Combined administration of microdoses of growth hormone and erythropoietin: Effects on performance and evaluation of GH detection capability using anti‐doping methods

The combination of growth hormone (GH) and recombinant erythropoietin (rEPO) is thought to be used particularly in endurance sports. Our objective was to reproduce a 2‐week administration of rEPO microdoses alone or in combination with GH microdoses (three times a week) on healthy and athletic male subjects and to evaluate if GH had any additional effects compared to EPO treatment alone. The effects of the treatments on hematological parameters and VO2max were studied as well as the detection of GH in serum. While the rEPO microdose regimen was associated with a significant increase in reticulocytes, no clear elevation in hemoglobin concentration (HGB) was observed. Using a correction by plasma volume did not reveal more effects of EPO on HGB. Our results did not show any additional effect when the GH microdoses were co‐administered. In addition, no clear increase in VO2max was observed after treatment, with an elevation in only half the subjects in both groups (EPO and EPO+GH). A clear effect of GH on insulin‐like growth factor I (IGF‐I) was seen but it was lower on procollagen III amino‐terminal propeptide (P‐III‐NP). GH detection using the direct isoform test identified only one subject 24 hours after receiving GH. The GH biomarker test combining IGF‐I and P‐III‐NP was not able to detect the GH administration. However, a longitudinal follow‐up of the intraindividual variations showed a significant increase in IGF‐I 24 and 48 hours after GH administration in most subjects, while the effect of GH microdoses on P‐III‐NP was less straightforward.     

Differences in cardiovascular safety with non‐steroidal anti‐inflammatory drug therapy—A nationwide study in patients with osteoarthritis

Osteoarthritis (OA) and the non‐steroidal anti‐inflammatory drugs (NSAIDs) used to relieve OA‐associated pain have been linked independently to increased cardiovascular risk. We examined the risk of cardiovascular events associated with NSAID use in patients with OA. We employed linked nationwide administrative registers to examine NSAID use between 1996 and 2015 by Danish patients with OA aged ≥18 years. Using adjusted Cox proportional hazard analyses, we calculated the risk of the composite outcome of cardiovascular death, non‐fatal myocardial infarction and non‐fatal ischaemic stroke/TIA, and of each outcome separately, up to 5 years after OA diagnosis. Of 533 502 patients included, 64.3% received NSAIDs and 38 226 (7.2%) experienced a cardiovascular event during follow‐up. Compared with non‐use, all NSAIDs were associated with increased risk of the composite outcome: hazard ratio (HR) for rofecoxib, 1.90 (95% confidence interval, 1.74‐2.08); celecoxib, 1.47 (1.34‐1.62); diclofenac, 1.44 (1.36‐1.54); ibuprofen, 1.20 (1.15‐1.25); and naproxen, 1.20 (1.04‐1.39). Similar results were seen for each outcome separately. When celecoxib was used as reference, ibuprofen (HRs: 0.81 [CI: 0.74‐0.90]) and naproxen (HRs: 0.81 [0.68‐0.97]) exhibited a lower cardiovascular risk, even when low doses were compared. Low‐dose naproxen and ibuprofen were associated with the lowest risks of the composite outcome compared to no NSAID use: HRs: 1.12 (1.07‐1.19) and 1.16 (0.92‐1.42), respectively. In patients with OA, we found significant differences in cardiovascular risk among NSAIDs. Naproxen and ibuprofen appeared to be safer compared to celecoxib, also when we examined equivalent low doses. In terms of cardiovascular safety, naproxen and ibuprofen, at the lowest effective doses, may be the preferred first choices among patients with OA needing pain relief.     

Interaction between warfarin and cannabis

Delta‐9‐tetrahydrocannabinol (THC), the main psychoactive cannabinoid in cannabis, may inhibit the cytochrome P450 enzyme CYP2C9. Consequently, cannabis use might infer a risk of drug‐drug interaction with substrates for this enzyme, which includes drugs known to have a narrow therapeutic window. In this study, we describe a case report of a 27‐year‐old man treated with warfarin due to mechanical heart valve replacement who presented with elevated international normalized ratio (INR) value (INR = 4.6) following recreational cannabis use. We conducted a review of the available literature, using the PubMed and EMBASE databases while following PRISMA guidelines. Following screening of 85 articles, three eligible articles were identified, including one in vitro study and two case reports. The in vitro study indicated that THC inhibits the CYP2C9‐mediated metabolism of warfarin. One case study reported of a man who on two occasions of increased marijuana use experienced INR values above 10 as well as bleeding. The other case study reported of a patient who initiated treatment with a liquid formulation of cannabidiol for the management of epilepsy, ultimately necessitating a 30% reduction in warfarin dose to maintain therapeutic INR values. The available, although sparse, data suggest that use of cannabinoids increases INR values in patients receiving warfarin. Until further data are available, we suggest patients receiving warfarin be warned against cannabis use.     

Trefoil factors in inflammatory bowel disease

Inflammatory bowel disease(IBD),which comprises ulcerative colitis and Crohn’s disease,is characterized by inflammation of the gastrointestinal tract.The trefoil factors 1,2,and 3(TFF1-3)are a family of peptides that play important roles in the protection and repair of epithelial surfaces,including the gastrointestinal tract.TFFs may be involved in IBD pathogenesis and are a potential treatment option.In the present review,we describe the TFF family and their potential role in IBD by summarizing the current knowledge of their expression,possible function and pharmacological role in IBD.     

Targeting Matrix Metalloproteinase Activity and Expression for the Treatment of Viral Myocarditis

Infectious agents including viruses can infect the heart muscle, resulting in the development of heart inflammation called myocarditis. Chronic myocarditis can lead to dilated cardiomyopathy (DCM). DCM develops from the extensive extracellular matrix (ECM) remodeling caused by myocarditis and may result in heart failure. Epidemiological data for viral myocarditis has long suggested a worse pathology in males, with more recent data demonstrating sex-dependent pathogenesis in DCM as well. Matrix metalloproteinases (MMPs), long known modulators of the extracellular matrix, have important roles in mediating heart inflammation and remodeling during disease and in convalescence. This ability of MMPs to control both the inflammatory response and ECM remodeling during myocarditis makes them potential drug targets. In this review, we analyze the role of MMPs in mediating myocarditis/DCM disease progression, their sex-dependent expression, and their potential as drug targets during viral myocarditis and DCM.     

Role of Human Cytomegalovirus Tegument Proteins in Virion Assembly

Like other herpesviruses, human cytomegalovirus (HCMV) contains a unique proteinaceous layer between the virion envelope and capsid, termed the tegument. Upon infection, the contents of the tegument layer are delivered to the host cell, along with the capsid and the viral genome, where they facilitate the initial stages of virus replication. The tegument proteins also play important roles in virion assembly and this dual nature makes them attractive potential targets for antiviral therapies. While our knowledge regarding tegument protein function during the initiation of infection has been the subject of intense study, their roles in assembly are much less well understood. In this review, we will focus on recent studies that highlight the functions of HCMV tegument proteins during assembly, and pose key questions for further investigation.