BOTANICAL SUPPLEMENTS FOR GUT HEALTH
P. Morazzoni
Indena S.p.A. Milan, Italy GUT HEALTH
A term widely "abused" in the medical literature and by the food industry.
It includes gut health and gastrointestinal health. Other abdominal organs, such as liver, pancreas, spleen or kidney are usually not associated with gut health. Bischoff S.C., BMC Medicine 2011, 9:24 KEY FUNCTIONAL ENTITIES
FOR
ACHIEVING/MAINTAINING
GUT HEALTH
● GASTROINTESTINAL MICROBIOME
● GASTROINTESTINAL BARRIER
INDIVIDUAL GI-COMPLAINTS* PROMPTING TO DOCTOR ●Flatulence ●Bloating ●Regurgitation ●Heart burn ●Nausea ●Vomiting ●Constipation ●Diarrhoea ●Food intolerance ●Incontinence ●Abdominal pain ●Cramps ●Loss of appetite ●Weight loss ●Blood in stools *usually associated to functional dyspepsia and IBS BOTANICAL INGREDIENTS FOR HEALTHY DIGESTION
"Given the limited efficacy of the majority of conventional drugs, it is not surprising that up to 50% of subjects with functional dyspepsia seek out alternative therapies. However, for acupunture, homeophaty or probiotics, evidence-based support is lacking. In this context, botanical supplements showed great potential". PLANTS TRADITIONALLY USED
FOR
THE RELIEF OF
GI-COMPLAINTS HERBAL BITTERS ● ANDROGRAPHIS [Andrographis paniculata (Burm. F.) Wall.] ● ARTICHOKE LEAF [Cynara cardunculus L. var. scolymus] ● BARBERRY [Berberis species] ● BONESET [Eupatorium species] ● CALAMUS [Acorus calamus L.] ● CASCARA SAGRADA [Rhamnus purshiana] ● CHAMOMILE [Matricaria chamomilla L.] ● DANDELION [Taraxacum officinale Weber] ● GENTIAN [Gentiana species] ● GOLDEN SEAL [Hydrastis canadensis L.] ● HOPS [Humulus lupulus L.] ● HOREHOUND [Marrubium vulgare L.] ● MOTHERWORT [Leonurus cardiac L.] ● OREGON GRAPE [Mahonia aquifolium] ● SAGE [Salvia species] ● SKULLCAP [Scutellaria species] ● VERVAIN [Verbena species] ● WORMWOOD [Artemisia absinthium L.] ● YARROW [Achillea millefolium L.] ACTIONS Enhance almost every aspect of digestion (salivation, digestive juice from stomach and pancreas, bile flow from the gallbladder, tone of the esophageal sphincter) HERBAL DEMULCENTS ● ALOE VERA [Aloe vera]
● CALENDULA [Calendula officinalis L.]
● CHAMOMILE [Matricaria chamomilla L.]
● COMFREY [Symphytum officinale L.]
● HOLY BASIL [Ocimum tenuiflorum L.]
● LICORICE [Glycyrrhiza glabra L.]
● MARSHMALLOW [Althaea officinalis L.]
● MEADOWSWEET [Filipendula ulmaria (L.) Maxim]
● SLIPPERY ELM [Ulmus rubra Muhl.] → FDA approved
● WILD YAM [Dioscorea villosa L.]
ACTIONS Soothe, coat and/or protect GI-mucosa HERBAL ANTISPASMODICS (Most carminatives fall into this category) ● ANGELICA [Angelica species]
● ANISE [Pimpinella anisum L.]
● CARAWAY [Carum carvi L.]
● CHAMOMILE [Matricaria chamomilla L.]
● CINNAMON [Cinnamomum verum J. Presl ]
● DILL [Anethum graveolens L.]
● FENNEL [Foeniculum vulgare Mill.]
● GINGER [Zingiber officinale Roscoe]
● HOPS [Humulus lupulus L.]
● LEMON BALM [Melissa officinalis L.]
● PEPPERMINT [Mentha x piperita]
● SAGE [Salvia species]
● THYME [Thymus vulgaris L.]
● WILD YAM [Dioscorea villosa L.]
ACTIONS Inhibit intestinal contractions via a number of mechanisms HERBAL ASTRINGENTS ● AGRIMONY [Agrimonia eupatoria L.]
● BAYBERRY [Myrica species]
● BLACKBERRY [Rubus species]
● CRANESBILL [Geranium species]
● GOLDEN SEAL [Hydrastis canadensis L.]
● HORSE CHESTNUT [Aesculus hippocastanum L.]
● MEADOWSWEET [Filipendula ulmaria (L.) Maxim]
● OAK LEAF/BARK [Quercus species]
● PLANTAIN [Musa species]
● RASPBERRY LEAF [Rubus species]
● SAGE [Salvia species]
● TEA [Camellia sinensis (L.) Kuntze]
● VERVAIN [Verbena species]
● WITCH HAZEL [Hamamelis species]
● WOOD BETONY [Stachys officinalis (L.) Trevis]
● YARROW [Achillea millefolium L.] ACTIONS Binding action on tissue (usually due to tannins). Reduce irritation, inflammation, create protective barrier. BOTANICALS AND GUT HEALTH (PRESENT AND FUTURE)
●Traditional use of botanicals for the relief of GI-complaints has a limited amount of supporting evidence-based medicine
●Lack of standardized products is one of the detrimental aspects limiting RCTs in this area
●Respect of GAP/GMP guidelines coupled with modern analytical approaches allow the setting up of high quality products MODERN APPROACH FOR
THE DEVELOPMENT OF
NEW BOTANICAL SUPPLEMENTS
FOR
GI-FUNCTIONAL DISORDERS
(A RECENT EXAMPLE) PRODIGEST®: A new patented and clinically tested combination for functional dyspepsia INTEGRATED AND UPDATED DEFINITION OF FUNCTIONAL DYSPEPSIA . Chronic and recurrent pain or discomfort centered in the upper abdomen in the absence of any known structural cause and without features of irritable bowel syndrome or of gastroesophageal reflux.
. Symptoms (frequently associated to meals) may include abdominal pain, bloating, early satiety, fullness, belching, nausea. Talley N.J. et al., GUT 45(2), 1137, 1999; Ford A.C. et al., Gastroenterology 146(4), 932, 2014; Moayyedi P.M. et al., Am J Gastroenterol 112 (7), 988-1013, 2017. EPIDEMIOLOGY OF FUNCTIONAL DYSPEPSIA The prevalence of functional dyspepsia at
global level varies between 11.0 and 29.2% of
adult population with relevant geographical
variation, being a very frequent clinical
finding in the western world.
Mahadeva S., Goh K.L., World J Gastroenterol. 12(17), 2661, 2006 CAUSES OF FUNCTIONAL DYSPEPSIA PATHOGENESIS OF FUNCTIONAL DYSPEPSIA ALGORITHM FOR THE TREATMENT OF FUNCTIONAL DYSPEPSIA
Moayyedi P.M. et al., Am J Gastroenterol 112 (7), 988-1013, 2017 FUNCTIONAL DYSPEPSIA - THERAPEUTIC OPTIONS
Therapeutic intervention Efficacy Subgroup most likely to benefit
Helicobacter pylori eradication Superior to placebo EPS Proton pump inhibitors Superior to placebo EPS H2-receptor antagonists Superior to placebo EPS Prokinetics Superior to placebo PDS Buspirone Superior to placebo PDS Superior to placebo if Antidepressants-TCAs EPS normal gastric emptying Antidepressants-SSRI, SNRI No better than placebo Antacids No better than placebo Bismuth salts No better than placebo Sucralfate No better than placebo
EPS, epigastric pain syndrome; PDS, postprandial distress syndrome; TCA, tricyclic antidepressant; SSRI, selective serotonin reuptake inhibitor; SNRI, selective norepinephrine reuptake inhibitor. RESTRICTIONS ON PROKINETICS (EUROPE)
EUROPE
DOMPERIDONE: new recommendations to minimize cardiac risks.
Restrictions on the use of domperidone-containing medicines
METOCLOPRAMIDE: updated indications and posology to minimize the risk of undesirable effects (mainly neurological)
European Medicines Agency recommends changes to the use of metoclopramide Changes aim mainly to reduce the risk of neurological side effects RESTRICTIONS ON PROKINETICS (OUTSIDE EUROPE) USA FDA Requires Boxed Warning and Risk Mitigation Strategy for Metoclopramide-Containing Drugs. Agency warns against chronic use of these products to treat gastrointestinal disorders.
CANADA
Health Canada is informing health professionals and Health Canada Endorsed Important Safety consumers that the labelling information for the drug Information on domperidone maleate. metoclopramide is being updated to include stronger Domperidone should be used at the lowest warnings on the risk of a movement disorder known as effective dose to a maximum recommended "tardive dyskinesia". daily dose of 30 mg and for the shortest possible duration. AUSTRALIA
TGA: The Product Information for metoclopramide has TGA: Domperidone should be used at the been updated to include a new contraindication and lowest effective dose for the shortest time changes to dosing and duration of use to reduce the possible. risk of neurological adverse events. PRODIGEST®: WHAT IS IT? PRODIGEST®: A PATENTED COMBINATION OF EXTRACTS FROM TWO FOOD PLANTS
Lipophilic CO2 extract of Zingiber officinalis (roots and rhyzomes) 20 mg/cps
A unique Indena standardized extract of Artichoke leaves 100 mg PRODIGEST®: A SYNERGISTIC COMBINATION OF DIETARY INGREDIENTS
Antispasmodic function (cynaropicrin) Choleretic and cholagogue function (caffeoylquinic acid and cynaropicrin) Reduction of swelling and sense of gatric fullness Gastrointestinal motility increase Anti-dyspeptic action Antioxidant function Gastroprotection Improvement of digestion
Antiemetic function (inhibition of receptors M3 and 5-HT3) Acts on gastrointestinal motility Gastric emptying increase Antioxidant/anti-inflammatory function Gastric protection Gastroprotection PRODIGEST®: STANDARDIZED EXTRACTS OF ARTICHOKE LEAVES AND GINGER
Capsule average content:
PYCRINIL® GINGER 100 mg/cps 20 mg/cps > 20% caffeoylquinic acids • 25-33% gingerols and > 5% flavonoids shogaols > 5% cynaropicrin PYCRINIL® vs STANDARD ARTICHOKE EXTRACTS
STANDARD PYCRINIL® ARTICHOKE EXTRACTS > 20% caffeoylquinic acids > 5% caffeoylquinic acid > 5% flavonoids > 0.3 flavonoids > 5% cynaropicrin Traces cynaropicrin PRODIGEST®: STABILITY AND SAFETY DATA STABILITY DATA
CAPSULES PACK
• In the original sealed pack, the product PRODIGEST® 10 capsules pack should be used preferably within 36 months from the manufacturing date.
CAPSULES BULK
• In the original sealed pack, the product should be used preferably within 12 months from the manufacturing date.
ARTICHOKE - ZINGIBER PREMIX
• In the original sealed pack, the product should be used preferably within 24 months from the manufacturing date. WHAT IS AVAILABLE: SAFETY STUDIES
TOXICOLOGICAL STUDIES
The acceptable daily intake (ADI), calculated on the basis of NOAEL (Artichoke extract), is equal to: PRODIGEST® ADI: 4 mg/kg /day ( ̴280 mg/person/day)
PRODIGEST® IS SAFE ACCORDING TO THE DAILY DOSAGE OF EACH INGREDIENT ADMINISTERED
PRODIGEST®: CLINICAL DATA FUNCTIONAL DYSPEPSIA STUDY PRODIGEST® is effective in subjects with functional dyspepsia - protocol
NATURE: double-blind, placebo-controlled randomized clinical trial (Gastroenterology Department, Gruppo Sanitario Policlinico di Monza, Italy)
DOSAGE: 1 capsule b.i.d for 4 week
POPULATION: 126 patients
PRIMARY END POINT: overall reduction of symptomatology after 2 and 4 wks of treatment
SECONDARY END POINT: variation of specific symptoms (epigastric fullness, bloating, early satiety, nausea, vomiting, epigastric pain) PRODIGEST® is effective for the primary end-point
PRODIGEST® 33.7% (+Δ) effective global after short- response term between treatment PRODIGEST® (14 d) vs Placebo
0: not improved or worsened, 1: slightly improved, 2: markedly improved, 3: completely improved PRODIGEST® is effective for the secondary end-points
Epigastric fullness Bloating PRODIGEST® is effective for the secondary end-points
Early satiety Nausea PRODIGEST® is effective for the secondary end-points
Vomiting Epigastric pain CONCLUSIONS - STUDY ON DYSPEPSIA
• PRODIGEST® effective after short-term treatment (14 d)
• 33.7% (+Δ) global response between PRODIGEST® and Placebo GASTRIC MOTILITY STUDY GASTRIC MOTILITY STUDY
NATURE: placebo-controlled, cross-over clinical study (Gastroenterology Department, Gruppo Sanitario Policlinico di Monza, Italy)
DOSAGE: 1 capsule (100 mg Pycrinil®, 20 mg ginger extract)
END POINTS: a) overall acceleration of gastric empting as ………………………..evaluated by ultrasonography b) safety and tolerability STUDY DESIGN STUDY DESIGN 1. EVALUATION OF BASELINE AREA OF GASTRIC VOLUME (time 0)
2. TREATMENT OR PLACEBO AND STANDARD MEAL (time 10 min)
100 g 100 g 300 mL 3. EVALUATION OF POST-PRANDIAL AREA OF GASTRIC VOLUME (time 60 min)
4. CROSSOVER (one week wash-out) VARIATION IN GASTRIC AREA BETWEEN BASELINE AND AFTER-MEAL After meal, After meal, Difference between Patient Baseline PRODIGEST® placebo PRODIGEST® and placebo (age, gender) (cm2) (cm2) (cm2) (%) 1 (60, F) 3.2 9.4 12.6 25.0 2 (55, F) 2.5 7.6 8.2 7.5 3 (28, F) 3.4 8.6 11.4 24.4 4 (34, M) 3.7 8.4 12.1 31.4 5 (45, F) 2.8 7.4 10.5 30.6 6 (46, F) 3.2 7.5 9.6 22.1 7 (39, M) 3.0 8.6 10.5 19.9 8 (48, M) 3.3 8.9 9.4 6.4 9 (41, M) 4.2 9.4 12.6 26.4 10 (24, M) 3.6 8.9 13.4 34.6 11 (32, F) 3.0 8.0 11.5 30.4 Mean±SD 3.2±0.5 8.4±0.7* 11.0±1.5* 24±9*** *p<0.001 vs baseline; *** p<0.001 for PRODIGEST® vs placebo. ENDOSCOPICAL EXAMINATION OF THE GASTROANTRAL AREA
1 h after meal 1 h after meal (plus placebo) (plus PRODIGEST) CONCLUSIONS - GASTRIC MOBILITY STUDY
Significantly Promotes It is Well Tollerated Gastric Emptying TAKE HOME MESSAGES . GUT HEALTH MAINTENANCE IS AN AREA OF INCREASING DEMAND IN THE CONSUMER HEALTH ARENA
. GI-COMPLAINTS PROMPTING INDIVIDUALS TO DOCTOR ARE FREQUENTLY ASSOCIATED TO GI-FUNCTIONAL DISORDERS WHICH HAMPER AN "HEALTHY DIGESTION"
. COMPLEMENTARY/ALTERNATIVE REMEDIES ARE INCREA- SING IN POPULARITY AS GUT-HEALTH AIDS, BUT RARELY SUPPORTED BY EVIDENCE-BASED MEDICINE
. BOTANICAL SUPPLEMENTS CAN REPRESENT A VALID OPTION STATED THAT QUALITY (GAP-GMP GUIDELINES), PRE-CLINICAL/CLINICAL EFFICACY AND SAFETY WOULD CONSTITUTE THE MAINSTREAM OF THEIR DEVELOPMENT (e.g. PRODIGEST® FOR FUNCTIONAL DYSPEPSIA)