J. Inher. Metab. Dis. 21 (Suppll) (1998) 101-111
`© SSIEM and Kluwer Academic Publishers. Printed in the Netherlands
`
`Alternative pathway therapy for urea cycle
`disorders
`F. FEILLET and J. V. LEONARD*
`Biochemistry, Endocrine and Metabolic Unit, Institute of Child Health, 30 Guilford
`Street, London WCIN IEH, UK
`* Correspondence
`
`Summary: In man the major pathway for the disposal of waste nitrogen is the
`urea cycle; in inborn errors of this pathway, nitrogen flux is reduced. As a
`result there is accumulation of ammonia and glutamine with disordered metab(cid:173)
`olism of other amino acids. Nitrogen homeostasis can be restored in these
`patients with a low-protein diet combined with compounds that create alterna(cid:173)
`tive pathways for nitrogen excretion. The introduction of these compounds has
`been a major advance in the management of these inborn errors and as a result
`the outcome, particularly for those treated early. has improved.
`
`THE UREA CYCLE
`
`Surplus nitrogen cannot be stored and has to be excreted. In mammals the major
`pathway for the metabolism of waste nitrogen is the urea cycle. In children on a
`protein intake of 1.25 g/kg, about 50% of the urinary nitrogen is excreted as urea
`(Brusilow and Maestri 1996). Quantitatively, 1 g of protein contains approximately
`0.16 g of nitrogen which, if catabolized completely, will be converted to 5.7 mmol of
`urea.
`The net effect of the urea cycle is to convert two nitrogen atoms derived from
`ammonia and aspartate to urea. The biochemical steps in the cycle are shown in
`Figure 1. Ammonia is probably derived from several sources (Brusilow and Horwich
`1995) and is converted to carbamoyl phosphate by carbamoyl-phosphate synthase.
`This enzyme requires an allosteric activator N -acetylglutamate for full activity. The
`carbamoyl phosphate condenses with ornithine to form citrulline which then reacts
`with aspartate to form argininosuccinate. This compound is then hydrolysed to
`arginine and fumarate. The arginine is cleaved by arginase, releasing urea with orni(cid:173)
`thine being reformed. Within the urea cycle, ornithine acts as a carrier, being neither
`formed nor lost.
`
`INBORN ERRORS OF THE UREA CYCLE
`
`Defects of each step have now been described and are listed in Figure 1. The presen(cid:173)
`tation is highly variable: those presenting in the newborn period usually have an
`
`101
`
`

`

`102
`
`F eillet and Leonard
`
`-
`
`· Phenylbutyrate , x
`
`' Phenylbutyryl CoA.
`
`....
`
`HEPATIC NITROGEN
`POOL
`
`· Phenytacetate
`·~ Phenyl acetyl-
`~ glutamine
`
`Glutamine _;_~~ .... Glutamine
`Ala~ine ,
`Benzoate ~ Benzoyl CoA
`·· ·
`\
`-
`··
`Aspartate ,
`' 1Giycine --11--·'_':-I··~·,··Giycin'e·:·· ~·c
`~ Hippurate
`
`1
`
`~· ·:
`
`Glutamate--+----
`
`N-acetyl ....,.®..._..,~
`glutamate
`
`0
`
`.------------· :carbamoyl
`.. .. phosphate
`
`I mitochondrion I
`
`Citrulline,
`
`Ornithine
`
`Ornithine
`
`I cytosol I
`
`Urea+
`
`~[-u_n_i-ne-
`
`.. · oroti~ acid '·· .
`:.~·: orotidine ·
`····
`
`Arginine.·,
`
`'i-
`
`i
`
`J. I nher. M etab. Dis. 21 (1998) Sllppl: 1'
`
`:"'-
`
`. ~
`
`J'
`
`"
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`Alternative pathway therapy
`
`103
`
`overwhelming illness but it may be subtle in those who present later in childhood or
`adult life (Brusilow and Horwich 1995; Leonard 1995). As a result of the inborn
`error, the flux in the pathway is reduced and all the defects are associated with
`hyperammonaemia and increased concentrations of glutamine in plasma (Brusilow
`and Horwich 1995). The metabolism of other amino acids is disordered depending
`on the site of the metabolic block. The concentrations of amino acids in the
`pathway immediately proximal to the enzyme defect will be increased and of those
`beyond the block decreased (Figure 1). For many years the mainstay of treatment
`was a low-protein diet but the metabolic control was frequently not satisfactory.
`The development of compounds that increase the excretion of nitrogen by alterna(cid:173)
`tive pathways has been an important breakthrough in the management of these
`disorders (Brusilow et al 1979).
`
`NEUROTOXICITY OF UREA CYCLE INTERMEDIATES
`
`Ammonia increases the transport of tryptophan across the blood-brain barrier with
`consequent increase in the production and release of serotonin (Bachmann and
`Colombo 1983). Some of the symptoms of hyperammonaemia can be explained on
`this basis and restriction of dietary tryptophan reverses some symptoms, particu(cid:173)
`larly anorexia, in patients with these disorders (Hyman et al 1987). Ammonia
`induces many other electrophysiological, vascular and biochemical changes in
`experimental models, but it is not known to what extent these are relevant to the
`problems ofhyperammonaemia in man (Surtees and Leonard 1989).
`Glutamine can also be shown to accumulate at high concentrations both in
`experimental models (Brusilow and Horwich 1995) and also in man in vivo using
`proton nuclear magnetic resonance spectroscopy (Connelly et a11993). The concen(cid:173)
`trations are such that the increase in osmolality could be responsible for changes in
`the intracellular water content and cerebral oedema.
`
`(opposite) Pathways for the disposal of waste nitrogen: The urea cycle and alterna(cid:173)
`Figure 1
`tive pathways of nitrogen excretion
`
`Enzymes
`1. Carbamoyl-phosphate synthase
`
`2. Ornithine transcarbamoylase
`3. Argininosuccinate synthetase
`4. Argininosuccinate lyase
`5. Arginase
`6. N-Acetylglutamate synthase
`
`Inborn error of metabolism
`Carbamoyl-phosphate synthase
`deficiency
`Ornithine transcarbamoylase deficiency
`Citrullinaemia
`Argininosuccinic aciduria
`Arginase deficiency
`N-Acetylglutamate synthase deficiency
`
`Benzoate and phenylbutyrate are activated, conjugated to glycine and glutamine respectively
`and excreted, thereby creating an alternative pathway for nitrogen excretion
`
`J. Inher. Metab. Dis. 21 (1998) Suppl. 1
`
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`104
`·. ·The· clinical problems· of arginase deficiency; are distinct from: other' urea cycle
`disorders· and: it seems· probable thaf the high\ arginine> concentrations are
`neurotoxic, although the mechanism is unknown. Arginine deficiency may also con(cid:173)
`tribute to the same symptoms in other disorders (Kline et al 1981 ). '
`
`F eillet and Leonard
`
`-
`
`l •• •. ~ ~ -~ ~ •
`
`; "
`
`. ;, ,.
`
`TREATMENT
`The laim'of tre~tment is· to correct .. the bio'chemicaVab:O.onnalities and yet at the
`same time·"eilsure that'all the nutritional needs are met. The strate"gies used are to
`redui.£proteill intake to reduce the nitrogen flux through the urea cyde; secondly to
`utilize alternative pathways of nitrogen excretion; and -thirdly to replace nutrients
`that are deficient.
`· ··
`
`Low-protein diet ,.
`
`Most' patients with urea cycle disorders require a low-protein' diet:· The exact quan(cid:173)
`tity of protein;wil(depend'On the inborn er~of:· the a"ge of the'patient and tl1e''sever(cid:173)
`ity" of.the ''disorder .. For'soiii.e'patients. particularly 'inose with severe disorders and
`those with marked pr~tein~:aversion, the,diet:may~need to be'supplemented with
`essentiai amin~· acids (B~usilow and Horwich T995; Leonard 1995):'
`,, . '
`'
`
`Alternative patb\Vay~·ror.~itrogen excretion
`
`•
`
`'
`
`c j\
`
`·i :,01
`
`~' ' " ;.;
`
`• ~
`
`'
`
`'
`
`' •
`
`In many patients diet alone is not sufficient. to- control the metabolic derangement,
`so that additional therapy is necessary. A major advance in this field has been the
`..
`.
`. ..
`-
`..
`.
`.
`_..
`, ...... -
`..
`r
`development of compounds that increase the removal of waste nitrogen (Brusilow et
`al 1979). By giving_these.substances, nitrogen is converted to compounds other than
`urea and is excreted. Hence the load on the urea cycltds reduced (Figure J). The first
`compounds introduced were arginine and sodium benzoate ... Later ·phenylacetate
`was used but this has now been superseded by ph~enylbutyrate.
`
`Sodium benzoate: ·· Benzoate· is.:: conjugated·~ with ., glycine · to:: form hippurate
`(Tremblay and Qureshi 1993) which is rapidly 'excreted in the urine'(Figi.ire 1). The
`possibility that sodium benzoate could be used to increase waste nitrogen excretion
`was first recognized by Lewis early this century (Lewis 1914) and it is.well'suited for
`this because its_ renal clearance is five times the glomerular filtration rate (Brusilow
`et al1979). Fof each mole of h~nz~ate givei{i mole of nitrogen is removed.:' In "practi·
`cal terms 1 g of benzoate would, if completely converted to hippurate and 'excreted,
`result in the removal of the equivalent of 0.6 g protein.
`-.. ··
`Sodium benzoate is·usually given'in doses up to 250mgfkg per'day;·but in ·acute
`emergencies this can be jncreased to 500 mgjk:g per day. Following a dose of
`250 mgjkg, the nitrogen removed by sodium benzoate, i~ conjugation is complete,
`
`J. Inher: Metab. Dis:21 (1998)Suppl. 1·
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`Alternative pathway therapy
`
`105
`
`will be equivalent 0.15 gjkg of protein. Plasma ammonia and glutamine concentra(cid:173)
`tions decrease (Brusilow and Maestri 1996). This, combined with a low-protein diet,
`may be sufficient in those with mild defects and it has been used widely with benefi(cid:173)
`cial effects (Batshaw 1983; Letarte et al1985; Takeda et al1983).
`Pharmacokinetics: Studies of the pharmacokinetics have shown that benzoate is
`rapidly converted to hippurate which is then cleared more slowly (Kubota and Ishi(cid:173)
`zaki 1991). In this study, the mean maximum rate of clearance was 23 mgjh per kg,
`which is close to the maximum dose used clinically. However, there is wide variation
`in the recovery of the benzoate reported, which may be as low as 41% (Barshop et
`al1989). The reasons for this have not been investigated, although a small quantity
`may be excreted as the glucuronide, which will reduce its efficacy. Studies of patients
`on their regular medication confirm that sodium benzoate is rapidly converted to
`hippurate but cleared more slowly (Figure 2). It has been recommended that plasma
`concentrations should not exceed 4.5 mmol/L (Simell et al 1986). In the neonatal
`period, induction of hippurate synthesis may be delayed, so that plasma benzoate
`concentrations may reach potentially toxic concentrations and should therefore be
`monitored (C. Bachmann, personal communication).
`Adverse effects: In animal studies sodium benzoate induces a rise in plasma
`ammonia concentrations coupled to a decrease in ATP and acetyl-CoA (Palekar
`and Kalbag 1991). This was thought to be caused by competition for free CoA (Griffith
`et al1989) and the effect could be reversed with N·carbamoyl glutamate or carnitine
`(O'Connor et al 1987, 1989). In sparse-fur mouse benzoate impairs several mito(cid:173)
`chondrial pathways including the urea cycle, fatty acid oxidation and the citric acid
`
`llmolll
`
`600
`
`500
`
`400
`
`300
`
`zoo
`
`100
`
`• ,,
`
`\
`
`I
`I
`
`\
`
`\
`
`'
`
`\
`
`\
`
`I
`
`'
`
`I
`
`I
`I
`
`I
`I
`
`'
`
`I
`I
`I
`I
`
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`
`0
`
`SH
`
`9H
`
`10H
`
`11 H
`
`,.
`'
`
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`
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`-+- Hippurate
`-•· Benzoate
`
`\
`
`\
`
`\
`
`\
`
`\
`
`\
`\
`\
`
`\
`
`' \
`
`13 H
`
`12 H
`Time of day
`
`14 H
`
`15 H
`
`16 H
`
`Figure 2 Late-onset ornithine transcarbamylase deficiency in a boy (S.H.) treated with
`sodium benzoate (375 mg/kg per day). Profile of plasma benzoate and hippurate during
`routine therapy. Arrows indicate each dose of 125mg/kg
`
`J. Inher. Metab. Dis. 21 (1998) Suppl. 1
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`106
`
`F eillet and Leonard
`
`cycle, probably mediated through a decrease in acetyl-CoA (Kalbag and Palekar
`1988; Ratnakumari et al 1993b). In rats the rate of glycine production may also be
`rate limiting (Gregus et al 1992) and benzoate therapy could deplete the hepatic
`glycine pool. In the urease-treated rats benzoate, but not hippurate, has been shown
`to increase the rate of uptake of tryptophan into the brain (Bachmann et al1986).
`Despite the animal studies, few adverse effects have been described in man
`(Batshaw and Brusilow 1981). No evidence could be found that benzoate impaired
`ureagenesis (Kubota and Ishizaki 1993). However, availability of glycine may limit
`its efficacy (Barshop et al 1989). Decreased carnitine concentrations have been
`described and carnitine supplements are reported to improve metabolic control
`(Michalak et al 1990; Ohtani et al 1988; Ratnakumari et al 1993a), but carnitine
`supplements do not appear to be used widely. There are no systematic studies of
`adverse effects and it seems that the most common side-effects are nausea and
`vomiting. Tinnitus and visual disturbance have also been recorded (Kubota and
`Ishizaki 1993; Simell et al 1986). However, side-effects may be underrecognized as it
`can be difficult to distinguish those of benzoate toxicity and of hyperammonaemia
`since both may increase the uptake of tryptophan into the brain (Bachmann et al
`1986).
`
`Sodium phenylacetate and phenylbutyrate: The next compound introduced was
`phenylacetate but this has now been superseded by the congener phenylbutyrate,
`because the former has a peculiarly unpleasant, clinging odour. Phenylbutyrate is
`activated to the CoA ester, which is metabolized by .B-oxidation in the liver to
`phenylacetyl-CoA, which is then conjugated with glutamine (Figure 1). The resulting
`phenylacetylglutamine is excreted in the urine and hence 2 moles of nitrogen are
`excreted for each mole of phenylbutyrate. In practical terms, the conversion and
`excretion of 1 g of phenylbutyrate to phenylacetylglutamine would mean the
`removal of the equivalent of 1 g of protein.
`Phenylbutyrate is usually given as the sodium salt in doses of 250 mgjkg per day
`but has been given in doses of up to 630mg/kg per day (Brusilow 1991).It is usually
`thought that conjugation and excretion are almost complete, but recoveries appear
`to be variable (Piscitelli et al1995) and further studies are warranted. If conjugation
`and excretion were complete, the nitrogen removed following 250 mg/kg and
`630 mgjkg would be equivalent to 0.24 g and 0.6 g of protein/kg, respectively.
`Pharmacokinetics: After an intravenous load, Piscitelli and colleagues (1995)
`showed that phenylbutyrate was quickly converted to phenylacetate with saturable
`nonlinear kinetics. The subsequent conjugation to phenylacetylglutamine was more
`rapid, so that the concentrations of phenylacetate remained low. The peak concen(cid:173)
`tration of phenylacetate was between 1 and 2 h and that of phenylacetylglutamine
`after 1 to 3.5 h.
`When it was given orally (Brusilow and Maestri 1996) the phenylbutyrate peak
`concentration was between 1 and 2 h post dose and the concentrations of phenylace(cid:173)
`tate and phenylacetylglutamine peaked simultaneously at 3 h. When repeated doses
`were given, the concentration of phenylacetate increased during the day (Brusilow
`and Maestri 1996 and Figure 3), only returning to baseline overnight.
`
`J. Inlier. Metab. Dis. 21 (1998) Suppl. 1
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`Alternative pathway therapy
`
`107
`
`J.imOI/1
`
`l
`
`450
`
`400
`
`350
`
`300
`
`250
`
`200
`
`150
`
`100
`
`50
`
`---+·
`
`Phenyl butyrate
`Phenyl acetate
`Benzoate
`
`.... -------· -------
`
`~---·---
`
`SH
`
`9H
`
`10 H
`
`11 H
`
`12 H
`
`13 H
`Time of day
`
`14H
`
`15 H
`
`16 H
`
`Figure 3 Late onset ornithine transcarbamylase deficiency in a boy (B.H.) treated with
`sodium benzoate (200mg(k:g per day) and sodium phenylbutyrate (300mgfkg per day). Profile
`of plasma phenylbutyrate. phenylacetate and benzoate concentrations during routine therapy.
`Arrows indicate each dose of soruum benzoate (67 mg(k:g) and sodium phenylbutyrate
`(100mg/kg)
`
`Adverse effects: Wiech and colleagues (1997) have recently reported a
`retrospective study of the side-effects of sodium phenylbutyrate, but it was not
`always easy to distinguish between the effects of the disease and of the medication.
`The most common was menstrual disturbance in 23% of females at risk. Other
`problems included anorexia and a number of biochemical abnormalities including
`acidosis and alkalosis, hypoalbuminaemia, and hyper- and hypophosphataemia.
`Fanconi syndrome has been reported in two patients on an inborn error network on
`the Internet (Metab-1). On the same network it has also been reported that patients
`who do not swallow sodium phenylbutyrate quickly may develop oral mucositis.
`
`In man arginine is normally a nonessential amino acid
`Arginine and citrulline:
`(Snyderman et al 1959) because it is synthesized within the urea cycle. However,
`where there is a block in the cycle it becomes essential or at least semi-essential. For
`this reason, all patients with urea cycle disorders except those with arginase defi(cid:173)
`ciency are likely to need a supplement of arginine to replace that which is not
`synthesized (Brusilow 1984). Brusilow showed that in the patients with urea cycle
`defects withdrawal of oral arginine led to a rise in plasma ammonia and glutamine,
`one reason for which was that patients became arginine deficient with net protein
`breakdown.
`For deficiencies of ornithine transcarbamylase (OTC) and carbamoyl-phosphate
`synthase (CPS) a dose of arginine of 100~150mgjkg per day appears to be sufficient
`for most patients. However, in severe variants of OTC and CPS deficiencies citrul(cid:173)
`line may be substituted for arginine in doses up to 170 mg/kg per day as this will
`
`J.Inher. Metab. Dis. 21 (1998) Suppl. 1
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`108
`
`F eillet and Leonard
`
`Carbamoyl
`phosphate
`
`/---~--
`
`Citrulline
`
`Citrulline
`
`.....................
`
`' ' '
`Ornithine
`
`! I CD
`Ornithine • I
`
`Figure 4 Argininosuccinic aciduria. As a result of the metabolic block, ornithine is not recy(cid:173)
`cled and this is replaced by supplements of arginine. Argininosuccinate is excreted in the
`urine, thereby creating an alternative pathway for nitrogen excretion
`
`utilize an additional molecule of nitrogen. In patients with citrullinaemia and argin(cid:173)
`inosuccinic aciduria there is a break in the cycle and ornithine is not reformed
`(Figure 4). Giving arginine which is converted to ornithine replaces that which is
`lost. In citrullinaemia patients receiving arginine therapy, plasma and, more impor(cid:173)
`tantly, urine citrulline concentrations rise markedly creating an alternative pathway
`for nitrogen excretion, but the overall nitrogen excretion remains relatively small
`(Brusilow et al 1979). Similarly, in argininosuccinic aciduria plasma concentrations
`of argininosuccinate increase, but, as the renal clearance of argininosuccinate is
`high, a more effective pathway for removing waste nitroten is created (Brusilow and
`Batshaw 1979). Doses of arginine of up to 700 mg/kg per day may be needed
`(Maestri et al1991). The increased plasma concentrations of citrulline and arginino(cid:173)
`succinic acid could be toxic, but any problems appear to be less important than
`those caused by the accumulation of ammonia and glutamine.
`
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`Alternative pathway therapy
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`109
`
`Treatment of acute hyperammonaemia: Both sodium benzoate and sodium phenyl(cid:173)
`butyrate can used intravenously during episodes of acute hyperammonaemia. The
`doses are similar to those for chronic long-term treatment, but care must be taken in
`calculating all doses, particularly when given intravenously. Two patients have died
`in the United States when given the wrong doses of the combined solution of
`sodium benzoate/sodium phenylacetate (S. W. Brusilow 1993, Memorandum to all
`investigators using sodium benzoate/sodium phenylacetate, 21 January 1993).
`
`Long-term management of patients with urea cycle disorders: The protein intake,
`growth rate and requirements of the patients vary widely. For example some
`patients have a marked aversion to protein with consequently a low intake, while
`others eat normally. Amino acid utilization will increase during phases of rapid
`growth and decrease after puberty when growth ceases. As a result of the many
`factors that affect nitrogen utilization, the waste nitrogen load varies and hence the
`dose of alternative pathway medicines will also vary. The aim should be to maintain
`good metabolic control with plasma ammonia concentrations less than 80 .umol(L
`(normal < SO pmol/L) and plasma glutamine ideally less than 800 pmol/L, though in
`practice less than 1000 ,umoljL is probably more realistic, particularly for those
`more severely affected (Maestri et al 1992).
`
`Long-term effects of alternative pathway therapy: No controlled trials have been
`done to test the effect of alternative pathway medication and it is doubtful that
`such a trial would now ever be ethically acceptable. It is necessary to rely on bio(cid:173)
`chemical changes and historical comparisons. The introduction of arginine, sodium
`benzoate and phenylbutyrate has improved both biochemical control and neuro(cid:173)
`logical outcome (Letarte et al1985; Maestri et a11991, 1995, 1996; Msall et al1984;
`Wildham et a11992).
`In a recent review of 28 patients (23 females, 5 males) with late-presenting OTC
`deficiency, 12 patients are of normal cognitive ability (IQ > 85) but all the others are
`handicapped, ranging from mild to severe (P. Nicolaides, R. A. Surtees, J. V.
`Leonard, unpublished data). Analysing the data further, the 5 girls treated prospec(cid:173)
`tively are normal. Of 7 patients with normal cognitive ability who presented symp(cid:173)
`tomatically. 2 are still pre-school age, 2 others have specific learning difficulties and
`2 presented late at 8 years and 12 years respectively.
`
`CONCLUSIONS
`Alternative pathway therapy combined with diet has proved remarkably effective,
`restoring nitrogen homeostasis in patients with urea cycle disorders. The drugs
`appear to be safe, although information is limited. The outcome is less good and is
`particularly dependent on the neurological status at the time of diagnosis and the
`response to treatment. Patients treated prospectively do better, so that every effort
`needs to continue to be made to establish diagnoses early.
`
`J.lnher. Metab. Dis. 21 (1998) Suppl. 1
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`110
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`F eillet and Leonard
`
`ACKNOWLEDGEMENTS
`The authors thank Dr Anne Green, Mrs Mary-Anne Preece and Ian Sewell for the
`assays of benzoate and phenylbutyrate and Dr Paula Nicolaides and Dr Robert
`Surtees for the outcome data of the patients they have studied.
`
`REFERENCES
`Bachmann C, Colombo JP (1983) Incrased tryptophan uptake into the brain in hyper(cid:173)
`ammonaemia. Life Sci 33:2417-2424.
`Bachmann C, Liithi H, Gradwohl M, Colombo JP (1986) Brain uptake of tryptophan in
`urease-injected hyperammonaemic rats after treatment with benzoate or hippurate.
`Biochem Med Metab Bio/36: 214-219.
`Barshop BA, Breuer J, Holm J, Leslie J, Nyhan WL (1989) Excretion of hippuric acid during
`sodium benzoate therapy in patients with hyperglycinaemia or hyperammonaemia. J Inher
`Metab Dis 12: 72-79.
`Batshaw ML (1983) Sodium benzoate and arginine: alternative pathway therapy in inborn
`errors of urea synthesis. Prog Clin Bioi Res 121: 69-83.
`Batshaw ML, Brusilow SW (1981) Evidence of lack of toxicity of sodium phenylacetate and
`sodium benzoate in treating urea cycle enzymopathies. J Inher Metab Dis 4: 231.
`Brusilow SW (1984) Arginine, an indispensable amino acid for patients with inborn errors of
`urea synthesis. J Clin Invest 74: 2144-2148.
`Brusilow SW (1991) Phenylacetylglutamine may replace urea as a vehicle for waste nitrogen
`excretion. Pediatr Res 29: 147-150.
`Brusilow SW, Batshaw ML (1979) Arginine treatment of argininosuccinase deficiency. Lancet
`1: 124-126.
`Brusilow SW, Horwich AL (1995) Urea cycle enzymes. In. Scriver CR, Beaudet AL, Sly WS,
`Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease, 7th edn. New York:
`McGraw-Hill, 1187-1232.
`Brusilow SW, Maestri NE (1996) Urea cycle disorders: diagnosis, pathophysiology, and
`therapy. Adv Pediatr 43: 127-170.
`Brusilow SW, Valle DL, Batshaw M (1979) New pathways of nitrogen excretion in inborn
`errors of urea synthesis. Lancet 2: 452-454.
`Connelly A, Cross JH, Gadian DG, Hunter JV, Kirkham FJ, Leonard JV (1993) Magnetic
`resonance spectroscopy shows increased brain glutamine in ornithine carbamoyl trans(cid:173)
`ferase deficiency. Pediatr Res 33: 77-81.
`Gregus Z, Fekete T, Varga F, Klaassen CD (1992) Availability of glycine and coenzyme A
`limits glycine conjugation in vivo. Drug Metab Dispos 20: 234-240
`Griffith AD, Cyr DM, Egan SG, et al (1989) Inhibition of pyruvate carboxylase by seque(cid:173)
`stration of coenzyme A with sodium benzoate. Arch Biochem Biophys 269: 201-207.
`Hyman SL, Porter CA, Page TJ, Iwata BA, Kissel R, Batshaw ML (1987) Behavior manage(cid:173)
`ment of feeding disturbances in urea cycle and organic acid disorders. J Pediatr 111: 558-
`562.
`Kalbag SS, Palekar AG (1988) Soidum benzoate inhibits fatty acids oxidation in rat liver.
`Effect on ammonia levels. Biochem Metab Bio/40: 133-142.
`Kline JJ, Hug G, Schubert WK, Berry H (1981) Arginine deficiency syndrome. Am J Dis
`Child 135: 437-442.
`Kubota K, lshizaki T (1991) Dose-dependent pharmacokinetics of benzoic acid following oral
`administration of sodium benzoate to humans. Eur J Clin Pharmaco/41: 363-368.
`Kubota K, lshizaki T (1993) Effect of single oral dose of sodium benzoate on ureagenesis in
`healthy men and two patients with late onset citrullinaemia. Eur J Clin Pharmacal 45:
`465-468.
`
`J. lnher. Metab. Dis. 21 (1998) Suppl. 1
`
`PAR-GPB-ANDA009420
`
`

`

`Alternative pathway therapy
`
`111
`Leonard JV (1995) Urea cycle disorders. In Fernandes J, Sa~dubray]M, Van den Berghe G,
`eds. Inborn Metabolic Diseases: Diagnosis and Treatment, 2nd ed. Berlin: Springer-Verlag,
`Hi7-176.
`Letarte J, Qureshi lA, Ouellet R, Godard M (1985) Chronic benzoate therapy in a boy with
`partial ornithine transcarbamylase deficiency. JPediatr 106:}94:-797 ...
`f
`-~,.
`··>'
`-
`.•• ,
`Lewis HB (1914) Studies in the synthesis of hippuric acid in the animal organism.· J Biol
`Chern 18: 225-231.
`,; ··.~ ·
`~ 1,
`''CP:; ·•
`.
`::
`Maestri NE, Hauser ER, Bartholomew D, Brusilow SW (1991) Prospective treatment .of urea
`cycle disorders. J Pediatr 119: 923-928.
`Maestri NE, McGowan KD, Brusilow SW (1992) Pl<isma ghitarriine concentnition': a guide
`to the management of urea cycle disorders. J Pediatr 121: 259--261. I
`·
`t
`Maestri NE, Clissold DB, Brusilow SW (1995) Long-term survival of patients with arginino~
`succinate synthetase deficiency. J Pediatr 127: 929-935. · i
`.
`• .
`•
`Maestri NE, Brusi1ow SW, Clissold DB, Bassett SS (1996) Long-term treatment of girls with
`ornithine transcarbamylase deficiency. N Engl J Med 335: 855-859. _ ··
`, ·
`Michalak A, Lambert MA, Dallaire L, et al (1990)Hypocarnitinemie chezles patierits'atteints
`d'un defaut primaire du metabolisme de l'ammoniaque traites avec Ie benzoate de sodium.
`Diabete Metab 16: 226-233.
`·
`·
`: .
`.
`. .
`'· · ·:
`Msall M, Batshaw ML, Suss R, Brusilow SW, Mellits ED (1984).Neurologic outcome in
`children with inborn errors of urea synthesis. N Eng/ J Med 310: 1500-1505.
`O'Connor JE, Costell M, Grisolia S (1987) The potentiation of ammonia toxicity by sodium
`benzoate is prevented by L-carnitine. Biochem Bi(iphys Res Com1nun 145:-817-824 .. ·" -
`O'Connor JE, Castell M, Grisolia S (1989) Carbamyl glutamate prevents the potentiation of
`· > •c
`ammonia toxicity by sodium benzoate. Eur J Pediatr 148: 540-542.
`,,:• • •.• ·
`Ohtani Y, Ohyagani K, Yamamoto S, Mats11da, I (1988) Secondary carnitine deficiency in
`hyperammonemic attacks of ornithine transcarbamylase deficiency: J Pediatr.112: 409-414.
`Palekar AG, Kalbag SS (1991) Amino acids in the rat liver 'ai:tdplasnia and somemetabolites
`in the liver after sodium benzoate treatment. Biochem Med Metab Biol46: 52-58. 1
`Piscitelli SC, Thibault A, Figg WD, et al (1995)Disposition of phenylbutyrate arid its metab(cid:173)
`olites, phenylacetate and phenylacetylglutamine. J Clin Pharmaco/35: 368-373., , ."
`Ratnakumari L, Qureshi IA, Butterworth RF:(1993a) Effect ofL-dlmitine on, cerebral and
`hepatic energy metabolites in congenitally h)'Perammoneinic"sparse-fur nuceand its role
`. ~:''''
`y:~i :,
`: .:~:,,
`during benzoate therapy. Metabolism 42: 1039;:)046.
`Ratnakumari L, Qureshi IA, Butterworth RF (1993b) Effect of sodium benzoate on cerebral
`and hepatic energy metabolites in spf mice with congenital· hyperammonemia. Biochem
`Pharmacal 45: 137 146.
`.
`·",
`-"
`:· :'iii 'f . ~.·l
`""'
`Simell 0, Sipila I, Rajantie J, Valle DL, Brusilow SW (1986) Waste nitrogen excretion yia
`amino acid acylation: benzoate and phenylacetate in lysi!luric 'protein intolerance. Pediatr
`Res 20: 1117-1121.
`··.~·.~
`:.·- ·~
`· ~":·--··
`··
`'
`" .. •. ·
`·:
`Snyderman SE, Boyer A, Holt EL (1959) The arginine requirement of the'infaniAm :fDis
`>'
`:'.r<:n·c
`Child 97: 192-195.
`,. _ , ·
`Surtees RJ, Leonard JV (1989) Acute metabolic, encephalopathy. J ·Inher :·Metab .. Dis 12
`(supplement 1): 42-54.
`:·, ;w: :·
`~.:·'•.--
`c-:j'"~£' .
`. .. ,
`Takeda E, Kuroda Y, Toshima K, Watanabe T, Naito E, Miyao,M (1983)Effect of long term
`administration of sodium benzoate to a patient with partial'ornithine carbamoyl trans-
`ferase deficiency. Clin Pediatr Phi/a 22: 206-208.
`..
`. ...
`·'·'
`''· ,
`,·.;
`·
`'
`Tremblay GC, Qureshi IA (1993) The biochemistry and toxicology of benzoic acidmetabo(cid:173)
`lism and its relationship to the elimination ofwaste nitrogen; Pharinac Ther 60: 63-90.
`Wiech NL, Clissold DM, MacArthur RB (1997) Safety and efficacy of buphenyl (sodium
`phenylbutyrate) tablets and powder (Abstract). Advances in Inherited Urea Cycle Disorders,
`Satellite to the 7th International Congress for Inborn Errors of Metabolism, Vienna.
`Wildham K, Koch S, Scheibenreiter S, et al (199f) Long-term, follow-up of 12 patients with
`late onset variant of argininosuccinic acid lys~se deficiency":· rio'impairment of intellectual
`and psychomotor development during therapy. Pediatrics 89: ·1182-1184;
`
`··
`
`, J,.'Inhe.r. Metab~ms: 21 (1998) srippL ·1
`
`PAR-GPB-ANDA009421
`
`