Mitoxantrone: Difference between revisions

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			{{Short description\|Chemical compound}}
	{{Drugbox		{{Drugbox
		⚫	\| verifiedrevid = 462252883
	\| Verifiedfields = changed
⚫	\| verifiedrevid = ~~414758221~~
	\| IUPAC_name = 1,4-dihydroxy-5,8-bis-anthracene-9,10-dione		\| IUPAC_name = 1,4-dihydroxy-5,8-bis-anthracene-9,10-dione
	\| image = Mitoxantrone skeletal.svg		\| image = Mitoxantrone skeletal.svg
			\| image2 = Mitoxantrone ball-and-stick.png

	<!--Clinical data-->		<!--Clinical data-->
	\| tradename = Novantrone		\| tradename = Novantrone
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	\| pregnancy_US = D		\| pregnancy_US = D
	\| legal_status = Rx-only		\| legal_status = Rx-only
	\| routes_of_administration = ~~'''Exclusively'''~~ ]		\| routes_of_administration = Mainly ]

	<!--Pharmacokinetic data-->		<!--Pharmacokinetic data-->
	\| bioavailability = n/a		\| bioavailability = n/a
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	\| elimination_half-life = 75 hours		\| elimination_half-life = 75 hours
	\| excretion = ]		\| excretion = ]

	<!--Identifiers-->		<!--Identifiers-->
			\| IUPHAR_ligand = 7242
	\| CASNo_Ref = {{cascite\|correct\|CAS}}
	\| CAS_number_Ref = {{cascite\|correct\|??}}		\| CAS_number_Ref = {{cascite\|correct\|??}}
	\| CAS_number = 65271-80-9		\| CAS_number = 65271-80-9
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	\| PubChem = 4212		\| PubChem = 4212
	\| DrugBank_Ref = {{drugbankcite\|correct\|drugbank}}		\| DrugBank_Ref = {{drugbankcite\|correct\|drugbank}}
	\| DrugBank = ~~APRD00371~~		\| DrugBank = DB01204
	\| ChemSpiderID_Ref = {{chemspidercite\|correct\|chemspider}}		\| ChemSpiderID_Ref = {{chemspidercite\|correct\|chemspider}}
	\| ChemSpiderID = 4067		\| ChemSpiderID = 4067
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	\| KEGG_Ref = {{keggcite\|correct\|kegg}}		\| KEGG_Ref = {{keggcite\|correct\|kegg}}
	\| KEGG = D08224		\| KEGG = D08224
	\| ChEBI_Ref = {{ebicite\|~~changed~~\|EBI}}		\| ChEBI_Ref = {{ebicite\|correct\|EBI}}
	\| ChEBI = 50729		\| ChEBI = 50729
	\| ChEMBL_Ref = {{ebicite\|correct\|EBI}}		\| ChEMBL_Ref = {{ebicite\|correct\|EBI}}
	\| ChEMBL = 58		\| ChEMBL = 58
			\| PDB_ligand = MIX

	<!--Chemical data-->		<!--Chemical data-->
	\| C=22 \| H=28 \| N=4 \| O=6		\| C=22 \| H=28 \| N=4 \| O=6
		⚫	\| SMILES = O=C2c1c(c(NCCNCCO)ccc1NCCNCCO)C(=O)c3c2c(O)ccc3O
	\| molecular_weight = 444.481 ]/]
⚫	\| ~~smiles~~ = O=C2c1c(c(NCCNCCO)ccc1NCCNCCO)C(=O)c3c2c(O)ccc3O
	\| InChI = 1/C22H28N4O6/c27-11-9-23-5-7-25-13-1-2-14(26-8-6-24-10-12-28)18-17(13)21(31)19-15(29)3-4-16(30)20(19)22(18)32/h1-4,23-30H,5-12H2
	\| InChIKey = KKZJGLLVHKMTCM-UHFFFAOYAS
	\| StdInChI_Ref = {{stdinchicite\|correct\|chemspider}}		\| StdInChI_Ref = {{stdinchicite\|correct\|chemspider}}
	\| StdInChI = 1S/C22H28N4O6/c27-11-9-23-5-7-25-13-1-2-14(26-8-6-24-10-12-28)18-17(13)21(31)19-15(29)3-4-16(30)20(19)22(18)32/h1-4,23-30H,5-12H2		\| StdInChI = 1S/C22H28N4O6/c27-11-9-23-5-7-25-13-1-2-14(26-8-6-24-10-12-28)18-17(13)21(31)19-15(29)3-4-16(30)20(19)22(18)32/h1-4,23-30H,5-12H2
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	\| StdInChIKey = KKZJGLLVHKMTCM-UHFFFAOYSA-N		\| StdInChIKey = KKZJGLLVHKMTCM-UHFFFAOYSA-N
	}}		}}
	'''Mitoxantrone''' is an ~~anthracenedione~~ ~~(not~~ an ~~anthracycline~~) ] agent.		'''Mitoxantrone''' (INN, BAN, USAN; also known as '''Mitozantrone''' in Australia; trade name '''Novantrone''') is an ] ] agent.

	==Uses==		==Uses==
	It is used in ~~the treatment of~~ certain types of cancer, mostly ~~] ],~~ ], and ]. It ~~was also shown to improve~~ the survival of children suffering from ~~first relapse of~~ ].<ref name="Parker">{{cite journal \|~~author~~=Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, Morgan M, Masurekar A, Goulden N, Green N, Révész T, Darbyshire P, Love S, Saha V \|title=Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial \|journal=Lancet \|volume= 376\|issue= 9757\|pages= 2009–2017\|~~year~~=2010 \|pmid=21131038 \|doi=10.1016/S0140-6736(10)62002-8 ~~\|pmc=3010035~~}}</ref>		Mitoxantrone is used to treat certain types of cancer, mostly ]. It improves the survival rate of children suffering from ] relapse.<ref name="Parker">{{cite journal \| vauthors = Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, Morgan M, Masurekar A, Goulden N, Green N, Révész T, Darbyshire P, Love S, Saha V \| display-authors = 6 \| title = Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial \| journal = Lancet \| volume = 376 \| issue = 9757 \| pages = 2009–2017 \| date = December 2010 \| pmid = 21131038 \| pmc = 3010035 \| doi = 10.1016/S0140-6736(10)62002-8 }}</ref>

⚫	The combination of mitoxantrone and ] is approved as a second-line treatment for metastatic hormone-refractory ]. This combination ~~has~~ ~~been~~ the first line of treatment~~, until~~ ~~recently~~, ~~when~~ combination of ] and prednisone ~~has~~ ~~been~~ ~~shown~~ to ~~improve~~ ~~survival and~~ disease-free period.<ref>{{cite book \|chapter=Cancer Chemotherapy \|~~author~~=Katzung, ~~Bertram G.~~ \|title=Basic and clinical pharmacology \|publisher=McGraw-Hill Medical Publishing Division \|location=New York \|year=2006 \|isbn=0-07-145153-6 \|edition=10th \|oclc=157011367}}</ref>

		⚫	The combination of mitoxantrone and ] is approved as a second-line treatment for metastatic hormone-refractory ]. This combination was once the first line of treatment; however, a combination of ] and prednisone improves survival rates and lengthens the disease-free period.<ref>{{cite book \|chapter=Cancer Chemotherapy \| vauthors = Katzung BG \|title=Basic and clinical pharmacology \|publisher=McGraw-Hill Medical Publishing Division \|location=New York \|year=2006 \|isbn=0-07-145153-6 \|edition=10th \|oclc=157011367}}</ref>

	Mitoxantrone is also used to treat ] (MS), most notably the subset known as secondary progressive MS. ~~Mitoxantrone~~ ~~will~~ ~~not~~ ~~cure~~ ~~multiple~~ ~~sclerosis~~, ~~but~~ is effective in slowing the progression of secondary progressive MS and extending the time between relapses in relapsing-remitting MS and progressive relapsing MS.<ref name="Fox">{{cite journal \|~~author~~=Fox E \|title=Management of worsening multiple sclerosis with mitoxantrone: a review \|journal=~~Clin~~ ~~Ther~~ \|volume=28 \|issue=4 \|pages=~~461–74~~ \|~~year~~=2006 \|pmid=16750460 \|doi=10.1016/j.clinthera.2006.04.013}}</ref>		Mitoxantrone is also used to treat ] (MS), most notably the ] known as secondary-progressive MS. In the absence of a cure, mitoxantrone is effective in slowing the progression of secondary-progressive MS and extending the time between relapses in both relapsing-remitting MS and progressive-relapsing MS.<ref name="Fox">{{cite journal \| vauthors = Fox EJ \| title = Management of worsening multiple sclerosis with mitoxantrone: a review \| journal = Clinical Therapeutics \| volume = 28 \| issue = 4 \| pages = 461–474 \| date = April 2006 \| pmid = 16750460 \| doi = 10.1016/j.clinthera.2006.04.013 }}</ref>

⚫	==Mechanism of action==

	Mitoxantrone is a ] ]; it disrupts ] and ] in both healthy cells and cancer cells.

	It also engages in ].<ref name="pmid">{{cite journal \|author=Mazerski J, Martelli S, Borowski E \|title=The geometry of intercalation complex of antitumor mitoxantrone and ametantrone with DNA: molecular dynamics simulations \|journal=Acta Biochim. Pol. \|volume=45 \|issue=1 \|pages=1–11 \|year=1998 \|pmid= 9701490\|doi= \|url=}}</ref>

	==Side effects==		==Side effects==
	As other drugs in its class, ~~mitoxantrone~~ may cause ~~several~~ ]s of varying severity, ~~such as~~ ], ], ], heart damage, and ]. ~~Some~~ ~~side effects may have~~ delayed onset. ] is a particularly concerning effect as it is irreversible; regular monitoring with ]s or ]s is recommended for ~~people taking mitoxantrone~~.		Mitoxantrone, as with other drugs in its class, may cause ] of varying severity, including ], ], ], heart damage and ], possibly with delayed onset. ] is a particularly concerning effect as it is irreversible; thus regular monitoring with ]s or ]s is recommended for patients.

			Because of the risk of cardiomyopathy, mitoxantrone carries a limit on the cumulative lifetime dose (based on body surface area) in MS patients.<ref name="FDA Postmarket Drug Safety">{{cite web\|title=Mitoxantrone Hydrochloride (marketed as Novantrone and generics) – Healthcare Professional Sheet text version\|url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126445.htm\|publisher=U.S. Food and Drug Administration\|access-date=19 September 2014\|ref=fdapostmarket}}</ref>
	The medication carries a total lifetime dose based on body surface area.<ref name="Fox"/>

		⚫	==Mechanism of action==
	==Synthesis==
			Mitoxantrone is a ] ]; it disrupts ] and ] in both healthy cells and cancer cells by ]<ref name="pmid">{{cite journal \| vauthors = Mazerski J, Martelli S, Borowski E \| title = The geometry of intercalation complex of antitumor mitoxantrone and ametantrone with DNA: molecular dynamics simulations \| journal = Acta Biochimica Polonica \| volume = 45 \| issue = 1 \| pages = 1–11 \| year = 1998 \| pmid = 9701490 \| doi = 10.18388/abp.1998_4280 \| doi-access = free }}</ref><ref>{{cite journal \| vauthors = Kapuscinski J, Darzynkiewicz Z \| title = Interactions of antitumor agents Ametantrone and Mitoxantrone (Novatrone) with double-stranded DNA \| journal = Biochemical Pharmacology \| volume = 34 \| issue = 24 \| pages = 4203–4213 \| date = December 1985 \| pmid = 4074383 \| doi = 10.1016/0006-2952(85)90275-8 }}</ref> between DNA bases. It is also classified as an antibiotic.<ref>{{Cite web \| url=https://livertox.nlm.nih.gov/Mitoxantrone.htm \| title=Mitoxantrone}}</ref>
	]
			]

	{{Cite journal\|doi=10.1021/jm00195a002\|title=Antitumor agents. 1. 1,4-Bis-9,10-anthracenediones\|pmid=490545\|year=1979\|last1=Murdock\|first1=K. C.\|last2=Child\|first2=R. G.\|last3=Fabio\|first3=P. F.\|last4=Angier\|first4=Robert D.\|last5=Wallace\|first5=Roslyn E.\|last6=Durr\|first6=Frederick E.\|last7=Citarella\|first7=R. V.\|journal=Journal of Medicinal Chemistry\|volume=22\|issue=9\|pages=1024}}

	==See also==		== See also ==
	*], a mitoxantrone ] under development		* ], a mitoxantrone ] under development
			* ]
	* Naphtoquinoxalinediones, potential antitumorals, obtained from diamino-1,2 anthraquinones using a regioselective synthesis.<ref>{{cite journal \|author=Baron M, Giorgi-Renault S, Renault J, ''et al.'' \|title=Heterocycles with a quinone function.5.An abnormal reaction of butanedione with 1,2-diaminoanthraquinone - Crystalline structure obtained from naphto(2,3-f) quinoxaline-7,12 dione \|journal=Can. J. Chem. \|volume=62 \|issue=3 \|pages=526–530 \|year=1984 \|doi=10.1139/v84-087 \|url=http://www.nrcresearchpress.com/doi/abs/10.1139/v84-087 \|language=French}}</ref>
	*]
	*]

	==References==		== References ==
	{{Reflist}}		{{Reflist}}

			== External links ==
			* {{cite web \| url = https://druginfo.nlm.nih.gov/drugportal/name/mitoxantrone \| publisher = U.S. National Library of Medicine \| work = Drug Information Portal \| title = Mitoxantrone }}

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	{{Chemotherapeutic agents}}		{{Chemotherapeutic agents}}
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Latest revision as of 13:28, 29 May 2024

Chemical compound Pharmaceutical compound

Mitoxantrone
Clinical data


Trade names	Novantrone
AHFS/Drugs.com	Monograph
MedlinePlus	a608019
Routes of administration	Mainly intravenous
ATC code	L01DB07 (WHO)
Legal status
Legal status	US: WARNING In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	n/a
Protein binding	78%
Metabolism	Hepatic (CYP2E1)
Elimination half-life	75 hours
Excretion	Renal
Identifiers
IUPAC name 1,4-dihydroxy-5,8-bis-anthracene-9,10-dione
CAS Number	65271-80-9
PubChem CID	4212
IUPHAR/BPS	7242
DrugBank	DB01204
ChemSpider	4067
UNII	BZ114NVM5P
KEGG	D08224
ChEBI	CHEBI:50729
ChEMBL	ChEMBL58
PDB ligand	MIX (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID4046947
Chemical and physical data
Formula	C₂₂H₂₈N₄O₆
Molar mass	444.488 g·mol
3D model (JSmol)	Interactive image
SMILES O=C2c1c(c(NCCNCCO)ccc1NCCNCCO)C(=O)c3c2c(O)ccc3O
InChI InChI=1S/C22H28N4O6/c27-11-9-23-5-7-25-13-1-2-14(26-8-6-24-10-12-28)18-17(13)21(31)19-15(29)3-4-16(30)20(19)22(18)32/h1-4,23-30H,5-12H2 Key:KKZJGLLVHKMTCM-UHFFFAOYSA-N
(verify)

Mitoxantrone (INN, BAN, USAN; also known as Mitozantrone in Australia; trade name Novantrone) is an anthracenedione antineoplastic agent.

Uses

Mitoxantrone is used to treat certain types of cancer, mostly acute myeloid leukemia. It improves the survival rate of children suffering from acute lymphoblastic leukemia relapse.

The combination of mitoxantrone and prednisone is approved as a second-line treatment for metastatic hormone-refractory prostate cancer. This combination was once the first line of treatment; however, a combination of docetaxel and prednisone improves survival rates and lengthens the disease-free period.

Mitoxantrone is also used to treat multiple sclerosis (MS), most notably the subset of the disease known as secondary-progressive MS. In the absence of a cure, mitoxantrone is effective in slowing the progression of secondary-progressive MS and extending the time between relapses in both relapsing-remitting MS and progressive-relapsing MS.

Side effects

Mitoxantrone, as with other drugs in its class, may cause adverse reactions of varying severity, including nausea, vomiting, hair loss, heart damage and immunosuppression, possibly with delayed onset. Cardiomyopathy is a particularly concerning effect as it is irreversible; thus regular monitoring with echocardiograms or MUGA scans is recommended for patients.

Because of the risk of cardiomyopathy, mitoxantrone carries a limit on the cumulative lifetime dose (based on body surface area) in MS patients.

Mechanism of action

Mitoxantrone is a type II topoisomerase inhibitor; it disrupts DNA synthesis and DNA repair in both healthy cells and cancer cells by intercalation between DNA bases. It is also classified as an antibiotic.

References

"FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, et al. (December 2010). "Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial". Lancet. 376 (9757): 2009–2017. doi:10.1016/S0140-6736(10)62002-8. PMC 3010035. PMID 21131038.
Katzung BG (2006). "Cancer Chemotherapy". Basic and clinical pharmacology (10th ed.). New York: McGraw-Hill Medical Publishing Division. ISBN 0-07-145153-6. OCLC 157011367.
Fox EJ (April 2006). "Management of worsening multiple sclerosis with mitoxantrone: a review". Clinical Therapeutics. 28 (4): 461–474. doi:10.1016/j.clinthera.2006.04.013. PMID 16750460.
"Mitoxantrone Hydrochloride (marketed as Novantrone and generics) – Healthcare Professional Sheet text version". U.S. Food and Drug Administration. Retrieved 19 September 2014.
Mazerski J, Martelli S, Borowski E (1998). "The geometry of intercalation complex of antitumor mitoxantrone and ametantrone with DNA: molecular dynamics simulations". Acta Biochimica Polonica. 45 (1): 1–11. doi:10.18388/abp.1998_4280. PMID 9701490.
Kapuscinski J, Darzynkiewicz Z (December 1985). "Interactions of antitumor agents Ametantrone and Mitoxantrone (Novatrone) with double-stranded DNA". Biochemical Pharmacology. 34 (24): 4203–4213. doi:10.1016/0006-2952(85)90275-8. PMID 4074383.
"Mitoxantrone".
Wu CC, Li YC, Wang YR, Li TK, Chan NL (December 2013). "On the structural basis and design guidelines for type II topoisomerase-targeting anticancer drugs". Nucleic Acids Research. 41 (22): 10630–10640. doi:10.1093/nar/gkt828. PMC 3905874. PMID 24038465.

External links

"Mitoxantrone". Drug Information Portal. U.S. National Library of Medicine.

Demyelinating diseases of the central nervous system

Signs and symptoms

Investigations and diagnosis

Clinical
- Clinically isolated syndrome
- Expanded Disability Status Scale
Serological and CSF
- Oligoclonal bands
Radiological
Frexalimab

Approved treatment

Other treatments

Former
- Daclizumab
Research in multiple sclerosis

Demyelinating diseases

Autoimmune	Neuromyelitis optica spectrum disorder Diffuse myelinoclastic sclerosis MOG antibody disease Multiple sclerosis Chronic inflammatory demyelinating polyneuropathy
Inflammatory	Acute disseminated encephalomyelitis Balo concentric sclerosis Marburg acute multiple sclerosis Neuromyelitis optica spectrum disorder Diffuse myelinoclastic sclerosis Tumefactive multiple sclerosis Experimental autoimmune encephalomyelitis
Hereditary	Adrenoleukodystrophy Alexander disease Canavan disease Krabbe disease Metachromatic leukodystrophy Pelizaeus–Merzbacher disease Leukoencephalopathy with vanishing white matter Megalencephalic leukoencephalopathy with subcortical cysts CAMFAK syndrome
Other	Central pontine myelinolysis Marchiafava–Bignami disease Mitochondrial DNA depletion syndrome

Other

v t e Merck Serono
Products	Avelumab Bisoprolol Cetuximab Cladribine Efalizumab Gonadotropin preparations Human chorionic gonadotropin Interferon beta-1a Levothyroxine Luteinizing hormone Metformin Mitoxantrone Saizen Serostim Tegafur/uracil
Related	Merck Group Serono

Intracellular chemotherapeutic agents / antineoplastic agents (L01)

SPs/MIs
(M phase)

Block microtubule assembly	Vinca alkaloids (Vinblastine Vincristine Vindesine Vinflunine Vinorelbine)
Block microtubule disassembly	Taxanes (Cabazitaxel Docetaxel Larotaxel Ortataxel Paclitaxel Tesetaxel) Epothilones (Ixabepilone)

DNA replication
inhibitor

DNA precursors/
antimetabolites
(S phase)

Folic acid	Dihydrofolate reductase inhibitor (Aminopterin Methotrexate Pemetrexed Pralatrexate) Thymidylate synthase inhibitor (Pemetrexed Raltitrexed)
Purine	Adenosine deaminase inhibitor (Pentostatin) Halogenated/ribonucleotide reductase inhibitors (Cladribine Clofarabine Fludarabine) Nelarabine Rabacfosadine Thiopurine (Mercaptopurine Tioguanine)
Pyrimidine	Thymidylate synthase inhibitor (Capecitabine Carmofur Doxifluridine Floxuridine Fluorouracil Tegafur (+gimeracil/oteracil)) DNA polymerase inhibitor (Cytarabine +daunorubicin) Ribonucleotide reductase inhibitor (Gemcitabine) Hypomethylating agent (Azacitidine Decitabine)
Deoxyribonucleotide	Ribonucleotide reductase inhibitor (Hydroxycarbamide)

Topoisomerase inhibitors
(S phase)

I	Camptotheca (Belotecan Camptothecin Cositecan Etirinotecan pegol Exatecan Gimatecan Irinotecan Lurtotecan Rubitecan Silatecan Topotecan)
II	Podophyllum (Etoposide Teniposide)
II+Intercalation	Anthracyclines (Aclarubicin Amrubicin Daunorubicin (+cytarabine) Doxorubicin Epirubicin Idarubicin Pirarubicin Valrubicin Zorubicin) Anthracenediones (Losoxantrone Mitoxantrone Pixantrone) Amsacrine Bisantrene Crisnatol Menogaril

Crosslinking of DNA
(CCNS)

Alkylating	Nitrogen mustards: Bendamustine Chlormethine Cyclophosphamide (Ifosfamide Trofosfamide) Chlorambucil Melphalan (Melphalan flufenamide) Prednimustine Uramustine Nitrosoureas: Carmustine Fotemustine Lomustine (Semustine) Nimustine Ranimustine Streptozocin Alkyl sulfonates: Busulfan (Mannosulfan Treosulfan) Aziridines: Carboquone Thiotepa Triaziquone Triethylenemelamine
Platinum-based	Carboplatin Cisplatin Dicycloplatin Nedaplatin Oxaliplatin Satraplatin
Nonclassical	Altretamine Hydrazines (Procarbazine) Etoglucid Mitobronitol Pipobroman Triazenes (Dacarbazine Mitozolomide Temozolomide)
Intercalation	Streptomyces (Dactinomycin Bleomycin Mitomycins Plicamycin)

Photosensitizers/PDT