11/12/13 •  Apresentação de uma proposta de estudo clínico •  Discussão e contribuições Aloysia polystachia (Griseb.) Moldenke: um ansiolí<co promissor? Encontro de Fitoterapia da Farmácia da Natureza Terra de Ismael -­‐ Dezembro de 2013 A ansiedade é uma reação normal do organismo ao estresse. Estado emocional vivenciado com a qualidade subje5va do medo ou da emoção a ela relacionada, desagradável, dirigida ao futuro, desproporcional a uma ameaça reconhecível, com desconforto somá5co subje5vo e alterações somá5cas manifestas (Aubrey Lewis) Tais reações exageradas ao esEmulo ansiogênico se desenvolvem, mais comumente, em indivíduos com uma predisposição neurobiológica herdada. (Rosen, Shilkin, 1998) -­‐ Doenças mentais são transtornos heterogêneos com manifestações muito variadas; -­‐ Fortes evidências que recomendam o uso de fitoterápicos são escassas. (Ernst, 2000). Neurobiologia da ansiedade •  Circuito neural das emoções: córtex, hipocampo, amígdala e hipotálamo. •  Alvos terapêuNcos: Sistema serotoninérgico e Gabaérgico. •  Diferenças clínicas e biológicas entre os vários TA. •  Importante aspecto de pesquisa neurobiológica moderna: encontrar semelhanças entre esses transtornos, pois muitas vezes respondem ao mesmo espectro de tratamento. (Cannistraro et al., 2003; Katzung, 2007). q  S i n t o m a s T s i c o s ( m u s c u l a r e s , cardiovasculares, viscerais, endócrinas) q Sintomas psíquicos (sensação de tensão e apreensão, hipervigilância, irritabilidade, medo) Categorias diagnósNcas: Ø  Transtorno de ansiedade generalizada Ø  Transtorno do pânico Ø  Transtornos fóbico-­‐ansiosos: Fobia social, fobia especifica, agorafobia Ø  Transtorno obsessivo-­‐compulsivo Ø  Transtornos ligados ao estresse: estresse agudo, estresse pós-­‐
traumáNco,transtorno de adaptação Psicofarmacologia da ansiedade Medicamentos sinté4cos •  ISRS: primeira linha (Bandelow, 2008) •  BZDs: efeito agudo e tempo de uso limitado •  Buspirona •  Pregabalina q 
análogo do ácido gama-­‐aminobuarico (GABA) q 
impede a liberação pré-­‐sinápNca de neurotransmissores excitatórios q 
TAG 1 isolated compounds. Forty-seven patent registrations for plant preparations to be used for the
treatment of anxiety were included.
Keywords: anxiolytic compounds, anxiolytic extracts, clinical trials, patents, mechanism of
action
Introduction
Anxiety disorders are considered to be a major cause of disability worldwide, and
comprise generalized anxiety disorder and other commonly associated conditions,
such as phobias, postmenopausal stress, post-traumatic syndrome, somatization and
cognitive dysfunction, among others. Patients diagnosed with generalized anxiety
disorder exhibit functional impairment as well as a tendency to develop comorbid
psychiatric disorders.1 Effective treatments for this condition are usually focused on
eliminating anxiety symptoms and restoring normal function. Conventional anxiolytic
drug therapy is considered to be effective, safe, and broad-spectrum in action,2 but
side effects often reduce quality of life, discouraging patients
to follow medication
Botanics: Targets and Therapy
Dovepress
Correspondence: María Luisa Villarreal
protocols. Moreover, many of the medicines used for anxiety include antidepressants,
Centro de Investigación en Biotecnología,
REVIEW
Universidad Autónoma del Estado de
and the use of such agents can cause troubling side effects, ie, cholinergic symptoms,
Morelos, Av Universidad 1001,
A systematic updated review of scientifically
gain, sleep disturbances, sexual dysfunction, medication
dependence, or
Col Chamilpa, Cuernavaca,
Botanics: Targets weight
and Therapy
Dovepress
tested selected plants used for anxiety
open access to scientific and medical research
Morelos 62209, México
gastrointestinal problems.
Tel 52 777 329 7057
disorders
Open Access Full Text Article
REVIEW
The use of herbal remedies for the treatment of anxiety is an ancient
practice
Fax 52 777 329 7030
Email [email protected]
that nowadays has become popular in Western societies. Plant-based medicines repBurrito, Té de burro, Hierba de burro. 11/12/13 open access to scientific and medical research
Open Access Full Text Article
A systematic updated review of scientifically
tested selected plants used for anxiety
disorders Botanics: Targets and Therapy 2012:2 21–39
Ashutosh Sharma
Alexandre Cardoso-Taketa
Griselda García
María Luisa Villarreal
submit your manuscript | www.dovepress.com
Dovepress
http://dx.doi.org/10.2147/BTAT.S20593
© 2012 Sharma et al, publisher and licensee Dove Medical Press Ltd. This
is an
Open Access
article
Centro
de Investigación
en
Biotecnología, Universidad Autónoma
which permits unrestricted noncommercial use, provided the original work
is properly
del Estado
de Morelos, cited.
Cuernavaca,
Mexico
Ashutosh cSharma
Abstract: The aim of this review is to provide a summary on multidisciplinary scientific
Espécies om efeitos ansiolí4cos information obtained from medicinal plants used worldwide to treat anxiety, focusing on pharAlexandre Cardoso-Taketa
macological and clinical studies. The bibliographical investigation was carried out by consulting
Griselda García
five peer-reviewed worldwide database publications for references, and patents. The information
María Luisa Villarreal
gathered on plants with attributed anxiolytic properties are presented as follows: (1) plant extracts
•  112 espécies: testadas em modelos animais (teste do labirinto em with anxiolytic properties evaluated in animal models; (2) plants with clinical trials; (3) identified active compounds in plants that have been assayed in animal models; (4) mechanism of
cruz elevado em 80% das publicações) action of anxiolytic plant extracts and compounds; and (5) registered patents for anxiolytic plant
preparations. We recorded 112 plant species belonging to 63 botanical families for which the
anxiolytic properties had been tested in animal models. Eleven plant species to treat general
anxiety disorders as well as eleven species to treat anxiety-associated conditions, had been
•  Maioria possui registros etnomedicinais em diferentes países documented by clinical trials. Thirty-three registers for active compounds belonging to five
general types of secondary metabolites had also been recorded. The mechanism of action at the
central nervous system level had been determined in 33 plant species, either in their extracts or
isolated compounds. Forty-seven patent registrations for plant preparations to be used for the
•  Não há estudos clínicos com Aloysia p. até o momento. treatment of anxiety were included.
Centro de Investigación en
Biotecnología, Universidad Autónoma
del Estado de Morelos, Cuernavaca,
Mexico
Correspondence: María Luisa Villarreal
Centro de Investigación en Biotecnología,
Universidad Autónoma del Estado de
Morelos, Av Universidad 1001,
Col Chamilpa,
Cuernavaca,
Keywords: anxiolytic compounds, anxiolytic extracts, clinical trials,
patents,
mechanism of
Morelos 62209, México
Tel 52 777 329 7057
action
Fax 52 777 329 7030
Email [email protected]
Abstract: The aim of this review is to provide a summary on multidisciplinary scientific
information obtained from medicinal plants used worldwide to treat anxiety, focusing on pharmacological and clinical studies. The bibliographical investigation was carried out by consulting
five peer-reviewed worldwide database publications for references, and patents. The information
gathered on plants with attributed anxiolytic properties are presented as follows: (1) plant extracts
with anxiolytic properties evaluated in animal models; (2) plants with clinical trials; (3) identified active compounds in plants that have been assayed in animal models; (4) mechanism of
action of anxiolytic plant extracts and compounds; and (5) registered patents for anxiolytic plant
preparations. We recorded 112 plant species belonging to 63 botanical families for which the
anxiolytic properties had been tested in animal models. Eleven plant species to treat general
anxiety disorders as well as eleven species to treat anxiety-associated conditions, had been
documented by clinical trials. Thirty-three registers for active compounds belonging to five
general types of secondary metabolites had also been recorded. The mechanism of action at the
central nervous system level had been determined in 33 plant species, either in their extracts or
isolated compounds. Forty-seven patent registrations for plant preparations to be used for the
treatment of anxiety were included.
Keywords: anxiolytic compounds, anxiolytic extracts, clinical trials, patents, mechanism of
action
•  Verbenaceae •  Descrita por Griseb. e Moldenke (1940) •  ArgenNna (províncias centro-­‐norte) e Paraguai (região oriental) •  Planta aromáNca, consumida habitualmente em forma de chá (sabor e aroma agradáveis). •  É também uNlizada para dar sabor ao mate ou ao tereré. •  Industrialmente: erva mate ‘composta’ (Ilex paraguayensis, Aloysia p., Tea sinensis, Mentha etc). •  Uso popular muito difundido (forma silvestre ou domesNcada). 21
Introduction
Anxiety disorders are considered to be a major cause of disability worldwide, and
comprise generalized anxiety disorder and other commonly associated conditions,
such as phobias, postmenopausal stress, post-traumatic syndrome, somatization and
cognitive dysfunction, among others. Patients diagnosed with generalized anxiety
disorder exhibit functional impairment as well as a tendency to develop comorbid
psychiatric disorders.1 Effective treatments for this condition are usually focused on
eliminating anxiety symptoms and restoring normal function. Conventional anxiolytic
drug therapy is considered to be effective, safe, and broad-spectrum in action,2 but
side effects often reduce quality of life, discouraging patients to follow medication
protocols. Moreover, many of the medicines used for anxiety include antidepressants,
and the use of such agents can cause troubling side effects, ie, cholinergic symptoms,
weight gain, sleep disturbances, sexual dysfunction, medication dependence, or
gastrointestinal problems.
The use of herbal remedies for the treatment of anxiety is an ancient practice
that nowadays has become popular in Western societies. Plant-based medicines rep-
Introduction
Anxiety disorders are considered to be a major cause of disability worldwide, and
Dovepress
comprise generalized anxiety disorder and other commonly associated conditions,
such as phobias, postmenopausal stress, post-traumatic syndrome, somatization and
cognitive dysfunction, among others. Patients diagnosed with generalized anxiety
disorder exhibit functional impairment as well as a tendency to develop comorbid
psychiatric disorders.1 Effective treatments for this condition are usually focused on
eliminating anxiety symptoms and restoring normal function. Conventional anxiolytic
drug therapy is considered to be effective, safe, and broad-spectrum in action,2 but
side effects often reduce quality of life, discouraging patients to follow medication
protocols. Moreover, many of the medicines used for anxiety include antidepressants,
and the use of such agents can cause troubling side effects, ie, cholinergic symptoms,
weight gain, sleep disturbances, sexual dysfunction, medication dependence, or
gastrointestinal problems.
The use of herbal remedies for the treatment of anxiety is an ancient practice
that nowadays has become popular in Western societies. Plant-based medicines repsubmit your manuscript | www.dovepress.com
http://dx.doi.org/10.2147/BTAT.S20593
Correspondence: María Luisa Villarreal
Centro de Investigación en Biotecnología,
Universidad Autónoma del Estado de
Morelos, Av Universidad 1001,
Col Chamilpa, Cuernavaca,
Morelos 62209, México
Tel 52 777 329 7057
Fax 52 777 329 7030
Email [email protected]
Uso etnomedicinal No Paraguai: •  digesNvo e doenças respiratórias (González Torres, 1996) submit your manuscript | www.dovepress.com
Dovepress
http://dx.doi.org/10.2147/BTAT.S20593
Botanics: Targets and Therapy 2012:2 21–39
© 2012 Sharma et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
which permits unrestricted noncommercial use, provided the original work is properly cited.
Botanics: Targets and Therapy 2012:2 21–39
© 2012 Sharma et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
which permits unrestricted noncommercial use, provided the original work is properly cited.
21
Aspectos botânicos ü  SubarbusNva, cresce até 1,5 m; ü  Ramos finos, quebradiços; ü  Folhas pequenas (3 cm), verde claras, flores brancas. 21
Na ArgenNna: •  doenças respiratórias (resfriados e tosse) e dores GI (Filipoy, 1994) •  anNeméNco (MarNnez Croveno, 1981) •  sedaNvo (Del Vino et al., 1997) ü  Aspectos agronômicos ü  Cresce melhor em solo bem, drenado, férNl e areno-­‐argiloso; ü  CulNvo a pleno sol; ü  Floresce final do outono/
início do inverno. Extrato hidroalcoólico: aNvidade ansiolíNca (Mora et al., 2005; Hellion-­‐ Ibarrola et al., 2006). Carvona: provável responsável pelo efeito ansiolíNco e caminaNvo (Mora et al., 2005). (Pereira et al, 2011) Composição química Óleo essencial (folhas) •  Monoterpenos: carvacrol, carvona, eucarvona, limoneno, (−)limoneno, alfa-­‐pinene, sabineno, (+)sabineno, (−)thujona, alfa-­‐thujona, alfa-­‐(−)thujona, beta-­‐thujona, isothujona, (+)isothujona (Fester et al., 1956; Huergo et Retamar, 1973; Gano et al., 1981). •  99% dos consNtuintes químicos são monoterpenos e sesquiterpenos. ü  Principais consNtuintes: carvona (~ 78%) e limoneno (~ 15%) (Pina et al, 2012) The anxiolytic-like effects of Aloysia polystachya (Griseb.)
Moldenke (Verbenaceae) in mice
M.C. Hellión-Ibarrola a,∗ , D.A. Ibarrola a , Y. Montalbetti a , M.L. Kennedy a ,
O. Heinichen a , M. Campuzano a , J. Tortoriello b , S. Fernández c , C. Wasowski c ,
M. Marder c , T.C.M. De Lima d , S. Mora e
a
Laboratory of Psychopharmacology, Department of Pharmacology, Facultad de Ciencias Quı́micas, Universidad Nacional de Asunción,
Campus Universitario, P.O. Box 1055, San Lorenzo, Paraguay
b Centro de Investigación Biomédica del Sur, IMSS, Xochipetec, Morelos, Mexico
c IQUIFIB, Faculty of Pharmacy and Biochemistry Buenos Aires, Argentina
d Laboratory of Neuropharmacology, Department of Pharmacology, Universidade Federal de Santa Catarina, Santa Catarina, Brazil
e Program of Molecular and Clinical Pharmacology, Biomedical Sciences Institute, Faculty of Medicine, University of Chile, Chile
•  Determinação da toxicidade aguda (DL50): Doses até 3000.0 mg/kg VO não produziram sintomas tóxicos evidentes nos camundongos em 2 semanas. •  Determinação dos efeitos ansiolíNcos do extrato hidroetanólico: ação não-­‐sedaNva e não-­‐hipnóNca; sem efeito na coordenação motora; efeitos ansiolíNcos (teste da cruz). Abstract
The aim of the present work is to demonstrate the putative sedative and anxiolytic-like effects of a hydro-ethanolic extract obtained from the
aerial parts of Aloysia polystachya (Verbenaceae) in male mice using several behavioural assays. Groups of male mice orally treated with doses of
1.0, 10.0 and 100.0 mg/kg of the extract did not show any significant alteration of their locomotor activity, body temperature or motor coordination.
The same treatment increased the duration of the sleeping time induced by 30.0 mg/kg i.p. of sodium pentobarbital. However, the sleeping time
induced by ethyl ether was not modified by the oral administration of the extract, not confirming the putative sedative effect of the plant. The
ethanolic extract also significantly increased the percentage of both entries (1.0 and 100.0 mg/kg) and the time spent (10.0 and 100.0 mg/kg) into the
open arms of the elevated plus maze (EPM). Nevertheless, the binding of 3 H-flunitrazepam (3 H-FNZ) to the benzodiazepine binding site (BDZ-bs),
in washed crude synaptosomal membranes from rat cerebral cortex, was not affected by the semi-purified components from Aloysia polystachya.
These results indicate an anxiolytic-like profile of action for the extract of Aloysia polystachya without sedative side effect, being this activity
probably mediated by other mechanism than BDZ-bs modulation at the GABAA receptors.
•  Mec. ação: provavelmente outro mecanismo que não a modulação do receptor BZD (do GABA-­‐A) Keywords: Aloysia polystachya; Verbenaceae; Anxiolytic; Elevated plus maze; Hole-board; Open-field; Benzodiazepine binding assay
1. Introduction
The family Verbenaceae comprises about 175 genus and
2300 species, distributed in the tropics and subtropics, mainly
in the temperate zone of Southern Hemisphere (Oliveira de
Figueiredo et al., 2002). Mental ailments are heterogeneous diseases and will probably require a selected arsenal of drugs with
different modes of action for successful treatment of their various manifestations (Baldessarini, 1990). Anxiety disorders are
among the most prevalent of all psychological problems worldwide (Roselind Lieba et al., 2005). Benzodiazepines (BDZs) are
∗
Corresponding author. Tel.: +595 21 58 55 62/3; fax: +595 21 58 55 64.
E-mail address: [email protected] (M.C. Hellión-Ibarrola).
considered safe drugs and are widely prescribed for their anxiolytic, muscle relaxant, sedative-hypnotic and anticonvulsant
actions (Woods et al., 1992). However, they may produce side
effects, such as sedation and myorelaxation that are considered
as unwanted effects in an anxiolytic drug (Thiebot, 1985; Nutt,
1986; Griffiths and Sannerud, 1987; Kales et al., 1987; Miller et
al., 1989; Izquierdo et al., 1990; Rickels et al., 1990; Pratt, 1991;
Gallagher and Primus, 1992). On the other hand, the existence of
natural flavonoids that possess anxiolytic effect not associated
with myorelaxant, amnestic or sedative actions has been demonstrated (Medina and Marder, 1996; Marder and Paladini, 2002).
Although alternative treatments are increasingly being used to
alleviate affective disorders, strong evidence to recommend the
use of herbal medicines for several illnesses is still scarce (Ernst,
2000).
2 kept or deposited.
2. Description of any special testing/purity testing (e.g.,
heavy metal or other contaminant testing) undertaken,
which unwanted components were removed and how
(i.e., methods).
Phenomenex Luna 5-!m C18 (2) column with
dimensions 250 ! 2.00 mm at 45 °C with a one-step
linear gradient using acetonitrile:formic acid (0.3%) at
a flow rate of 0.4 mL/min (20). The analysis was done
by an individual with 12 years’ experience in the
methods, at an independent laboratory, CanHerba
Labs Inc. (Windsor, Ontario, Canada). The product
sample is also kept at CanHerba Labs Inc.
Laboratory personnel were blinded to the identity of the
extract and control capsules. Concentrations (!g/g) of
lead, mercury, and arsenic were measured by x-ray
fluorescence spectroscopy 23 equipped with a
tungsten x-ray tube, a Si(Li)-semiconductor detector,
and software version 2.2R03 I (Spectro Analytical
Instruments, Kleve, Germany). National Institute of
Standards and Technology solid standard reference
materials 2709, 2710, 2711, 24, and liquid certified
standards (SCP Science, Champlain, New York)
containing specified heavy metal concentrations
served as positive and negative controls (21).
11/12/13 Continued on following page
Academia and Clinic
Annals of Internal Medicine
• 
Reporting Randomized, Controlled Trials of Herbal Interventions:
An Elaborated CONSORT Statement
ü  nome cienEfico da planta medicinal Joel J. Gagnier, ND, MSc; Heather Boon, PhD; Paula Rochon, MD, MPH; David Moher, PhD; Joanne Barnes, PhD, MRPharmS FLS; and
Claire Bombardier, MD, for the CONSORT Group*
www.annals.org
Herbal medicinal products are widely used, vary greatly in content
and quality, and are actively tested in randomized, controlled trials
(RCTs). The authors’ objective was to develop recommendations
for reporting RCTs of herbal medicine interventions, based on the
need to elaborate on the 22-item CONSORT (Consolidated Standards of Reporting Trials) checklist. Telephone calls were made and
a consensus meeting was held with 16 participants in Toronto,
Canada, to develop these recommendations. The group agreed on
context-specific elaborations of 9 CONSORT checklist items for
ü  nome do extrato patenteado 7 March 2006 Annals of Internal Medicine Volume 144 • Number 5 365
ü  autorização ou registro da planta no país RCTs of herbal medicines. Item 4, concerning the herbal medicine
intervention, required the most extensive elaboration. These recommendations have been developed to improve the reporting of RCTs
using herbal medicine interventions.
ü  parte da planta usada 1. Introdução 3. Resultados Ann Intern Med. 2006;144:364-367.
www.annals.org
For author affiliations, see end of text.
2. Métodos *The members of the CONSORT
Group are listed
the following Web site:
•  ParNcipantes: fluxograma e on
recrutamento. www.consort-statement.org/profiles/partners.html.
•  Caracterização clínica e demográfica de •  ParNcipantes cada grupo •  Intervenções andomized, controlled trials (RCTs) of herbal inter-•  Análises required for
trials of herbal interventions. He
e ereporting
sNmaNvas •  ventions
ObjeNvos often inadequately describe important aspects
asked participants to nominate revisions or new items on
• 
dversos of
methods (1– 4). Although the quality of reporting Efeitos the basisaof
empirical evidence that not reporting the item
•  their
Desfechos of these trials may be improving with time, many still lack would bias estimates of treatment effect. When no empir•  Tamanho da aparticularly
mostra about the composition
important
information,
ical evidence was available, commonsense reasoning was
4. Discussão of
herbal intervention (4, 5). Crude herbal drugs are
acceptable. After completing all telephone calls, the inves•  theRandomização natural products and their chemical composition varies de- tigator thematically grouped items and circulated them by
•  Blinding pending
on several factors, such as geographic source of the
e-mail to each participant for review.
plant
material, climate
in which it was grown, and time of•  Interpretação Fourteen participants attended the consensus meeting.
•  Métodos estaasNcos harvest. Commercially available herbal medicinal products•  Validade The meeting
began with a review of the premeeting checkexterna ü  5po do produto ü  5po e concentração do solvente u5lizado ü  proporção produto/solvente ü  método de auten5cação da espécie e número do lote da planta fresca R
also vary in their content and concentration of chemical
constituents from batch to batch and when products containing the same herbal ingredient are compared among
manufacturers (6 –14). Even when herbal products are
standardized for content of known active or marker compounds to achieve more consistent pharmaceutical quality,
there is variation in the concentrations of other constituents. These variations can result in differences in pharmacologic activity in vitro (15) and in bioavailability in humans (16). Mindful of these issues, we elaborated on the
22-item checklist of the Consolidated Standards of Reporting Trials (CONSORT) statement (17) to help authors
and editors improve reporting of RCTs of herbal interventions.
METHODS
We developed these reporting recommendations in 3
phases that included premeeting item generation, a consensus meeting, and postmeeting feedback. The individuals
who participated are listed in the Appendix (available at
www.annals.org). To generate items, 1 investigator conducted telephone interviews of 16 participants with expertise in the method and reporting of RCTs (5 participants),
pharmacognosy (4 participants), herbal medicinal products
(5 participants), medical statistics (1 participant), and
herbal product manufacturing (1 participant). The investigator asked participants to suggest revisions to existing
CONSORT checklist items and also to additional items
Intervenções – ítem 4 (detalhes precisos das intervenções pretendidas para cada grupo, como e quando elas serão administradas) ü  posologia e descrição quan5ta5va (conteúdo dos cons5tuintes químicos e marcadores padronizados) ü  testagens qualita5vas (dados cromatográficos, laboratório que fez a análise, amostra foi guardada, testes de pureza e padronização) ü  descrição do 5po de placebo e dos profissionais envolvidos list item suggestions. We emphasized minimizing item
elaborations and additions and basing elaborations on evidence whenever possible. Each item suggestion was presented and followed by debate for its inclusion, deletion, or
modification. This process was repeated until all items
were reviewed and a consensus emerged.
After the consensus meeting, we circulated a draft
summary report to all participants to ensure that it accurately represented decisions made during the consensus
meeting. We then circulated the report to the wider CONSORT Group for input and revised it on the basis of their
suggestions. Ethical approval was obtained from The University of Toronto Health Sciences Ethics Review Committee on 23 January 2004.
Financial support for the consensus meeting was provided by the Canadian Institutes of Health Research. The
funding body had no role in the design, conduct, or analysis of this study and did not influence the decision to submit the manuscript for publication. All researchers are independent of the funders.
P Em sujeitos com sintomas ansiosos, I a administração de A. polystachia TM, C comparando-­‐se antes e depois do tratamento, O resulta em redução de pelo menos 10 pontos na escala HAM-­‐A, T após 8 semanas? Métodos See also:
Web-Only
Appendix
Appendix Table
Conversion of figure and tables into slides
364 © 2006 American College of Physicians
ParNcipantes: recrutados mediante divulgação da pesquisa na comunidade e selecionados conforme critérios de inclusão e exclusão. Intervenções: A. polystachya TM (doses escalonadas) via oral durante 8 semanas. Aplicação das escalas em T0, T1, T2, T3, T4. Métodos Fases do estudo Semanas 7 e 8 Semanas 5 e 6 Semanas 3 e 4 Semanas 1 e 2 • 1 gota/kg/dia • 2 gotas/kg/dia • 3 gotas/kg/dia • 4 gotas/kg/dia •  Tamanho da amostra: 20 sujeitos (mínimo 11) •  Desfecho: Redução de 10 pontos da pontuação do Hamilton-­‐A •  Instrumentos: ü  Hamilton anxiety scale (Hamilton MC. Diagnosis and raNng of anxiety. Br J Psychiatry. 1969;3:76–79) ü  SF-­‐B Sleep QuesNonnaire •  Delineamento do estudo: Estudo clínico fase II aberto (não-­‐
controlado) com escalonamento de dose. •  Métodos estaasNcos: ANOVA de medidas repeNdas 3 Tiragem: 1.ª edição – 2008 – 3.000 exemplares
Versão original publicada pela Organização Mundial da Saúde sem ISBN.
Elaboração, distribuição e informações:
MINISTÉRIO DA SAÚDE
Secretaria de Ciência, Tecnologia e Insumos Estratégicos Departamento de Ciência e Tecnologia
Esplanada dos Ministérios, bloco G,
Edifício Sede, 8.º andar, sala 845
CEP: 70058-900, Brasília-DF
Tel: (61) 3315 -3197
Fax: (61) 3223 - 0799
E-mail: [email protected]
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OPAS / OMS
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Brasília-DF
Brasil 70800-400
Tel: +55 (61) 3426 - 9595
Fax: +55 (61) 3426 - 9591
Tradução:
Rossana M F Pontes – Universidade de Brasília – UnB
Revisão e adaptação do texto para língua
portuguesa:
Damaris Silveira – Curso de Ciências
Farmacêuticas, Universidade de Brasília
– UnB
Wladimir Queiroz – Instituto de
Infectologia Emílio Ribas, Foro Lationoamericano de Comitês de Ética em
Inverstigación
11/12/13 Revisão Final:
Dirce Guilhem – Universidade de
Brasília – UnB, Foro Latinoamericano
de Comités de Ética en Investigación en
Salud – FLACEIS
Fabio Zicker – Programa Especial de
Pesquisa e Treinamento em Doenças
Tropicais – TDR/OMS, Genebra, Suiça.
Impresso no Brasil / Printed in Brazil
Ficha Catalográfica
Brasil. Ministério da Saúde.
Instruções operacionais: informações necessárias para a condução de ensaios clínicos com Fitoterápicos / Ministério da Saúde, Organização Mundial da Saúde. – Brasília : Ministério da Saúde, 2008.
20 p. – (Série A. Normas e Manuais Técnicos)
Obje4vos Tradução de: Operational guidance:
Information needed
to support clinical trials of herbal products
Sistema
Parâmetros
de segurança
•  Avaliar os efeitos ansiolíNcos da Aloysia polystachia em doses escalonadas. •  Avaliar os efeitos posiNvos na qualidade do sono em doses escalonadas. •  Avaliar efeitos adversos e toxicidade. Neurológico:
ISBN 978-85-334-1452-5
Pele:
ausência de sintomas neurológicos
evidências clínicas da ausência de reações alérgicas
ausência
de artrites
ou mialgias,
normais
Músculo-esquelético:
1. Medicamentos Fitoterápicos. 2.
Ensaios Clínicos.
I. Organização
Mundialvalores
da Saúde.
II. Título. de
III. CPK
Série
(creatina fosfoquinase)
NLM WB 925
evidência clínica de tolerância
Gastrointestinal:
Catalogaçãovalores
na fontenormais
– Coordenação-Geral
de Documentação e Informação –
de TGP (alaninaaminotransferase)
Fígado:
Editora MS – OS 2007/0787
e TGO (aspartato aminotransferase), ALP (fosfatase
alcalina) e bilirrubina total
Títulos para indexação:
valores normais de BUN (urobilinogênio) ou creatinina
Rim:
Em inglês: Operational guidance: Information needed to support clinical trials of herbal products
Em
Espanhol:
Directrices Operacionales:
necesária
para la
conducción
análisis
valoresinformación
normais de
albumina
ou
proteína de
total,
ácido
Sistema
endócrino
e
clínicos en fitoterapia
úrico, glicose, colesterol, amilase ou lipase, sódio/
metabolismo:
potássio e cálcio
Sistema
cardiovascular:
ECG e pressão sanguínea normais
Sistema
hematopoético:
valores normais no hemograma total
Adicionalmente:
investigação mais intensa de algum sistema que possa
ser afetado em particular pelo produto em particular
4.3
t
t
t
Delineamento do estudo Sujeitos elegíveis Informação necessária para conduzir ensaios clínicos de Fase III
Dados de segurança como os apresentados como no item 4.2. Se a população
tiver características mais diversificadas, quando comparadas com as populações
dos ensaios prévios, o perfil favorável de segurança mostrado para as populações
restritas nos ensaios prévios pode ou não ser inferido para a população estudada
nos ensaios de Fase III. A informação quanto à provável segurança do produto para
a população mais ampla deve ser fornecida, e o protocolo da Fase III deve incluir
uma nova avaliação dos parâmetros de segurança. Uma outra razão para reexaminar os parâmetros de segurança é a maior probabilidade de identificação de eventos adversos raros devido ao maior número de participantes incluídos na Fase III.
Dados preliminares da eficácia das experimentações da Fase II.
Evidências, a partir dos ensaios com variação de dose, de que a posologia escolhida é a que mais se assemelha à posologia considerada ótima no que diz respeito
à segurança e à eficácia.
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13
Exclusão: ansiedade psicóNca ou secundária ao uso de SP; uso de psicotrópicos nas duas úlNmas semanas Perda de seguimento Sujeitos eleitos Sujeitos pesquisados 4