Tohoku J. exp. Med., 1982. 137. 213-220
`
`Diurnal Fluctuation of Blood Ammonia Levels
`
`in Adult-Type Citrullinemia
`
`YOSHIAKI YAJIMA. TAKASHI HIRASAWA and TAKEYDRI
`SAHEKi’l‘
`
`(flit-nit: of Internal Medici-rte, In'olci-Kyorits-u Gene-mt Hospital.
`Iii-oh 972 and *Deprmmem of Biochemistry, Toko-i (Fairer-Sim
`School of Medicine, helium L594!
`
`'l‘. Diurnal fluctuation of Blood.
`YAJIMA. Y" “IRASAWA. T. and SAHEKI.
`Ammonia Levels
`in Adult—Type
`(.‘itruili‘ne-mz'o.
`Tohoku J. exp. Med..
`1982,
`137(2), 213—220 ——A 48—year—old man, who was diagnosed as adult-type
`citrnllinemia by quantitative estimation of urea cycle enzymes in the liver.
`showed a regular nocturnal rise of blood iimmuiia level.
`In order to elucidate the
`mechanism of diurnal fluctuation of blood um monia level. the patient was put into
`fasting state. for four days.
`The. blood ammonia level rose at the night of the
`first Fasting day even though no food was taken. then it decreased gradually and
`reached the lowest
`level
`in the. morning of the third fasting day.
`intravenous
`administration of amino acids mixture under the same starved condition gave rise
`to .1 significant elevation of blood ammonia level. Based on these results. it was
`concluded that hyperanimonemia of adult-type. eitrullinemiu could result
`from
`the accumulation of free ammonia which was produced from the catabolism of
`amino acids absorbed from the. small intestine and surpassed the urea synthesis
`of defective urea cycle to flood into the blond. Furthermore.
`the rise of blood
`ammonia level at the night. of the first fasting day suggested that
`the circadian
`rhythm of amino acid-mirhohydrate metabolim might superimpcsc on the process
`mentioned above.
`adult—type cit-ruliinemia: hyperammonemia; diurnal
`Fluctuation
`
`A 48—year—old man with adult—type citrullinemia has been described in our
`previous report (Yajima et a1. 1981). He showed repetitive episodes of encephalo-
`pathy and was diagnosed by quantitative estimation of amino acids and urea cycle
`enzymes in the liver.
`In this case, a regular diurnal fluctuation of the blood
`ammonia level was seen and the drip infusion of gilltamate—arginine mixture and
`oral administration of citrate lowored the Inlood ammonia level. But
`the liver
`
`function tests of the patient became worse one month after the laparotoniy for
`the evaluation of urea cycle. enzymes and he clinically deteriorated to the state
`of general
`liver failure with jaundica and aseites. He died two months after the
`laparotomy. At the stage of general liver failure, citrate ingestion was inelfective
`and regular diurnal fluctuation of blood ammonia was no longer Seen.
`
`Received for publication. October 5. 1981.
`Dr. Yajima's present. address: The Third Department of Internal Medicine.
`University School of Medicine, Sendai £18”.
`2113
`
`'1‘ohoku
`
`Par Pharmaceutical, Inc. Ex. 1023
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 1 of 8
`
`

`

`214
`
`Y. Yajima et al.
`
`This paper discusses the mechanism of regular diurnal fluctuation of blood
`ammonia characteristic of this case from the data obtained in a starvation test,
`
`ammonia tolerance test.
`
`intravenous amino acids loading test and variation of
`
`blood ammonia during the period of general liver failure.
`
`METHOD AND SUBJECTS
`
`A case of adultetype citrullinemia and, as controls, five cases of deeompenaated liver
`cirrhosis were. studied. Case 1 of control group was a 40—year-old male who had a mesocaval
`shunt operation for the esophageal varices and liypersplenism. Case 2 was a 53-year-old
`male in whom hepatic encephalopathy appeared following the rupture of the esophageal
`varices and thereafter encephalopathy of grade 1 to 2 according to Sherlock’s classification
`lasted. Case 3 was a fil-year-old female who was a deeompensated cirrhotic patient with a
`triad of ascites. jaundice and encephalopathy and in whom lactulmu: administration of 60
`ml a day after the onset of encephalopathy lowered blood ammonia level. Case 4 was a 08-
`year-old female who had intractable asoites refractory to bot-b strict salt restriction and
`the use of potent diuretics during the three—months‘ hospitalization. Case 5 was a 40-
`year-old male who was admitted to our hospital because of ascitcs and responded well to
`medical treatment. The ascites was not present at the time of blood ammonia determina-
`tion. Blood ammonia was measured by the modified method of Okuda and Fujii [1966)
`(normal range 40-80 lag} 100 ml}.
`
`RESULT
`
`Variation of blood ammonia tenets in adult-type cit-Hilliardth
`
`The effect of starvation. To prevent the hyperammonemia. protein intake was
`restricted to less than 50 g a day and the clinical course was observed. Symptoms
`of encephalopathy and asterixis occurred at night. The blood ammonia was
`measured four times a day,
`i.e., 9:00 a.m., 2:00 p.m.. 8:00 p.m. and 11:00 p.m.
`during three consecutive days in order to elucidate the correlation between hyper-
`ammonemia and encephalopathy.
`lt revealed that the level of blood ammonia
`depicted a gentle curve which had its peak between 8:00 p.m. and 11:00 p.m.
`Blood ammonia was then measured at 9:00 a.m. and 8:00 p.m. every day. The
`average of fasting levels was 120i38 pgi100 ml at 9:00 am. and 4301—79 ,ugflOO ml
`at 8:00 p.m.
`
`Siorvulion
`
`
`
`
`
`Bloodammonialevelilugml}
`
`‘
`
`I
`
`kWh-0"
`
`33-h...-
`
`_‘__
`..._ :3”
`4—.
`
`In"
`_._J___
`
`.I
`
` ,.-I
`
`2
`
`3
`
`4
`
`Days
`
`Fig. 1. Variation of blood ammonia levels during starvation. The night of the first fasting
`day had a rise of blood ammonia level without taking any food, since then it decreased
`gradually to reach the lowest level in the morning of the third day. 0.
`levels at 9:00
`a.rn.; 0.
`levels at 8:00 p.m.
`Second starvation trial was stopped on the third
`fasting day.
`
`Par Pharmaceutical, Inc. Ex. 1023
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 2 of 8
`
`

`

`Diurnal Fluctuaiiion of Blood Ammonia
`
`215
`
`[:1 order to investigate the mechanism of the nocturnal rise of blood ammonia.
`level the patient was put into a. fasting state for four days. During the starvation
`period. water. electrolyte and 200 g glucose were supplemented intravenously and
`the blood ammonia level was measured at 9:00 a.m. and 8:00 p.111. every day. The
`blood ammonia level rose in the night of the first fasting day, but since then it
`decreased ,Igrraduall}.r and reached the lowest level in the morning of the third fasting
`day. But after the night of the third day the blood ammonia level began to rise
`again. Another starvation trial lmder the same condition performed a week later
`showed the same result.
`
`The rifled of inc-ravenous rid-ministration of amino acids. Under the same con-
`dition as the previous two starvation trials, an amino acids mixture was adminisv
`tered intravenously in the night of the first and the second day and the morning of
`the third day. The amino acids mixture was a commercially available one which
`was synthesized after
`the. constituent of'
`the human milk.
`500 n11 of a 5%
`solution of the amino acids mixture was administered by drip infusion for 2 hr
`and the blood ammonia level was measured immediately after the end of the in-
`fusion.
`In each occasion, the blood ammonia levels rose considerably by 100—
`
`three
`111 deeornpensated cirrhotic case {Case 4) with an ascites,
`200 ,ugflOO ml.
`trials of amino acids infusiou in the fasting state in the early morning had no
`influence on the blood ammonia levels.
`
`7"::-
`2’ _.
`u E
`s 0
`? sE “s.
`a
`'3'.
`8 H
`_°to
`
`After
`
`
`Control 4
`
`LE1-
`
`Before
`
`i510 [—
`
`I00
`
`50
`
`O
`
`
`
`3
`
`Days
`
`Fig. 2. The effect of the intravenous administration of amino acids mixture during the
`starvation period. Two broken lines indicate starvation trials without amino acids
`administration.
`a. blood ammonia levels after amino acids administration.
`
`Ammonia tolerance test. Ammonium chloride. 0.5 gi‘ l0 kg body weight, was
`loaded orally and blood ammonia was measured every half an hour. Blood ammonia
`had its peak at 60 min after loading and got to the initial value 2 hr later (Fig. 3).
`
`Variation of blood memento level during the stage of general tine? failure. The
`liver function tests of the patient became worse a month after the laperotomy
`for liver biopsy and clinically deteriorated to the state of general liver failure with
`
`Par Pharmaceutical, Inc. Ex. 1023
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 3 of 8
`
`

`

`216
`
`‘I'. Yajima et- al.
`
`aoo —
`
`NH4C! {0.5 13/10 kg 3. w.)
`
`300 -
`
`200 -
`
`
`
`I00 -
`
`0 ~—-—_|__._..L.._—...I—_L.——__—J
`O
`30
`50
`90
`l20
`fime iminl
`
`E E
`
`;
`.g E'6 o
`E ‘2
`E ‘x
`D u-
`U 1a ..
`
`2t
`
`o
`
`Fig. 3. Ammonia tolerance test.
`
`800
`
`E3
`
`
`
`E H 600a _
`
`«— anrovenous nyperalimenfafion —-
`
`.E g
`E 9 400
`E “a:L
`‘8 u 200
`
`2m
`
`Days
`
`Fig. 4. Variation of blood ammonia levels in the stage of general liver failure.
`9:00 o-.m.; 0,
`levels at 81H) p.1n.
`
`0,
`
`levels at.
`
`jaundice and ascites. He was not fed and was maintained with intravenous hyper—
`alimentation. At
`this. stage,
`regular diurnal
`fluctuation of blood ammonia
`characteristic of this; patient was no longer seen (Fig. 4).
`
`Variation of blood ammonia level in decompensoted liver cirrhosis
`
`In the following five cases, protein intake was restricted to lees than 50 g a day.
`As a rule, blood ammonia was measured twice a day, 9:00 a.m. and 8:00 p.111. except
`Case 1.
`
`A case of mesoceml sham (Case 1}. Blood ammonia measurement was done
`twelve times serially over two days. There was no regularity observed in the
`variation of the blood ammonia level (Fig. 5).
`
`In Case 2. the variation pattern was no longer diurnal
`Cocos of encephalopathy.
`but rather fluctuating with cycle of several days each.
`[n Uch 3, a trend of slight
`nocturnal rise of blood ammonia was seen before the onset of encephalopathy but
`the trend became unclear after the onset. (Fig. 6).
`
`Par Pharmaceutical, Inc. Ex. 1023
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 4 of 8
`
`

`

`300
`
`I;5
`1’
`
`9% 200
`30ED
`g:
`D,
`“‘51
`2CD
`
`I00
`
`0
`
`Diurnal Fluctuation of Blond Ammonia
`
`217
`
`Conlrol
`
`l
`
`8100
`
`PZIOO
`
`$00
`
`8100
`
`1 200
`
`F800
`
`Hours
`
`Diurnal fluctuation of H1? hlnnd ammonia.
`Fig. 5.
`mvsucaval armatnmnsis.
`
`luvs-19.
`
`in the cirrhotic
`
`patient with
`
`Control 2
`
`300 -
`
`200 l»
`
`
`
`Encephalopolhy
`
`0W
`300 -—
`
`Control 5
`
`
`
`
`
`Encephalopathy
`3/
`/
`
`100—
`
`0
`300
`
`l Control 4
`
`lOO -
`
`O In...
`
`.._|_.__ |
`
`l
`
`_J_
`
`l
`
`l.
`
`Control 5
`
`300 -—
`
`200
`
`100 I-
`
`
`
`
`
`
`
`Bloodommonmlevel[,Lg/lOOmll
`
`O _,_._|—L_._._.L_...._..1___1_—l——
`l
`3
`5
`7"
`
`Days
`
`Variation oft-he blond ammonia low-1:4.
`Fig. 6.
`at 9:110 :1.m.: l. low-l3 at 3:04] p.m.
`
`in th-cmnpensated cirrhotic cases. 0, levels
`
`Par Pharmaceutical, Inc. Ex. 1023
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 5 of 8
`
`

`

`218
`
`Y. Yajima et a].
`
`blood
`seen in Fig. 6,
`In Cases 4 and 5, as
`Cases without encephalopathy.
`ammonia levels were lower than the levels of those cases with encephalopathy and
`depicted a gentle curve with a cycle of several to ten days.
`
`Drse ussron
`
`The contribution of' ammonia to the pathogenesis of hepatic encephalopathy has
`been widely investigated {Walker and Selicnker IQTO; Schenker et al. 1974). Amino
`acids imbalance (Fischer et al. 191'5} and short—chain Fatty acid {Chen et a1. 1970;
`Zieve et al. 1974) have recently been proposed as etiological
`factors
`in hepatic
`encephalopathy. Among them. ammonia is the most important in the treatment of
`hepatic encephalopathy in the sense that we can control it to some extent.
`In
`patients with portal~systemio shunt and experimental animals with hepatic damage
`or Eek fistula, meat intoxication or protein intoxication has been known (Nencki
`et al. 1896; Monguio and Krause 1934). and protein restriction is effective for lower-
`ing the blood ammonia level and improving the clinical course.
`There was no
`report. however. dealing with hepatic encephalopathy which referred to the varia-
`tion of blood ammonia level from the view point of' diurnal fluctuation. The case
`with mesocaval shunt, one of the controls, showed no trends of blood ammonia to
`
`fluctuate diurnally and other four controls of deeompensated cirrhosis also did not
`show the regular fluctuation pattern of blood ammonia.
`On the other hand, in the field of congenital hyperammonemia. Batshaw et al.
`(1975)
`reported a case of
`thirteen~year-old female with
`carhainyl phosphate
`synthetase deficiency in which nocturnal rise of' blood ammonia was
`Moser
`et a1.
`(1967) reported twu cases of argininosuccinic aciduria in which the blood
`ammonia levels were normal or slightly elevated in the fasting state but a marked
`elevation occurred postprandially.
`In the fields of adult—type citrullinemia, Suzuki
`et al. (1980} reported a case in which the variation of blood ammonia was closely
`associated with food ingestion.
`In our case. the measurement of blood ammonia
`over a two months period revealed rises of blood ammonia level every night even
`when encephalopathy was not seen. These results suggested that postprandial
`elevation, or regular nocturnal rise, of blood ammonia should be a pathognomonic
`sign of the abnormality in urea cycle.
`Therefore.
`in the hyperammonemia caused by portal-systemic shunt, blood
`for the determination of ammonia. need not necessarily be sampled in the fasting
`state in the mornng and if adult-type citrullinemia is suspected, blood samples must
`be collected postprandially.
`The starvation test. performed to clarify the mechanism of the nocturnal rise
`of blood ammonia, showed a gradual decrease of blood ammonia.
`level. supporting
`the hypothesis that orally taken nitrogens are elm;er associated with the elevation
`of blood ammonia level.
`
`Incidentally, the blood ammonia levels in the night of' the first fasting day were
`significantly elevated compared with those in the morning and re—elevation of
`levels began since the night of the third fasting day. As to the former, it was
`
`Par Pharmaceutical, Inc. Ex. 1023
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 6 of 8
`
`

`

`Diurnal Fluctuation of Blood Ammonia
`
`219
`
`postulated that nocturnal rise of blood ammonia was not only caused by the meal
`but also can be influenced by the circadian rhythm of amino acid—carbohydrate
`metabolism regulated by the circadian rhythm of hormone secretion. The most
`probable explanation of the re-elevatiou of blood ammonia since the third day is
`the generation of free ammonia in the catabolism of endogenous amino acids.
`Intravenous administration of amino acids mixture under the same starved
`
`condition showed a remarkable elevation of ammonia in the adult-type citrullinemia
`
`but no eiTect in a decompcnsated cirrhotic patient. And, the ammonia tolerance
`test showed a peak at 80 min after ammonium ingestion, a little later than in
`cirrhosis. Murawaki et al.
`(1977]
`reported a case of 23-year—old male with
`ornithine transearbamylase (OTC) deficiency in which the ammonia tolerance
`test showed a unique curve abruptly rising at 75 min after loading, which is
`obviously distinct from that seen in cirrhosis. But
`in two cases of adult-type
`OTC deficiency, reported by Short et al. (1973), both of tbern showed peaks at 30
`min,
`inconsistent with the case reported by Murawaki et al.
`(1977}.
`As regards adult-type citrullinemia, in the case of Suzuki et al. [1980) and the
`case of Yamauchi et al.
`(1980},
`the results of ammonia tolerance test were
`reported.
`In both of them, ammouia tolerance curves rosc slowly until 60 min,
`but it was not clear whether the value at 60 min was a peak value or not because
`
`in general, most of the cirrhotic cases
`the data after 60 min were not presented.
`have their peak values at 15 to 45 min (Conn 1960].
`It may be said that the
`patients with deficiency of urea cycle enzyme have their peaks later than the
`liver cirrhotics. But there is a question in diagnosing the deficiency of urea cycle
`enzyme from the ammonia tolerance test because some of the cirrhotics have their
`peaks at 60 or 90 min (Ohwada et al.
`[917}. On the other hand,
`the intravenous
`amino acids loading test is thought to be a. useful test
`for
`the diagnosis of the
`deficiency of urea cycle enzyme.
`From these data. we proposed the following mechanism for the diurnal fluctua—
`tion of the blood ammonia in our patient: Hyperammonemia of portal-systemic
`encephalopathy due to liver cirrhosis results from the generation of free ammonia
`by intestinal bacterial flora in the large intestine.
`It takes 4 hr on the average for
`non-digestible nitrogenous source to arrive at the large intestine (Read et al. 1980)
`and generate free ammonia and 50 hr on the average to be evacuated from the
`rectum [Cummings et al. 1976).
`It Follows. therefore, that the nitrogenous source
`in a meal brings about the rise of blood ammonia. with a time lag of ‘1
`to 50 hr.
`Because of' this time lag, regular diurnal fluctuation of blood ammonia associated
`with meal ingestion is not seen in the portal—systemic encephalopathy.
`0n the
`other hand, hyperammonemia of adult-type citrullinemia could result From the
`accumulation of free ammonia which was produced from the eatabolism of amino
`
`acids absorbed from the small intestine and surpassed the urea synthesis of defec-
`tive urea cycle to flood into the blood.
`in the night of the first fasting
`Furthermore. the rise of blood ammonia level
`day suggested that the circadian rhythm of amino acid—carbohydrate metabolism
`might superimpose the process mentioned above.
`
`Par Pharmaceutical, Inc. Ex. 1023
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 7 of 8
`
`

`

`220
`
`Y. Ynjima ct al.
`
`Acknowledgment
`
`We are indebted to Prof. Y. Goto, The Third Department of Internal Medicine,
`thuku University School of Medicine.
`for his valuable advices and encouragement
`in
`preparing this paper.
`
`References
`
`1)
`
`2)
`
`3)
`
`4}
`
`a)
`
`ti)
`
`7}
`
`3}
`
`9)
`
`10}
`
`ll)
`
`12}
`
`13}
`
`14)
`
`15}
`
`16)
`
`[7}
`
`Is}
`
`19)
`
`(1975} Treatment of narhamy] phosphate
`\Vulser, M.
`BMShflW, M.. Brusilow. S. 3:.
`Synthctase deficiency with keteanalogues of essential amino acids. New Engi. J.
`JIed.. 292. 10354090.
`Chen. 8., Mahndevsn. V. &. Zieve. L. “970) Volatile fatty acids in the breath of patients
`with cirrhosis of the liver.
`J. Lab. din. JIed..
`'15, 622-4527.
`Conn. H.0. (1960) Ammonia tolerance in liver disease.
`J. Lab. elf-n. Med“ 55. 855-
`871.
`
`Cummings. J.H.. Jenkins. D.J.A. Gr Wiggins. H.S. [1976) Measurement of the mean
`transit. time of dietary residue through the human gut.
`(his. 17, 210-218.
`Fischer. E.J., Funovics. J.M.. Aguirre. A... James. J.H.. Keane. J.M. & W'esdorp, R.I.C.
`(1975) The role of‘plasma amino acids in hepatic encephalopathy. Surgery, 78, 278—
`290.
`
`Monguio, J. 35 Krause. F. (1934) Uber die Bodeutung des NH3 Gehaltes des Blot-es fiir
`die. Beurteilung der Leber Function. Kim.
`It'schr., 13. 11-12—1149.
`Moser. H.W.. Efren. M.L.. Brown. H.. Diamond. R. &. Neuman. CH. [1957} Argin-
`inosueeinic aciduria. Report
`of two cases
`and demonstration of intermittent.
`elevation of blood ammonia. Amer. J.
`.lieri.. 42. EJ—26.
`Murawaki. Y.. Yoshirla. K., Hirsyama. C.. Nakao. T. 3:. Nuke-ya. Y. (1977} Inherited
`hyperammonemia in adult. Acts hepotol. jeep" [8, 856—863. [Japanese]
`Nencki. M.. Pawlow, J.P. it; Zaleski, J. (ISQt‘i) Ueber den Ammoniakgehalt des Blutes
`und dor Orgsne und die Hornstot’fhildung bei den Singethieren. Neanyau‘lckmirleberg's
`Arch. exp. Path. Pkrirmok., 37, 26—51.
`(1977) Studies on ammonia
`31, Anezaki. T.
`Ohwada, Y., Koyams, K., Takagi, Y.
`metabolism in the rat liver in biliary obstruction. Ania hepritol.
`jun-31., 18. 333—340.
`(Japanese)
`(I966) Direct spectrophotometrical determination of blood
`Okuda, T. E: Fujii. S.
`ammonia. Saishio-Igaku, 21, 622—627. (Japanese)
`Read. N.W.. Miles, (1A.. Fisher, D.. Holgate. A.M., Kime. N.D., Mitchell. M.A., Reeve,
`A.M.. Roche, TB.
`E: Wlaker, M.
`(1980} Transit
`time of a- meal
`through the
`stomach, small intestine. and colon in normal subjects and its role in the pathogenesis
`of diarrhea. Gristroenteroiogy, 79.
`I276—l282.
`Schenker. 8.. Breen, KJ.
`it: Hoyumpa. A.M., Jr.
`current status. Guatroenteroiogy, 66. 12l—l5l.
`Short, E.M.. Conn. H.0.. Shodgrsss. [’.J.. Campbell. A.G.M. it: Rosenberg. LP}. {[973}
`Evidence for X—linked dominance of ornithine transcarbamylaee delieieey. New Engl.
`J. riled" 288, 7—12.
`Suzuki. Y.. Yamaura, N.. Nozawa. K.. Akahane. Y.. Kiyosawa. K.. Nagato. .—\., Furnta.
`S. & Chiba. K. (1980} A case of adult-type congenital cit-rullinemia. Ami,
`lie-petal.
`jri.p.. 21. 1215—122]. (Japanese)
`“'alker. (1.0.
`(it Schenker, S. {1970] Pathogenesis of hepatic: encephalopathy -—-- with
`special reference to the role of ammonia. Amer. J. din. Nutr.. 23. 619—632.
`Yamsuchi. M.. Kitaham.
`'[‘.. FujiSriwa. K.. Kameda. H.. Takasaki, S., Komori, R.,
`Saheki. T.. Katsunuma. T. &. Katsunuma, .N. (1980] An autopsied case of liypercitrnl—
`line-min.
`in adult caused by partial deficiency of liver argininomlctinate synthetase.
`Asia heimtol. jnp., 21. 326—334. {Japanese}
`Yajima. Y.. Hirnsawa. T. it, Sahel-ii. T. (HIE-ll} Treatment ofadultdype citrullinemia with
`administration rt citrate. Tohokii J. exp. Med" 134, 321—330.
`b'yuergism between
`Zieve. F.J.. Zil-ve. L.. Doizaki. WJI.
`it: Gilsdort’. RB. (“374)
`ammonia and fatty acids-i in the production of coma:
`Implications for hepatic coma.
`J. Phafimmoi. exp. Then. [91.
`ill—Hi.
`
`(1974} Hepatic encephalopathy:
`
`Par Pharmaceutical, Inc. Ex. 1023
`Par v. Horizon, IPR of Patent Nos. 9,254,278, 9,095,559, and 9,326,966
`Page 8 of 8
`
`