Research ArticlePhytopharmacovigilance in the Elderly Highlights fromthe Brazilian Amazon

Carolina Miranda de Sousa Lima 1 Mayara Amoras Teles Fujishima1

Braacuteulio Eacuterison Franccedila dos Santos2 Bruno de Paula Lima2 Patr-cia CarvalhoMastroianni3

Francisco Faacutebio Oliveira de Sousa4 and Jocivacircnia Oliveira da Silva1

1Toxicology Laboratory Pharmacy Course Departament of Biological and Health Sciences Federal University of AmapaJuscelino Kubitschek Highway KM-02 Jardim Marco Zero ZIP Code 68903-419 Macapa - AP Brazil

2Medicine Course Department of Biological and Health Sciences Federal University of Amapa Juscelino Kubitschek HighwayKM-02 JardimMarco Zero ZIP Code 68903-419 Macapa - AP Brazil

3Faculty of Pharmaceutical Sciences State University Paulista Julio Mesquita Filho Araraquara Rodovia Araraquara-Jau KM 01Machados ZIP Code 14800-901 SP Brazil

4Quality Control and Bromatology Laboratory Pharmacy Course Department of Biological and Health SciencesFederal University of Amapa Juscelino Kubitschek Highway KM-02 JardimMarco Zero ZIP Code 68903-419Macapa - AP Brazil

Correspondence should be addressed to Carolina Miranda de Sousa Lima carolinams1yahoocombr

Received 24 October 2018 Revised 12 December 2018 Accepted 6 January 2019 Published 3 February 2019

Academic Editor Mohammed S Ali-Shtayeh

Copyright copy 2019 Carolina Miranda de Sousa Lima et al This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

Practices described as traditional medicine may coexist with formalized science-basedmedicine In this context the present studyaimed to verify the profile of the elderly who consumed herbalmedicines concomitantly withmedications and to identify suspectedadverse drug reactions (ADRs) in the Brazilian Amazon (MacapaAmapa)The study was carried out in two steps a cross-sectionalstudy (structured questionnaire) and a clinical study (pharmacotherapeutic follow-up) Out of 208 participants 788 were femalewith age between 60 and 69 years (587) 591used herbalmedicines concurrentlywithmedications and 409did not report useof herbal medicine Losartan was the most used medication and Lippia alba (Mill) NE Br was the most common herbal medicineused The total prevalence of suspected ADRs among the elderly who answered the structured questionnaire was 413 with274 being in the elderly who used herbal medicines and medications and 139 being in the elderly who used only medicationsMeanwhile the total prevalence of suspected ADRs was 710 among the elderly patients who underwent pharmacotherapeuticfollow-up 605 in elderly who used herbal medicines and medications and 105 in elderly who used only medications Themost reported ADR symptoms were related to disorders that affect the nervous system (384) in the structured questionnaire andrelated to digestive disorders (364) in the pharmacotherapeutic follow-up The probability associated with the occurrence of agiven ADR in the face of a set of demographic socioeconomic and clinical variables was estimated the results showed that inthe studied population only sex (p = 0030) had an influence on the occurrence of ADR The prevalence of ADRs with probablecausality was high in this study population but it was only sex-related although more prevalent in the elderly who consume herbalmedicines

1 Introduction

Herbal medicines are widely used in healthcare worldwidemainly in local communities that have a long history of theiruse in traditional medicine defined by World Health Orga-nization (WHO) as ldquothe sum total of the knowledge skillsand practices based on the theories beliefs and experiences

indigenous to different cultures whether explicable or notused in the maintenance of health as well as in the preventiondiagnosis improvement or treatment of physical and mentalillnessrdquo [1] In Brazil traditional medicine was historicallybuilt from a combination of knowledge and practices ofdifferent peoples especially indigenous groups Europeansand Africans [2 3]

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2019 Article ID 9391802 12 pageshttpsdoiorg10115520199391802

2 Evidence-Based Complementary and Alternative Medicine

The phytomedicine (the use of herbal medicines withtherapeutic properties) in the Brazilian Amazon has emergedfrom a long historical tradition of using products from naturefor curing diseases Several factors contribute to the increaseddemand for these products such as rich biodiversity culturalknowledge and social and economic factors [4] Medicinalplants are customarily cultivated or extracted from nativevegetation and are increasingly being purchased in localmarkets pharmacies and other establishments

Many countries have practices described as traditionalmedicine which may coexist with formalized science-basedand institutionalized systems of medical practice representedby biomedicine here defined as the hegemonic medicalsystem based on the principles of Western science whereboth are considered as complementary [4ndash6]

Since the late 70s in various statements and resolutionsthe WHO has expressed its commitment to encouragethe formulation and implementation of public policies forintegrated and rational use of traditional medicine (comple-mentaryalternative medicine) and biomedicine in nationalhealthcare as well as the development of studies for bet-ter scientific knowledge about its safety and efficacy [7]The documents ldquoWHO Strategy on Traditional Medicine2002ndash2005rdquo [8] ldquoWHO Guidelines on Safety Monitoring ofHerbal Medicines in Pharmacovigilance Systemsrdquo [9] andldquoNational Policy on Traditional Medicine and Regulation ofHerbal Medicinesrdquo [10] reaffirm the development of theseprinciples

In 2006 Brazilrsquos Ministry of Health Brazilian estab-lished a National Policy for Integrative and Complemen-tary Practices (PNPIC) which include traditional medicineThis policy caters mainly the need to understand supportincorporate and implement experiences with integrativepractices (which include traditional medicine) that hadalready been developed in primary healthcare in manycities and states [11 12] This system is contemplating thedoctrinal principles of Unified Health System (SUS) asuniversality equity and integrality and helps to strengthenthe system which is a social victory of the Brazilian people[7]

During the last years many countries have establishedor initiated the process of establishing national regulationsregarding herbal medicines which is a key mean to ensurethe safety efficacy and quality of herbal medicinal prod-ucts Adverse events arising from consumption of herbalmedicines may be due to any one of a number of factorsThese include the use of the wrong species of plant bymistake adulteration of herbal products with other unde-clared medicines contamination with toxic or hazardoussubstances overdosage misuse of herbal medicines eitherby the healthcare providers or the consumers and use ofthe herbal medicines concomitantly with other medicationsTherefore the analysis of adverse events related to the use ofherbal medicines is more complicated than in the case of themedication [9 10]

Ethnobotanicalethnopharmacological studies have beenused extensively to describe uses doses dosages and sourcesand methods of preparation of traditional herbal medicinesbut their application to date in examining adverse effects

responses to adverse effects contraindications toxicity andother aspects relevant to safety is limited [13]

In recent years there has been increasing recognition ofthe need to develop pharmacovigilance (safety monitoring)systems for herbal medicines In Brazil as in other countriesmedicinal herbs are traditionally considered to be ldquonaturaland therefore free of risksrdquo [13 14] Pharmacovigilancepractices and tools though have developed in the context ofthe biomedicine have rarely considered the complexities ofmonitoring the safety of medicines sourced from plants [15]and require collecting more information about their methodsof preparation administration adverse events contraindica-tions and precautions [13]

Herbal medicines use is relatively common amongelderly However these individuals are considered a lsquospecialpopulationrsquo because they differ from younger adults interms of comorbidity polypharmacy pharmacokinetics andgreater vulnerability to adverse drug reactions (ADRs) [16ndash18] defined as any harmful unintentional or undesirableeffect caused by a medication at doses used in humansfor prophylaxis diagnosis or therapy [19ndash21] Therefore anherbal medicine surveillance scheme is essential to promotetheir safe use among the elderly and identify probable ADRs

In this context the present study aimed to verify theprofile of the elderly who consumed herbal medicines con-comitantly with medications and to identify suspected ADRsthrough a structured questionnaire and pharmacotherapeu-tic follow-up in the Brazilian Amazon (Macapa Amapa)

2 Methods

Study design and setting This study was carried out in twostages (1) a cross-sectional study and (2) a clinical study usedto obtain further information especially on suspected ADRsAll steps were carried out from May 1 2016 to October 12017 at the Frei Daniel de Samarate Primary Healthcare Unitin the city of Macapa (latitude 00∘021015840188410158401015840N and longitude51∘031015840591010158401015840W) located in the north of Brazil The town hasan estimated area of 6503458 km2 with a population ofover 398204 out of which 20508 are elderly individuals[27] Macapa is situated in the Plateau of the Guianas in thesoutheast of the state of Amapa and the state is bounded bythe state of Para in the west and south by French Guianain the north by the Atlantic Ocean to the northeast by themouth of the Amazon River to the east and by Suriname tothe northwest with few land connections with other parts ofBrazil [27]

Participants (recruitment inclusion and exclusion cri-teria) Elderly users of the basic health unit who met thefollowing inclusion criteria were invited to participate in thestudy people were at least 60 years of age were nonindige-nous (according to ethical criteria (because studies involvingindigenous people and their knowledgeculture must followspecific ethical recommendations) were in perfect mentalhealth (determined throughmedical record review) and havehad provided free and informed consent Those who did notmeet the inclusion criteria were excluded from the study

Variables Data collection was performed using struc-tured questionnaires and pharmacotherapeutic follow-up

Evidence-Based Complementary and Alternative Medicine 3

The information obtained included participants sociode-mographic characteristics (age sex marital status incomeschooling and income source) clinical factors (pharma-cotherapy polypharmacy ge5 drugs [23] herbal medicinesused pharmacotherapeutic experience the results of labo-ratory tests therapy safety social drug use immunizationsallergies and alerts) and suspected ADRs

Data sourcesmeasurement In the structured ques-tionnaire prepared by the authors data were obtainedthrough face-to-face interviews and pharmacotherapy anal-ysis included prescription medications over-the-counter(OTC) medications and herbal medicines The instrumentused for the research (structured questionnaire) is a methodused widely in collecting pharmacoepidemiological data [2829] We considered as medicines over-the-counter (OTC)those reported by the elderly to be used without guid-ancemedical prescription and which were contained in theOTC list [30] which defines medicines that can be soldwithout a prescription in Brazilian territory and they wereanalyzed as the other medicinal products without distinc-tion

Pharmacotherapeutic follow-up is a practice that can beperformed by several methodsmdashsuch as SOAP SubjectiveObjective Assessment Plan [31] Dader [32] and the PWDTPharmacistrsquos Workup of Drug Therapy [33 34]mdashand wasdeveloped by pharmacists in response to a need for ongo-ing treatment of medication-based health problems and tohelp achieve the patientrsquos therapy goals thereby optimizingthe patientrsquos medical experience The pharmacotherapeuticfollow-up is very useful and efficient for the detection of drug-related problems (DRP) that may indicate suspected adversedrug reactions

In this study the method used was the PharmacistrsquosWorkup of Drug Therapy (PWDT) [33 34] the standard forpharmacotherapy follow-up and ADR investigation The planof pharmaceutical care was built up in the first consultationsaccording to the recommendations of the chosen methodstarting from the detection of drug-related problems (DRP)and analysis of these problems to define the necessaryinterventions Subsequently the impact of the interventionswas assessed through their clinical significance and codesthat describe whether the intervention was appropriateindifferent or inappropriate [35 36] The entire workingprocedure during the consultations was duly documentedand recorded as recommended by the method [33 34]and this information was also used to observe or measurethe patients positive experience with drug therapies (effec-tiveness) and to verify or measure any undesirable effectsthe patient may have experienced during the drug therapy(safety) Only the initial steps of the follow-up (drug-relatedproblems and analysis of these problems) were analyzedin the present study and no information was used on theinterventions

From both instruments it was necessary to obtaininformation regarding (1) the identification of suspectedADR related to herbal medicines and medications and (2)identification of the drug therapy problems especially thoseconcerning safety The observations and inferences wereanalyzed in pairs Confirmation and management of the

suspected ADRs were carried out by evaluating the potentialcausality and temporal association between the occurrenceof the event and the use of medications [16ndash20] orandcomparing the events in our study with ADRs previouslyreported in the scientific literature

Bias Information about the possible ADRs was initiallyobtained through a structured questionnaire suspected casesof ADRwere then sent to the pharmacotherapeutic follow-upservice for amore detailed evaluation However adherence tothe service was low and may have led to an underestimationof the information

Sample size and quantitative variables All the elderlywho met the inclusion criteria were enrolled in the studytotaling 208 participants The selected patients answered thestructured questionnaire and after analysis of the data thosewith suspected ADR were invited to participate in the nextstep the pharmacotherapeutic follow-up of those invitedonly 38 agreed to participate

Statistical analyses BioEstat 53 software was used forstatistical analyses the hypotheses were bidirectional (1205831= 1205830) and 120572 = 005 Descriptive statistic (mean standard

deviation frequency) was used to characterize the populationand its variables Student T-test was also used to checkthe difference between medication used health problemspolypharmacy and ADR potentially (discrete quantitativevariables) Logistic regression was used to estimate the proba-bility associated with the occurrence of a given event (ADRs)in the face of a set of explanatory variables (demographicsocioeconomic clinical variables)

Ethical aspects This study was performed following theCode of Ethics of the World Medical Association It wasapproved by the Human Research Ethics Committee of theFederal University of Amapa (CAAE 38400314900000003)and all the patients signed a free and informed consent termauthorizing the study

3 Results

In total 208 patients were interviewed representing 1 ofthe elderly population of the city of Macapa [9] and 12of the elderly population assisted by the Brazilian HealthUnit System Table 1 shows that the mean age of the elderlyparticipants was 694plusmn75 and themajority of the participantsin the study were female (798) 60 to 69 years old theyoungest age group (587) either not married widowed ordivorced (688) and educated at the primary level (511)Additionally most study participants had an average incomeof le$58880 (740)

Out of the 100 patients (208) analyzed 591 (123)used herbal medicines concurrently with medications and409 (85) did not report the use of any herbal medicinein their pharmacotherapy Hypertension rheumatic diseasesdiabetes gastritis and dyslipidemia were the most prevalentdiseases (Table 2) constituting the average number of dis-eases with a value of 22plusmn11 and elderly people who usedherbal medicines in combination with medications presentedmore health issues (16plusmn10) comparedwith patients whousedonlymedications (19plusmn10)Most of the elderly (817) did notpractice polypharmacy (ge5 medications)

4 Evidence-Based Complementary and Alternative Medicine

Table 1 Demographic and socioeconomic characteristics of theelderly participants obtained through the structured questionnaire(N = 208) Macapa Brazil 2016-2017

Demographic and Socioeconomic IndexStructured

questionnaireN

GenderFemale 166 798Male 42 202

Total 208 100Age group (years)

60-69 122 58770-79 62 298ge80 24 115

Total 208 100Marital status

Not married widower and divorced 143 688Married 65 312

Total 208 100Education levelNot formal education 48 231

Primary education 105 501Secondary or postsecondary education 55 264

Total 208 100Household incomemonthlowast

le$58880 154 740gt$58880 ge$265000 46 221gt$265000 08 39Total 208 100lowastIn US dollars according to the Brazilian Central Bank [22] in 01082018(R$324)

In order to estimate the probability associated with theoccurrence of a given event (ADRs) in the face of a setof demographic socioeconomic and clinical variables amultiple logistic regression was performed The dependentvariable (Y) was the suspected ADR and the independentvariables were age schooling sex number of health prob-lems polypharmacy and usage of herbal medicines Theresults showed that in the studied population only sex (p= 0030 CI 95 023 to 093) had an influence on theoccurrence of suspected ADR However when estimatingthe Y value it was possible to observe that the elderly whouse herbal medicines have a 934 probability of developingADR while the elderly who do not use herbal medicines havea probability of 9051

The medications most commonly prescribed (struc-tured questionnaire) and used were losartan glibenclamideomeprazole and metformin (Table 3) and the mean numberwas 29plusmn14 by patient

Table 4 shows the most frequently reported herbalmedicines used by elderly participants according the struc-tured questionnaire along with their botanical names

reported properties and uses Lippia alba (Mill) NE Br(Cidreira 199) and the Peumus boldus Molina (Boldo111) were the most frequently consumed

According to the elderly the herbal medicines weremostly obtained in fairs or popular markets (516) and ingarden (370) while health establishments and pharma-cies were the last options (114) Presentations of herbalmedicines especially used were infusiontea (595) andplant extracts (275) Oral use (842) was the most com-mon mode of use of herbal medicines in this population(Table 5)

Compared with the results obtained in the structuredquestionnaire the pharmacotherapeutic follow-up was per-formed through the PWDT methodology standard methodand validated for clinical follow-up of pharmacotherapy Allthe elderly with potential ADRs were invited to participate inthis stage of the study but only 38 accepted 33 of whomwereelderly who used herbal medicines andmedicines and 5 usedonly medicines The medicines most commonly prescribedand used by the elderly who underwent pharmacotherapeuticfollow-up were losartan and omeprazole (Table 6)

Table 7 shows the most frequently reported herbalmedicines used by the elderly participants of pharmacother-apeutic follow-up along with their botanical names reportedproperties and uses The Peumus boldus Molina (Boldo194) and Lippia alba (Mill) NE Br (Cidreira 167) werethe most frequently consumed as well as the refueling in thepharmacotherapeutic follow-up

Regarding the potential ADRs among the elderly whoanswered the structured questionnaire there was a totalprevalence of 413 with 274 being in the elderly who usedherbal medicines and medicines and 139 in the elderlywho used only medicines Among the elderly people withsuspected ADRs selected by the structured questionnairewho agreed to continue the investigation 710 (27) had theirADRs confirmed It was only possible to define the ADRsin the structured questionnaire and pharmacotherapeuticfollow-up as shown in Table 8

The most frequently reported ADR symptoms wererelated to nervous system disorders (384) in the structuredquestionnaire and related to digestive disorders (364) inthe pharmacotherapeutic follow-up (Table 9)

4 Discussion

As a result increased use of herbal medicines in the Brazilianprimary healthcare system has been stimulated [11ndash37] notonly because of the international trend toward the use ofmore natural treatments but because these treatments arepart of the local culture Therefore facilitating improvedcommunication in pharmacovigilance is necessary [38 39] bycreating databases for phytotherapy programs and develop-ing and implementing bettermethods for causal investigationof adverse reactions to herbal medicines

It was possible to associate suspected ADR with sexindicating that women are more likely to develop ADR asalready shown in other studies where hormonal factors mayinfluence the establishment of an ADR [40 41] Besides thatwithin the elderly population in this study we observed a high

Evidence-Based Complementary and Alternative Medicine 5

Table 2 Clinic characteristics regarding only medication and herbal medicines in combination with medication use reported by the elderlyparticipants (N=208) Macapa Brazil 2016-2017

Clinic Index Onlymedications use n()

Herbal medicines andmedications use n () Total n () p valuelowastlowast

Health problems

p = 0004

Hypertension 58 (358) 64 (330) 122 (343)Rheumatic diseases 29 (179) 44 (227) 73 (205)Diabetes 19 (117) 28 (144) 47 (132)Heart problems 12 (74) 8 (41) 20 (56)Gastritis 4 (25) 12 (62) 16 (45)Dyslipidemias 8 (50) 6 (31) 14 (39)Depression 4 (25) 4 (21) 8 (225)Labyrinthitis 2 (12) 6 (31) 8 (225)Others 26 (172) 22 (113) 48 (135)Total 162 (100) 194 (100) 356 (100)

Polypharmacylowast

p lt 00001Yes 10 (118) 36 (293) 46 (221)No 75 (882) 87 (707) 162 (779)Total 85 (100) 123 (100) 208 (100)

Adverse Drug Reaction (ADR) suspectedYes 29 (341) 57 (463) 86 (413) p = 0045No 56 (659) 66 (537) 122 (587)Total 85 (100) 123 (100) 208 (100)

lowastClassification according to Kennerfalk et al (2002) [23] Polypharmacy ge5 medicineslowastlowastStudent T-test

prevalence of the use of herbal medicines as the majority ofthe participants were females whichmay have influenced theresultsThe high consumption of herbal medicines associatedwith the high level of female participation in this studyis supported by the findings of gender-based comparativestudies of the knowledge about medicinal plants Regardingsocial roles women are classified as wives and daughterswho oversee family health including diagnosing illnessesand knowing their prognosis they are also responsible forimplementing the first treatments [42ndash44]

Most of the elderly participants in this study were 60to 69 years of age the youngest category probably due tothe demographic characteristics of the region where thelife expectancy is not high Age did not show a significantinfluence on the occurrence of ADRs although many studiesindicate an increased risk of ADRswith age [15ndash41] so studiesin this population with a larger age group should clarify thisprobability better

Polypharmacy is an important concern for elderly peoplebecause they use multiple medications for long periods oftime increasing the likelihood of medication interactionsand ADRs [45ndash47] The clinical profile of the elderly inthis study was relatively comparable to their pharmacother-apeutic profile specifically the most prevalent diseases werehypertension rheumatic diseases diabetes and gastritis andthe medications used to treat them were losartan gliben-clamide and omeprazole These data also demonstrated thatrheumatic diseases although reported by the participantswere not frequently treated using medications

While medications are primarily used for blood pressureproblems general pain and endocrine and nutritional dis-eases [4] herbal medicines typically are used to treat simpleconditions such as digestive and respiratory problems andgeneral pain [48]This is supported by the data in the presentstudy wherein the herbal medicines most often reported bythe elderly participants were Lippia alba (Mill) NE Br andP boldus (Molina) the main indications for both of thesemedicines are for relaxation and digestive problems anddigestive system problems were the third most cited healthproblem

Studies of the medicinal use of herbs in Brazil haveshown that the most used dosage forms were infusion anddecoction followed by the use of fresh herbs and their usein bathing [49] In this study the most frequently reportedpharmaceutical formulations were infusiontea with herbsMost likely infusiontea is most commonly used due to thesimplicity of the preparation techniques Findings fromotherstudies corroborated this showing that the main sourcesof herbal medicines were free markets traditional healinghomes other sources and lastly drugstore [49 50] Themethods of administration of the herbal medicines identifiedin this study were oral and topical but another studydemonstrated that in African populations the main routes ofadministration in addition to oral and topical also includedrespiratory [51]

It is important to note that certain ethnobotanicaleth-nopharmacology aspects can be influenced by the regionalenvironmental conservation and storage factors of herbal

6 Evidence-Based Complementary and Alternative Medicine

Table 3 Medications reported by the elderly participants on the structured questionnaire (N=208) Macapa Brazil 2016-2017

Medications ATClowast Only medication usen () Herbal medicines andmedication use n ()

Acetylsalicylic acid N02BA01 15 (60) 10 (28)Alprazolam N05BA12 3 (12) 0 (00)Amiodarone C01B 1(04) 7 (20)Amitriptyline N06AA 1(04) 1 (03)Amlodipine C08CA01 2 (08) 6 (17)Atenolol C07A 2 (08) 4 (11)Atenolol C07AB03 5 (20) 4 (11)Calcium A12A 8 (32) 10 (28)Captopril C09AA01 6 (24) 7 (20)Carisoprodol M03 6 (24) 10 (28)Carvedilol C07A 2 (08) 4 (11)Chlorpheniramine R06AB02 2 (08) 3 (08)Clopidogrel B01A 2(08) 3 (08)Compounded drugs 11 (43) 15 (42)Diazepam N05BA01 5 (20) 5 (14)Diclofenac M01AB05 8 (32) 12 (34)Digoxin C01A 1(04) 3 (08)Dimenhydrinate A04AD 3 (12) 4 (11)Esomeprazole A02B 1(04) 1 (03)Ferrous Sulphate B03A 2 (08) 1 (03)Glibenclamide A10BB01 10 (40) 19 (53)Haloperidol N05B 1(04) 1 (03)Hydrochlorothiazide C03AA03 9 (36) 7 (20)Ibuprofen M01A 5 (20) 12 (34)Insulin A10AC01 3 (12) 8 (22)Losartan C09AA01 26 (103) 33 (92)Meloxicam M01AC06 6 (24) 1 (03)Metformin A10BA02 6 (24) 13 (36)Naproxen M01A 3 (12) 4 (11)Nifedipine C08CA05 5 (20) 6 (17)Nimesulide M01AX17 1 (04) 9 (25)Omeprazole A02BC01 9 (36) 15 (42)Pantoprazole A02B 1(04) 1 (03)Paracetamol N02BE01 1 (04) 12 (34)Propranolol C07A 3 (12) 3 (08)Ranitidine A02BA02 3 (12) 3 (08)Salbutamol R03 1(04) 3 (08)Scopolamine A03BB01 3 (12) 6 (17)Sertraline N06A 2 (08) 1 (03)Simvastatin C10AA01 9 (36) 4 (11)Zolpidem N05 5 (20) 7 (20)Others 53 (210) 78 (218)Total 251 (100)lowastlowast 358 (100)lowastlowastlowastClassification according to the Anatomical Therapeutic Chemical Code (ATC code) [24]lowastlowastWithout statistical meaningful difference between the amount of medications used in the groups (student t p = 04470)

Evidence-Based Complementary and Alternative Medicine 3

The information obtained included participants sociode-mographic characteristics (age sex marital status incomeschooling and income source) clinical factors (pharma-cotherapy polypharmacy ge5 drugs [23] herbal medicinesused pharmacotherapeutic experience the results of labo-ratory tests therapy safety social drug use immunizationsallergies and alerts) and suspected ADRs

Data sourcesmeasurement In the structured ques-tionnaire prepared by the authors data were obtainedthrough face-to-face interviews and pharmacotherapy anal-ysis included prescription medications over-the-counter(OTC) medications and herbal medicines The instrumentused for the research (structured questionnaire) is a methodused widely in collecting pharmacoepidemiological data [2829] We considered as medicines over-the-counter (OTC)those reported by the elderly to be used without guid-ancemedical prescription and which were contained in theOTC list [30] which defines medicines that can be soldwithout a prescription in Brazilian territory and they wereanalyzed as the other medicinal products without distinc-tion

Pharmacotherapeutic follow-up is a practice that can beperformed by several methodsmdashsuch as SOAP SubjectiveObjective Assessment Plan [31] Dader [32] and the PWDTPharmacistrsquos Workup of Drug Therapy [33 34]mdashand wasdeveloped by pharmacists in response to a need for ongo-ing treatment of medication-based health problems and tohelp achieve the patientrsquos therapy goals thereby optimizingthe patientrsquos medical experience The pharmacotherapeuticfollow-up is very useful and efficient for the detection of drug-related problems (DRP) that may indicate suspected adversedrug reactions

In this study the method used was the PharmacistrsquosWorkup of Drug Therapy (PWDT) [33 34] the standard forpharmacotherapy follow-up and ADR investigation The planof pharmaceutical care was built up in the first consultationsaccording to the recommendations of the chosen methodstarting from the detection of drug-related problems (DRP)and analysis of these problems to define the necessaryinterventions Subsequently the impact of the interventionswas assessed through their clinical significance and codesthat describe whether the intervention was appropriateindifferent or inappropriate [35 36] The entire workingprocedure during the consultations was duly documentedand recorded as recommended by the method [33 34]and this information was also used to observe or measurethe patients positive experience with drug therapies (effec-tiveness) and to verify or measure any undesirable effectsthe patient may have experienced during the drug therapy(safety) Only the initial steps of the follow-up (drug-relatedproblems and analysis of these problems) were analyzedin the present study and no information was used on theinterventions

From both instruments it was necessary to obtaininformation regarding (1) the identification of suspectedADR related to herbal medicines and medications and (2)identification of the drug therapy problems especially thoseconcerning safety The observations and inferences wereanalyzed in pairs Confirmation and management of the

suspected ADRs were carried out by evaluating the potentialcausality and temporal association between the occurrenceof the event and the use of medications [16ndash20] orandcomparing the events in our study with ADRs previouslyreported in the scientific literature

Bias Information about the possible ADRs was initiallyobtained through a structured questionnaire suspected casesof ADRwere then sent to the pharmacotherapeutic follow-upservice for amore detailed evaluation However adherence tothe service was low and may have led to an underestimationof the information

Sample size and quantitative variables All the elderlywho met the inclusion criteria were enrolled in the studytotaling 208 participants The selected patients answered thestructured questionnaire and after analysis of the data thosewith suspected ADR were invited to participate in the nextstep the pharmacotherapeutic follow-up of those invitedonly 38 agreed to participate

Statistical analyses BioEstat 53 software was used forstatistical analyses the hypotheses were bidirectional (1205831= 1205830) and 120572 = 005 Descriptive statistic (mean standard

deviation frequency) was used to characterize the populationand its variables Student T-test was also used to checkthe difference between medication used health problemspolypharmacy and ADR potentially (discrete quantitativevariables) Logistic regression was used to estimate the proba-bility associated with the occurrence of a given event (ADRs)in the face of a set of explanatory variables (demographicsocioeconomic clinical variables)

Ethical aspects This study was performed following theCode of Ethics of the World Medical Association It wasapproved by the Human Research Ethics Committee of theFederal University of Amapa (CAAE 38400314900000003)and all the patients signed a free and informed consent termauthorizing the study

3 Results

In total 208 patients were interviewed representing 1 ofthe elderly population of the city of Macapa [9] and 12of the elderly population assisted by the Brazilian HealthUnit System Table 1 shows that the mean age of the elderlyparticipants was 694plusmn75 and themajority of the participantsin the study were female (798) 60 to 69 years old theyoungest age group (587) either not married widowed ordivorced (688) and educated at the primary level (511)Additionally most study participants had an average incomeof le$58880 (740)

Out of the 100 patients (208) analyzed 591 (123)used herbal medicines concurrently with medications and409 (85) did not report the use of any herbal medicinein their pharmacotherapy Hypertension rheumatic diseasesdiabetes gastritis and dyslipidemia were the most prevalentdiseases (Table 2) constituting the average number of dis-eases with a value of 22plusmn11 and elderly people who usedherbal medicines in combination with medications presentedmore health issues (16plusmn10) comparedwith patients whousedonlymedications (19plusmn10)Most of the elderly (817) did notpractice polypharmacy (ge5 medications)

4 Evidence-Based Complementary and Alternative Medicine

Table 1 Demographic and socioeconomic characteristics of theelderly participants obtained through the structured questionnaire(N = 208) Macapa Brazil 2016-2017

Demographic and Socioeconomic IndexStructured

questionnaireN

GenderFemale 166 798Male 42 202

Total 208 100Age group (years)

60-69 122 58770-79 62 298ge80 24 115

Total 208 100Marital status

Not married widower and divorced 143 688Married 65 312

Total 208 100Education levelNot formal education 48 231

Primary education 105 501Secondary or postsecondary education 55 264

Total 208 100Household incomemonthlowast

le$58880 154 740gt$58880 ge$265000 46 221gt$265000 08 39Total 208 100lowastIn US dollars according to the Brazilian Central Bank [22] in 01082018(R$324)

In order to estimate the probability associated with theoccurrence of a given event (ADRs) in the face of a setof demographic socioeconomic and clinical variables amultiple logistic regression was performed The dependentvariable (Y) was the suspected ADR and the independentvariables were age schooling sex number of health prob-lems polypharmacy and usage of herbal medicines Theresults showed that in the studied population only sex (p= 0030 CI 95 023 to 093) had an influence on theoccurrence of suspected ADR However when estimatingthe Y value it was possible to observe that the elderly whouse herbal medicines have a 934 probability of developingADR while the elderly who do not use herbal medicines havea probability of 9051

The medications most commonly prescribed (struc-tured questionnaire) and used were losartan glibenclamideomeprazole and metformin (Table 3) and the mean numberwas 29plusmn14 by patient

Table 4 shows the most frequently reported herbalmedicines used by elderly participants according the struc-tured questionnaire along with their botanical names

reported properties and uses Lippia alba (Mill) NE Br(Cidreira 199) and the Peumus boldus Molina (Boldo111) were the most frequently consumed

According to the elderly the herbal medicines weremostly obtained in fairs or popular markets (516) and ingarden (370) while health establishments and pharma-cies were the last options (114) Presentations of herbalmedicines especially used were infusiontea (595) andplant extracts (275) Oral use (842) was the most com-mon mode of use of herbal medicines in this population(Table 5)

Compared with the results obtained in the structuredquestionnaire the pharmacotherapeutic follow-up was per-formed through the PWDT methodology standard methodand validated for clinical follow-up of pharmacotherapy Allthe elderly with potential ADRs were invited to participate inthis stage of the study but only 38 accepted 33 of whomwereelderly who used herbal medicines andmedicines and 5 usedonly medicines The medicines most commonly prescribedand used by the elderly who underwent pharmacotherapeuticfollow-up were losartan and omeprazole (Table 6)

Table 7 shows the most frequently reported herbalmedicines used by the elderly participants of pharmacother-apeutic follow-up along with their botanical names reportedproperties and uses The Peumus boldus Molina (Boldo194) and Lippia alba (Mill) NE Br (Cidreira 167) werethe most frequently consumed as well as the refueling in thepharmacotherapeutic follow-up

Regarding the potential ADRs among the elderly whoanswered the structured questionnaire there was a totalprevalence of 413 with 274 being in the elderly who usedherbal medicines and medicines and 139 in the elderlywho used only medicines Among the elderly people withsuspected ADRs selected by the structured questionnairewho agreed to continue the investigation 710 (27) had theirADRs confirmed It was only possible to define the ADRsin the structured questionnaire and pharmacotherapeuticfollow-up as shown in Table 8

The most frequently reported ADR symptoms wererelated to nervous system disorders (384) in the structuredquestionnaire and related to digestive disorders (364) inthe pharmacotherapeutic follow-up (Table 9)

4 Discussion

As a result increased use of herbal medicines in the Brazilianprimary healthcare system has been stimulated [11ndash37] notonly because of the international trend toward the use ofmore natural treatments but because these treatments arepart of the local culture Therefore facilitating improvedcommunication in pharmacovigilance is necessary [38 39] bycreating databases for phytotherapy programs and develop-ing and implementing bettermethods for causal investigationof adverse reactions to herbal medicines

It was possible to associate suspected ADR with sexindicating that women are more likely to develop ADR asalready shown in other studies where hormonal factors mayinfluence the establishment of an ADR [40 41] Besides thatwithin the elderly population in this study we observed a high

Evidence-Based Complementary and Alternative Medicine 5

Table 2 Clinic characteristics regarding only medication and herbal medicines in combination with medication use reported by the elderlyparticipants (N=208) Macapa Brazil 2016-2017

Clinic Index Onlymedications use n()

Herbal medicines andmedications use n () Total n () p valuelowastlowast

Health problems

p = 0004

Hypertension 58 (358) 64 (330) 122 (343)Rheumatic diseases 29 (179) 44 (227) 73 (205)Diabetes 19 (117) 28 (144) 47 (132)Heart problems 12 (74) 8 (41) 20 (56)Gastritis 4 (25) 12 (62) 16 (45)Dyslipidemias 8 (50) 6 (31) 14 (39)Depression 4 (25) 4 (21) 8 (225)Labyrinthitis 2 (12) 6 (31) 8 (225)Others 26 (172) 22 (113) 48 (135)Total 162 (100) 194 (100) 356 (100)

Polypharmacylowast

p lt 00001Yes 10 (118) 36 (293) 46 (221)No 75 (882) 87 (707) 162 (779)Total 85 (100) 123 (100) 208 (100)

Adverse Drug Reaction (ADR) suspectedYes 29 (341) 57 (463) 86 (413) p = 0045No 56 (659) 66 (537) 122 (587)Total 85 (100) 123 (100) 208 (100)

lowastClassification according to Kennerfalk et al (2002) [23] Polypharmacy ge5 medicineslowastlowastStudent T-test

prevalence of the use of herbal medicines as the majority ofthe participants were females whichmay have influenced theresultsThe high consumption of herbal medicines associatedwith the high level of female participation in this studyis supported by the findings of gender-based comparativestudies of the knowledge about medicinal plants Regardingsocial roles women are classified as wives and daughterswho oversee family health including diagnosing illnessesand knowing their prognosis they are also responsible forimplementing the first treatments [42ndash44]

Most of the elderly participants in this study were 60to 69 years of age the youngest category probably due tothe demographic characteristics of the region where thelife expectancy is not high Age did not show a significantinfluence on the occurrence of ADRs although many studiesindicate an increased risk of ADRswith age [15ndash41] so studiesin this population with a larger age group should clarify thisprobability better

Polypharmacy is an important concern for elderly peoplebecause they use multiple medications for long periods oftime increasing the likelihood of medication interactionsand ADRs [45ndash47] The clinical profile of the elderly inthis study was relatively comparable to their pharmacother-apeutic profile specifically the most prevalent diseases werehypertension rheumatic diseases diabetes and gastritis andthe medications used to treat them were losartan gliben-clamide and omeprazole These data also demonstrated thatrheumatic diseases although reported by the participantswere not frequently treated using medications

While medications are primarily used for blood pressureproblems general pain and endocrine and nutritional dis-eases [4] herbal medicines typically are used to treat simpleconditions such as digestive and respiratory problems andgeneral pain [48]This is supported by the data in the presentstudy wherein the herbal medicines most often reported bythe elderly participants were Lippia alba (Mill) NE Br andP boldus (Molina) the main indications for both of thesemedicines are for relaxation and digestive problems anddigestive system problems were the third most cited healthproblem

Studies of the medicinal use of herbs in Brazil haveshown that the most used dosage forms were infusion anddecoction followed by the use of fresh herbs and their usein bathing [49] In this study the most frequently reportedpharmaceutical formulations were infusiontea with herbsMost likely infusiontea is most commonly used due to thesimplicity of the preparation techniques Findings fromotherstudies corroborated this showing that the main sourcesof herbal medicines were free markets traditional healinghomes other sources and lastly drugstore [49 50] Themethods of administration of the herbal medicines identifiedin this study were oral and topical but another studydemonstrated that in African populations the main routes ofadministration in addition to oral and topical also includedrespiratory [51]

It is important to note that certain ethnobotanicaleth-nopharmacology aspects can be influenced by the regionalenvironmental conservation and storage factors of herbal

6 Evidence-Based Complementary and Alternative Medicine

Table 3 Medications reported by the elderly participants on the structured questionnaire (N=208) Macapa Brazil 2016-2017

Medications ATClowast Only medication usen () Herbal medicines andmedication use n ()

Acetylsalicylic acid N02BA01 15 (60) 10 (28)Alprazolam N05BA12 3 (12) 0 (00)Amiodarone C01B 1(04) 7 (20)Amitriptyline N06AA 1(04) 1 (03)Amlodipine C08CA01 2 (08) 6 (17)Atenolol C07A 2 (08) 4 (11)Atenolol C07AB03 5 (20) 4 (11)Calcium A12A 8 (32) 10 (28)Captopril C09AA01 6 (24) 7 (20)Carisoprodol M03 6 (24) 10 (28)Carvedilol C07A 2 (08) 4 (11)Chlorpheniramine R06AB02 2 (08) 3 (08)Clopidogrel B01A 2(08) 3 (08)Compounded drugs 11 (43) 15 (42)Diazepam N05BA01 5 (20) 5 (14)Diclofenac M01AB05 8 (32) 12 (34)Digoxin C01A 1(04) 3 (08)Dimenhydrinate A04AD 3 (12) 4 (11)Esomeprazole A02B 1(04) 1 (03)Ferrous Sulphate B03A 2 (08) 1 (03)Glibenclamide A10BB01 10 (40) 19 (53)Haloperidol N05B 1(04) 1 (03)Hydrochlorothiazide C03AA03 9 (36) 7 (20)Ibuprofen M01A 5 (20) 12 (34)Insulin A10AC01 3 (12) 8 (22)Losartan C09AA01 26 (103) 33 (92)Meloxicam M01AC06 6 (24) 1 (03)Metformin A10BA02 6 (24) 13 (36)Naproxen M01A 3 (12) 4 (11)Nifedipine C08CA05 5 (20) 6 (17)Nimesulide M01AX17 1 (04) 9 (25)Omeprazole A02BC01 9 (36) 15 (42)Pantoprazole A02B 1(04) 1 (03)Paracetamol N02BE01 1 (04) 12 (34)Propranolol C07A 3 (12) 3 (08)Ranitidine A02BA02 3 (12) 3 (08)Salbutamol R03 1(04) 3 (08)Scopolamine A03BB01 3 (12) 6 (17)Sertraline N06A 2 (08) 1 (03)Simvastatin C10AA01 9 (36) 4 (11)Zolpidem N05 5 (20) 7 (20)Others 53 (210) 78 (218)Total 251 (100)lowastlowast 358 (100)lowastlowastlowastClassification according to the Anatomical Therapeutic Chemical Code (ATC code) [24]lowastlowastWithout statistical meaningful difference between the amount of medications used in the groups (student t p = 04470)

4 Evidence-Based Complementary and Alternative Medicine

Table 1 Demographic and socioeconomic characteristics of theelderly participants obtained through the structured questionnaire(N = 208) Macapa Brazil 2016-2017

Demographic and Socioeconomic IndexStructured

questionnaireN

GenderFemale 166 798Male 42 202

Total 208 100Age group (years)

60-69 122 58770-79 62 298ge80 24 115

Total 208 100Marital status

Not married widower and divorced 143 688Married 65 312

Total 208 100Education levelNot formal education 48 231

Primary education 105 501Secondary or postsecondary education 55 264

Total 208 100Household incomemonthlowast

le$58880 154 740gt$58880 ge$265000 46 221gt$265000 08 39Total 208 100lowastIn US dollars according to the Brazilian Central Bank [22] in 01082018(R$324)

In order to estimate the probability associated with theoccurrence of a given event (ADRs) in the face of a setof demographic socioeconomic and clinical variables amultiple logistic regression was performed The dependentvariable (Y) was the suspected ADR and the independentvariables were age schooling sex number of health prob-lems polypharmacy and usage of herbal medicines Theresults showed that in the studied population only sex (p= 0030 CI 95 023 to 093) had an influence on theoccurrence of suspected ADR However when estimatingthe Y value it was possible to observe that the elderly whouse herbal medicines have a 934 probability of developingADR while the elderly who do not use herbal medicines havea probability of 9051

The medications most commonly prescribed (struc-tured questionnaire) and used were losartan glibenclamideomeprazole and metformin (Table 3) and the mean numberwas 29plusmn14 by patient

Table 4 shows the most frequently reported herbalmedicines used by elderly participants according the struc-tured questionnaire along with their botanical names

reported properties and uses Lippia alba (Mill) NE Br(Cidreira 199) and the Peumus boldus Molina (Boldo111) were the most frequently consumed

According to the elderly the herbal medicines weremostly obtained in fairs or popular markets (516) and ingarden (370) while health establishments and pharma-cies were the last options (114) Presentations of herbalmedicines especially used were infusiontea (595) andplant extracts (275) Oral use (842) was the most com-mon mode of use of herbal medicines in this population(Table 5)

Compared with the results obtained in the structuredquestionnaire the pharmacotherapeutic follow-up was per-formed through the PWDT methodology standard methodand validated for clinical follow-up of pharmacotherapy Allthe elderly with potential ADRs were invited to participate inthis stage of the study but only 38 accepted 33 of whomwereelderly who used herbal medicines andmedicines and 5 usedonly medicines The medicines most commonly prescribedand used by the elderly who underwent pharmacotherapeuticfollow-up were losartan and omeprazole (Table 6)

Table 7 shows the most frequently reported herbalmedicines used by the elderly participants of pharmacother-apeutic follow-up along with their botanical names reportedproperties and uses The Peumus boldus Molina (Boldo194) and Lippia alba (Mill) NE Br (Cidreira 167) werethe most frequently consumed as well as the refueling in thepharmacotherapeutic follow-up

Regarding the potential ADRs among the elderly whoanswered the structured questionnaire there was a totalprevalence of 413 with 274 being in the elderly who usedherbal medicines and medicines and 139 in the elderlywho used only medicines Among the elderly people withsuspected ADRs selected by the structured questionnairewho agreed to continue the investigation 710 (27) had theirADRs confirmed It was only possible to define the ADRsin the structured questionnaire and pharmacotherapeuticfollow-up as shown in Table 8

The most frequently reported ADR symptoms wererelated to nervous system disorders (384) in the structuredquestionnaire and related to digestive disorders (364) inthe pharmacotherapeutic follow-up (Table 9)

4 Discussion

As a result increased use of herbal medicines in the Brazilianprimary healthcare system has been stimulated [11ndash37] notonly because of the international trend toward the use ofmore natural treatments but because these treatments arepart of the local culture Therefore facilitating improvedcommunication in pharmacovigilance is necessary [38 39] bycreating databases for phytotherapy programs and develop-ing and implementing bettermethods for causal investigationof adverse reactions to herbal medicines

It was possible to associate suspected ADR with sexindicating that women are more likely to develop ADR asalready shown in other studies where hormonal factors mayinfluence the establishment of an ADR [40 41] Besides thatwithin the elderly population in this study we observed a high

Evidence-Based Complementary and Alternative Medicine 5

Table 2 Clinic characteristics regarding only medication and herbal medicines in combination with medication use reported by the elderlyparticipants (N=208) Macapa Brazil 2016-2017

Clinic Index Onlymedications use n()

Herbal medicines andmedications use n () Total n () p valuelowastlowast

Health problems

p = 0004

Hypertension 58 (358) 64 (330) 122 (343)Rheumatic diseases 29 (179) 44 (227) 73 (205)Diabetes 19 (117) 28 (144) 47 (132)Heart problems 12 (74) 8 (41) 20 (56)Gastritis 4 (25) 12 (62) 16 (45)Dyslipidemias 8 (50) 6 (31) 14 (39)Depression 4 (25) 4 (21) 8 (225)Labyrinthitis 2 (12) 6 (31) 8 (225)Others 26 (172) 22 (113) 48 (135)Total 162 (100) 194 (100) 356 (100)

Polypharmacylowast

p lt 00001Yes 10 (118) 36 (293) 46 (221)No 75 (882) 87 (707) 162 (779)Total 85 (100) 123 (100) 208 (100)

Adverse Drug Reaction (ADR) suspectedYes 29 (341) 57 (463) 86 (413) p = 0045No 56 (659) 66 (537) 122 (587)Total 85 (100) 123 (100) 208 (100)

lowastClassification according to Kennerfalk et al (2002) [23] Polypharmacy ge5 medicineslowastlowastStudent T-test

prevalence of the use of herbal medicines as the majority ofthe participants were females whichmay have influenced theresultsThe high consumption of herbal medicines associatedwith the high level of female participation in this studyis supported by the findings of gender-based comparativestudies of the knowledge about medicinal plants Regardingsocial roles women are classified as wives and daughterswho oversee family health including diagnosing illnessesand knowing their prognosis they are also responsible forimplementing the first treatments [42ndash44]

Most of the elderly participants in this study were 60to 69 years of age the youngest category probably due tothe demographic characteristics of the region where thelife expectancy is not high Age did not show a significantinfluence on the occurrence of ADRs although many studiesindicate an increased risk of ADRswith age [15ndash41] so studiesin this population with a larger age group should clarify thisprobability better

Polypharmacy is an important concern for elderly peoplebecause they use multiple medications for long periods oftime increasing the likelihood of medication interactionsand ADRs [45ndash47] The clinical profile of the elderly inthis study was relatively comparable to their pharmacother-apeutic profile specifically the most prevalent diseases werehypertension rheumatic diseases diabetes and gastritis andthe medications used to treat them were losartan gliben-clamide and omeprazole These data also demonstrated thatrheumatic diseases although reported by the participantswere not frequently treated using medications

While medications are primarily used for blood pressureproblems general pain and endocrine and nutritional dis-eases [4] herbal medicines typically are used to treat simpleconditions such as digestive and respiratory problems andgeneral pain [48]This is supported by the data in the presentstudy wherein the herbal medicines most often reported bythe elderly participants were Lippia alba (Mill) NE Br andP boldus (Molina) the main indications for both of thesemedicines are for relaxation and digestive problems anddigestive system problems were the third most cited healthproblem

Studies of the medicinal use of herbs in Brazil haveshown that the most used dosage forms were infusion anddecoction followed by the use of fresh herbs and their usein bathing [49] In this study the most frequently reportedpharmaceutical formulations were infusiontea with herbsMost likely infusiontea is most commonly used due to thesimplicity of the preparation techniques Findings fromotherstudies corroborated this showing that the main sourcesof herbal medicines were free markets traditional healinghomes other sources and lastly drugstore [49 50] Themethods of administration of the herbal medicines identifiedin this study were oral and topical but another studydemonstrated that in African populations the main routes ofadministration in addition to oral and topical also includedrespiratory [51]

It is important to note that certain ethnobotanicaleth-nopharmacology aspects can be influenced by the regionalenvironmental conservation and storage factors of herbal

6 Evidence-Based Complementary and Alternative Medicine

Table 3 Medications reported by the elderly participants on the structured questionnaire (N=208) Macapa Brazil 2016-2017

Medications ATClowast Only medication usen () Herbal medicines andmedication use n ()

Acetylsalicylic acid N02BA01 15 (60) 10 (28)Alprazolam N05BA12 3 (12) 0 (00)Amiodarone C01B 1(04) 7 (20)Amitriptyline N06AA 1(04) 1 (03)Amlodipine C08CA01 2 (08) 6 (17)Atenolol C07A 2 (08) 4 (11)Atenolol C07AB03 5 (20) 4 (11)Calcium A12A 8 (32) 10 (28)Captopril C09AA01 6 (24) 7 (20)Carisoprodol M03 6 (24) 10 (28)Carvedilol C07A 2 (08) 4 (11)Chlorpheniramine R06AB02 2 (08) 3 (08)Clopidogrel B01A 2(08) 3 (08)Compounded drugs 11 (43) 15 (42)Diazepam N05BA01 5 (20) 5 (14)Diclofenac M01AB05 8 (32) 12 (34)Digoxin C01A 1(04) 3 (08)Dimenhydrinate A04AD 3 (12) 4 (11)Esomeprazole A02B 1(04) 1 (03)Ferrous Sulphate B03A 2 (08) 1 (03)Glibenclamide A10BB01 10 (40) 19 (53)Haloperidol N05B 1(04) 1 (03)Hydrochlorothiazide C03AA03 9 (36) 7 (20)Ibuprofen M01A 5 (20) 12 (34)Insulin A10AC01 3 (12) 8 (22)Losartan C09AA01 26 (103) 33 (92)Meloxicam M01AC06 6 (24) 1 (03)Metformin A10BA02 6 (24) 13 (36)Naproxen M01A 3 (12) 4 (11)Nifedipine C08CA05 5 (20) 6 (17)Nimesulide M01AX17 1 (04) 9 (25)Omeprazole A02BC01 9 (36) 15 (42)Pantoprazole A02B 1(04) 1 (03)Paracetamol N02BE01 1 (04) 12 (34)Propranolol C07A 3 (12) 3 (08)Ranitidine A02BA02 3 (12) 3 (08)Salbutamol R03 1(04) 3 (08)Scopolamine A03BB01 3 (12) 6 (17)Sertraline N06A 2 (08) 1 (03)Simvastatin C10AA01 9 (36) 4 (11)Zolpidem N05 5 (20) 7 (20)Others 53 (210) 78 (218)Total 251 (100)lowastlowast 358 (100)lowastlowastlowastClassification according to the Anatomical Therapeutic Chemical Code (ATC code) [24]lowastlowastWithout statistical meaningful difference between the amount of medications used in the groups (student t p = 04470)

Evidence-Based Complementary and Alternative Medicine 5

Table 2 Clinic characteristics regarding only medication and herbal medicines in combination with medication use reported by the elderlyparticipants (N=208) Macapa Brazil 2016-2017

Clinic Index Onlymedications use n()

Herbal medicines andmedications use n () Total n () p valuelowastlowast

Health problems

p = 0004

Hypertension 58 (358) 64 (330) 122 (343)Rheumatic diseases 29 (179) 44 (227) 73 (205)Diabetes 19 (117) 28 (144) 47 (132)Heart problems 12 (74) 8 (41) 20 (56)Gastritis 4 (25) 12 (62) 16 (45)Dyslipidemias 8 (50) 6 (31) 14 (39)Depression 4 (25) 4 (21) 8 (225)Labyrinthitis 2 (12) 6 (31) 8 (225)Others 26 (172) 22 (113) 48 (135)Total 162 (100) 194 (100) 356 (100)

Polypharmacylowast

p lt 00001Yes 10 (118) 36 (293) 46 (221)No 75 (882) 87 (707) 162 (779)Total 85 (100) 123 (100) 208 (100)

Adverse Drug Reaction (ADR) suspectedYes 29 (341) 57 (463) 86 (413) p = 0045No 56 (659) 66 (537) 122 (587)Total 85 (100) 123 (100) 208 (100)

lowastClassification according to Kennerfalk et al (2002) [23] Polypharmacy ge5 medicineslowastlowastStudent T-test

prevalence of the use of herbal medicines as the majority ofthe participants were females whichmay have influenced theresultsThe high consumption of herbal medicines associatedwith the high level of female participation in this studyis supported by the findings of gender-based comparativestudies of the knowledge about medicinal plants Regardingsocial roles women are classified as wives and daughterswho oversee family health including diagnosing illnessesand knowing their prognosis they are also responsible forimplementing the first treatments [42ndash44]

Most of the elderly participants in this study were 60to 69 years of age the youngest category probably due tothe demographic characteristics of the region where thelife expectancy is not high Age did not show a significantinfluence on the occurrence of ADRs although many studiesindicate an increased risk of ADRswith age [15ndash41] so studiesin this population with a larger age group should clarify thisprobability better

Polypharmacy is an important concern for elderly peoplebecause they use multiple medications for long periods oftime increasing the likelihood of medication interactionsand ADRs [45ndash47] The clinical profile of the elderly inthis study was relatively comparable to their pharmacother-apeutic profile specifically the most prevalent diseases werehypertension rheumatic diseases diabetes and gastritis andthe medications used to treat them were losartan gliben-clamide and omeprazole These data also demonstrated thatrheumatic diseases although reported by the participantswere not frequently treated using medications

While medications are primarily used for blood pressureproblems general pain and endocrine and nutritional dis-eases [4] herbal medicines typically are used to treat simpleconditions such as digestive and respiratory problems andgeneral pain [48]This is supported by the data in the presentstudy wherein the herbal medicines most often reported bythe elderly participants were Lippia alba (Mill) NE Br andP boldus (Molina) the main indications for both of thesemedicines are for relaxation and digestive problems anddigestive system problems were the third most cited healthproblem

Studies of the medicinal use of herbs in Brazil haveshown that the most used dosage forms were infusion anddecoction followed by the use of fresh herbs and their usein bathing [49] In this study the most frequently reportedpharmaceutical formulations were infusiontea with herbsMost likely infusiontea is most commonly used due to thesimplicity of the preparation techniques Findings fromotherstudies corroborated this showing that the main sourcesof herbal medicines were free markets traditional healinghomes other sources and lastly drugstore [49 50] Themethods of administration of the herbal medicines identifiedin this study were oral and topical but another studydemonstrated that in African populations the main routes ofadministration in addition to oral and topical also includedrespiratory [51]

It is important to note that certain ethnobotanicaleth-nopharmacology aspects can be influenced by the regionalenvironmental conservation and storage factors of herbal

6 Evidence-Based Complementary and Alternative Medicine

Table 3 Medications reported by the elderly participants on the structured questionnaire (N=208) Macapa Brazil 2016-2017

Medications ATClowast Only medication usen () Herbal medicines andmedication use n ()

Acetylsalicylic acid N02BA01 15 (60) 10 (28)Alprazolam N05BA12 3 (12) 0 (00)Amiodarone C01B 1(04) 7 (20)Amitriptyline N06AA 1(04) 1 (03)Amlodipine C08CA01 2 (08) 6 (17)Atenolol C07A 2 (08) 4 (11)Atenolol C07AB03 5 (20) 4 (11)Calcium A12A 8 (32) 10 (28)Captopril C09AA01 6 (24) 7 (20)Carisoprodol M03 6 (24) 10 (28)Carvedilol C07A 2 (08) 4 (11)Chlorpheniramine R06AB02 2 (08) 3 (08)Clopidogrel B01A 2(08) 3 (08)Compounded drugs 11 (43) 15 (42)Diazepam N05BA01 5 (20) 5 (14)Diclofenac M01AB05 8 (32) 12 (34)Digoxin C01A 1(04) 3 (08)Dimenhydrinate A04AD 3 (12) 4 (11)Esomeprazole A02B 1(04) 1 (03)Ferrous Sulphate B03A 2 (08) 1 (03)Glibenclamide A10BB01 10 (40) 19 (53)Haloperidol N05B 1(04) 1 (03)Hydrochlorothiazide C03AA03 9 (36) 7 (20)Ibuprofen M01A 5 (20) 12 (34)Insulin A10AC01 3 (12) 8 (22)Losartan C09AA01 26 (103) 33 (92)Meloxicam M01AC06 6 (24) 1 (03)Metformin A10BA02 6 (24) 13 (36)Naproxen M01A 3 (12) 4 (11)Nifedipine C08CA05 5 (20) 6 (17)Nimesulide M01AX17 1 (04) 9 (25)Omeprazole A02BC01 9 (36) 15 (42)Pantoprazole A02B 1(04) 1 (03)Paracetamol N02BE01 1 (04) 12 (34)Propranolol C07A 3 (12) 3 (08)Ranitidine A02BA02 3 (12) 3 (08)Salbutamol R03 1(04) 3 (08)Scopolamine A03BB01 3 (12) 6 (17)Sertraline N06A 2 (08) 1 (03)Simvastatin C10AA01 9 (36) 4 (11)Zolpidem N05 5 (20) 7 (20)Others 53 (210) 78 (218)Total 251 (100)lowastlowast 358 (100)lowastlowastlowastClassification according to the Anatomical Therapeutic Chemical Code (ATC code) [24]lowastlowastWithout statistical meaningful difference between the amount of medications used in the groups (student t p = 04470)

6 Evidence-Based Complementary and Alternative Medicine

Table 3 Medications reported by the elderly participants on the structured questionnaire (N=208) Macapa Brazil 2016-2017

Medications ATClowast Only medication usen () Herbal medicines andmedication use n ()

Acetylsalicylic acid N02BA01 15 (60) 10 (28)Alprazolam N05BA12 3 (12) 0 (00)Amiodarone C01B 1(04) 7 (20)Amitriptyline N06AA 1(04) 1 (03)Amlodipine C08CA01 2 (08) 6 (17)Atenolol C07A 2 (08) 4 (11)Atenolol C07AB03 5 (20) 4 (11)Calcium A12A 8 (32) 10 (28)Captopril C09AA01 6 (24) 7 (20)Carisoprodol M03 6 (24) 10 (28)Carvedilol C07A 2 (08) 4 (11)Chlorpheniramine R06AB02 2 (08) 3 (08)Clopidogrel B01A 2(08) 3 (08)Compounded drugs 11 (43) 15 (42)Diazepam N05BA01 5 (20) 5 (14)Diclofenac M01AB05 8 (32) 12 (34)Digoxin C01A 1(04) 3 (08)Dimenhydrinate A04AD 3 (12) 4 (11)Esomeprazole A02B 1(04) 1 (03)Ferrous Sulphate B03A 2 (08) 1 (03)Glibenclamide A10BB01 10 (40) 19 (53)Haloperidol N05B 1(04) 1 (03)Hydrochlorothiazide C03AA03 9 (36) 7 (20)Ibuprofen M01A 5 (20) 12 (34)Insulin A10AC01 3 (12) 8 (22)Losartan C09AA01 26 (103) 33 (92)Meloxicam M01AC06 6 (24) 1 (03)Metformin A10BA02 6 (24) 13 (36)Naproxen M01A 3 (12) 4 (11)Nifedipine C08CA05 5 (20) 6 (17)Nimesulide M01AX17 1 (04) 9 (25)Omeprazole A02BC01 9 (36) 15 (42)Pantoprazole A02B 1(04) 1 (03)Paracetamol N02BE01 1 (04) 12 (34)Propranolol C07A 3 (12) 3 (08)Ranitidine A02BA02 3 (12) 3 (08)Salbutamol R03 1(04) 3 (08)Scopolamine A03BB01 3 (12) 6 (17)Sertraline N06A 2 (08) 1 (03)Simvastatin C10AA01 9 (36) 4 (11)Zolpidem N05 5 (20) 7 (20)Others 53 (210) 78 (218)Total 251 (100)lowastlowast 358 (100)lowastlowastlowastClassification according to the Anatomical Therapeutic Chemical Code (ATC code) [24]lowastlowastWithout statistical meaningful difference between the amount of medications used in the groups (student t p = 04470)

Evidence-Based Complementary and Alternative Medicine 7

Table4Herbalm

edicines

repo

rted

bythee

lderlyparticipantson

thes

tructuredqu

estio

nnaire

(N=123)MacapaBrazil2016-2017

Herbalm

edicineslowast

popu

larn

ame

Therapeutic

Indicatio

nsStructured

questio

nnaire

N

Lippia

alba

(Mill)NEB

rCidreira

Relaxatio

nanddigestive

prob

lems

63199

Peum

usboldus

Molina

Boldo

Digestiv

eand

liver

prob

lems

35111

Cymbopogoncitratus(DC)S

tapf

Capim

-marinho

Relaxatio

nanddigestive

prob

lems

3198

Carapa

guianensisAu

bl

And

iroba

Inflammation

bruises

1857

Matric

ariacham

omillaL

Cam

omila

Relaxatio

nnauseacolic

1135

Stryphnodend

ronadstringens

(Mart)

Barbatim

aoInfectionsw

ound

healingpaininfl

ammation

1135

Copaifera

langsdorffiiD

esf

Cop

aıba

Inflammation

Infections

928

Cinn

amom

umzeylan

icumBlum

eCanela

Digestiv

eenergystim

ulationprob

lems

825

Arrabidaea

chica

(Bon

pl)Ve

rlParir

iPainfeverinfl

ammationandor

spam

s8

25

Dysphan

iaanthelm

intica(L)Mosyakin

ampClem

ants

Mastruz

Parasiticinfection

722

Costu

sspicatus(Jacq)Sw

Cana-do

-brejo

Kidn

eyprob

lems

(diuretic

effect)

619

Veronica

officin

alisL

Veronica

Painfeverinfl

ammation

619

Menthaalaica

Boris

sHortela

Nausedigestiv

eproblem

s6

19

Phyllanthu

sniru

riL

Quebra-Pedra

Kidn

eyprob

lems

(diuretic

andsto

ne-preventinge

ffects)

516

Aesculus

hippocastanu

mL

Castanh

adaIndia

Bloo

dcirculationvaric

oseinflammation

413

Pentaclethraeetveld

eana

DeW

ildamp

TDurand

Pracaxi

Infections

413

Zingiber

officin

aleR

oscoe

Gengibre

Energystim

ulationprob

lems

206

Aloe

vera

(L)Bu

rmf

Babo

saHealin

gprotectoro

fthe

gastr

icandintestinalm

ucosa

206

Others

68215

Total

316

100

lowastTh

eclassificatio

nof

botanicaln

ames

was

accordingto

THEPL

ANTS

LIST

database

[25]Th

ebotanicalidentifi

catio

nof

theh

erbalm

edicines

obtained

inph

armaciesw

asderiv

edfrom

thelabelspackagesand

theherbalmedicines

obtained

ingardensfairs

and

popu

larm

arketswe

reidentifi

edby

visualstimuliin

theform

ofpictures

andim

ages

from

onlin

eherbariums(repo

rtedlyused

bytheinterviewe

esto

provide

reliefagainstillnesses)

8 Evidence-Based Complementary and Alternative Medicine

Table 5 Characteristics of herbalmedicine use reported by the elderly participants on the structured questionnaireMacapa Brazil 2016-2017

Characteristics Structured questionnaireN

Origin of herbal medicineslowastFairs or popular markets 95 516Garden 68 370

Drugstore 21 114Total 184 100

PresentationslowastlowastInfusionTea 188 595Plant extracts 87 275Gel with plant ingredients 23 73Oils 18 57Total 316 100

Mode of administrationlowastlowastOral 266 842Topic 50 158Total 316 100lowastSome herbal medicines according to the self-report of the elderly were obtained in more than one place according to availabilitylowastlowastThe 316 herbal medicines used by the elderly were classified according to the mode of preparation (pharmaceutical form) and the route of administrationaccording to the structured questionnaire

Table 6 Medications used in combination or not with herbal medicines by elderly participants as determined by pharmacotherapeuticfollow-up (N=38) Macapa Brazil 2016-2017

Medications ATClowastPharmacotherapeutic follow-up

Only medication use n()

Herbal medicines andmedication use n ()

Losartan C09AA01 3 (115) 25 (123)Omeprazole A02BC01 4 (154) 24 (118)Diclofenac M01AB05 2 (77) 15 (73)Glibenclamide A10BB01 3 (115) 12 (59)Hydrochlorothiazide C03AA03 2 (77) 12 (59)Insulin A10AC01 1 (39) 9 (44)Acetylsalicylic acid N02BA01 3 (115) 9 (44)Nimesulide M01AX17 1 (39) 7 (34)Others 7 (269) 91 (446)Total 26 (100)lowastlowast 204 (100)lowastlowastlowastClassification according to the Anatomical Therapeutic Chemical Code (ATC code) [24]lowastlowastThere was statistical meaningful difference between the amount of medications used in the groups (Student t p = 00004)

medicines For the pharmacovigilance of herbal medicinesthe composition of the medicine the therapeutic use thepreparation and storage the route of administration thedose and the duration of administration are importantfactors Concerns about special patient groups includingchildren and older patients emphasize the importance of col-lecting this information in pharmacoepidemiological studiesof medicinal plants [13] In addition to providing moredetailed information on the standards for use new tools forinvestigating the causality of ADRs associated with herbalmedicines [52] have been developed to better elucidatesuspected cases

Although the pharmacotherapeutic follow-up (PWDT) isa recommendedmethod to assess the safety of pharmacother-apy [33 34] it is not readily applicable in places where thereis a scarcity of pharmacists or inadequate infrastructure andtraining Besides the population does not recognize yet thebenefits and necessity of pharmacotherapeutic monitoringdemonstrated in this study with the lack of availability by theelderly population to be monitored Therefore it is possibleto suggest the necessity and feasibility of using the structuredquestionnaire as a screening tool for ADRs that may helpestablish an active phytopharmacovigilance in regions with-out pharmacotherapeutic follow-up services widely availableand without the infrastructure for its implementation

8 Evidence-Based Complementary and Alternative Medicine

Table 5 Characteristics of herbalmedicine use reported by the elderly participants on the structured questionnaireMacapa Brazil 2016-2017

Characteristics Structured questionnaireN

Origin of herbal medicineslowastFairs or popular markets 95 516Garden 68 370

Drugstore 21 114Total 184 100

PresentationslowastlowastInfusionTea 188 595Plant extracts 87 275Gel with plant ingredients 23 73Oils 18 57Total 316 100

Mode of administrationlowastlowastOral 266 842Topic 50 158Total 316 100lowastSome herbal medicines according to the self-report of the elderly were obtained in more than one place according to availabilitylowastlowastThe 316 herbal medicines used by the elderly were classified according to the mode of preparation (pharmaceutical form) and the route of administrationaccording to the structured questionnaire

Table 6 Medications used in combination or not with herbal medicines by elderly participants as determined by pharmacotherapeuticfollow-up (N=38) Macapa Brazil 2016-2017

Medications ATClowastPharmacotherapeutic follow-up

Only medication use n()

Herbal medicines andmedication use n ()

Losartan C09AA01 3 (115) 25 (123)Omeprazole A02BC01 4 (154) 24 (118)Diclofenac M01AB05 2 (77) 15 (73)Glibenclamide A10BB01 3 (115) 12 (59)Hydrochlorothiazide C03AA03 2 (77) 12 (59)Insulin A10AC01 1 (39) 9 (44)Acetylsalicylic acid N02BA01 3 (115) 9 (44)Nimesulide M01AX17 1 (39) 7 (34)Others 7 (269) 91 (446)Total 26 (100)lowastlowast 204 (100)lowastlowastlowastClassification according to the Anatomical Therapeutic Chemical Code (ATC code) [24]lowastlowastThere was statistical meaningful difference between the amount of medications used in the groups (Student t p = 00004)

medicines For the pharmacovigilance of herbal medicinesthe composition of the medicine the therapeutic use thepreparation and storage the route of administration thedose and the duration of administration are importantfactors Concerns about special patient groups includingchildren and older patients emphasize the importance of col-lecting this information in pharmacoepidemiological studiesof medicinal plants [13] In addition to providing moredetailed information on the standards for use new tools forinvestigating the causality of ADRs associated with herbalmedicines [52] have been developed to better elucidatesuspected cases

Although the pharmacotherapeutic follow-up (PWDT) isa recommendedmethod to assess the safety of pharmacother-apy [33 34] it is not readily applicable in places where thereis a scarcity of pharmacists or inadequate infrastructure andtraining Besides the population does not recognize yet thebenefits and necessity of pharmacotherapeutic monitoringdemonstrated in this study with the lack of availability by theelderly population to be monitored Therefore it is possibleto suggest the necessity and feasibility of using the structuredquestionnaire as a screening tool for ADRs that may helpestablish an active phytopharmacovigilance in regions with-out pharmacotherapeutic follow-up services widely availableand without the infrastructure for its implementation

Evidence-Based Complementary and Alternative Medicine 9

Table7Herbalm

edicines

mostfrequ

ently

used

byelderly

participantsas

determ

ined

throug

hph

armacotherapeuticfollo

w-up(N

=33)M

acapaBrazil2016-2017

Herba

lmed

icines

Popu

larn

ame

Indicatio

nsPh

armacotherape

utic

follo

w-up

N

Peum

usboldus

Molina

Boldo

Digestiv

eand

liver

prob

lems

14194

Lippia

alba

(Mill)NEB

rCidreira

Relaxatio

nanddigestive

prob

lems

12167

Cymbopogoncitratus(DC)S

tapf

Capim

-marinho

Relaxatio

nanddigestive

prob

lems

12167

Carapa

guianensisAu

bl

And

iroba

Inflammation

bruises

11153

Phyllanthu

sniru

riL

Quebra-Pedra

Kidn

eyprob

lems(diureticandsto

ne-preventinge

ffects)

683

Matric

ariacham

omillaL

Cam

omila

Relaxatio

nnauseacolic

342

Others

14194

Total

72100

lowastTh

eclassificatio

nof

botanicaln

ames

was

accordingto

THEPL

ANTS

LIST

database

[25]Th

ebotanicalidentifi

catio

nof

theh

erbalm

edicines

obtained

inph

armaciesw

asderiv

edfrom

thelabelspackagesand

theherbalmedicines

obtained

ingardensfairs

and

popu

larm

arketswe

reidentifi

edby

visualstimuliin

theform

ofpictures

andim

ages

from

onlin

eherbariums(repo

rtedlyused

bytheinterviewe

esto

provide

reliefagainstillnesses)

10 Evidence-Based Complementary and Alternative Medicine

Table 8 Frequencyof ADRs in elderly participants based on theADR causality assessmentmethodsWHO [19 20]Macapa Brazil 2016-2017

ADR causalityassessment

Structured questionnaire Pharmacotherapeuticfollow-up

Only medicationuse n ()

Herbal medicinesand medication

use n ()

Only medicationuse n ()

Herbal medicinesand medication

use n()Defined 0 (00) 0 (00) 2 (500) 9 (391)Probable 4 (138) 2 (35) 1 (250) 8 (348)Possible 21 (724) 46 (807) 1 (250) 5 (213)Unlikely 4 (138) 9 (158) 0 (00) 1 (43)Total 29 (100) 57 (100) 4 (100) 23 (100)

Table 9 Frequency of ADRs confirmeddefined in elderly participants based on the terminology for coding clinical information in relationto medical therapy [26] Macapa Brazil 2016-2017

Variable Structuredquestionnaire n ()

Pharmacotherapeuticfollow-up n ()

Nervous system 28 (384) 5 (227)Digestive system 19 (260) 8 (364)Symptoms signs and abnormalclinical and laboratory findingsnot classified elsewhere

13 (178) 5 (227)

Circulatory system 7 (96) 2 (91)Skin and subcutaneous tissue 5 (68) 2 (91)Respiratory system 1 (14) 0 (00)Total 73 (100) 22 (100)

It is important to emphasize that a suspected ADR needsto be evaluated through algorithms to determine the causalityof an ADR as described by Naranjo [53] Karch amp Lasagna[54] WHO [20] and Mastroianni et al [52] This demon-strates how important it is to evaluate pharmacotherapyand the complexity of investigating ADRs associated withherbal medicines It was also observed that the identificationof definitive ADRs was possible only through pharma-cotherapeutic follow-up but probable and possible eventswere identified by both tools (structured questionnaire andpharmacotherapeutic follow-up) ADRs were very frequentlyidentified using the questionnaire probably because unlikethe pharmacotherapeutic follow-up only limited informa-tion is needed

It was also possible to verify that polymedication mayincrease the probability of ADRs because the average numberof medications identified by elderly participants in the phar-macotherapeutic follow-upwasmuchhigher than the averagenumber of medications reported in the structured question-naire corroborating other studies [19ndash55] The classificationof ADRs according to the WHO system [20] revealed thehigh frequency of ADRs related to the nervous and digestivesystems suggesting the hypothesis that herbal medicines arebeing used to treat ADR symptoms because they are used as arelaxation and in the combat of digestive discomfort or painand not health problems as described by the elderly and theclassifications of ADRs Another explanation is that herbalmedicines are generally used to treat simple diseases such asdigestive respiratory or general pain [4]

Encouraging routine reporting of adverse events relatedto herbal medicines and promoting studies of the interactionbetween herbal medicines and medications are also essentialso that this information can be used to guide clinical practiceIn addition to be able to effectively recommend the useof phytotherapy as a therapeutic option for health systempatients increased investment in studies to develop morereliable data collection methods according to the existingrecommendations [56] is necessary to obtain better informa-tion for both passive and active pharmacovigilance Informa-tion obtained from spontaneous reports case series cross-sectional studies case-control studies and cohort studiesis important [19ndash21 23 27ndash29] to better evaluate the risksand consequences of the use of herbs in combination withmedications As a result more data regarding the safety andefficacy of phytotherapy would be generated leading to agreater incentive for biomedical medicine to provide morefeasible integrative medicine services

Limitations of the study are as follows botanical identifi-cation of medicinal plants has not been done some variationsin the scientific species may occur in addition the samplesize of the study can be also considered as one of thelimitations

5 Conclusion

This study showed that in a region of the Brazilian Amazon(Macapa Amapa) the elderly people who consume the mostherbal medicines are younger female of low-income and

Evidence-Based Complementary and Alternative Medicine 11

literate The prevalence of ADRs with probable causality washigh in this study population but it was only sex-relatedalthough more prevalent in the elderly who consume herbalmedicines

Regarding the potential ADRs among the elderly whoanswered the structured questionnaire there was a totalprevalence of 413 of ADRs with 274 being in the elderlywho used herbal medicines and medicines and 139 beingin the elderly who used only medicines it was also possibleto observe that when used the herbal medicines had asmain objective to combat symptoms of diseases or possiblyto combat ADR symptoms caused by the medications usedto treat chronic diseases The results of this study showedthe need to actively investigate suspected ADRs and thestructured questionnaire used was an effective and low-cost alternative tool for the screening of suspected ADRsin this study population In view of the unique regionalcharacteristics adequate phytopharmacovigilance systemswith multiple approaches are needed to overcome the specialchallenges and the structured questionnaires as well as atherapeutic follow-up can be useful approaches to increasethe likelihood of ADR detection

Data Availability

The data used to support the findings of this study areavailable from the corresponding author upon request

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

The authors thank the Federal University of Amapa and theundergraduate students Aline Mariana Lopes Martins AnnaElayne da Silva e Silva Nayara dos Santos Raulino da Silvaand Samara Graziela Guimaraes da Silva for assistance in datacollection and the American Journal Experts for assistancewith manuscript language review

References

[1] WHO ldquoTraditional medicinerdquo Fact sheet N134 Geneva 2008httpwwwwhointmediacentre

[2] E C S Oliveira and D M B M Trovao ldquoO uso de plantas emrituais de rezas e benzeduras um olhar sobre esta pratica noestado da Paraıbardquo Revista Brasileira de Biociencias vol 7 no 3pp 245ndash251 2009

[3] G S Da Silva ldquoBenzedores e raizeiros saberes partilhadosna comunidade remanescente de quilombo de Santana daCaatingardquo Revista Mosaico vol 3 no 1 pp 33ndash48 2010

[4] S Zank N Hanazaki and R Bussmann ldquoThe coexistence oftraditionalmedicine and biomedicine A study with local healthexperts in two Brazilian regionsrdquo PLoS ONE vol 12 no 4 pe0174731 2017

[5] J Mignone J Bartlett J OrsquoNeil and T Orchard ldquoBest practicesin intercultural health Five case studies in Latin Americardquo

Journal of Ethnobiology and Ethnomedicine vol 3 article no 312007

[6] I Vandebroek ldquoIntercultural health and ethnobotany How toimprove healthcare for underserved and minority communi-tiesrdquo Journal of Ethnopharmacology vol 148 no 3 pp 746ndash7542013

[7] C da Rosa ldquoTraditional Medicine and ComplementaryAlter-native Medicine in Primary Health Care The BrazilianExperiencerdquo Primary Care at a Glance - Hot Topics and NewInsights DrOreste Capelli httpwwwintechopencombooksprimary-care-at-aglance-hot-topics-and-new-insightstradi-tional-medicine-and-complementary-alternative-in-primary-healthcare-the-brazilian-experience

[8] World Health Organization (WHO) ldquoTraditional MedicineStrategy 2002ndash2005 Geneva Switzerlandrdquo 2002 httpwhqlib-docwhointhq2002who edm trm 20021pdf

[9] World Health Organization WHO Guidelines on Safety Moni-toring of HerbalMedicines in Pharmacovigilance Systems WHOGeneva Switzerland 2004

[10] World Health Organization ldquoNational Policy on TraditionalMedicine And Regulation of Herbal Medicinesrdquo 2005 httpappswhointmedicinedocspdfs7916es7916epdf

[11] Ministerio da Saude andGabinete doMinistro ldquoPortaria n∘ 971de 3 de maio de 2006 Aprova a Polıtica Nacional de PraticasIntegrativas e Complementares (PNPIC) no Sistema Unicode Saude Brasılia (DF)rdquo 2006 httpbvsmssaudegovbrbvssaudelegisgm2006prt0971 03 05 2006html

[12] Ministerio da Saude Decreto nž 5813 de 22 de junho de 2006Aprova a Polıtica Nacional de Plantas Medicinais e Fitoterapicose da outras providencias Diario Oficial da Uniao Secao 1 2010

[13] E Rodrigues and J Barnes ldquoPharmacovigilance of herbalmedicines The potential contributions of ethnobotanical andethnopharmacological studiesrdquo Drug Safety vol 36 no 1 pp1ndash12 2013

[14] J Lanini J M Duarte-Almeida S Nappo and E A CarlinildquoldquoNatural and therefore free of risksrdquo - Adverse effects poi-sonings and other problems related to medicinal herbs by ldquoraizeirosrdquo inDiademaSPrdquordquoRevista Brasileira de Farmacognosiavol 19 no 1 A pp 121ndash129 2009

[15] J Barnes ldquoPharmacovigilance of herbal medicines A UKperspectiverdquoDrug Safety vol 26 no 12 pp 829ndash851 2003

[16] A A Mangoni and S H D Jackson ldquoAge-related changes inpharmacokinetics and pharmacodynamics basic principles andpractical applicationsrdquo British Journal of Clinical Pharmacologyvol 57 no 1 pp 6ndash14 2004

[17] E A Davies and M S OrsquoMahony ldquoAdverse drug reactions inspecial populations - The elderlyrdquo British Journal of ClinicalPharmacology vol 80 no 4 pp 796ndash807 2015

[18] M van denAkker F Buntinx and J A Knottnerus ldquoComorbid-ity ormultimorbidityrdquoTheEuropean Journal of General Practicevol 2 no 2 pp 65ndash70 1996

[19] I R Edwards and J K Aronson ldquoAdverse drug reactionsdefinitions diagnosis and managementrdquo The Lancet vol 356no 9237 pp 1255ndash1259 2000

[20] World Alliance for Patien Safety WHO draft guidelines foradverse event reporting and learning systems From informationto actionWorldHealthOrganization (WHO)Geneva Switzer-land 2005

[21] Organizacao Pan-Americana da Saude ldquoBoas praticas de far-macovigilancia para as Americasrdquo in Rede PAHRF DocumentoTecnico Nordm5 Washington DC USA 2011

10 Evidence-Based Complementary and Alternative Medicine

Table 8 Frequencyof ADRs in elderly participants based on theADR causality assessmentmethodsWHO [19 20]Macapa Brazil 2016-2017

ADR causalityassessment

Structured questionnaire Pharmacotherapeuticfollow-up

Only medicationuse n ()

Herbal medicinesand medication

use n ()

Only medicationuse n ()

Herbal medicinesand medication

use n()Defined 0 (00) 0 (00) 2 (500) 9 (391)Probable 4 (138) 2 (35) 1 (250) 8 (348)Possible 21 (724) 46 (807) 1 (250) 5 (213)Unlikely 4 (138) 9 (158) 0 (00) 1 (43)Total 29 (100) 57 (100) 4 (100) 23 (100)

Table 9 Frequency of ADRs confirmeddefined in elderly participants based on the terminology for coding clinical information in relationto medical therapy [26] Macapa Brazil 2016-2017

Variable Structuredquestionnaire n ()

Pharmacotherapeuticfollow-up n ()

Nervous system 28 (384) 5 (227)Digestive system 19 (260) 8 (364)Symptoms signs and abnormalclinical and laboratory findingsnot classified elsewhere

13 (178) 5 (227)

Circulatory system 7 (96) 2 (91)Skin and subcutaneous tissue 5 (68) 2 (91)Respiratory system 1 (14) 0 (00)Total 73 (100) 22 (100)

It is important to emphasize that a suspected ADR needsto be evaluated through algorithms to determine the causalityof an ADR as described by Naranjo [53] Karch amp Lasagna[54] WHO [20] and Mastroianni et al [52] This demon-strates how important it is to evaluate pharmacotherapyand the complexity of investigating ADRs associated withherbal medicines It was also observed that the identificationof definitive ADRs was possible only through pharma-cotherapeutic follow-up but probable and possible eventswere identified by both tools (structured questionnaire andpharmacotherapeutic follow-up) ADRs were very frequentlyidentified using the questionnaire probably because unlikethe pharmacotherapeutic follow-up only limited informa-tion is needed

It was also possible to verify that polymedication mayincrease the probability of ADRs because the average numberof medications identified by elderly participants in the phar-macotherapeutic follow-upwasmuchhigher than the averagenumber of medications reported in the structured question-naire corroborating other studies [19ndash55] The classificationof ADRs according to the WHO system [20] revealed thehigh frequency of ADRs related to the nervous and digestivesystems suggesting the hypothesis that herbal medicines arebeing used to treat ADR symptoms because they are used as arelaxation and in the combat of digestive discomfort or painand not health problems as described by the elderly and theclassifications of ADRs Another explanation is that herbalmedicines are generally used to treat simple diseases such asdigestive respiratory or general pain [4]

Encouraging routine reporting of adverse events relatedto herbal medicines and promoting studies of the interactionbetween herbal medicines and medications are also essentialso that this information can be used to guide clinical practiceIn addition to be able to effectively recommend the useof phytotherapy as a therapeutic option for health systempatients increased investment in studies to develop morereliable data collection methods according to the existingrecommendations [56] is necessary to obtain better informa-tion for both passive and active pharmacovigilance Informa-tion obtained from spontaneous reports case series cross-sectional studies case-control studies and cohort studiesis important [19ndash21 23 27ndash29] to better evaluate the risksand consequences of the use of herbs in combination withmedications As a result more data regarding the safety andefficacy of phytotherapy would be generated leading to agreater incentive for biomedical medicine to provide morefeasible integrative medicine services

Limitations of the study are as follows botanical identifi-cation of medicinal plants has not been done some variationsin the scientific species may occur in addition the samplesize of the study can be also considered as one of thelimitations

5 Conclusion

This study showed that in a region of the Brazilian Amazon(Macapa Amapa) the elderly people who consume the mostherbal medicines are younger female of low-income and

Evidence-Based Complementary and Alternative Medicine 11

literate The prevalence of ADRs with probable causality washigh in this study population but it was only sex-relatedalthough more prevalent in the elderly who consume herbalmedicines

Regarding the potential ADRs among the elderly whoanswered the structured questionnaire there was a totalprevalence of 413 of ADRs with 274 being in the elderlywho used herbal medicines and medicines and 139 beingin the elderly who used only medicines it was also possibleto observe that when used the herbal medicines had asmain objective to combat symptoms of diseases or possiblyto combat ADR symptoms caused by the medications usedto treat chronic diseases The results of this study showedthe need to actively investigate suspected ADRs and thestructured questionnaire used was an effective and low-cost alternative tool for the screening of suspected ADRsin this study population In view of the unique regionalcharacteristics adequate phytopharmacovigilance systemswith multiple approaches are needed to overcome the specialchallenges and the structured questionnaires as well as atherapeutic follow-up can be useful approaches to increasethe likelihood of ADR detection

Data Availability

The data used to support the findings of this study areavailable from the corresponding author upon request

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

The authors thank the Federal University of Amapa and theundergraduate students Aline Mariana Lopes Martins AnnaElayne da Silva e Silva Nayara dos Santos Raulino da Silvaand Samara Graziela Guimaraes da Silva for assistance in datacollection and the American Journal Experts for assistancewith manuscript language review

References

[1] WHO ldquoTraditional medicinerdquo Fact sheet N134 Geneva 2008httpwwwwhointmediacentre

[2] E C S Oliveira and D M B M Trovao ldquoO uso de plantas emrituais de rezas e benzeduras um olhar sobre esta pratica noestado da Paraıbardquo Revista Brasileira de Biociencias vol 7 no 3pp 245ndash251 2009

[3] G S Da Silva ldquoBenzedores e raizeiros saberes partilhadosna comunidade remanescente de quilombo de Santana daCaatingardquo Revista Mosaico vol 3 no 1 pp 33ndash48 2010

[4] S Zank N Hanazaki and R Bussmann ldquoThe coexistence oftraditionalmedicine and biomedicine A study with local healthexperts in two Brazilian regionsrdquo PLoS ONE vol 12 no 4 pe0174731 2017

[5] J Mignone J Bartlett J OrsquoNeil and T Orchard ldquoBest practicesin intercultural health Five case studies in Latin Americardquo

Journal of Ethnobiology and Ethnomedicine vol 3 article no 312007

[6] I Vandebroek ldquoIntercultural health and ethnobotany How toimprove healthcare for underserved and minority communi-tiesrdquo Journal of Ethnopharmacology vol 148 no 3 pp 746ndash7542013

[7] C da Rosa ldquoTraditional Medicine and ComplementaryAlter-native Medicine in Primary Health Care The BrazilianExperiencerdquo Primary Care at a Glance - Hot Topics and NewInsights DrOreste Capelli httpwwwintechopencombooksprimary-care-at-aglance-hot-topics-and-new-insightstradi-tional-medicine-and-complementary-alternative-in-primary-healthcare-the-brazilian-experience

[8] World Health Organization (WHO) ldquoTraditional MedicineStrategy 2002ndash2005 Geneva Switzerlandrdquo 2002 httpwhqlib-docwhointhq2002who edm trm 20021pdf

[9] World Health Organization WHO Guidelines on Safety Moni-toring of HerbalMedicines in Pharmacovigilance Systems WHOGeneva Switzerland 2004

[10] World Health Organization ldquoNational Policy on TraditionalMedicine And Regulation of Herbal Medicinesrdquo 2005 httpappswhointmedicinedocspdfs7916es7916epdf

[11] Ministerio da Saude andGabinete doMinistro ldquoPortaria n∘ 971de 3 de maio de 2006 Aprova a Polıtica Nacional de PraticasIntegrativas e Complementares (PNPIC) no Sistema Unicode Saude Brasılia (DF)rdquo 2006 httpbvsmssaudegovbrbvssaudelegisgm2006prt0971 03 05 2006html

[12] Ministerio da Saude Decreto nž 5813 de 22 de junho de 2006Aprova a Polıtica Nacional de Plantas Medicinais e Fitoterapicose da outras providencias Diario Oficial da Uniao Secao 1 2010

[13] E Rodrigues and J Barnes ldquoPharmacovigilance of herbalmedicines The potential contributions of ethnobotanical andethnopharmacological studiesrdquo Drug Safety vol 36 no 1 pp1ndash12 2013

[14] J Lanini J M Duarte-Almeida S Nappo and E A CarlinildquoldquoNatural and therefore free of risksrdquo - Adverse effects poi-sonings and other problems related to medicinal herbs by ldquoraizeirosrdquo inDiademaSPrdquordquoRevista Brasileira de Farmacognosiavol 19 no 1 A pp 121ndash129 2009

[15] J Barnes ldquoPharmacovigilance of herbal medicines A UKperspectiverdquoDrug Safety vol 26 no 12 pp 829ndash851 2003

[16] A A Mangoni and S H D Jackson ldquoAge-related changes inpharmacokinetics and pharmacodynamics basic principles andpractical applicationsrdquo British Journal of Clinical Pharmacologyvol 57 no 1 pp 6ndash14 2004

[17] E A Davies and M S OrsquoMahony ldquoAdverse drug reactions inspecial populations - The elderlyrdquo British Journal of ClinicalPharmacology vol 80 no 4 pp 796ndash807 2015

[18] M van denAkker F Buntinx and J A Knottnerus ldquoComorbid-ity ormultimorbidityrdquoTheEuropean Journal of General Practicevol 2 no 2 pp 65ndash70 1996

[19] I R Edwards and J K Aronson ldquoAdverse drug reactionsdefinitions diagnosis and managementrdquo The Lancet vol 356no 9237 pp 1255ndash1259 2000

[20] World Alliance for Patien Safety WHO draft guidelines foradverse event reporting and learning systems From informationto actionWorldHealthOrganization (WHO)Geneva Switzer-land 2005

[21] Organizacao Pan-Americana da Saude ldquoBoas praticas de far-macovigilancia para as Americasrdquo in Rede PAHRF DocumentoTecnico Nordm5 Washington DC USA 2011

Evidence-Based Complementary and Alternative Medicine 11

literate The prevalence of ADRs with probable causality washigh in this study population but it was only sex-relatedalthough more prevalent in the elderly who consume herbalmedicines

Regarding the potential ADRs among the elderly whoanswered the structured questionnaire there was a totalprevalence of 413 of ADRs with 274 being in the elderlywho used herbal medicines and medicines and 139 beingin the elderly who used only medicines it was also possibleto observe that when used the herbal medicines had asmain objective to combat symptoms of diseases or possiblyto combat ADR symptoms caused by the medications usedto treat chronic diseases The results of this study showedthe need to actively investigate suspected ADRs and thestructured questionnaire used was an effective and low-cost alternative tool for the screening of suspected ADRsin this study population In view of the unique regionalcharacteristics adequate phytopharmacovigilance systemswith multiple approaches are needed to overcome the specialchallenges and the structured questionnaires as well as atherapeutic follow-up can be useful approaches to increasethe likelihood of ADR detection

Data Availability

The data used to support the findings of this study areavailable from the corresponding author upon request

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

Acknowledgments

The authors thank the Federal University of Amapa and theundergraduate students Aline Mariana Lopes Martins AnnaElayne da Silva e Silva Nayara dos Santos Raulino da Silvaand Samara Graziela Guimaraes da Silva for assistance in datacollection and the American Journal Experts for assistancewith manuscript language review

References

[1] WHO ldquoTraditional medicinerdquo Fact sheet N134 Geneva 2008httpwwwwhointmediacentre

[2] E C S Oliveira and D M B M Trovao ldquoO uso de plantas emrituais de rezas e benzeduras um olhar sobre esta pratica noestado da Paraıbardquo Revista Brasileira de Biociencias vol 7 no 3pp 245ndash251 2009

[3] G S Da Silva ldquoBenzedores e raizeiros saberes partilhadosna comunidade remanescente de quilombo de Santana daCaatingardquo Revista Mosaico vol 3 no 1 pp 33ndash48 2010

[4] S Zank N Hanazaki and R Bussmann ldquoThe coexistence oftraditionalmedicine and biomedicine A study with local healthexperts in two Brazilian regionsrdquo PLoS ONE vol 12 no 4 pe0174731 2017

[5] J Mignone J Bartlett J OrsquoNeil and T Orchard ldquoBest practicesin intercultural health Five case studies in Latin Americardquo

Journal of Ethnobiology and Ethnomedicine vol 3 article no 312007

[6] I Vandebroek ldquoIntercultural health and ethnobotany How toimprove healthcare for underserved and minority communi-tiesrdquo Journal of Ethnopharmacology vol 148 no 3 pp 746ndash7542013

[7] C da Rosa ldquoTraditional Medicine and ComplementaryAlter-native Medicine in Primary Health Care The BrazilianExperiencerdquo Primary Care at a Glance - Hot Topics and NewInsights DrOreste Capelli httpwwwintechopencombooksprimary-care-at-aglance-hot-topics-and-new-insightstradi-tional-medicine-and-complementary-alternative-in-primary-healthcare-the-brazilian-experience

[8] World Health Organization (WHO) ldquoTraditional MedicineStrategy 2002ndash2005 Geneva Switzerlandrdquo 2002 httpwhqlib-docwhointhq2002who edm trm 20021pdf

[9] World Health Organization WHO Guidelines on Safety Moni-toring of HerbalMedicines in Pharmacovigilance Systems WHOGeneva Switzerland 2004

[10] World Health Organization ldquoNational Policy on TraditionalMedicine And Regulation of Herbal Medicinesrdquo 2005 httpappswhointmedicinedocspdfs7916es7916epdf

[11] Ministerio da Saude andGabinete doMinistro ldquoPortaria n∘ 971de 3 de maio de 2006 Aprova a Polıtica Nacional de PraticasIntegrativas e Complementares (PNPIC) no Sistema Unicode Saude Brasılia (DF)rdquo 2006 httpbvsmssaudegovbrbvssaudelegisgm2006prt0971 03 05 2006html

[12] Ministerio da Saude Decreto nž 5813 de 22 de junho de 2006Aprova a Polıtica Nacional de Plantas Medicinais e Fitoterapicose da outras providencias Diario Oficial da Uniao Secao 1 2010

[13] E Rodrigues and J Barnes ldquoPharmacovigilance of herbalmedicines The potential contributions of ethnobotanical andethnopharmacological studiesrdquo Drug Safety vol 36 no 1 pp1ndash12 2013

[14] J Lanini J M Duarte-Almeida S Nappo and E A CarlinildquoldquoNatural and therefore free of risksrdquo - Adverse effects poi-sonings and other problems related to medicinal herbs by ldquoraizeirosrdquo inDiademaSPrdquordquoRevista Brasileira de Farmacognosiavol 19 no 1 A pp 121ndash129 2009

[15] J Barnes ldquoPharmacovigilance of herbal medicines A UKperspectiverdquoDrug Safety vol 26 no 12 pp 829ndash851 2003

[16] A A Mangoni and S H D Jackson ldquoAge-related changes inpharmacokinetics and pharmacodynamics basic principles andpractical applicationsrdquo British Journal of Clinical Pharmacologyvol 57 no 1 pp 6ndash14 2004

[17] E A Davies and M S OrsquoMahony ldquoAdverse drug reactions inspecial populations - The elderlyrdquo British Journal of ClinicalPharmacology vol 80 no 4 pp 796ndash807 2015

[18] M van denAkker F Buntinx and J A Knottnerus ldquoComorbid-ity ormultimorbidityrdquoTheEuropean Journal of General Practicevol 2 no 2 pp 65ndash70 1996

[19] I R Edwards and J K Aronson ldquoAdverse drug reactionsdefinitions diagnosis and managementrdquo The Lancet vol 356no 9237 pp 1255ndash1259 2000

[20] World Alliance for Patien Safety WHO draft guidelines foradverse event reporting and learning systems From informationto actionWorldHealthOrganization (WHO)Geneva Switzer-land 2005

[21] Organizacao Pan-Americana da Saude ldquoBoas praticas de far-macovigilancia para as Americasrdquo in Rede PAHRF DocumentoTecnico Nordm5 Washington DC USA 2011

12 Evidence-Based Complementary and Alternative Medicine

[22] Banco Central do Brasil ldquoCambio e capitais internacionaisTaxas de cambiordquoDolar americano 2017 httpwwwbcbgovbr

[23] A Kennerfalk A Ruigomez M-A Wallander L Wilhelmsenand S Johansson ldquoGeriatric drug therapy and healthcareutilization in theUnitedKingdomrdquoAnnals of Pharmacotherapyvol 36 no 5 pp 797ndash803 2002

[24] WHO Collaboranting Centre for Drug Statistics MethodologyldquoATC codes 2003rdquo Oslo Norwey 2003 httpwwwwhoccnmdno

[25] The Plants ListDatabase ldquoThe Plant List is a working list of allknown plant speciesrdquo 2017 httpwwwtheplantlistorg

[26] World Health Organization ldquoInternational monitoring ofadverse reactions to drugs adverse reaction terminologyrdquo inWHO collaborating Centre for International Drug MonitoringUppsala Sweden 1992

[27] Instituto Brasileiro de Geografia e Estatıstica ldquoAnalise dopanorama das cidades brasileiras Dados populacionais deMacapardquo 2017 httpsibgegovbr

[28] D Shaw ldquoToxicological risks of Chinese herbsrdquo Planta Medicavol 76 no 17 pp 2012ndash2018 2010

[29] S Mulkalwar N Munjal P Worlikar and L Behera ldquoPharma-covigilance in IndiardquoMedical Journal ofDr DY Patil Universityvol 6 no 2 pp 126ndash131 2013

[30] Rdc 982016 Resolucao Da Diretoria Colegiada ndash Rdc N∘ 98 De1∘ De Agosto De 2016 Dispoe sobre os criterios e procedimentospara o enquadramento de medicamentos como isentos deprescricao e o reenquadramento como medicamentos sobprescricao e da outras providencias 2016

[31] S Cameron and I Turtle-Song ldquoLearning to write case notesusing the SOAP formatrdquo Journal of Counseling amp Developmentvol 80 no 3 pp 286ndash292 2002

[32] M Machuca F Fernandez-Llim andM J FausMetodo DaderGuıa de seguimiento farmacoterapeutico Grupo de Investiga-cion en Atencion Farmaceutica (GIAF) 2003

[33] L M Strand R J Cipolle P C Morley and M J Frakes ldquoTheimpact of pharmaceutical care practice on the practitioner andthe patient in the ambulatory practice setting Twenty-five yearsof experiencerdquo Current Pharmaceutical Design vol 10 no 31pp 3987ndash4001 2004

[34] R J Cipolle L Strand L and P Morley Pharmaceutical CarePractice The ClinicanrsquoS Guide The McGrw Companies NewYork NY USA 2nd edition 2014

[35] R F Riba A C Estela M L S Esteban et al ldquoIntervencionesfarmaceuticas (parte I) metodologıa y evaluacionrdquo FarmaciaHospitalaria vol 24 no 3 pp 136ndash144 2000

[36] D Sabater F Fernandez-LLimos M Parras and M J FausldquoTypes of pharmacist intervention in pharmacotherapy follow-uprdquo Seguimiento Farmacoteraeutico vol 3 no 2 pp 90ndash972005

[37] Ministerio da Saude Portaria nordm 886 de 20 de abril de 2010Institui a Farmacia Viva no ambito do Sistema Unico de Saude(SUS) Diario Oficial da Uniao Secao 1 2010

[38] Agencia Nacional de Vigilancia Sanitaria [Brasil] EsolucaoDa Diretoria Colegiada Nordm18 De 03 De Abril De 2013 DispoeSobre as Boas Praticas De Processamento E ArmazenamentoDe Plantas Medicinais Preparacao E Dispensacao De ProdutosMagistrais E Oficinais De Plantas Medicinais E Fitoterapicos EmFarmacias Vivas No Ambito Do Sistema Unico De Saude (SUS)Diario Oficial da Uniao Secao1 Portuguese 2000

[39] Agencia Nacional de Vigilancia Sanitaria (ANVISA) ldquoGeren-ciamento do Risco em Farmacovigilanciardquo 2008 httpportalanvisagovbr

[40] H V Ratajczak ldquoDrug-induced hypersensitivity Role in drugdevelopmentrdquoToxicological Reviews vol 23 no 4 pp 265ndash2802004

[41] L S Resende and E T Santos-Neto ldquoRisk factors associ-ated with adverse reactions to antituberculosis drugsrdquo JornalBrasileiro de Pneumologia vol 41 no 1 pp 77ndash89 2015

[42] M Umair M Altaf A M Abbasi and R Bussmann ldquoAn eth-nobotanical survey of indigenousmedicinal plants inHafizabaddistrict Punjab-Pakistanrdquo PLoS ONE vol 12 no 6 p e01779122017

[43] ldquoUnderstanding gender health and globalization opportuni-ties and challengesrdquo inGlobalization Women and Health in the21st Century Palgrave Macmillan New York NY USA 2015

[44] A Abdelhalim T Aburjai J Hanrahan and H Abdel-HalimldquoMedicinal plants used by traditional healers in Jordan theTafila regionrdquoPharmacognosyMagazine vol 13 no 49 pp S95ndashS101 2017

[45] R Delgoda N Younger C Barrett J Braithwaite and D DavisldquoThe prevalence of herbs use in conjunction with conventionalmedicines in Jamaicardquo Complementary Therapies in Medicinevol 18 no 1 pp 13ndash20 2010

[46] D Picking N Younger S Mitchell and R Delgoda ldquoTheprevalence of herbal medicine home use and concomitantuse with pharmaceutical medicines in Jamaicardquo Journal ofEthnopharmacology vol 137 no 1 pp 305ndash311 2011

[47] J J Bruno and J J Ellis ldquoHerbal use among US elderly 2002National Health Interview SurveyrdquoAnnals of Pharmacotherapyvol 39 no 4 pp 643ndash648 2005

[48] P M de Medeiros A H Ladio and U P AlbuquerqueldquoPatterns of medicinal plant use by inhabitants of Brazilianurban and rural areas a macroscale investigation based onavailable literaturerdquo Journal of Ethnopharmacology vol 150 no2 pp 729ndash746 2013

[49] L C Di Stasi G P Oliveira M A Carvalhaes et al ldquoMedicinalplants popularly used in the Brazilian Tropical Atlantic ForestrdquoFitoterapia vol 73 no 1 pp 69ndash91 2002

[50] N S Olisa and F T Oyelola ldquoEvaluation of use of herbalmedicines among ambulatory hypertensive patients attending asecondary health care facility in Nigeriardquo International Journalof Pharmacy Practice vol 17 no 2 pp 101ndash105 2009

[51] K D Kassaye A Amberbir B Getachew and Y Mussema ldquoAhistorical overview of traditional medicine practices and policyin Ethiopiardquo Ethiopian Journal of Health Development vol 20no 2 pp 127ndash134 2006

[52] P D Carvalho Mastroianni F Rossi Varallo M Amaral Costaand L V Da Silva Sacramento ldquoDevelopment of Instrumentto Report And Assess Causality of Adverse Events Related toHerbal Medicinesrdquo Revista Vitae vol 24 no 1 pp 13ndash22 2017

[53] C A Naranjo U Busto and E M Sellers ldquoA method forestimating the probability of adverse drug reactionsrdquo ClinicalPharmacology ampTherapeutics vol 30 no 2 pp 239ndash245 1981

[54] F E Karch and L Lasagna ldquoEvaluating Adverse Drug Reac-tionsrdquoAdverseDrugReaction Bulletin vol 59 no 1 pp 204ndash2071976

[55] I Kosalec J Cvek and S Tomic ldquoContaminants of medicinalherbs and herbal productsrdquo Archives of Industrial Hygiene andToxicology vol 60 no 4 pp 485ndash501 2009

[56] ldquoICH Topic E2E pharmacovigilance planning (PVP)rdquo CPMPICH571603 June 2005

Stem Cells International

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

MEDIATORSINFLAMMATION

of

EndocrinologyInternational Journal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Disease Markers

Hindawiwwwhindawicom Volume 2018

BioMed Research International

OncologyJournal of

Hindawiwwwhindawicom Volume 2013

Hindawiwwwhindawicom Volume 2018

Oxidative Medicine and Cellular Longevity

Hindawiwwwhindawicom Volume 2018

PPAR Research

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwwwhindawicom Volume 2018

Journal of

ObesityJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Computational and Mathematical Methods in Medicine

Hindawiwwwhindawicom Volume 2018

Behavioural Neurology

OphthalmologyJournal of

Hindawiwwwhindawicom Volume 2018

Diabetes ResearchJournal of

Hindawiwwwhindawicom Volume 2018

Hindawiwwwhindawicom Volume 2018

Research and TreatmentAIDS

Hindawiwwwhindawicom Volume 2018

Gastroenterology Research and Practice

Hindawiwwwhindawicom Volume 2018

Parkinsonrsquos Disease

Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwwwhindawicom

Submit your manuscripts atwwwhindawicom