Supporting Active Pharmacovigilance via IT Tools in the Clinical Setting and Beyond: Regulatory and Management Aspects.

Information Technology (IT) could have a prominent role towards the "Active Pharmacovigilance" (AP) paradigm by facilitating the analysis of potential Adverse Drug Reactions (ADRs). PVClinical project aims to build an IT platform enabling the investigation of potential ADRs in the clinical environment and beyond. In this paper, we outline the respective EU regulatory framework and the related Business Processes (BPs), elaborated based on input from clinicians and PV experts as part of the project's "user requirements analysis" phase, highlighting their potential pivotal role in the design of IT tools aiming to support AP.

Start low, go slow, but look far: the case of geriatric medicine in Balkan countries.

PURPOSE: To present an insight of the situation of geriatric medicine in Balkan countries, as it was presented in the context of the 2nd pre-congress seminar of the 16th European Geriatric Medicine Society (EuGMS) Congress Athens 2021. METHODS: Representatives from 8 Balkan countries (Albania, Croatia, Greece, Republic of North Macedonia, Romania, Serbia, Slovenia, Turkey) answered 3 questions to reflect the state of geriatric medicine in their country: education on geriatrics; systems/methods for assessment of functional status and frailty; pre-operative risk assessment. An open discussion followed. RESULTS: Undergraduate education in geriatric medicine seems underestimated in medical faculties of Balkan countries, whereas a high heterogeneity is observed at a post-graduate level. Only a few Balkan countries have geriatric medicine as a recognized medical specialty or subspecialty. Functional status and frailty are only sporadically assessed, and pre-operative risk assessment is very rarely performed with a geriatric focus. Scarcity of expertise and structures relevant to geriatric medicine seems to be common. Developing a training curriculum and geriatrics-related structures are two interconnected aspects. Cooperation among physicians and multidisciplinary teams are essential for the practice of geriatric medicine. A functional geriatric network is eventually necessary and ambulatory geriatric expertise is probably a feasible and clinically relevant starting point. Providing pragmatic solutions to the pressing challenges in variable clinical settings, supplementing and working in harmony with existing components of each health system, is probably the most convincing strategy to gain political support in developing geriatric medicine. CONCLUSION: Balkan countries share common experiences and challenges in developing geriatrics. Whilst the principles of geriatric medicine are perhaps universal, proposed solutions should be adapted to each country's specific circumstances. Cooperation of the Balkan countries could promote in each the development of geriatric medicine. EuGMS is willing to foster relevant actions.

Association between cardiotrophin 1 levels and central blood pressure in untreated patients with essential hypertension.

BACKGROUND: Cardiotrophin 1 (CT-1) is an interleukin 6-related cytokine recently implicated in cardiac hypertrophy and vascular damage in essential hypertension (EH). We aimed first to determine CT-1 levels in naive, untreated patients with grade I EH (UH) as compared with normotensive (NT) individuals and, second, to investigate a possible association of CT-1 levels with indices of arterial stiffness. METHODS: We enrolled 45 consecutive untreated patients recently diagnosed with grade I EH by means of office and ambulatory blood pressure (BP) measurements and 25 age- and sex-matched NT subjects. CT-1 levels were measured with a commercially available enzyme-linked immunosorbent assay kit, and indices of arterial stiffness were determined by applanation tonometry. RESULTS: CT-1 levels were significantly elevated in UH patients compared with NT subjects (P < 0.001). Furthermore, CT-1 levels correlated positively with office, ambulatory and central BP. A significant bivariable correlation was also found between CT-1 levels and pulse wave velocity (P = 0.02). In the multivariable analysis, central systolic and diastolic BP proved the only significant predictors of CT-1 levels after controlling for other related factors. CONCLUSIONS: To our knowledge, this is the first study that correlates CT-1 levels with ambulatory and central BP, as well as with pulse wave velocity in patients with essential hypertension. Thus, studying the effects of CT-1 in the cardiovascular system in patients with EH represents a promising area of investigation in the future.

Comparison of the diagnostic accuracy of ischemia-modified albumin and echocardiography in patients with acute chest pain.

BACKGROUND: Several imaging tests and biomarkers have been proposed for the identification of patients with unstable angina among those presenting to the emergency department with acute chest pain. Preliminary data suggest that ischemia-modified albumin (IMA) may represent a potentially useful biomarker in these patients. OBJECTIVE: To compare IMA and echocardiography in excluding unstable angina in patients with acute chest pain. METHODS: Thirty-three patients (mean [± SD] age 59.8±10.8 years; 28 men) presenting to the emergency department with acute chest pain lasting <3 h suggestive of acute coronary syndrome, with normal or non-diagnostic electrocardiograms, and creatine kinase MB and troponin levels within the normal range, were included in the present study. RESULTS: After further diagnostic evaluation, five patients (15.2%) were diagnosed with unstable angina. The sensitivity, specificity, positive predictive value and negative predictive (NPV) value of echocardiography for diagnosing unstable angina was 60.0%, 89.3%, 50.0% and 92.6%, respectively. The area under the ROC curve for diagnosing unstable angina based on the serum IMA levels was 0.193 (95% CI 0.047 to 0.339; P<0.05). Based on ROC curve analysis, serum IMA levels ≥31.95 IU/mL yielded the optimal combination of sensitivity and specificity for diagnosing unstable angina. The sensitivity, specificity, positive predictive value and NPV of serum IMA levels ≥31.95 IU/mL for diagnosing unstable angina was 40.0%, 28.6%, 9.1% and 72.7%, respectively. CONCLUSIONS: Measurement of serum IMA levels appears to represent a useful tool for excluding unstable angina in patients presenting to the emergency department with acute chest pain. Moreover, IMA shows an NPV that is comparable with echocardiography.

Divergent retinal vascular abnormalities in normotensive persons and patients with never-treated, masked, white coat hypertension.

BACKGROUND: Hypertensive patients with retinal arteriolar abnormalities are at increased risk for cardiovascular events. However, the extent of retinal microvascular changes in naïve, never-treated patients with hypertension of short duration has not been established. In addition to this, the lack of relevant data about other phenotypes of hypertension (masked and white-coat hypertension) determined by ambulatory blood-pressure measurement (ABPM) is notable, despite their relationship to increased cardiovascular risk mediated by underlying target-organ and vascular damage. METHODS: We conducted a study in which nonmydriatic retinal photography was used to assess central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) diameters and the retinal arteriovenus ratio (AVR) in a group of 103 individuals with never-treated hypertension of recent (< 1 year) appearance, 28 individuals with masked and 20 with white-coat hypertension, and 50 normotensive individuals, as appropriately classified by ABPM. RESULTS: Patients with sustained and masked hypertension had narrower values of CRAE than did normotensive individuals (86.7±10.1 and 87.6±9.2 vs. 94.8±10.6, P < 0.001 and P = 0.02, respectively). The AVR was lower in patients with sustained hypertension (0.736±0.102), masked hypertension (0.716±0.123), and white-coat hypertension (0.739±0.127) than in normotensive subjects (0.820±0.095), P < 0.001, P < 0.001, and P = 0.03, respectively. Both AVR and CRAE were negatively associated with mean systolic and diastolic daytime, nighttime, and 24-hour blood pressures, even after adjustment for other factors. CONCLUSIONS: Subtle retinal microvascular signs of pathology are observed in hypertensive patients at early stages of hypertension and in patients with both masked and white coat hypertension. These changes may be indicative or may mediate the differences in cardiovascular mortality in persons with masked and white-coat hypertension, and relevant information about this can be easily accessed with retinal photography.

Leiomyosarcoma of renal vein, initially resembling pheochromocytoma.

We report the case of a 43-year-old woman who presented with mild left-sided abdominal pain. Computed tomography and MRI findings revealed a 10.7 × 8.5 × 12 cm left-sided soft tissue mass on the renal vessels pushing away the left kidney. The combination of the patient's medical history (episodes of paroxysmal hypertension accompanied with dizziness and sweating) and radiological findings initially pointed toward the diagnosis of a paraganglioma or ectopic pheochromocytoma. Surgical removal of the tumor and left nephrectomy was performed. Histological findings were consistent with a renal vein leiomyosarcoma of a high malignancy grade. There is no evidence of local recurrence or metastatic disease for more than 2 years postoperatively, although the patient did not receive adjuvant chemotherapy or radiation therapy.

Surgical management of primary aldosteronism. not everything that shines is gold.

BACKGROUND: Primary aldosteronism (PA) is a syndrome which includes a group of clinical entities in which aldosterone production is inappropriately high and nonsupressible by sodium loading. The most frequent causes of PA are adrenal adenoma and unilateral or bilateral primary hyperplasia. METHODS: We report a case of a 55-year-old man with a 10-year history of hypertension in whom functional hormonal studies were indicative of PA. Because adrenal venus sampling was not available at our hospital, the investigation was conducted with a computed tomography (CT) scan and a scan with 131-iodocholesterol (NP-59) which both revealed a left adrenal adenoma. RESULTS: The tumor was excised laparoscopically without any complications and the histological findings confirmed the diagnosis of an aldosterone-producing adenoma. Blood pressure remained normal despite the discontinuation of antihypertensive drugs, further supporting that the adrenal tumor was indeed the cause of high blood pressure. Unfortunately, blood pressure began to rise again 2 months later, and laboratory findings indicated the presence of PA once again. Spironolactone was instituted and blood pressure significantly improved and was finally controlled by the addition of amlodipine. CONCLUSION: We report this case to underline the difficulties in the discrimination between adenoma and hyperplasia in everyday clinical practice. Although the CT and scintigraphic findings strongly pointed toward an adenoma, the fact that PA re-appeared shortly after the operation, indicated that the underlying cause of the PA was hyperplasia and not adenoma after all.

Carotid baroreceptor stimulation for the treatment of resistant hypertension.

Interventional activation of the carotid baroreflex has been an appealing idea for the management of resistant hypertension for several decades, yet its clinical application remained elusive and a goal for the future. It is only recently that the profound understanding of the complex anatomy and pathophysiology of the circuit, combined with the accumulation of relevant experimental and clinical data both in animals and in humans, has allowed the development of a more effective and well-promising approach. Indeed, current data support a sustained over a transient reduction of blood pressure through the resetting of baroreceptors, and technical deficits have been minimized with a subsequent recession of adverse events. In addition, clinical outcomes from the application of a new implantable device (Rheos) that induces carotid baroreceptor stimulation point towards a safe and effective blood pressure reduction, but longer experience is needed before its integration in the everyday clinical practice. While accumulating evidence indicates that carotid baroreceptor stimulation exerts its benefits beyond blood pressure reduction, further research is necessary to assess the spectrum of beneficial effects and evaluate potential hazards, before the extraction of secure conclusions.

Double probe pH-monitoring findings in patients with benign lesions of the true vocal folds: comparison with typical GERD and the effect of smoking.

We conducted a pH-monitoring study to determine the prevalence of pathologic gastroesophageal reflux (GER+) and laryngopharyngeal reflux (LPR+) in patients with resected benign true vocal fold lesions (TVFLs) and positive reflux finding score (RFS). We compared our findings with those of patients with typical GER disease (GERD) symptoms and normal laryngoscopy. In the group of patients with TVFLs, we compared the pH-monitoring findings of smokers with those of non-smokers. Seventy-two [females 32, mean (SD) age 49.3 (13.1) years] patients with resected TVFLs (polyps: 32, nodules: 20, Reinke's edema: 12, granulomas: 4, leukoplakia: 4) and 24 [females 14, mean (SD) age 42.2 (13.4) years] patients with typical GERD symptoms, who served as controls for the hypopharyngeal measurements, underwent 24-h double probe, hypopharyngeal and distal esophageal, ambulatory pH monitoring. Thirty-eight (52.8%) patients with TVFLs had GER+ and 52 (72.2%) had LPR+. More laryngopharyngeal reflux episodes (LPREs) were detected in patients with TVFLs compared to those with GERD (P < 0.001). With respect to the specific TVFLs, 12 (37.5%) patients with polyps had GER+ and 24 (75%) had LPR+, 6 (30%) patients with nodules had GER+ and 12 (60%) had LPR+, 6 (50%) patients with Reinke's edema had GER+ and 8 (66.7%) had LPR+ and all the patients with granuloma or leucoplakia had both GER+ and LPR+. Twenty (55.6%) of the 36 smokers and 32 (88.9%) of the 36 non-smokers with TVFLs had LPR+ (P = 0.003), while GER+ was recorded in 16 (44.4%) smokers and 22 (61.1%) non-smokers (P = 0.238). Smokers had significantly less LPREs (P < 0.001). In conclusion, 24-h double probe pH monitoring may detect GER+ and/or LPR+ in a substantial proportion of patients with resected TVFLs and positive RFS. Our study suggests that LPR+ is more prevalent in patients with TVFLs compared with typical GERD patients and that non-smokers with TVFLs are more likely to have LPR+ than smokers with TVFLs.

Prevalence, awareness, treatment and control of hypertension in an elderly population in Greece.

INTRODUCTION: Hypertension is a major public health problem and its prevalence increases with age. Despite an aging population, only a limited number of population-based studies, and fewer Greek studies, have focused exclusively on the elderly. The objective of this study was to investigate the prevalence, awareness, treatment and control of hypertension in the rural residents of Paliouri village in Greece who were aged 65 years and older. METHODS: In total there were 171 participants (response rate 89.5%). Six blood pressure (BP) measurements were obtained in two visits and hypertension was defined as a mean systolic BP >or= 140 mmHg and/or mean diastolic BP >or= 90 mmHg, and/or current use of an antihypertensive medication. RESULTS: The prevalence of hypertension was 89%. Of the 137 hypertensive patients, 89.8% were aware of their disease, 89.1% were receiving treatment, and the hypertension of 32.8% was controlled. Awareness of hypertension was significantly higher among those with a high frequency of BP measurements, a history of coronary or other chronic disease, lower education, and those living with a spouse. CONCLUSION: The findings indicate that hypertension is highly prevalent in this Greek elderly population. Similarly high is the awareness and treatment of hypertension. However, the control rates were relatively low, suggesting that the local health system requires a greater orientation to the prevention and control of hypertension.

Platelet activation in essential hypertension: implications for antiplatelet treatment.

Essential hypertension is associated with increased risk of arterial thrombotic disease. Among other factors, enhanced platelet activity contributes significantly to this phenomenon. An increased level of circulating monocyte-platelet aggregates (MPAs) represents one of the most robust markers of platelet activation; furthermore, these aggregates are also believed to contribute to the pathophysiology of atherothrombotic disease. Putative mechanisms that contribute to platelet activation in essential hypertension include endothelial dysfunction, neurohumoral (sympathetic and renin-angiotensin systems) overactivity, decreased platelet nitric oxide (NO) biosynthesis, and platelet degranulation secondary to increased shear. Current recommendations are that hypertensive patients receive aspirin therapy only if their calculated cardiovascular risk is high and their blood pressure (BP) is adequately controlled. By contrast, the use of antiplatelet treatment in low-risk hypertensive patients is not established and merits further investigation. Moreover, the place of alternative antiplatelet agents other than aspirin, such as clopidogrel, is unclear at present. Some experimental evidence suggests that clopidogrel may confer an additive protective effect over and above aspirin in hypertensive patients, by virtue of effects on the evolution of the atherosclerotic process. This now needs to be investigated in long-term clinical outcome studies.

Benefits from treatment and control of patients with resistant hypertension.

Resistant hypertension is commonly found in everyday clinical practice. However, the risks of resistant hypertension, as well as the benefits of treatment and control of blood pressure in patients with resistant hypertension remain vaguely clarified. Data from small clinical studies and observational cohorts suggest that patients with resistant hypertension are at increased cardiovascular risk, while control of blood pressure offers substantial benefits. It has to be noted however that data from appropriate large randomized studies are missing, and resistant hypertension remains remarkably understudied. Resistant hypertension has attracted significant scientific interest lately, as new therapeutic modalities become available. The interventional management of resistant hypertension either by carotid baroreceptor stimulation or renal sympathetic denervation is currently under investigation with promising preliminary results. This review presents available evidence regarding the benefits of treatment and control of blood pressure in patients with resistant hypertension and offers a critical evaluation of existing data in this field.

Nitric oxide dysfunction in vascular endothelium and platelets: role in essential hypertension.

Both endothelial and platelet-derived nitric oxide have important vasculoprotective properties. Increasing evidence suggests a dysfunctional platelet nitric oxide synthase type 3 (NOS3) pathway in essential hypertension, whereas for endothelial-derived nitric oxide the picture is more complicated, with many studies suggesting an impairment of endothelial nitric oxide generation, whilst others have suggested that the endothelial nitric oxide pathway is preserved. Controversy also exists as to whether any observed reduction in endothelial or platelet-derived nitric oxide exerts a pathogenetic role or is simply the result of the raised blood pressure. In this review, we examine the evidence that endothelial and/or platelet-derived nitric oxide are disturbed in essential hypertension, and whether such disturbances are cause or effect.

Decreased platelet nitric oxide contributes to increased circulating monocyte-platelet aggregates in hypertension.

AIMS: The aim of this study was to determine the effect of blood pressure (BP) on platelet nitric oxide (NO) signalling and on formation of circulating monocyte-platelet aggregates (MPA), as well as the role of platelet NO in modulating MPA in hypertension. METHODS AND RESULTS: We first examined platelet NO signalling in 23 untreated hypertensive (UH) and 23 normotensive (NT) subjects. Platelets from hypertensives exhibited reduced NO synthase activation by albuterol or collagen, as well as suppressed basal and stimulated NO-attributable cyclic guanosine-3',5'-monophosphate, compared with NT. In a second study, comprising 106 subjects with a wide BP range, circulating MPA showed a strong positive correlation with BP. On multiple regression analysis, using a model incorporating systolic BP (SBP), diastolic BP, age, lipids, gender, and smoking status, the only independent predictor of MPA was SBP. Nitric oxide synthase inhibition with N(G)-monomethyl-L-arginine increased MPA in NT but not in hypertensives, whereas the NO donor spermine NONOate (SNO) decreased MPA in NT but not in hypertensives. Platelet P-selectin expression was higher in hypertensives than in NT, and its expression was suppressed by SNO in NT only. CONCLUSION: Platelet NO production and responsiveness are suppressed with raised BP, and this may contribute to the increase in platelet P-selectin and hence in circulating MPA in hypertension.

Molecular basis of statin-associated myopathy.

Coronary artery disease (CAD) constitutes the most common cause of morbidity and mortality in developed countries. Statins effectively reduce low-density lipoprotein cholesterol, an important risk factor for CAD and related acute coronary syndromes. They are an extensively studied group of drugs with versatile properties. Overall, they are safe and effective drugs but their myotoxic potential cannot be overlooked. In this review we focus on the pathogenesis of statins' myopathic side effects. Statins can interfere with protein modification at multiple levels. They can affect protein prenylation, an important post-translational modification of membrane bound proteins. They can also adversely affect selenoprotein synthesis, or can interfere with the biosynthesis of dolichols, which are involved in the process of protein glycosylation. Statin-induced myopathy may be also associated with mitochondrial dysfunction. Statins remain the spearhead of our armamentarium in treating atherosclerotic disease. Consistent with their versatile properties it is anticipated to see in the future their indications to expand. Better understanding of the molecular mechanisms involved in statin-induced myopathy may help identify patient groups susceptible to statins' side effects, thereby increasing their safety.

Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study.

BACKGROUND: Results of several studies published since 1999 suggest that primary hyperaldosteronism (also known as Conn's syndrome) affects more than 10% of people with hypertension; however, such a high prevalence has also been disputed. Experts generally agree that resistant hypertension has the highest prevalence of primary hyperaldosteronism, on the basis of small studies. We aimed to assess the prevalence of primary hyperaldosteronism in a large group of patients with resistant hypertension. METHODS: Patients with resistant hypertension (blood pressure >140/90 mm Hg despite a three drug regimen, including a diuretic) who attended our outpatient clinic were assessed for primary hyperaldosteronism. Serum aldosterone and plasma renin activity were determined and their ratio was calculated. Patients with a positive test (ratio >65.16 and aldosterone concentrations >416 pmol/L) underwent salt suppression tests with intravenous saline and fludrocortisone. Diagnosis of primary hyperaldosteronism was further confirmed by the response to treatment with spironolactone. FINDINGS: Over 20 years, we studied 1616 patients with resistant hypertension. 338 patients (20.9%) had a ratio of more than 65.16 and aldosterone concentrations of more than 416 pmol/L. On the basis of salt suppression tests, 182 (11.3%) patients had primary hyperaldosteronism, and response to spironolactone treatment further confirmed this diagnosis. Hypokalaemia was seen only in 83 patients with primary hyperaldosteronism (45.6%). INTERPRETATION: Although the prevalence of primary hyperaldosteronism in patients with resistant hypertension was high, it was substantially lower than previously reported. On the basis of this finding, we could assume that the prevalence of primary hyperaldosteronism in the general unselected hypertensive population is much lower than currently reported. Thus, the notion of an epidemic of primary hyperaldosteronism is not supported.

The interaction of vasoactive substances during exercise modulates platelet aggregation in hypertension and coronary artery disease.

BACKGROUND: Acute vigorous exercise, associated with increased release of plasma catecholamines, transiently increases the risk of primary cardiac arrest. We tested the effect of acute submaximal exercise on vasoactive substances and their combined result on platelet function. METHODS: Healthy volunteers, hypertensive patients and patients with coronary artery disease (CAD) performed a modified treadmill exercise test. We determined plasma catecholamines, thromboxane A2, prostacyclin, endothelin-1 and platelet aggregation induced by adenosine diphosphate (ADP) and collagen at rest and during exercise. RESULTS: Our results during exercise showed a) platelet activation (increased thromboxane B2, TXB2), b) increased prostacyclin release from endothelium and c) decreased platelet aggregation in all groups, significantly more in healthy volunteers than in patients with CAD (with hypertensives lying in between these two groups). CONCLUSION: Despite the pronounced activation of Sympathetic Nervous System (SNS) and increased TXB2 levels during acute exercise platelet aggregation decreases, possibly to counterbalance the prothrombotic state. Since this effect seems to be mediated by the normal endothelium (through prostacyclin and nitric oxide), in conditions characterized by endothelial dysfunction (hypertension, CAD) reduced platelet aggregation is attenuated, thus posing such patients in increased risk for thrombotic complications.

Pheochromocytoma presenting as diabetic ketoacidosis.

Pheochromocytoma is a rare form of secondary hypertension and may be potentially lethal if left untreated. The classical symptoms are paroxysmal hypertension, headaches, palpitations and sweating. They are caused by sudden catecholamine release. Hyperglycemia is reported in some patients with pheochromocytoma but diabetic ketoacidosis is an extremely rare complication of pheochromocytoma with only four cases reported. We report a case of a young woman with pheochromocytoma manifested as diabetic ketoacidosis.