Transcript Antileprotic drugs 抗麻风病药

Antimycobacterial drugs（抗结核
分枝杆菌药）
and
antileprotic drugs（抗麻风病药）
2011.12
Shanghai Jiao Tong University
Mycobacterium tuberculosis
亦称结核杆菌: 结核分枝杆菌（M.
tuberculosis), 牛分枝杆菌(M. bovis)
waxy coating
(primarily mycolic
acid)
M. tuberculosis bacterial colonies
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Mycobacterium tuberculosis (stained red) in tissue (blue)
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形态与染色
细长略带弯曲，分枝状，有荚膜，抗酸染色阳性
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Tuberculosis-related data
tuberculosis：lung, bone, kidney, intestine, lymph
node; tuberculous meningitis, …
One third of population infected (?) in the world,
with 70% in Asia
Two millions death each year
Chinese patients, 14.3%; Shanghai 5000/year; China
> 1.07 million/2009
World tuberculosis day：March 24, in memory of
the day when Robert Koch discovered the bacillus
in 1882. Nobel prize in 1905
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Therapeutic history
Before 1930’s：nutrition therapy：rest,
nutrition, fresh air, cure rate 25%
1930～1950’s： nutrition therapy + physical
therapy (artificial pneumothorax) , cure rate
40%
Drugs difficulty in entering the cells
1950’s：streptomycin, isoniazid, rifampicin；
cure rate >90%
21 century：multidrug resistance, TB
incidence ↑
The evolution of antitubercular agents
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The discovery of the
antitubercular activity
of aminoglycoside
antibiotics streptomycin
by Waksman et al in
1944 ushered in the
modern era of
tuberculosis
treatment.
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1952, p-amino-salicylic acid(PAS)
1952, isoniazid
Ethambutol
1959, rifampicin
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Anti-TB drugs
First-line drugs:
Isoniazid（异烟肼）
Rifampicin（利福平）
Ethambutol（乙胺丁醇）
Pyrazinamide（吡嗪酰胺）
Streptomycin（链霉素）
Second-line drugs:
Ethionamide（乙硫异烟胺）
Para-aminosalicylic acid（对氨水杨酸）
rifapentine（利福喷丁）
sparfloxaxcin（司帕沙星）
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Isoniazid
异烟肼
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isoniazid
discovered in 1912
1951, found to be effective against
tuberculosis
never used on its own because resistance
develops quickly
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Mechanism of isoniazid
Prodrug
activated by bacterial catalase（过氧化氢酶）peroxidase（过氧化物酶） enzyme called KatG
KatG couples the isonicotinic acyl with NADH（烟酰
胺腺嘌呤二核苷酸，辅酶I）
form isonicotinic acyl-NADH complex
complex binds tightly to ketoenoylreductase（酮烯
醇还原酶）
blocking the natural enoyl-AcpM substrate and the
action of fatty acid synthase （acyl carrier protein)
the process inhibits the synthesis of mycolic acid（分
枝菌酸）, required for the mycobaterial cell wall.
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Mechanism of action
InhA catalyzes the NADH-dependent reduction of 2-transenoyl-ACP’s and is involved in the biosynthesis of mycolic
acid, a critical component of the mycobacterial cell wall. This
enzyme is the target for the anti-tubercular drugs isoniazid
and ethionamide （乙硫异烟胺）
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Pharmacogenetic consideration
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Side effects of isoniazid
① Peripheral neuropathy（外周神经炎）；CNS
excitement
INH → Vit B6↓→ GABA↓→ CNS excitement
seen in slow acetylation，Vit B6 prevention
② hepatic injury
acetylated products—monoacetyl isoniazid（liver
toxic）
seen in rapid acetylation，hepatic function test
needed
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rifampicin（利福平）
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discovery of rifampicin
1957，soil from pine wood, French Riviera
Piero Sensi, Italy, found new bacterium
Researchers fond of French crime story
Rififi (about a jewel heist and rival gangs )
Named “Rifamycins”
1959, rifampicin discovered
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Actions and mechanism
Anti-bacterial spectrum：
 Mycobacterium tuberculosis;
Mycobacterium leprae （麻风分枝杆菌）
 Gram-positive and Gram-negative bacteria
 Cytochrome 450 inducer: CYP2C9 and
CYP3A4
Inhibitor of prokaryotic （原核） DNAprimed RNA polymerase
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Clinical uses of rifampicin
tuberculosis
leprosy
Infections caused by G+ or G－ bacteria
including resistant S. aureus
Trachoma（沙眼），Conjunctivitis（结膜炎）
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Side effects of rifampicin
Liver toxicity
Allergic reaction
Teratogenesis
Red metabolites appearing in feces,
urine, sweat, tear, sputum
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Ethambutol（乙胺丁醇）
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ethambutal
Mechanism: disrupting arabinogalactan（阿拉
伯半乳聚糖） synthesis by inhibiting the
enzyme arabinosyl transferase, leading to
increased permeability of the cell wall.
Side effect: optic neuritis（视神经炎）, dose
and time related
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Pyrazinamide（吡嗪酰胺）
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pyrazinamide
killing the bacteria inside the cells,
especially in acidic situation
Liver toxic (long term use)
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streptomycin
Listed in aminoglycosides （氨基糖苷
类）
Used when bacteria produce
resistance to other durgs
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Second-line drugs
Ethionamide（乙硫异烟胺）
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Para-aminosalicylic acid（对氨水杨酸）
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Rifapentine（利福喷丁）
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TB therapeutic principles
Early use
Combination therapy (always), usually
4 drugs
Enough doses, regular and long term
（６months or more)
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Why combination therapy
A major advance in the treatment of
tuberculosis was signaled by the introduction
of the antibiotic rifampin into therapy.
Clinical studies: rifampin is included in the
regimen, particularly in combination with
isoniazid and ethambutol (or pyrazinamide),
the period required for successful therapy is
shortened significantly( 6-9 months, 2 ys
without rifampin).
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Antileprotic drugs
抗麻风病药
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Morphology
staining
≈
tuberculosis
Biology of M. leprae
and
M.
Living
inside
the
cells——Leprosy cells
In
vitro
unsuccessful
culture
Previously vaccinated
in armadillo（犰狳）
Now in the naked mice
犰狳
Leprosy pathogenic data
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Spreading modes
• Respiratory tract（main）
• Direct contact
Slow onset, lasting long
Nerve and skin mainly invaded
6603 patients in 2009 in China
Distribution:云南、贵州和四川
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Drugs used for leprosy
Dapsone（氨苯砜）
Inhibiting bacterial synthesis of dihydrofolic acid of
Mycobacterium leprae
First choice in treating leprosy patients
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Thalidomide（沙利度胺）
Combined use with other anti-leprosy drugs
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>10000 baby in 46 countries
were born with deformities
1962 photo of a baby born to a mother who had taken
thalidomide while pregnant; note the extra appendage connected
to the foot and the malformation of the right arm.
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Frances Oldham Kelsey, MD, US FDA
inspector, pharmacologist
Refused FDA to approve
more study was needed
Richardson Merrell gave the tablets to
doctors on the understanding that the drug
was still under investigation
17 were born with the deformities
1962, US laws, safety test during pregnancy
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1962: FDA inspector Frances Oldham Kelsey receives an award from
President John F. Kennedy for blocking sale of thalidomide in the United
States
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阅读材料：Dover LG, Coxon GD.
Current status and research
strategies in tuberculosis drug
development. J Med Chem 2011;
54(18):6157-65
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Anti-fungal drugs
抗真菌药
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Dermatophytes（皮肤癣菌）
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Biology of fungus
Fungus: heterogeneous organisms（异养生
物） with eukaryotic and cell wall
300,000 kinds of fungi, only 270 of which
cause disease in humans and animals
Systemic fungal infections（深部感染）:
organ and tissue infections: Candida
albicans（白念珠菌）； Cuyitococcus
Neofonmans (新型隐球菌）；…
Topical fungal infections（表浅部感染）:
ringworm（癣）
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足癣
体癣
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体癣
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头癣
Fungal infections
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In recent
year, the incidence of fungal infections has reached
alarming proportions. This duo to a number of factors .
intensive uses of antibiotics
for bacterial infections
surgery operation and
organ transplant
Fungal
Infections
chemotherapy of cancers
immune systems diseses
such as AIDS
Development of anti-fungal drugs
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1903，Beurmann: potassium iodide for
Sporotrichosis（孢子丝菌病）
1939，griseofulvin（灰黄霉素） discovered
by British scientist
1950’s, nystatin（制菌霉素）; amphotericin B
（两性霉素B）
1960’s, azolee（唑类）：fluconazole（氟康
唑），itraconazole（伊曲康唑），…
2000’s, caspofungin（卡泊芬净）;
micafungin（米卡芬净），…
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Classification of anti-fungal drugs
based on mechanism and structure
Drugs affecting cell membrane: polyenes(多
烯类): amphotericin B, nystatin；azoles:
clotrimazole（克霉唑), fluconazole, …；
acrylamides: terbinafine（特比萘芬）;
Morpholines: amorolfines （阿莫罗芬）
Drugs affecting cell wall：echinocandins
（棘白菌素类）：caspofungin（卡泊芬净), …
Others: flucytosine（氟胞嘧啶）
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Mechanism of anti-fungal drugs
Mechanism of action
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Squalene
Epoxidase
Allyamines; Thioureas
Lanosterol
Azoles
Cytochrome
p
450
14
Demethyllanosterol
Ergosterol
Polyenes; Morphilines
Cell membranes
Grisofulvin
Mitosis( sliding of microtubules)
Cell nucles
Fluorocytosine
Nucleic acid
Drugs affecting fungus cell membrane
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Amphotericin B（两性霉素B）
Streptomyces nodosus in Venezuela in 1955.
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Mechanism of amphotericin B
Inhibiting synthesis of ergosterol（麦角甾
醇）, which forms a transmembrane channel.
Amphotericin B molecules can form pores in
the host membrane as well as the fungal
membrane.
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Actions and uses
Powerful, and wide anti-fungal and
antiprotozoan（抗原虫） activities
IV for fungal pneumonia(肺炎）, meningitis
（脑膜炎）, endocarditis（心内膜
炎）, …(critically ill, comorbidly infected or
immunocompromised patients)
Visceral leishmaniasis（内脏利什曼病）
Oral preparation for thrush（鹅口疮）
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Adverse drug effects
mammalian and fungal membranes: similar in
structure and composition—— basis of cellular
toxicity
severe and potentially lethal side effects
high fever, shaking chills, nausea, vomiting, …
long term use, nephrotoxicity(80%)
…
amphotericin B liposome:
fewer side-effects
similar efficacy
more expensive（1000元/瓶）
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amphotericin B
liposome:
fewer side-effects
similar efficacy
more expensive
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Ketoconazole（酮康唑）
1976, discovered
1981, approved
Oral anti-fungal drug after griselfulvin（灰黄霉素）
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Similar drugs
Itrazonazole（异曲康唑）
Fluconazole（氟康唑）
Clotrimazole （克霉唑）
Econazole （益康唑）
Miconazole（咪康唑）
…
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ketoconazole
cytochrome p450 14-alpha-demethylase
↓－
lanosterol（羊毛甾醇）→ ergosterol（麦角甾醇）
Clinical uses and adverse drug effects
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Systemic and topical
fungal infections
Hair loss
Liver toxicity;
Pregnancy category C
drug, animal test:
teratogenesis
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Terbinafine（特比萘芬）
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squalene epoxidase （角鲨烯单加氧酶）
↓
squalene→ lanosterol
mainly effective on the dermatophytes（皮肤癣
菌） group of fungi
antifungal drugs
for mucocutaneous infections
Drugs affecting cell wall
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Caspofungin 卡泊芬净
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Indications of caspofungin
fungal infections in febrile, neutropenic adult
patients
Invasive aspergillosis（曲菌病）in adult patients
whose disease is refractory to, or who are intolerant
of, other antifungal agents (i.e., conventional or lipid
formulations of amphotericin B and/or itraconazole).
Candidemia（白念株菌病） and Candida infections
(intra-abdominal abscesses, peritonitis, pleural
cavity infections and oesophagitis（食管炎）
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Other anti-fungal drugs
Flucytosine（氟胞嘧啶）
Indications: serious infections caused by
susceptible strains of Candida or Cryptococcus
neoformans
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Converted products interfering with RNA and DNA
biosynthesis
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阅读材料：Zhai B, Lin X. Recent
progress on antifungal drug
development. Curr Pharm Biotechnol
2011; 12(8):1255-62