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The effect of restacorin on the monooxygenase activities in rat liver microsomes
TRFJlWEllT OF CHRfflIC ACTIVE TVPE a HEPATITIS (CMH). A PKOT SNaV. (1) JN lkrrcr,ar. JM ValMolld.V6 Villarrubia. 11JiaCnu.6 Lda. 56 Vilchcz. FL Elonl. Scnicio de A,WsrO DigcStiVO. lbsp*ts1 virgen sk.ren..
AH3
Lsb.
(lmrmnofcronR.
solysaccharide/orotein ;at&nts of
wIth~;erologlc
CAB"
during
inducer; IIKwSSSS undemnt
St
Rationa:e
entry.
phsrmaco,og,cal It
5psin.
Andrdmaco.
naWrb.
Spain).
wss given
and hcpsti;
lssst for
dsts:
1 yew
orsl
cams
Bw(
f&t"nS
l-5 YClrS) fr(l
of
HIV nHlatlva
to 13
(liver-biopsy)
(rsngc
trestmsnt
I"
Partial hepatectomyinduces liver proliferation and the remnant liver restores its original mass and cell count. We found, that 50 h after Z/3 oartial hepatectomyan extract can be obtained frbm the remnant liver which induces a oroliferationin normal liver cells in viva and in iitro. The extract of three remnant livers was injected into four normal mice or one normal rat and caused an enhancementof 3H-incorporationinto nuclear liver cell ONA by 3- to 4-fold. This proliferationactivity we tailed He,atopoietin.Hepatopoietinis heat- and acid-stableand species non specific. By chloroformextractionand dialysis we got an enhancement in proliferationactivi y to about 15fold coeoareti with the controls. This value corresponds tb a %cZ partial hepatectomy.The crude liver extract. however. not onlv increases uroliferation activity of liver cell;. but. even lower, also of other Oroans like soleen and kidnev. Fiv DEAE gel chromatigraphywe Gould completei; scparate different non liver activities from the liver activity, though we could net obtain pure Hepatopoietin till new. This demonstratesthat Hepatopoietin really is organ specific.
the
kfore
fbllowing
the drug Is a" bsrly -type intwfercw
enhances
bws-msrrw oncologic
5will&
ORGAN SPECIFITY OF HEFATOPOIETIN G. Hoffmann. S. Vogl, G. fiuhenstroth-Eauer Exoerimental Hedwlne. flax-Planck-lnstltut fiiraiochemie. O-8033 Martinsried,FRG.
NK
and
recovery radio and/or
mscrophsgc in
rctivitics:
CslKLr
psticnts
chnotheropy.
it who
A11 prticnts
(ages rangrd fran 13 to 54 years old) received AH3 daily
(3
9ldsy = 2 caps, t.1.d) during 12 nanlbs. At the end of tresbssnt, 8 patients have reached canplate response (CR): "BY-DNA (fras 559 + 497 c.p.n tg zero) and HkAg together with seroconvcrsion (fran
213.5
+
239.2
to
clesrsn~cs.
to anti-e snd ALT non"sliZstlon 27.5
2
8.83).
The
other
5.
reduced HBVDNA sewn levels (fras 1065+ 927 to 168 :‘, 125 c.p.m) slthwgh the other psrrmters raalned unchanged.In fact, they did not negatlvirc HEeAg snd ALT levels remainedinaltered (fran 169.8 i 107.4 to 198 + 73.8 M/L). One of the CE is I Down’s syndrcw+.None Of the patients negativlzed HBsAg. The route of admlnistratlon. the absenceof side effects and the mechanism of action (see other abstr&) justify the entry into st”dleJ with s greater numberof patients.
significatively
THE EFFECT OF RESTACORINON THE MONOOXYGENASE ACTIVITIESIN RAT LIVER MICROSOMES
K. Hackerate&: 3. Fiisteli,L. Risteli DepartKent of %rgery, Fielsxki Uruverslty, Helstii*, 2nd Q~lu, Finland. B&enter, Culu University,
M.Huszka and F.Teichmann,Medical Research Oepartment,BiochemicalWorkingGroup, BIOGAL PharmaceuticalWorks, Ltd., Oebrecen, Hungary.
i%rkers of collagen metabolism are increase3 in certain lJ.:;er diseases. We stud&i the aminotermirxl propepticle of type PIImP of procollagen in the senr of 20 patients with prirrary biliary cirrhosis
RESTACORINis a new antiarrhythmicdrug under development.The structure resemblesthat of lidocaine, but with more favourablepharmacokinetic wooerties. We studied some effects thdt RESTACORiN exerts on the microsomal ronooxygenase sys-
(WC) uncZee_sooing liver transplantation,and 6 PEC patients not transplanted. An assay based on humn
antigen >.:,a;used. lhe Wilcoxon’s tests were used for cornarisons of resfilts (ug:l, mean*SPJQ. Referexe izlues of 88 healthy people: 1.7-h-2 w/l. l?efcr~ transplantation PIIINP was 14.5i1.4 conpa-
tem to oather information which could enable us to pred;ct possible drug interactions.
In vivo studies on Wistar male rats showed no signs of induction or inhibition of the monooxygenase enzymeactivities. The drug gave a Type II. difference soectrum. Liver microsome Drsoaration supplementebwith a NAOFH-generating‘sy&n
red with 5. liO.5 in the 6 PBCpatients sent for ewluation but not transplanted (~(0.001). Results after trar,spl2ntation: (l-year survival 85%) t.g.3
1 z-k
7&7
1 rronth 6 mo
10:6+2.8 5X0.9
;:g!%g
24 Im 5.5t0.6
did not dealkylate the molecule. In vitro sane of the microscmal monooxygenaseenzymeswere inhibitad by RESTACORIN.Aniline hydroxylase and ethyl-
1 wek after transplantation patients with rejection of infection &d 2 PIIINP concentration of 9.120.8 compared with 5.320.6 in non-conplication cases (~(0.01). At 1 month patients with infection had 2 PIIDIP of 15.9Q.8 comparedwith 5.3iO.6 in
morphinedemethylase were inhibited noncompetitively with Ki values of 3.7 and 10 mM, respectively. p-Nitroanisole demethylpse was inhibited competitively, with Ki of 0.32 Wl. On the glucuronidation of artiiiclal substrates, measured
patients -ithout infection or other comlications. We conclude thar. serumPIIWP concentration could be used as one of the rrerkers of end-stage disease i-, ?EC patients. Near-norms1vslues are seen iwe-diately after transplantation. ConplicaLions -2Lss the PIILVPvalues, \,hich are restored after
co?plicatior.s
2.1~ successfully
in vitro,
treated.
s92
RESTACORINhad no effect.
AH3
Lsb.
(lmrmnofcronR.
solysaccharide/orotein ;at&nts of
wIth~;erologlc
CAB"
during
inducer; IIKwSSSS undemnt
St
Rationa:e
entry.
phsrmaco,og,cal It
5psin.
Andrdmaco.
naWrb.
Spain).
wss given
and hcpsti;
lssst for
dsts:
1 yew
orsl
cams
Bw(
f&t"nS
l-5 YClrS) fr(l
of
HIV nHlatlva
to 13
(liver-biopsy)
(rsngc
trestmsnt
I"
Partial hepatectomyinduces liver proliferation and the remnant liver restores its original mass and cell count. We found, that 50 h after Z/3 oartial hepatectomyan extract can be obtained frbm the remnant liver which induces a oroliferationin normal liver cells in viva and in iitro. The extract of three remnant livers was injected into four normal mice or one normal rat and caused an enhancementof 3H-incorporationinto nuclear liver cell ONA by 3- to 4-fold. This proliferationactivity we tailed He,atopoietin.Hepatopoietinis heat- and acid-stableand species non specific. By chloroformextractionand dialysis we got an enhancement in proliferationactivi y to about 15fold coeoareti with the controls. This value corresponds tb a %cZ partial hepatectomy.The crude liver extract. however. not onlv increases uroliferation activity of liver cell;. but. even lower, also of other Oroans like soleen and kidnev. Fiv DEAE gel chromatigraphywe Gould completei; scparate different non liver activities from the liver activity, though we could net obtain pure Hepatopoietin till new. This demonstratesthat Hepatopoietin really is organ specific.
the
kfore
fbllowing
the drug Is a" bsrly -type intwfercw
enhances
bws-msrrw oncologic
5will&
ORGAN SPECIFITY OF HEFATOPOIETIN G. Hoffmann. S. Vogl, G. fiuhenstroth-Eauer Exoerimental Hedwlne. flax-Planck-lnstltut fiiraiochemie. O-8033 Martinsried,FRG.
NK
and
recovery radio and/or
mscrophsgc in
rctivitics:
CslKLr
psticnts
chnotheropy.
it who
A11 prticnts
(ages rangrd fran 13 to 54 years old) received AH3 daily
(3
9ldsy = 2 caps, t.1.d) during 12 nanlbs. At the end of tresbssnt, 8 patients have reached canplate response (CR): "BY-DNA (fras 559 + 497 c.p.n tg zero) and HkAg together with seroconvcrsion (fran
213.5
+
239.2
to
clesrsn~cs.
to anti-e snd ALT non"sliZstlon 27.5
2
8.83).
The
other
5.
reduced HBVDNA sewn levels (fras 1065+ 927 to 168 :‘, 125 c.p.m) slthwgh the other psrrmters raalned unchanged.In fact, they did not negatlvirc HEeAg snd ALT levels remainedinaltered (fran 169.8 i 107.4 to 198 + 73.8 M/L). One of the CE is I Down’s syndrcw+.None Of the patients negativlzed HBsAg. The route of admlnistratlon. the absenceof side effects and the mechanism of action (see other abstr&) justify the entry into st”dleJ with s greater numberof patients.
significatively
THE EFFECT OF RESTACORINON THE MONOOXYGENASE ACTIVITIESIN RAT LIVER MICROSOMES
K. Hackerate&: 3. Fiisteli,L. Risteli DepartKent of %rgery, Fielsxki Uruverslty, Helstii*, 2nd Q~lu, Finland. B&enter, Culu University,
M.Huszka and F.Teichmann,Medical Research Oepartment,BiochemicalWorkingGroup, BIOGAL PharmaceuticalWorks, Ltd., Oebrecen, Hungary.
i%rkers of collagen metabolism are increase3 in certain lJ.:;er diseases. We stud&i the aminotermirxl propepticle of type PIImP of procollagen in the senr of 20 patients with prirrary biliary cirrhosis
RESTACORINis a new antiarrhythmicdrug under development.The structure resemblesthat of lidocaine, but with more favourablepharmacokinetic wooerties. We studied some effects thdt RESTACORiN exerts on the microsomal ronooxygenase sys-
(WC) uncZee_sooing liver transplantation,and 6 PEC patients not transplanted. An assay based on humn
antigen >.:,a;used. lhe Wilcoxon’s tests were used for cornarisons of resfilts (ug:l, mean*SPJQ. Referexe izlues of 88 healthy people: 1.7-h-2 w/l. l?efcr~ transplantation PIIINP was 14.5i1.4 conpa-
tem to oather information which could enable us to pred;ct possible drug interactions.
In vivo studies on Wistar male rats showed no signs of induction or inhibition of the monooxygenase enzymeactivities. The drug gave a Type II. difference soectrum. Liver microsome Drsoaration supplementebwith a NAOFH-generating‘sy&n
red with 5. liO.5 in the 6 PBCpatients sent for ewluation but not transplanted (~(0.001). Results after trar,spl2ntation: (l-year survival 85%) t.g.3
1 z-k
7&7
1 rronth 6 mo
10:6+2.8 5X0.9
;:g!%g
24 Im 5.5t0.6
did not dealkylate the molecule. In vitro sane of the microscmal monooxygenaseenzymeswere inhibitad by RESTACORIN.Aniline hydroxylase and ethyl-
1 wek after transplantation patients with rejection of infection &d 2 PIIINP concentration of 9.120.8 compared with 5.320.6 in non-conplication cases (~(0.01). At 1 month patients with infection had 2 PIIDIP of 15.9Q.8 comparedwith 5.3iO.6 in
morphinedemethylase were inhibited noncompetitively with Ki values of 3.7 and 10 mM, respectively. p-Nitroanisole demethylpse was inhibited competitively, with Ki of 0.32 Wl. On the glucuronidation of artiiiclal substrates, measured
patients -ithout infection or other comlications. We conclude thar. serumPIIWP concentration could be used as one of the rrerkers of end-stage disease i-, ?EC patients. Near-norms1vslues are seen iwe-diately after transplantation. ConplicaLions -2Lss the PIILVPvalues, \,hich are restored after
co?plicatior.s
2.1~ successfully
in vitro,
treated.
s92
RESTACORINhad no effect.