rimonabanto escola nacional de saúde pública (ensp) fiocruz escola nacional de saúde pública...

RimonabantoRimonabanto

Escola Nacional de Saúde Pública (ENSP)

FIOCRUZ

Escola Nacional de Saúde Pública (ENSP)

FIOCRUZ

FIOCRUZ ENSP

Francisco José Roma PaumgarttenFrancisco José Roma Paumgartten

Cannabis sativa

Droga ilícita mais amplamente usada pela humanidade

Alteração senso-percepção

Euforia

Longa história

Uso medicinal indianos (‘bhang”) e chineses há mais de 3000 anos

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.

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

Existe ligante endógeno do receptor endocanabinóide ?

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 ill-

defined constellation of neurological signs and symptoms, and

seizures. Based on these concerns DMEP sent Sanofi-

Aventis 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 vendem “doenças”

que podem ser tratadas pelos

medicamentos que estão lançando,

em vez do contrário.”

Marcia Angell

A. Renoir F. Botero

Obrigado !OBRIGADO !!!