Il bambino allergico ed i farmaci farmaci... · Ocular score during 3 years of open treatment with...

Nuovi aspetti terapeutici

Il bambino allergico ed i farmaci Firenze, 31 maggio – 1 giugno 2013

Neri Pucci SOD di Allergologia, AOU “A.Meyer”, Firenze

Nuovi farmaci “intelligenti”

Relovair

Dymista

Stemox

FK-506 e

plasminogeno

Nanocapsule

Relovair

http://www.faqs.org/sec-filings/100114/THERAVANCE-INC_8-K/

Fluticasone furoato

vilanterolo

Pulm Pharmacol Ther. 2013 Apr;26(2):256-64. Vilanterol trifenatate, a novel inhaled long-acting beta2 adrenoceptor agonist, in subjects with asthma and COPD.Kempsford R, Norris V, Siederer S.

Vilanterol produced a rapid and prolonged

bronchodilation over 24 h suggesting

the potential for once daily administration

Mean FEV1 profile (0–24h) following single dose VILANTEROL

Respir Med. 2013 Apr;107(4):550-9.

Fluticasone furoate/vilanterol (100/25; 200/25 μg) improves lung function in COPD: a randomised trial.

Martinez FJ, Boscia J, Feldman G, et al.

SourceUniversity of Michigan, Ann Arbor, MI, USA. fmartine@med.umich.edu

CONCLUSIONS: FF/VI provides rapid and significant sustained improvement in FEV1 in subjects with moderate-to-severe COPD, which was not influenced by the dose of FF. These data suggest that FF/VI may offer clinical efficacy in COPD and warrants additional study.

Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD Mark T Dransfield MD , et al.

InterpretationAddition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD in patients with a history of exacerbation, but was also associated with an increased pneumonia risk.

Volume 1, Issue 3, Pages 210 - 223, May 2013

Clin Transl Allergy. 2012 Jun 27;2(1):11..

Combined fluticasone furoate/vilanterol reduces decline in lung function following inhaled allergen 23 h after dosing in adult asthma: a randomised, controlled trial.Oliver A, Quinn D, Goldfrad C, van Hecke B, Ayer J, Boyce M.

CONCLUSIONS: FF 100 alone and in combination with VI 25 provides significant bronchoprotection in subjects with mild asthma. That this protection is provided at 23 h post last dose, supports the utility of FF 100 and FF/VI 100/25 as viable once-daily therapies.

Thorax. 2013 Jun;68(6):513-20. Safety and tolerability of the novel inhaled corticosteroid fluticasone furoate in combination with the β2 agonist vilanterol administered once daily for 52 weeks in patients >=12 years old with asthma: a randomised trial.Busse WW, O'Byrne PM, Bleecker ER, et al ED.

CONCLUSIONS: FF/VI (100/25 µg or 200/25 µg)

administered once daily over 52 weeks was well

tolerated by patients ≥12 years with asthma. The overall

safety profile of FF/VI did not reveal any findings of signifi-

cant clinical concern.

Clin Respir J. 2013 Apr 12. doi: 10.1111/crj.12026. Inhaled fluticasone furoate/vilanterol does not affect hypothalamic-pituitary-adrenal axis function in adolescent and adult asthma: randomised, double-blind, placebo-controlled study.

Allen A, Schenkenberger I, Trivedi R, et al

FF/VI was found to be non-inferior to placebo on HPA axis function, with no indication of significant cortisol suppression after 42 days.

… a new dry powder device ?

Relovair

Dymista

Stemox

FK-506 e

plasminogeno

Nanocapsule

Dymista

FLUTICASONE PROPIONATO AZELASTINA

Dymista : un farmaco intelligente

Dymista (azelastine hydrochloride and fluticasone propionate) Nasal Spray, 137 mcg / 50 mcg contains 0.1% solution of azelastine hydrochloride and 0.037% suspension of micronized fluticasone propionate in an isotonic aqueous suspension.

Meltzer E, et al. Int Arch Allergy Immunol 2013;161:369-77.

MP29-02

Relovair

Dymista

Stemox

FK-506 e

plasminogeno

Nanocapsule

Stemox

Conservante Antimicrobico a base di acido benzoico (sostanza particolarmente tossica). Ha proprietà batte-riostatiche e fungistatiche, ed è utilizzato come additivo alimen-tare (E211) come conservante

benzoato di sodio è il sale di sodio dell‘ acido benzoico

Wikipedia

AMOXICILLINA + Ac CLAVULANICO

Le formulazioni di questi farmaci contengono circa 178.6mg/100ml di sodio benzoato

Mori F, et al. Curr Drug Safety 2012;7:87-91.

Cutaneous Adverse Reactions to Amoxicillin-Clavulanic Acid Suspension in Children: The Role of Sodium Benzoate

n.89 bambini con rea- zione cutanea (esantema, orticaria) nell’ultimo anno dopo assunzione di Amoxicillina-Clavulanico

AMOXICLAV (8)

Na-BENZOATO (10)

AMOXICLAV + Na-Benz (3)

Cutaneous Adverse Reactions to Amoxicillin-Clavulanic Acid Suspension in Children: The Role of Na-Benzoate

tot 89

COMPOSIZIONE amoxicillina triidrato corrispondente a amoxicillina 400mg, potassio clavulanato = acido clavulanico 57mg

ECCIPIENTI gomma antano, aspartame, silice colloidle anidra, acido citrico anidro, silicio diossido, ipromellosa, aroma arancia, aroma lampone, aroma golden syrup

NO SODIO BENZOATO !

OPT : positivi con Na-benzoato e negativi con Amoxiclav

Relovair

Dymista

Stemox

FK-506 e

plasminogeno

Nanocapsule

FK-506 e plasminogeno

Cheratocongiuntivite Vernal severa

Papille giganti tarsali

Ulcera a scudo

9 8 7 6 5 4 3 2 1

T0 3wk

p = 0.35

TACROLIMUS

p < 0.001

CYCLOSPORINE

7days washout

Score oculare in 30 bambini con VKC grave trattati con tacrolimus e ciclosporina per via oculare. N.Pucci, Caputo R, L.Di Grande, C.De Libero, et al. AOU “A.Meyer”, Firenze

FARM6FYZB3

p < 0.001

p = 0.055

CYCLOSPORINE

TACROLIMUS

4wk 7wk

p<0.001

base 1-3mts end

3.32 ± 2.01 months2nd

p<0.001

155.14 ± 1.89 months

p=0.003

p=0.002 p=0.27

155.36 ±1.62 months

base 1-3mts end base 1-3mts end

Fig 3. Ocular score during 3 years of open treatment with Tcr eyedrops in 65 patients .(mean±SD). In red : no. of patientsp<0.001

1° year

2° year

p<0.001

E START 2-4 MONTHS

Numbers within columns = number of patients

p=0.001

Qualità di vita prima e durante il trattamento con tacrolimus per via oculare

Efficacia della ciclosporina per via oculare nella VKC

tacrolimus

87%100%

Efficacia del tacrolimus per via oculare nella VKC

AOU “A.Meyer”, 2013.

prima dopo 3 settimane

Taddio A, Cimaz R, Pucci N, et al. 2009

Associazione tra Vernal KC e Uveite anteriore ed efficacia del trattamento con tacrolimus oculare

LA CONGIUNTIVITE LIGNEA

• CONGIUNTIVITE MEMBRANOSA– MEMBRANE FORMATE

PREVALENTEMENTE DA FIBRINA

• ESTREMA GRAVITA’• PUO’ PORTARE ALLA PERDITA

FUNZIONALE E ANATOMICA DELL’OCCHIO

SEPTEMBER 2006

Caputo R, Pucci N, et al. 2009

LA CAUSA

• 1994 trovata associazione tra IPOPLASMINOGEMIA TIPO 1 E CONGIUNTIVITE LIGNEA

• GENE PLASMINOGENO 6q26-q27

MECCANISMO

PLASMINOGENO

PLASMINA

TPA UPA

FIBRINOLISI RIMODELLAMENTO TISSUTALE

FIBRINA CICATRICI

SEPTEMBER 2006

FIRST PATIENT• PLG EYE DROP

with Sodium Hyaluronate

• Surgery• No relapses• 5ys follow up

Caputo R, Pucci N,Mori F, Novembre E. Thromb Haemost

2008;100:1196-8

SECOND PATIENT• 5 prior surgeries• Bulbar pseudomembrane covering completely

the LEFT eye• US: endophthalmitis total retinal detachment

SECOND PATIENT• PLG DROPS WITH SODIUM

HYALURONATE BOTH EYES

1 WEEK TREATMENTLEFT EYE

SECOND PATIENT

• SURGERY

LEFT EYE

TAPERING FROM 8/DAY TO 4/DAY WORSENING OF CLINICAL SITUATION

STUDY PROTOCOL PLG EYE DROPS

4 WEEK TREATMENT

SURGERY

NOT SURGERY

8 WEEK TREATMENT

Relovair

Dymista

Stemox

FK-506 e

plasminogeno

Nanocapsule

Nanoparticelle 10-1000nm di polimeri legati da forze elettrostatiche contenenti farmaco che viene rilasciato

Possono essere aggiunti recettori senza alterare la struttura del farmaco

BioImpacts 2012;2:71-81.

Vantaggi dell’utilizzo di nanocapsule :

minima degradazione del farmaco

aumento della

biodisponibilità riduzione

del dosaggio fino a10.000 volte

minima tossicità

Nanocapsule : applicazioni

Pavankumar K. BioImpacts 2012;2:71-81.

GRAZIE PER L

’ATTENZIONE!

•FINE

Phase III study results

The companies presented top-line results from two Phase III studies comparing

Relovair over Advair in COPD treatment. Data from the first study showed superiority

of once daily Relovair over twice daily Advair on a pre-defined primary endpoint of 0-

24 hour weighted mean FEV1 (p<0.001) in COPD patients.

In the second study, Relovair demonstrated numerical improvements but not

statistical superiority over Advair on the 0-24 hour weighted mean FEV1 (p=0.267) in

COPD. In the 24-week Phase III registrational program (n=330) Relovair met the

primary endpoint of statistically-significant change from baseline in trough evening

FEV1 compared to placebo (p=0.009) in adults and adolescents with persistent

asthma. The most common adverse events were bronchitis, headache,

nasopharyngitis, upper respiratory tract infection, pharyngitis, and sinusitis

AMOXICLAV (8)

Na-BENZOATO (10)

tot 89

Nuovi aspetti terapeutici

Relovair

Dymista

Stemox

FK-506 e

plasminogeno

Nanocapsule

Relovair

Fluticasone furoato

vilanterolo

Pulm Pharmacol Ther. 2013 Apr;26(2):256-64. Vilanterol trifenatate, a novel inhaled long-acting beta2 adrenoceptor agonist, in subjects with asthma and COPD.Kempsford R, Norris V, Siederer S.

Vilanterol produced a rapid and prolonged

bronchodilation over 24 h suggesting

the potential for once daily administration

Mean FEV1 profile (0–24h) following single dose VILANTEROL

Respir Med. 2013 Apr;107(4):550-9.

Fluticasone furoate/vilanterol (100/25; 200/25 μg) improves lung function in COPD: a randomised trial.

Martinez FJ, Boscia J, Feldman G, et al.

SourceUniversity of Michigan, Ann Arbor, MI, USA. fmartine@med.umich.edu

CONCLUSIONS: FF/VI provides rapid and significant sustained improvement in FEV1 in subjects with moderate-to-severe COPD, which was not influenced by the dose of FF. These data suggest that FF/VI may offer clinical efficacy in COPD and warrants additional study.

Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD Mark T Dransfield MD , et al.

InterpretationAddition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD in patients with a history of exacerbation, but was also associated with an increased pneumonia risk.

Volume 1, Issue 3, Pages 210 - 223, May 2013

Clin Transl Allergy. 2012 Jun 27;2(1):11..

Combined fluticasone furoate/vilanterol reduces decline in lung function following inhaled allergen 23 h after dosing in adult asthma: a randomised, controlled trial.Oliver A, Quinn D, Goldfrad C, van Hecke B, Ayer J, Boyce M.

CONCLUSIONS: FF 100 alone and in combination with VI 25 provides significant bronchoprotection in subjects with mild asthma. That this protection is provided at 23 h post last dose, supports the utility of FF 100 and FF/VI 100/25 as viable once-daily therapies.

Thorax. 2013 Jun;68(6):513-20. Safety and tolerability of the novel inhaled corticosteroid fluticasone furoate in combination with the β2 agonist vilanterol administered once daily for 52 weeks in patients >=12 years old with asthma: a randomised trial.Busse WW, O'Byrne PM, Bleecker ER, et al ED.

CONCLUSIONS: FF/VI (100/25 µg or 200/25 µg)

administered once daily over 52 weeks was well

tolerated by patients ≥12 years with asthma. The overall

safety profile of FF/VI did not reveal any findings of signifi-

cant clinical concern.

Clin Respir J. 2013 Apr 12. doi: 10.1111/crj.12026. Inhaled fluticasone furoate/vilanterol does not affect hypothalamic-pituitary-adrenal axis function in adolescent and adult asthma: randomised, double-blind, placebo-controlled study.

Allen A, Schenkenberger I, Trivedi R, et al

FF/VI was found to be non-inferior to placebo on HPA axis function, with no indication of significant cortisol suppression after 42 days.

… a new dry powder device ?

Relovair

Dymista

Stemox

FK-506 e

plasminogeno

Nanocapsule

Dymista

FLUTICASONE PROPIONATO AZELASTINA

Dymista (azelastine hydrochloride and fluticasone propionate) Nasal Spray, 137 mcg / 50 mcg contains 0.1% solution of azelastine hydrochloride and 0.037% suspension of micronized fluticasone propionate in an isotonic aqueous suspension.

Meltzer E, et al. Int Arch Allergy Immunol 2013;161:369-77.

MP29-02

Relovair

Dymista

Stemox

FK-506 e

plasminogeno

Nanocapsule

Stemox

Conservante Antimicrobico a base di acido benzoico (sostanza particolarmente tossica). Ha proprietà batte-riostatiche e fungistatiche, ed è utilizzato come additivo alimen-tare (E211) come conservante

Wikipedia

Le formulazioni di questi farmaci contengono circa 178.6mg/100ml di sodio benzoato

Cutaneous Adverse Reactions to Amoxicillin-Clavulanic Acid Suspension in Children: The Role of Sodium Benzoate

n.89 bambini con rea- zione cutanea (esantema, orticaria) nell’ultimo anno dopo assunzione di Amoxicillina-Clavulanico

AMOXICLAV (8)

Na-BENZOATO (10)

tot 89

COMPOSIZIONE amoxicillina triidrato corrispondente a amoxicillina 400mg, potassio clavulanato = acido clavulanico 57mg

ECCIPIENTI gomma antano, aspartame, silice colloidle anidra, acido citrico anidro, silicio diossido, ipromellosa, aroma arancia, aroma lampone, aroma golden syrup

NO SODIO BENZOATO !

OPT : positivi con Na-benzoato e negativi con Amoxiclav

Relovair

Dymista

Stemox

FK-506 e

plasminogeno

Nanocapsule

FK-506 e plasminogeno

Cheratocongiuntivite Vernal severa

Papille giganti tarsali

Ulcera a scudo

9 8 7 6 5 4 3 2 1

T0 3wk

p = 0.35

TACROLIMUS

p < 0.001

CYCLOSPORINEC

7days washout

Score oculare in 30 bambini con VKC grave trattati con tacrolimus e ciclosporina per via oculare. N.Pucci, Caputo R, L.Di Grande, C.De Libero, et al. AOU “A.Meyer”, Firenze

FARM6FYZB3

p < 0.001

p = 0.055

CYCLOSPORINE

TACROLIMUS

4wk 7wk

p<0.001

base 1-3mts end

3.32 ± 2.01 months2n

p<0.001

155.14 ± 1.89 months

p=0.003

p=0.002 p=0.27

155.36 ±1.62 months

base 1-3mts end base 1-3mts end

Fig 3. Ocular score during 3 years of open treatment with Tcr eyedrops in 65 patients .(mean±SD). In red : no. of patientsp<0.001

1° year

2° year

p<0.001Q

RE START 2-4 MONTHS

Numbers within columns = number of patients

p=0.001

Qualità di vita prima e durante il trattamento con tacrolimus per via oculare

Efficacia della ciclosporina per via oculare nella VKC

tacrolimus

87%100%

Efficacia del tacrolimus per via oculare nella VKC

AOU “A.Meyer”, 2013.

prima dopo 3 settimane

Taddio A, Cimaz R, Pucci N, et al. 2009

Associazione tra Vernal KC e Uveite anteriore ed efficacia del trattamento con tacrolimus oculare

LA CONGIUNTIVITE LIGNEA

• CONGIUNTIVITE MEMBRANOSA– MEMBRANE FORMATE

PREVALENTEMENTE DA FIBRINA

• ESTREMA GRAVITA’• PUO’ PORTARE ALLA PERDITA

FUNZIONALE E ANATOMICA DELL’OCCHIO

SEPTEMBER 2006

LA CAUSA

• 1994 trovata associazione tra IPOPLASMINOGEMIA TIPO 1 E CONGIUNTIVITE LIGNEA

• GENE PLASMINOGENO 6q26-q27

MECCANISMO

PLASMINOGENO

PLASMINA

TPA UPA

FIBRINOLISI RIMODELLAMENTO TISSUTALE

FIBRINA CICATRICI

SEPTEMBER 2006

FIRST PATIENT• PLG EYE DROP

with Sodium Hyaluronate

• Surgery• No relapses• 5ys follow up

Caputo R, Pucci N,Mori F, Novembre E. Thromb Haemost

2008;100:1196-8

SECOND PATIENT• 5 prior surgeries• Bulbar pseudomembrane covering completely

the LEFT eye• US: endophthalmitis total retinal detachment

SECOND PATIENT• PLG DROPS WITH SODIUM

HYALURONATE BOTH EYES

1 WEEK TREATMENTLEFT EYE

SECOND PATIENT

• SURGERY

LEFT EYE

TAPERING FROM 8/DAY TO 4/DAY WORSENING OF CLINICAL SITUATION

STUDY PROTOCOL PLG EYE DROPS

4 WEEK TREATMENT

SURGERY

NOT SURGERY

8 WEEK TREATMENT

Relovair

Dymista

Stemox

FK-506 e

plasminogeno

Nanocapsule

Nanoparticelle 10-1000nm di polimeri legati da forze elettrostatiche contenenti farmaco che viene rilasciato

Possono essere aggiunti recettori senza alterare la struttura del farmaco

Vantaggi dell’utilizzo di nanocapsule :

minima degradazione del farmaco

aumento della

biodisponibilità riduzione

del dosaggio fino a10.000 volte

minima tossicità

GRAZIE PER L

’ATTENZIONE!

•FINE

Phase III study results

The companies presented top-line results from two Phase III studies comparing

Relovair over Advair in COPD treatment. Data from the first study showed superiority

of once daily Relovair over twice daily Advair on a pre-defined primary endpoint of 0-

24 hour weighted mean FEV1 (p<0.001) in COPD patients.

In the second study, Relovair demonstrated numerical improvements but not

statistical superiority over Advair on the 0-24 hour weighted mean FEV1 (p=0.267) in

COPD. In the 24-week Phase III registrational program (n=330) Relovair met the

primary endpoint of statistically-significant change from baseline in trough evening

FEV1 compared to placebo (p=0.009) in adults and adolescents with persistent

asthma. The most common adverse events were bronchitis, headache,

nasopharyngitis, upper respiratory tract infection, pharyngitis, and sinusitis

AMOXICLAV (8)

Na-BENZOATO (10)

tot 89

Il bambino allergico ed i farmaci farmaci... · Ocular score during 3 years of open treatment with...

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