Lomitapide is an inhibitor of MTP, an enzyme located in the endoplasmic reticulum of hepatocytes and enterocytes. This enzyme is responsible for the synthesis of very low-density lipoproteins in the liver and chylomicrons in the intestine. Lomitapide has been approved by the US Food and Drug Administration, European Medicines Agency, and other regulatory agencies for the treatment of hypercholesterolemia in adult patients with homozygous familial hypercholesterolemia. Clinical trials have shown that lomitapide reduces low-density-lipoprotein cholesterol levels by around 40% in homozygous familial hypercholesterolemia patients on treatment with statins with or without low-density-lipoprotein apheresis, with an acceptable safety and tolerance profile. The most common adverse events are gastrointestinal symptoms that decrease in frequency with long-term treatment, and the increase in liver fat remains stable. This review analyzes the clinical use, efficacy, and tolerability of lomitapide.
Substance P has recently received much attention as a mediator of adverse heart remodelling and cardiac inflammation by releasing proinflammatory cytokines and matrix metalloproteases from immune and cardiac mast cells. Based on animal models, Substance P is highly associated with the development of cardiomyopathies, subsequently leading to heart failure. After a brief overview of the pathological role of Substance P in cardiac remodelling and cardiac inflammation, this review summarizes the limited, existing data of Substance P blood levels in adults with cardiovascular diseases, demonstrating a high variability of blood concentrations. The investigation of blood levels led to the conclusion that variability is mainly caused by differences in blood sampling and determination. Furthermore, this review illustrates alternate strategies to investigate human Substance P levels as deeper knowledge of them enables further insights into the potential role of Substance P in cardiovascular diseases.
Embodiments are disclosed that relate to enforcement of user policies in a multi-user interactive computing environment by end user review. For example, one disclosed embodiment provides, on a computing device, a method comprising receiving a notification of a current policy controversy, and sending information regarding the current policy controversy to each end user reviewer of a plurality of end user reviewers, each end user reviewer being a member of an enforcement federation of a plurality of enforcement federations. The method further comprises receiving enforcement decisions from one or more responding end user reviewers of the plurality of end user reviewers, and if the enforcement decisions received meet an enforcement threshold, then automatically enforcing a policy rule.
Di Stefano, Giulia; Di Lionardo, Andrea; Galosi, Eleonora; Truini, Andrea; Cruccu, Giorgio
Acetyl-L-carnitine (ALC) has shown a neuroprotective effect in patients with peripheral neuropathies of different etiologies. Preclinical studies demonstrated a central anti-nociceptive action, both in neuropathic and nociceptive pain models. The present review aims to provide the knowledge on the efficacy of ALC in patients with painful peripheral neuropathy, based on the evidence. Consistent with the PRISMA statement, authors searched PubMed, Embase and the Cochrane Database of Systematic Reviews for relevant papers, including those issued before April 2018. Two authors independently selected studies for inclusion and data extraction: only trials including patients with a diagnosis of peripheral neuropathy and involving at least 10 patients were considered for the purposes of this review. Fourteen clinical trials were revised, to provide the level of evidence for neuropathy. To assess the global efficacy of ALC in painful peripheral neuropathy, a meta-analysis of four randomized controlled trials was performed. Mean difference in pain reduction as measured on a 10-cm VAS, and 95% CIs were used for pooling continuous data from each trial. Four randomized controlled trials tested ALC in patients with neuropathy secondary to diabetes and to antiretroviral therapy for HIV. Compared to placebo, ALC produced a significant pain reduction equal to 20.2% (95% CI: 8.3%-32.1%, P<0.0001) with respect to baseline. Clinical trials also showed beneficial effects on nerve conduction parameters and nerve fiber regeneration, with a good safety profile. These data indicate that ALC provides an effective and safe treatment in patients with painful peripheral neuropathy. We recommend further studies to assess the optimal dose and duration of the therapeutic effect (also after treatment withdrawal).
Different literature reviews of gambling disorder (GD) neurobiology have been focused on human studies, others have focused on rodents, and others combined human and rodent studies. The main question of this review was: which are the main neurotransmitters systems and brain structures relevant for GD based on recent rodent studies? This work aims to review the experimental findings regarding the rodent ' s neurobiology of GD. A search in the Pub Med database was set (October 2012-October 2017) and 162 references were obtained. After screening, 121 references were excluded, and only 41 references remained from the initial output. More, other 25 references were added to complement (introduction section, neuroanatomical descriptions) the principal part of the work. At the end, a total of 66 references remained for the review. The main conclusions are: 1) according to studies that used noninvasive methods for drug administration, some of the neurotransmitters and receptors involved in behaviors related to GD are: muscarinic, N-methyl-D-aspartate (NMDA), cannabinoid receptor 1 (CB1), cannabinoid receptor 2 (CB2), dopamine 2 receptor (D-2), dopamine 3 receptor (D-3), and dopamine 4 receptor (D-4); 2) moreover, there are other neurotransmitters and receptors involved in GD based on studies that use invasive methods of drug administration (eg, brain microinjection); example of these are: serotonin 1A receptor (5-HT1A), noradrenaline receptors, gamma-aminobutyric acid receptor A (GABAA), and gamma-aminobutyric acid receptor B (GABA(B)); 3) different brain structures are relevant to behaviors linked to GD, like: amygdala (including basolateral amygdala (BLA)), anterior cingulate cortex (ACC), hippocampus, infralimbic area, insular cortex (anterior and rostral agranular), nucleus accumbens (NAc), olfactory tubercle (island of Calleja), orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), prefrontal cortex (PFC)-subcortical network, striatum (ventral) and the subthalamic nucleus (STN); and 4) the search for GD treatments should consider this diversity of receptor/neurotransmitter systems and brain areas.