Acid addition salts of dextrorotatory ergot alkaloids, a process for the preparation thereof as well as their use as medicines

Medicine containing salts of ergotaminine, ergosinine, ergocryptinine, ergocristinine, and ergocorninine and use for treating arterial hypertension, heart insufficiency, heart arrhythmia or cephalalgia.

The present invention relates to acid addition salts of dextrorotatory 
ergot alkaloids, a process for the preparation thereof as well as their 
use as medicines. 
More particularly, the present invention relates to acid addition salts of 
ergotaminine, ergosinine, ergocryptinine, ergocristinine and ergocorninine 
of the general formula 
##STR1## 
wherein the meanings for R.sub.1 and R.sub.2 are 
______________________________________ 
R.sub.1 R.sub.2 
______________________________________ 
in ergotaminine 
CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 
in ergosinine CH.sub.3 
##STR2## 
in ergocryptinine 
##STR3## 
##STR4## 
in ergocristinine 
##STR5## CH.sub.2 C.sub.6 H.sub.5 
in ergocorninine 
##STR6## 
##STR7## 
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which salts are suitable for the treatment of arterial hypertension, heart 
insufficiency, heart arrhythmia and cephalalgia. 
Ergotaminine, ergosinine, ergocryptinine, ergocristinine and ergocorninine 
differ from native levorotatory ergot alkaloids in the configuration at 
8-position. They result from the epimerisation of native alkaloids (A. 
Hofmann, Die Mutterkornalkaloide, F. Enke Verlag, Stuttgart 1964, pp. 
20-30). They are 5R,8S-lysergic acid derivatives and D-isolysergic acid 
derivative, respectively. 
So far they have been considered as not pharmacologically active and as 
such not useful in therapy, whereby they differed from levorotatory 
isomers ergotamine, ergosine, ergocryptine, ergocristine and ergocornine, 
which are lysergic acid derivatives. 
Consequently, in patent literature as well as in other literature several 
processes for isolation of levorotatory isomers, which are largely used in 
medicine, are described, whereas processes for isolation of dextrorotatory 
isomers, which have not been in use till now, are not present in said 
literature. Hitherto only processes for mutual conversion of the two 
isomeric forms by means of heating in methanol or formation of insoluble 
salts have been disclosed, which processes can only be used for scientific 
purposes (A. Stoll, A. Hofmann. Helv. chim. acta 26, 1943, p. 1570; A. 
Stoll, Helv. chim. acta 28, 1945, p. 1283; A. Hofmann, Die 
Mutterkornalkaloide, F. Enke Verlag, Stuttgart 1964). Fresh ergots contain 
only a small amount of dextrorotatory isomers. Greater quantities of said 
isomers can be found in the drug stored for some time. As both isomeric 
forms are reversible and easily pass from one form into another, the 
dextrorotatory isomers are formed during the production process in spite 
of various precautions taken in order to inhibit said passing. The 
greatest concentration of ergotaminine, ergosinine, ergocryptinine, 
ergocristinine and ergocorninine is achieved in crystallization liquors 
left after the crystallization of levorotatory isomers and amounts to 
50-80%. Beside alkaloids said liquors also contain considerable amounts of 
coloured ballast materials and decomposition products. 
In our Yugoslavian patent application P 1465/78 a process for isolation of 
pure ergotaminine, ergosinine, ergocryptinine, ergocristinine and 
ergocorninine from the crystallization liquors left after the 
crystallization of levorotatory isomers is disclosed, which is 
characterized in that dried crystallization liquors are dissolved in an 
about 10-fold amount of methylene chloride and cromatographed in the ratio 
1:100 over neutral aluminum oxide (activity III to IV according to 
Brockmann) by means of a 100:0.2-1.4 (vol./vol.) mixture of methylene 
chloride and n-propanol. 
Thus the production of the dextrorotatory isomers on industrial scale as 
well as their use in therapy becomes possible. 
Since dextrorotatory ergot alkaloids are weakly water-soluble and as such 
not suitable for therapeutic use, they are converted into their 
physiologically compatible acid addition salts. The biological activity of 
dextrorotatory ergot alkaloids can be characterized as distinctly 
surprising, as it has been the general opinion up to now that said ergot 
alkaloids are biologically inactive (L. Goodman and A. Gilman, The 
Pharmaceutical Basis of Therapeutics, 5th ed., New York 1975; P. A. 
Stadler and P. Stutz, The Alkaloids, Vol. XV, The Ergot Alkaloids, 
Chemistry and Physiology 1975, Academic Press, New York, p. 30 ff.) and do 
not form stable salts with acids at all (The Merck Index, 9th ed., Merck & 
Co., Inc., 1976, pp. 476, and 479; A. Hofmann, Die Mutterkornalkaloide, F. 
Enke Verlag, Stuttgart 1964, pp. 21-28). 
It has now been found that acid addition salts of dextrorotatory ergot 
alkaloids ergotaminine, ergosinine, ergocryptinine, ergocristinine and 
ergocorninine are prepared by dissolving said dextrorotatory ergot 
alkaloids in a solvent, which is inert against reaction partners and which 
contains 1 to 1.7 moles of required inorganic or organic acid per mole of 
said dextrorotatory ergot alkaloid, and by precipitating the acid addition 
salt with addition of a precipitation solvent. 
As the solvent which is inert against the reaction partners, preferably 
alkanol with 1 to 3 carbon atoms or ketone with 3 to 6 carbon atoms is 
used. 
As the precipitation solvent preferably an aliphatic ether with 4 to 8 
carbon atoms is used. 
As the acid a strong inorganic or a strong organic acid with 
physiologically compatible anion can be employed. As inorganic acids e.g. 
hydrochloric acid, hydrobromic acid, nitric acid are suitable, as organic 
acids methanesulfonic acid, ethanesulfonic acid and haloacetic acids, such 
as trichloroacetic acid, trifluoroacetic acid etc. can be used. As 
previously mentioned, the acid addition salts of said dextrorotatory ergot 
alkaloids exhibit interesting pharmacological properties as follows. 
1. ACUTE TOXICITY 
The mean lethal dose LD.sub.50 was determined in male mice weighing 18 to 
25 g at intraperitoneal administration. The volume of injected solution 
was 0.01 ml/g of body weight. In the following Table I acute toxicity of 
dextrorotatory ergot alkaloids in comparison with levorotatory ergot 
alkaloids 24 hours after the intraperitoneal administration is given. 
TABLE I 
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Substance LD.sub.50 (mg/kg of body weight) 
______________________________________ 
ergotaminine methanesulfonate 
&gt;300 
ergosinine methanesulfonate 
244.7++ 
ergocryptinine methanesulfonate 
&gt;520 
ergocristinine methanesulfonate 
&gt;600 
ergocorninine methanesulfonate 
&gt;520 
ergotamine tartrate 
412.0 (322.4 to 526.5)+ 
ergosine methanesulfonate 
206.3 (158.2 to 268.9)+ 
ergocryptine methanesulfonate 
187.9++ 
ergocristine methanesulfonate 
234.0 (123.0 to 44.6)+ 
______________________________________ 
.sup.+ calculated by method of J. Litchfield and F. Wilcoxon, J. 
Pharmacol. exp. Therap. 96 (1949), 99. 
.sup.++ calculated by method of G. Korber, Arch. exp. path.Pharmakol. 162 
(1931), 480. 
It is evident from the above results that dextrorotatory ergot alkaloids 
are less toxic than levorotatory ergot alkaloids. 
2. THE EFFECT ON ARTERIAL PRESSURE 
(a) The effect on blood pressure and heart pulsation in normotensive 
narcotized rats 
The artery Carotis communis was cannulated in narcotized rats (variety 
Wistar) and the blood pressure was recorded on a dynograph (type Beckmann) 
over a mini-transducer. The frequency of heart pulsation was recorded by a 
cardiotachometer on the same dynograph. Dextrorotatory ergot alkaloids 
were administered in the form of methanesulfonate salt into Vena jugularis 
by means of an apparatus for slow infusion (B. Melsungen) in doses of 
0.15, 0.45 and 1.5 mg/kg of body weight. 
The results of experiments showed that dextrorotatory ergot alkaloids did 
not affect blood pressure and frequency of heart pulsation. 
(b) The effect on blood pressure drop in rats with cut spinal cord 
Rats (variety Wistar) in urethane narcosis were cut their spinal cord in 
the region of the second cervical vertebra and connected to an artificial 
breathing apparatus (B. Melsungen). By this intervention the central 
regulation of blood pressure was eliminated. In so treated animals blood 
pressure dropped for about 50 mm Hg. The experiment was supposed to show 
whether the examined substances directly affected the smooth muscles of 
blood vessels. 
The results of the experiments showed that the acid addition salts of 
ergotaminine, ergocryptinine and ergocorninine in a dose of 1.5 mg/kg of 
body weight caused a long-duration hypertension lasting more than 60 
minutes. 
The same effect was induced by ergosinine only in a dose of 4.5 mg/kg of 
body weight, whereas ergocristinine showed no effect even in a dose of 4.5 
mg/kg of body weight. 
The frequency of heart pulsation was reduced during the experiment with any 
of said dextrorotatory ergot alkaloids except with ergocristinine. 
It is evident from the above results that ergotaminine, ergocryptinine, 
ergosinine and ergocorninine, similar as dihydroergotoxine and 
dihydroergotamine, show vasoconstrictory effect, i.e. they cause the 
contraction of smooth muscles of blood vessels (E. Rothlin and A. 
Cerletti, Verh. dtsch. Ges. Kreislaufforsch. 15, 1949, 158). 
(c) The effect on arterial pressure of spontaneously hypertensive rats 
For the experiment groups of 10 spontaneously hypertensive rats (variety 
Okamoto Aoki F.sub.32) of both sexes, weighing from 200 to 250 g, were 
used. The acid addition salts of said dextrorotatory ergot alkaloids were 
administered intraperitoneally in doses of 50 mcg/kg of body weight and 
systolic blood pressure was measured on the rats' tails by means of 
plethysmographic method (K. Okamoto and K. Aoki, Jap. Circulat. J. 27, 
1963, 282). 
The results of experiments are cited in the following Table II. 
TABLE II 
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Systolic blood pressure in mm Hg 
day 
Substance control 2 4 6 8 10 
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ergotaminine 189 162 143 131 144 150 
methanesulfonate 
ergosinine 180 169 152 140 141 138 
methanesulfonate 
ergocryptinine 
189 181 176 168 161 160 
methanesulfonate 
ergocristinine 
187 183 177 169 160 152 
methanesulfonate 
ergocorninine 
190 182 176 166 160 161 
methanesulfonate 
ergotamine tartrate 
179 174 170 172 173 172 
ergosine 188 183 178 176 175 177 
methanesulfonate 
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The results of experiments show that all mentioned dextrorotatory alkaloids 
gradually induce systolic blood pressure drop in spontaneously 
hypertensive rats. The strongest effect is exhibited by ergosinine and 
ergotaminine. 
Most levorotatory ergot alkaloids do not affect the systolic blood pressure 
of spontaneously hypertensive rats. 
2. THE EFFECT ON HEART 
In experiments in normotensive narcotized rats with cut spinal cord, the 
dextrorotatory ergot alkaloids in active doses induce slower heart action, 
i.e. bradycardia. This effect is established for all known ergot alkaloids 
and the derivatives thereof, e.g. ergotoxine, ergotamine, 
dihydroergotoxine, dihydroergotamine and others (E. Rothlin, Wien. Klin. 
Wschr. 62, 1950, 893). 
The effect of dextrorotatory ergot alkaloids according to the invention on 
heart in vitro was examined on isolated heart of a guinea pig by the 
modified Langendorff's method (Zalar et al., Poll. Chim. Farmac. 114, 
1975, 146). Alkaloids were infused by an apparatus for slow infusion (B. 
Melsungen). 
The results of the experiments are shown in the following Table III. 
TABLE III 
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Dose (+)inotropic 
(-)chronotropic 
(mcg/g (maximum) (maximum) 
Substance of heart) 
in % in % 
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ergotaminine 
5.59 32 20 
methanesulfonate 
ergosinine 0.65 103 23 
methanesulfonate 
ergocryptinine 
0.04 111 21 
methanesulfonate 
ergocristinine 
4.98 9 12 
methanesulfonate 
ergocorninine 
4.90 -- 11 
methanesulfonate 
ergotamine 0.65 75 30 
tartrate 
ergosine 0.57 49 17 
methanesulfonate 
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From the given results it is evident that ergotaminine, ergosinine and 
ergocryptinine exhibit an effect on isolated heart, which is qualitatively 
similar to that of ergotamine, ergosine and dihydroergotamine. 
Ergosinine and especially ergocryptinine have a quantitatively greater 
effect on the strength of heart contraction. 
The effect of ergotaminine, ergosinine and ergocrystinine on heart in situ 
was examined in rats. The thorax of narcotized rats (0.7 ml of 25% 
urethane solution per 100 g of the body weight, administered 
subcutaneously) was opened. The heart was placed into a special basket 
with a balloon, which was connected over a polyethylene cannula to a 
transducer "Mini Pressure Transducer--Beckmann" and dynograph Beckmann. As 
the left wall of the ventricle leant against the balloon, the contraction 
of the ventricle could be recorded. Over a tracheal tube the rats were 
connected to an artificial breathing apparatus. 
The results showed that ergotaminine, ergosinine and ergocristinine in 
doses of 250 and 300 mcg/kg intravenously (with the apparatus for slow 
infusion B. Melsungen) increased the strength of heart contraction for 15% 
and 30%, resp. 
4. THE EFFECT ON ARRHYTHMIA INDUCED BY ADRENALIN 
It is well known that levorotatory ergot alkaloids and derivatives thereof 
totally or partly inhibit the occurrence of heart arrhythmias induced by 
adrenalin. 
For experiments, guinea pigs of both sexes, weighing from 400 to 550 g, 
were used. The narcotized animals (urethane 1.6 g/kg of body weight, 
intraperitoneally) were at first intravenously administered adrenalin 
(0.02 mg/kg) and then dextrorotatory ergot alkaloids. 1 hour and 1.5 hours 
after the administration of dextrorotatory ergot alkaloids, adrenalin was 
again administered intravenously (0.02 mg/kg) and the presence as well as 
duration of arrhythmias was ascertained. 
The results of experiments are shown in the following Table IV. 
TABLE IV 
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Dose Shortening of 
(mg/kg arrhythmia duration 
Substance intraperitoneally) 
in % of control 
______________________________________ 
ergotaminine 2.0 28 
methanesulfonate 
ergosinine 2.0 79 
methanesulfonate 
ergocryptinine 
2.0 63 
methanesulfonate 
ergocristinine 
2.0 32 
methanesulfonate 
ergocorninine 
2.0 46 
methanesulfonate 
ergotamine tartrate 
2.0 63 
ergosine 2.0 84 
methanesulfonate 
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It is evident from the shown results that the duration of arrhythmia is 
most efficiently shortened by ergosinine, followed by ergocryptinine, 
ergocorninine, ergocristinine and ergotaminine. Levorotatory ergot 
alkaloids exhibit a somewhat stronger effect against arrhythmia and 
adrenalin. 
5. THE EFFECT ON THE FUNCTION OF THE PUPIL 
The phenomenon of mydriasis induced by ergot alkaloids results from the 
stimulation of alpha-adrenergic receivers of the dilatating pupil muscle 
(Z. Votava et al., Arch. int. Pharmacodin. 45, 1958, 114). 
The mydriatic effect of dextrorotatory ergot alkaloids administered 
intravenously was determined with a monocular measuring magnifying glass 
by Polewka's method (A. R. Turner, Screening Methods in Pharmacology, 
1965, p. 174 ff.). 
The size of the pupil was measured at first before the administration of 
the substance and then 15, 30 and 60 minutes after intravenous 
administration of alkaloids into the mouse tail (dose 5 mg/kg of body 
weight). 
The results of experiments are shown in the following Table V. 
TABLE V 
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The increase of pupil widening 
in comparison with the control in % 
Substance after 15 min. 
after 30 min. 
after 60 min. 
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ergotaminine 
66.3 69.8 30.3 
methanesulfonate 
ergosinine 135.0 122.5 32.5 
methanesulfonate 
ergocryptinine 
117.4 91.6 32.2 
methanesulfonate 
ergocristinine 
48.7 10.3 2.5 
methanesulfonate 
ergocorninine 
52.7 36.1 19.4 
methanesulfonate 
ergotamine tartrate 
73.3 22.8 4.6 
ergosine 115.6 110.5 39.7 
methanesulfonate 
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It is evident from the shown results that dextrorotatory ergot alkaloids 
induce a mydriatic effect similar to the effect of levorotatory ergot 
alkaloids. The strongest mydriatic effect was exhibited by ergosinine and 
ergocryptinine. 
On the basis of pharmacological properties it can be established that the 
dextrorotatory ergot alkaloids according to the invention 
have a hypotensive effect, as shown by experiments on spontaneously 
hypertensive rats, 
affect the contraction strength of the heart ventricle and the frequency of 
heart pulsation, as shown by experiments on the isolated heart of guinea 
pig and on the heart of rat in situ, 
are effective against arrhythmias, as shown by experiments on guinea pigs 
at arrhythmias induced by adrenalin, 
have a spasmogenic effect, as shown by experiments on spinal rats, and an 
agonistic effect on alpha-receivers, as shown by experiments on the mouse 
pupil. 
On the basis of said properties, the dextrorotatory ergot alkaloids 
ergotaminine, ergosinine, ergocryptinine, ergocristinine and ergocorninine 
can be used in the treatment of arterial hypertension, heart 
insufficiency, heart arrhythmia and cephalalgia. 
Said dextrorotatory alkaloids in the form of their physiologically 
compatible acid addition salts are used as medicines for enteral and 
parenteral administration. The pharmaceutical compositions are formulated 
by adding usual inorganic and organic adjuvants. For tablets and dragees 
there are added e.g. lactose, starch, talc, magnesium stearate etc. For 
solutions and suspensions there are added e.g. water, alcohols, glycerine, 
vegetable oils etc. For suppositories there are added e.g. vegetable oils, 
hardened oils and waxes. The formulations can also contain suitable 
preservatives, stabilizers, surfactants, dissolving imtermediaries, 
sweetening agents and dye stuffs. 
A suitable daily dose for dextrorotatory ergot alkaloids according to the 
invention in the form of their physiologically compatible acid addition 
salts amounts to 0.01-1.0 mg/kg of body weight.

The invention is illustrated by the following Examples. 
EXAMPLE 1 
Ergocristinine methanesulfonate 
Ergocristinine (1.25 g; 0.05 mmoles) was dissolved in absolute ethanol (25 
ml), containing methanesulfonic acid (0.15 ml; 2.31 mmoles). After 
clarifying, the solution was slowly poured into absolute diethylether (350 
ml) while stirring. The precipitated salt was filtered off and dried in 
vacuo. Ergocristinine methanesulfonate (1.40 g; 96.4% of the theory) with 
a melting point of 170.degree.-180.degree. C. was obtained. 
EXAMPLE 2 
Ergocorninine methanesulfonate 
Ergocorninine (1.50 g; 2.67 mmoles) was dissolved in absolute ethanol (20 
ml), containing methanesulfonic acid (0.21 ml; 2.93 mmoles). The clear 
solution was poured into absolute diethylether (300 ml) while stirring. 
The precipitated salt was filtered off and dried in vacuo. Ergocorninine 
methanesulfonate (1.64 g; 98.2% of the theory) with a melting point of 
178.degree.-179.degree. C. was obtained. 
EXAMPLE 3 
Ergocryptinine methanesulfonate 
Ergocryptinine (2.30 g; 4 mmoles) was dissolved in absolute ethanol (20 
ml), containing methanesulfonic acid (0.3 ml; 4.62 mmoles). The clear 
solution was poured into absolute diethylether (300 ml) while stirring. 
The precipitated salt was filtered off and dried in vacuo. Ergocryptinine 
methanesulfonate (2.5 g; 97.6% of the theory) with a melting point of 
174.degree.-175.degree. C. was obtained. 
EXAMPLE 4 
Ergosinine methanesulfonate 
Ergosinine (5.48 g; 10 mmoles) was dissolved in absolute ethanol (60 ml), 
containing methanesulfonic acid (0.72 ml; 11 mmoles). The clear solution 
was poured into absolute diethylether (600 ml). The precipitated salt was 
filtered off and dried in vacuo. Ergosinine methanesulfonate (6.05 g; 
98.7% of the theory) with a melting point of 190.degree.-192.degree. C. 
was obtained. 
EXAMPLE 5 
Ergotaminine methanesulfonate 
Ergotaminine (1.25 g; 2.15 mmoles) was dissolved in absolute ethanol (53 
ml), containing methanesulfonic acid (0.16 ml; 2.46 mmoles). The clear 
solution was poured into absolute diethylether (430 ml). The precipitated 
salt was filtered off and dried in vacuo. Ergotaminine methanesulfonate 
(1.3 g; 99.2% of the theory) with a melting point of 
184.degree.-187.degree. C. was obtained. 
EXAMPLE 6 
Ergotaminine ethanesulfonate 
Ergotaminine (0.58 g; 1 mmole) was converted, as in Example 5, to an 
addition salt with ethanesulfonic acid (0.12 g; 1.1 mmoles). Ergotaminine 
ethanesulfonate (0.63 g; 91.3% of the theory) with a melting point of 
171.degree.-173.degree. C. was obtained. 
EXAMPLE 7 
Ergotaminine hydrochloride 
Ergotaminine (0.58 g; 1 mmole) was converted, as in Example 5, to an 
addition salt with concentrated hydrochloric acid (0.16 ml; 1.6 mmoles). 
Ergotaminine hydrochloride (0.59 g; 95.1% of the theory) with a melting 
point of 205.degree. C. (dec.) was obtained. 
EXAMPLE 8 
Ergotaminine trifluoroacetate 
Ergotaminine (0.58 g; 1 mmoles) was converted, as in Example 5, to an 
addition salt with trifluoroacetic acid (0.13 g; 1.14 mmoles). 
Ergotaminine trifluoroacetate (0.47 g; 67.7% of the theory) with a melting 
point of 178.degree.-180.degree. C. was obtained. 
EXAMPLE 9 
Ergotaminine trichloroacetate 
Ergotaminine (0.58 g; 1 mmole) was converted, as in Example 5, to an 
addition salt with trichloroacetic acid (0.18 g; 1.1 mmoles). Ergotaminine 
trichloroacetate (0.21 g; 28.3% of the theory) with a melting point of 
238.degree. C. (dec.) was obtained. 
EXAMPLE 10 
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Tablets 
Composition mg/tablet 
______________________________________ 
the active substance according to 
30 
the invention 
lactose 218 
starch 27 
talc 13 
tragacanth 10 
magnesium stearate 2 
total 300 mg 
______________________________________ 
EXAMPLE 11 
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Capsules 
Composition mg/capsule 
______________________________________ 
the active substance according to 
20 
the invention 
lactose 280 
total 300 mg 
______________________________________ 
EXAMPLE 12 
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Injection solution 
Composition weight in mg 
______________________________________ 
Active substance according to 
1.00 
the invention 
sodium carboxymethylcellulose 
1.50 
polyvinyl pyrrolidone 
5.50 
lecithin 3.20 
benzyl alcohol 0.01 
buffer q.s. 
bidistilled water ad 1 ml 
total 1 ml 
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