Multitarget Antioxidant NO-Donor Organic Nitrates: A Novel Approach to Overcome Nitrates Tolerance, an Ex Vivo Study

Chronic use of glyceryl trinitrate (GTN) is limited by serious side effects, such as tolerance and endothelial dysfunction of coronary and resistance arteries. Although GTN is used as a drug since more than 130 years, the mechanisms of the vasodilatory effects and of tolerance development to organic nitrates are still incompletely elucidated. New synthesized organic nitrates with and without antioxidant properties were characterized for their ex vivo tolerance profile, in order to investigate the oxidative stress hypothesis of nitrate tolerance. The organic nitrates studied showed different vasodilation and tolerance profiles, probably due to the ability or inability of the compounds to interact with the aldehyde dehydrogenase-2 enzyme (ALDH-2) involved in bioactivation. Furthermore, nitrooxy derivatives endowed with antioxidant properties did not determine the onset of tolerance, even if bioactivated by ALDH-2. The results of this study could be further evidence of the involvement of ALDH-2 in the development of nitrate tolerance. Moreover, the behavior of organic nitrates with antioxidant properties supports the hypothesis of the involvement of ROS in inactivating ALDH-2.

Cannabis: Joints of Mental Illness

With the increasing push to legalise cannabis in western nations there is an estimation that the potential impact of this policy change on vulnerable population such as those with mental illness, including schizophrenia, mood and anxiety disorders. Cannabis is the most likely used illicit drug worldwide. Cannabis sativa is an important herbaceous species originating from central Asia which has been used in folk medicine. Despite the widespread use of cannabis among young people little research attention has been given to the development of pscyhometrically sound measures specific to cannabis related problems. The laws governing cannabis are evolving worldwide are associated with changing pattern of use. Patients with a serious mental illness often use cannabis at higher rates than the general population. Cannabis may induce or exaberate a number of mental health problems. The main psychoactive drug in cannabis is ?9 tetrahydrocannabinol (THC). Cannabidiol, a non-toxicating cannabinoid found in some forms of cannabis, may offset some of these acute effects. Chronic use of cannabis is associated with psychiatric, respiratory, cardiovascular and bone effects. It also has oncogenic, teratogenic and mutagenic effects, all of which depend upon dose and duration of use. The present article mainly reviews about the association between cannabis and mental health.

Prevalence and factors associated with chronic use of levothyroxine: A cohort study

Importance Levothyroxine prescriptions are rising worldwide. However, there are few data on factors associated with chronic use. Objective To assess the prevalence of chronic levothyroxine use, its rank among other chronic drugs and factors associated with chronic use. To assess the proportion of users outside the therapeutic range of thyroid-stimulating hormone (TSH). Design Cohort study (CoLaus|PsyCoLaus) with recruitment from 2003 to 2006. Follow-ups occurred 5 and 10 years after baseline. Participants A random sample of Lausanne (Switzerland) inhabitants aged 35–75 years. Main outcomes We evaluated the prevalence of chronic levothyroxine use and we then ranked it among the other most used chronic drugs. The ranking was compared to data from health insurance across the country. We assessed the association between each factor and chronic levothyroxine use in multivariable logistic regression models. The proportion of chronic levothyroxine users outside the usual TSH therapeutic range was assessed. Results 4,334 participants were included in the analysis (mean±SD age 62.8±10.4 years, 54.9% women). 166 (3.8%) participants were chronic levothyroxine users. Levothyroxine was the second most prescribed chronic drug after aspirin in the cohort (8.2%) and the third most prescribed when using Swiss-wide insurance data. In multivariable analysis, chronic levothyroxine use was associated with increasing age [odds ratio 1.03, 95% confidence interval 1.01–1.05 per 1-year increase]; female sex [11.87 (5.24–26.89)]; BMI [1.06 (1.02–1.09) per 1-kg/m2 increase]; number of concomitant drugs [1.22 (1.16–1.29) per 1-drug increase]; and family history of thyroid pathologies [2.18 (1.37–3.48)]. Among chronic levothyroxine users with thyroid hormones assessment (n = 157), 42 (27%) were outside the TSH therapeutic range (17% overtreated and 10% undertreated). Conclusions In this population-based study, levothyroxine ranked second among chronic drugs. Age, female sex, BMI, number of drugs and family history of thyroid pathologies were associated with chronic levothyroxine use. More than one in four chronic users were over- or undertreated.

E-Cigarette Use: Device Market, Study Design, and Emerging Evidence of Biological Consequences

Electronic cigarettes are frequently viewed as a safer alternative to conventional cigarettes; however, evidence to support this perspective has not materialized. Indeed, the current literature reports that electronic cigarette use is associated with both acute lung injury and subclinical dysfunction to the lung and vasculature that may result in pathology following chronic use. E-cigarettes can alter vascular dynamics, polarize innate immune populations towards a proinflammatory state, compromise barrier function in the pulmonary endothelium and epithelium, and promote pre-oncogenic phenomena. This review will summarize the variety of e-cigarette products available to users, discuss current challenges in e-cigarette study design, outline the range of pathologies occurring in cases of e-cigarette associated acute lung injury, highlight disease supporting tissue- and cellular-level changes resulting from e-cigarette exposure, and briefly examine how these changes may promote tumorigenesis. Continued research of the mechanisms by which e-cigarettes induce pathology benefit users and clinicians by resulting in increased regulation of vaping devices, informing treatments for emerging diseases e-cigarettes produce, and increasing public awareness to reduce e-cigarette use and the onset of preventable disease.

Patterns of pre-operative opioid use affect the risk for complications after total joint replacement

Preoperative opioid use has been shown to increase the risk for complications following total joint arthroplasty (TJA); however, these studies have not always accounted for differences in co-morbidities and socio-demographics between patients that use opioids and those that do not. They have also not accounted for the variation in degree of pre-operative use. The objective of this study was to determine if preoperative opioid use is associated with risk for surgical complications after TJA, and if this association varied by degree of use. Population-based retrospective cohort study. Older adult patients undergoing primary TJA of the hip, knee and shoulder for osteoarthritis between 2002 and 2015 in Ontario, Canada were identified. Using accepted definitions, patients were stratified into three groups according to their preoperative opioid use: no use, intermittent use and chronic use. The primary outcome was the occurrence of a composite surgical complication (surgical site infection, dislocation, revision arthroplasty) or death within a year of surgery. Intermittent and chronic users were matched separately to non-users in a 1:1 ratio, matching on TJA type plus a propensity score incorporating patient and provider factors. Overall, 108,067 patients were included in the study; 10% (N = 10,441) used opioids on a chronic basis before surgery and 35% (N = 37,668) used them intermittently. After matching, chronic pre-operative opioid use was associated with an increased risk for complications after TJA (HR 1.44, p = 0.001) relative to non-users. Overall, less than half of patients undergoing TJA used opioids in the year preceding surgery; the majority used them only intermittently. While chronic pre-operative opioid use is associated with an increased risk for complications after TJA, intermitted pre-operative use is not.

P.056 Optimizing IVIg Use for Neuromuscular Conditions in British Columbia, Canada – Targeting High and Chronic User Groups

Background: Neuromuscular conditions account for 1/3 of IVIg use in BC and costs over $10 million annually. Since 2013, the BC Neuromuscular Review Panel has developed diagnostic and treatment algorithms for the use of IVIg. A framework was created to review high dose and chronic users. Methods: Utilizing Central Transfusion Registry data, all patients treated with IVIg for approved neuromuscular conditions (CIDP, MG, MMN) since April 1, 2013 were identified. Annual cohorts for patients using higher than usual dose and chronic use (>3 years) were established, and evaluated annually. Patient specific recommendations were made. Results: The initial cohort identified 38 high users of 377 patients receiving IVIg. 27 appropriate, 9 “not appropriate”. Subsequent cohorts showed a decrease in number of patients receiving inappropriate IVIg doses. In BC there has been a 36% increase in neuromuscular patients treated with IVIg (377 in 2013/14 to 512 in 2016/17). Despite this, IVIg the program has effectively reduced the annual grams/patient from 516 gm/patient in 2013/14 to 489 gm/patient in 2016/17. Conclusions: The BC Neuromuscular IVIg Review confirms that the majority of IVIg use is appropriate. Following yearly cohorts of chronic and high dose users helps optimize IVIg use, which may lead to improved patient care.

Mechanisms of Action of Flavonoids in the Management of Diabetes mellitus

Management of diabetes mellitus is a challenge for clinicians. Uncontrolled hyperglycemia increases the risk of microvascular and macrovascular complications, damaging the body systems. Although a number of antidiabetic drugs are available for therapeutic intervention, toxicity, loss of efficacy in chronic use and high cost of treatment have necessitated the search for new molecules to manage diabetes. Safety and cost are the main prerequisite for the new antidiabetic molecules. Medicinal plants and their purified phytochemicals have shown promising antidiabetic potential in the past few years. The flavonoids can be widely classified into different categories like anthocyanins, catechins, flavanols, flavones, flavanones etc. Some flavonoids have hypoglycemic properties. They may improve al-tered glucose and oxidative metabolisms of diabetic states. The hypoglycemic effect of some herbal extracts has been confirmed in human and animal models of type 2 diabetes mellitus (T2DM). Some of the important phytoconstituents from the classes of flavonoid have been discussed here. The current review summarizes the antidiabetic activity of flavonoids, the mechanism-based action of flavonoids that target the various metabolic pathways in humans. Keywords: Diabetes mellitus, Flavonoids, Medicinal plants, mechanisms of action, T2DM