Pharmacological & Clinical Aspects of Nadifloxacin
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Transcript of Pharmacological & Clinical Aspects of Nadifloxacin
A k F k l i & Kli iAspek Farmakologi & KlinisNadifloxacinNadifloxacin
Abraham SimatupangAbraham Simatupang
Bagian Farmakologi FK UKI
Isi:Isi:
• Aspek Farmakologik (FarmakokinetikAspek Farmakologik (Farmakokinetik, Farmakodinamik)
• Aspek Farmakoterapi (Uji klinik)• Aspek Farmakoterapi (Uji klinik)
Dose of Drugadministered
Absorption Distribution
cokine
tics
Drug concentration in systemic circulation
Dose in tissuesof distribution
Pharmac
Drug concentration t it f ti
Drug metabolised or excreted
at site of actionElimination
amics
Pharmacologic effect
Clinical response rmacod
yna
Toxicity Efficacy
Pha
k difl i
Report No. 005434. Study No. 006650. Pharmacokinetics and safety evaluation of OPC‐7251 cream after topical Application in healthy volunteers.
Struktur Nadifloxacin
Termasuk fluorokuinolon topikal yang menghambat konfigurasi supercoiledDNA dengan menghambat DNA‐gyrase.
Spektrum‐luas terhadap bakteria Gr+, termasuk coagulase‐negative Staph. Spp danPropionibacterium acnes et granulosum.
Kadar obat dalam plasma
Ek i l t iEksresi lewat urin
Absorption, distribution and excretion of 14C‐labeled OPC‐7251 l ti i t7251 lotion in rats (Fujio N et al. Jpn Pharmacol Ther 1998; 26: 1119‐ 32)
Percutaneus application:Percutaneus application: • kulit normal: 7.4 mg/kg (rat), Cmax = 36 ng.eq/mL dan menghilang 4 jam kemudianng.eq/mL dan menghilang 4 jam kemudiandengan T½el. = 1.3 jam
• Stripped skin: Cmax = 1416 ng.eq/mL , TmaxStripped skin: Cmax 1416 ng.eq/mL , Tmax20 menit dan menghilang dalam waktu 4 jam dgn T½el. = 1.5 jam.
• Bila diberikan berturut‐turut 7 hari, kadar danpola di hari 1 dan 7 identik.
Kadar radioaktifitas OPC‐7251Kadar radioaktifitas OPC 7251
Mekanisme kerjaMekanisme kerja
• Antibiotika (menghambat DNA‐gyrase)Antibiotika (menghambat DNA gyrase)
• Berpengaruh terhadap sitokin (Kuwahara et al. J. Dermatol. Sci., 38, 47‐55 2005 2005):Dermatol. Sci., 38, 47 55 2005 2005):
1. Inhibits the up-regulation of IL-12 and IFN-γ in PBMC stimulated by P. acnes.
2. Inhibits pro-inflammatory cytokine productions by epidermal keratinocytes stimulated with IFN-γ plus IL-1β.
A ti d i ti it f difl i• Anti‐androgenic activity of nadifloxacin (Inui, S. et al.:J. Dermatol. Sci., 36, 97‐101, 2004).
Effects of nadifloxacin on the production of cytokines by Inhibition of Cytokine Production in vitro
heat-killed P. acnes-treated PBMC in vitro
○: Control ●: Nadifloxacin(NDFX)
IL-1α
5
10
15
20 IL-1β
48
121620
ntra
tion
IL-6
2468
10
○: Control ●: Nadifloxacin(NDFX)
0 0
mR
NA
con
cen
ndar
d)
0
IL-8
10
20
30
40 IL-10
10
20
30
40 IL-12 p40
100200300400500
Rel
ativ
e m
(% o
f sta 0 0 0
100
IFN-γ
5
10
15 TNF-α
102030405060 GM-CSF
5
10
15
20
00 4 8 12 16 20 24 0
10
0 4 8 12 16 20 24
Hours after P. acnes stimulation
00 4 8 12 16 20 24
▪ Cytokine productions were up-regulated by the treatment of PBMC with heat-killed P. acnes.Nadifloxacin inhibited the production of IL 12p 40 and IFN γ▪ Nadifloxacin inhibited the production of IL-12p 40 and IFN-γ.
▪ Nadifloxacin did not inhibit IL-1α and TNF-α production.
Kuwahara, K. et al.:J. Dermatol. Sci., 38, 47-55, 2005
Effects of nadifloxacin on the production of cytokines by Inhibition of Cytokine Production in vitro
heat-killed P. acnes-treated PBMC in vitro
○: Control ●: Nadifloxacin(NDFX)
IL-1α
5
10
15
20 IL-1β
48
121620
ntra
tion
IL-6
2468
10
○: Control ●: Nadifloxacin(NDFX)
0 0
mR
NA
con
cen
ndar
d)
0
IL-8
10
20
30
40 IL-10
10
20
30
40 IL-12 p40
100200300400500
Rel
ativ
e m
(% o
f sta 0 0 0
100
IFN-γ
5
10
15 TNF-α
102030405060 GM-CSF
5
10
15
20
00 4 8 12 16 20 24 0
10
0 4 8 12 16 20 24
Hours after P. acnes stimulation
00 4 8 12 16 20 24
▪ Cytokine productions were up-regulated by the treatment of PBMC with heat-killed P. acnes.Nadifloxacin inhibited the production of IL 12p 40 and IFN γ▪ Nadifloxacin inhibited the production of IL-12p 40 and IFN-γ.
▪ Nadifloxacin did not inhibit IL-1α and TNF-α production.
Kuwahara, K. et al.:J. Dermatol. Sci., 38, 47-55, 2005
Effects of Roxithromycin and Nadifloxacin (in vitro)
English version
Effects of Roxithromycin and Nadifloxacin (in vitro)
1.25 1.5
n=3Mean±S.D.*p<0.05
1.25
1
* n=3Mean±S.D.*p<0.05
1.5
1
*
t-test0.75
0.5
RLU t-test
1
0 5
RLU
0.25
0
4
0.5
0
Roxithromycin
R1881
0
0
0 1 5
1nmol/L
μg/mL
1 2 3 4 0
1 2 3 4 5 6
Nadifloxacin
R1881
0
0
0 1 5
1nmol/L
μg/mL10 50
R1881: synthetic androgen
Inui, S. et al.:J. Dermatol. Sci., 36, 97-101, 2004
Topical quinolone nadifloxacin (OPC‐7251) in bacterial skin disease: clinical evaluation in a multicenter open trial and in
vitro antimicrobial susceptibility testing(J Dermatologic Treatment 1997; 8: 87‐92)
• Desain: Open phase II pilot study, melihat efikasi dantolerabilitas nadifloxacin pada infeksi kulit superfisial.
• 101 pasien (70 pria 31 wanita) usia: 18 65 tahun• 101 pasien (70 pria, 31 wanita), usia: 18‐65 tahundirekrut dari 9 center. 9 DO, 2 dikeluarkan krnmenyalahi protokol.
• Kriteria inklusi: folikulitis/sycosis vulgaris, impetigo contagiosa, impetiginized dermatitis (mis. atopic dermatitis) atau ada gejala‐gejala: sekurang‐kurangnyadermatitis) atau ada gejala‐gejala: sekurang‐kurangnya5 lesi/krusta, eritema sedang s.d. berat, moderate to severe scaling, moderate to severe erosion and
llswelling.
• Infeksi kulit sekunder: mengandung 3 dari 5 g ggejala: moderate to severe erythema, moderate to severe scaling, moderate to severe exudation, moderate to severe erosion moderate to severemoderate to severe erosion, moderate to severe swelling.
• Kriteria eksklusi: folikulitis berat, sycosis vulgaris, impetigo contagiosa, dan infeksi kulit ygmemerlukan ab sistemik. Alergi terhadapkuinolon alkoholismus atau drug‐abusekuinolon, alkoholismus atau drug abuse.
• Obat uji: Nadifloxacin 1% topical cream (Otsuka, Japan)
Causative bacteria classified by diagnosisCausative organism
Number of patients
FolliculitisaSuper‐infected dermatitis
Impetigo SycosisSecondarily infected wound
Staph. aureus 22 7 2 8 1 4
β‐hemolytic streptococci
2 1 1
Staph aureus+ streptococci
2 1 1
Coagulase‐negative 47 33 3 4 7negative staph
47 33 3 4 7
P. acnes 1 1
P gran lat mP. granulatum 1 1
Total 75 42 5 14 8 6
a: one patient with a furuncle was included in folliculitisp
Lesions & crusts counting per patient before and after t t t ith difl itreatment with nadifloxacin
Number of patients Lesions (mean) Crust (mean)
P t t t 82 15 87 6 45Pre‐treatment 82 15.87 6.45
Post‐treatment 81 5.70 2.10
P‐value <0.0001 <0.0001
Global assessment of therapeutic effect by physician and patients
Global assessment
Very good Moderate Slight Unchanged Aggravated
and patients
By physician
51 (56.7%) 28 (31.1%) 8 (8.9%) 2 (2.2%) 1 (1.1%)
By patient 50 (57%) 26 (30%) 9 (10%) 1 (1%) 2 (2%)By patient 50 (57%) 26 (30%) 9 (10%) 1 (1%) 2 (2%)
Judgment of objective symptoms pre‐ and after treatment with nadifloxacin
Symptom Not present
Mild Moderate
Severe Total P‐value
ErythemaPre‐treatment 0 0
52 (57.8%)
38 (42.2%) 90
<0 0001(100%)
<0.0001
Post‐treatment28
(31.1%)49
(54.4%)13
(14.5%)0
ScalingPre‐treatment
14 (15.6%)
26 (28.9%)
39 (43.3%)
11 (12.2%) 90
0 000190
(100%)<0.0001
Post‐treatment64
(71.1%)25
(27.8%)1
(1.1%)0
ExudationPre‐treatment 0 9 (10%)
57 (63.3%)
24 (26.7%) 90(63.3%) (26.7%) 90
(100%)<0.0001
Post‐treatment61
(67.8%)24
(26.7%)4 (4.4%)
1 (1.1%)
ErosionPre‐treatment
3 (3 3%)
5 (5 6%)
56 (62 2%)
26(28 9%)(3.3%) (5.6%) (62.2%) (28.9%) 90
(100%)<0.0001
Post‐treatment66
(73.3%)21
(23.3%)3
(3.3%)0
SwellingPre‐treatment
7 16 49 18 Pre treatment
(7.8%) (17.8%) (54.4%) (20%) 90 (100%)
<0.0001
Post‐treatment60
(66.7%)22
(24.4%)8
(8.9%)0
Eradication of causative organismEradication of causative organism
Causative organismNumber of strains Eradicated/total
(%)Before treatment After treatment
Staph. aureus 24 420/24 (83%)
β‐hemolytic 4 04/4 β hemolytic
streptococci 4 0/
(100%)
Coagulase‐negative staph 47 15
32/47(68%)
P. acnes 1 10/1(0%)
P granulatum 1 01/1
P. granulatum 1 0(100%)
Total 77 2057/77 (74%)
Number of bacterial strains inhibited at the concentrations of nadifloxacin shown comparing pre & post treatment
Organism MIC (μg/ml)
<0.05 0.1 0.2 0.39 0.78 1.56 3.13 6.25 12.5 50 ≥100 Total
Staph Pre 20 3 1Staphaureus
Pre‐th/
20 83%
313%
14%
24
Post‐th/
583%
117%
6
β‐hemolytic streptococci
Pre‐th/ 1
25%2
50%1
25%4
P 1 1Post‐th/
150%
150%
2
Coagulase‐negstaph
Pre‐th/
4671%
1117%
11%
35%
11%
35%
65staph
Post‐th/
4066%
1321%
12%
12%
35%
23%
12%
61
P acnesPre‐ 3 6 14 8 3
34P. acnesth/ 9% 18% 41% 24% 9%
34
Post‐th/
1020%
1326%
1428%
1224%
12%
50
Effect of nadifloxacin on atopic dermatitis with methicillin‐resistant staphylococcus aureus in young p y y g
children (Kimata H. Eur J Pediatr 1999; 158: 949‐54)
• Desain open label parallel group pada 35Desain open label, parallel group, pada 35 anak (20 laki, 15 perempuan) usia 2‐11 bulan.
• Control (n=17): NSAID ointment (bufexamac)• Control (n=17): NSAID‐ointment (bufexamac) 3 dd 1
N difl ( 18) N difl i b f• Nadifl. (n=18) : Nadifloxacin + bufexamac3 dd 1
Effect of nadifloxacinEffect of nadifloxacin
GSkin culture Skin score Anti‐SEA IgE Anti‐SEB IgE
GroupBefore After Before After Before After Before After
Control 17/17 17/17 19 ± 5 18 ± 4 0.5 ± 0.3 0.6 ± 0.4 0.7 ± 0.4 0.8 ± 0.4
Nadifloxacin 18/18a 0/18b 20 ± 4c 9 ± 3d 0.6 ± 0.4e0.3 ±0.1f
0.8 ±0.3c
0.3 ± 0.1d
* Number of patients with MRSA/total number of patients are shownSkin score, anti‐SEA IgE and anti‐SEB IgE (OD 410 mm) are expressed as mean ± SDa versus b p < 0.0001 (paired sign test)c versus d p < 0.0001 (paired t‐test)e versus f p < 0.001 (paired t‐test)e versus f p < 0.001 (paired t test)
Tidak ditemukan adverse events: Articular cartilago formationTidak ditemukan kelainan darah dan urinTidak ditemukan induksi fluoroquinolone‐resistant bacteria Follow‐up 3 bulan: tdk ditemukan MRSA
Mechanisms of Nadifloxacin in Acne Vulgaris
Open comedon
Micro comedon Closed comedon Inflammatorylesions
N t hil /
Sebumsecretion Keratinization
Neutrophils/Lymphocytes/Keratinocytes
NDFX
P. acnesCytokines
IL‐1αAndrogen
Inflammatory/Immuneresponse to P acnesresponse to P. acnes(CD4+ T, MΦ, Keratinocyte)
Dr.med. Abraham Simatupang, MKes.Email: [email protected]