Showing papers in "Advances in Therapy in 2020"

Silymarin as Supportive Treatment in Liver Diseases: A Narrative Review

Abstract: Silymarin, an extract from milk thistle seeds, has been used for centuries to treat hepatic conditions. Preclinical data indicate that silymarin can reduce oxidative stress and consequent cytotoxicity, thereby protecting intact liver cells or cells not yet irreversibly damaged. Eurosil 85® is a proprietary formulation developed to maximize the oral bioavailability of silymarin. Most of the clinical research on silymarin has used this formulation. Silymarin acts as a free radical scavenger and modulates enzymes associated with the development of cellular damage, fibrosis and cirrhosis. These hepatoprotective effects were observed in clinical studies in patients with alcoholic or non-alcoholic fatty liver disease, including patients with cirrhosis. In a pooled analysis of trials in patients with cirrhosis, silymarin treatment was associated with a significant reduction in liver-related deaths. Moreover, in patients with diabetes and alcoholic cirrhosis, silymarin was also able to improve glycemic parameters. Patients with drug-induced liver injuries were also successfully treated with silymarin. Silymarin is generally very well tolerated, with a low incidence of adverse events and no treatment-related serious adverse events or deaths reported in clinical trials. For maximum benefit, treatment with silymarin should be initiated as early as possible in patients with fatty liver disease and other distinct liver disease manifestations such as acute liver failure, when the regenerative potential of the liver is still high and when removal of oxidative stress, the cause of cytotoxicity, can achieve the best results.

Barriers to the Wider Use of Pre-exposure Prophylaxis in the United States: A Narrative Review

Abstract: Antiretroviral pre-exposure prophylaxis (PrEP) to prevent HIV transmission was first approved by the US Food and Drug Administration in 2012. Despite correlations of decreases in new HIV infections being greatest where PrEP has been deployed, the uptake of PrEP is lagging, particularly among populations with disproportionate HIV burden. This narrative review seeks to identify individual and systemic barriers to PrEP usage in the USA. A comprehensive search of recent literature uncovered a complex array of structural, social, clinical, and behavioral barriers, including knowledge/awareness of PrEP, perception of HIV risk, stigma from healthcare providers or family/partners/friends, distrust of healthcare providers/systems, access to PrEP, costs of PrEP, and concerns around PrEP side effects/medication interactions. Importantly, these barriers may have different effects on specific populations at risk. The full potential of PrEP for HIV prevention will not be realized until these issues are addressed. Strategies to achieve this goal should include educational interventions, innovative approaches to delivery of HIV care, financial support, and destigmatization of PrEP and PrEP users. Until then, PrEP uptake will continue to be suboptimal, particularly among those who need it most.

Efficacy and Safety of Intravitreal Aflibercept Treat-and-Extend Regimens in Exudative Age-Related Macular Degeneration: 52- and 96-Week Findings from ALTAIR : A Randomized Controlled Trial

Abstract: To evaluate efficacy and safety of intravitreal injections of aflibercept (IVT-AFL) treat-and-extend (TE mean change in central retinal thickness was − 134.4 µm and − 126.1 µm (week 52) and − 130.5 µm and − 125.3 µm (week 96). Last injection interval before week 52 was at least 12 weeks in 42.3% and 49.6% of patients and 56.9% and 60.2% before week 96. Over 96 weeks, mean number of injections was 10.4 (both groups). The safety profile of IVT-AFL was consistent with previous reports. IVT-AFL administered using two different T&E regimens for treatment-naive exudative AMD improved functional and anatomic outcomes at week 52 and outcomes were maintained to week 96. Outcomes were similar between the 2- and 4-week groups. ClinicalTrials.gov identifier, NCT02305238.

Pathophysiology and Therapeutic Perspectives of Oxidative Stress and Neurodegenerative Diseases: A Narrative Review.

Abstract: Neurodegeneration is the term describing the death of neurons both in the central nervous system and periphery. When affecting the central nervous system, it is responsible for diseases like Alzheimer’s disease, Parkinson’s disease, Huntington’s disorders, amyotrophic lateral sclerosis, and other less frequent pathologies. There are several common pathophysiological elements that are shared in the neurodegenerative diseases. The common denominators are oxidative stress (OS) and inflammatory responses. Unluckily, these conditions are difficult to treat. Because of the burden caused by the progression of these diseases and the simultaneous lack of efficacious treatment, therapeutic approaches that could target the interception of development of the neurodegeneration are being widely investigated. This review aims to highlight the most recent proposed novelties, as most of the previous approaches have failed. Therefore, older approaches may currently be used by healthcare professionals and are not being presented. This review was based on an electronic search of existing literature, using PubMed as primary source for important review articles, and important randomized clinical trials, published in the last 5 years. Reference lists from the most recent reviews, as well as additional sources of primary literature and references cited by relevant articles, were used. Eighteen natural pharmaceutical substances and 24 extracted or recombinant products, and artificial agents that can be used against OS, inflammation, and neurodegeneration were identified. After presenting the most common neurodegenerative diseases and mentioning some of the basic mechanisms that lead to neuronal loss, this paper presents up to date information that could encourage the development of better therapeutic strategies. This review shares the new potential pharmaceutical and not pharmaceutical options that have been recently introduced regarding OS and inflammatory responses in neurodegenerative diseases.

Dyspnea in COPD: New Mechanistic Insights and Management Implications

Abstract: Dyspnea is the most common symptom experienced by patients with chronic obstructive pulmonary disease (COPD). To avoid exertional dyspnea, many patients adopt a sedentary lifestyle which predictably leads to extensive skeletal muscle deconditioning, social isolation, and its negative psychological sequalae. This “dyspnea spiral” is well documented and it is no surprise that alleviation of this distressing symptom has become a key objective highlighted across COPD guidelines. In reality, this important goal is often difficult to achieve, and successful symptom management awaits a clearer understanding of the underlying mechanisms of dyspnea and how these can be therapeutically manipulated for the patients’ benefit. Current theoretical constructs of the origins of activity-related dyspnea generally endorse the classical demand–capacity imbalance theory. Thus, it is believed that disruption of the normally harmonious relationship between inspiratory neural drive (IND) to breathe and the simultaneous dynamic response of the respiratory system fundamentally shapes the expression of respiratory discomfort in COPD. Sadly, the symptom of dyspnea cannot be eliminated in patients with advanced COPD with relatively fixed pathophysiological impairment. However, there is evidence that effective symptom palliation is possible for many. Interventions that reduce IND, without compromising alveolar ventilation (VA), or that improve respiratory mechanics and muscle function, or that address the affective dimension, achieve measurable benefits. A common final pathway of dyspnea relief and improved exercise tolerance across the range of therapeutic interventions (bronchodilators, exercise training, ambulatory oxygen, inspiratory muscle training, and opiate medications) is reduced neuromechanical dissociation of the respiratory system. These interventions, singly and in combination, partially restore more harmonious matching of excessive IND to ventilatory output achieved. In this review we propose, on the basis of a thorough review of the recent literature, that effective dyspnea amelioration requires combined interventions and a structured multidisciplinary approach, carefully tailored to meet the specific needs of the individual.

Current Perspectives on Gut Microbiome Dysbiosis and Depression.

Abstract: The human gut microbiome partakes in a bidirectional communication pathway with the central nervous system (CNS), named the microbiota-gut-brain axis. The microbiota-gut-brain axis is believed to modulate various central processes through the vagus nerve as well as production of microbial metabolites and immune mediators which trigger changes in neurotransmission, neuroinflammation, and behavior. Little is understood about the utilization of microbiome manipulation to treat disease. Though studies exploring the role of the microbiome in various disease processes have shown promise, mechanisms remain unclear and evidence-based treatments for most illnesses have not yet been developed. The animal studies reviewed here offer an excellent array of basic science research that continues to clarify mechanisms by which the microbiome may affect mental health. More evidence is needed, particularly as it relates to translating this work to human subjects. The studies presented in this paper largely demonstrate encouraging results in the treatment of depression. Limitations include small sample sizes and heterogeneous methodology. The exact mechanism by which the gut microbiota causes or alters neuropsychiatric disease states is not fully understood. In this review, we focus on recent studies investigating the relationship between gut microbiome dysbiosis and the pathogenesis of depression. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Burden of Community-Acquired Pneumonia and Unmet Clinical Needs

Abstract: Community-acquired pneumonia (CAP) is the leading cause of death among infectious diseases and an important health problem, having considerable implications for healthcare systems worldwide. Despite important advances in prevention through vaccines, new rapid diagnostic tests and antibiotics, CAP management still has significant drawbacks. Mortality remains very high in severely ill patients presenting with respiratory failure or shock but is also high in the elderly. Even after a CAP episode, higher risk of death remains during a long period, a risk mainly driven by inflammation and patient-related co-morbidities. CAP microbiology has been altered by new molecular diagnostic tests that have turned viruses into the most identified pathogens, notwithstanding uncertainties about the specific role of each virus in CAP pathogenesis. Pneumococcal vaccines also impacted CAP etiology and thus had changed Streptococcus pneumoniae circulating serotypes. Pathogens from specific regions should also be kept in mind when treating CAP. New antibiotics for CAP treatment were not tested in severely ill patients and focused on multidrug-resistant pathogens that are unrelated to CAP, limiting their general use and indications for intensive care unit (ICU) patients. Similarly, CAP management could be personalized through the use of adjunctive therapies that showed outcome improvements in particular patient groups. Although pneumococcal vaccination was only convincingly shown to reduce invasive pneumococcal disease, with a less significant effect in pneumococcal CAP, it remains the best therapeutic intervention to prevent bacterial CAP. Further research in CAP is needed to reduce its population impact and improve individual outcomes.

Ibuprofen Safety at the Golden Anniversary: Are all NSAIDs the Same? A Narrative Review

Abstract: Ibuprofen first came to market about 50 years ago and rapidly moved to over-the-counter (OTC) sales. In April 2019, the National Agency for the Safety of Medicines and Health Products (ANSM) of France issued a warning for NSAID uses by patients with infectious diseases based on an analysis of 20 years of real-world safety data on ibuprofen and ketoprofen. Nevertheless, ibuprofen remains a mainstay in the analgesic armamentarium and with numerous randomized clinical trials, head-to-head studies, and decades of clinical experience. The authors offer a review of the safety of ibuprofen and how it may differ from other NSAIDs. Ibuprofen is associated with certain well-known gastrointestinal adverse effects that are related to dose and patient population. Among nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen has a comparatively low risk of cardiovascular adverse effects. It has been associated with renal and hepatic adverse effects, which appear to depend on dose, concomitant medications, and patient population. The association of ibuprofen with infections is more complex in that it confers risk in some situations but benefits in others, the latter in cystic fibrosis. Emerging interest in the literature is providing evidence of the role of ibuprofen as a possible endocrine disrupter as well as its potential antiproliferative effects for cancer cells. Taken altogether, ibuprofen has a favorable safety profile and is an effective analgesic for many acute and chronic pain conditions, although it—like other NSAIDs—is not without risk. After 50 years, evidence is still emerging about ibuprofen and its unique safety profile among NSAIDs. The Rapid Service Fee was funded by Abbott Established Pharmaceuticals Division (EPD).

Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Outcomes with Nivolumab in Pretreated Non-Small Cell Lung Cancer (NSCLC): A Large Retrospective Multicenter Study

Abstract: Immune checkpoint inhibitors have provided substantial benefit in non-small cell lung cancer (NSCLC) with unprecedented results in terms of survival. However, the identification of reliable predictive biomarkers to these agents is lacking and multiple clinicopathological factors have been evaluated. The aim of this study was to analyze the potential role of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) levels in patients with pretreated NSCLC receiving nivolumab. This was a retrospective multicenter study involving 14 Italian centers, evaluating the role of some laboratory results in patients with NSCLC treated with nivolumab in the second or later lines of therapy for at least four doses and with a disease re-staging. A total of 187 patients with available pretreatment laboratory results were included. NLR levels below 5 were associated with an improvement in terms of both progression-free survival (PFS) (p = 0.028) and overall survival (OS) (p = 0.001), but not in terms of overall response rate (ORR) or disease control rate (DCR). Moreover, PLR levels below 200 were associated with longer PFS (p = 0.0267) and OS (p = 0.05), as well as higher ORR (p = 0.04) and DCR (p = 0.001). In contrast, LDH levels above the upper normal limit (UNL) were not associated with significant impact on patient outcomes. Patients with pretreated NSCLC and high pretreatment levels of NLR and PLR may experience inferior outcomes with nivolumab. Therefore, in this subgroup of patients with poor prognosis the use of alternative therapeutic strategies may be a valuable option, especially in programmed cell death ligand 1 (PD-L1)-negative patients and/or in the presence of other additional poor prognostic factors.

Papillary Thyroid Cancer—Aggressive Variants and Impact on Management: A Narrative Review

Abstract: Aggressive variants of papillary thyroid cancer (PTC) have been described with increasing frequency. These variants include diffuse sclerosing variant, tall cell variant, columnar cell variant, solid variant, and hobnail variant. We have performed a review of the more aggressive variants of PTC with respect to main characteristics, histological and molecular features, and the consequences that the knowledge of these variants should have in the treatment of the patients. At the present time, we do not know the prognostic value of these aggressive PTC variants. The extent of the surgical treatment and adjuvant therapy necessary should be decided on the basis of the extent of the tumor at presentation and the opinion of experienced clinicians. These aggressive variants should be known by clinicians, to avoid underdiagnosis, and treated according to the latest recommendations in the literature.

SABINA: An Overview of Short-Acting β2-Agonist Use in Asthma in European Countries.

Abstract: Globally, individuals with asthma tend to overrely on short-acting β2-agonists (SABAs) and underuse inhaled corticosteroids, thereby undertreating the underlying inflammation. Such relief-seeking behavior has been reinforced by long-standing treatment guidelines, which until recently recommended SABA-only use for immediate symptom relief. We aimed to describe the current burden of SABA use among European individuals with asthma within the SABA use IN Asthma (SABINA) program. Prescription and/or dispensing data during 2006–2017 from electronic medical records and/or national patient registries in the United Kingdom (UK), Germany, Italy, Spain, and Sweden were analyzed. Individuals aged at least 12 years old with a current asthma diagnosis and no other chronic respiratory conditions were included. Asthma treatment step and severity were based on treatment guidelines in use in each individual country. The proportion of individuals prescribed SABA was measured during a 12-month period. SABA overuse was defined as at least three SABA canisters per year. More than one million individuals with asthma were included across five European countries. Overall, the majority of individuals were over 45 years of age, except in Sweden (mean age 27.6 years) where individuals aged over 45 years were excluded to avoid a potential chronic obstructive pulmonary disease co-diagnosis. The study population was predominantly female (55–64%), except in the UK (46%). The prevalence of SABA overuse was 9% in Italy, 16% in Germany, 29% in Spain, 30% in Sweden, and 38% in the UK. In the UK, SABA overuse was greater in individuals with moderate-to-severe asthma versus individuals with mild asthma (58% versus 27%, respectively), while SABA overuse was similar in individuals with both mild (9–32%) and moderate-to-severe (8–31%) asthma in the other European countries. The findings of this study from the SABINA program show that SABA overuse (at least three canisters per year) is common across Europe, despite the different healthcare and reimbursement policies of each country.

Psoriasis and Cardiovascular Risk: A Comprehensive Review.

Abstract: Psoriasis is a systemic inflammatory disorder that involves complex pathogenic interactions between the innate and adaptive immune systems. Individuals with psoriasis have an increased risk of developing other chronic health diseases such cardiovascular disorders. The high incidence of cardiovascular events in the population with psoriasis could be explained by several mechanisms. The high prevalence of traditional cardiovascular risk factors and metabolic abnormalities contributes to the high cardiovascular burden in patients with psoriasis. Likewise, the presence of systemic inflammation in combination with metabolic abnormalities may act in a synergistic manner to increase cardiovascular risk in these patients. This review focused on epidemiologic and clinical evidence linking psoriasis to cardiovascular risk factors and cardiovascular disease. We described the possible pathophysiological mechanisms that justify this association and analyzed the best way to stratify the cardiovascular risk in patients with psoriasis. We also described the usefulness of the therapies frequently used in cardiovascular prevention and analyzed the impact of the specific psoriasis medication on cardiovascular risk factors or major atherosclerotic events. Knowledge of the application of different cardiovascular prevention strategies could mean an advantage in performing the difficult task of estimating cardiovascular risk and treating cardiovascular risk factors in this particular group of patients.

Effect of Empagliflozin on Liver Steatosis and Fibrosis in Patients With Non-Alcoholic Fatty Liver Disease Without Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial.

Abstract: Despite the high prevalence of non-alcoholic fatty liver disease (NAFLD) and its associated co-morbidities, no efficient treatment in a high percentage of individuals is available. Beneficial effects of sodium–glucose co-transporter 2 inhibitors on fatty liver have been investigated in people with type 2 diabetes (T2DM). The aim of this study was to explore the effect of empagliflozin on liver steatosis and fibrosis in patients with NAFLD without T2DM. In this prospective randomized, double-blind, placebo-controlled clinical trial, participants with NAFLD were randomized to empagliflozin (10 mg/day) (n = 43) or placebo (n = 47) for 24 weeks. Hepatic steatosis and fibrosis were assessed using transient elastography to measure the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). The primary outcome was the change in CAP score at 24 weeks. There was significant decrease in CAP score in both groups but no significant difference was observed between the two groups (P = 0.396). LSM was significantly decreased in the empagliflozin-treated group (6.03 ± 1.40 to 5.33 ± 1.08 kPa; P = 0.001), while no change was found in the placebo group. In subgroups analysis of patients with significant steatosis at baseline (CAP ≥ 302 dB/m), steatosis significantly improved in the empagliflozin group (37.2% vs. 17%; P = 0.035). There was a significant decrease in the grade of liver fat on visual analysis of ultrasound images, AST, ALT, and fasting insulin levels in the empagliflozin group, while no changes were observed in the placebo group. Empagliflozin improves liver steatosis and, more importantly, measures of liver fibrosis in patients with NAFLD without T2DM. ClinicalTrials.gov identifier, IRCT20190122042450N1.

The Promise for Histone Methyltransferase Inhibitors for Epigenetic Therapy in Clinical Oncology: A Narrative Review.

Abstract: Epigenetic processes are essential for normal development and the maintenance of tissue-specific gene expression in mammals. Changes in gene expression and malignant cellular transformation can result from disruption of epigenetic mechanisms, and global disruption in the epigenetic landscape is a key feature of cancer. The study of epigenetics in cancer has revealed that human cancer cells harbor both genetic alterations and epigenetic abnormalities that interplay at all stages of cancer development. Unlike genetic mutations, epigenetic aberrations are potentially reversible through epigenetic therapy, providing a therapeutically relevant treatment option. Histone methyltransferase inhibitors are emerging as an epigenetic therapy approach with great promise in the field of clinical oncology. The recent accelerated approval of the enhancer of zeste homolog 2 (EZH2; also known as histone-lysine N-methyltransferase EZH2) inhibitor tazemetostat for metastatic or locally advanced epithelioid sarcoma marks the first approval of such a compound for the treatment of cancer. Many other histone methyltransferase inhibitors are currently in development, some of which are being tested in clinical studies. This review focuses on histone methyltransferase inhibitors, highlighting their potential in the treatment of cancer. We also discuss the role for such epigenetic drugs in overcoming epigenetically driven drug resistance mechanisms, and their value in combination with other therapeutic approaches such as immunotherapy.

Asthma-Related Health Outcomes Associated with Short-Acting β2-Agonist Inhaler Use: An Observational UK Study as Part of the SABINA Global Program

Abstract: Patients with asthma typically increase short-acting β2-agonists (SABA) use with worsening symptoms. Excessive SABA use may lead to a higher risk of adverse outcomes. We evaluated, in a large population cohort, an association between SABA inhaler use and asthma exacerbations and healthcare utilization. As part of the SABINA (SABA use IN Asthma) global program, we conducted a retrospective longitudinal observational study (SABINA I) using UK primary care electronic healthcare records (Clinical Practice Research Datalink; 2007–2017) from asthma patients aged ≥ 12 years. SABA inhaler use was classified as ‘high use’, ≥ 3 canisters/year versus ‘low use’, 0–2 canisters/year. Taking into consideration all their asthma prescriptions, patients were categorized into a treatment step according to 2016 British Thoracic Society (BTS) asthma management guidelines. Multivariable regression assessed the association of SABA inhaler use by BTS treatment steps (grouped as BTS steps 1/2 and 3–5), separately, and with outcomes of exacerbations or asthma-related healthcare utilization (primary care and hospital outpatient consultations); only patients with linked hospital data were included in this analysis. Of the 574,913 patients included, 218,365 (38%) had high SABA inhaler use. Overall, 336,412 patients had linked hospital data. High SABA inhaler use was significantly associated with an increased risk of exacerbations [adjusted hazard ratio, 95% confidence interval (CI): BTS steps 1/2 = 1.20, 1.16–1.24; BTS steps 3–5 = 1.24, 1.20–1.28], asthma-related primary care consultations [adjusted incidence rate ratio (IRR), 95% CI: BTS steps 1/2 = 1.24, 1.23–1.26; BTS steps 3–5 = 1.13, 1.11–1.15], and asthma-related hospital outpatient consultations (adjusted IRR, 95% CI: BTS steps 1/2 = 1.19, 1.12–1.27; BTS steps 3–5 = 1.19, 1.13–1.26). High SABA inhaler use was frequent across BTS steps and was associated with a significant increase in exacerbations and asthma-related healthcare utilization.

Etrolizumab for the Treatment of Ulcerative Colitis and Crohn’s Disease: An Overview of the Phase 3 Clinical Program

Abstract: Etrolizumab is a next-generation anti-integrin with dual action that targets two pathways of inflammation in the gut. A robust phase 3 clinical program in ulcerative colitis (UC) and Crohn’s disease is ongoing and will evaluate the efficacy and safety of etrolizumab in well-defined patient populations in rigorous trials that include direct head-to-head comparisons against approved anti-tumor necrosis factor alpha agents (anti-TNF). The etrolizumab phase 3 clinical program consists of six randomized controlled trials (RCTs; UC: HIBISCUS I and II, GARDENIA, LAUREL, HICKORY; Crohn’s disease: BERGAMOT) and two open-label extension trials (OLEs; UC: COTTONWOOD; Crohn’s disease: JUNIPER) evaluating patients with moderately to severely active UC or Crohn’s disease. In the UC RCTs, patients are randomly assigned according to each protocol to receive etrolizumab, adalimumab, infliximab, or placebo. In BERGAMOT, patients are randomly assigned to receive etrolizumab 105 mg, etrolizumab 210 mg, or placebo. The primary outcomes for the UC RCTs are Mayo Clinic score-based clinical response, remission, and clinical remission; for BERGAMOT, the co-primary outcomes are clinical remission (based on abdominal pain and stool frequency) and endoscopic improvement (based on the Simple Endoscopic Score for Crohn’s disease). The OLEs will primarily assess long-term efficacy and safety. Secondary and exploratory endpoints include endoscopy, histology, quality of life, and biomarkers at various timepoints. The etrolizumab phase 3 clinical program is the largest and most comprehensive in inflammatory bowel disease, enrolling more than 3000 patients. The program explores both induction and maintenance regimens. HIBISCUS I and II and GARDENIA are among the first head-to-head trials in UC against an anti-TNF and are the first registrational trials making that comparison. This program will also help address unanswered clinical questions on evaluation of treatment effects and treatment selection across a range of patients with varying treatment histories using an extensive repository of patient samples and data. ClinicalTrials.gov: HIBISCUS I (NCT02163759), HIBISCUS II (NCT02171429), GARDENIA (NCT02136069), LAUREL (NCT02165215), HICKORY (NCT02100696), COTTONWOOD (NCT02118584), BERGAMOT (NCT02394028), JUNIPER (NCT02403323).

New Perspectives for Mucolytic, Anti-inflammatory and Adjunctive Therapy with 1,8-Cineole in COPD and Asthma: Review on the New Therapeutic Approach.

Abstract: The mucolytic monoterpene 1,8-cineole (eucalyptol), the major constituent of eucalyptus species, is well known for its anti-inflammatory, antioxidant, bronchodilatory, antiviral and antimicrobial effects. The main protective antiviral, anti-inflammatory and mucolytic mechanisms of 1,8-cineole are the induction of interferon regulatory factor 3 (IRF3), the control of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) along with decreasing mucin genes (MUC2, MUC19). In normal human monocytes direct inhibition was shown of reactive oxygen species (ROS)-mediated mucus hypersecretion and of steroid resistence inducing superoxides (O2·−) and pro-inflammatory hydrogen peroxides (H2O2) with partial control of superoxide dismutase (SOD), which enzymatically metabolizes O2·− into H2O2. By inhibition of NF-κB, 1,8-cineole, at relevant plasma concentrations (1.5 µg/ml), strongly and significantly inhibited in normal human monocyte lipopolysaccharide (LPS)-stimulated cytokines relevant for exacerbation (tumour necrosis factor alpha (TNFα), interleukin (IL)-1β and systemic inflammation (IL-6, IL-8). Infectious agents and environmental noxa have access via TNFα and IL-1β to the immune system with induction of bronchitis complaints and exacerbations of chronic obstructive pulmonary disease (COPD), asthma and asthma–COPD overlap. In lymphocytes from healthy human donors 1,8-cineole inhibited TNFα, IL-1β, IL-4 and IL-5 and demonstrated for the first time control of Th1/2-type inflammation. 1,8-Cineole at relevant plasma levels increased additively in vitro the efficacy of inhaled guideline medications of budesonide (BUD) and budesonide + formoterol ,and preliminary data also showed increased efficacy of long-acting muscarinic receptor antagonist (LAMA)-mediated cytokine inhibition in vitro. On the basis of the preclinical data, earlier randomised controlled studies with adjunctive therapy of 1,8-cineole (3 × 200 mg/day) for 6 months showed improvement of uncontrolled asthma by significant improvement of lung function, nocturnal asthma and quality of life scores and in COPD decrease of exacerbations (− 38.5%) (during wintertime). This review reports an update with reference to the literature of 1,8-cineole, also as adjunctive therapy, as a therapeutic agent for the protection and control of inflammatory airway diseases.

Fatigue in Inflammatory Bowel Diseases: Etiologies and Management

Abstract: Fatigue is a burdensome, multidimensional, and multifactorial symptom that is associated with a wide array of chronic illnesses, specifically occurring in nearly 50% of patients with inflammatory bowel disease (IBD). Although common, given its subjective nature, physicians often under-recognize and undertreat this debilitating symptom. There are multiple etiologies that can contribute to fatigue in patients with IBD, including disease activity, anemia, medications, psychosomatic symptoms, and alterations to the gut–brain axis. The management of fatigue in IBD can be challenging, as it is often times multifaceted. In this review, we summarize the available tools for the diagnosis and measurement of fatigue, discuss etiologies, and make recommendations for their management. We identify knowledge gaps for the workup and treatment of fatigue and propose an algorithm to aid physicians in the evaluation and management of fatigue in this unique population. However, future research is needed to address several areas of knowledge deficits and improve the management of fatigue in IBD.

Sex-Related Differences in Pharmacokinetics and Pharmacodynamics of Frequently Prescribed Drugs: A Review of the Literature.

Abstract: While there is considerable evidence about sex-related differences between men and women in drug metabolism, efficacy and safety of frequently prescribed drugs such as analgesics, tranquillizers, statins and beta-blockers, clinicians’ awareness of the implications on dosing and adverse event monitoring in routine practice is inadequate. Some drugs are more effective in men than women (e.g. ibuprofen) or vice versa (e.g. opioids, benzodiazepine), typically owing to pharmacodynamic causes. The 5-hydroxytryptamine (5-HT) receptor 3 antagonist alosetron is approved for women only since it largely lacks efficacy in men. For statins, equal efficacy was demonstrated in secondary prevention of cardiovascular events, but primary prevention is still under debate. For some drugs (e.g. paracetamol, metoprolol), women are at significantly higher risk of adverse effects. Therefore, considering sex-specific features in clinical trials and therapeutic guidelines is warranted to ensure efficacy and safety of medicines.

Cellular Senescence as a Therapeutic Target for Age-Related Diseases: A Review

Abstract: Life expectancy has increased substantially over the last few decades, leading to a worldwide increase in the prevalence and burden of aging-associated diseases. Recent evidence has proven that cellular senescence contributes substantially to the development of these disorders. Cellular senescence is a state of cell cycle arrest with suppressed apoptosis and concomitant secretion of multiple bioactive factors (the senescence-associated secretory phenotype—SASP) that plays a physiological role in embryonic development and healing processes. However, DNA damage and oxidative stress that occur during aging cause the accumulation of senescent cells, which through their SASP bring about deleterious effects on multiple organ and systemic functions. Ablation of senescent cells through genetic or pharmacological means leads to improved life span and health span in animal models, and preliminary evidence suggests it may also have a positive impact on human health. Thus, strategies to reduce or eliminate the burden of senescent cells or their products have the potential to impact multiple clinical outcomes with a single intervention. In this review, we touch upon the basics of cell senescence and summarize the current state of development of therapies against cell senescence for human use.

Impact of Endometriosis Diagnostic Delays on Healthcare Resource Utilization and Costs.

Abstract: Endometriosis symptoms are nonspecific and overlap with other gynecologic and gastrointestinal diseases, leading to long diagnostic delays. The burden of endometriosis has been documented; however, little is known about the impact of diagnostic delays on healthcare costs leading up to diagnoses. The purpose of this study was to examine the economic impact of diagnostic delays on pre-diagnosis healthcare utilization and costs among patients with endometriosis. This was a retrospective database study of adult patients with a diagnosis of endometriosis from 1 January 2004 to 31 July 2016. Patients had continuous health plan enrollment 60 months prior to and 12 months following the earliest endometriosis diagnosis and ≥ 1 pre-diagnosis endometriosis symptom (dyspareunia, generalized pelvic pain, abdominal pain, dysmenorrhea, or infertility). Patients were assigned to short (≤ 1 year), intermediate (1–3 years), or long (3–5 years) delay cohorts based on the length of their diagnostic delay (time from first symptom to diagnosis). Healthcare resource utilization and costs were calculated and compared by cohort in the 60-month pre-diagnosis period. A total of 11,793 patients were included in the study, of which 37.7% (4446/11,793), 27.0% (3179/11,793), and 35.3% (4168/11,793) had short, intermediate, and long delays, respectively. Patients with intermediate or long diagnostic delays had consistently more all-cause and endometriosis-related emergency visits and inpatient hospitalizations in the pre-diagnosis period than patients with short delays. Pre-diagnosis all-cause healthcare costs were significantly higher among patients with longer diagnostic delays, averaging $21,489, $30,030, and $34,460 among patients with a short, intermediate, and long delay, respectively (p < 0.001 for all pairwise comparisons). Endometriosis-related costs accounted for 12.5% ($3553/$28,376) of all-cause costs and followed a similar pattern. Patients with endometriosis who had longer diagnostic delays had more pre-diagnosis endometriosis-related symptoms and higher pre-diagnosis healthcare utilization and costs compared with patients who were diagnosed earlier after symptom onset, providing evidence in support of earlier diagnosis.

Effectiveness and Safety of High Dose Tigecycline for the Treatment of Severe Infections: A Systematic Review and Meta-Analysis

Abstract: Studies assessing the effect of high dose tigecycline on severe infections are limited and remain controversial. To assess systematically the effectiveness and safety of high dose tigecycline in the treatment of severe infections. Pubmed, Web of Science, Embase, MEDLINE, Cochrane Library and ClinicalTrials were searched up to February 20, 2019 for studies that compared the effectiveness and safety of high dose tigecycline with standard dose tigecycline or other non-tigecycline-containing regimens in the treatment of severe infections. Rates for all-cause mortality, clinical cure, microbiological eradication and adverse events were analysed. Ten studies with 593 patients were included. The results indicated that using high dose tigecycline resulted in better outcomes compared with controls with lower all-cause mortality (OR 0.44, 95% CI 0.30–0.66, p < 0.0001), higher clinical cure (OR 3.43, 95% CI 2.09–5.63, p < 0.00001), higher microbiological eradication (OR 2.25, 95% CI 1.44–3.50, p = 0.0003), and without increasing adverse events rates. Subgroup analysis showed that high dose tigecycline reduced all-cause mortality in nosocomial acquired pneumonia (OR 0.39, 95% CI 0.22–0.70, p = 0.002), bloodstream infections (OR 0.19, 95% CI 0.06–0.58, p = 0.004) and mixed infections (OR 0.20, 95% CI 0.07–0.59, p = 0.003), with no statistical differences in complicated intra-abdominal infections (OR 2.04, 95% CI 0.80–5.23, p = 0.14). In carbapenem-resistant pathogens, the microbiological eradication rate in those given high dose tigecycline did not differ from controls (OR 1.07, 95% CI 0.44–2.60, p = 0.87), although mortality was reduced (OR 0.20, 95% CI 0.09–0.45, p = 0.0001). The main limitation of the review is that most of the included studies are observational studies with small sample sizes and high risks of bias. High dose tigecycline treatment is effective and safe for severe infections owing to its lower all-cause mortality, higher clinical cure, microbiological eradication and comparable adverse events. However, as a result of the high risks of bias of the included studies, well-designed randomised clinical trials are warranted to establish the effectiveness and safety of high dose tigecycline compared with standard dose tigecycline and other commonly used antibiotics.

Prevalence and Management Challenges in Central Post-Stroke Neuropathic Pain: A Systematic Review and Meta-analysis.

Abstract: Central post-stroke pain (CPSP) is defined as the neuropathic pain that arises either acutely or in the chronic phase of a cerebrovascular event and is a result of central lesions of the somatosensory tract. The aim of this systematic review and meta-analysis was to establish the prevalence of CPSP, to describe its characteristics, and to discuss the associated management challenges. After a systematic Medline search, we identified 69 papers eligible to be included. The pooled prevalence of CPSP in patients with stroke at any location was 11% (95% CI 7–18%), which can increase to more than 50% in the subgroups of patients with medullary or thalamic strokes. CPSP onset coincides with stroke occurrence in 26% of patients (95% CI 18–35%); CPSP manifests within a month since symptom onset in 31% of patients (95% CI 22–42%), and occurs between the first month and the first year in 41% of patients (95% CI 33.9–49.0%). CPSP develops more than 12 months after stroke onset in 5% of patients (95% CI 3–8%). Clinicians should look for any evidence of central neuropathic pain for at least 12 months after stroke. Both pharmacological and non-pharmacological interventions can be used for the management of CPSP. Lamotrigine has the strongest evidence (Level II of evidence, derived from small randomized controlled trials) for being effective in the management of CPSP. Future research should focus on well-designed trials of pharmacological and non-pharmacological interventions aiming to relief CPSP, which is a very common but often neglected pain syndrome.

Dysfunctional Coagulation in COVID-19: From Cell to Bedside.

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which can induce multisystem disease. Human angiotensin-converting enzyme 2 (ACE2) widely expressing in arterial and venous endothelial cells and arterial smooth muscle cells has been identified as a functional receptor for SARS-CoV-2. Dysfunction of ACE2 leads to abnormal activation of the renin-angiotensin system and a systemic endotheliitis that may relate to abnormal coagulation and sepsis. Meanwhile, innate immune response and inflammation activation participate in dysfunctional coagulation. Previous research indicated that dysfunctional coagulation was one of the important risk factors accountable for a high risk of severe disease and death in patients with COVID-19. Understanding the possible mechanisms of dysfunctional coagulation and appropriate anticoagulation therapeutic strategies are important to prevent disease deterioration and reduce fatality rates during the ongoing COVID-19 pandemic.

Long-Term Safety of Adalimumab in 29,967 Adult Patients From Global Clinical Trials Across Multiple Indications: An Updated Analysis.

Abstract: The safety profile of adalimumab was previously reported in 23,458 patients across multiple indications. Here we report the long-term safety of adalimumab in adults with plaque psoriasis (Ps), hidradenitis suppurativa (HS), rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis, non-radiographic axial spondyloarthritis, peripheral spondyloarthritis, Crohn’s disease (CD), ulcerative colitis (UC), and non-infectious uveitis (UV). Safety data from 77 clinical trials were pooled. Safety assessments included adverse events (AEs) and serious AEs (SAEs) that occurred after the first study dose and within 70 days (5 half-lives) after the last study dose. A total of 29,967 patients were included, representing 56,916 patient-years (PY) of exposure. The most frequently reported SAE of interest was infection (3.7/100 PY) with highest incidences in CD, RA, UV, and UC (3.5/100 PY–6.9/100 PY); serious infections in Ps (1.8/100 PY) and HS (2.8/100 PY) were lower. The observed number of deaths was below what would be expected in an age- and sex-adjusted population for most adalimumab-treated patients (including Ps). Lack of real-life data and limited long-term data (> 5 years) for most patients are limitations of this analysis. The safety profile of adalimumab was consistent with previous findings and no new safety signals were observed.

Ability of Serum IgE Concentration to Predict Exacerbation Risk and Benralizumab Efficacy for Patients with Severe Eosinophilic Asthma.

Abstract: For patients with eosinophilic asthma with allergic characteristics, understanding the key drivers of exacerbations is important to identify optimal treatment strategies. Benralizumab is an interleukin-5 receptor alpha–directed cytolytic monoclonal antibody that significantly reduces exacerbation frequency for patients with severe, uncontrolled eosinophilic asthma. We evaluated the predictive value of baseline blood eosinophil counts vs. serum immunoglobulin E (IgE) concentrations on exacerbation risk and the association of these variables with benralizumab treatment effect. Analyses were performed with data pooled from the phase III SIROCCO and CALIMA benralizumab trials. Crude annual asthma exacerbation rates (AERs) were determined for placebo as a function of baseline blood eosinophil counts and serum IgE concentrations with prespecified blood eosinophil count categories (< 150, ≥ 150 to < 300, ≥ 300 to < 450, ≥ 450 cells/µL) and IgE concentration quartiles (< 62.0, ≥ 62.0 to < 176.2, ≥ 176.2 to < 453.4, and ≥ 453.4 kU/L). We compared AERs for patients receiving benralizumab 30 mg every 8 weeks (first three doses every 4 weeks) vs. placebo for overlapping baseline blood eosinophil count categories and serum IgE concentration quartiles via a regression approach and by continuously using locally weighted regression smoothing analysis. Exacerbation risk for patients with severe asthma receiving placebo increased with increasing baseline blood eosinophil counts but not with increasing serum IgE concentrations. Addition of baseline atopy status did not influence the relationship between IgE concentrations and exacerbation risk for patients receiving placebo. Patients with blood eosinophil counts ≥ 300 cells/µL had consistent decreases in exacerbation risk with benralizumab relative to placebo across all serum IgE concentration quartiles. Baseline blood eosinophil counts, but not serum IgE concentrations, are an important predictor of exacerbation risk. Patients with severe eosinophilic asthma treated with benralizumab had consistent reductions in exacerbation risk, regardless of IgE concentrations. ClinicalTrials.gov: SIROCCO, NCT01928771; CALIMA, NCT01914757. Many patients with severe asthma have elevated numbers of eosinophils (a subset of white blood cells) and raised serum concentrations of immunoglobulin E (IgE; antibodies). Elevated eosinophil counts together with IgE concentrations are associated with more frequent asthma attacks. Benralizumab is a drug that almost completely depletes eosinophils and significantly reduces asthma attacks for patients with severe, uncontrolled asthma and elevated blood eosinophil counts. The individual influence of eosinophils and IgE on benralizumab efficacy has been published. In this study, we further extend the analyses to evaluate the interrelationship of eosinophil counts and IgE concentrations with asthma attack frequency and benralizumab efficacy for patients with severe, uncontrolled asthma. We evaluated the association of blood eosinophil counts and IgE concentrations with asthma attack frequency for patients with severe asthma who received high-dosage inhaled corticosteroids plus additional controller medications but did not receive benralizumab in the benralizumab clinical trials. We observed that increased blood eosinophil counts were associated with greater asthma attack frequency, while serum IgE concentrations had no influence on asthma attack frequency. We also evaluated patients who received benralizumab and determined that benralizumab can reduce the occurrence of these attacks for patients with elevated blood eosinophil counts regardless of their serum IgE concentrations. Frequency of asthma attacks also decreased with benralizumab for patients with elevated serum IgE concentrations, but serum IgE concentrations did not influence benralizumab efficacy. Benralizumab is an efficacious treatment for patients with uncontrolled eosinophilic asthma, regardless of their IgE concentrations.

Fact vs Fallacy: The Anti-Vaccine Discussion Reloaded.

Abstract: In the light of the COVID-19 pandemic, anti-vaccine sentiments have been on the rise, with a recent seminal study on the development of anti-vaccine views in social media even making its way into Nature Communications. Yet, with the current scientific consensus being in overwhelming agreement over the safety and efficacy of vaccines, many scientists lose their grasp on the fears, concerns, and arguments that the opposition may hold. This paper discusses and evaluates vaccine-hesitant individuals on a socioeconomic, historical, and philosophical landscape. It also provides an analysis of common argumentative patterns and the psychological impact that these arguments may have on undecided individuals. The discussion also explores why anti-vaccine sentiments are on the rise, and how members of the scientific and medical community require a more structured approach to communicating key arguments. This is particularly important if vaccination rates and herd immunity are to be sustained. No longer is it sufficient to win arguments based on a factual and scientific basis, but rather scientists and medical practitioners have to focus on conveying confidence and reassurance on both an informative and emotional level to those with doubts and fears.

New Technologies and Applications in Sacral Neuromodulation: An Update.

Abstract: Recently rechargeable devices have been introduced for sacral neuromodulation (SNM) with conditional safety for full-body magnetic resonance imaging (MRI). Currently a recharge-free SNM device represents the standard implant; however, it is only approved for MRI head scans. As further new technologies with broader MRI capabilities are emerging, the advantages as well as disadvantages of both rechargeable versus recharge-free devices will be briefly discussed in this commentary from the perspective of patients, healthcare professionals, and providers.

Anti COVID-19 Drugs: Need for More Clinical Evidence and Global Action.

Abstract: The World Health Organization (WHO) called the outbreak of coronavirus infectious disease-2019 (COVID-19) a "Public Health Emergency of International Concern" (PHEIC). According to the WHO, Centers for Disease Control and Prevention (CDC), and the US Food and Drug Administration (FDA), currently there are no medicines or vaccines that have been claimed to be useful in the prevention or treatment of COVID-19. Several existing antiviral drugs, previously developed or used as treatments for severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), human immunodeficiency virus (HIV), and malaria, are being investigated as COVID-19 treatments and some of them are being used in clinical trials. According to the CDC and Chinese treatment guidelines for COVID-19, chloroquine, hydroxychloroquine, lopinavir/ritonavir, and one of the investigational agents (remdesivir) are recommended in critically ill older patients. The use of other potential drugs reported in different studies may be considered if treatment with first-line drugs is ineffective. There are currently no complete data available from large randomized clinical trials (RCTs) to provide clinical guidance on the use, dosing, or duration to validate the effective role, safety profile, and adverse effects of all of the trial drugs for prophylaxis or treatment of COVID-19. Until now, it is still unclear which drug can successfully fight against the disease. Therefore, for the better safety of patients with COVID-19, further clinical trials and large randomized controlled studies are needed to validate the effective role, safety profile, and adverse effects of all the potential drugs. Such a measure requires action at the global level.

Recognising Skin Cancer in Primary Care.

Abstract: Skin cancer, including melanoma, basal cell carcinoma and cutaneous squamous cell carcinoma, has one of the highest global incidences of any form of cancer. In 2016 more than 16,000 people were diagnosed with melanoma in the UK. Over the last decade the incidence of melanoma has increased by 50% in the UK, and about one in ten melanomas are diagnosed at a late stage. Among the keratinocyte carcinomas (previously known as non-melanoma skin cancers), basal cell carcinoma is the most common cancer amongst Caucasian populations. The main risk factor for all skin cancer is exposure to ultraviolet radiation-more than 80% are considered preventable. Primary care clinicians have a vital role to play in detecting and managing patients with skin lesions suspected to be skin cancer, as timely diagnosis and treatment can improve patient outcomes, particularly for melanoma. However, detecting skin cancer can be challenging, as common non-malignant skin lesions such as seborrhoeic keratoses share features with less common skin cancers. Given that more than 80% of skin cancers are attributed to ultraviolet (UV) exposure, primary care clinicians can also play an important role in skin cancer prevention. This article is one of a series discussing cancer prevention and detection in primary care. Here we focus on the most common types of skin cancer: melanoma, squamous cell carcinoma and basal cell carcinoma. We describe the main risk factors and prevention advice. We summarise key guidance on the symptoms and signs of skin cancers and their management, including their initial assessment and referral. In addition, we review emerging technologies and diagnostic aids which may become available for use in primary care in the near future, to aid the triage of suspicious skin lesions.