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!!!!