Download Folie 1

Rimonabanto
Francisco José Roma Paumgartten
ENSP
FIOCRUZ
Escola Nacional de Saúde Pública (ENSP)
FIOCRUZ
 Droga ilícita mais amplamente usada
pela humanidade
Alteração senso-percepção
Euforia
 Longa história
 Uso medicinal indianos (‘bhang”)
e chineses há mais de 3000 anos
Cannabis sativa
 Introduzida no Ocidente pelos
árabes no século XIX.
 Charles Baudelaire “ “Les Paradis
Artificiels”
Gaoni & Mechoulam (1964):
Identificação da estrutura do ingrediente psicoativo
(9-tetrahidrocanoabinol) e outros ingredientes da
maconha.
 De > 60 fitocanabinoides, apenas 9 THC é psicoativo
(estereoisomero l)

Devane et al, 1988; Herkenham et al, 1991, Matsuda et al, 1990.
 Por meio de ligantes, receptores canabinóides (acoplados a
uma proteína G) foram identificados no cérebro e sistema
nervoso
periférico de mamíferos. (receptor CB1)
Munro et al 1993
 Um segundo receptor (CB2) foi identificado no sistema imune e
hematopoiético de roedores.
Existe ligante endógeno do receptor endocanabinóide ?
Devane et al 1993
 Identificação de ligante endódeno (anandamida), derivado do
ácido araquidônico extraído de tecido nervoso de porcos,
 Injetada em roedores a anandamida reproduz efeitos do THC
Rimonabanto

(SR 141716)
Rimonabanto (SR141716)

A partir dos resultados de estudos
experimentais, o rimonabanto foi desenvolvido
inicialmente como medicamento para tratar tabagismo
(possivelmente também para outras adições /
dependências a drogas).
 Não funcionou satisfatóriamente nos ensaios
clínicos.
FDA não aprovou esta indicação.
Rimonabanto (SR141716)
 Pacientes dos ensaios clínicos para tratamento
do tabagismo exibiam perda de peso consistente.
 Ensaios clínicos para tratamento obesidade.
Índice de Massa Corporal (IMC, BMI)
IMC(kg/m 2) = [peso (kg)] ÷ [altura (m) x altura (m)]
Obeso: IMC > 30,0
Classes IMC:
< 18,5
baixo peso
18,5 - 24.59
normal
25,0 – 29,9
sobrepeso
30,0 - 34,9
obesidade grau I
35,0 – 39.9
obesidade grau II
> 40,0
obesidade mórbida
Saudável
Obeso
IMC > 30 kg/m2
CA ♀ > 80 cm
♂ > 94 cm

Risco CV
Eficácia
Segurança
Segurança.
Até 2 anos
A partir de 18 anos
01 comprimido de 20 mg / dia
FDA
Histórico regulatório do rimonabanto
US FDA
1999: IND (Investigational New Drug Application)
“An investigational new drug (IND) application for
rimonabant was submitted by Sanofi-Aventis to the
Division of Metabolism and Endocrinology Products
(DMEP) in May 1999.”
US FDA
April 2005: NDA (New Drug Application)
“...seeking approval of 20 mg once-daily rimonabant for
weight loss, weight maintenance, and prevention of weight
regain (hereafter weight management) in patients with a body
mass index (BMI) of > 30 kg/m 2 or > 27 kg/m 2 when
accompanied by at least one risk factor such as hypertension
or type 2 diabetes. Sanofi-Aventis also requested approval of
rimonabant for the treatment of type 2 diabetes, dyslipidemia,
and metabolic syndrome.”
April 2005: NDA (New Drug Application)
“...data from 13,011 subjects/patients from 36 Phase 1
studies, 5 Phase 2 studies (2 studies in weight
management, 1 study in smoking cessation, 1 study in
the treatment of schizophrenia, and 1 study in the
prevention of relapse in alcohol-dependent individuals
post detoxification), and 8 Phase 3 studies (4 studies in
weight management and 4 studies in smoking
cessation).”
April 2005: NDA (New Drug Application)
“Four Phase 3 studies were submitted in support of the
requested indications. These trials are referred to as
Rimonabant in Obesity or RIO North America, RIO
Europe, RIO Diabetes, and RIO Lipids. Two doses of
rimonabant were examined in the studies, 5 mg and 20
mg once-daily.).”
FDA’s conclusions on EFFICACY
Based on the efficacy data from the RIO trials DMEP
concluded that rimonabant 20 mg, but not 5 mg, was
effective for weight management, but did not believe, for
reasons beyond the scope of this document, that the data
should be viewed as supporting a specific indication for
rimonabant as a primary treatment of type 2 diabetes,
dyslipidemia, or the metabolic syndrome.
FDA’s conclusions on SAFETY:
“...preclinical
and
clinical
data
raised
concern
about
associations between rimonabant and increased frequencies
of psychiatric adverse events, including suicidality, an illdefined constellation of neurological signs and symptoms,
and seizures. Based on these concerns DMEP sent SanofiAventis an approvable letter in February 2006, requesting that
they provide additional data and analyses to more precisely
characterize these potential drug-related adverse events.
FDA’s conclusions on SAFETY after resubmission:
“... Following review of the NDA resubmission, we remained
concerned about rimonabant’s adverse event profile,
specifically adverse psychiatric reactions, and therefore
decided to convene an advisory committee to publicly discuss
and seek recommendations concerning the potential benefits
and harms of rimonabant.adverse events” .
Rimonabant 20 mg daily vs. placebo was associated with statistically
and clinically significant weight loss. Rimonabant 5 mg daily vs. placebo was
associated with statistically significant but clinically insignificant weight loss. In
RIO Lipids, rimonabant 20 mg daily vs. placebo was associated with a
statistically significant 8% increase in HDL-C and a statistically significant 12%
decrease in TG levels. There were no significant improvements in levels of
total or LDL-C in the rimonabant 20 mg daily vs. placebo group. In RIO
Diabetes, rimonabant 20 mg compared with placebo was associated with a
statistically significant 0.7% reduction in HbA1c in overweight and obese
subjects with type 2 diabetes taking either metformin or a sulfonylurea.
In general, there were small improvements in systolic and diastolic
blood pressure in subjects treated with rimonabant 20 mg daily compared with
placebo.
Síndrome metabólica (Existe ?)
Não é doença
 É agregação (clustetring) de fatores de risco da
doença CV sem implicações etiológicas
(I.e. conjunto de fatores que ocorrem juntos e sugerem a
presença de doença CV ou maior probalidade de
desenvolvê-la.)
As evidências até agora disponíveis não provam
que as modificações causadas pelo rimonabanto (e.g.
HDL, TG) reduzem risco/morbidade de doença CV nas
populações tratadas. Estudos mais prolongados ainda em
curso poderão ou não demonstrar esse fato (Crescendo)
“As companias (farmacêuticas)
frequentemente
que
podem
vendem
ser
“doenças”
tratadas
pelos
medicamentos que estão lançando,
em vez do contrário.”
Marcia Angell
A. Renoir
F. Botero
Obrigado !
OBRIGADO !!!