Download Bleomycin - pharmphriends

Antibiotics
Peptides
Bleomycin
Source/Chemistry
 Mixture of cytotoxic glycopeptide antibiotics isolated as their water soluble sulfate salts from cultures of a strain
of Streptomyces verticillus
 Isolated as a blue-colored Cu(II) coordinated complex
 Complexes (chelates) in vitro with divalent and trivalent cations
Complexes (Chelates)
 Complex
o One or more molecules – ligands
 ligare (L) – to bind
o A central cation (ligate)
 Ligand
o Molecule bound to the central cation
o Lewis Base (electron pair donor)
o Coordinates with metals in an aqueous environment
 Ligate
o Metal cation in aqueous solution
 Surrounded by electrons
 Usually a Lewis Acid (electron pair receiver)
 Chelate
o Chēlē (Gr.) – Claw, hoof
o Complex of metal cation with two or more groups on a multidentate ligand
o Ring compound
Chemistry
PROPIONAMIDE
 AMINOALANINE
OH(R)
 Group of peptides with an identical central core
AMIDE
O
O
NH
2
(bleomycinic acid) but different terminal
NH2
H
N
alkylamine groups
N
NH2
S
 Bleomycin A2 predominates in the therapeutic
O
CH3 H
O
N
N
N
mixture
O HO
N
S
O
N
H2N
 Many analogs isolated or prepared but none
O
H
CH3 N
superior to the current market product
N
CH3 HO
CH3
H
PYRIMIDINE
N
H
BITHIAZOLE
CARBOXYLIC
ACID
O
HO
N
H
O
HO
OH
O
OH
O
OH
O
L-GULOSE
CARBAMOYL MANNOSE
OH
O
NH2
BLEOMYCINIC ACID
+
[BLEOMYCIN A2 (BLEOCIN); R = -NH(CH2)3S(CH3)2]
Mechanism of Action
 Contains an iron-binding region and a DNA-binding region at opposite ends of the molecule
 Iron is a mandatory co-factor for free radical generation and resulting cytotoxicity of bleomycin
 Cytotoxicity results from activated oxygen free radical species which produce single- and double-strand DNA
breaks
MECHANISM OF ACTION
DAMAGE DNA AND
PREVENT REPAIR;
DEOXYRIBONUCLEOTIDES
PRODUCE CHROMOSOMAL
ABERRATIONS AND DNA
SCISSION
BLEOMYCIN
Bleomycin complex with DNA
DEOXYRIBONUCLEIC ACIDS (DNA)
MAJOR EFFECTS - G2 AND M
PHASES; CELL CYCLE PHASE
SPECIFIC
RIBONUCLEIC ACIDS (RNA)
PROTEINS
Common Applications
 Hodgkin’s and Non-Hodgkin’s lymphomas
 Germ cell tumors
 Head and neck squamous cell carcinoma
 Skin, cervix, vulvar squamous cell carcinoma
Special Adverse Effects
 Pulmonary toxicity
o Most severe toxicity
o Pneumonitis – 10% patients
o Pulmonary fibrosis – 1% patients
o Age and dose-related, but may be unpredictable
o Monitor pulmonary function tests (decrease of 15% or more mandates immediate stoppage)
 Dermatological
o Desquamation – fingers/elbows
o Rash
o Hyperpigmentation
o Hyperkeratosis
Uncommon Route of Administration
 IM, SC, Intrapelural (BESIDE IV)
 Sometimes used as a sclerosing agent for malignant pleural effusion and ascites
Incompatibilities
 Divalent and trivalent cations due to chelation
Resistance
 Increased expression of DNA repair enzymes, resulting in enhanced repair of DNA damage
 Decreased drug accumulation through altered uptake
Dactinomycin
History/Source
 Dactinomycin = Actinomycin D
 Major antibiotic of a mixture of actinomycins produced by strains of Streptomyces parvulus
Chemistry
 Heteroaromatic chromopeptide
 Planar phenoxazone chromophore
o Actinocin
o Red-to-yellowish color
 Various naturally occurring actinomycins vary via peptide side chains (control by variation in amino acid content
of media)
MECHANISM OF ACTION
INTERCALATION INTO A
PURINE-PYRIMIDINE BASE
PAIR, INHIBITING MESSENGER
RNA SYNTHESIS
(A PHENOXAZONE)
"ONE" "PHEN" "OX"
CH3
O
O
H2N
N
DACTINOMYCIN
CO
"AZ"
PEPTIDE
PEPTIDE
DACTINOMYCIN (COSMEGEN)
METHYLVALINE
D-VALINE
DEOXYRIBONUCLEIC ACIDS (DNA)
DACTINOMYCIN-DNA COMPLEX
WITH GREAT STABILITY;
BLOCKS TRANSCRIPTION OF
RIBONUCLEIC ACIDS (RNA)
DNA BY RNA POLYMERASES
CO
PEPTIDE = THREONINE
DEOXYRIBONUCLEOTIDES
PROLINE
INTERCALATION
INTER (L.) - BETWEEN
CALARE (L.) - TO CALL, SUMMON
"TO INSERT BETWEEN"
PROTEINS
N-METHYLGLYCINE
Mechanism of Action
 Preferentially binds to guanine-cytidine base pairs
 Binds to single- and double-stranded DNA as an intercalator with formation of toxic oxygen free radicals that
promote strand breaks
Common Applications
 Wilms’ tumor **
 Rhabdomyosarcoma **
 Choriocarcinoma
 Ewing’s sarcoma
 ** Curative in combination with primary surgery + radiotherapy + other chemotherapy
Special Adverse Effects
 Dermatological
o Hyperpigmentation – “radiation recall”
o Extravasation – Extremely corrosive to soft tissue (contracture has resulted – use cold compresses and
local injection of corticosteroids)
 Red-orange color – body fluids
Uncommon Route of Administration
 Perfusion techniques sometimes
Resistance
 Increased expression of the multidrug-resistant gene with elevated P170 glycoprotein levels
o Enhanced efflux of drug
o Decreased drug accumulation through altered uptake
Mitosanes
Mitomycin
History/Source
 First isolated from cultures of Streptomyces caespitosus in 1958
 Commonly called Mitomycin C or Mutamycin
 One member of a group of antitumor antibiotics isolated from cultures of S. caespitosus
Chemistry
 Only compound in nature to contain an
 Unique chemical structure
aziridine ring
 Mitosanes – 1,2-disubstituted indoloquinones
 Water soluble
 Pyrrolo [1,2-a] indole nucleus
 Blue-violet colored solution
 Contains quinone, aziridine, and carbamate
 Unstable in both acidic and alkaline media
functions
 Limited stability of reconstituted solutions
c
b
a
N
2
3
N H H
4
1
5
PYRROLO[1,2-a]INDOLE
NH2
O
CARBAMATE
O
O
H2 N
H
c
b
a
N
H3 C
OCH3
H
NH
NH
AZIRIDINE
H
O
MITOMYCIN C
[MITOMYCIN (MUTAMYCIN)]
MECHANISM OF ACTION
BIFUNCTIONAL OR
TRIFUNCTIONAL ALKYLATING
AGENT THAT INHIBITS DNA
SYNTHESIS AND FORMS
ADDUCTS WITH DNA
MITOMYCIN
INHIBITS TRANSCRIPTION
BY TARGETING DNA-DEPENDENT
RNA POLYMERASE
DEOXYRIBONUCLEOTIDES
Alkylated DNA complex formed by covalent
linkage of mitomycin to guanine of DNA
DEOXYRIBONUCLEIC ACIDS (DNA)
RIBONUCLEIC ACIDS (RNA)
PROTEINS
Common Applications
 Disseminated adenocarcinoma of the stomach and pancreas
 Unlabeled used
o Superficial bladder cancer (Intravesical/IV)
o Adjunct to surgical excision in primary or recurrent pterygia (web-like superficial growth on the
subconjunctiva) – NONMALIGNANT CONDITION
Special Adverse Effects
 Hemolytic-uremic syndrome
o Dose related
o 50% fatality rate
 Dermatologic
o Necrosis, cellulitis, ulceration on extravasation
 Pulmonary
o Interstitial pneumonitis – infrequent occurrence but life-threatening
Resistance
 Increased expression of the multidrug-resistant gene with elevated P170 glycoprotein levels
o Enhanced efflux of drug
o Decreased drug accumulation through altered uptake
 Increased activity of DNA excision repair enzymes
Methylnitrosoureas
Streptozocin
History/Source
 Fermentation product of Streptomyces achromogenes
Chemistry
 Pale gold water soluble nitrosourea
 2-Deoxy-2-(3-methyl-3-nitrosoureido)-D-glucopyranose
 Mixture of  and  anomers, with solutions undergoing mutarotation
MECHANISM OF ACTION
STREPTOZOCIN
D-GLUCOPYRANOSE
6
OH
4
HO
HO
5
3
ANOMERIC CARBON
(MUTAROTATION)
(
)
O
2
OH
HN
1
1
C
2
CH3
N
3
N
PURINE BASES
DECOMPOSES TO FORM
CARBONIUM IONS THAT
ARE ELECTROPHILIC AND
CAN ALKYLATE OR
CARBAMOYLATE VARIOUS
PURINES OR PYRIMIDINES
TO FORM ADDUCTS INVOLVED
IN INTER- OR INTRASTRAND
DNA CROSS-LINKING
STREPTOZOCIN
PYRIMIDINE BASES
RIBONUCLEOTIDES
DEOXYRIBONUCLEOTIDES
O
ALSO, METHYLATES GUANINE
AT THE O-6 POSITION AND
O
IRREVERSIBLY INACTIVATES
DEOXYRIBONUCLEIC ACIDS (DNA)
2-DEOXY-2-(3-METHYL-3-NITROSOUREIDO)-D-GLUCOPYRANOSE DNA-REPAIR ENZYME
MAMMALIAN ALKYL TRANSFERASE
STREPTOZOCIN (ZANOSAR)
Common Applications
 Metastatic islet pancreatic carcinoma
Special Adverse Effects
 Very severe nausea and vomiting
 Nephrotoxicity
o Dose-related
o Sometimes irreversible
Resistance
 Enhanced activity of DNA repair enzymes
Anthracyclines
Doxorubicin
History/Source
 First isolated in 1967 from cultures of Streptomyces peucetius var. caesius at Farmitalia (Milan)
 Introduced into USA in 1974
Chemistry
 Cytotoxic glycosidic anthracycline
 Color is pH dependent
o Acidic pH – Yellow-orange
 Part of the rhodomycin group of compounds
o Neutral pH – Orange-red
o Orgin - Streptomyces spp.
o Alkaline pH – Violet-blue
 Planar anthraquinone nucleus linked
glycosidically to an aminosugar (daunosamine)
 Quinine and hydroquinone moieties are present
on adjacent rings, allowing these molecules to
serve as electron-donating and electronaccepting agents
 HCl salt is water soluble and used in dosage
forms
O
4
OH
5
6
O
7
OH
8
3
OH
2
9
12
1
11
OCH3 O
OH
H3C
O
OH
10
O
NH2
ADRIAMYCINONE
(AN ANTHRAQUINONE)
(GENIN OR AGLYCONE)
DAUNOSAMINE
(AN AMINO SUGAR)
(GLYCONE)
DOXORUBICIN (ADRIAMYCIN)
Mechanism of Action
 Topoisomerases
o The process of DNA replication puts great torsional (twisting) strain on the chromosomal circle of DNA
o This strain is relieved by topoisomerases (gyrases)
MECHANISM OF ACTION
DEOXYRIBONUCLEOTIDES
Idarubicin intercalating with DNA
ANTHRACYCLINE
ANALOGS
DEOXYRIBONUCLEIC ACIDS (DNA)
INTERCALATES BETWEEN
BASE PAIRS IN DNA DOUBLE RIBONUCLEIC ACIDS (RNA)
HELIX, AFFECTING DNA AND
RNA SYNTHESIS
(GENERATES REACTIVE OXYGEN
INTERMEDIATES AND FREE RADICALS)
PROTEINS
INHIBITS TOPOISOMERASE-II
Common Applications (Nonliposomal)
 MANY
 Acute lymphoblastic leukemia (ALL)
 Hodgkin’s and non-Hodgkin’s lymphomas
 Sarcomas
o Kaposi’s sarcoma (AIDSrelated)(liposomal)
Special Adverse Effects
 Cardiovascular
o Dose related
o Arrhythmias
o CHF – cumulative dose-related
 Discoloration of body fluids
o Urine – Red-to-orange
 Strong vesicant
Uncommon Route of Administration
 Conventional aqueous solution and lipid complex
 Intravesical (bladder) instillation (carcinoma in situ)
Available Liposomal

Carcinomas
o Breast
o Ovarian (liposomal)
o Bladder (via instillation)
Recent News
 Administration of doxorubicin, followed 24h later by zoledronic acid (Reclast® [Novartis]), stopped 99.99% of
new cancer cell growth in tumors in mice in European tests (Britain + Finland)
 Human trials expected to begin in late, 2008
Resistance to Anthracyclines
Doxorubicin and other Anthracyclines
Resistance
 Increased expression of the multidrug-resistant gene with elevated P170 glycoprotein levels
o Enhanced efflux of drug
o Decreased drug accumulation through altered uptake
 Decreased expression of topoisomerase II
 Mutation in topoisomerase II with decreased binding affinity for drug
 Increased expression of sulfhydryl proteins, including glutathione and glutathione-dependent enzymes
Epirubicin
Source
 Semisynthetic analog of doxorubicin
 Water soluble HCl salt is employed
Chemistry
 C-4’ epimer of doxorubicin
 Same physical/chemical properties as
doxorubicin
 Red-orange color
OH
O
4
5
O
7
6
OH
8
3
R
OH
2
9
12
1
OCH3 O
6'
H3C
HO
4'
4'
OH
6'
H3C
O
5'
O
2'
NH2
5'
4'
1'
3'
O
1'
10
11
4'
3'
O
2'
OH NH2
DOXORUBICIN (ADRIAMYCIN)
EPIRUBICIN (ELLENCE)
(AN EPIMER OF DOXORUBICIN)
Mechanism of Action
 Same as doxorubicin
Common Applications
 Adjuvant for early stage breast cancer that has spread to the regional (axillary) lymph nodes but has been
treated surgically with removal of all known tumor
 Metastatic breast carcinoma
 Gastric carcinoma
Special Adverse Effects
 Same as doxorubicin
 Slightly less cardiotoxicity
Daunorubicin
History/Source
 Also called daunomycin
 Originally isolated from cultures of Streptomyces peucetius var. caesius in 1964
 Also obtained from cultures of Streptomyces coeruleorubidus
Chemistry
 A C-8 deoxy-doxorubicin derivative
 Same physical and chemical properties as
doxorubicin


Red-orange color
Water soluble HCl salt used
OH
O
4
5
6
12
11
O
7
8
3
2
9
1
OH
CH3 C-8 =
OH
DOXORUBICIN
DAUNOMYCINONE
(AN ANTHRAQUINONE)
(GENIN OR AGLYCONE)
10
OCH3 O
OH
H3C
O
OH
O
O
DAUNOSAMINE
(AN AMINO SUGAR)
(GLYCONE)
NH2
DAUNORUBICIN (DAUNOMYCIN, DAUNOXOME)
Mechanism of Action
 Same as doxorubicin
Common Applications
 Acute leukemias (lymphoblastic and myelogenous)
 Kaposi’s Sarcoma (AIDS-related)
 Daunorubicin citrate liposomal
Special Adverse Effects
 Same as doxorubicn
Products – Available as Liposomal – Daunorubicin citrate
Daunorubicin Citrate Liposomal
 Aqueous solution of daunorubicin citrate encapsulated with liposomes
o Lipid bilayer
o Distearoylphosphatidyl choline + cholesterol
o 2:1 (aqueous:lipid bilayer)
 Aids in the protection of entrapped drug from enzymatic and chemical degradation
 Decreased uptake by “normal” tissues (nonreticuloendothelial)
 Minimizes protein binding
 Released over time from within tumor
Idarubicin
Source/Chemistry
 Synthetic analog of daunorubicin
 1-Demethoxydaunorubicin
 High degree of lipophilicity affords increased
rate of cellular uptake
 Same physical/chemical properties as
doxorubicin
 Red-orange color
 Water soluble HCl salt used
O
4
OH
5
6
O
7
8
CH3
OH
3
2
9
1
12
O
11
OH
10
O
1-DEMETHOXYO
H3C
NH2
OH
IDARUBICIN (IDAMYCIN)
(1-DEMETHOXYDAUNORUBICIN)
Mechanism of Action
 Same as doxorubicin
Common Applications
 Acute leukemias (AML, ALL)
 Chronic leukemia (CML) in blast crisis
Special Adverse Effects
 Same as doxorubicin
Valrubicin
Source/Chemistry
 Semisynthetic analog of doxorubicin
 Valeric acid ester of the N-trifluoroacetylamide
of doxorubicin
o Basic amine nitrogen of doxorubicin is
lost, and replaced with neutral amidic
nitrogen
o Water solubility is low
 High degree of lipophilicity affords increased
rate of cellular uptake
 Same physical/chemical properties as
doxorubicin
 Red-orange color
 Supplied in Cremophor EL/Dehydrated Alcohol
mixture as a solution
o
Cremophor – an emulsifying agent for
pharmaceuticals that is mainly a
glycerol – PEG – ricinoleate + fatty acid
esters of PEG
ESTER
OH
O
4
5
6
O
7
8
3
13
14
O
CH3
OH
2
9
12
1
11
OCH3 O
OH
H3C
O
N C O
O
10
O
VALERIC ACID
[CH3(CH2)3COOH]
TRIFLUOROACETYLAMIDE
OH H CF3
VALRUBICIN (VALSTAR)
(A DOXORUBICIN ANALOG)
Mechanism of Action
 Same as doxorubicin
o Less bound to DNA
 Interacts with topoisomerase II
o Mediated via metabolites
 N-Trifluoroacetyldoxorubicin
 N-Trifluoroacetyldoxorubicinol
Common Applications
 Intravesical therapy of BCG-refractory carcinoma in situ (CIS) of the urinary bladder in patients who would be
poor candidates for immediate cystectomy
o Drug does NOT penetrate the bladder wall
Special Adverse Effects
 Local reactions
o Irritation
o Urgency
o Frequency
o Dysuria
 Systemic reactions are uncommon as total recovery of voided anthracyclines is 99%, with systemic exposure
being negligible
Uncommon Route of Adminsitration
 Via urethral catheter into the urinary bladder
 Retain drug for two hours
 Adequate posturination hydration is mandatory
Anthracenediones
Mitoxantrone
History/Source
 Many multiringed planar anthracyclines have been synthesized
 A synthetic dihydroxyanthracenedione
Chemistry
 Blue-black solid
 Amphoteric
o Hydrogen-bonded phenolic groups
 Forms water soluble HCl salt
o 4 basic amine nitrogen atoms
 Not glycosylated (as doxorubicin family)
ANTHRACENE
OH
O
4
H
N
HN
10
OH
5
3
6
2
7
BASIC AMINES
9
1
OH
O
8
HN
N
H
OH
MITOXANTRONE (NOVANTRONE)
(A DIHYDROXYANTHRACENEDIONE)
Mechanism of Action
 Same as doxorubicin
 Not as completely understood as doxorubicin family
Common Applications
 Acute myelogenous leukemia (AML)
 Advanced hormone-refractory prostate cancer
 Non-Hodgkin’s lymphoma
Uncommon Clinical Application
 Reduction of neurologic disability or frequency of relapses in multiple sclerosis (MS) patients
o Not for patients with primary progressing MS
Special Adverse Effects
 Same as doxorubicin
 Cardiotoxicity (esp CHF) may occur at any time; increases with cumulative dosage – monitoring mandatory
 Special cardiac monitoring instructions for MS patient therapy
Macrolides
Temsirolimus
History/Source
 A semisynthetic derivative of sirolimus (rapamycin)
o Rapamycin – Orally administered immunosuppressant in transplantation (renal)
Chemistry
 Macrolide (macrocyclic lactone) skeleton
 Rapamycin derivative
o Rapamycin, 42-[3-hydroxy-2H
H
H
O
(hydroxymethyl)-2-methylpropanoate]
CH3
 Colorless solid
O
O
O
O
OH
 No ionizable functional groups
H3C
O
H3C
H
 Water insoluble
CH3
O
O
OCH3
CH3
OH
MACROCYCLIC
LACTONE
OH
H3C
H3CO
OH
O
H3CO
CH3
CH3
TEMSIROLIMUS (TORISEL)
Mechanism of Action
 An inhibitor of the enzyme mTOR (mammalian Target Of Rapamycin – a key regulatory kinase)
 Binds to an intracellular protein (FKBP-12)
 This protein-drug complex inhibits the activity of mTOR that controls cell division
 Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells
Common Application
 Renal cell carcinoma
Uncommon Route of Administration
 None
 Solubilizing diluent is a mixture of polysorbate 80 + PEG 400 + dehydrated alcohol
Special Adverse Effects
 Hyperlipidemia and hyperglycemia
Everolimus
History/Source
 Early, 2008 - Granted priority review by FDA for approval for treatment of advanced renal cancer
 September, 2008 – FDA granted priority review status
 A semisynthetic derivative of sirolimus (rapamycin) designated as RAD001 by Novartis
Chemistry
 Macrolide (macrocyclic lactone) skeleton
 Rapamycin derivative
o 42-O-(2-hydroxy)ethyl rapamycin
 Colorless solid
 No ionizable functional groups
 Water insoluble
O
H
CH3
O
O
H3C
O
OH
O
H
OCH3
H
H
OH
O
O
MACROCYCLIC
LACTONE
H3C
OH
H3C
H3CO
CH3
O
H3CO
CH3
CH3
EVEROLIMUS (CERTICAN)
Mechanism of Action
 Same as Temsirolimus
 Acts as an inhibitor of the enzyme mTOR (mammalian Target Of Rapamycin – a key regulatory kinase)
Common Application
 Renal carcinoma
 Late stage studies in patients who had failed standard treatment
o Extended the time without tumor growth to 4 months (from 1.9 months) and reduced the risk of
disease progression by 70%
Uncommon Route of Administration
 Once daily oral administration
Other
 Also used in Europe as an drug-eluting immunosuppressant (Xience V® - Abbott Vascular Products) to prevent
restenosis in coronary stents
 IND in USA and Japan
 Private label version called PROMUS Everolimus-Eluting Coronary Stent System available in most major
European and Asia-Pacific markets
Epothilones
Ixabepilone
History/Source
 A semisynthetic derivative of the polyketide macrolactone (macrolide) Epothilone B
 Introduced (FDA approved) in October, 2007
 The first of the epothilones, a new class of cytotoxic compounds
Source, Chemistry
 Epothilones were first isolated from a common soil myxobacterium, Sorangium cellulosum, in 1987
o Exhibited a narrow antifungal spectrum
o Too toxic for human use
 Three lead compounds were identified
o Epothilone A
o Epothilone B
o Epothilone D
Chemistry
 Ixabepilone is the macrolactam derivative of the
CH3
macrolactone Epothilone B
O
N
 No readily ionizable functional groups
CH3
H3C
H3C
o Lactam N atom is neutral
OH
S
H3C
CH3
o Thiazole N atom electrons are
N
delocalized in ring current and
H
CH3
unavailable for salt formation
O
O
OH
 Solubility is achieved via incorporation into
IXABEPILONE
solution in a mixture of
o Polyoxyethylated castor oil (52.8%)
o Dehydrated alcohol (39.8%)
Mechanism of Action - Epothilones
 Function similar to the taxanes
 Bind directly to the αβ-tubulin heterodimer subunit on microtubules
 Once bound, the rate of heterodimeric tubulin dissociation decreases ->-> stabilizes the microtubules ->->
inhibits microtubule depolymerization
 Antimitotic - blocks the metaphase -> anaphase step in mitosis
 Leads to apoptosis/cell death
 Low in vitro susceptibility to multiple tumor resistance mechanisms
 Binds in a unique manner to β-tubulin and appears to be active against taxane-resistant tumor cell lines
Common Application
 Combination with Capecitabine (Xeloda®) in the therapy of metastatic or locally advanced breast cancer patients
after failure of an anthracycline and a taxane
 Monotherapy of metastatic or locally advanced breast cancer in patients after failure of an anthracycline, a
taxane, and capecitabine
Special Adverse Effects
 Peripheral neuropathies, mainly sensory (20%)
Uncommon Route of Administration
 None
 Solubilizing diluent is a mixture of polyoxyethylated castor oil + dehydrated alcohol
Epothilone biosynthesis
 Thiazole ring
o L-Cysteine + AcetylCoA
 Macrolide ring
o Three malonate units; Five methylmalonate extender units
Incyclinide



A chemically modified tetracycline
o 4-dedimethylamino, 6-demethyl-6deoxytetracycline
Retains nonantibiotic properties that make it
useful in the therapy of diseases involving
o Inflammation (acute)
o Destruction of connective tissue
Clinical evaluations ongoing in patients
o Kaposi’s sarcoma
o Rosacea
o Acne
o Acute respiratory distress syndrome
7
H
6
5
H
4
OH
8
9
D
10
OH
C
11
O
B
12
A
3
2
NH2
1
OH
OH O
O
INCYCLINIDE (METASTAT)