Reassessment of vasodilator therapy in angina: Effects of oral isosorbide dinitrate and hydralazine on exercise tolerance in patients receiving propranolol

Nitrates, predominantly venodilators, are commonly used in the treatment of angina pectoris, whereas hydralazine, a potent systemic and coronary arterial vasodllator, is usually contraindicated. Hydralazine might be useful in therapy of angina H tachycardia could be prevented by beta adrenergic blockade. Consequently, treadmill exercise tolerance was determined in 20 patients with chronic stable angina during treatment with oral propranolol, 60 mg four times daily (control), propranolol plus 20 mg of oral isosorbide dinitrate, propranolol plus 100 mg of oral hydralazine, and all three drugs combined. The mean heart rate at rest in patients recelving propranolol was 54.0 ± 1.7 beats/min (mean ± standerd error of the mean). It increased 6.8 beats/min with the additlon of hydralazine (p < 0.005) and 7.2 beats/min with Isosorbide dlnitrate and hydralazine comblned (p < 0.005), but was unchanged with Isosorbide dinitrarate alone. Systoilc blood pressure decreased 13.5 mm Hg with Isosorbide dinitrate (p < 0.05) and 28.3 mm Hg with Isosorbide dinitrate and hydralazine combined (p < 0.005), but did not change significantly with hydralazine alone (average decrease 4.1 mm Hg). The mean duration of exercise increased by 24.1 seconds with Isosorbide dinitrate (p < 0.05), and almost twice that (42.4 seconds longer than the control value) with Isosorbide dinitrate and hydralazine (p < 0.005). With hydralazine alone, exercise duration was decreased by 24.7 seconds (p < 0.05). Rate-pressure product at symptom-tolerated maximal exercise was unchanged with Isosorbide dinitrarate or hydralazine alone, but lower than the control value with the two agents combined. It Is concluded that Isosorbide dinitrate Improves exercise tolerance in patients with angina who are being treated with propranolol, but hydralazine remains detrlmental despite the use of the beta blocking agent. However, when Isosorbide dinitrate is combined with hydralazine, the detrimental effects of hydralazine on exercise tolerance are reversed.     

Endocannabinoids and liver disease--review.

AIMS: Endocannabinoids are endogenous compounds that bind to the same receptors as tetrahydrocannabinol, the active component in marijuana and hashish. They have been found to have many physiological and patho-physiological functions, including mood alteration, control of feeding and appetite, motor and co-ordination activities, analgesia, immune modulation and gut motility. In this review we aim to elucidate current knowledge as to their role in liver physiology and disease. METHODS: The major findings published to date concerning endocannabinoids and liver disease are described, and their implications with regard to understanding disease mechanisms, and the development of new treatments is considered. RESULTS: Recently, endocannabinoids have been implicated in the hemodynamic alterations occurring in cirrhosis. These changes appear to be mediated via specific cannabinoid receptors (CB1) on splanchnic and hepatic vascular endothelium. Plasma levels of endocannabinoids also seem to be elevated in hepatitis, and are involved in apoptosis of hepatocytes by a membrane mechanism not related to a specific receptor. Other studies suggest a beneficial role for cannabinoids in reducing the inflammation of experimental hepatitis. In an animal model of acute hepatic failure, both endocannabinoids and the antagonist to the CB1 receptor have been found to have a beneficial effect on neurological and cognitive function. CONCLUSIONS: Endocannabinoids appear to be involved in several aspects of acute and chronic liver disease, including vascular changes, modulation of inflammatory process and neurological function, Further research may provide new insights into the pathophysiology of liver disease, as well as a basis for novel treatment modalities.     

Duodenal epithelial thymidine uptake in patients with duodenal ulcer or endoscopic duodenitis

To evaluate the relationship between duodenal ulcer disease and duodenitis, duodenal epithelial cell renewal was measured in mucosal biopsies by the incorporation of [³H]thymidine. When 14 patients with duodenal ulcer were compared to 13 control subjects or 7 with endoscopic duodenitis alone, the crypt size was the same in all groups. Similar to other inflammatory processes of the gastrointestinal tract, patients with endoscopic duodenitis showed increased proliferative indices including a greater number of cells incorporating [³H]thymidine. In contrast, the proliferative indices from the duodenal mucosa of patients with duodenal ulcers did not differ from a control group. In a group of 6 patients with both endoscopic duodenitis and duodenal ulcer, the [³H]thymidine incorporation was intermediate between control subjects or patients with duodenal ulcer alone and those with endoscopic duodenitis alone. When subjects were divided according to the histologic appearance of the duodenal mucosa, those having chronic duodenitis demonstrated enhanced [³H]thymidine incorporation in comparison to a control group or patients with chronic active duodenitis (polymorphonuclear leukocytes present). Although there are many possible explanations of these findings, one may speculate that duodenal ulceration does not stimulate duodenal epithelial proliferation. This project was supported by the Yale Digestive Cancer Research Fund. Dr. Gorelick was supported by a Research Fellowship Award from the National Foundation for Ileitis and Colitis during a portion of this study and is currently a recipient of a Clinical Investigator Award (KO8-AM-00659) from the National Institute of Arthritis, Metabolism and Digestive Diseases.     

In vivo metabolism of the designer anabolic steroid hemapolin in the thoroughbred horse

Hemapolin (2α,3α‐epithio‐17α‐methyl‐5α‐androstan‐17β‐ol) is a designer steroid that is an ingredient in several “dietary” and “nutritional” supplements available online. As an unusual chemical modification to the steroid A‐ring could allow this compound to pass through antidoping screens undetected, the metabolism of hemapolin was investigated by an in vivo equine drug administration study coupled with GC‐MS analysis. Following administration of synthetically prepared hemapolin to a thoroughbred horse, madol (17α‐methyl‐5α‐androst‐2‐en‐17β‐ol), reduced and dihydroxylated madol (17α‐methyl‐5α‐androstane‐2β,3α,17β‐triol), and the isomeric enone metabolites 17β‐hydroxy‐17α‐methyl‐5α‐androst‐3‐en‐2‐one and 17β‐hydroxy‐17α‐methyl‐5α‐androst‐2‐en‐4‐one, were detected and confirmed in equine urine extracts by comparison with a library of synthetically derived reference materials. A number of additional madol derivatives derived from hydroxylation, dihydroxylation, and trihydroxylation were also detected but not fully identified by this approach. A yeast cell‐based androgen receptor bioassay of available reference materials showed that hemapolin and many of the metabolites identified by this study were potent activators of the equine androgen receptor. This study reveals the metabolites resulting from the equine administration of the androgen hemapolin that can be incorporated into routine GC‐MS antidoping screening and confirmation protocols to detect the illicit use of this agent in equine sports.     

Physical activity,mental health and well-being of adults during initial COVID-19 containment strategies: A multi-country cross-sectional analysis

ObjectivesTo assess physical activity (PA), mental health and well-being of adults in the United Kingdom (UK), Ireland, New Zealand and Australia during the initial stages of National governments’ Coronavirus disease (COVID-19) containment responses.DesignObservational, cross-sectional.MethodsAn online survey was disseminated to adults (n = 8,425; 44.5 ± 14.8y) residing in the UK, Ireland, New Zealand and Australia within the first 2-6 weeks of government-mandated COVID-19 restrictions. Main outcome measures included: Stages of Change scale for exercise behaviour change; International Physical Activity Questionnaire (short-form); World Health Organisation-5 Well-being Index; and the Depression Anxiety and Stress Scale-9.ResultsParticipants who reported a negative change in exercise behaviour from before initial COVID-19 restrictions to during the initial COVID-19 restrictions demonstrated poorer mental health and well-being compared to those demonstrating either a positive-or no change in their exercise behaviour (p < 0.001). Whilst women reported more positive changes in exercise behaviour, young people (18-29y) reported more negative changes (both p < 0.001). Individuals who had more positive exercise behaviours reported better mental health and well-being (p < 0.001). Although there were no differences in PA between countries, individuals in New Zealand reported better mental health and well-being (p < 0.001).ConclusionThe initial COVID-19 restrictions have differentially impacted upon PA habits of individuals based upon their age and sex, and therefore have important implications for international policy and guideline recommendations. Public health interventions that encourage PA should target specific groups (e.g., men, young adults) who are most vulnerable to the negative effects of physical distancing and/or self-isolation.     

Supervised Patient Self-Testing of Warfarin Therapy Using an Online System

Background

Point-of-care international normalized ratio (INR) monitoring devices simplify warfarin management by allowing selected patients to monitor their own therapy in their homes. Patient self-testing (PST) has been shown to improve the clinical outcomes of warfarin therapy compared to usual care.

Objective

To compare management of warfarin therapy using PST combined with online supervision by physicians via a custom system with usual warfarin management, which involved laboratory testing and physician dosing.

Methods

Interested patients were recruited via community pharmacies to participate in a warfarin PST training program. Participants were required to have a long-term indication for warfarin, have been taking warfarin for at least 6 months, and have Internet access in their home. The training involved two sessions covering theoretical aspects of warfarin therapy, use of the CoaguChek XS, and the study website. Following training, patients monitored their INR once weekly for up to 3 months. Patients and physicians utilized a secure website to communicate INR values, dosage recommendations, and clinical incidents. Physicians provided a 6-12 month history of INR results for comparison with study results. The percentage of time spent within the therapeutic INR range (TTR) was the primary outcome, with participants acting as their own historical controls. The percentage of INR tests in range and participant satisfaction were secondary outcomes.

Results

Sixteen patients completed training requirements. The mean age of participants was 69.8 (SD 10.1) years. TTR improved significantly from 66.4% to 78.4% during PST (P=.01), and the number of tests within the target range also improved significantly (from 66.0% at prior to the study to 75.9% during PST; P=.04). Patients and physicians expressed a high degree of satisfaction with the monitoring strategy and online system.

Conclusions

PST supported by an online system for supervision was associated with improved INR control compared to usual care in a small group of elderly patients. Further research is warranted to investigate the clinical outcomes and cost-effectiveness of online systems to support patients monitoring medications and chronic conditions in the home.