Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults. Lorazepam is likely to be a better therapy than diazepam.

CENTAUR is the first prospective study evaluating an oral agent exclusively enrolling subjects with NASH and liver fibrosis, with increased risk of developing cirrhosis. It will compare shorter versus longer CVC treatment and assess correlations between decreased inflammation and fibrosis.

N ASH affects more 80 million people worldwide and represents one of our most urgent and neglected global health crises, with broad implications on public health. 1,2 It is associated with increased risks of cirrhosis, hepatic decompensation, hepatocellular carcinoma, liver transplantation, and death. The prevalence of NASH and NASH-related end-stage liver disease are predicted to increase significantly over the next decade. 3 There are currently no approved therapies for NASH.NASH is characterized histologically by hepatocellular injury, inflammation, steatosis, and may be accompanied by fibrosis, an important predictor of disease progression and mortality. [4][5][6][7] At present, the US Food and Drug Administration and European Medicines Agency support the use of the histologic end points of fibrosis improvement and NASH resolution for accelerated or conditional approval. 8,9 The pathogenesis of NASH is incompletely understood, although several hypotheses have been proposed. 10 Developing therapeutics for NASH poses a vexing challenge for clinicians and researchers, as none of the agents tested to date has been able to demonstrate concurrent histologic improvement in both fibrosis and NASH resolution. [11][12][13][14][15][16] Aldafermin (also known as NGM282 or M70) is an engineered, non-tumorigenic analog of the human gut hormone, fibroblast growth factor 19 (FGF19). [17][18][19] FGF19 plays a central role in regulating bile acid, carbohydrate, and energy metabolism. 20,21 Physiologically, FGF19 is secreted from the ileum in response to farnesoid X receptor activation, leading to the postulation that the effect of farnesoid X receptor agonists may be largely dependent on the induction of its target gene, FGF19. Aldafermin acts on 2 receptor complexes, FGFR1c-KLB and FGFR4-KLB. Activation of the FGFR1c-KLB receptor leads to reduction in liver steatosis and improvement in insulin sensitivity in patients. 22,23 Activation of the FGFR4-KLB receptor potently suppresses the expression of CYP7A1, which encodes the first and ratelimiting enzyme in the de novo synthesis of bile acids. 17,24 Emerging evidence reveals bile acids as an important risk factor for chronic liver diseases including NASH 25 ; accumulation of bile acids induces hepatic stellate cell activation, mitochondrial dysfunction and endoplasmic reticulum stress, leading to cell death, inflammation and liver injury. 26,27 Given aldafermin's mechanism of action, reducing bile acid burden may contribute to additional antiinflammatory and anti-fibrotic benefits beyond those associated with liver fat reduction.We have previously shown that a 12-week treatment with aldafermin produced reductions in liver fat content (LFC) and liver enzymes, and in an open-label study, improvements in liver histology. 28,29 In the current study, we investigated the efficacy and safety of longer treatment with aldafermin 1 mg compared with placebo in patients with biopsy-proven NASH and stage 2 or stage 3 liver fibrosis.

Cenicriviroc, a dual CCR2/CCR5 antagonist, is being evaluated for treatment of nonalcoholic steatohepatitis and liver fibrosis (CENTAUR; NCT02217475). As it is metabolized by the liver, cenicriviroc was investigated in hepatic‐impaired participants for pharmacokinetic changes. Participants with mild‐to‐moderate hepatic impairment (HI) (Child–Pugh class A (N  =  7) or B (N = 8)) and matched controls (N = 15) received cenicriviroc 150 mg once daily for 14 days. Serial blood samples were obtained on Days 1 and 14. Safety, tolerability, and effects on CCR2/CCR5 ligands, cytokines, and bacterial translocation biomarkers were evaluated. Cenicriviroc exposures were increased by moderate HI (AUC0‐τ 55%, Cmax 29% higher) but were not with mild HI (AUC0‐τ 38%, Cmax 40% lower). Cenicriviroc was well tolerated. Rapid and potent CCR2/CCR5 blockade was observed, not associated with increases in hepatic inflammation or bacterial translocation biomarkers. Study findings suggest that cenicriviroc 150 mg can be used in patients with mild‐to‐moderate HI.

Existing and emerging strategies for managing L-dopa-induced dyskinesias (LIDs) in patients with Parkinson disease have involved either delaying the introduction of L-dopa therapy, treatment with an antidyskinetic agent, using a therapy or delivery system that can provide continuous dopaminergic stimulation, or using novel agents that target receptors implicated in the mechanisms underlying LIDs. Treatment with dopamine agonists such as pramipexole or ropinirole allows levodopa to be delayed, but once levodopa is added to the drug regimen the usual course of onset of dyskinesias is observed. Amantadine, an N-methyl-D-aspartate antagonist, is so far the only approved compound with evidence of providing a sustained antidyskinetic benefit in the absence of unacceptable side effects. These findings support the hypothesis of glutamate overactivity in the development of dyskinesias. More continuous delivery of dopaminergic medication, such as through intraintestinal or subcutaneous routes, is promising but invasive and associated with injection site reactions. As a result of molecular research and elucidation of the role of a variety of neurotransmitters in the mechanism of LIDs, new compounds have been identified, including those that modulate the direct and indirect striatal output pathways; some of these new agents are in the early stages of development or undergoing proof-of-concept evaluation as antidyskinetic agents.