were: [ 3- ( 4 , 5-dimethylthiazol-2- yl ) -5- ( 3-carboxymethoxyphenyl ) -2- ( 4-sulfophenyl ) -2H- tetrazolium, (MTS) to determine mitochondrial functionality, adenosine triphosphate (ATP) levels to determine cellular energy levels, lactate dehydrogenase (LDH) release to determine membrane damage and reactive oxygen species (ROS) determination for reactive oxygen species .
- the inhibitory activity of the compounds was calculated from dose-response curves and expressed as concentration inhibiting 50% cell growth (IC50) in treated cultures relative to untreated controls. For ROS detection the results were expressed as the percentage of increase or decrease of ROS values in treated samples compared to CTR values.
- the IC50 values obtained for MTS endpoint were respectively 248.2 ⁇ for nimesulide, 664.8 ⁇ for 4-
- ROS detection an increase of the reactive oxygen species compared to the specific controls (DMSO, PBS or distilled water) was observed for nimesulide starting from 250 ⁇ , for diclofenamic acid sodium salt (Diclofenac Na) starting from 500 ⁇ , while for 4- Hydroxy nimesulide only at the highest dose tested.
- DMSO diclofenamic acid sodium salt
- NAC 4- Hydroxy nimesulide only at the highest dose tested.
- NAC the ROS detection demonstrated a reduction of the reactive oxygen species, when compared to the control, at all the doses tested.
- Nimesulide 198.4 248.2 total LDH
- the values obtained for the ATP were respectively of 46.24%, 55.61% and 77.75% of cell growth for nimesulide at the doses of 350, 250 and 150 ⁇ in presence of NAC 800 ⁇ (now of pre-incubation) .
- the data obtained in absence of NAC were 51.21%, 63.82% and 80.62% of cell growth at the same doses.
- the results of the screening with nimesulide and diclofenamic acid sodium salt (Diclofenac Na) in combination with NAC on primary culture of fresh human hepatocytes showed a protective effect of NAC on the hepatotoxicity induced by the test items with respect to the endpoint expressing the mitochondrial functionality, but not with ATP and ROS detection. No toxicity was observed for NAC when administered alone.
- Example 1 Nimesulide/NAC 100/200 immediate release conventional tablets
- Example 2 Nimesulide 100 /NAC 200 Sachets
- Citric acid Aromatizer 5 0.25 anhydrous
- Nimesulide/NAC 100/180 immediate release bilayered tablets, 510 mg (wet granulation procedure)
- Example 5 Diclofenamic acid sodium ( Diclofenac Na ) /NAC 75/150 vials (3 mL) for parenteral injection.
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Abstract
Description
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BR112014003167A BR112014003167A2 (en) | 2011-08-11 | 2011-08-11 | pharmaceutical composition consisting of a drug containing at least one toxicophor function and n-acetyl-1-cysteine |
MX2014001679A MX2014001679A (en) | 2011-08-11 | 2011-08-11 | Pharmaceutical composition comprising a drug containing at least one toxicophore function and n-acetyl-l-cysteine. |
EP11748619.1A EP2741742A1 (en) | 2011-08-11 | 2011-08-11 | Pharmaceutical composition comprising a drug containing at least one toxicophore function and n-acetyl-l-cysteine |
PCT/EP2011/063829 WO2013020600A1 (en) | 2011-08-11 | 2011-08-11 | Pharmaceutical composition comprising a drug containing at least one toxicophore function and n-acetyl-l-cysteine |
KR1020147006481A KR20140147799A (en) | 2011-08-11 | 2011-08-11 | Pharmaceutical composition comprising a drug containing at least one toxicophore function and n-acetyl-l-cysteine |
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WO2020129509A1 (en) * | 2018-12-21 | 2020-06-25 | 富士フイルム株式会社 | Phototoxicity or photoallergy measurement method and reagent for use in said measurement method |
WO2023076282A1 (en) * | 2021-10-28 | 2023-05-04 | The Texas A&M University System | Stable pharmaceutical compositions of varenicline with control on nitroso impurities |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998047534A1 (en) * | 1997-04-18 | 1998-10-29 | Klinge Pharma Gmbh | Stabilized medicaments containing cysteinyl derivatives |
EP1574221A1 (en) * | 2004-03-10 | 2005-09-14 | Shimoda Biotech (PTY) LTD | Stable injectable diclofenac compositions |
-
2011
- 2011-08-11 WO PCT/EP2011/063829 patent/WO2013020600A1/en active Application Filing
- 2011-08-11 EP EP11748619.1A patent/EP2741742A1/en not_active Withdrawn
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- 2011-08-11 MX MX2014001679A patent/MX2014001679A/en unknown
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998047534A1 (en) * | 1997-04-18 | 1998-10-29 | Klinge Pharma Gmbh | Stabilized medicaments containing cysteinyl derivatives |
EP1574221A1 (en) * | 2004-03-10 | 2005-09-14 | Shimoda Biotech (PTY) LTD | Stable injectable diclofenac compositions |
Non-Patent Citations (21)
Title |
---|
ACUTE LIVER FAILURE STUDY GROUP ET AL: "Intravenous N-Acetylcysteine Improves Transplant-Free Survival in Early Stage Non-Acetaminophen Acute Liver Failure", GASTROENTEROLOGY, ELSEVIER, PHILADELPHIA, PA, vol. 137, no. 3, 1 September 2009 (2009-09-01), pages 856 - 864.E1, XP026792978, ISSN: 0016-5085, [retrieved on 20090612] * |
AMAR PJ, SCHIFF ER: "Acetaminophen safety and hepatotoxicity-where do we go from here?", EXPERT OPIN DRUG SAF., vol. 6, no. 4, July 2007 (2007-07-01), pages 341 - 55 |
BERNAREGGI A: "Clinical pharmaco-kinetics of nimesulide", CLIN.PHARMACOKINET., vol. 35, 1998, pages 247 - 274 |
BORT R, PONSODA X, JOVER R, GOMEZ-LECHON MJ, CASTELL JV: "Diclofenac toxicity to hepatocytes: a role for drug metabolism in cell toxicity.", J PHARMACOL EXP THER., vol. 288, no. 1, January 1999 (1999-01-01), pages 65 - 72 |
CUMBO-NACHELI GUSTAVO ET AL: "Anticonvulsant hypersensitivity syndrome: is there a role for immunomodulation?", EPILEPSIA DEC 2008 LNKD- PUBMED:18637830, vol. 49, no. 12, December 2008 (2008-12-01), pages 2108 - 2112, XP002671733, ISSN: 1528-1167 * |
EFRATI SHAI ET AL: "N-acetylcysteine attenuates NSAID-induced rat renal failure by restoring intrarenal prostaglandin synthesis", NEPHROLOGY DIALYSIS TRANSPLANTATION, vol. 22, no. 7, July 2007 (2007-07-01), pages 1873 - 1881, XP002671734, ISSN: 0931-0509 * |
FENGPING LI ET AL.: "In Vitro nimesulide Studies toward Understanding Idiosyncratic Hepatotoxicity: diiminoquinone formation and conjugation", CHEM. RES. TOXICOL., vol. 22, 2009, pages 72 - 80 |
FONTANA, MED CLIN N AM, vol. 92, 2008, pages 761 - 794 |
GHABRIL MARWAN ET AL: "Drug-induced liver injury: a clinical update.", CURRENT OPINION IN GASTROENTEROLOGY, May 2010 (2010-05-01), pages 1 - 8, XP002671732, ISSN: 1531-7056, Retrieved from the Internet <URL:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156474/pdf/nihms-313388.pdf> [retrieved on 20120319] * |
JACOBSEN W, KUHN B, SOLDNER A, KIRCHNER G, SEWING KF, KOLLMAN PA, BENET LZ, CHRISTIANS U: "Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin", DRUG METAB DISPOS., vol. 28, no. 11, November 2000 (2000-11-01), pages 1369 - 78, XP001069416 |
KALGUTKAR AS, HENNE KR, LAME ME, VAZ AD, COLLIN C, SOGLIA JR, ZHAO SX, HOP CE: "Metabolic activation of the nontricyclic antidepressant trazodone to electrophile quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4", CHEM BIOL INTERACT., vol. 155, no. 1-2, 18 April 2005 (2005-04-18), pages 10 - 20 |
KAPLOWITZ N.: "Idiosyncratic drug hepatotoxicity", NAT REV DRUG DISCOV., vol. 4, no. 6, June 2005 (2005-06-01), pages 489 - 99 |
LARSON AM, POLSON J ET AL.: "Acute Liver Failure Study Group. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study", HEPATOLOGY., vol. 42, no. 6, December 2005 (2005-12-01), pages 1364 - 72 |
SAITO ET AL., HEPATHOLOGY, vol. 51, 2010, pages 246 - 254 |
SENIOR JR.: "What is idiosyncratic hepatotoxicity? What is it not?", HEPATOLOGY., vol. 47, no. 6, June 2008 (2008-06-01), pages 1813 - 5 |
UETRECHT J.: "Idiosyncratic drug reactions: past, present, and future", CHEM RES TOXICOL., vol. 21, no. 1, 4 December 2007 (2007-12-04), pages 84 - 92 |
WARING JF, ANDERSON MG: "Idiosyncratic toxicity: mechanistic insights gained from analysis of prior compounds", CURR OPIN DRUG DISCOV DEVEL., vol. 8, no. 1, January 2005 (2005-01-01), pages 59 - 65 |
WHO TECHNICAL REPORT SERIES, 2005, pages 107 |
WILLIAMS DP, PARK BK: "Idiosyncratic toxicity: the role of toxicophores and bioactivation", DRUG DISCOV TODAY., vol. 8, no. 22, 15 November 2003 (2003-11-15), pages 1044 - 50 |
ZHANG X. ET AL., DRUG METAB. PHARMACOKINET, vol. 26, no. 1, 2011, pages 47 - 59 |
ZHANG X. ET AL., DRUG METAB. PHARMACOKINET., vol. 26, no. 1, 2011, pages 47 - 59 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020129509A1 (en) * | 2018-12-21 | 2020-06-25 | 富士フイルム株式会社 | Phototoxicity or photoallergy measurement method and reagent for use in said measurement method |
JPWO2020129509A1 (en) * | 2018-12-21 | 2021-11-04 | 富士フイルム株式会社 | Methods for measuring phototoxicity or photoallergy and reagents for use in the above measuring methods |
WO2023076282A1 (en) * | 2021-10-28 | 2023-05-04 | The Texas A&M University System | Stable pharmaceutical compositions of varenicline with control on nitroso impurities |
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EP2741742A1 (en) | 2014-06-18 |
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