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/nl,,"ationul Jour",,1 of Obesity (1979) 3, 133-140
The effect of mazindol on metabolic and
regulatory changes in obese women
during weight reduction
SecO"d Medical Deparrmenl. Thomaye,'s Hospilal; Cenl,e of Metabolism and
:\'tl f riliun: fnSfiw(e 01 Clinical and Experimental Medicine, Budejovicka 800.
?rugue 4-krc, C:!echoslavakia.
-The effect of mazindol (1 mg/day) on some metabolic and regulatory values was
in len adult obese women and compared with the same number of
controls during weight reduction in hospital (a five-times repeated cycle of 5
days complete starvation and 3 days on a 500 kcal(2.1MJ)/ day die!.)
Mazindol caused a rise of hydroxyacyl eoA dehydrogenase in striated muscle
by 70 per cent and a marked decline in malic dehydrogenase. Mazindol also
produced higher levels of non-esterified fatty acids-significantly higher during
the fift..h starvation period; a small decrease in blood glucose, JRl and glucosel
IRI ratio being unaffected. a signjficantly greater decrease of serum
cholesterol; a significant increase of thc noradrenaline elimination compared
with a decrease in controls and in increa:!c in triiodothyronine binding globulin
towards the upper range of normal;J
Obesity is a difficult therapeutic problem. An effective hypocalorie diet, or total
starvati on and physical activi ty arc the main procedures used. In addilion, the
regulation of energy baJance can be influenced by drugs inducing anorexia.
Among these mazindol appears to be very effective' -1 ,
In View of the effect of mazindol on blood lipjds:!' ", glucose tolerance
, 10 and
body composition
, 12 :lnd the very impressive effect on weight loss in out
in a double-blind st udy" , we decided to study its influence during a
period of controlled reduction on:
(I) nonestuifi cd fatty acids (NEFA) and glucose;
(2) some
(3) the aCljvities of energy-regulating enzymes in striated muscle.
To investigate the effcct of mazindol, a group of 20 obese women was used. One
half was given mazindol (l mg), administered regularly at 9 am for a period of
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8 am. Blood
Table 2. EHecr of
cvcl=s, each comp{
.!' s.d.
"( .test: KO.05
Table 3. EHect of mazi
women during thl! Tedu
blood leVel, (
mazindol a i
. of IRJ an,
4. Effect of mazin
and glUCOS6 tGl an
1 iiJustrales t
d in the energy
40 days, the rest served as control (without any drug). The characteristics of the
groups are given in Table 1. After a preparatory period, ""'hen a detailed clinical.
Table 1.
Characteris1iC1 of obese and con1fol women (mean

Age Helgh1 Weigh1 Broc6 Body
Gro up Treatment
index fat
{yea,,1 leml
{kgJ (%) (%)
Mazindal 37.4 171 .2 107.1 150.4 42 2
:1:8.2 15.2 13.2 13.9 :t 7.1
3. 80
Control 36.4 164.6 101.5 157.0 43.1
!7.B !5.6 B.S 14.7 ::3.9
and laboratory examination was made, a diet 2100 kcal /day was
(protein 100 g, fa l 80 g, carbohydrate 2501); the weight reduction
consisted of a fi ve-day period of compktt: (with an ad liballJn
in take of beverages), fo Ilowed by tllr Jays on a 500 I<.c 111 (2 .J \"J])
Iday diet (protein 60 g, fat 10 g, carbohydrate 40 g). The cycle of starvat ion 'i, J
rcfecding WiLh 50J kcal(2.1 " lJj/da)' wos repca led five times.
Fasting blood samples were coUeeted in the moming betwcen 7
levels of cholesterop3 ,non-esterified fatty aeids glucose
l S
immunoreactive insulin (lRl)1 sand the hinding capacity of serum proteins for
thyroid hormones were assessed'?
From 24-hour urine samples kept in the refrigcrator at 5 0 C adrenaline and
noradrenaline were estimated 13, 19 and the results were expressed in absolute
values and in relation to creatinine:.
Body wei glll was mea'5urcd on a Tonava scale under standard conditions at
7 am, fasting, after emptying the bladder and, jf possible, after defaeeation.
At the beginning and end of therapy, muscle-tissue specimens were taken
(m.quadraceps femoris parlateralis) by means of a bioptie needle of the
authors' own dcsign10. In Lhe tissue specimtn the following en'l.)-mes werc
assessed: hexolOnase (HK) (EC2. 7.1.1.), trios ephos phat e dehydrogenase IT","" l'
(ECl.Z.1.12).iaetic dehydrogenase (LDH) (ECl.l.1.27), glycerolphosphate
dehydrogenase (GPDH) (ECl.l.1.8). citrate synthase (CS) (EC4.1.3.7 7) , malic
dehydrogenase (MDH) (ECl.l.1.37). hydroxyacvl CoA dehydrogenase (I I
(ECl.l.1.35). for the assessmer'll of enzyme activities optical methocts ""ere
used wlth the modification described by Bucher el al] \. CS was estimated
according to Stem e( ul.ll and HOADH lIceording to Wakil
. The activities
expressed in international units per gram fresh \\'cight14.
Thf' effn;l of mazjndol on body weight under the conditions of a well
c:urllrfJlled sc:::verc::: reducing rcgimen is su mmarised in Table 2.
After mazindol, markedly higher NEFA concentrations werc found {Table 3
which were significantly higher during the last s tage of the trial, in parti cui(lr
during the fif t h starvation period. Table 4 iUustratcs the effect of mazindol
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The: characteristics o[ th e
when a dctruled diniea.l
1: s.d.)
! 7.1
ling 2100 kcal/day was
10 g); the weight
lsting (with an ad /lbmun
. "ys on a 500 kcal(2.1MJ)
I"he cycle of starvation and
:lVe lImes. between 7 8 am. Blood
F.FA)", glucose", of serum proteins for
.tor at S C adrenaline and
vere in absolute
standa..rd conditions (1t
, ..,ie, after defaecation.
'uC were taken
bioptic needle o[ the
'-"" allowing enzymes were
phate dehydrogenase (TPDIl)
1.27), glyenolphosphate
5< (CS) (EC4.J.3.77), malic
C0A dehydrogenase (HOADH)
.i ties optical methods were
' ?:l CS was estimated
)1 Wakiln. The activities arc

:onditlons. of a well
.n Tahle 2.
trations were found (Table 3),
'C of the trial in particul;1f
the effect mazindol on
Table 2. Effect of mazir.dol an weight loss during reducing regimen consisting at five
cycles, each comprising 5 days of fasting and 3 days 01 500 12.1 MJ} dieT. Mean values
! s.d.
Total Fall in
GrOUP 2 3 4
5 loss Broca IndllX
(kg) 1%)
Mal.rndol 4.84 2.70 2.24 2.24 2.03 14.05 19.80
<0.52 '0.51 0.70 0.37 W.33 !: 1.27 2.93
Control 3.80 1.73' 1.82 2.35 1.56 11.25 ' 17.30
.1.61 to.65 to.90 1.62 0.S6 '2.12 3.02
",test: .0<0.05 - otherWise
Table 3. Effect of mazindo! on the blood levels of non-esterified fatty acids !NEFA) in obese
wor.-..en during the reducing regimen. Mean values! S.d.

8e1ore Fasting (1) Contra! B Fasting (51
12100 kcal/d) 3d 5d 1500 k""l/d) 3d 5d
Miwodo! 1052 1486 1727 1519' 1359' 1628"
(n' 61 !215 790 370 344 =119 1591
Control 805 1189 1383 960 977 944
(n' 61 306 !:300 <407 470 311 1285
.1- tes I: 1'<0.05 .0<0.01
glucose blood levels (G) , lRJ levels and the C/lR.I ratio. After weighl reduction
\'11th mazindol a signific<tll tly smalJer decline of the glucose level was recorded;
dlangc:s of JRJ and the G/JRI ratio were not si.e,n.ificant.
Table 4. Effect of malindo! and The loss of wtlight on blood le\lels of immunoreact;\le insulin
(IRIl and glucose (G) and on G/IRI ratio. Mean values s.d.
Before treatment After treatment 6 ab
1- al Ib)
IRI G Imgl IRI G Img/ IRI G Imgl
("u/mll 100mll GIIRI ",u/ml) 100mll GIIRI [,uu/ml) 100ml) G/IRI
Mazindal 48.4 100.2 2.10 44.0 H6.5 1.96 4.4 13.7 0. 14
In" 81 :ta., .:!:: 15.1 :.!:O.32 17.9 27.7 to.50 lO.O !:35.7 O.SO
Control 26.0 118.3 5.87 13.3 78.3 8.42 12. 7 40.0 2.55
In. 61 .:tHl.9 :t49.7 3.49 9 .4 l0.9 <5.26 :::12.4 t:41.6 t5.70
(- lest 1'<0.01
Figure 1 j[Justcatts the effect of malindol on the activities of enzymes
in volved in the energy mctaholism of skekla..l muscle. The most significant
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changes were seen in activities of HOADH, which increased almost by 70 peT celH
Table 5. Effect
dl1ring administrati.on. There was a more marked dec1ine of MDB after
urine of obese
ma:z.indol. Significant differences WLTe found .in SLIum choleste:rollevcls. 1hc
absolute decllne in the group un mllzinuol was morC thcn doublc that of the
control group (Fig. 2).
Ok ChOleSlerol

: Ams'108ml

160 ,.,
Fig. 1. Comparison of the reducing regime
with mazindol (striped bars) and without it
on the enzymatic activity of the
m. quadriceps femoris musde. Changes
expressed as percentage of initial values
(for symbols of enzymes see Methods)
Fig. 2. Comparison of the reducing regime
with mazindol (T +) and without it (T) on
the !erum cholesterol levels.
(Left: K=control period, R=after reducing
regime. Right: with mazinda! - striped bar,
without - solid bar)
Urinary adrenaline and noradrenaline excretion is summarized in Table 5.
,' In the con trol group, after weight reduction, a signiEcan t decline of
noradrenaline excretion occurred; while, in the group which received mazindol,
the noradrenaline elimination increase:d, the differences when calculated in
relation [0 r.reatirune being significant. AnaJogous, though not significant, are
the changes in adrenaline: e:xcre:tion (Fig. 3).
Changes in the transport capacities of serum proteins for thyroid hormones
and iodine-bound protein after mazindol are recorded in Table 6. T) BG
increa"ed signi ricantly.
Body weight decrease in the mazindol group was significantly hiRher aftOT the
second period (5 days of fasting, 30 days of 500 kcal (2.1M]) rdeeding period
and after the total reducing regimen (differences at other selected intervals
not significant). This difference may be explained not only by lhe simple
anorexic effect but also by the effect of mazindol on the mobilization of
non-esterified fatty acids from adipose tissue and their utilization in muscles.
The higher differences between maL.lndol and placebo observed in thc
treated at the outpatient clinie are [,robably due to the anorexic effect of
pc: 0.001
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'1creased almost by 70 per
-ked decline of MDH ,
o.d cholestcrollc",ls. The
'e (hen double that of lhe
Iparison 01 the reducing regime
dol (T +) and without it IT) on
mtrol period, R=after reducing
ht: with mazindol - striped bar ,
;olid bar)
Table 5.
" ;lIll declim of
"--" up' which received mazindol,
'nces when crucUh.1 led in
though not significant, are
tcins for thYToid hormones
led in Table 6. T, BG
gnificantly after the
al (2.1MJ) refeeding period)
other selected inteTVals were
lol only by the simple
)n the mobilization of
1eir utilization in muscles.
lcebo observed in the obese
lhe 3.11orexic effect of
on the adrenaline {Al and nondren!line (NA) elimination in
i,ug/24 hi
"-,gil 00 mg erl
00 mg erl
I,;Jg!24 hi
I,;Jgll 00 mg crl
(ug/24 hi
(ug/100 crl
... KO. 00 1, vs control value
A/ lOO mg CS'
0 .
p < 0.00\
Control After la'>s
period of body weight
(=.1 (=bl
4.73 4.85
!2.93 !3.75
0.58 0.70 +0.12
'0.36 0.27 0.46
4.52 7.68 +3.16
;2. 55 :t3.38 !5.31
0.35 1.39 +1.04
':0.19 :to 67 :to.68
4. 20 318 - 1.02
<2.15 2.06 to.95
0.38 0.30 - 0_08
'0. 10 :to.16 W_19
9.86 5.88 - 3.97
6.56 4.11 3.92
1. 10 0_61
- 0.49
to.81 to_59 to.58
Fig. 3. Comparison of .he reducing regime
with mnindol (striped bars) and without
{solid bars} on the changes of nOladrenaline
INA) and adrenaline (A) in urine in the
relation fO the creatinine {cd elimination
5. EHe!;t of rf"Ialindol
of obese women. Mean values 1 s.d.
NA.!100 mg c(
1. 0
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Table 6 . Effect of mal-indol on the blood levels of thyroxins binding globulin IT" BG),
triiodothyronine binding globulin (Tl BG) and protein-bound iodine IPS I) in obeie women
during t:1e reducing regimen (a=before and b=after treatment). Mean vzlues s.d .
Tot 8G T, SG PSI
(%1 (%1
b a b
Ma:zindol 70.3 61.5 57.3 46.1" 6.6 7.5
:t9.6 9.1 7.3 10.8 1.7 3.4
Control 68.4 67.1 48.3 55.8 6.6 7.8
8.4 !:11.9 10.0 10.9 1.9 3.7
... (. P<O.01
The:: decrease of body wei ght obtained in the other mazindol group of OUr
obc.::c at thc o utp<lt ir:nl clinic was significantly highcr th"n in the plClCL'bo
gC(lIJ pll . l3a.ird & How:.lrd
, using formuhl die t , obsnvcd higher
but insignificant average values of weight decrease in obese: tre:at(d with maz incl ol
compared with controls. Our r(;sults differ from thost obtained in outpatients
who received no instructions or information abouL a h ypocaloric diet.
The results of the investigation reveaJed s ome important e ffects of mazindol
on skeletal muscle) the ehief energy consumer , as well as in blood Jevel s of the
chief energy substrates - gJucose and fatt y acids - and other regulators of
energy metabolism.
Stuclles o f enzyme activities in striated muscle showed that mazindol caused
marked increase of HOADH activity (by 68 pcr cent), ie of an enzyme which is
involved in fatty acid degradalion. At the same time the CS activities remained
practically unchanged which suggests that the magnitude of Krebs cycle was
affected. The ffiaTked decline of MDH during weight reduction, in particular
during administration of mazindol, would sl.lggest a dec rease in its extramito
chondrial activity, a reduction of NADP and hence in synthetic processes (in
particular synthesis of fatty acids). The activity of HK and gl ycolytic enzymes
during weight reduction declined, but the effect was less marked when m;uincloll
vvas given. A major decJine:: of LDH acti vi ty \"'as found with mazindol which
would suggest a reduction of anacrobic gl ycolysis which is marked in obese
.su bJects'l".
to the effect of mazindol on the main energy substrates, higher blood :
glucose and i'\EFA levels were recorded during the last (fifth) st arvation period
and during the check-up examination before discharge. The predominance of
fatty acids suggests an adipokinetic e ffect of mazindol, which is in accord 'y\i
its lipid-mobilizing effeet on human adipose tissue in vitro 11, :no
The reduction of basal serum insulin after weight reduction with mazindol
not significa.ntly different from the control group. Thus we cannot eonfinn
'hyperinsulinism' found by Sinori ef 01.
nOT the reduction of IRllevels rep
by Harriso n el al. ' 0. However, the latter prescribed a 8001000 kcal (3.34.n
die t.
The effect of
.cap"",ic!> of t.r:iiOdj ........,.",
g an IlInc.
reg" .. "o,n of the cf,
m c nt of obcsi
by prolong:
lorm'Dncs) reveale
ficantly (t his a
creatinine). Wit
re-naJine vaiues
noradft"naiint fo'
rnlal dctoxifi catt'
wi th the
ocr"",,-,.I C{ lflH nuni c
In the wi t h
[ llle Ic;,, !u.i.bilit y
ncy. A red\.
;',HiOj) ,) f [he org, '
:\'jazindol, by p.
a beneficial eW
Hadler, )\J. (1972)
P.'mfl'lOcol. t2, 45.3.
De felice, E.A.. Cb
dl!)..(rOOl m
Ref. 15..SS8.
GraphJo. B. &- Co.
mnindo!. Tnl. Att:d.
Dol:cck. R. (.! 975)
En"..!:!. C., Duitussio
clirucal evah..... lion;
obesiry. J. Int. MM.
C.,nJorbe. P., Bornic
44 8) uans Ie (raltern.
j\'hclay, W P & Wall
t he- I(CalmCn l o{ of.. '
Woodhouse, S.P . .
bUnd ,,;,1 w;,h
398. London: 1'Xr;
SITton , C., HUTwit:l.
ldministralion of
H4IT1son, l..C .. King.
druc dnd injul;n met'
A. & i'liJij

R"h. K .. Vond" K1
Icrapi..j obczily, iCho '
1,. & Eitb
m H
acid in c.sli01 "
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I binding globulin (14 BGl.
dine (PBI) in obese women
Aeo.n .... Cllues
zL7 <3.4
:r ma7.indol gTonp of our
Jy higher lhan in the pl.dccb Cl
)(Tnllla diet. observed hI
obese lfc:Heo. WIth mar.ln dol
... e ob tained in outp a tien t s
, hypocal oric diet.
JorlUllt t:ffects of mazindol
eU as in bl ood le .... els of th e
and other regulators of
owed that mazindol caused a
t) , ie of an enzyme is
e the CS activiti es remaIned
.tde of Krebs cy cle was not
icduction, in particular
. dc::crtase in its ex trarniLO
ill $ynthetic processes {in
HK and glycolytic onzymes
\5 kss marked when mazindol
md \ mazindol whi<:h
vhieh is marked in obese
-- hi gh er blood .
. last (fifth) starvation penod
u,ge. The predominance o.f
ldol, which is in accord Wlth
in vitro 11, 11 .
It reducti o n with mazindo
ThLlS we cannot confinn th?t
'eduction of TRI IC'Iels report ed,
d > 800 1000 kc aJ (3.3-4 .2MJI
Tht:: dft:ct of mazindol on the thyroJd hormones was sl udied in changes in
PSI concentration and tht: of saturation of the serum globuli n transport
capacities o f triiodothyronine and thyroxine. M2\Zindol increased T:J GB,
::iuggesting an increase in activit y of the thyroid gland . From the :l.Sp ect o f ge neral
regulation of the energy metabobsm this change wo uld be an advantage in the
treatmt::nt of obesity, in particular by delaying the onset of adaptati o naJ changes
ca used by prolonged e nergy restriction.
Urinary excretion of adrenaline and noradrenal ine, the main lipidmobilizing
hormones, revealed that after weight reduction noradrenaline excretion declines
significantly (this applies to absolute values as welJ as those calculated in relation
to creatinine). Whh rnazindoI this declinc did n ot OCCLU but increased nor
ad renaline values were recorded. Maz. indol would probably increase t he amount
o f noradrenaline found in urint:: bec ause it protects noradrenaline from the
normal de toxi fication mechanism (re uptake by neurons). Maz.indol would not
interfere with the ctetermini\tlon of noradremJine in the u ri ne sample. U. Gogarty,
personal co mmunication).
In the grO! lp .. m;.:z: r:(: )1 th'..: rc we re no ndvt"rse subjective ef fects, no signs
of the' irril a bility 0f eNS and nl,; d if ft:fe nces in b lo ud pressure and pu lse
fTey ueIH;Y A reduc ed eliminati o n or noradrenal ine In ay be import an t in the
adilpl.ion of the orh"dl llsm [0 a caJone int ake which hi nders further weight
loss. Ma7,indo l, by preventing a decline uf noradrenaline elimination , may thus
have a beneficia.] effect on adipose tissue lipolysi s.
Rden: nce..s
Hadl er, A.J . (1972): Mazindol, <! new I'IO narnpht::tamine.a norc!< i)l;enie Clin..
Phamll1CO( t 2, 453.
2 De Felice, E. . A., Cha ykin, L.B . & Cohen 1\. (197:\): Doubleblind cvalu.:tt!on of
mazi ndol, dcxlro<tmpht: t.amine, and placebo in rreatmcn[ of t:: xogcnous obesit y. Curr. Ther.
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4 Dolced. R. (1975) Mazindol . anorektikum nove v lecbe Cas. Lek. Ces. 114,
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clauc;!.1 eV:lluaLiOf! of a nonaruphe tamini c: anorexiuu (mazindol) in the treatmenl of
obesity . 1. Inf. Ref. 4, 305.
6 eanlorbe, P., .I:lo rnich c, I'. & Toublllnc , J.t: ! 1976) : Essai cont role d un (AN
448) dans Ie trdil emeol de 1' le de I"en(an t. Nouy. PresseMt:d. 5, l( )ti l.
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thc treatment of obesi ty. hac/inoner 28, 431.
'W oodhouse, S.P. &: .Y;yc t.R. , K. & Rawlings, J. (19 15): Report on it doubic
bli.'1 J trial wi th mninuo!' In Recw[ advance! If! obesity researcJi, 1, c.d A. N. HO"WiU"d, pp.396.
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adm..i nistJa!i on of maz: indol and damphetaminc. A m. J. Med. SrL .26 1, 341.
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J. Ctin..ln 35, 150.
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18 Cohen, C., & M. (l957) : The simuJtaneous flu orim/!mc determination of
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747 747 .
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25 McLea .) BaIrd, A.N. Howard (1977): A dou bic bli:1d cn<'ll o r ma 'Lindol low
caloric formuJa diet. Int. J. 1, 271.
26 Vondra, K .. Ralh, R., Bass, A. & Vitek, V. (1974); Aklivily
me:taboli.smu v m. quadriceps femoris u obeznich a ne:obeznich osob.
Cas. Lek. Ces.. 113, C. 29, s. 886 886.
27 Rath. R., Vondra, K., .Bass, A. & V. (I n press): Mazindolu na nektere
ukazntele regulace e:nergetlckeho meta.bolismu pn reclukci vahy obhnich. B,arUl. LeI<..

Effects 0
Dennis R. BRIG
.Veterans Admini"
"''''Present addres.'
Veterans Medical
rThe effects of anj'
programme were'
instruction. Grou '
a food di.
"WaS Instructed in
30 mg for eight
eight and phen
bo for eight
! 4UlllOJlaL eight '" "

.UU'''IO'n, a group 0
0.2 kg) per week '.
weight than a
maintained fo'

ly _,
[his approaehj
for use wit
overcome. .
Patienr selection)
behavioral pro,
attempL [0 ove
lor therapy ha j
is a re vised Vento
. UC, OClObc .
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