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The Cochrane Database of Systematic... Aug 2018Cystic fibrosis (CF) is a common life-shortening condition caused by mutation in the gene that codes for that codes for the cystic fibrosis transmembrane conductance... (Review)
Review
BACKGROUND
Cystic fibrosis (CF) is a common life-shortening condition caused by mutation in the gene that codes for that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions as a salt transporter. F508del, the most common CFTR mutation that causes CF, is found in up to 80% to 90% of people with CF. In people with this mutation, a full length of protein is transcribed, but recognised as misfolded by the cell and degraded before reaching the cell membrane, where it needs to be positioned to effect transepithelial salt transport. This severe mutation is associated with no meaningful CFTR function. A corrective therapy for this mutation could positively impact on an important proportion of the CF population.
OBJECTIVES
To evaluate the effects of CFTR correctors on clinically important outcomes, both benefits and harms, in children and adults with CF and class II CFTR mutations (most commonly F508del).
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register. We also searched reference lists of relevant articles and online trials registries. Most recent search: 24 February 2018.
SELECTION CRITERIA
Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to placebo in people with CF with class II mutations. We also included RCTs comparing CFTR correctors combined with CFTR potentiators to placebo.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data, assessed risk of bias and quality of the evidence using the GRADE criteria. Study authors were contacted for additional data.
MAIN RESULTS
We included 13 RCTs (2215 participants), lasting between 1 day and 24 weeks. Additional safety data from an extension study of two lumacaftor-ivacaftor studies were available at 96 weeks (1029 participants). We assessed monotherapy in seven RCTs (317 participants) (4PBA (also known as Buphenyl), CPX, lumacaftor or cavosonstat) and combination therapy in six RCTs (1898 participants) (lumacaftor-ivacaftor or tezacaftor-ivacaftor) compared to placebo. Twelve RCTs recruited individuals homozygous for F508del, one RCT recruited participants with one F508del mutation and a second mutation with residual function.Risk of bias varied in its impact on the confidence we have in our results across different comparisons. Some findings were based on single RCTs that were too small to show important effects. For five RCTs, results may not be applicable to all individuals with CF due to age limits of recruited populations (i.e. adults only, children only) or non-standard design of converting from monotherapy to combination therapy.Monotherapy versus placeboNo deaths were reported and there were no clinically relevant improvements in quality of life in any RCT. There was insufficient evidence available from individual studies to determine the effect of any of the correctors examined on lung function outcomes.No placebo-controlled study of monotherapy demonstrated a difference in mild, moderate or severe adverse effects; however, it is difficult to assess the clinical relevance of these events with the variety of events and the small number of participants.Combination therapy versus placeboNo deaths were reported during any RCT (moderate- to high-quality evidence). The quality of life scores (respiratory domain) favoured combination therapy (both lumacaftor-ivacaftor and tezacaftor-ivacaftor) compared to placebo at all time points. At six months lumacaftor (600 mg once daily or 400 mg once daily) plus ivacaftor improved Cystic Fibrosis Questionnaire (CFQ) scores by a small amount compared with placebo (mean difference (MD) 2.62 points (95% confidence interval (CI) 0.64 to 4.59); 1061 participants; high-quality evidence). A similar effect size was observed for twice-daily lumacaftor (200 mg) plus ivacaftor (250 mg) although the quality of evidence was low (MD 2.50 points (95% CI 0.10 to 5.10)). The mean increase in CFQ scores with twice-daily tezacaftor (100 mg) and ivacaftor (150 mg) was approximately five points (95% CI 3.20 to 7.00; 504 participants; moderate-quality evidence). Lung function measured by relative change in forced expiratory volume in one second (FEV) % predicted improved with both combination therapies compared to placebo at six months, by 5.21% with once daily lumacaftor-ivacaftor (95% CI 3.61% to 6.80%; 504 participants; high-quality evidence) and by 2.40% with twice-daily lumacaftor-ivacaftor (95% CI 0.40% to 4.40%; 204 participants; low-quality evidence). One study reported an increase in FEV with tezacaftor-ivacaftor of 6.80% (95% CI 5.30 to 8.30%; 520 participants; moderate-quality evidence).More participants receiving the lumacaftor-ivacaftor combination reported early transient breathlessness, odds ratio 2.05 (99% CI 1.10 to 3.83; 739 participants; high-quality evidence). In addition, participants allocated to the 400 mg twice-daily dose of lumacaftor-ivacaftor experienced a rise in blood pressure over the 120-week period of the initial studies and the follow-up study of 5.1 mmHg (systolic blood pressure) and 4.1 mmHg (diastolic blood pressure) (80 participants; high-quality evidence). These adverse effects were not reported in the tezacaftor-ivacaftor studies.The rate of pulmonary exacerbations decreased for participants receiving and additional therapies to ivacaftor compared to placebo: lumacaftor 600 mg hazard ratio (HR) 0.70 (95% CI 0.57 to 0.87; 739 participants); lumacaftor 400 mg, HR 0.61 (95% CI 0.49 to 0.76; 740 participants); and tezacaftor, HR 0.64 (95% CI, 0.46 to 0.89; 506 participants) (moderate-quality evidence).
AUTHORS' CONCLUSIONS
There is insufficient evidence that monotherapy with correctors has clinically important effects in people with CF who have two copies of the F508del mutation.Combination therapies (lumacaftor-ivacaftor and tezacaftor-ivacaftor) each result in similarly small improvements in clinical outcomes in people with CF; specifically improvements quality of life (moderate-quality evidence), in respiratory function (high-quality evidence) and lower pulmonary exacerbation rates (moderate-quality evidence). Lumacaftor-ivacaftor is associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (high-quality evidence). These adverse effects were not observed for tezacaftor-ivacaftor. Tezacaftor-ivacaftor has a better safety profile, although data are not available for children younger than 12 years. In this age group, lumacaftor-ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns, but this should be balanced against the increase in blood pressure and shortness of breath seen in longer-term data in adults when considering this combination for use in young people with CF.
Topics: Adult; Aminophenols; Aminopyridines; Benzodioxoles; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Genetic Therapy; Humans; Indoles; Mutation; Phenylbutyrates; Quinolones; Randomized Controlled Trials as Topic
PubMed: 30070364
DOI: 10.1002/14651858.CD010966.pub2 -
The American Journal of Clinical... Jun 2011Phenylbutyrate is a drug used in patients with urea cycle disorder to elicit alternative pathways for nitrogen disposal. However, phenylbutyrate administration decreases...
Phenylbutyrate improves nitrogen disposal via an alternative pathway without eliciting an increase in protein breakdown and catabolism in control and ornithine transcarbamylase-deficient patients.
BACKGROUND
Phenylbutyrate is a drug used in patients with urea cycle disorder to elicit alternative pathways for nitrogen disposal. However, phenylbutyrate administration decreases plasma branched-chain amino acid (BCAA) concentrations, and previous research suggests that phenylbutyrate administration may increase leucine oxidation, which would indicate increased protein degradation and net protein loss.
OBJECTIVE
We investigated the effects of phenylbutyrate administration on whole-body protein metabolism, glutamine, leucine, and urea kinetics in healthy and ornithine transcarbamylase-deficient (OTCD) subjects and the possible benefits of BCAA supplementation during phenylbutyrate therapy.
DESIGN
Seven healthy control and 7 partial-OTCD subjects received either phenylbutyrate or no treatment in a crossover design. In addition, the partial-OTCD and 3 null-OTCD subjects received phenylbutyrate and phenylbutyrate plus BCAA supplementation. A multitracer protocol was used to determine the whole-body fluxes of urea and amino acids of interest.
RESULTS
Phenylbutyrate administration reduced ureagenesis by ≈15% without affecting the fluxes of leucine, tyrosine, phenylalanine, or glutamine and the oxidation of leucine or phenylalanine. The transfer of (15)N from glutamine to urea was reduced by 35%. However, a reduction in plasma concentrations of BCAAs due to phenylbutyrate treatment was observed. BCAA supplementation did not alter the respective baseline fluxes.
CONCLUSIONS
Prolonged phenylbutyrate administration reduced ureagenesis and the transfer of (15)N from glutamine to urea without parallel reductions in glutamine flux and concentration. There were no changes in total-body protein breakdown and amino acid catabolism, which suggests that phenylbutyrate can be used to dispose of nitrogen effectively without adverse effects on body protein economy.
Topics: Adolescent; Adult; Aged; Amino Acids; Amino Acids, Branched-Chain; Child; Female; Glutamine; Humans; Male; Metabolic Networks and Pathways; Middle Aged; Nitrogen; Ornithine Carbamoyltransferase Deficiency Disease; Phenylbutyrates; Proteins; Urea; Young Adult
PubMed: 21490144
DOI: 10.3945/ajcn.110.009043 -
International Journal of Experimental... Jun 2017Phenylbutyrate (PB) acts as chemical chaperone and histone deacetylase inhibitor, which is used to decrease ammonia in urea cycle disorders and has been investigated for...
Phenylbutyrate (PB) acts as chemical chaperone and histone deacetylase inhibitor, which is used to decrease ammonia in urea cycle disorders and has been investigated for use in the treatment of a number of lethal illnesses. We performed in vivo and in vitro experiments to examine the effects of PB on glutamine (GLN), branched-chain amino acid (BCAA; valine, leucine and isoleucine) and protein metabolism in rats. In the first study, animals were sacrificed one hour after three injections of PB (300mg/kg b.w.) or saline. In the second study, soleus (SOL, slow twitch) and extensor digitorum longus (EDL, fast twitch) muscles were incubated in a medium with or without PB (5 mM). L-[1- C] leucine was used to estimate protein synthesis and leucine oxidation, and 3-methylhistidine release was used to evaluate myofibrillar protein breakdown. PB treatment decreased GLN, BCAA and branched-chain keto acids (BCKAs) in blood plasma, decreased BCAA and increased GLN concentrations in muscles, and increased GLN synthetase activities in muscles. Addition of PB to incubation medium increased leucine oxidation (55% in EDL, 29% in SOL), decreased BCKA and increased GLN in medium of both muscles, increased GLN in muscles, decreased protein synthesis in SOL and increased proteolysis in EDL. It is concluded that PB decreases BCAA, BCKA and GLN in blood plasma, activates BCAA catabolism and GLN synthesis in muscle and exerts adverse effects on protein metabolism. The results indicate that BCAA and GLN supplementation is needed when PB is used therapeutically and that PB may be a useful prospective agent which could be effective in management of maple syrup urine disease.
Topics: Amino Acids, Branched-Chain; Animals; Glutamine; Leucine; Male; Muscle Proteins; Muscle, Skeletal; Oxidation-Reduction; Phenylbutyrates; Protein Biosynthesis; Rats, Wistar; Tissue Culture Techniques
PubMed: 28621016
DOI: 10.1111/iep.12231 -
Molecular Genetics and Metabolism Nov 2012We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
UNLABELLED
We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD).
STUDY DESIGN
These analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6-17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine.
RESULTS
Patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5 to 31.8 g/day and of sodium phenylbutyrate ranging from 1.3 to 31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979% to 5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881% to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r = 0.730, p < 0.001) or as total 24-hour excretion (r = 0.791 p<0.001), followed by plasma phenylacetylglutamine AUC(24-hour), plasma phenylacetic acid AUC(24-hour) and phenylbutyric acid AUC(24-hour). Plasma phenylacetic acid levels in adult and pediatric patients did not show a consistent relationship with either urinary phenylacetylglutamine or ammonia control.
CONCLUSION
The findings are collectively consistent with substantial yet variable pre-systemic (1st pass) conversion of phenylbutyric acid to phenylacetic acid and/or phenylacetylglutamine. The variability of blood metabolite levels during the day, their weaker correlation with dose, the need for multiple blood samples to capture trough and peak, and the inconsistency between phenylacetic acid and urinary phenylacetylglutamine as a marker of waste nitrogen scavenging limit the utility of plasma levels for therapeutic monitoring. By contrast, 24-hour urinary phenylacetylglutamine and morning spot urine phenylacetylglutamine correlate strongly with dose and appear to be clinically useful non-invasive biomarkers for compliance and therapeutic monitoring.
Topics: Adolescent; Adult; Ammonia; Biomarkers, Pharmacological; Child; Cross-Over Studies; Drug Administration Schedule; Female; Glutamine; Glycerol; Humans; Male; Phenylacetates; Phenylbutyrates; Urea Cycle Disorders, Inborn
PubMed: 22958974
DOI: 10.1016/j.ymgme.2012.08.006 -
Journal of Cellular and Molecular... Jan 2021Dent disease type 1 is caused by mutations in the CLCN5 gene that encodes CLC5, a 2Cl /H exchanger. The CLC5 mutants that have been functionally analysed constitute...
Dent disease type 1 is caused by mutations in the CLCN5 gene that encodes CLC5, a 2Cl /H exchanger. The CLC5 mutants that have been functionally analysed constitute three major classes based on protein expression, cellular localization and channel function. We tested two small molecules, 4-phenylbutyrate (4PBA) and its analogue 2-naphthoxyacetic acid (2-NOAA), for their effect on mutant CLC5 function and expression by whole-cell patch-clamp and Western blot, respectively. The expression and function of non-Class I CLC5 mutants that have reduced function could be restored by either treatment. Cell viability was reduced in cells treated with 2-NOAA. 4PBA is a FDA-approved drug for the treatment of urea cycle disorders and offers a potential therapy for Dent disease.
Topics: Cell Survival; Chemokine CCL5; Dent Disease; Glycolates; HEK293 Cells; Humans; Mutation; Phenylbutyrates; Small Molecule Libraries
PubMed: 33200471
DOI: 10.1111/jcmm.16091 -
International Journal of Molecular... Oct 2020Opioids are potent analgesics widely used to control acute and chronic pain, but long-term use induces tolerance that reduces their effectiveness. Opioids such as...
Opioids are potent analgesics widely used to control acute and chronic pain, but long-term use induces tolerance that reduces their effectiveness. Opioids such as morphine bind to mu opioid receptors (MORs), and several downstream signaling pathways are capable of inducing tolerance. We previously reported that signaling from the endoplasmic reticulum (ER) contributed to the development of morphine tolerance. Accumulation of misfolded proteins in the ER induced the unfolded protein response (UPR) that causes diverse pathological conditions. We examined the effects of pharmacological chaperones that alleviate ER stress on opioid tolerance development by assessing thermal nociception in mice. Pharmacological chaperones such as tauroursodeoxycholic acid and 4-phenylbutyrate suppressed the development of morphine tolerance and restored analgesia. Chaperones alone did not cause analgesia. Although morphine administration induced analgesia when glycogen synthase kinase 3β (GSK3β) was in an inactive state due to serine 9 phosphorylation, repeated morphine administration suppressed this phosphorylation event. Co-administration of chaperones maintained the inactive state of GSK3β. These results suggest that ER stress may facilitate morphine tolerance due to intracellular crosstalk between the UPR and MOR signaling. Pharmacological chaperones may be useful in the management of opioid misuse.
Topics: Analgesics, Opioid; Animals; Drug Tolerance; Endoplasmic Reticulum Stress; Glycogen Synthase Kinase 3 beta; Male; Mice; Mice, Inbred C57BL; Morphine; Nociception; Phenylbutyrates; Taurochenodeoxycholic Acid
PubMed: 33066035
DOI: 10.3390/ijms21207536 -
Human Molecular Genetics Feb 2011Therapy with sodium phenylacetate/benzoate or sodium phenylbutyrate in urea cycle disorder patients has been associated with a selective reduction in branched-chain... (Clinical Trial)
Clinical Trial
Therapy with sodium phenylacetate/benzoate or sodium phenylbutyrate in urea cycle disorder patients has been associated with a selective reduction in branched-chain amino acids (BCAA) in spite of adequate dietary protein intake. Based on this clinical observation, we investigated the potential of phenylbutyrate treatment to lower BCAA and their corresponding α-keto acids (BCKA) in patients with classic and variant late-onset forms of maple syrup urine disease (MSUD). We also performed in vitro and in vivo experiments to elucidate the mechanism for this effect. We found that BCAA and BCKA are both significantly reduced following phenylbutyrate therapy in control subjects and in patients with late-onset, intermediate MSUD. In vitro treatment with phenylbutyrate of control fibroblasts and lymphoblasts resulted in an increase in the residual enzyme activity, while treatment of MSUD cells resulted in the variable response which did not simply predict the biochemical response in the patients. In vivo phenylbutyrate increases the proportion of active hepatic enzyme and unphosphorylated form over the inactive phosphorylated form of the E1α subunit of the branched-chain α-keto acid dehydrogenase complex (BCKDC). Using recombinant enzymes, we show that phenylbutyrate prevents phosphorylation of E1α by inhibition of the BCKDC kinase to activate BCKDC overall activity, providing a molecular explanation for the effect of phenylbutyrate in a subset of MSUD patients. Phenylbutyrate treatment may be a valuable treatment for reducing the plasma levels of neurotoxic BCAA and their corresponding BCKA in a subset of MSUD patients and studies of its long-term efficacy are indicated.
Topics: 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); Adolescent; Adult; Amino Acids, Branched-Chain; Animals; Cells, Cultured; Child; Child, Preschool; Female; Fibroblasts; Humans; Inhibitory Concentration 50; Keto Acids; Male; Maple Syrup Urine Disease; Mice; Mice, Inbred C57BL; Phenylbutyrates; Phosphorylation; Young Adult
PubMed: 21098507
DOI: 10.1093/hmg/ddq507 -
PloS One 20214-phenylbutyrate (4-PBA), a terminal aromatic substituted fatty acid, is used widely to specifically attenuate endoplasmic reticulum (ER) stress and inhibit histone...
4-phenylbutyrate (4-PBA), a terminal aromatic substituted fatty acid, is used widely to specifically attenuate endoplasmic reticulum (ER) stress and inhibit histone deacetylases (HDACs). In this study, we investigated the effect of 4-PBA on cardiac differentiation of mouse embryonic stem (ES) cells. Herein, we found that 4-PBA regulated cardiac differentiation in a stage-specific manner just like trichostatin A (TSA), a well-known HDAC inhibitor. 4-PBA and TSA favored the early-stage differentiation, but inhibited the late-stage cardiac differentiation via acetylation. Mechanistic studies suggested that HDACs exhibited a temporal expression profiling during cardiomyogenesis. Hdac1 expression underwent a decrease at the early stage, while was upregulated at the late stage of cardiac induction. During the early stage of cardiac differentiation, acetylation favored the induction of Isl1 and Nkx2.5, two transcription factors of cardiac progenitors. During the late stage, histone acetylation induced by 4-PBA or TSA interrupted the gene silence of Oct4, a key determinant of self-renewal and pluripotency. Thereby, 4-PBA and TSA at the late stage hindered the exit from pluripotency, and attenuated the expression of cardiac-specific contractile proteins. Overexpression of HDAC1 and p300 exerted different effects at the distinct stages of cardiac induction. Collectively, our study shows that timely manipulation of HDACs exhibits distinct effects on cardiac differentiation. And the context-dependent effects of HDAC inhibitors depend on cell differentiation states marked by the temporal expression of pluripotency-associated genes.
Topics: Animals; Cell Differentiation; Gene Expression; Histone Deacetylase Inhibitors; Hydroxamic Acids; Mice; Mouse Embryonic Stem Cells; Phenylbutyrates
PubMed: 33882103
DOI: 10.1371/journal.pone.0250267 -
Scientific Reports May 2021Glioblastoma (GBM) is an aggressive brain tumor with a strong tendency of relapse and resistance to chemotherapy, but we currently lack non-toxic agents that effectively...
Glioblastoma (GBM) is an aggressive brain tumor with a strong tendency of relapse and resistance to chemotherapy, but we currently lack non-toxic agents that effectively treat GBM. In this study, high-throughput screening of FDA-approved drugs was performed to identify safe and effective molecules and test their effect on GBM cell lines, LN229, U87 and T98G. Cough suppressants, oxelaidin and butamirate inhibited GBM growth. A Ras family GTPase, Ras-related associated with diabetes (RRAD), contributes to activation of STAT3, which is essential for survival and growth of many cancer types. Interestingly, oxelaidin and butamirate did not affect proliferation in RRAD negative GBM cells. Docking simulation analyses revealed selective interactions between oxelaidin and RRAD. The mechanism by which butamirate and oxelaidin inhibits GBM cell growth involves the suppression of STAT3 transcriptional activity, leading to down-regulation of cyclin D1 and survivin. In addition, components of RRAD-associated signaling cascades, including p-EGFR, p-Akt, and p-STAT3, were inhibited upon oxelaidin treatment. Intraperitoneal administration of oxelaidin or butamirate markedly suppressed tumor growth in a glioblastoma xenograft mouse model without significant adverse effects. Our collective findings indicate that oxelaidin and butamirate exert anti-tumor effects in glioblastoma, supporting its utility as a novel therapeutic candidate for glioblastoma.
Topics: Animals; Antineoplastic Agents; Antitussive Agents; Apoptosis; Binding Sites; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Repositioning; Drug Screening Assays, Antitumor; ErbB Receptors; Gene Expression Regulation, Neoplastic; Glioma; Humans; Mice; Models, Molecular; Phenylbutyrates; Protein Binding; STAT3 Transcription Factor; Signal Transduction; Structure-Activity Relationship; Xenograft Model Antitumor Assays
PubMed: 33980886
DOI: 10.1038/s41598-021-89238-9 -
Molecular Genetics and Metabolism Nov 2017Glycerol phenylbutyrate (GPB) is approved in the US for the management of patients 2months of age and older with urea cycle disorders (UCDs) that cannot be managed with...
INTRODUCTION
Glycerol phenylbutyrate (GPB) is approved in the US for the management of patients 2months of age and older with urea cycle disorders (UCDs) that cannot be managed with protein restriction and/or amino acid supplementation alone. Limited data exist on the use of nitrogen conjugation agents in very young patients.
METHODS
Seventeen patients (15 previously on other nitrogen scavengers) with all types of UCDs aged 2months to 2years were switched to, or started, GPB. Retrospective data up to 12months pre-switch and prospective data during initiation of therapy were used as baseline measures. The primary efficacy endpoint of the integrated analysis was the successful transition to GPB with controlled ammonia (<100μmol/L and no clinical symptoms). Secondary endpoints included glutamine and levels of other amino acids. Safety endpoints included adverse events, hyperammonemic crises (HACs), and growth and development.
RESULTS
82% and 53% of patients completed 3 and 6months of therapy, respectively (mean 8.85months, range 6days-18.4months). Patients transitioned to GPB maintained excellent control of ammonia and glutamine levels. There were 36 HACs in 11 patients before GPB and 11 in 7 patients while on GPB, with a reduction from 2.98 to 0.88 episodes per year. Adverse events occurring in at least 10% of patients while on GPB were neutropenia, vomiting, diarrhea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash/papule.
CONCLUSION
GPB was safe and effective in UCD patients aged 2months to 2years. GPB use was associated with good short- and long-term control of ammonia and glutamine levels, and the annualized frequency of hyperammonemic crises was lower during the study than before the study. There was no evidence for any previously unknown toxicity of GPB.
Topics: Ammonia; Child, Preschool; Cough; Disease Management; Drug-Related Side Effects and Adverse Reactions; Female; Fever; Glutamine; Glycerol; Humans; Infant; Male; Neutropenia; Phenylbutyrates; Prospective Studies; Retrospective Studies; Urea Cycle Disorders, Inborn
PubMed: 28916119
DOI: 10.1016/j.ymgme.2017.09.002