PlantLIBRA EU Project

PlantLIBRA EU ProjectRome - Ministry of Health - Sept 21, 2012

Report WP4Investigations on adverse effects to botanicals and plant food supplements (PFS):

Methods, biological markers, and network of Poisons Centres

Alessandro Ceschi, M.D.Head, Division of Science

Swiss Toxicological Information Centre, Assoc. Inst. University of Zurich

on behalf of the WP4 partners

2

WP4 Partners

Swiss Toxicological Information Centre (STIC) (9 PM)(WP Leader)

Hugo KupferschmidtAlessandro CeschiSaskia Lüde

Università degli studi di Milano (UMIL) (13 PM)

Patrizia RestaniChiara Di LorenzoAriana dos Santos

Universidade de São Paulo (USP) (14 PM)

Elizabeth de Souza Nascimento

REPORT WP4 – ROME – MINISTRY OF HEALTH – SEPT 21, 2012

3

WP4 Objectives – DoW

• Investigation of adverse effects to botanicals andPFS via the collection of existing data (literature)

• Production of experimental results to support asustainable integrated meta-database (to beenclosed in WP6), particularly...


4

WP4 Objectives – DoW (2)...particularly

• case data with information and characterization of botanical ingredients, their role in adverse effects, their misidentification with poisonous plants, the interactions with nutrients or drug bioavailability (data from European Poisons Centres)

• identification of suitable biomarkers to easily recognizeadverse effects and poisonings

• additional data relative to new poisoning cases

• a connection to the existing international network ofPoisons Centres to collect scientific data on adverseeffects in humans of plants used as food or food supplements


5

WP4 – Summary Aims

Risks - Adverse effects and poisoning

1. From regular intake

2. Through misidentification with edible plants

3. Through interactions with pharmaceuticals and food

4. Implementation of alerts and warnings


6

WP4 – Tasks («methods»)

1. Literature search

2. Retrospective Study («cases»)

3. Prospective Study («samples»)

4. Implementation of databaseCase reports, analytical results, biomarkers of exposure and biomarkes of adverse effects

5. Alert network (from and to Poisons Centres)


7


1. Literature searchOn the basis of the PFS/plant list: Done

2. Retrospective StudyAnalysis of data, preparation of report: Almost done

3. Prospective StudyPreparation of the study protocol: In progress

4. Implementation of databasePending; Import of literature data by evaluators: In progress

5. Alert networkContact with EAPCCT: Done


8








9

WP4 – LiteratureLiterature references on adverse effects (MWP4.1)

PFS/Plant name AE No.Cinnamomum verum yes 39Glycyrrhiza glabra yes 36Camellia sinensis yes 26Cicimifuga racemosa yes 24Ginkgo biloba yes 22Cinnamomum zeylanicum yes 13Vitex agnus castus yes 13Hypericum perforatum yes 11Citrus aurantium yes 10Panax ginseng yes 10Citrus sinensis yes 9Foeniculum vulgare yes 8Echinacea purpurea yes 7Valeriana officinalis yes 7Taraxacum officinale yes 5Matricaria recutita yes 4Aloe ferox yes 3Echinacea pallida yes 3Vitis vinifera yes 3Melissa officinalis yes 2Olea europea yes 2Passiflora incarnata yes 2Silybum marianum yes 2

PFS/Plant name AE No.Aesculus hippocastanum yes 1Cassia angustifolia yes 1Hibiscus sabdariffa yes 1Lavandula intermedia yes 1Pelargonium sidoides yes 1Peumus boldus yes 1Pimpinella anisum yes 1Trifolium pratense yes 1


10

WP4 – Literature

Literature refs on interactions (MWP4.3)

PFS/Plant name IA No.Ginkgo biloba yes 18Glycyrrhiza glabra yes 14Valeriana officinalis yes 5Vitex agnus castus yes 5Cicimifuga racemosa yes 4Citrus aurantium yes 4Hypericum perforatum yes 4Panax ginseng yes 4Camellia sinensis yes 3Echinacea purpurea yes 2Artemisia abrotanum yes 1Cuminum cyminum yes 1Hibiscus sabdariffa yes 1Passiflora incarnata yes 1Silybum marianum yes 1

Literature refs on misidentifications (MWP4.2)

PFS/Plant name MIS No.Panax ginseng yes 2Passiflora incarnata yes 1


11








12

WP4 - Retrospective Study - Introduction

Background and rationale

•There is a lack of studies in the medical literature investigating the issues of PFS-related adverse effects and poisoning due to plants ingested because of misidentification

•To our knowledge, the few studies that have been performed to date, include data from a confined geographic area and no studies investigated the problem from a „Europe-wide perspective“


13

WP4 - Retrospective Study - Methods

Retrospective Poisons Centres Survey – Data acquisition

•Systematic multicentre retrospective review of data from selected European (and Brazilian) Poisons Centres •Using the EAPCCT network (63 PCs in 33 countries)•Study protocol presented and discussed in Brasov, May 2011•Study protocol sent to PCs in December 2011


14

WP4 - Retrospective Study - MethodsCase collection

• Adverse effects or poisoning• Adult or pediatric• PFS or plants from the list consumed as food, or

ingestion due to misidentification• 2006 – 2010

•Anonymized case data•In English (French, Italian, Spanish, German)

•Return of case data in March/April 2012 Answer from 41 PCs, 11 provided cases 527 cases

→ Data analysis and evaluationREPORT WP4 – ROME – MINISTRY OF HEALTH – SEPT 21, 2012

15

WP4 - Retrospective Study - Methods

Cases assessed for• Association between symptoms/signs and ingestion

with modified WHO-UMC standardised case causality assessment criteria• certain / probable / possible / unlikely• co-morbidities, (over)dose and co-ingestions considered

• Poisoning Severity Score (Persson H et al. Clin Toxicol. 1998)

• minor / moderate / severe / fatal

By an expert panel including1) Pharmacist with expertise in plants2) Clinical pharmacologist and toxicologist with

additional qualifications in general internal medicine


16

WP4 - Retrospective Study - ResultsCases - exclusion process and composition•527 cases initially reported to the STIC•374 (71%) excluded due to:

• insufficient causal relationship between ingested plant/PFS and observed symptoms and signs

• no PFS and plant not on the list• circumstances of ingestion• year of occurrence

•153 (29%) included for analysis Adverse effects after intentional ingestion

(therapeutic/supratherapeutic & food): 92 cases Misidentification: 60 cases Interaction: 1 case


17

WP4 - Retrospective Study - Results

Cases provided by countries

• Italy 59

• France 54

• Finland 11

• Switzerland 6

• Germany 5

• Sweden 5

• Serbia 5

• Brazil 5

• Austria 3


18


PFS/plants with the highest number of cases


19


Type of PFS – one vs multiple ingredient(s)

• PFS with > 1 ingredient («PFS multi») showed a tendency towards more severe clinical courses compared to PFS with 1 ingredient («PFS mono») (OR 3.91; 95% CI, 0.38-40.11; p=0.32)


20

WP4 - Retrospective Study - ResultsAdverse effects after intentional ingestion

PFS/Plants & Severity


21

WP4 - Retrospective Study - ResultsAdverse effects after intentional ingestionDemographic characteristics & Severity

91.3%


22


Severity

•Most cases showed a benign clinical courseInferential statistics (preliminary results):

ORs with 95% CIs & Fisher exact probability test with two-tailed p-value

•Children had a tendency towards more “minor clinical courses” (OR 1.48; 95% CI, 0.36-5.98; p=0.74)

•Adults > 65 y showed a tendency towards more moderate and severe clinical courses compared to younger patients (OR 1.93; 95% CI, 0.80-4.62; p=0.17)


23


Severe cases of adverse effects after intentional ingestion


24


Adverse effects after intentional ingestion Organ toxicities & Gender

• No stat. significant differences found between genders for occurrence of organ toxicities (e.g. neurotoxicity - but for some organ toxicities unfortunately insufficient number of cases to perform inferential statistics)


25

WP4 - Retrospective Study - ResultsPoisoning due to misidentification with edible plants

PFS/Plant & Severity


26


Severe cases of poisoning due to misidentification with edible plants


27


Only 1 case

•67 y/o male

•PFS containing Ginkgo biloba

•Acetylsalicylic acid (Aspirin cardio®)

Bleeding (epistaxis)

Interactions


28

WP4 - Retrospective Study - Limitations• Mainly related to the retrospective nature of the study

design, e.g. incompleteness of data, lack of uniform data classification

• Related to the object of the study, e.g. lack of uniform categorization of PFS

• Reporting bias to PCs:

• Delayed acute/subacute effects and chronic toxicity probably underrepresented

• Severe cases probably overrepresented

• Relatively few cases, especially for some PFS/plants & some organ toxicities due to strict inclusion criteria


29

WP4 - Retrospective Study - Conclusions• PFS-related adverse effects are relatively infrequent

issues for poisons centres

• Most cases in this study showed mild symptoms and a benign clinical course

• Nevertheless, the occurrence of some severe adverse effects and the increasing popularity of PFS, requires continuous active surveillance, especially of vulnerable groups such as the elderly

• There is a need for further investigations to validate the preliminary results of this study, and a multidisciplinary approach with an international perspective should be prioritised


30








31

WP4 – Prospective Study

Background

• In other WPs of PlantLIBRA, biomarkes of1) exposure and 2) adverse effects will be identified

• Selected clinical cases of adverse effects and poiso-ning will be studied to evaluate (new) biological markers

• Calls to partner Poisons Centres (from the retrospec-tive study) will be used to prospectively identify newcases


32


Aims

• To identify new clinical cases of adverse effects andpoisoning due to PFS in order to be studied to confirm known biological markers or define new indexes of exposure to plants consumed as foods or food supplements


33


Methods

Inclusion criteria:•Patients complaining about adverse effects after the consumption of PFS

or poisoning with plants (from the list)

after ingestion due to misidentification


34

WP4 – Prospective StudyMethods (recruiting process)• Participating Poisons Centres will report new cases

immediately to the WP4 team (Zurich), if callingphysician give consent

• Study material (study protocol, protocol summary, consent forms) will be immediately sent to the treating physician• by the Poisons Center receiving the call, or• by the Zurich WP4 team, or• it can be downloaded from the PlantLIBRA website

• If blood and urine samples are obtained (clinical indication, not for the study!) treating physicians are asked to store them for possible later use


35


Methods (2)

• Patients will be informed about the study and will be asked for informed consent

• Study protocol will be submitted to the local Ethics Committee for approval

• Only if Ethics Committee approves ANDif patient signs informed consent, then case will be included in the study and samples will be shipped to the lab (UMIL) for analyses

• Lab sends shipping material to the treating physician


36


Methods (3)

A full clinical case data set is obtained:• Case identifier (anonymized)• Date of exposure• Duration of exposure (acute single, repeated)• Age, sex, weight• Ingested agent (PFS, plant) – identification• Symptoms, signs, lab values• Treatments and decontamination procedures• Outcome


37








38

WP4 - Alert network

Implementation of the international alert network

•Development of a wider alert system for adverse effects via a link with European Poisons Centres (EAPCCT network) & laboratories The membership section of the EAPCCT website has: a forum to post messages to the EAPCCT members an alerting function which forwards posted messages to all

members by e-mail

Members of the EAPCCT can be reached very quicklyThis could be used to spread alerts concerning PFS


Documents

PlantLIBRA EU Project