Shuji

Inoue,

Masato

Masakazu

Abe,

Chikayuki

Naito, The

the

reduced

action food

Shinobu

Kumagai,

and

ABSTRACT gated

Egawa,

Akira

Toshio

hypothalamus,

Japanese

Mazindol

activity,

decreased

cretion.

It thus

glucose

acid

Hiroyo

petite

in the

majority

the

of obese

mazindol is effective after obesity therapy eases

and

main

it

in the lateral

increased inhibited

effect

patients.

that ofsimple

insulin

se-

of mazindol

in the maintenance and in the treatment

is to

as diabetes, hypertension, Nutr l992;55:I99S-202S.

KEY

WORDS

experimental

Mazindol, obesity,

human

double-

was superior to the We also suggest that

weight

ofreduced body ofobesity-related

dis-

Am

or hyperlipidemia.

antiobesity

agent,

food

intake,

obesity

Mazindol,

an imidazoisoindole

tion, suppresses has been utilized

permission study more zindol.

for its clinical it organized

group basic

center

in the

the results the

hypothalamus, which may

hypothalamus.

ofShiraishi activity

et al (6) found

that

anorectic

mazindol

the

to apply

drug

Japanese

as an antiobesity

Mazindol

locomotor

activity,

which

may

expenditure Usami

(7). et al (8)

found

that

hypersecretion sioned (VMH)

of insulin obese rats

nornenon to anorectic

was produced effect and/or

tivity.

also

We

with

these

aspects

Mazindol

studies, group

it proceeded chaired

with

to get of ma-

a clinical

by Y Kumahara,

trial

found

proposed

systems

to suppress

feeding

(3). In the Japanese

by stimulating Pharmacological

Sikdar et al (4) found that mazindol significantly supthe firing rate ofglucose-sensitive neurons in the lateral

hypothalamus,

Am J C/in Nuir

implying

study

that

l992;55:l99S-202S.

mazindol

Printed

directly

in USA.

suppresses

that

a

© 1992 International

meal

ofthis mazindol

contribute

sistent From

with

the

the Third

finding needs further treatment increased in energy

treatment

suppressed

ventromedial-hypothalamic-lein vitro and suggested that

mazindol

this

phe-

of body weight due of vagal hyperac-

treatment

attenuated

hy-

in vivo in VMH obese rats (9). We are this depends upon the reduction of body effect of mazindol. we found

mazindol

intestine

ma-

median emnucleus in

in

that

group,

mazindol

prolonged

intake. of infused

to an increase

mazindol

lateral

secretion, Fujimoto

size and

of food effect

through reduction due to suppression

that

is more

obesity

that

directly

in the

of gastric acid of appetite.

mazindol

and the fatty liver of this obesity at a smaller dose than was effective

small

I

Osaka

of mazindol has been

In this obesity intake

the

Pharmacological

neurons

decreased

The significance also found that

found

agent

are consistent

mazindol

on food intake appeared in the area of the that is 2-cm posterior to the suprachiasmatic

system-induced

for an official

that

in the reduction that the strongest

the hypothalamus. investigation. They

ac-

findings

found

of glucose-sensitive

meal interval, resulting Nagai et al (7) found zindol inence

The

(5) who

resulting in inhibition contribute to the suppression

suggested decided

use ofthis

a multicenter

catecholaminergic study, pressed

with

chaired by Y Oomura, Kyushu University, pharmacological information on the action

Along

that used University.

Basic

derivative

feeding in both humans (1) and animals (2). It clinically as an antiobesity drug in about 50

all over the world. Sandoz Pharmaceutical

in Japan,

Kumahara,

Shimizu,

persecretion of insulin inclined to believe that weight due to anorectic

Introduction

countries When

with

inhibited

motor

A multicenter

mazindol obesity.

such

iC/in

Yuichi

Naokata

feeding

that

decrease food intake through suppressing feeding centers in the hypothalamus. A multicenter open study of mazindol in Japan revealed that loss of body weight and relative body weight in 14 wk were 4.6 kg and 9.2%, respectively, with suppression of apblind study demonstrated placebo in the treatment

Suzuki,

Shizume,

investi-

found

neurons

secretion,

absorption, that

Saito, Kazuo

group

and

suppressing

gastric

appears

study

mazindol,

by directly

inhibited

Marl Goto,

Onishi

of an anorexiant,

intake

Satoh,

Yuichiro

mazindol,

than

treatment of rats findings

effective

other

decreased

(10).

This

of inhibition

Department

types

oflnternal

reversed

VMH

by decreasing in normal rats. for

central-nervous-

of obesity glucose

phenomenon of villous Medicine,

food This

(9). We absorption

also by

may

be con-

width

of the

Yokohama

City

University, Yokohama; the Department of Medicine and Geriatrics, Osaka University, Osaka; the Department of Internal Medicine, The likei University, Tokyo; the Second Department of Internal Medicine, Chiba University, Chiba; the First Department and the Department of Internal Medicine, Tokai University, Isehara; the Second Department oflnternal Medicine, Tokyo Women’s Medical College, Tokyo; the Third Department oflnternal Medicine, Teikyo University, Ichihara; and the Department oflnternal Medicine, Tokyo Teishin Hospital, Tokyo. 2 Address reprint requests to S Inoue, The Third Department of Internal Medicine, Yokohama City University, 3-9 Fukuura, Kanazawaku, Yokohama 236, lapan.

Association

for the Study

of Obesity

1 99S

Downloaded from https://academic.oup.com/ajcn/article-abstract/55/1/199S/4715324 by McMaster University Library user on 08 February 2019

Clinical and basic aspects of an anorexiant, as an antiobesity agent in Japan1’2

INOUE

200S TABLE

ET

AL

I

Comparison

of food

body

intake,

Food

weight,

intake

and hepatic Body

g

29.0 ± 3.6 9.6 ± l.6t 11.50±0.74 9.09 ± 0.63f

15.1 4.Ot 10.0 7.8j

___ ______

8w 3.19’ lOw 3.29 12w

8)

4) I..

intestine

in goldthioglucose-treated

dol treatment

reported

We further

obese

by Ohminami

investigated

the effects

by mazin-

more

that

1). After

7)

(II)

(7$)

rats obesity

is more

FIG 2. Time

(lbH

(315)

t15(

(

(100)

):No.ofcases

(100)

(95)

(95)

6)

‘-

-4-’u

2 .

Observation

...

6

4

8

10

Treatment

12

14

2

,

period

12

Fig.

Change.

In

body

weight

weeks

of

115

(at) (135)

35

(115)

Mean±SE

f 1H)f

+

kff

t15

(115)

0

( ) : No.

of

cases

(tOO)

(3003

it now

-4

-2

0

2

Observation

period

FIG 1. Changes ofbody treatment (0.5-3 mg/d). weight.

4

6

8

Treatmentperiod

10

12

14

2 Follow-up

of appetite

suppression

appears

that

the main

by mazindol.

action

by directly inhibiting with some additional

of mazindol

the feeding actions.

centers

of mazindol

conducted

obesity

of basic

and

a multicenter

chaired

clinical

(40

results

(1-3),

institute)

open

Osaka

University

by K Kumahara,

the

study

in

(12),

along with the above mentioned Japanese Pharmacological Study. Simple or symptomatic obese patients (376 vs 12 patients) who were > 20% overweight (average overweight = 47.9 ± 1.3%) in this

study.

to the fixed-flexible

Mazindol

schedule

was administered

(0.5-3

mg/d,

4

14

F 2 F 4 weeks

period

weight and relative body weight after mazindol < 0.001 compared with pretreated body

in Figure 1, obese the whole period

patients

according

every

in 14 wk. thickness

the

upper

thickness

of the

dorsal

treated

lost 4.6

9.2% of relative overweight nificantly decreased skinfold

2 or 4 wk)

for

arm

and

in 7 1.3% This

percent

who

showed

suppression was decreased Average

a body

continued until

the

suppressed.

until

follow

weight

reduction

part

the end of mazindol period

at 4 wk,

of food

intake

by mazindol

sigby

of the

ofthe

patients,

similar

(79.5%).

up

to the Appetite

treatment although

and the

rate

(Fig 2). reduction

153 ± 10 kcal/d. Reduction of food intake the follow-up period at 4 wk. Interestingly, significantly treatment,

was

and

treatment as assessed

lower

slightly

mazindol weight

Mazindol in females

rating

to markedly

with

kg ofbody

scapular subcutaneous adipose tissue. Appetite was suppressed by mazindol

beyond,

_1 -

and the degree

As shown who completed

casee

45

V .

course

suppressed

14 wk.

N.S.

4c

Increased

participated

414F2F4

‘----,

Followup period

penod

-C V

:

on the reports

human

SE.

1

study

company

(115)

±

-91)

suppressed

Slightly Unchanged

aspects

Based

N.S.

(ItS)

Mean

]9

effective

Open

(115)

#{149}8 a

:

7!

suppressed

D :

In summary,

H5fkkkj

(315)

49

(n

is suppression ofappetite in the hypothalamus,

V

d

29 8#{176}

: Markedly : Moderately

Clinical

OO

LI

8 wk of

75

-C

4.8#{176}c

/

4w

greater in VMH (Table 1). The de-

mazindol obesity.

36.2%

1jo

on two types

was less apparent in mazindol-treated obesity compared with VMH

(Table I). These results confirmed for central-nervous-system-induced

)..:..;.:..i34.50o::...:::..:J

7

obesity in rats. Main VMH obesity

than in high-fat-diet-induced obesity (Table mazindol treatment, weight loss was significantly obesity than in high-fat-diet-induced obesity

259)

(n=256)

2.1%

of mazindol

ofobesity: VMH and high-fat-diet-induced zindol reduced food intake significantly

crease in hepatic lipid with high-fat-diet-induced

mice

=

(n=249)

44.0%

tj.2

2.79’

et al (1 1).

n

42.3%

40.6%

2w small

(

1

1.8%

00

3’7o

43O.

14w 0.

.

t:...:.::.:.:::134.49::....;.:.: 2.3%

_______

2.3%

t P < 0.001. P