Treatment of Cough Newly developed Antitussive and

Expectorant Drug

Young Joo Cho Division of Allergy and Clinical Immunology

Department of Medicine Ewha Womans University Mokdong Hospital

Cough?

• Physiologic cough

• Pathologic cough

Why does cough patient visit a doctor?

Adverse Occurrence Frequency, % Adverse Occurrence Frequency, %

Needs reassurance nothing is serious

77 Dizziness 21

Concerned something is wrong 72 Excessive sweating 21

Frequent retching 56 Achiness 21

Exhaustion 54 Hurts to breathe 16

Others think something is wrong with me

53 Stopped going to movies 16

Embarrassment 49 Headaches 14

Self-consciousness 46 Fear of AIDS or TB 13

Difficulty speaking on the telephone 39 Concern of cancer 11

Hoarseness 39 Absences from school or work 11

Had to Change lifestyle 36 Lost appetite 11

Cannot sleep at night 34 Sick to stomach or vomiting 11

Can no longer sing in church 31 Soiling of pants 8

Spouse cannot tolerate cough 30 Broken ribs 8

Wetting pants 30 Lost job 5

Concerned something is seriously wrong

28

Psychosocial impact of cough : Adverse symptoms associated with cough

Lung (2008) 186 (Suppl 1):S55–S58

Physical Psychological Social

Syncope Depression Relationship tensions

Vomiting Anxiety Fear of public places

Chest pains Embarrassment Avoidance of social events

Hoarse voice Fear of serious illness Interference with work

Headache Frustration Interrupt telephone calls

Incontinence Interrupt meals

Hernia

Sleep deprivation

Lethargy

Psychosocial impact of cough

CES-D score: Center for Epidemiological Studies -Depression scale (score ‡ 16 indicates significant depressive symptomatology and risk for clinical depression)

Depressive symptomatology is very common in patients with chronic cough

Lung (2008) 186 (Suppl 1):S55–S58

AsthmaChronic

cough

COPDHF

DiabetesIHD

Hypertension

0

10

20

30

40

50

60

Patients(%) with CES-D Score>16

Etiology of cough

Upper airway cough syndrome Asthma GERD COPD Respiratory tract infection ACE inhibitors Chronic bronchitis Bronchiectasis Lung cancer Nonasthmatic eosinophilic bronchitis Foreign body Tuberculosis especially endobronchial tuberculosis Miscellaneous Chronic aspiration , Vocal cord dysfunction Chronic granulomatous inflammation Bronchogenic carcinoma DILD

Duration of Cough

3 wks 8 wks

Acute Chronic Sub-Acute Chronic

Acute cough

• Common cold

• Allergic rhinitis

• Acute bacterial sinusitis

• Exacerbation of chronic obstructive pulmonary disease

• Bordetella pertussis infection

Subcute cough

• Postinfection

• B. pertussis infection

• Subacute bacterial sinusitis

• Asthma

Chronic cough • Post nasal SD • Nonallergic rhinitis • Allergic rhinitis • Chronic bacterial sinusitis • Asthma • GE reflux • Chronic bronchitis • Angitensin-converting enzyme inhibitors • Eosinophilic bronchitis

Causes of chronic cough

Irwin et al. Am Rev Respir Dis 1990;141:640-647

100

50

0

PND Asth GER Chr. Bronch

Bron- chiect

MISC PND Asthma +/or GER

41%

24% 21%

5% 4% 5%

86%

Psychogenic cough

• Not frequent as diagnosed by doc. • 23% :misdiagnosed

• Consequence of the cough itself

• No specific symptoms • Daytime cough without night cough(?)

• GERD

• Chronic bronchitis

• Barking cough(?) • Other organic problem

Refractory idiopathic cough

• Very small portion • No response to specific treatment • Require nonspecific antitussive therapy

• Dextromethorohan • Ipratropium bromide • Narcoics

• Other trial • Baclofen • Nebulized anesthetics

PATHOPHYSIOLOGY OF COUGH TREATMENT OF COUGH

Mangement of Cough

Common pitfall..

Failing to consider that more than one…. Failing to consider that another obvious

cause

Diagnostic work up

• Repeating diagnostic evaluations

• Reinterpreting diagnostic results

Clinical features and Treatment of common conditions

History Treatment

Smoking-related

cough

Typically productive morning cough

>3 months per year for more than 1 year.

History of smoking

Stop smoking. Remove other potential

irritants

ACE cough Cough onset often, but not always

temporarily related to starting ACE

inhibitor

Drug withdrawal. Substitution with

alternative if appropriate

Eosinophilic airway

diseases

Nocturnal cough, cough after exercise in

asthma. Wheeze might be heard in

asthma

Inhaled corticosteroid.

Prednisolone 30 mg

daily for 14 days in selected cases.

Bronchodilator therapy for asthma

Rhinitis

Rhinorrhoea, nasal obstruction, sinus

pain,

sneezing, nasal itch, postnasal drip

Topical corticosteroid. In selected cases:

topical ipratropium bromide 40 μg twice

daily, oral antihistamine

Gastro-oesophageal

Reflux

Heartburn, flatulence, water brash.

Cough

might be the only manifestation

Weight reduction, raising of head in bed,

avoid eating within 2 h of bedtime, acid

suppression with PPI. Prokinetic agent in

selected cases

Postinfection Onset after viral upper respiratory tract

infection

Observation

Treatments of cough

• Treating the Specific Underlying Cause

• Symptomatic Treatment

Peripheral antitussive : theobromine, levodropropizine

Opiates: Codeine (15 mg qid), morphine

Non-narcotic: Dextromethorphan (Romilar® ) 15 mg qid

Ipratropium bromide (2-4 puffs qid)

; inhibiting the efferent limb of the cough reflex

• Cough receptor (shown in red color)

Thorax Extrathorax

Trachea Bronchi Pleura Diaphragm pericardium

Nose Sinus Pharynx Larynx Stomach Outer ear

Location of cough receptors

Interaction between causes and cough pathway

Causes

URTI GERD Eosinophil-associated ACE inhibitor Rhinosinusitis COPD

Cough afferent pathways

Airway inflammation Tissue remodelling

Enhanced cough reflex

Chronic cough

Triggers URTI Pollutants Mucus secretion Deep breath Acute cough

(self-limiting)

Opiates Dextomethorphen Baclofen Nociceptin CB2 agonist NK1-3 antagonist

A Fibre C Fibre Lidocaine RSD931

Lidocaine Opiates(?) Naciceptin CBT agonist

Smooth muscle contraction Edema Mucus secretion Acid reflux

2-agonist LK antagonist Glucocorticoids Muscarinic antagonist NK1-3 antagonist

Cough Reflex and sites of action of antitussive medication

Postinfectious cough

Dexbrompheniramine + pseudoephedrinc

Ipratropium puff

1-3wks

1 wk

steroid tapered 2-3wks

Central antitussive

New product: AG NPP 709

Antitussive and Expectorant

Synergistic effect of α-hederin and Berberine

Synergy of …….. 아이비엽 황련

α-hederin Berberine

Synatura

Endocytosis 억제

ß2 adrenergic 자극 증가

cAMP 증가

Synatura Mechanism

Ivy leaf ext 약리작용

α-hederin 효과

점액 점성을 낮춤 기침 억제 작용 기관지 이완작용

Secretolytic cough-

relieving spasmolytic

Berberine 효과

기관지 확장 효과 Tachykinin NK1, NK2 5-LO 억제

PDE4억제 염증인자 억제

Berberine : Newly Developed Anti-Inflammatory Natural Product

▪ A quaternary ammonium salt from the group of isoquinoline

alkaloids

Found in such plants as Berberis, goldenseal (Hydrastis

canadenis), and Coptis chinensis in the roots, rhizomes, and

stem bark

A bitter-tasting, yellow, plant alkaloid with a long history of

medicinal use in Chinese and Ajurvedic medicine

Plants as a source of berberine Berberis…쌍떡잎식물.. “깽깽이 풀”

Goldenseal

Dried root Chinese golden thread(황련)

Traditional use of berberine

▪ Alcoholic liver disease, liver disease

▪ Antibacterial activity against bacteria, viruses, fungi,

protozoans/ UTI / yeast infection/ Eye infection

▪ Cancer, leukemia

▪ Cardiovascular disease, high blood pressure, leukopenia

▪ Dental condition and dental hygiene

▪ Fatigue, fever, headache, IBS

▪ Osteoporosis

▪ Respiratory disorder

▪ Skin disorders

Newer and experimental uses

• Activity against fungal infections, candida albicans, yeast, parasites, and bacterial/viral infections.

• Possible use against MRSA infection. • A component of some eye drop formulations.

• There is some evidence it is useful in the treatment of traucoma

• Prevents and suppresses proinflammatory cytokines, E-selectin and genes,

• Increases adiponectin expression which partly explains its versatile health effects.

• A nucleic acid-binding isoquinolone alkaloid with wide potential therapeutic properties

Evidence-based medicine on berberine :

▪ Heart failure (Grade B)

▪ Chloroquine-resistant malaria (Grade C)

▪ Diabetes (type 2) (Grade C)

▪ Glaucoma (Grade C)

▪ H. pylori infection (Grade C)

▪ Hypercholesterolemia (Grade C)

▪ Infectious diarrhea (Grade C)

▪ Parasitic infection (leishmania) (Grade C)

▪ Thrombocytopenia (Grade C)

▪ Trachoma (Grade C)

GANGNAM

Severance

In Vitro and Vivo Experiment

Expectorant Anti-inflammatory

Experimental study in Korea

Effects of Baicalein, Berberine, Curcumin and Hesperidin on Mucin Release from Airway Goblet Cells

• Pharmacology Planta Med 2003; 69(6): 523-526

• Choong Jae Lee1, Jae Heun Lee1, Jeong Ho Seok1, Gang Min Hur1, Yang Chun Park2, In Chan Seol2, Yun Hee Kim2

• Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon, Korea 2 Department of Oriental Medicine, College of Oriental Medicine, Daejeon University, Daejeon, Korea

• Abstract ; Baicalein, berberine, curcumin and hesperidin are the major components derived from Scutellaria baicalensis, Coptis japonica, Curcuma longa and Poncirus trifoliata, respectively. These plants have been used for the treatment of diverse chronic inflammatory diseases including respiratory disease in oriental medicine and their respective major components were reported to have various biological effects including anti-inflammatory activity. In the present study, we investigated whether these four natural products affect mucin release from airway goblet cells and compared the possible activities of these agents with the inhibitory action on mucin release by PLL and the stimulatory action by ATP. Confluent primary hamster tracheal surface epithelial (HTSE) cells were metabolically radiolabeled using 3H-glucosamine for 24 h and chased for 30 min in the presence of varying concentrations of each agent to assess the effects on 3H-mucin release. The results were as follows: (i) baicalein did not affect mucin release significantly; (ii) berberine, curcumin and hesperidin increased mucin release at the highest concentration (10 - 4 M); (iii) PLL inhibited and ATP increased mucin release.

• We conclude that berberine, curcumin and hesperidin can increase mucin release by directly acting on airway mucin-secreting cells and suggest that

these agents be further studied for possible use as mild expectorants during

Expectorant assay on phenol red secretion in mice’s tracheas

Aim: To examine expectorant effect

Method: 2.5% phenol red, injection i.p. (0.2 ml/10 g)

sacrifice 30 min after phenol red injection

dissection of trachea

0.1 mL NaOH (1 mol/L), check O.D. (570 nm)

▶ 효력시험

normal

NPP709 - 400mpk

occlusion of

air way

inflammatory cell filtration

NC

montelukast- 30mpk

• in vivo 기도 개형 억제 - OVA induced murine airway remodeling model

Lung bronchiole histopathology

The cysteinyl leukotriene1 (CysLT1) receptor antagonist montelukast significantly

reduced the airway eosinophil infiltration, mucus plugging, smooth muscle hyperplasia, and subepithelial fibrosis in the OVA sensitized/challenged mice.

• in vitro mechanism studies (100 µg/ml ,% inhibition)

0 20 40 60 80 100 120

Lipoxygenage 5-Lo

Matrix metalloproteinase-2(MMP-2)

Matrix metalloproteinase-9(MMP-9)

Phosphodiesterase4(PDE4)

Adenosine A1

Adenosine A2

Adenosine A3

Histamine H1

Leukotriene BLT(LTB4)

Leukotriene Cysteinyl CysLT1

Platelet Activating Factor(PAF)

Prostanoid Thromboxane A2

Tachykinin NK1

Tachykinin NK2

Tachykinin NK3

Vanilloid

황련 약리작용

in vitro mechanism studies (100 µg/ml ,% inhibition)

▶ 기전연구 물리,화학적 자극

APC

T cell

Mast cell

Membrane phospholipids

Arachidonic acid

Prostaglandin H2

Thromboxane (TXA2 )

5-LO

Leukotriene A4

Leukotriene B4 Leukotriene C4

Leukotriene D4

Leukotriene E4

Mediator release

: Histamine

Tryptase

Prostaglandins

PAF

Cytokines

Eosinophil

Inflammatory mediators

MMP-2

MMP-9

Smooth muscle cell

Proliferation

Smooth muscle cell

Contraction

Sensory nerve activation

Tachykinin NK1

Tachykinin NK2

CysLT1

Receptor

PDE4

Adenosine A3

PDE4

AMP

Adenosine

Antitusssive effect of berberine as PDE4 inhibitor

berberine

신약의 개발경위 및 과정

천연싞약물 5호

허가신청자료_개발경위

1. 개발목적

: 호흡기질환에 사용될 우수하고 안전핚 신규 천연물신약 개발

2. 개발경위

1) 기성핚약서 및 전래처방을 바탕으로 호흡기계 질환에 유의하게 작용핛 것으로 예상되는 300여종의 1차 후보생약 선별.

2) 각종 과학 journal에 보고된 생리활성 및 임상자료 검토, 양질의 원료생

약 수급 안정성을 고려하여 30여종의 2차 후보생약 선별.

3) 항히스타민, Hyaluronidase 억제, 항산화 및 항균시험 등 진해, 거담활

성 관렦 Screening을 통해 12종의 후보생약 선정.

4) 가장 높은 시너지 활성을 보인 AG NPP709 선정

cough 1 cough 2

cough 3

Antitussive assay on citric acid-induced

cough in guinea pigs

페놀 레드 배출 정도 (mean±SEM), PC (ambroxol, 250mpk), 시험군 (Ivy:황련, 200mpk)

*p <0.05 , **p<0.01, ***p<0.001

▶ 최종 선정 생약 2종의 비율별 활성비교 (in vivo 거담활성)

AG NPP 709

황련수포화부탄올·아이비엽30%에탄올건조엑스

개발 경위_처방 근거(최적 처방 연구)

페놀 레드 배출 정도 (mean±SEM), PC (ambroxol, 250mpk), 후보생약 (500mpk)

*p <0.05 , **p<0.01

▶ 3차 후보생약으로 선정된 12종 생약의 in vivo 거담활성

개발 경위_처방 근거(거담활성)

기침수 억제 정도 (mean±SEM), PC (theobromine, 50mpk), 후보생약 (200mpk)

*p <0.05 , **p<0.01

▶ 거담활성 우수 5종 생약의 in vivo 진해활성

개발 경위_처방 근거(진해활성)

• in vivo 진해 활성 – guinea pig model • in vivo 거담 활성 – mouse model

기침수 억제 정도 (mean±SEM)

*p <0.05, **p <0.01, ***p <0.001

페놀 레드 배출 정도 (mean±SEM)

*p <0.05 , **p<0.01, ***p <0.001

Berberine Theobromine Berberine Ambroxol

▶ 효력시험

비임상시험 결과

페놀 레드 배출 정도 (mean±SEM), PC (ambroxol, 250mpk), 후보생약 (1:1, 500mpk)

*p <0.05 , **p<0.01

▶ 5종 활성생약의 혼합(총 10가지 경우의 수)에 의한 시너지 활성 비교 (in vivo 거담활성)

개발 경위_처방 근거(활성 Synergy 확인)

IVY + 황련

▶ 시너지 활성 확인 (Dose response)

• in vivo 진해 활성 • in vivo 거담 활성

기침수 억제 정도 (mean±SEM)

PC (theobromine, 50mpk)

*p <0.05, **p <0.01, ***p <0.001

페놀 레드 배출 정도 (mean±SEM)

PC (ambroxol, 250mpk)

*p <0.05 , **p<0.01, ***p <0.001

개발 경위_처방 근거(활성 Synergy 확인)

국내 3상 임상시험

Contents

▣ Clinical Development

▣ 임상시험용 의약품

▣ Study Design(Phase III)

▣ 유효성평가

▣ 안전성 평가

▣ Summary

시험제목 급성 상기도감염 혹은 염증성 만성 기관지염 홖자에서 시네츄라의 안전성

과 유효성을 평가하기 위한 치료적 확증 목적의 임상시험

시험방법 Double blinded, Randomized, Placebo and active drug comparative,

Parallel designed study

피험자수

- 목표피험자수 : 236명

-ITT (Intention to treat) 분석 대상자수 : 235명 (시:대 = 118:117)

- PP (Per Protocol) 분석 대상자수 : 217명 (시:대 = 107:110)

임상시험용

의약품

- 시험약: 시네츄라 현탁액

(황련수포화부탂올.아이비엽30%에탂올건조엑스) 129명

- 대조약: 푸로스판 시럽

(아이비엽 30% 에탂올엑스) 126명

국내 3상 임상 결과

임상시험용 의약품

구분 시험약 대조약

임상 의약품 시네츄라 시럽 현탁액 푸로스판 시럽

분류번호 222 / 진해거담제 222 / 진해거담제

성분/함량

100mL 중

Dried coptis rhizoma extract – 87.5mg

Dried Ivy leaf 30% ethanol extract – 262.5mg

100mL 중

Dried Ivy leaf 30% ethanol extract 700mg

효능/효과

다음 질병으로 인한 기침 가래

급성 상기도 감염, 만성 염증성 기관지염

만성 염증성 기관지 질홖의 증상 개선

기침을 동반한 호흡기의 급성 염증 완화

용법/용량

연령에 따라 아래의 용량으로 1일 3회 경구투여

2~6세 : 1회 5ml

7~14세 : 1회 10ml

15세 이상 : 1회 15ml

연령에 따라 아래의 용량으로 1일 2회 경구투여

5세이하 1회 2.5ml

6~14세 1회 5ml

15세 이상 5ml~7.5ml

■ 임상시험 결과 평가지표

유효성

- 주평가변수

1) 증상개선여부 (5-Scales) (완전치유, 확실한 개선일 경우 유효로 평가)

- 부평가변수

1) 증상별 자가평가 증상개선도

2) 증상별 완치율 및 완치소요기간

안전성

- 이상반응: 치료굮별 발생한 이상반응 분석

- 홗력징후: 투여 전후 비교

-실험실적 검사치: 투여 전후 비교, 정상/비정상치 분석

- ECG 검사/ 싞체검사

■ 시험기관

시험기관

경희대학교병원 소아청소년과 – 나영호 교수

경희대학교 동서신의학병원 소아청소년과 – 최선희 교수

인하대학교병원 소아청소년과 –임대현 교수

이화여자대학교 목동병원 알레르기내과 – 조영주교수

한양대학교병원 호흡기내과 – 윤호주 교수

건국대학교병원 호흡기알레르기내과 – 유광하 교수

국내 3상 임상 결과

■유효성 평가 (증상개선여부)

* 시네츄라는 시험자가 판단한 증상 개선 여부에서 27.1%의 홖자에서 완전치유를 나타내었으며, 80%의 홖자에서 증상개선 이상의 반응을 나타내었습니다.

국내 3상 임상 결과

0

10

20

30

40

50

60

70

80

유효율 무효율 유효율 무효율

급성상기도감염 염증성 만성기관지염

Synatura

Ivy leaf

•염증성 만성기관지염에서 시네츄라 유효율은 62.5%로 아이비엽 단일제제의 유효율인 28.6% 보다 두 배 이상의 높은 효과를 보였습니다.

■유효성 평가 (증상개선여부)

국내 3상 임상 결과

•객담 증상 개선도에서는 대조약 보다 9%이상 더 높은 수치를 보였으며 완치율에서는 대조약에 비해 12% 이상의 효과를 보였습니다.

61%

52%

국내 3상 임상 결과

■유효성 평가 (증상별- 객담증상 개선도 및 완치율)

이상반응 시네츄라

N (%)

대조군

n (%)

Gastrointestinal 2 (1.7%) 2 (1.7%)

Nausea 1 (0.8%) 1 (0.9%)

Vomiting 1 (0.8%) 1 (0.9%)

Neurology 1 (0.8%) 0

Dizziness 1 (0.8%) 0

Pain 0 1 (0.9%)

Pain-Gastrointestinal(abdomen)

0 1 (0.9%)

합계 3 (2.5%) 3 (2.6%)

국내 3상 임상 결과

■안전성 확증 실험(인과관계 있는 이상반응)

비임상연구/ 임상연구: 결과 요약

1. Berberine은 mucin 생성을 억제하고 진해, 거담 및 항염, 항균 활성

도가 우수하였다.

2. 아이비엽과 berberine을 혼합사용 시 우수핚 synergy 효과를 보였

다.

3. 이 둘의 혼합제제인 Synatura는 강력하고 우수핚 진해 거담효과를

보였다.

4. 이러핚 결과를 바탕으로 급성 상기도 감염을 비롯하여 부비동염,

인두염 및 급성 하기도 감염 등에 효과적이고 안전하게 사용핛 수

있으리라 생각핚다.

결론

• 기침의 치료… 원인을 찾고 원인별 치료가 가장 중요

• 기침으로 인한 홖자의 정싞적 싞체적 고통에서 해방시켜

줄 기침 억제제가 보조적으로 필요.

• 특히 기침억제와 가래제거능력이 뛰어나고,항염증 작용

까지 갖춘, 부작용까지 적은 약이 절실함…

새로운 조성의 천연물 신약 강력하고 우수한 진해 거담 효과 우수한 Synergy 효과 뛰어난 안전성

Synatura is

대단히 감사합니다. 즐거운 점심식사시간 되세요!!!!