Duloxetine in the management of diabetic peripheral neuropathic pain

Diabetic neuropathy affects up to 70% of diabetics, and diabetic peripheral neuropathic pain (DPNP) is the most common and debilitating of the diabetic neuropathies. DPNP significantly reduces quality of life and increases management costs in affected patients. Despite the impact of DPNP, management is poor with one-quarter of patients receiving no treatment and many treated with medications having little or no efficacy in managing DPNP. Duloxetine is one of two drugs approved by the United States Food and Drug Administration for DPNP management. Duloxetine is a serotonin and norepinephrine reuptake inhibitor (SNRI) proven safe, effective, and cost-saving in reducing DPNP symptoms at a dose of 60 mg/day. Duloxetine doses greater than 60 mg/day for DPNP management are not recommended since they are no more efficacious and associated with more side effects; addition of pregabalin or gabapentin for these patients may be beneficial. Side effects of duloxetine are generally mild and typical for the SNRI class including nausea, dizziness, somnolence, fatigue, sweating, dry mouth, constipation, and diarrhea. Given its other indications, duloxetine is a particularly good choice for DPNP treatment in patients with coexisting depression, anxiety, fibromyalgia, or chronic musculoskeletal pain. Duloxetine treatment had no clinically significant effect on glycemic control and did not increase the risk of cardiovascular events in diabetes patients. However, duloxetine use should be avoided in patients with hepatic disease or severe renal impairment. Given its safety, efficacy, and tolerability, duloxetine is an excellent choice for DPNP treatment in many patients

Milnacipran for the management of fibromyalgia syndrome

Fibromyalgia syndrome (FMS) is a widespread pain condition associated with fatigue, cognitive dysfunction, sleep disturbance, depression, anxiety, and stiffness. Milnacipran is one of three medications currently approved by the Food and Drug Administration in the United States for the management of adult FMS patients. This review is the second in a three-part series reviewing each of the approved FMS drugs and serves as a primer on the use of milnacipran in FMS treatment including information on pharmacology, pharmacokinetics, safety and tolerability. Milnacipran is a mixed serotonin and norepinephrine reuptake inhibitor thought to improve FMS symptoms by increasing neurotransmitter levels in descending central nervous system inhibitory pathways. Milnacipran has proven efficacy in managing global FMS symptoms and pain as well as improving symptoms of fatigue and cognitive dysfunction without affecting sleep. Due to its antidepressant activity, milnacipran can also be beneficial to FMS patients with coexisting depression. However, side effects can limit milnacipran tolerability in FMS patients due to its association with headache, nausea, tachycardia, hyper- and hypotension, and increased risk for bleeding and suicidality in at-risk patients. Tolerability can be maximized by starting at low dose and slowly up-titrating if needed. As with all medications used in FMS management, milnacipran works best when used as part of an individualized treatment regimen that includes resistance and aerobic exercise, patient education and behavioral therapies

The non-coding RNA interactome in joint health and disease

Non-coding RNAs have distinct regulatory roles in the pathogenesis of joint diseases including osteoarthritis (OA) and rheumatoid arthritis (RA). As the amount of high-throughput profiling studies and mechanistic investigations of microRNAs, long non-coding RNAs and circular RNAs in joint tissues and biofluids has increased, data have emerged that suggest complex interactions among non-coding RNAs that are often overlooked as critical regulators of gene expression. Identifying these non-coding RNAs and their interactions is useful for understanding both joint health and disease. Non-coding RNAs regulate signalling pathways and biological processes that are important for normal joint development but, when dysregulated, can contribute to disease. The specific expression profiles of non-coding RNAs in various disease states support their roles as promising candidate biomarkers, mediators of pathogenic mechanisms and potential therapeutic targets. This Review synthesizes literature published in the past 2 years on the role of non-coding RNAs in OA and RA with a focus on inflammation, cell death, cell proliferation and extracellular matrix dysregulation. Research to date makes it apparent that \u27non-coding\u27 does not mean \u27non-essential\u27 and that non-coding RNAs are important parts of a complex interactome that underlies OA and RA

A Network Biology Approach to Understanding the Tissue-Specific Roles of Non-Coding RNAs in Arthritis

Discovery of non-coding RNAs continues to provide new insights into some of the key molecular drivers of musculoskeletal diseases. Among these, microRNAs have received widespread attention for their roles in osteoarthritis and rheumatoid arthritis. With evidence to suggest that long non-coding RNAs and circular RNAs function as competing endogenous RNAs to sponge microRNAs, the net effect on gene expression in specific disease contexts can be elusive. Studies to date have focused on elucidating individual long non-coding-microRNA-gene target axes and circular RNA-microRNA-gene target axes, with a paucity of data integrating experimentally validated effects of non-coding RNAs. To address this gap, we curated recent studies reporting non-coding RNA axes in chondrocytes from human osteoarthritis and in fibroblast-like synoviocytes from human rheumatoid arthritis. Using an integrative computational biology approach, we then combined the findings into cell- and disease-specific networks for in-depth interpretation. We highlight some challenges to data integration, including non-existent naming conventions and out-of-date databases for non-coding RNAs, and some successes exemplified by the International Molecular Exchange Consortium for protein interactions. In this perspective article, we suggest that data integration is a useful in silico approach for creating non-coding RNA networks in arthritis and prioritizing interactions for further in vitro and in vivo experimentation in translational research

Net cholesterol efflux capacity of HDL enriched serum and coronary atherosclerosis in rheumatoid arthritis

Background/objectives: Cardiovascular (CV) risk is increased in patients with rheumatoid arthritis (RA), but not fully explained by traditional risk factors such as LDL and HDL cholesterol concentrations. The cholesterol efflux capacity of HDL may be a better CV risk predictor than HDL concentrations. We hypothesized that HDL's cholesterol efflux capacity is impaired and inversely associated with coronary atherosclerosis in patients with RA. Methods: We measured the net cholesterol efflux capacity of apolipoprotein B depleted serum and coronary artery calcium score in 134 patients with RA and 76 control subjects, frequency-matched for age, race and sex. The relationship between net cholesterol efflux capacity and coronary artery calcium score and other clinical variables of interest was assessed in patients with RA. Results: Net cholesterol efflux capacity was similar among RA (median [IQR]: 34% removal [28, 41%]) and control subjects (35% removal [27%, 39%]) (P = 0.73). In RA, increasing net cholesterol efflux capacity was not significantly associated with decreased coronary calcium score (OR = 0.78 (95% CI 0.51–1.19), P = 0.24, adjusted for age, race and sex, Framingham risk score and presence of diabetes). Net cholesterol efflux capacity was not significantly associated with RA disease activity score, C-reactive protein, urinary F2-isoprostanes, or degree of insulin resistance in RA. Conclusions: Net cholesterol efflux capacity is not significantly altered in patients with relatively well-controlled RA nor is it significantly associated with coronary artery calcium score