Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Improves Cognitive Functions in Mice after Controlled Cortical Impact Injury.

Traumatic brain injury (TBI) is a major health concern, sometimes leading to long-term neurological disability, especially in children, young adults and war veterans. Although research investigators and clinicians have applied different treatment strategies or neurosurgical procedures to solve this health issue, we are still in need of an effective therapy to halt the pathogenesis of brain injury. Earlier, we reported that sodium benzoate (NaB), a metabolite of cinnamon and a Food and Drug Administration-approved drug against urea cycle disorders and glycine encephalopathy, protects neurons in animal models of Parkinson's disease and Alzheimer's disease. This study was undertaken to examine the therapeutic efficacy of NaB in a controlled cortical impact (CCI)-induced preclinical mouse model of TBI. Oral treatment with NaB, but not sodium formate (NaFO), was found to decrease the activation of microglia and astrocytes and to inhibit the expression of inducible nitric oxide synthase (iNOS) in the hippocampus and cortex of CCI-insulted mice. Further, administration of NaB also reduced the vascular damage and decreased the size of the lesion cavity in the brain of CCI-induced mice. Importantly, NaB-treated mice showed significant improvements in memory and locomotor functions as well as displaying a substantial reduction in depression-like behaviors. These results delineate a novel neuroprotective property of NaB, highlighting its possible therapeutic importance in TBI.

Formulation and Clinical Evaluation of Sodium Benzoate Oral Solution for the Treatment of Urea Cycle Disorders in Pediatric Patients.

BACKGROUND: Sodium benzoate, a common food preservative, is used in the treatment of patients with urea cycle disorders (UCDs) as it stimulates ammonia removal by a non-urea cycle-based pathway. Despite its use in the clinical routine, no commercially available oral formulations currently exist. Liquid formulation is normally well accepted in pediatric age and allows precise dosage according to the children's needs. AIMS: (1) To prepare an oral sodium benzoate solution in different tastes and determine its stability, palatability, and tolerability and (2) to describe the long-term follow-up of two pediatric patients with UCDs treated with our formulation. METHODS: We prepared five oral solutions of sodium benzoate (200 mg/ml) by adding different flavoring agents. We measured drug concentration in the samples by high-performance liquid chromatography (HPLC). We evaluated palatability and tolerability with adult volunteers. Long-term drug compliance and metabolic control were appraised in two pediatric patients. RESULTS: All the oral solutions remained stable at room temperature along the 96-day test period, and they were well tolerated. The mint-flavored solution resulted the most palatable and preferred by adult volunteers. We report good drug compliance and good metabolic outcomes for both pediatric patients during the entire follow-up. CONCLUSIONS: Our study highlighted the stability and tolerability of flavored sodium benzoate oral solutions. These solutions were well accepted during a long-term follow-up and guaranteed a good metabolic control. Since taste attributes are critical to ensure acceptable medication adherence in the pediatric age, flavored liquid formulations of sodium benzoate may be an efficient strategy to achieve therapeutic outcomes in UCD pediatric patients.

Influence of implementing a protocol for an intravenously administered ammonia scavenger on the management of acute hyperammonemia in a pediatric intensive care unit.

The purpose of the study was to evaluate the influence of establishing a protocol for the use of combined sodium benzoate and sodium phenylacetate (SBSP) (Ammonul®) to treat acute hyperammonemia. This was a retrospective, single-center study in a 24-bed medical and surgical pediatric intensive care unit (PICU) in a tertiary care teaching maternal-child hospital in Canada. Inclusion criteria were age < 18 years, PICU admission between 1 January 2000 and 30 June 2016, and SBSP treatment. An SBSP delivery protocol was implemented in our hospital on 30 August 2008 in order to improve management of acute hyperammonemia. Patients were assigned to one of the two groups, without or with protocol, depending on date of admission. SBSP was ordered 34 times during the study period, and 23 orders were considered for analysis (14 with and 9 without protocol). Patient characteristics were similar between groups. The median time from diagnosis to prescription was significantly shorter in the protocol group [40 min (21-82) vs 100 min (70-150), p = 0.03)] but the median time from diagnosis to administration of the treatment was equivalent [144 min (90-220) vs 195 (143-274), (p = 0.2)]. Other clinical outcomes did not differ. This study is the first to compare two SBSP delivery strategies in the treatment of acute hyperammonemia in this PICU setting. Implementation of a delivery protocol shortened the time from diagnosis of hyperammonemia to prescription of SBSP and helped us identify other parameters that can be improved to optimize treatment delivery.

Hyperammonaemia in Neonates and Young Children: Potential Metabolic Causes, Diagnostic Approaches and Clinical Consequences

Hyperammonaemia is a metabolic disturbance characterized by accumulation of ammonia in the blood. Entry of ammonia into the brain via the blood-brain barrier leads to hyperammonaemic encephalopathy. The causes of hyperammonaemia in paediatric patients vary. We present 3 cases of hyperammonaemia in critically ill children in whom an inborn metabolic disorder was identified and provide insights into the phenotypes, diagnostic approaches and management. In children with acute overwhelming illness and progressive neurological deterioration plasma ammonia measurement should be included in the urgent diagnostic work-up. We here raise the awareness that hyperammonaemia is a metabolic emergency requiring prompt recognition and treatment to avoid subsequent complications.

Sodium benzoate induced developmental defects, oxidative stress and anxiety-like behaviour in zebrafish larva.

Sodium benzoate (SB) is a common food preservative. Its FDA described safety limit is 1000 ppm. Lately, increased use of SB has prompted investigations regarding its effects on biological systems. Data regarding toxicity of SB is divergent and controversial with studies reporting both harmful and beneficial effects. Therefore, we did a systematic dose dependent toxicity study of SB using zebrafish vertebrate animal model. We also investigated oxidative stress and anxiety-like behaviour in zebrafish larva treated with SB. Our results indicate that SB induced developmental (delayed hatching), morphological (pericardial edema, yolk sac edema and tail bending), biochemical (oxidative stress) and behavioural (anxiety-like behaviour) abnormalities in developing zebrafish larva. LC50 of SB induced toxicity was approximately 400 ppm after 48 h of SB exposure. Our study strongly supports its harmful effects on vertebrates at increasing doses. Thus, we suggest caution in the excessive use of this preservative in processed and convenience foods.

Effects of sodium benzoate, a commonly used food preservative, on learning, memory, and oxidative stress in brain of mice.

Sodium benzoate (SB) is a widely used preservative and antimicrobial substance in many foods and soft drinks. However, this compound is generally recognized as safe food additives, but evidence has suggested that a high intake of SB may link to attention deficit-hyperactivity disorder in children. Present study investigate the effects of oral administration of different concentrations of SB (0.56, 1.125, and 2.25 mg/mL) for 4 weeks, on the learning and memory performance tests, and also the levels of malondialdehyde (MDA), reduced glutathione (GSH), and acetylcholinesterase activity (AChE) in the mouse brain. The results showed that SB significantly impaired memory and motor coordination. Moreover, SB decreased reduced GSH and increased the MDA level in the brain significantly (P < 0.001). However, nonsignificant alteration was observed in the AChE activity. These findings suggest that short-term consumption of SB can impair memory performance and increased brain oxidative stress in mice.

An evaluation of the effectiveness of a chemical additive based on sodium benzoate, potassium sorbate, and sodium nitrite on the fermentation and aerobic stability of corn silage.

We evaluated the effectiveness of an additive comprising sodium benzoate, potassium sorbate, and sodium nitrite (SSL) as active ingredients for its ability to improve the aerobic stability of corn silages made in North America. In experiment 1, treatment with SSL (1.5 and 2.0 L/t) on whole-plant corn (WPC) was compared with treatment with an additive containing buffered propionic acid and citric acid (BPA; 2 L/t) on corn harvested at 32 and 38% dry matter and ensiled for 120 d. Silage treated with BPA was higher in ammonia-N and propionic acid relative to other treatments. Treatments with all of the additives had numerically, but not statistically, fewer yeasts compared with untreated silage. Both application rates of SSL resulted in lower concentrations of ethanol compared with untreated and BPA silages. Treatment with BPA improved the aerobic stability of silages compared with untreated silage, but the effect from SSL was markedly greater. In experiment 2, WPC was untreated or treated with 2 or 3 L of SSL/t or a microbial inoculant containing Enterococcus faecium M74, Lactobacillus plantarum CH6072, and Lactobacillus buchneri LN1819 (final total lactic acid bacteria application rate of 150,000 cfu/g of fresh forage). Silages were air stressed for 24 h at 28 and 42 d of storage and ensiled for 49 d before opening. Inoculation had no effect on acid end products, ethanol, number of yeasts, or aerobic stability compared with other treatments. Treatment with SSL decreased the amount of ethanol, had no effect on number of yeasts, and improved aerobic stability in a dose-dependent manner compared with other treatments. In experiment 3, WPC was untreated or treated with 2 L of SSL/t and ensiled for 5, 15, and 30 d. Treatment with SSL resulted in silage with fewer yeasts and lower concentrations of ethanol after all times of ensiling compared with untreated silage. In addition, SSL improved aerobic stability after each period of ensiling, but the effect was more at 15 and 30 d compared with 5 d of storage. Treating WPC with SSL can improve the aerobic stability of corn silage made in North America, and the effect can be observed as soon as 5 d after ensiling.

Assessment of the Target Engagement and D-Serine Biomarker Profiles of the D-Amino Acid Oxidase Inhibitors Sodium Benzoate and PGM030756.

Irregular N-methyl-D-aspartate receptor (NMDAR) function is one of the main hypotheses employed to facilitate understanding of the underlying disease state of schizophrenia. Although direct agonism of the NMDAR has not yielded promising therapeutics, advances have been made by modulating the NMDAR co-agonist site which is activated by glycine and D-serine. One approach to activate the co-agonist site is to increase synaptic D-serine levels through inhibition of D-amino acid oxidase (DAO), the major catabolic clearance pathway for this and other D-amino acids. A number of DAO inhibitors have been developed but most have not entered clinical trials. One exception to this is sodium benzoate which has demonstrated efficacy in small trials of schizophrenia and Alzheimer's disease. Herein we provide data on the effect of sodium benzoate and an optimised Takeda compound, PGM030756 on ex vivo DAO enzyme occupancy and cerebellar D-serine levels in mice. Both compounds achieve high levels of enzyme occupancy; although lower doses of PGM030756 (1, 3 and 10 mg/kg) were required to achieve this compared to sodium benzoate (300, 1000 mg/kg). Cerebellar D-serine levels were increased by both agents with a delay of approximately 6 h after dosing before the peak effect was achieved. Our data and methods may be useful in understanding the effects of sodium benzoate that have been seen in clinical trials of schizophrenia and Alzheimer's disease and to support the potential clinical assessment of other DAO inhibitors, such as PGM030756, which demonstrate good enzyme occupancy and D-serine increases following administration of low oral doses.

Characterization of Ocular Iontophoretic Drug Transport of Ionic and Non-ionic Compounds in Isolated Rabbit Cornea and Conjunctiva.

Ocular iontophoresis (IP) in isolated rabbit cornea and conjunctiva was examined in terms of transport enhancement, tissue viability and integrity using electrophysiological parameters by the Ussing-type chamber technique. Lidocaine hydrochloride (LC, a cationic compound), sodium benzoate (BA, anionic compound), and fluorescein isothiocyanate labeled dextran (molecular weight 4400 Da, FD-4, hydrophilic large compound) were used as model permeants. Direct electric current was applied at 0.5-5.0 mA/cm(2) for the cornea and 0.5-20 mA/cm(2) for the conjunctiva for 30 min. LC and BA fluxes across the cornea and conjunctiva were significantly increased by the application of electric current up to 2.3- and 2.5-fold and 4.0- and 3.4-fold, respectively, and returned to their baseline level on stopping the current. Furthermore, a much higher increase by IP application was obtained for the FD-4 transport. The increased FD-4 flux in the conjunctiva returned to baseline on stopping the current, whereas the flux in the cornea was sustained at a higher level after stopping the current. The transepithelial electric resistance of the cornea and conjunctiva was lowered by electric current application but fully recovered after stopping the current up to 2.0 mA/cm(2) for the cornea and 10 mA/cm(2) for the conjunctiva, suggesting that the corneal and conjunctival viability and integrity are maintained even after application of these current densities. These results indicate that ocular IP may be a useful non-invasive technique to achieve drug delivery of hydrophilic large molecules into the eyes.

Effects of sodium benzoate, a widely used food preservative, on glucose homeostasis and metabolic profiles in humans.

Sodium benzoate is a widely used preservative found in many foods and soft drinks. It is metabolized within mitochondria to produce hippurate, which is then cleared by the kidneys. We previously reported that ingestion of sodium benzoate at the generally regarded as safe (GRAS) dose leads to a robust excursion in the plasma hippurate level [1]. Since previous reports demonstrated adverse effects of benzoate and hippurate on glucose homeostasis in cells and in animal models, we hypothesized that benzoate might represent a widespread and underappreciated diabetogenic dietary exposure in humans. Here, we evaluated whether acute exposure to GRAS levels of sodium benzoate alters insulin and glucose homeostasis through a randomized, controlled, cross-over study of 14 overweight subjects. Serial blood samples were collected following an oral glucose challenge, in the presence or absence of sodium benzoate. Outcome measurements included glucose, insulin, glucagon, as well as temporal mass spectrometry-based metabolic profiles. We did not find a statistically significant effect of an acute oral exposure to sodium benzoate on glucose homeostasis. Of the 146 metabolites targeted, four changed significantly in response to benzoate, including the expected rise in benzoate and hippurate. In addition, anthranilic acid, a tryptophan metabolite, exhibited a robust rise, while acetylglycine dropped. Although our study shows that GRAS doses of benzoate do not have an acute, adverse effect on glucose homeostasis, future studies will be necessary to explore the metabolic impact of chronic benzoate exposure.

Use of parenteral caffeinum natrio-benzoicum: an underestimated risk factor for HCV transmission in China.

BACKGROUND: Fuyu city in China has a high prevalence of hepatitis C virus (HCV) infection resulting in a high morbidity and mortality from chronic liver disease and hepatocellular carcinoma. This study was conducted to identify the risk factors for HCV infection in Fuyu city. METHODS: Recruitment of study subjects involved a cross-sectional survey using non-random, convenience sampling. Information on demographic variables, risk factors for HCV infection, clinical manifestations, behavioral practices and family history was collected by administering a questionnaire. Anti-HCV antibody was detected using Abbott ARCHITECT i2000SR. HCV infection was confirmed by HCV-RNA testing by the Roche Taqman HCV test. Univariate and multivariate analyses were performed to identify the factors associated with HCV infection. RESULTS: Out of 3,228 persons that participated in the survey, 3,219 were enrolled in the study. The prevalence of HCV infection was 42.1 % (1355/3219). Among 734 patients with chronic HCV infection whose HCV-RNA genotyping was performed, genotype 1b was the most common (58.0 %), followed by genotype 2a (40.2 %), while co-infection with genotypes 1b and 2a was detected in 1.8 % of the subjects. On univariate analysis, male gender, older age, parenteral caffeinum natrio-benzoicum and share syringes (PCNBSS), and nine other factors were significantly associated with HCV infection. After adjusting for potential confounders, male gender, old age, cigarette smoking, lower education level, history of blood transfusion, blood donation, prior dental surgery, and PCNBSS were found to be independently associated with HCV infection. CONCLUSIONS: The prevalence of HCV infection is likely to be high among residents in Fuyu and we observed that genotypes 1b and 2a dominated in the city. Our findings support the hypothesis that PCNBSS which became endemic in Fuyu city during 1970s-1980s is strongly associated with HCV positivity.

Short communication: Use of a mixture of sodium nitrite, sodium benzoate, and potassium sorbate in aerobically challenged silages.

Aerobic instability is still a common problem with many types of silages, particularly well-fermented silages. This study evaluated the effect of adding an additive mixture based on sodium nitrite, sodium benzoate, and potassium sorbate to a variety of crop materials on fermentation quality and aerobic stability of silages. Ensiling conditions were challenged by using a low packing density (104±4.3kg of dry matter/m(3)) of forage and allowing air ingression into silos (at 14 and 7 d before the end of the storage, for 8 h per event). Additive-treated silages were found to have significantly lower pH and reduced formation of ammonia-N, 2.3-butanediol, and ethanol compared with untreated control silages. Yeast growth was significantly reduced by additive treatment in comparison with untreated control silage. Consequently, additive-treated silages were considerably more aerobically stable (6.7 d) than untreated control silages (0.5 d). Overall, adding 5mL/kg of fresh crop of the additive based on sodium nitrite, sodium benzoate, and potassium sorbate reduced undesirable microorganisms in silages and thereby provided suitable ensiling conditions and prolonged aerobic stability, even under air-challenged laboratory ensiling conditions.

Comparison of film-coated retarded release pellets manufactured by layering technique or by bed rotor pelletization.

In order to investigate the influence of coatings for controlled active pharmaceutical ingredient (API) release, two types of pellets were used. Microcrystalline pellets were coated with a model API using the Wurster fluidized bed technique in laboratory scale (layered Cellets). Another type of pellets consisting of microcrystalline cellulose and model API was manufactured by fluidized bed rotor pelletization (matrix pellets (MP)). Both kinds of pellets were coated in a Wurster fluidized bed process with a polymer mixture of ethylcellulose to achieve retarded API release. With layered Cellets and an increased thickness of the ethylcellulose layer, the lag-time was increased and the release rate was decreased. In the case of MP, retardation was less pronounced probable due to inhomogeneous polymer film formation as a result of the porous particle surface. To reduce the surface roughness, the MP were coated with polyvinylpyrrolidone (PVP) as an intermediate smoothing layer, in a first trial step by step. In a second trial, pelletization and the coating steps were performed in an uninterrupted process. Intermediate PVP coating improved the ethylcellulose film formation and led to a more pronounced retardation of API release. The uninterrupted process of matrix pellet manufacturing and coating results in a product with only low retarded release.

Effect of Sodium Benzoate on Cognitive Function Among Patients With Behavioral and Psychological Symptoms of Dementia: Secondary Analysis of a Randomized Clinical Trial.

Importance: Female gender is a major risk factor for dementia; however, gender has not yet been adequately addressed by clinical trials. A recent study demonstrated that sodium benzoate, a D-amino acid oxidase inhibitor, improved cognitive function in early-phase Alzheimer disease. Objective: To examine the potential gender difference in the effects of benzoate treatment on the behavioral and psychological symptoms of dementia (BPSD). Design, Setting, and Participants: This post hoc secondary analysis used data from a randomized, double-masked, placebo-controlled trial conducted in 3 major medical centers in Taiwan and enrolled 97 patients with BPSD. Data were analyzed between February 2014 and November 2017. Interventions: Six weeks of treatment of 250 to 1500 mg/d of sodium benzoate or placebo. Main Outcomes and Measures: The primary outcome measures were Alzheimer disease assessment scale-cognitive subscale (ADAS-cog) and Behavioral Pathology in Alzheimer Disease Rating Scale (BEHAVE-AD) scores. Results: Among 97 total participants (62 [64%] women; mean [SD] age, 75.4 [7.7] years), 49 patients (30 women and 19 men) were randomized to sodium benzoate, and 48 (32 women and 16 men) were randomized to placebo. Among 62 women, 6-week benzoate treatment significantly surpassed placebo in the effects on ADAS-cog performance (mean [SD] difference in score between baseline and end point, -3.1 [6.4] points vs 0 [4.5] points; Cohen d = 0.56; P = .04) but not BEHAVE-AD performance. In contrast, among 35 men, the 2 treatment groups did not differ significantly in both ADAS-cog and BEHAVE-AD scores. Compared with placebo, benzoate treatment also increased estradiol to follicle-stimulating hormone ratios among women (mean [SD] difference between baseline and end point, 0 [0.2] vs -0.1 [0.3]; P = .03). Conclusions and Relevance: These findings suggest that benzoate treatment may improve cognitive function in women with later-phase dementia. In the future, longer dose-finding trials are warranted to further clarify the efficacy of benzoate for later-phase dementia and investigate the role of sex hormones and other factors in the pathogenesis of dementia. Trial Registration: ClinicalTrials.gov Identifier: NCT02103673.

Spinal D-amino acid oxidase contributes to neuropathic pain in rats.

D-amino acid oxidase (DAO) is an enzyme catalyzing oxidative deamination of neutral and polar d-amino acids and is expressed in the kidneys, liver, and central nervous system (CNS) including the spinal cord. We have previously demonstrated that DAO gene deletion/mutation by using mutant ddY/DAO(-/-) mice and systemic administration of the DAO inhibitor sodium benzoate blocked formalin-induced hyperalgesia in mice. In this study, we further investigated the potential role of DAO in neuropathic pain in a rat model of tight L(5)/L(6) spinal nerve ligation. After L(5)/L(6) spinal nerve ligation, the mRNA expression (measured by real-time quantitative polymerase chain reaction) and enzyme activity (measured by a colorimetric method) of DAO in the lumbar spinal cord were markedly increased, in agreement with the development of neuropathic pain (mechanical allodynia). Intraperitoneal injection of sodium benzoate (400 mg/kg) specifically blocked mechanical allodynia in neuropathic rats and formalin-induced hyperalgesia but did not suppress acute pain responses in the tail-flick test or formalin test. Systemic injection of sodium benzoate also inhibited DAO activity in the lumbar spinal cord of rats. Furthermore, direct intrathecal (spinal cord) injection of benzoate (30 mug/rat) specifically blocked spinal nerve ligation-induced mechanical allodynia in neuropathic rats and formalin-induced hyperalgesia (but not acute pain) in the formalin test. Based on the above results, we conclude that spinal DAO plays a pronociceptive (rather than an antinociceptive) role and might be a target molecule for the treatment of chronic pain of neuropathic origin.

Metabolic investigations prevent liver transplantation in two young children with citrullinemia type I.

Acute liver failure may be caused by a variety of disorders including inborn errors of metabolism. In those cases, rapid metabolic investigations and adequate treatment may avoid the need for liver transplantation. We report two patients who presented with acute liver failure and were referred to our center for liver transplantation work-up. Urgent metabolic investigations revealed citrullinemia type I. Treatment for citrullinemia type I avoided the need for liver transplantation. Acute liver failure as a presentation of citrullinemia type I has not previously been reported in young children. Although acute liver failure has occasionally been described in other urea cycle disorders, these disorders may be underestimated as a cause. Timely diagnosis and treatment of these disorders may avoid liver transplantation and improve clinical outcome. Therefore, urea cycle disorders should be included in the differential diagnosis in young children presenting with acute liver failure.

Differences in gut microbial metabolism are responsible for reduced hippurate synthesis in Crohn's disease.

BACKGROUND: Certain urinary metabolites are the product of gut microbial or mammalian metabolism; others, such as hippurate, are mammalian-microbial 'co-metabolites'. It has previously been observed that Crohn's disease (CD) patients excrete significantly less hippurate than controls. There are two stages in the biosynthesis of this metabolite: 1) gut microbial metabolism of dietary aromatic compounds to benzoate, and 2) subsequent hepatorenal conjugation of benzoate with glycine, forming hippurate. Differences in such urinary co-metabolites may therefore reflect systemic consequences of altered gut microbial metabolism, though altered host metabolic pathways may also be involved. METHODS: It was hypothesised that reduced hippurate excretion in CD patients was due to alterations in the gut microbiota, and not differences in dietary benzoate, nor defective host enzymatic conjugation of benzoate. 5 mg/kg sodium benzoate were administered orally to 16 CD patients and 16 healthy controls on a low-benzoate diet. Baseline and peak urinary hippurate excretion were measured. RESULTS: Baseline hippurate levels were significantly lower in the CD patients (p = 0.0009). After benzoate ingestion, peak urinary levels of hippurate did not differ significantly between the cohorts. Consequently the relative increase in excretion was significantly greater in CD (p = 0.0007). CONCLUSIONS: Lower urinary hippurate levels in CD are not due to differences in dietary benzoate. A defect in the enzymatic conjugation of benzoate in CD has been excluded, strongly implicating altered gut microbial metabolism as the cause of decreased hippurate levels in CD.

Peripheral venous route for administration of ammonul infusion for treatment of acute hyperammonemia. An experience from a tertiary center in Saudi Arabia.

OBJECTIVES: To determine the local effects of peripheral Ammonul infusion on the skin and the subcutaneous tissues.  Methods: This retrospective study was conducted at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. All children less than 16 years of age admitted between December 2015 and October 2018 with hyperammonemia and received Ammonul infusion for treatment were recruited. Results: Twenty-one patients received the Ammonul infusion. They were admitted 58 times with acute hyperammonemia during the study period, with an average of 2.8 admissions per patient. The mean age of the included patients was 49.5 months. The most frequent underlying diagnoses were propionic acidemia (n=9), urea cycle disorders (n=5), and intrinsic liver disease (n=3). All participants received Ammonul through peripheral lines except 3 who received it through central lines. No extravasation, burns, or other local side effects were observed in this cohort. CONCLUSION: This data indicate that the use of Ammonul through a peripheral venous route appears to be safe and not associated with infusion-related local adverse effects.

Effect of Sodium Benzoate vs Placebo Among Individuals With Early Psychosis: A Randomized Clinical Trial.

Importance: There is evidence that sodium benzoate (BZ) may be an effective adjunctive treatment for schizophrenia. The clinical efficacy of BZ has been investigated in chronic schizophrenia; however, the efficacy of this agent has not been studied in individuals with early psychosis. Objective: To examine the clinical efficacy of the adjunctive use of BZ for symptoms in people with early psychosis. Design, Setting, and Participants: Using a placebo-controlled double-masked parallel-group design, this randomized clinical trial was conducted from August 2015 to July 2018. Participants aged between 15 and 45 years experiencing early psychosis were enrolled from 5 major clinical sites in Queensland, Australia. Data analysis was conducted from October 2018 to February 2020. Interventions: Participants were randomized 1:1 (50 participants in each group) to receive 500 mg of sodium benzoate twice daily or placebo for 12 weeks. Main Outcomes and Measures: The primary efficacy outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 12 weeks. The key secondary efficacy measures were (1) the Clinical Global Impression score, (2) the Hamilton Depression Rating Scale for depression, (3) functioning as assessed by the clinician-rated Global Assessment of Function, and (4) the Assessment of Quality of Life Scale. The PANSS subscale scores and impact on selected amino acid concentrations were also assessed. Results: The study comprised 100 participants with a mean (SD) age of 21.4 (4.1) years, of whom 73 (73%) were male individuals. The mean (SD) baseline PANSS score was 75.3 (15.4). We found no improvement in total PANSS score in the BZ group compared with the placebo group. The end result of least-squares mean difference (SE) for total PANSS was -1.2 (2.4) (P = .63). There were no differences in any subscales of the PANSS, any secondary measures, nor any amino acid concentrations. The dose of BZ was well tolerated without any clinically significant treatment-emergent adverse event differences between BZ and placebo groups. Conclusions and Relevance: In this randomized clinical trial, there was no evidence that adjunctive use of 500 mg of BZ twice daily is an effective treatment for individuals with early psychosis. Trial Registration: anzctr.org.au Identifier: ACTRN12615000187549.