Safety and efficacy of glycerol phenylbutyrate for management of urea cycle disorders in patients aged 2months to 2years.

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.

The safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of RO5068760, an MEK inhibitor, in healthy volunteers: assessment of target suppression.

RO5068760, a substituted hydantoin, represents a new class of potent, highly selective, non-adenosine triphosphate (ATP)-competitive MEK1/2 inhibitors. The study aimed to determine the safety/tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of RO5068760 in human healthy volunteers. All participants received a single dose followed by 48 hours of pharmacokinetics, pharmacodynamics, and safety/tolerability assessments. The pharmacodynamics were measured by changes in ERK phosphorylation (pERK) in peripheral blood mononuclear cells, ex vivo stimulated by phorbol 12-myristate 13-acetate (PMA). Forty-eight participants received 6 doses (50, 100, 200, 400, 600, 800 mg). RO5068760 was well tolerated up to 800 mg. There were no clinically significant safety findings, including laboratory, electrocardiogram, ophthalmological assessment, and fecal occult blood tests. Of the total 13 adverse events (n = 12), 11 were mild, 2 were moderate, and none were severe, and only 5 were considered by the investigator as possibly related to treatment. RO5068760 was absorbed with a t(max), of 2 hours. Disposition appeared to be biphasic with a terminal elimination t(1/2) of 5 to 9 hours. The variability was moderate to high, ranging from 38% to 62% for C(max) and 41% to 69% AUC. Within the dose range tested, pERK inhibition was relatively modest with a mean maximal pERK suppression of 55%.

A study of the relative hepatotoxicity in vitro of the non-steroidal anti-inflammatory drugs ibuprofen, flurbiprofen and butibufen.

1. The cytotoxic and metabolic effects of ibuprofen, flurbiprofen and butibufen have been studied in primary cultured hepatocytes. Toxic effects were observed for all three drugs at 10 times the therapeutic plasma concentration. 2. None of the drugs affected cell survival after 48 h of continuous exposure at their therapeutic plasma concentration, although significant increases of LDH leakage were detected. 3. Ibuprofen and butibufen were the most active in impairing gluconeogenesis from lactate (88% and 76% inhibition respectively) after 6 h exposure at therapeutic plasma concentrations. 4. At 5 times therapeutic plasma concentrations, albumin synthesis was inhibited 40% (ibuprofen), 35% (flurbiprofen) and 100% (butibufen) after 6 h exposure and significant effects were also observed after 24 h exposure. 5. Urea synthesis was inhibited 11% by butibufen at its therapeutic plasma concentration but only at higher concentrations by the other drugs. 6. Butibufen was potentially the most hepatotoxic drug as it has the highest therapeutic plasma concentration and had the lowest margin between therapeutic and toxic concentrations.

Some aspects of the pharmacology of butibufen, a non-steroidal anti-inflammatory agent.

The anti-inflammatory, analgesic and antipyretic properties of butibufen, a non-steroidal compound, were assessed by a battery of standard tests. It activity as an anti-inflammatory agent was equivalent to ibuprofen and phenylbutazone. Butibufen was within the potency range of ibuprofen as an antipyretic and analgesic agent and greater than that of acetylsalicylic acid. The compound possesses the advantage of a low order to toxicity. Its ulcerogenicity was much lower than that of phenylbutazone. Therefore, butibufen appears to offer potential safety and efficacy in the treatment of rheumatic diseases.