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Herbal Medicines in Pregnancy
                                         June-Seek Choi, M.D., PhD

Korean Motherisk Program
Div. of Maternal-Fetal Medicine,
Dept. of OB & GYN,
Cheil General Hospital & Women’s Healthcare Center,
School of Medicine, Kwan-dong University, Seoul, Korea
Contents
 • Definition

 • Introduction

 • Herbal medicines relate to uterine contraction (in
    animal study vs human)

 • Herbal medicines relate to spontaneous abortion
    (in animal study vs human)

 • Data of pregnancy outcomes of herbal medicine
    exposure in Korean Motherisk Program

 • Summary
Definition (1)

 • Herbal medicines: include herbs, herbal

   materials, herbal preparations and

   finished herbal products, that contain as

   active ingredients part of plants, or other

   plant materials, or combinations.




                                                 WHO
Definition (2)

 • Herbs: crude plant materials such as leaves,
   flowers, fruit, seed, stems, wood, bark, roots,
   rhizomes or other plant parts, which may be
   entire, fragmented or powdered.

 • Herbal materials: in addition to herbs, fresh
   juices, gums, fixed oils, essential oils, resins and
   dry powders of herbs.




                                                          WHO
Definition (3)

 • Herbal preparations: may include
   comminuted or powdered herbal materials, or
   extracts, tinctures and fatty oils of herbal
   materials. They are produced by extraction,
   fractionation, purification, concentration, or
   other physical or biological processes.

 • Finished herbal products: herbal
   preparations made from one or more herbs.




                                                    WHO
Introduction (1)
 • It is estimated that about 25% of all modern
    medicines are directly or indirectly derived from
    higher plants.                Farnsworth NR 1976, Shu YZ 1998


 • Anticancer and antimicrobial drugs, about 60%
    of the medicines currently available on the
                                                                    Illicii Fructus
    market and most of those in the late stages of
    clinical trials are derived from natural products,
    mainly from higher plants.                Gragg GM et al 1997
Introduction (2)
• Representing an annual global market of US $60
  billion every year, herbal medicines account for
  around 20% of the overall drug market.

• Africa- 80% of population

  China- 30-50% of total medical consumption

   Europe, North America- over 50% of population
  have used complementary or alternative medicine at

  least once.                                                       WHO news 2004


• Fee for herbal medical treatment was increased 57
  times in Korea [ US $ 19 million (1990) US $ 1.1 billion (2006)]
                   A study on the current status and prospect of CAM world market 2007
Important factors to growth of this worldwide
Introduction (3)                   complementary/alternative medicine(CAM)


 • Preference of consumers for natural therapies

 • Concern regarding undesirable side effects of
    modern medicines and the belief that herbal
    drugs are free from side effects

 • Great interest in alternative medicines

 • Herbal medicines might be of effective benefit in
    the treatment of certain diseases where
    conventional therapies and medicines have
    proven to be inadequate

 • High cost of synthetic medicines

                                                                   Grünwald J 1995
Compared with well-defined synthetic drugs,
Introduction (4)                   herbal medicines exhibit some marked difference

 •   Active principles are frequently unknown.

 •   Standardization, stability and quality control are
     feasible but not easy

 •   Availability and quality of raw materials are
     frequently problematic.

 •   Well-controlled double-blind clinical and
     toxicological studies to prove their efficacy and
     safety are rare.

 •   Wide range of therapeutic use and are suitable for
     chronic treatments.

 •   Usually cost less than synthetic drugs

                                                                    Calixto J.B. 2000
Side effects by Korean herbal medicines-drug interactions
                                                       Western Medicine             Drug interaction and results

 Angelicae Gigantis Radix(Dang gui),       Warfarin, Aspirin                    Decreased International Normalized
 Ginseng Radix, Extract of Ginkgonis                                            Ratio and anticoagulant effects
 Germen
 Glycyrrhizae Radix (Gam cho)              Digoxin, Furosemide,                 Licorice and digoxin may result in
                                           Hydrochlorothiazide                  increased risk of digoxin toxicity. Licorice
                                                                                and diuretics may result in increased risk
                                                                                of hypokalemia and/or reduced
                                                                                effectiveness of the diuretic.
 Ginseng Radix, Ephedrae Herba (Ma         Glyburide, Insulin, Metformin        Severe Hypoglycemia due to increase
 hwang) , Zinberis Rhizoma Recens (Saeng                                        insulin
 gang)
 Glycyrrhizae Radix (Gam cho)              Metoprolol, Verapamil, Diltiazem     Decrease drug effect and Hypertension


 Allii Bulbus (Ma neul)                    Isoniazid                            Decrease serum concentration of isoniazid

 Zinberis Rhizoma Recens (Saeng gang)      Nifedipine, Verapamil, Diltiazem     Severe Hypotension


 Extract of Ginkgonis Germen               Thiazide                             Hypertension

 Extract of Ginkgonis Germen, Ephedrae     Anticonvulsant                       Increase risk of seizure
 Herba (Ma hwang)
 Ginseng Radix                             Azathioprine, Cyclosporine,          Decrease effect of immunosuppressant
                                           Corticosteroid
 Ephedrae Herba (Ma hwang)                 Pseudoephedrine, MAO inhibitor       Hypertension

 Ephedrae Herba (Ma hwang)                 Amiodaron, Procainamide, Quinidine   Prolongation of QT interval
                                                                                                           Park YC et al 2011
Introduction (5)
 • Some Chinese medical (CM) natural herbs listed
    in the official Chinese Pharmacopoeia (CP), CP
    are considered poisonous or toxic due to the
    presence of poisonous or toxic chemical
    constituents in the herb.

 • Of which about 50 of animal, plant and mineral
    natural materials are included in the CP.

 • In the CP the words “toxic, non-toxic, very-toxic
    or slightly toxic” are often used in describing
    Chinese Materia Medica.


                                                       Chan K 2003
Herbs                 Toxicity                             Herbs                   Toxicity

Artemisiae Argyi Folium (황해쑥)     Slightly toxic   백화자                                            Toxic

초오두                               Slightly toxic   경대극                                            Toxic

조휴                                Slightly toxic   Meliae Cortex (고련피)                            Toxic

Toosendan Fructus (천련자)           Slightly toxic   Sulphur (유황)                                   Toxic

Carpesii Fructus (학슬)             Slightly toxic   Agkistrodon (살모사)                              Toxic

Euphorbiae Pekinesis Radix (대극)   Slightly toxic   Pharbitidis Semen (견우자)                        Toxic

Tribuli Fructus (백질려)             Slightly toxic   Calomelas (경분)                                 Toxic

금성자                               Slightly toxic   Scorpio (전갈)                                   Toxic

Picrasmae Lignum (고목)             Slightly toxic   Sophorae Subprostratae Radix (산두근)             Toxic

Armeniacae Semen (고행인)            Slightly toxic   Phytolaccae Radix (상륙)                         Toxic

남학슬                               Slightly toxic   Hirudo (수질)                                    Toxic

Cnidii Fructus (사상자)              Slightly toxic   Arisaematis Rhizoma (천남성)                      Toxic

Eupolyphaga (자충)                  Slightly toxic   Scolopendra (오공)                               Toxic

Evodiae Fructus (오수유)             Slightly toxic   선모                                             Toxic

소엽련                               Slightly toxic   향가피                                            Toxic

아담자                               Slightly toxic   Realgar (웅황)                                   Toxic

Gleditsiae Fructus (조협)           Slightly toxic   앵속각                                            Toxic

Typhonii Rhizoma (백부자)               Toxic         Genkwa Flos (원화)                               Toxic

Ginkgo Semen (백과(은행))                Toxic         Cinnabaris (주사)                                Toxic

Pinelliae Rhizoma (반하)               Toxic         Crotonis Semen (파두)                          Very toxic

Bufonis Venenum (섬수)                 Toxic         파두상                                          Very toxic

Dichroae Radix (상산)                  Toxic         Mylabris (반묘)                                Very toxic

Aconiti Tuber Laterale (부자)          Toxic         Aconiti Ciliare Tuber (초오)                   Very toxic

Lacca Sinica Exsiccata (건칠)          Toxic         Aconiti Radix (천오)                           Very toxic

Kansui Radix (감수)                    Toxic         Strychni Semen seu nux Vomicae Semen (마전자)   Very toxic
Very Toxic Herbal Medicine
Herbal name              Common name            Korean common   Binominal name                          Toxicity
                                                name

Crotonis Semen           Croton seed            Pa doo          Croton tiglium L. (Euphorbiaceae)       Very toxic

Mylabris                 Mylabris               Ban myo         1.   Mylabris cichorii Fabricius        Very toxic
                                                                     (Meloidae)
                                                                2.   Mylabris phalerata Pall.
                                                                     (Meloidae)
                                                                3.   Mylabris sidae Fabricius
                                                                     (Meloidae)


Aconiti Ciliare Tuber    Wild aconite (tuber)   Cho o           Aconitum ciliare DC.                    Very toxic
                                                                (Ranunculaceae)
Aconiti Kusnezoffii      Wild aconite (tuber)   Cho o           Aconitum kusnezoffii Reichb.            Very toxic
Radix                                                           (Ranunculaceae)
Aconiti Proliferum       Wild aconite (tuber)   Cho o           Aconitum proliferum Nakai               Very toxic
Radix                                                           (Ranunculaceae)

Aconiti Radix            Wild aconite (tuber)   Cho o           Aconitum triphyllum Nakai               Very toxic
                                                                (Ranunculaceae)

Aconiti Radix            Aconite main tuber     Chun o          1.   Aconitum carmichaeli Debx.         Very toxic
                                                                     (Ranunculaceae)
                                                                2.   Aconitum chinense Paxton
                                                                     (Ranunculaceae)

Strychni Semen seu nux   Nuxvomica              Ma jun ja       Strychnos nux-vomica L.                  Very toxic
Vomicae Semen                                                        (Loganiaceae)
                                                                                   The Pharmacopoeia Commission of PRC, 2000
Crotonis Semen (Pa Doo)
• Indications: Scabies ,Eczema, Abscess
        Constituents
           4-alpha-Deoxy-5-hydroxy-20-acetoxy-12-O-(2-methyl-amino-benzoyl)phorbol
           4-alpha-Deoxy-5-hydroxy-12-O-(N-deca-2,4,6-trienoyl)phorbol
           4-alpha-Deoxy-12-O-(2-methylbutyryl)-phorbol-13-acetate
           4-alpha-Deoxy-12-O-tiglyl-phorbol-13-acetate
• Pretreatment: Croton seed without husk, Croton seed plaster,
           4-alpha-Deoxy-12-O-tiglylphorbol-13-isobutyrate
           4-alpha-Deoxy-phorbol-13-acetate
           4-alpha-Phorbol
           Angelic acid

   Croton seed frost-like powder
           Cocacinogen A1
           Cocacinogen A2
           Cocacinogen A3
           Cocacinogen A4
           Cocacinogen B1

• Pharmacological action: increase GI movement (inhalation,
           Cocacinogen B2
           Cocacinogen B3
           Cocacinogen B4
           Cocacinogen B6
           Cocacinogen B7
   human), increase cell differentiation (in vitro)
           Crotin I
           Crotin tiglium lectin
           Crotonoside
           4-Deoxyphorbol tiglate acetate
           4-Deoxy-5,13,20-triacetoxy-12-O-(n-deca-2,4,6-trienoyl)phorol
           4,20-Dideoxy-5-hydroxy-12-O-(n-deca-2,4,6-trienoyl)-phorbol-13-acetate           Hanyak yangnihak 2001
           12-O-Acetylphorbol-13-acetate
           12-O-(alpha-Methyl-butyryl)-phorbol-13-decanoate
           Octyl acetate
           12-O-[2-Methyl-amino-benzoyl]-4-alpha-deoxy-5-Hydroxy-phorbol
• Toxicity: Croton oil has the ability to promote radiation
           12-O-[2-Methyl-amino-benzoyl]-4-alpha-deoxy-phorbol-5,13,20-triacetate
           12-O-[2-Methyl-amino-benzoyl]-4-deoxy-5-hydroxy-phorbol-13-acetate
           12-O-[2-Methyl-amino-benzoyl]-4,20-dideoxy-5-hydroxy-phorbol
           12-O-[2-Methyl-amino-benzoyl]-4,20-dideoxy-5-hydroxy-phorbol-13-acetate

   transformation. It is very toxic and carcinogenic (animal study).
           12-O-[2-Methyl-amino-benzoyl]-4,20-dideoxy-phorbol-5,13-diacetate
           12-O-(2-Methyl-butyryl)-phorbol-13-acetate
           12-O-(2-Methylbutyryl)-phorbol-13-isobutyrate
           12-O-[n-Deca-2,4,6-trienoyl]-4-deoxy-5-hydroxy-phorbol-13-acetate
                                  Huang, K.C., The pharmacology of Chinese herbs II, CRC press, 1999.
           12-O-[n-Tetradecanoyl]-4,20-dideoxy-5-hydroxy-phorbol-13-acetate
           12-O-Tigloylphorbol-13-(2-methyl)-butyrate
           12-O-Tiglylphorbol 13-isobutyrate
           12-O-Tiglylphorbol-13-acetate

• Caution: Not use in pregnancy
           Phorbol
           Phorbol 13-butyrate 12-tiglate
           Phorbol 13-caprylate 12-acetate
           Phorbol 13-caprylate 12-tiglate
           Phorbol 13-linoleate 12-acetate
           Phorbol 13-myristate 12-acetate

• Formula in Korea: 35/ OTC in Korea:1
           Phorbol-13-acetate
           Phorbol-12-tiglate

                                                               www.tradimed.co.kr
                                                                              www.tradimed.co.kr/www.kimsonline.co.kr
Mylabris (Ban Myo)
• Indications: Rabies, Scabies, Mercury intoxication, Hepatic
    Cantharidin
        cirrhosis due to Clonorchiasis, Tuberculosis, Tuberculous
     lymphadenitis, Eczema, Abscess, Atopic dermatitis, Fever and
    •   Phytochemical group: Monoterpenoid
     chill
    • Molecular weight: 196.2
• • Pretreatment: cause symptoms from dermal inflammation to
      Cantharidin may parched Mylabris with rice
    blisters. If ingested, it may cause irritation and burning of the
• Pharmacological action: intoxication of snake venom,
     increase urination, increase abortion GI tract, diarrhea, and
        mouth, severe vesication of the upper      Dong-Eui-Bo-Gam

        kidney and cardiovascular damage.
•    Caution: Not use in pregnancy
    • Ii is a weak experimental animal carcinogen.
• Formula in Korea: 4                                     www.tradimed.co.kr


                                     www.thomsonhc.com, www.tradimed.co.kr
Aconiti Ciliare Tuber, Aconiti Kusnezoffii Radix, Aconiti
Proliferum Radix, Aconiti Radix (Cho O)
• Indications: Beriberi Aconiti Ciliare Tuber Myalgia, Cold type
            Constituents of edema, Cold limbs,
            & Aconiti Porliferum Radix
    Aconitine    Aconitine
     dysentery, Epigastric pain, Child epilepsy, Chronic osteomyelitis,
                         Hypaconitine
                         Mesaconitine
    •     Phytochemical group: Alkaloid
        Hemiparalysis, Hemiplegia, Migratory arthropathy
    •  Molecular weight: 645.75
•    Pretreatment: processedKusnezoffii Radix tuber
               Constituents of Aconiti Wild aconite
    • Bioactivity: bind to neurotoxin binding site 2 of α-subunit of
               3-Acetylaconitine
               Aconitine
•    Pharmacological action:Na+ channel ,anti-inflammation,
               Acontine
       Na+ channel activation of analgesics, increase intracellular
               Beiwutine
                      Bullatine A(structure unknown){formula: C(21)H(31)NO(2)}
        vasodilatation, and local anesthetic action in animal study 2010
          Ca2+ arrhythmia
                  Bullatine C                        Hanbang Yangnihak
                     Chasmanine; 6-Epimer
                     Denudatine
• • Toxicity: Toxictoxic if swallowed orbradycardia and irregular
     Toxicity: Very symptoms include by skin absorption. Human
                     Hypaconitine
                     Lepenine
                     Mesaconitine
          systemic effects by ingestion. LD50 (mus, orl) 1 well LD50 (mus, of
        rhythm. Nausea and vomiting may occur, asmg/kg, as spasm ivn)
                     Neoline
                     Pendulin
           0.175 mg/kg, exp. lethal doses   by subcutaneous route reported. LD50 in mice
        extremities and cardiac arrhythmias. The intestinal absorption of
                     Songorine
           (mg/kg): 0.166 i.v.; 0.328 i.p.; approx 1 orally (Dybing); also reported as LD50 in
        the alkaloids 1.8 relatively s.c.; 0.380 i.p.; 0.12of this, gastric lavage is
           mice (mg/kg): is orally, 0.270 fast. Because i.v. (Sato).
                                                                                                      Aconiti Ciliare Tuber
                                                                                 www.tradimed.co.kr
        recommended in case of overdose.
                            Huang, K.C., The pharmacology of Chinese herbs II, CRC press, 1999.

                                                                                                                              Aconiti Kusnezoffii Radix
• Formula in Korea:                         16   / OTC in Korea: 10
                                                        www.tradimed.co.kr/www.kimsonline.co.kr
Aconiti Radix (Chun O)
• Indications: Beriberi edema, Myalgia, Cold type dysentery, Paxton
    Constituents of Aconitum carmichaeli Debx. Constituents of Aconitum chinense
      14-Acetyltalatizamine                                                                  Violdelphin
      Aconine
    Paresthesia, Child epilepsy, Epigastric pain, Chronic
      Aconitan A
      Aconitan B
      Aconitan C
      Aconitan D
    osteomyelitis, Vomiting and Diarrhea, Testiculitis
      Aconitine
      Aldohypaconitine
      Beiwutine
      Benzoylaconine
      Benzoylhypaconine

• Pretreatment: processed Aconite main tuber
      Benzoylmesaconine
      Chuanfumine
      Chuan-Wu base A (structure unknown)(Tertiary base with 20H, 20Me and one N-Et groups.)
      Chuan-Wu base B(structure unknown){formula: C(32)H(35)NO(4)}
      Coryeine
      Coryneine
• Pharmacological action: analgesics, anti-inflammation,
      Fuzitine
      Hokbusine A
      Hokbusine B
      Hypaconitine

    vasodilatation, and local anesthetic action in animal study
      Ignavine
      Isodelphinine
      Isotalatisamine
      Isotalatizamine
      Karakoline

• Caution: not
      Lipoaconitine (R = linoleoyl, palmitoyl, oleoyl, stearoyl, linolenoyl)
                                        use in pregnancy
      Lipodeoxyaconitine (R = linoleoyl, palmitoyl, oleoyl, stearoyl, linolenoyl)
      Lipohypaconitine (R = linoleoyl, palmitoyl, oleoyl, stearoyl, linolenoyl)
      Lipomesaconitine (R = linoleoyl, palmitoyl, oleoyl, stearoyl, linolenoyl)
      Mesaconitine

• Toxicity: headache, paralysis of tongue, paraplegia, pain on
      Neojiangyouaconitine
      Neoline
      Salsolinol
    upper extremity, nausea, vomiting, respiration difficulty, coma
      Senbusine A
      Senbusine B
      Senbusine C
      Songarine                                                                                            Hanyak yangnihak 2001
      Songorine
      Talatizamine
• Formula in Korea: 1/ OTC in Korea:
                     www.tradimed.co.kr                                                                    5
                                                                                       www.tradimed.co.kr/www.kimsonline.co.kr
How to make herbal medicine in Korea
Korean women have a chance to be exposed to herbal
medicine from marriage to lactation




             Increase   Decrease               Increase
  Promote                          Decreased
            pregnancy   nausea &                breast
   Health                           lochia
              chance    vomiting                 milk
Herbal Medicines relate to
  Uterine Contraction
          Animal study



                         Hanyak yangnihak 2001
Herbal name              Common name                Korean name                          Binominal name

Lycii Radicis Cortex         Lycium root bark               Ji gol pi        1.     Lycium chinense Mill. (Solanaceae)
                                                                             2.     Lycium barbarum L. (Solanaceae)
Dianthi Herba                Dianthus                       Gu mac           1.     Dianthus chinensis L. (Caryophyllaceae)
                                                                             2.     Dianthus superbus L. (Caryophyllaceae)
Aurantii Fructus Immaturus   Unripe bitter orange           Ji gac           Citrus aurantium var. daidai Makino (Rutaceae)

Crataegi Fructus             Crataegus fruit                San sa yug       Crataegus pinnatifida Bunge (Rosaceae)

Typhae Pollen                Typha pollen                   Po hwang         Typha angustifolia L. (Typhaceae)

Cnidii Rhizoma               Cnidium (root)                 Chun gung        Cnidium officinale Makino (Umbelliferae)

Chuanxiong Rhizoma           Cnidium rhizome                Chun gung        Ligusticum chuanxiong Hort. (Umbelliferae)

Ligustici Rhizoma            Ligusticum rhizome             Chun gung        Ligusticum wallichii var. officinale Yook (Umbelliferae)

Corydalis Tuber              Corydalis (tuber)              Hyun ho sac      1.   Corydalis ternata Nakai (Papaveraceae)
                                                                             2.   Corydalis ambigua Chamisso et Schlechtendal
                                                                                  (Papaveraceae)
                                                                             3.   Corydalis decumbens Pers. (Papaveraceae)
                                                                             4.   Corydalis nakaii Ishidoya (Papaveraceae)
Leonuri Herba                1.   Chinese motherwort        Ik mo cho        1.   Leonurus sibiricus L. (Labiatae)
                             2.   Motherwort                                 2.   Leonurus heterophyllus Sweet (Labiatae)
Carthami Flos                Carthamus flower (safflower)   Hong hwa         Carthamus tinctorius L. (Compositae)

Angelicae Gigantis Radix     Dang gui root                  Dang gui         Angelica gigas Nakai (Umbelliferae)

Angelicae Sinensis Radix     Dang gui root                  Dang gui         Angelica sinensis (Oliv.) Diels (Umbelliferae)

Angelicae Acutilobae Radix   Dang gui root                  Dang gui         Angelica acutiloba Kitagawa (Umbelliferae)

Cassiae Semen                Feotid cassia (seed)           Gyul myoung ja   1.   Cassia tora L. (Leguminosae)
                                                                             2.   Cassia obtusifolia L. (Leguminosae)
Cnidii Rhizoma (Chun gung) (1)
• Indications: Secondary amenorrhea, Muscle spasm,
           Constituents of Cnidii Rhizoma
             Adenosine
   Hemiplegia, Seborrheic dermatitis, Persistent headache,
             Apiol
             Butylidenephthalide
   Metrorrhagia, Thoracoabdominal pain, Consumptive disease,
             Butylphthalide
             Chlorogenic acid
             Cnidilide
   Abnormal menstruation, Syncope, Confusion, Pelvic mass,
             Coniferyl ferulate
             Ferulic acid
   Gingival bleeding, Gingivitis, Paresthesia, Pneumonia
             Ligustilide
             Ligustilidiol
             Neocnidilide
• Pharmacologic action: vasodilatation, analgesics, anti
             Pregnenolone
             Senkyunolide
             Senkyunolide B
   inflammation, and uterine contraction in animal
             Senkyunolide C
             Senkyunolide D
             Senkyunolide F
             Senkyunolide G
                                                        Hanyak yangnihak 2001
             Senkyunolide H
             Senkyunolide I
             Senkyunolide J
• Formula in Korea: 25
             Umbelliferose                                 www.tradimed.co.kr
             Vanillin
• OTC in Korea: 1,186
             Vitamin C
                                   www.tradimed.co.kr
                                                        www.kimsonline.co.kr
Cnidii Rhizoma (Chun gung) (2) (80cases)
                                             Median (Min.-Max)

Last exposure weeks                             4.6 (0.6-12.4)

Duration of exposure (days)                     2.0 (1.0-59.0)

Dosage (mg/day) (42/80)                       1,250 (9.3-9,000)

                                Number                      %
Spontaneous                       2/80                      2.5
abortion
IUFD                              4/78                      5.1
Preterm birth                     8/78                     10.3
LBW                               3/78                      3.8
Malformation                     2*/78                      2.6
* Mega-cysterna magna(11mm)
  Left ventriculomegaly of cerebrum (11mm)

                                                       Korean Motherisk Program, unpublished
Corydalis Tuber (Hyun ho sac) (1)
• Indications: Metrorrhagia, Nasal bleeding, Postpartum faint ,
  Chest pain, Bruise, Abnormal menstruation, Back and knee
  pain, Peptic ulcer, Pancreatitis, Hyperhidrosis, Postpartum
  lochiorrhea, Pelvic mass, Spontaneous abortion, Multiple
 Tetrahydropalmatine Dysentery and Diarrhea
  arthritis, Rheumatoid arthritis,

• Pretreatment: processed Corydalis tuber with vinegar

• Pharmacological action: muscle relaxation, hypotension,
 •Phytochemical group: Alkaloid
   anti-inflammatory action, decrease secretion of gastric acid,
 •Molecular weight: 355.44
   anti-ulcer action , and increase contraction of extract uterus in
 •Bioactivity: hypnotic activity exceedsHanyak yangnihak 2001
  animal                                 that of

• morphine Over dosage intoxication leads to CNS depression
   Toxicity:
                                                 www.tredimed.co.kr
   and muscle relaxation.

• Caution: Not recommend        in pregnancy

• Formula in Korea: 10/ OTC: 77

                                     www.tradimed.co.kr/www.kimsonline.co.kr
Corydalis Tuber (Hyun ho sac) (2) (25 cases)
                                                Median (Min.-Max)

Last exposure weeks                                5.4 (0.4-13.0)

Duration of exposure (days)                        3.0 (1.0-38.0)

Dosage (mg/day) (16/25)                          180 (75.0-7,200)


                                   Number                      %
Spontaneous                             1/25                   4.0
abortion
IUFD                                      -                     0
Preterm birth                           1/24                   4.2
LBW                                       -                     0
Malformation                            1*/24                  4.0
* Post axial polydactyly of left foot

                                                            Korean Motherisk Program, unpublished
Angelicae Gigantis Radix (Dang gui) (1)
• Indications: Secondary amenorrhea, Nausea, Laceration,
           Constituents of Angelicae Gigantis Radix
   Headache, Aegelinol
              Abdominal pain, Metrorrhagia, Hyperventilation,
   Severe palpitation, Arrhythmia, Carbuncle, Influenza,
              alpha-Pinene(+,-)
   Abnormal menstruation, Hemorrhage without trauma, Nasal
              Choline
   bleeding, Syncope, Confusion, Acute pulpitis, Toothache,
              Coumarin

   Multiple arthritis, Skin tumor, Skin ulcer or Skin abscess,
              Decursidin
              Decursin
   Cerebrovascular accident, Dysentery and Diarrhea, Fever and
              Decursinol
   chill, Tuberculosis, Anemia, Paresthesia
              Decursinol angelate

• Pretreatment:angelate
          Decusinol parched dang gui with soil, charred dang gui,
              Gigasol
   parched dang gui with liquor, ginger processed dang gui
             Imperatorin
              Isoimperatorin

• Pharmacologic action: Increase blood flow to heart,
         Marmesin
              Nodakenetin
   hypotension, anti ulcer effect, analgesic, anti-inflammatory
             Nodakenin

   effect, and p-Cymene contraction (aqueous extracts) in animal
               uterine
              Prenyletin
                                                         Hanbang Yangnihak 2010
              Umbelliferone
• Formula in Korea: 120             www.tradimed.co.kr        www.tradimed.co.kr

• OTC in Korea: 1,401                                        www.kimsonline.co.kr
Angelicae Gigantis Radix (Dang gui) (2) (74 cases)
                                        Median (Min.-Max)

 Last exposure weeks                       4.6 (0.6-12.6)

 Duration of exposure (days)              3.0 (1.0-59.0)

 Dosage (mg/day) (34/74)                1,250 (13.5-9,000)


                               Number                  %
 Spontaneous                    3/74                   4.1
 abortion
 IUFD                           2/71                   2.8
 Preterm birth                  6/71                   8.5
 LBW                            1/71                   1.4
 Malformation                   1*/71                  1.4
 * Mega-cysterna magna(11mm)                     Korean Motherisk Program, unpublished
Herbal Medicines relate to
 Spontaneous Abortion
          Animal study




                         Hanyak yangnihak 2001
Herbal name          Common name     Korean name                           Binominal name

Menthae Herba            Mint                 Bak ha          1.     Mentha arvensis var. piperascens Malinv. (Labiatae)
                                                              2.     Mentha haplocalyx Briq. (Labiatae)
Trichosanthis Radix      Trichosanthes root   Chun Hwa Boon   Trichosanthes kirilowii Maxim. (Cucurbitaceae)


Moutan Radicis Cortex    Moutan root bark     Mok dan pi      Paeonia suffruticosa Andr. (Paeoniaceae)

Lonicerae Flos           Lonicera flowers     Geum un hwa     1.   Lonicera japonica Thunb. (Caprifoliaceae)
                                                              2.   Lonicera confusa DC. (Caprifoliaceae)
Kansui Radix             Kansui root          Gam su          Euphorbia kansui Liou ex Wang (Euphorbiaceae)

Clematidis Radix         Clematis (root)      Wi ryung sun    1.   Clematis mandshurica Rupr. (Ranunculaceae)
                                                              2.   Clematis chinensis Osbeck (Ranunculaceae)
                                                              3.   Clematis hexapetala Pall. (Ranunculaceae)
Sulphur                  Sulphur              Yu hwang        Sulphur

Curcumae Longae Tuber    Common turmeric      Gang hwang      Curcuma longa L. (Zingiberaceae)

Curcumae Rhizoma         Zedoary              A chool         1.   Curcuma phaeocaulis Val. (Zingiberaceae)
                                                              2.   Curcuma kwangsiensis S. G. Lee et C. F. Liang
                                                                   (Zingiberaceae)
Achyranthis Radix        Achyranthes root     Oo seol         1.   Achyranthes japonica Nakai (Amaranthaceae)
                                                              2.   Achyranthes bidentata Bl. (Amaranthaceae)
                                                              3.   Achyranthes fauriei Leville et Vaniot (Amaranthaceae)
Pinelliae Rhizoma        Pinellia rhizome     Ban ha          Pinellia ternata (Thunb.) Breit (Araceae)

Aristolochiae Fructus    Aristolochia fruit   Ma doo ryung    1.   Aristolochia contorta Bunge (Aristolochiaceae)
                                                              2.   Aristolochia debilis Sieb.et Zucc. (Aristolochiaceae)
Albizziae Cortex         Silk tree bark       Hab han pi      Albizia julibrissin Durazz. (Leguminosae)

Moschus                  Musk                 Sa hyang        1.   Moschus moschiferus L. (Moschidae)
                                                              2.   Moschus berezovskii Flerov (Moschidae)
                                                              3.   Moschus sifanicus Przewalski (Moschidae)
Menthae Herba (Bak ha) (1)
• Indications: Common cold, Frozen shoulder, Fever
   accompanied with fear, Cholera, Acute gastric cramp, Aphthous
   stomatitis, Tuberculous lymphadenitis, Persistent headache,
   Measles, Nasal bleeding, Snake bite, Liver cirrhosis, Ascites,
   Urticaria, Palpebral conjunctivitis, Laryngitis or Laryngeal
   abscess, Suppurative otitis media, Aphasia in Stroke , Contact
   dermatitis, Burn , Headache, Rubella, Bloody dysentery,
   Pharyngitis

• Pharmacologic action: anti-inflammatory effects,                 anti-
   pyretic , vasodilatation, decrease secretion of bronchus (high
   conc.), and necrosis of placenta in animal.

                              Hanbang Yangnihak 2010, Hanyak yangnihak 2001

• Formula in Korea: 225                                  www.tradimed.co.kr

• OTC in Korea: 311                                    www.kimsonline.co.kr
Menthae Herba (Bak ha) (2) (48 cases)
                                       Median (Min.-Max)

Last exposure weeks                       4.3 (0.4-12.6)

Duration of exposure (days)              3.0 (1.0-46.0)

Dosage (mg/day) (25/48)                 852 (20.0-2,256)


                              Number                  %
Spontaneous                    1/48                   2.1
abortion
IUFD                            -                      0
Preterm birth                  3/47                   6.4
LBW                            2/47                   4.3
Malformation                    -                      0

                                                  Korean Motherisk Program, unpublished
Pinelliae Rhizoma (Ban ha) (1)
• Indications: Headache due to Brain tumor, Bronchial asthma,
   Dizziness, Stomach cancer, Pyloric stenosis, Gastric gaseous
   distension

• Pretreatment: purified Pinellia tuber, processed Pinellia
   tuber, processed Pinellia tuber with ginger

• Pharmacologic action:          antitussive effect, decrease
   vomiting, decrease gastric ulcer, decrease ocular pressure, and
   increase abortion in animal                   Hanyak yangnihak 2001


• Formula in Korea: 90                              www.tradimed.co.kr


• OTC in Korea: 587                               www.kimsonline.co.kr
Pinelliae Rhizoma (Ban ha) (2)                                  (43 cases)

                                       Median (Min.-Max)

Last exposure weeks                       4.5 (0.4-12.4)

Duration of exposure (days)              2.0 (1.0-53.0)

Dosage (mg/day) (18/43)                625.5 (2.67-3,340)


                              Number                  %
Spontaneous                      -                     0
abortion
IUFD                           2/43                   4.7
Preterm birth                  4/43                   9.3
LBW                            3/43                   7.1
Malformation                   1*/43                  2.3
* Mega cysterna magna (11mm)
                                                    Korean Motherisk Program, unpublished
Pregnancy Outcomes
   Korean Motherisk Program




                              Unpublished data
Demographic characteristics of participants(n=321)
Age (years)                                   32.0 ± 3.6         Comorbidities [n (%)]

Gravidity (n)                                  2.2 ± 1.3          a) type 2 diabetes mellitus                         1 (0.3)

Parity (n)                                    1.0 (0, 3.0)        b) hypertension                                     2 (0.6)

Body mass index (kg/m2)                       20.8 ± 3.2          c) thyroid disease                                  2 (0.6)

                                                                  d) cancer                                           1 (0.3)
Exposure to X-rays
                                                                  e) renal disease                                    1 (0.3)
 a) n (%)                                      54 (16.8)
                                                                 Education level [n (%)]
 b) total dose (mSv)                      0.005 (0.0005, 28.8)
                                                                  a) post-secondary education                        130 (40.5)
 c) gestational age at exposure (weeks)        4.8 ± 3.2
                                                                  b) high school                                      20 (6.2)
Exposure to alcohol (%)
                                                                  c) not answered                                    171(53.3)
 a) n (%)                                     128 (39.9)
                                                                 Occupation
 b) total dose (oz)                            1.6 ± 1.4
                                                                  a) professional, technical and related occupatio   54 (16.8)
 c) gestational age at exposure (weeks)        4.6 ± 2.3          ns
Smoking (%)                                                       b) executive, administrative, managerial and sal   136 (42.4)

 a) n (%)                                       23 (7.2)          es
                                                                       occupations
 b) cigarettes/day                             5.4 ± 4.4
                                                                  c) construction workers                            124 (38.6)
 c) gestational age at exposure (weeks)        6.3 ± 4.6
                                                                  d) unemployed                                       7 (2.2)


                                                                        Korean Motherisk Program, unpublished
Indications of herbal exposure (n=321)
 INDICATIONS              a                                                                    n (%)

 Analgesics                                                                                    8 (2.5)

 Anti-acne preparations                                                                        2 (0.6)

 Anti-emetics & anti-nauseants                                                                 1 (0.3)

 Anti-inflammatory enzymes                                                                     8 (2.5)

 Anti-inflammatory & anti-rheumatic products                                                   7 (2.2)

 Anti-obesity preparations                                                                     21 (6.5)

 Anti-thrombotic agents                                                                        2 (0.6)

 Cough and cold preparations                                                                   129 (40.2)

 Dermatological preparations                                                                   3 (0.9)
                                                                                                                      21 cases: Tonic
 Drugs for acid related disorder                                                               1 (0.3)
                                                                                                                      medicine
 Functional gastrointestinal disorders                                                         93 (29.0)

 Gynecological anti infectives and antiseptics                                                 11 (3.4)

 Psycholeptics                                                                                 2 (0.6)

 Sex hormones & modulators the genital system                                                  7 (2.2)

 Others                                                                                        26 (8.1)
aAccording to the pharmacological/therapeutic subgroups of the ATC classification system (World Health Organization      Korean Motherisk Program, unpublished
Collaborating Centre for Drug Statistics Methodology 2011)
Exposure to herbal medicine in pregnant women (n=321)


                                            Median (range)


 Numbers of herbal medicine including        7.0 (1.0 - 40.0)

 one prescription



 Duration of exposure (days)                3.0 (1.0 – 365.0)


 Gestational age at last dose (weeks)        4.7 (0.1 - 25.0)


 197 kinds of herbal medicines

                                        Korean Motherisk Program, unpublished
Frequencies of Herbal medicine (>10%)
   n             188
       200
       150
       100             75 91      81 71 103
        50                     46           65 71
                                                    57 57
                                                          48 43 45
             0                                                     43 45 41
                                                                            40 33




                                                     Korean Motherisk Program, unpublished
Fetal outcomes
                                                                                            Cases (n= 307)

Gestational age at birth (weeks)                                                               38.9 ± 2.4

Birth weight (g)                                                                            3,294.2 ± 511.8

Birth length (cm)                                                                              49.7 ± 2.2

Head circumference at birth (cm)                                                               34.6 ± 1.4

Apgar score, 1 min                                                                              8.3 ± 0.9

Apgar score, 5 min                                                                              9.0 ± 0.7

IUFD (%)                                                                                         6 (2.0)

Malformationsa (%)                                                                               7 (2.3)

NICU admission (%)                                                                               12 (3.9)

Duration of NICU admission (days)                                                              12.5 ± 9.2

Neonatal jaundice (%)                                                                            10 (3.3)

a   A baby born with megacisterna magna, second one with dysplastic change of left kidney, left ectopic ureteral

insertion, third one with small pulmonary artery, fourth one with polydactyly of 5th toe of left foot and cleft palate and

patent ductus arteriosus, fifth one with small echogenic foci of anterior papillary muclse of left ventricle heart, sixth

one with borderline left ventriculomegaly of cerebrum, and seventh one with patent ductus arteriosus
                                                                                                                            Korean Motherisk Program, unpublished
Summary (1)
•    Although herbal medicines have been used in
    clinical practice for thousands of years, basic
    research on herbal substances should be focused on
    the toxicity and efficacy relationship for those potent
    and poisonous herbal substances according to
    composite formula.

•    Most traditional medical herbs are used in the form
    of an aqueous decoction. Therefore research
    projects should be centered on development of
    analytical and biological procedures for use to give
    quality assurance, control, and clinical assessment of
    efficacy, and safety of products.
Summary (2)
•    Herbal medications should be regulated for safety,
    quality and for appropriate evidence of efficacy.

•    Dosage and indications for treatment should be
    standardized. And contraindications should be
    clearly identified.

•    Language problem is another aspect as herbal
    ingredients are supplied with similarly names
    substitutes that could be toxic.
Thank you for your attention

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Motherisk round herbal medicine/최준식 교수

  • 1. Herbal Medicines in Pregnancy June-Seek Choi, M.D., PhD Korean Motherisk Program Div. of Maternal-Fetal Medicine, Dept. of OB & GYN, Cheil General Hospital & Women’s Healthcare Center, School of Medicine, Kwan-dong University, Seoul, Korea
  • 2. Contents • Definition • Introduction • Herbal medicines relate to uterine contraction (in animal study vs human) • Herbal medicines relate to spontaneous abortion (in animal study vs human) • Data of pregnancy outcomes of herbal medicine exposure in Korean Motherisk Program • Summary
  • 3. Definition (1) • Herbal medicines: include herbs, herbal materials, herbal preparations and finished herbal products, that contain as active ingredients part of plants, or other plant materials, or combinations. WHO
  • 4. Definition (2) • Herbs: crude plant materials such as leaves, flowers, fruit, seed, stems, wood, bark, roots, rhizomes or other plant parts, which may be entire, fragmented or powdered. • Herbal materials: in addition to herbs, fresh juices, gums, fixed oils, essential oils, resins and dry powders of herbs. WHO
  • 5. Definition (3) • Herbal preparations: may include comminuted or powdered herbal materials, or extracts, tinctures and fatty oils of herbal materials. They are produced by extraction, fractionation, purification, concentration, or other physical or biological processes. • Finished herbal products: herbal preparations made from one or more herbs. WHO
  • 6. Introduction (1) • It is estimated that about 25% of all modern medicines are directly or indirectly derived from higher plants. Farnsworth NR 1976, Shu YZ 1998 • Anticancer and antimicrobial drugs, about 60% of the medicines currently available on the Illicii Fructus market and most of those in the late stages of clinical trials are derived from natural products, mainly from higher plants. Gragg GM et al 1997
  • 7. Introduction (2) • Representing an annual global market of US $60 billion every year, herbal medicines account for around 20% of the overall drug market. • Africa- 80% of population China- 30-50% of total medical consumption Europe, North America- over 50% of population have used complementary or alternative medicine at least once. WHO news 2004 • Fee for herbal medical treatment was increased 57 times in Korea [ US $ 19 million (1990) US $ 1.1 billion (2006)] A study on the current status and prospect of CAM world market 2007
  • 8. Important factors to growth of this worldwide Introduction (3) complementary/alternative medicine(CAM) • Preference of consumers for natural therapies • Concern regarding undesirable side effects of modern medicines and the belief that herbal drugs are free from side effects • Great interest in alternative medicines • Herbal medicines might be of effective benefit in the treatment of certain diseases where conventional therapies and medicines have proven to be inadequate • High cost of synthetic medicines Grünwald J 1995
  • 9. Compared with well-defined synthetic drugs, Introduction (4) herbal medicines exhibit some marked difference • Active principles are frequently unknown. • Standardization, stability and quality control are feasible but not easy • Availability and quality of raw materials are frequently problematic. • Well-controlled double-blind clinical and toxicological studies to prove their efficacy and safety are rare. • Wide range of therapeutic use and are suitable for chronic treatments. • Usually cost less than synthetic drugs Calixto J.B. 2000
  • 10. Side effects by Korean herbal medicines-drug interactions Western Medicine Drug interaction and results Angelicae Gigantis Radix(Dang gui), Warfarin, Aspirin Decreased International Normalized Ginseng Radix, Extract of Ginkgonis Ratio and anticoagulant effects Germen Glycyrrhizae Radix (Gam cho) Digoxin, Furosemide, Licorice and digoxin may result in Hydrochlorothiazide increased risk of digoxin toxicity. Licorice and diuretics may result in increased risk of hypokalemia and/or reduced effectiveness of the diuretic. Ginseng Radix, Ephedrae Herba (Ma Glyburide, Insulin, Metformin Severe Hypoglycemia due to increase hwang) , Zinberis Rhizoma Recens (Saeng insulin gang) Glycyrrhizae Radix (Gam cho) Metoprolol, Verapamil, Diltiazem Decrease drug effect and Hypertension Allii Bulbus (Ma neul) Isoniazid Decrease serum concentration of isoniazid Zinberis Rhizoma Recens (Saeng gang) Nifedipine, Verapamil, Diltiazem Severe Hypotension Extract of Ginkgonis Germen Thiazide Hypertension Extract of Ginkgonis Germen, Ephedrae Anticonvulsant Increase risk of seizure Herba (Ma hwang) Ginseng Radix Azathioprine, Cyclosporine, Decrease effect of immunosuppressant Corticosteroid Ephedrae Herba (Ma hwang) Pseudoephedrine, MAO inhibitor Hypertension Ephedrae Herba (Ma hwang) Amiodaron, Procainamide, Quinidine Prolongation of QT interval Park YC et al 2011
  • 11. Introduction (5) • Some Chinese medical (CM) natural herbs listed in the official Chinese Pharmacopoeia (CP), CP are considered poisonous or toxic due to the presence of poisonous or toxic chemical constituents in the herb. • Of which about 50 of animal, plant and mineral natural materials are included in the CP. • In the CP the words “toxic, non-toxic, very-toxic or slightly toxic” are often used in describing Chinese Materia Medica. Chan K 2003
  • 12. Herbs Toxicity Herbs Toxicity Artemisiae Argyi Folium (황해쑥) Slightly toxic 백화자 Toxic 초오두 Slightly toxic 경대극 Toxic 조휴 Slightly toxic Meliae Cortex (고련피) Toxic Toosendan Fructus (천련자) Slightly toxic Sulphur (유황) Toxic Carpesii Fructus (학슬) Slightly toxic Agkistrodon (살모사) Toxic Euphorbiae Pekinesis Radix (대극) Slightly toxic Pharbitidis Semen (견우자) Toxic Tribuli Fructus (백질려) Slightly toxic Calomelas (경분) Toxic 금성자 Slightly toxic Scorpio (전갈) Toxic Picrasmae Lignum (고목) Slightly toxic Sophorae Subprostratae Radix (산두근) Toxic Armeniacae Semen (고행인) Slightly toxic Phytolaccae Radix (상륙) Toxic 남학슬 Slightly toxic Hirudo (수질) Toxic Cnidii Fructus (사상자) Slightly toxic Arisaematis Rhizoma (천남성) Toxic Eupolyphaga (자충) Slightly toxic Scolopendra (오공) Toxic Evodiae Fructus (오수유) Slightly toxic 선모 Toxic 소엽련 Slightly toxic 향가피 Toxic 아담자 Slightly toxic Realgar (웅황) Toxic Gleditsiae Fructus (조협) Slightly toxic 앵속각 Toxic Typhonii Rhizoma (백부자) Toxic Genkwa Flos (원화) Toxic Ginkgo Semen (백과(은행)) Toxic Cinnabaris (주사) Toxic Pinelliae Rhizoma (반하) Toxic Crotonis Semen (파두) Very toxic Bufonis Venenum (섬수) Toxic 파두상 Very toxic Dichroae Radix (상산) Toxic Mylabris (반묘) Very toxic Aconiti Tuber Laterale (부자) Toxic Aconiti Ciliare Tuber (초오) Very toxic Lacca Sinica Exsiccata (건칠) Toxic Aconiti Radix (천오) Very toxic Kansui Radix (감수) Toxic Strychni Semen seu nux Vomicae Semen (마전자) Very toxic
  • 13. Very Toxic Herbal Medicine Herbal name Common name Korean common Binominal name Toxicity name Crotonis Semen Croton seed Pa doo Croton tiglium L. (Euphorbiaceae) Very toxic Mylabris Mylabris Ban myo 1. Mylabris cichorii Fabricius Very toxic (Meloidae) 2. Mylabris phalerata Pall. (Meloidae) 3. Mylabris sidae Fabricius (Meloidae) Aconiti Ciliare Tuber Wild aconite (tuber) Cho o Aconitum ciliare DC. Very toxic (Ranunculaceae) Aconiti Kusnezoffii Wild aconite (tuber) Cho o Aconitum kusnezoffii Reichb. Very toxic Radix (Ranunculaceae) Aconiti Proliferum Wild aconite (tuber) Cho o Aconitum proliferum Nakai Very toxic Radix (Ranunculaceae) Aconiti Radix Wild aconite (tuber) Cho o Aconitum triphyllum Nakai Very toxic (Ranunculaceae) Aconiti Radix Aconite main tuber Chun o 1. Aconitum carmichaeli Debx. Very toxic (Ranunculaceae) 2. Aconitum chinense Paxton (Ranunculaceae) Strychni Semen seu nux Nuxvomica Ma jun ja Strychnos nux-vomica L. Very toxic Vomicae Semen (Loganiaceae) The Pharmacopoeia Commission of PRC, 2000
  • 14. Crotonis Semen (Pa Doo) • Indications: Scabies ,Eczema, Abscess Constituents 4-alpha-Deoxy-5-hydroxy-20-acetoxy-12-O-(2-methyl-amino-benzoyl)phorbol 4-alpha-Deoxy-5-hydroxy-12-O-(N-deca-2,4,6-trienoyl)phorbol 4-alpha-Deoxy-12-O-(2-methylbutyryl)-phorbol-13-acetate 4-alpha-Deoxy-12-O-tiglyl-phorbol-13-acetate • Pretreatment: Croton seed without husk, Croton seed plaster, 4-alpha-Deoxy-12-O-tiglylphorbol-13-isobutyrate 4-alpha-Deoxy-phorbol-13-acetate 4-alpha-Phorbol Angelic acid Croton seed frost-like powder Cocacinogen A1 Cocacinogen A2 Cocacinogen A3 Cocacinogen A4 Cocacinogen B1 • Pharmacological action: increase GI movement (inhalation, Cocacinogen B2 Cocacinogen B3 Cocacinogen B4 Cocacinogen B6 Cocacinogen B7 human), increase cell differentiation (in vitro) Crotin I Crotin tiglium lectin Crotonoside 4-Deoxyphorbol tiglate acetate 4-Deoxy-5,13,20-triacetoxy-12-O-(n-deca-2,4,6-trienoyl)phorol 4,20-Dideoxy-5-hydroxy-12-O-(n-deca-2,4,6-trienoyl)-phorbol-13-acetate Hanyak yangnihak 2001 12-O-Acetylphorbol-13-acetate 12-O-(alpha-Methyl-butyryl)-phorbol-13-decanoate Octyl acetate 12-O-[2-Methyl-amino-benzoyl]-4-alpha-deoxy-5-Hydroxy-phorbol • Toxicity: Croton oil has the ability to promote radiation 12-O-[2-Methyl-amino-benzoyl]-4-alpha-deoxy-phorbol-5,13,20-triacetate 12-O-[2-Methyl-amino-benzoyl]-4-deoxy-5-hydroxy-phorbol-13-acetate 12-O-[2-Methyl-amino-benzoyl]-4,20-dideoxy-5-hydroxy-phorbol 12-O-[2-Methyl-amino-benzoyl]-4,20-dideoxy-5-hydroxy-phorbol-13-acetate transformation. It is very toxic and carcinogenic (animal study). 12-O-[2-Methyl-amino-benzoyl]-4,20-dideoxy-phorbol-5,13-diacetate 12-O-(2-Methyl-butyryl)-phorbol-13-acetate 12-O-(2-Methylbutyryl)-phorbol-13-isobutyrate 12-O-[n-Deca-2,4,6-trienoyl]-4-deoxy-5-hydroxy-phorbol-13-acetate Huang, K.C., The pharmacology of Chinese herbs II, CRC press, 1999. 12-O-[n-Tetradecanoyl]-4,20-dideoxy-5-hydroxy-phorbol-13-acetate 12-O-Tigloylphorbol-13-(2-methyl)-butyrate 12-O-Tiglylphorbol 13-isobutyrate 12-O-Tiglylphorbol-13-acetate • Caution: Not use in pregnancy Phorbol Phorbol 13-butyrate 12-tiglate Phorbol 13-caprylate 12-acetate Phorbol 13-caprylate 12-tiglate Phorbol 13-linoleate 12-acetate Phorbol 13-myristate 12-acetate • Formula in Korea: 35/ OTC in Korea:1 Phorbol-13-acetate Phorbol-12-tiglate www.tradimed.co.kr www.tradimed.co.kr/www.kimsonline.co.kr
  • 15. Mylabris (Ban Myo) • Indications: Rabies, Scabies, Mercury intoxication, Hepatic Cantharidin cirrhosis due to Clonorchiasis, Tuberculosis, Tuberculous lymphadenitis, Eczema, Abscess, Atopic dermatitis, Fever and • Phytochemical group: Monoterpenoid chill • Molecular weight: 196.2 • • Pretreatment: cause symptoms from dermal inflammation to Cantharidin may parched Mylabris with rice blisters. If ingested, it may cause irritation and burning of the • Pharmacological action: intoxication of snake venom, increase urination, increase abortion GI tract, diarrhea, and mouth, severe vesication of the upper Dong-Eui-Bo-Gam kidney and cardiovascular damage. • Caution: Not use in pregnancy • Ii is a weak experimental animal carcinogen. • Formula in Korea: 4 www.tradimed.co.kr www.thomsonhc.com, www.tradimed.co.kr
  • 16. Aconiti Ciliare Tuber, Aconiti Kusnezoffii Radix, Aconiti Proliferum Radix, Aconiti Radix (Cho O) • Indications: Beriberi Aconiti Ciliare Tuber Myalgia, Cold type Constituents of edema, Cold limbs, & Aconiti Porliferum Radix Aconitine Aconitine dysentery, Epigastric pain, Child epilepsy, Chronic osteomyelitis, Hypaconitine Mesaconitine • Phytochemical group: Alkaloid Hemiparalysis, Hemiplegia, Migratory arthropathy • Molecular weight: 645.75 • Pretreatment: processedKusnezoffii Radix tuber Constituents of Aconiti Wild aconite • Bioactivity: bind to neurotoxin binding site 2 of α-subunit of 3-Acetylaconitine Aconitine • Pharmacological action:Na+ channel ,anti-inflammation, Acontine Na+ channel activation of analgesics, increase intracellular Beiwutine Bullatine A(structure unknown){formula: C(21)H(31)NO(2)} vasodilatation, and local anesthetic action in animal study 2010 Ca2+ arrhythmia Bullatine C Hanbang Yangnihak Chasmanine; 6-Epimer Denudatine • • Toxicity: Toxictoxic if swallowed orbradycardia and irregular Toxicity: Very symptoms include by skin absorption. Human Hypaconitine Lepenine Mesaconitine systemic effects by ingestion. LD50 (mus, orl) 1 well LD50 (mus, of rhythm. Nausea and vomiting may occur, asmg/kg, as spasm ivn) Neoline Pendulin 0.175 mg/kg, exp. lethal doses by subcutaneous route reported. LD50 in mice extremities and cardiac arrhythmias. The intestinal absorption of Songorine (mg/kg): 0.166 i.v.; 0.328 i.p.; approx 1 orally (Dybing); also reported as LD50 in the alkaloids 1.8 relatively s.c.; 0.380 i.p.; 0.12of this, gastric lavage is mice (mg/kg): is orally, 0.270 fast. Because i.v. (Sato). Aconiti Ciliare Tuber www.tradimed.co.kr recommended in case of overdose. Huang, K.C., The pharmacology of Chinese herbs II, CRC press, 1999. Aconiti Kusnezoffii Radix • Formula in Korea: 16 / OTC in Korea: 10 www.tradimed.co.kr/www.kimsonline.co.kr
  • 17. Aconiti Radix (Chun O) • Indications: Beriberi edema, Myalgia, Cold type dysentery, Paxton Constituents of Aconitum carmichaeli Debx. Constituents of Aconitum chinense 14-Acetyltalatizamine Violdelphin Aconine Paresthesia, Child epilepsy, Epigastric pain, Chronic Aconitan A Aconitan B Aconitan C Aconitan D osteomyelitis, Vomiting and Diarrhea, Testiculitis Aconitine Aldohypaconitine Beiwutine Benzoylaconine Benzoylhypaconine • Pretreatment: processed Aconite main tuber Benzoylmesaconine Chuanfumine Chuan-Wu base A (structure unknown)(Tertiary base with 20H, 20Me and one N-Et groups.) Chuan-Wu base B(structure unknown){formula: C(32)H(35)NO(4)} Coryeine Coryneine • Pharmacological action: analgesics, anti-inflammation, Fuzitine Hokbusine A Hokbusine B Hypaconitine vasodilatation, and local anesthetic action in animal study Ignavine Isodelphinine Isotalatisamine Isotalatizamine Karakoline • Caution: not Lipoaconitine (R = linoleoyl, palmitoyl, oleoyl, stearoyl, linolenoyl) use in pregnancy Lipodeoxyaconitine (R = linoleoyl, palmitoyl, oleoyl, stearoyl, linolenoyl) Lipohypaconitine (R = linoleoyl, palmitoyl, oleoyl, stearoyl, linolenoyl) Lipomesaconitine (R = linoleoyl, palmitoyl, oleoyl, stearoyl, linolenoyl) Mesaconitine • Toxicity: headache, paralysis of tongue, paraplegia, pain on Neojiangyouaconitine Neoline Salsolinol upper extremity, nausea, vomiting, respiration difficulty, coma Senbusine A Senbusine B Senbusine C Songarine Hanyak yangnihak 2001 Songorine Talatizamine • Formula in Korea: 1/ OTC in Korea: www.tradimed.co.kr 5 www.tradimed.co.kr/www.kimsonline.co.kr
  • 18. How to make herbal medicine in Korea
  • 19. Korean women have a chance to be exposed to herbal medicine from marriage to lactation Increase Decrease Increase Promote Decreased pregnancy nausea & breast Health lochia chance vomiting milk
  • 20. Herbal Medicines relate to Uterine Contraction Animal study Hanyak yangnihak 2001
  • 21. Herbal name Common name Korean name Binominal name Lycii Radicis Cortex Lycium root bark Ji gol pi 1. Lycium chinense Mill. (Solanaceae) 2. Lycium barbarum L. (Solanaceae) Dianthi Herba Dianthus Gu mac 1. Dianthus chinensis L. (Caryophyllaceae) 2. Dianthus superbus L. (Caryophyllaceae) Aurantii Fructus Immaturus Unripe bitter orange Ji gac Citrus aurantium var. daidai Makino (Rutaceae) Crataegi Fructus Crataegus fruit San sa yug Crataegus pinnatifida Bunge (Rosaceae) Typhae Pollen Typha pollen Po hwang Typha angustifolia L. (Typhaceae) Cnidii Rhizoma Cnidium (root) Chun gung Cnidium officinale Makino (Umbelliferae) Chuanxiong Rhizoma Cnidium rhizome Chun gung Ligusticum chuanxiong Hort. (Umbelliferae) Ligustici Rhizoma Ligusticum rhizome Chun gung Ligusticum wallichii var. officinale Yook (Umbelliferae) Corydalis Tuber Corydalis (tuber) Hyun ho sac 1. Corydalis ternata Nakai (Papaveraceae) 2. Corydalis ambigua Chamisso et Schlechtendal (Papaveraceae) 3. Corydalis decumbens Pers. (Papaveraceae) 4. Corydalis nakaii Ishidoya (Papaveraceae) Leonuri Herba 1. Chinese motherwort Ik mo cho 1. Leonurus sibiricus L. (Labiatae) 2. Motherwort 2. Leonurus heterophyllus Sweet (Labiatae) Carthami Flos Carthamus flower (safflower) Hong hwa Carthamus tinctorius L. (Compositae) Angelicae Gigantis Radix Dang gui root Dang gui Angelica gigas Nakai (Umbelliferae) Angelicae Sinensis Radix Dang gui root Dang gui Angelica sinensis (Oliv.) Diels (Umbelliferae) Angelicae Acutilobae Radix Dang gui root Dang gui Angelica acutiloba Kitagawa (Umbelliferae) Cassiae Semen Feotid cassia (seed) Gyul myoung ja 1. Cassia tora L. (Leguminosae) 2. Cassia obtusifolia L. (Leguminosae)
  • 22. Cnidii Rhizoma (Chun gung) (1) • Indications: Secondary amenorrhea, Muscle spasm, Constituents of Cnidii Rhizoma Adenosine Hemiplegia, Seborrheic dermatitis, Persistent headache, Apiol Butylidenephthalide Metrorrhagia, Thoracoabdominal pain, Consumptive disease, Butylphthalide Chlorogenic acid Cnidilide Abnormal menstruation, Syncope, Confusion, Pelvic mass, Coniferyl ferulate Ferulic acid Gingival bleeding, Gingivitis, Paresthesia, Pneumonia Ligustilide Ligustilidiol Neocnidilide • Pharmacologic action: vasodilatation, analgesics, anti Pregnenolone Senkyunolide Senkyunolide B inflammation, and uterine contraction in animal Senkyunolide C Senkyunolide D Senkyunolide F Senkyunolide G Hanyak yangnihak 2001 Senkyunolide H Senkyunolide I Senkyunolide J • Formula in Korea: 25 Umbelliferose www.tradimed.co.kr Vanillin • OTC in Korea: 1,186 Vitamin C www.tradimed.co.kr www.kimsonline.co.kr
  • 23. Cnidii Rhizoma (Chun gung) (2) (80cases) Median (Min.-Max) Last exposure weeks 4.6 (0.6-12.4) Duration of exposure (days) 2.0 (1.0-59.0) Dosage (mg/day) (42/80) 1,250 (9.3-9,000) Number % Spontaneous 2/80 2.5 abortion IUFD 4/78 5.1 Preterm birth 8/78 10.3 LBW 3/78 3.8 Malformation 2*/78 2.6 * Mega-cysterna magna(11mm) Left ventriculomegaly of cerebrum (11mm) Korean Motherisk Program, unpublished
  • 24. Corydalis Tuber (Hyun ho sac) (1) • Indications: Metrorrhagia, Nasal bleeding, Postpartum faint , Chest pain, Bruise, Abnormal menstruation, Back and knee pain, Peptic ulcer, Pancreatitis, Hyperhidrosis, Postpartum lochiorrhea, Pelvic mass, Spontaneous abortion, Multiple Tetrahydropalmatine Dysentery and Diarrhea arthritis, Rheumatoid arthritis, • Pretreatment: processed Corydalis tuber with vinegar • Pharmacological action: muscle relaxation, hypotension, •Phytochemical group: Alkaloid anti-inflammatory action, decrease secretion of gastric acid, •Molecular weight: 355.44 anti-ulcer action , and increase contraction of extract uterus in •Bioactivity: hypnotic activity exceedsHanyak yangnihak 2001 animal that of • morphine Over dosage intoxication leads to CNS depression Toxicity: www.tredimed.co.kr and muscle relaxation. • Caution: Not recommend in pregnancy • Formula in Korea: 10/ OTC: 77 www.tradimed.co.kr/www.kimsonline.co.kr
  • 25. Corydalis Tuber (Hyun ho sac) (2) (25 cases) Median (Min.-Max) Last exposure weeks 5.4 (0.4-13.0) Duration of exposure (days) 3.0 (1.0-38.0) Dosage (mg/day) (16/25) 180 (75.0-7,200) Number % Spontaneous 1/25 4.0 abortion IUFD - 0 Preterm birth 1/24 4.2 LBW - 0 Malformation 1*/24 4.0 * Post axial polydactyly of left foot Korean Motherisk Program, unpublished
  • 26. Angelicae Gigantis Radix (Dang gui) (1) • Indications: Secondary amenorrhea, Nausea, Laceration, Constituents of Angelicae Gigantis Radix Headache, Aegelinol Abdominal pain, Metrorrhagia, Hyperventilation, Severe palpitation, Arrhythmia, Carbuncle, Influenza, alpha-Pinene(+,-) Abnormal menstruation, Hemorrhage without trauma, Nasal Choline bleeding, Syncope, Confusion, Acute pulpitis, Toothache, Coumarin Multiple arthritis, Skin tumor, Skin ulcer or Skin abscess, Decursidin Decursin Cerebrovascular accident, Dysentery and Diarrhea, Fever and Decursinol chill, Tuberculosis, Anemia, Paresthesia Decursinol angelate • Pretreatment:angelate Decusinol parched dang gui with soil, charred dang gui, Gigasol parched dang gui with liquor, ginger processed dang gui Imperatorin Isoimperatorin • Pharmacologic action: Increase blood flow to heart, Marmesin Nodakenetin hypotension, anti ulcer effect, analgesic, anti-inflammatory Nodakenin effect, and p-Cymene contraction (aqueous extracts) in animal uterine Prenyletin Hanbang Yangnihak 2010 Umbelliferone • Formula in Korea: 120 www.tradimed.co.kr www.tradimed.co.kr • OTC in Korea: 1,401 www.kimsonline.co.kr
  • 27. Angelicae Gigantis Radix (Dang gui) (2) (74 cases) Median (Min.-Max) Last exposure weeks 4.6 (0.6-12.6) Duration of exposure (days) 3.0 (1.0-59.0) Dosage (mg/day) (34/74) 1,250 (13.5-9,000) Number % Spontaneous 3/74 4.1 abortion IUFD 2/71 2.8 Preterm birth 6/71 8.5 LBW 1/71 1.4 Malformation 1*/71 1.4 * Mega-cysterna magna(11mm) Korean Motherisk Program, unpublished
  • 28. Herbal Medicines relate to Spontaneous Abortion Animal study Hanyak yangnihak 2001
  • 29. Herbal name Common name Korean name Binominal name Menthae Herba Mint Bak ha 1. Mentha arvensis var. piperascens Malinv. (Labiatae) 2. Mentha haplocalyx Briq. (Labiatae) Trichosanthis Radix Trichosanthes root Chun Hwa Boon Trichosanthes kirilowii Maxim. (Cucurbitaceae) Moutan Radicis Cortex Moutan root bark Mok dan pi Paeonia suffruticosa Andr. (Paeoniaceae) Lonicerae Flos Lonicera flowers Geum un hwa 1. Lonicera japonica Thunb. (Caprifoliaceae) 2. Lonicera confusa DC. (Caprifoliaceae) Kansui Radix Kansui root Gam su Euphorbia kansui Liou ex Wang (Euphorbiaceae) Clematidis Radix Clematis (root) Wi ryung sun 1. Clematis mandshurica Rupr. (Ranunculaceae) 2. Clematis chinensis Osbeck (Ranunculaceae) 3. Clematis hexapetala Pall. (Ranunculaceae) Sulphur Sulphur Yu hwang Sulphur Curcumae Longae Tuber Common turmeric Gang hwang Curcuma longa L. (Zingiberaceae) Curcumae Rhizoma Zedoary A chool 1. Curcuma phaeocaulis Val. (Zingiberaceae) 2. Curcuma kwangsiensis S. G. Lee et C. F. Liang (Zingiberaceae) Achyranthis Radix Achyranthes root Oo seol 1. Achyranthes japonica Nakai (Amaranthaceae) 2. Achyranthes bidentata Bl. (Amaranthaceae) 3. Achyranthes fauriei Leville et Vaniot (Amaranthaceae) Pinelliae Rhizoma Pinellia rhizome Ban ha Pinellia ternata (Thunb.) Breit (Araceae) Aristolochiae Fructus Aristolochia fruit Ma doo ryung 1. Aristolochia contorta Bunge (Aristolochiaceae) 2. Aristolochia debilis Sieb.et Zucc. (Aristolochiaceae) Albizziae Cortex Silk tree bark Hab han pi Albizia julibrissin Durazz. (Leguminosae) Moschus Musk Sa hyang 1. Moschus moschiferus L. (Moschidae) 2. Moschus berezovskii Flerov (Moschidae) 3. Moschus sifanicus Przewalski (Moschidae)
  • 30. Menthae Herba (Bak ha) (1) • Indications: Common cold, Frozen shoulder, Fever accompanied with fear, Cholera, Acute gastric cramp, Aphthous stomatitis, Tuberculous lymphadenitis, Persistent headache, Measles, Nasal bleeding, Snake bite, Liver cirrhosis, Ascites, Urticaria, Palpebral conjunctivitis, Laryngitis or Laryngeal abscess, Suppurative otitis media, Aphasia in Stroke , Contact dermatitis, Burn , Headache, Rubella, Bloody dysentery, Pharyngitis • Pharmacologic action: anti-inflammatory effects, anti- pyretic , vasodilatation, decrease secretion of bronchus (high conc.), and necrosis of placenta in animal. Hanbang Yangnihak 2010, Hanyak yangnihak 2001 • Formula in Korea: 225 www.tradimed.co.kr • OTC in Korea: 311 www.kimsonline.co.kr
  • 31. Menthae Herba (Bak ha) (2) (48 cases) Median (Min.-Max) Last exposure weeks 4.3 (0.4-12.6) Duration of exposure (days) 3.0 (1.0-46.0) Dosage (mg/day) (25/48) 852 (20.0-2,256) Number % Spontaneous 1/48 2.1 abortion IUFD - 0 Preterm birth 3/47 6.4 LBW 2/47 4.3 Malformation - 0 Korean Motherisk Program, unpublished
  • 32. Pinelliae Rhizoma (Ban ha) (1) • Indications: Headache due to Brain tumor, Bronchial asthma, Dizziness, Stomach cancer, Pyloric stenosis, Gastric gaseous distension • Pretreatment: purified Pinellia tuber, processed Pinellia tuber, processed Pinellia tuber with ginger • Pharmacologic action: antitussive effect, decrease vomiting, decrease gastric ulcer, decrease ocular pressure, and increase abortion in animal Hanyak yangnihak 2001 • Formula in Korea: 90 www.tradimed.co.kr • OTC in Korea: 587 www.kimsonline.co.kr
  • 33. Pinelliae Rhizoma (Ban ha) (2) (43 cases) Median (Min.-Max) Last exposure weeks 4.5 (0.4-12.4) Duration of exposure (days) 2.0 (1.0-53.0) Dosage (mg/day) (18/43) 625.5 (2.67-3,340) Number % Spontaneous - 0 abortion IUFD 2/43 4.7 Preterm birth 4/43 9.3 LBW 3/43 7.1 Malformation 1*/43 2.3 * Mega cysterna magna (11mm) Korean Motherisk Program, unpublished
  • 34. Pregnancy Outcomes Korean Motherisk Program Unpublished data
  • 35. Demographic characteristics of participants(n=321) Age (years) 32.0 ± 3.6 Comorbidities [n (%)] Gravidity (n) 2.2 ± 1.3 a) type 2 diabetes mellitus 1 (0.3) Parity (n) 1.0 (0, 3.0) b) hypertension 2 (0.6) Body mass index (kg/m2) 20.8 ± 3.2 c) thyroid disease 2 (0.6) d) cancer 1 (0.3) Exposure to X-rays e) renal disease 1 (0.3) a) n (%) 54 (16.8) Education level [n (%)] b) total dose (mSv) 0.005 (0.0005, 28.8) a) post-secondary education 130 (40.5) c) gestational age at exposure (weeks) 4.8 ± 3.2 b) high school 20 (6.2) Exposure to alcohol (%) c) not answered 171(53.3) a) n (%) 128 (39.9) Occupation b) total dose (oz) 1.6 ± 1.4 a) professional, technical and related occupatio 54 (16.8) c) gestational age at exposure (weeks) 4.6 ± 2.3 ns Smoking (%) b) executive, administrative, managerial and sal 136 (42.4) a) n (%) 23 (7.2) es occupations b) cigarettes/day 5.4 ± 4.4 c) construction workers 124 (38.6) c) gestational age at exposure (weeks) 6.3 ± 4.6 d) unemployed 7 (2.2) Korean Motherisk Program, unpublished
  • 36. Indications of herbal exposure (n=321) INDICATIONS a n (%) Analgesics 8 (2.5) Anti-acne preparations 2 (0.6) Anti-emetics & anti-nauseants 1 (0.3) Anti-inflammatory enzymes 8 (2.5) Anti-inflammatory & anti-rheumatic products 7 (2.2) Anti-obesity preparations 21 (6.5) Anti-thrombotic agents 2 (0.6) Cough and cold preparations 129 (40.2) Dermatological preparations 3 (0.9) 21 cases: Tonic Drugs for acid related disorder 1 (0.3) medicine Functional gastrointestinal disorders 93 (29.0) Gynecological anti infectives and antiseptics 11 (3.4) Psycholeptics 2 (0.6) Sex hormones & modulators the genital system 7 (2.2) Others 26 (8.1) aAccording to the pharmacological/therapeutic subgroups of the ATC classification system (World Health Organization Korean Motherisk Program, unpublished Collaborating Centre for Drug Statistics Methodology 2011)
  • 37. Exposure to herbal medicine in pregnant women (n=321) Median (range) Numbers of herbal medicine including 7.0 (1.0 - 40.0) one prescription Duration of exposure (days) 3.0 (1.0 – 365.0) Gestational age at last dose (weeks) 4.7 (0.1 - 25.0) 197 kinds of herbal medicines Korean Motherisk Program, unpublished
  • 38. Frequencies of Herbal medicine (>10%) n 188 200 150 100 75 91 81 71 103 50 46 65 71 57 57 48 43 45 0 43 45 41 40 33 Korean Motherisk Program, unpublished
  • 39. Fetal outcomes Cases (n= 307) Gestational age at birth (weeks) 38.9 ± 2.4 Birth weight (g) 3,294.2 ± 511.8 Birth length (cm) 49.7 ± 2.2 Head circumference at birth (cm) 34.6 ± 1.4 Apgar score, 1 min 8.3 ± 0.9 Apgar score, 5 min 9.0 ± 0.7 IUFD (%) 6 (2.0) Malformationsa (%) 7 (2.3) NICU admission (%) 12 (3.9) Duration of NICU admission (days) 12.5 ± 9.2 Neonatal jaundice (%) 10 (3.3) a A baby born with megacisterna magna, second one with dysplastic change of left kidney, left ectopic ureteral insertion, third one with small pulmonary artery, fourth one with polydactyly of 5th toe of left foot and cleft palate and patent ductus arteriosus, fifth one with small echogenic foci of anterior papillary muclse of left ventricle heart, sixth one with borderline left ventriculomegaly of cerebrum, and seventh one with patent ductus arteriosus Korean Motherisk Program, unpublished
  • 40. Summary (1) • Although herbal medicines have been used in clinical practice for thousands of years, basic research on herbal substances should be focused on the toxicity and efficacy relationship for those potent and poisonous herbal substances according to composite formula. • Most traditional medical herbs are used in the form of an aqueous decoction. Therefore research projects should be centered on development of analytical and biological procedures for use to give quality assurance, control, and clinical assessment of efficacy, and safety of products.
  • 41. Summary (2) • Herbal medications should be regulated for safety, quality and for appropriate evidence of efficacy. • Dosage and indications for treatment should be standardized. And contraindications should be clearly identified. • Language problem is another aspect as herbal ingredients are supplied with similarly names substitutes that could be toxic.
  • 42. Thank you for your attention