Safety, Tolerability, and Pharmacokinetics of Benralizumab: A Phase 1, Randomized, Single-Blind Study of Healthy Chinese Participants.

Purpose: Biological therapies targeting eosinophils have been shown to be effective in treating patients with severe eosinophilic asthma. Benralizumab (Fasenra®, AstraZeneca) is a humanized monoclonal antibody binding to the alpha subunit of the interleukin-5 receptor, which rapidly depletes eosinophils via antibody-dependent cellular cytotoxicity. The aim of this Phase 1 study was to assess the safety, tolerability, and pharmacokinetics of benralizumab in healthy Chinese individuals. Materials and Methods: In this randomized, single-blind study (NCT03928262), healthy Chinese adult participants aged 18 to 45 years, weighing 50 to 100 kg, were randomized 1:1:1 to receive a single subcutaneous (SC) injection of benralizumab 10 mg, 30 mg, or 100 mg in the upper arms on Day 1. Safety was monitored throughout the study (up to Day 85), and blood samples were taken to determine serum benralizumab concentrations and for detection of anti-drug antibody. A non-compartmental analysis was conducted to estimate the pharmacokinetic parameters. Results: Thirty-six healthy participants were enrolled, 12 in each dose group (mean [SD] age 26 [6] years). Following a single SC injection of benralizumab, 13 adverse events were reported by 10 participants (28%), with one mild injection-site reaction assessed as related. The mean serum benralizumab concentrations increased in a dose proportional manner, followed by exponential decreases. The mean terminal half-lives were 15.1 days for the 10 mg dose, 14.4 days for the 30 mg dose, and 15.4 days for the 100 mg dose. All doses resulted in near-complete depletion of eosinophils on Day 2, which was maintained throughout the study to Day 85. Conclusion: A single SC injection of benralizumab was well tolerated by healthy Chinese participants, with no new or unexpected safety findings. The pharmacokinetics of benralizumab in Chinese participants was dose-proportional and consistent with those of non-Chinese participants observed in previous studies. Clinical Trial Registration: NCT03928262 (https://clinicaltrials.gov/ct2/show/NCT03928262).

Blood lead level and risk of hypertension in the United States National Health and Nutrition Examination Survey 1999-2016.

Lead is a heavy metal without a biological role. High level of lead exposure is known to be associated with hypertension, but the risk at low levels of exposure is uncertain. In this study, data from US NHANES 1999-2016 were analyzed. Adults with blood lead and blood pressure measurements, or self-reported hypertension diagnosis, were included. If not already diagnosed, hypertension was defined according to the AHA/ACC 2017 hypertension guideline. Results were analyzed using R statistics version 3.5.1 with sample weight adjustment. Logistic regression was used to study the association between blood lead level and hypertension. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated. Altogether, 39,477 participants were included. Every doubling in blood lead level was associated with hypertension (OR [95%CI] 1.45 [1.40-1.50]), which remained significant after adjusting for demographics. Using quartile 1 as reference, higher blood lead levels were associated with increased adjusted odds of hypertension (Quartile 4 vs. Quartile 1: 1.22 [1.09-1.36]; Quartile 3 vs. Quartile 1: 1.15 [1.04-1.28]; Quartile 2 vs. Quartile 1: 1.14 [1.05-1.25]). In conclusion, blood lead level is associated with hypertension in the general population with blood lead levels below 5 µg/dL. Our findings suggest that reducing present levels of environmental lead exposure may bring cardiovascular benefits by reducing blood pressure.

Blood and Urine Inorganic and Organic Mercury Levels in the United States from 1999 to 2016.

BACKGROUND: Mercury is an environmental hazard. Organic mercury is biologically more toxic than inorganic mercury. Therefore, we studied recent trends in the blood levels of organic and inorganic mercury in the United States. METHODS: A total of 56,445 participants that had blood mercury and urine mercury measurements in National Health and Nutrition Examination Survey (NHANES) 1999-2016 were included. The organic mercury level was obtained by subtracting the inorganic mercury level from the total mercury level. Results were analyzed using SPSS complex sample module version 25. Pregnant women, children ages <20 years, and different ethnicities were analyzed as subgroups. RESULTS: Blood organic mercury level increased from (geometric mean [95% confidence interval]) 0.08 [0.07-0.10] to 0.17 [0.16-0.18] µg/L during 1999-2016. It increased significantly (P <0.001) from 0.03 [0.02-0.03] to 0.07 [0.06-0.07] µg/L in children ages <20 and from 0.14 [0.09-0.21] to 0.36 [0.16-0.83] µg/L in pregnant women in this period (P <0.001). In 2013-2016, non-Hispanic Asians had the highest blood organic mercury level among different ethnicities, 0.93 [0.82-1.05] µg/L (P <0.001). Blood inorganic mercury level decreased from 0.31 [0.31-0.31] in 1999-2000 to 0.21 [0.21-0.22] µg/L in 2015-2016 (P <0.001). Urine mercury level decreased from 0.75 [0.71-0.80] in 1999-2000 to 0.16 [0.16-0.17] µg/L in 2015-2016 (P <0.001). CONCLUSION: Blood organic mercury increased over the period 1999-2016 in the US population, including children and pregnant women, whereas there was a steady decline in both blood inorganic mercury and urine mercury levels.

Epidemiology of gout in Hong Kong: a population-based study from 2006 to 2016.

OBJECTIVE: To determine the incidence and prevalence of gout in the general population and the utilisation of urate-lowering therapy (ULT) among patients with gout in Hong Kong. METHODS: A total of 2,741,862 subjects who attended any outpatient clinics or accident and emergency department (with or without hospitalisation) in 2005 and did not die before 2006 were identified from the Clinical Data Analysis and Reporting System (CDARS) of the Hospital Authority in Hong Kong. All subjects were followed until the end of 2016 or death. Demographics, diagnosis of gout, serum urate levels, and ULT prescriptions were retrieved from CDARS. Gout was defined by the diagnosis codes in CDARS. The serum urate levels achieved after prescribing ULT were the means of all serum urate levels measured 6 months after prescriptions. Results were analysed by R version 3.3.3 with package 'prevalence' version 0.4.0. RESULTS: The crude incidence of gout increased from 113.05/100,000 person-years (PY) in 2006 to 211.62/100,000 PY in 2016. The crude prevalence of gout increased from 1.56% in 2006 to 2.92% in 2016. Only 25.55% of patients with gout were prescribed ULT in 2016. 35.8% of patients treated with ULT were able to achieve the target serum urate level of < 6 mg/dL. CONCLUSIONS: Population ageing as well as other risk factors contributed to an increase in the incidence and prevalence of gout in Hong Kong. In 2016, the crude prevalence of gout in Hong Kong was comparable to that in many western countries. However, only one in four patients with gout in Hong Kong was prescribed ULT.

Prevalence and Impact of Reported Drug Allergies among Rheumatology Patients.

BACKGROUND: Drug allergies (DA) are immunologically mediated adverse drug reactions and their manifestations depend on a variety of drug- and patient-specific factors. The dysregulated immune system underpinning rheumatological diseases may also lead to an increase in hypersensitivity reactions, including DA. The higher prevalence of reported DA, especially anti-microbials, also restricts the medication repertoire for these already immunocompromised patients. However, few studies have examined the prevalence and impact of reported DA in this group of patients. METHODS: Patients with a diagnosis of rheumatoid arthritis (RA), spondyloarthritis (SpA), or systemic lupus erythematosus (SLE) were recruited from the rheumatology clinics in a tertiary referral hospital between 2018 and 2019. Prevalence and clinical outcomes of reported DA among different rheumatological diseases were calculated and compared to a cohort of hospitalized non-rheumatology patients within the same period. RESULTS: A total of 6081 patients (2541 rheumatology patients: 1286 RA, 759 SpA, and 496 SLE; and 3540 controls) were included. DA was more frequently reported among rheumatology patients compared to controls (23.8% vs. 13.8%, p < 0.01). Antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) were the two most commonly reported categories of DA with a prevalence of 12.0% and 5.1%, respectively. Reported antibiotics allergies were more frequent in patients with RA (OR = 1.20, 95% CI = 1.02-1.62, p = 0.03) and SLE (OR = 4.69, 95% CI = 3.69-5.95, p < 0.01); and associated with increased infection-related admissions among rheumatology patients (OR = 1.79, 95% CI = 1.09-2.95, p = 0.02). Among the subgroup of patients referred for allergy testing, 85.7% of beta-lactam antibiotic allergy labels were found to be inaccurate and de-labelled after negative drug provocation testing. CONCLUSION: The prevalence of reported DA was significantly higher in rheumatology patients. Reported antibiotic allergy was associated with increased rate of infection-related admissions. However, the rate of genuine antibiotic allergy was low. Further studies are needed to guide proper assessment of reported DA and impact of comprehensive allergy testing in this group of patients.

Management of rheumatoid arthritis: 2019 updated consensus recommendations from the Hong Kong Society of Rheumatology.

The expanding range of treatment options for rheumatoid arthritis (RA), from conventional synthetic disease-modifying antirheumatic drugs (DMARDs) to biological DMARDs (bDMARDs), biosimilar bDMARDs, and targeted synthetic DMARDs, has improved patient outcomes but increased the complexity of treatment decisions. These updated consensus recommendations from the Hong Kong Society of Rheumatology provide guidance on the management of RA, with a focus on how to integrate newly available DMARDs into clinical practice. The recommendations were developed based on evidence from the literature along with local expert opinion. Early diagnosis of RA and prompt initiation of effective therapy remain crucial and we suggest a treat-to-target approach to guide optimal sequencing of DMARDs in RA patients to achieve tight disease control. Newly available DMARDs are incorporated in the treatment algorithm, resulting in a greater range of second-line treatment options. In the event of treatment failure or intolerance, switching to another DMARD with a similar or different mode of action may be considered. Given the variety of available treatments and the heterogeneity of patients with RA, treatment decisions should be tailored to the individual patient taking into consideration prognostic factors, medical comorbidities, drug safety, cost of treatment, and patient preference.

Network meta-analysis of cardiovascular outcomes in randomized controlled trials of new antidiabetic drugs.

BACKGROUND: Randomized controlled trials (RCTs) directly comparing cardiovascular outcomes of new antidiabetic drugs are lacking. We used network meta-analysis to compare new antidiabetic drug classes with respect to major adverse cardiovascular events (MACE) and mortality. METHODS: We searched MEDLINE, EMBASE, the Cochrane database, and ClinicalTrials.gov up to 30 December 2016 for RCTs involving SGLT-2 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors in diabetic patients that reported MACE and deaths. Outcomes were compared with frequentist and Bayesian methods using R statistics. RESULTS: Seven RCTs with altogether 62,268 patients were included in the network meta-analysis. The SGLT-2 inhibitor and GLP-1 RAs reduced MACE (OR 0.85, 95%CI 0.73-0.99 and 0.89, 0.82-0.97, respectively) and all-cause mortality (0.67, 0.55-0.81 and 0.89, 0.80-0.99, respectively) compared to placebo. Furthermore, the SGLT-2 inhibitor reduced all-cause mortality compared to GLP-1 RAs (0.76, 0.61-0.94). In contrast, DPP-4 inhibitors did not reduce MACE or mortality compared to placebo and were associated with higher all-cause mortality compared to the SGLT-2 inhibitor (1.53, 1.24-1.89) and GLP-1 RAs (1.16, 1.01-1.33). CONCLUSIONS: All-cause mortality and MACE were reduced by the SGLT-2 inhibitor and GLP-1 RAs, but not DPP-4 inhibitors. The SGLT-2 inhibitor had the most beneficial impact on all-cause mortality. DPP-4 inhibitors showed no cardiovascular benefit and were inferior to the other two drug classes in preventing deaths.

A Phase I, Single- and Multiple-dose Study to Evaluate the Pharmacokinetics of Elbasvir and Grazoprevir in Healthy Chinese Participants.

PURPOSE: This study evaluated the single- and multiple-dose pharmacokinetic (PK) variables of elbasvir and grazoprevir in healthy Chinese individuals. METHODS: This study was a 2-part, parallel-arm, open-label trial. In part 1, single-dose PK variables of elbasvir 10/50/100 mg and grazoprevir 50/100/200 mg were evaluated in 10 participants per drug. In part 2, 10-day multiple-dose PK variables of elbasvir 50 mg and grazoprevir 100 mg administered once daily alone and in combination were evaluated in 12 participants. Summary and inferential statistics of the PK parameters are reported. Elbasvir and grazoprevir PK parameters were also compared between Chinese participants and historical data from white participants. FINDINGS: Single-dose elbasvir and grazoprevir median Tmax were 2.9 to 4.0 and 1.9 to 3.0 hours after administration, respectively. Elbasvir AUC0-∞ and Cmax increased in a dose-proportional manner (slope estimate [90% CI], 0.92 [0.84-1.01] and 0.98 [0.86-1.09], respectively), whereas grazoprevir AUC0-∞ and Cmax increased in a greater-than-dose-proportional manner (slope estimate [90% CI], 1.42 [1.27-1.57] and 1.96 [1.64-2.29]). After repeated administration, the accumulation ratios for AUC0-24, 24-hour concentration, and Cmax were 1.55, 1.57, and 1.38 for elbasvir and 2.03, 1.23, and 2.51 for grazoprevir. Co-administration of elbasvir 50 mg and grazoprevir 100 mg once daily did not have a clinically relevant effect on the PK variables of either drug. Median Tmax after co-administration versus alone was 3.0 hours versus 3.0 hours for elbasvir and 3.1 hours versus 3.0 hours for grazoprevir. Geometric mean ratios (90% CI) for elbasvir and grazoprevir AUC0-24 (Chinese/white participants) were 1.58 (1.03-2.42) and 1.21 (0.76-1.92). Elbasvir and grazoprevir, administered alone or concomitantly, were well tolerated. IMPLICATIONS: In healthy Chinese individuals, administration of elbasvir and grazoprevir, alone or concomitantly, was generally well tolerated, with a thoroughly characterized PK profile. Elbasvir and grazoprevir exposures may trend higher in Chinese healthy participants relative to white healthy participants. Protocol number MK-8742 PN022.

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches.

Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: Meta-analysis of randomized controlled trials.

OBJECTIVE: After implantation of drug-eluting stents (DES), patients usually receive 6-12months of dual antiplatelet therapy (DAPT). However, the optimal duration of DAPT is controversial. Therefore, we performed a meta-analysis of randomized controlled trials to assess the risks and benefits of different DAPT durations. METHODS: We searched the literature using MEDLINE, Scopus, EMBASE, ISI Web of Science, Cochrane Library, ClinicalTrials.gov and recent conference proceedings, and included those trials randomizing patients to receive different durations of DAPT after DES implantation and reporting frequencies of cardiovascular and bleeding events. Data from eleven trials were analyzed using RevMan. RESULTS: Compared to 12-month DAPT treatment, extended DAPT significantly reduced the frequencies of myocardial infarction (OR 0.54 95% CI: 0.43-0.66; p<0.00001) and stent thrombosis (OR 0.36 95% CI: 0.24-0.55; p<0.00001), but the risks of major bleeding (OR 1.54 95% CI 1.22-1.96) and all-cause mortality (OR 1.43 95% CI 1.14-1.81) were substantially increased. There was no significant difference in stroke, cardiovascular mortality or repeat revascularization. Compared to short-term DAPT, 12-month DAPT or longer was associated with increased major bleeds (OR 1.98 95% CI: 1.26-3.11). No significant differences were found in the risk of other primary outcomes. CONCLUSION: 12-month DAPT appears to be a pragmatic compromise between preventing stent thrombosis and increasing bleeding risk. Patients at high bleeding risk should have shorter duration DAPT while those with low bleeding risk can be considered for DAPT beyond 12months.

Continual Decrease in Blood Lead Level in Americans: United States National Health Nutrition and Examination Survey 1999-2014.

BACKGROUND: Lead is toxic and affects neurodevelopment in children even at low levels. There has been a long-term effort in the United States to reduce exposure to lead in the environment. We studied the latest US population blood lead levels and analyzed its trend. METHOD: Blood lead levels in 63,890 participants of the National Health Nutrition and Examination Survey 1999-2014 were analyzed using SPSS Complex Samples v22.0 (IBM Corp, Armonk, NY). RESULTS: Mean blood lead levels and 95% confidence intervals (CIs) were 1.65 µg/dL (1.62-1.68), 1.44 µg/dL (1.42-1.47), 1.43 µg/dL (1.40-1.45), 1.29 µg/dL (1.27-1.32), 1.27 µg/dL (1.25-1.29), 1.12 µg/dL (1.10-1.14), 0.97 µg/dL (0.95-0.99), and 0.84 µg/dL (0.82-0.86) in 1999-2000, 2001-2002, 2003-2004, 2005-2006, 2007-2008, 2009-2010, 2011-2012, and 2013-2014, respectively. Blood lead levels decreased significantly (P <.001), and the trend remained significant when stratified by age, gender, ethnicity, and pregnancy status (P <.05). Estimated percentages of children with blood lead level ≥5 µg/dL were 9.9% (95% CI, 7.5-12.9), 7.4% (95% CI, 5.9-9.4), 5.3% (95% CI, 4.1-6.9), 2.9% (95% CI, 2.1-3.9), 3.1% (95% CI, 2.0-4.8), 2.1% (95% CI, 1.5-3.1), 2.0% (95% CI, 1.0-3.6), and 0.5% (95% CI, 0.3-1.0) in 1999-2000, 2001-2002, 2003-2004, 2005-2006, 2007-2008, 2009-2010, 2011-2012, and 2013-2014, respectively. The decreasing trend was significant (P <.05). In children aged 1 to 5 years in the National Health Nutrition and Examination Survey 2011-2014, the estimated 97.5 percentile of blood lead level was 3.48 µg/dL. CONCLUSIONS: Blood lead levels have been decreasing in the US population. The reference level also should decrease. It is still important to monitor blood lead levels in the population, especially among pregnant women and children aged 1 to 5 years.

Duration of dual antiplatelet therapy after drug-eluting stent implantation: Meta-analysis of large randomised controlled trials.

Patients receive dual antiplatelet therapy (DAPT) for 6-12 months after drug-eluting stents (DES) implantation. The efficacy and safety of prolonged DAPT has been questioned. Therefore, we performed a meta-analysis on randomised trials comparing different DAPT durations. Literature was searched on trials comparing different DAPT durations. For inclusion, reports must report frequency of cardiovascular and bleeding events. Ten trials were included. Compared to 12 months, DAPT beyond 12 months was associated with fewer myocardial infarctions (OR 0.58 95%CI: 0.40-0.84) and stent thrombosis (OR 0.35 95%CI: 0.20-0.62), but more major bleeds (OR 1.60 95%CI: 1.22-2.11) and all-cause (OR 1.30 95%CI: 1.02-1.66) mortality. There was no significant alteration in risk of stroke (OR 0.93 95%CI: 0.66-1.31) or cardiac (OR 1.12 95%CI: 0.73-1.71) mortality. Compared to less than 12 months DAPT, 12 months DAPT did not reduce risk of myocardial infarction, stent thrombosis, strokes, cardiac or all-cause mortality, but increased the risk of major bleeds (OR 1.60 95%CI: 1.22-2.11). DAPT beyond 12 months reduce risk of myocardial infarction and stent thrombosis, but there is substantial increase in major bleeding risk and all-cause mortality which need to be addressed. DAPT beyond 12 months does not appear to alter the risk of stroke.

Managing blood pressure control in Asian patients: safety and efficacy of losartan.

Hypertension is common in Asian populations and is a major cause of cardiovascular diseases. The prevalence of hypertension is increasing in many Asian countries. The overall prevalence of hypertension in India and the People's Republic of China has been estimated to be 20.6% in men and 22.6% in women. However, the rates of detection, treatment, and control of hypertension remain low in Asia. This reflects a low level of literacy and education, as well as a low level of access to medical care. To overcome these obstacles, strategies targeted at education, promotion, and optimization of medical care, are crucial to achieve target blood pressure control. Angiotensin receptor blockers are one of the first-line treatments for essential hypertension because they confer better cardiovascular outcomes. Losartan has been widely evaluated for the management of hypertension. Although some studies suggested that the blood pressure-lowering effect of losartan is perhaps lower than for other angiotensin receptor blockers, losartan has been demonstrated to be beneficial in terms of renal protection in patients with diabetes, heart failure resulting from either systolic or diastolic dysfunction, and diuretic-induced hyperuricemia. However, most of these data were obtained from Caucasian populations. The efficacy and safety of losartan in Asian populations may be different because of genetic and ethnic variations. Therefore, the efficacy and safety of losartan in Asian patients with hypertension warrant further study.

Safety of antiobesity drugs.

Obesity is a major health problem worldwide. Although diet and physical activity are crucial in the management of obesity, the long-term success rate is low. Therefore antiobesity drugs are of great interest, especially when lifestyle modification has failed. As obesity is not an immediate life-threatening disease, these drugs are required to be safe. Antiobesity drugs that have been developed so far have limited efficacies and considerable adverse effects affecting tolerability and safety. Therefore, most antiobesity drugs have been withdrawn. Fenfluramine and dexfenfluramine were withdrawn because of the potential damage to heart valves. Sibutramine was associated with an increase in major adverse cardiovascular events in the Sibutramine Cardiovascular Outcomes (SCOUT) trial and it was withdrawn from the market in 2010. Rimonabant was withdrawn because of significant psychiatric adverse effects. Orlistat was approved in Europe and the United States for long-term treatment of obesity, but many patients cannot tolerate its gastrointestinal side effects. Phentermine and diethylpropion can only be used for less than 12 weeks because the long-term safety of these drugs is unknown. Ephedrine and caffeine are natural substances but the effects on weight reduction are modest. As a result there is a huge unmet need for effective and safe antiobesity drugs. Recently lorcaserin and topiramate plus phentermine have been approved for the treatment of obesity but long-term safety data are lacking.

Adrenomedullin and cardiovascular diseases.

The cardiovascular system is regulated by the autonomic nervous system, the renin-angiotensin-aldosterone system, nitric oxide (NO) and other factors including neuropeptides. Research in neurohumoral factors has led to the development of many cardiovascular drugs. Adrenomedullin (ADM), initially isolated from the adrenal gland, has diverse physiological and pathophysiological functions in the cardiovascular system. It is produced in many organs and tissues including the vasculature. ADM has numerous actions, including vasodilation, natriuresis, antiapoptosis and stimulation of NO production. It might play a protective role in various cardiovascular pathologies, and its plasma level is elevated in patients with hypertension and heart failure. Administration of ADM is a possible therapeutic approach for treating cardiovascular diseases. A number of studies have investigated the infusion of ADM in humans, which seems to be benficial in heart failure and myocardial infarction. Instead of ADM infusion, augmentation of its endogenous level is another possible strategy. Gene therapy is feasible in animal models, but its application in humans is limited. At present, the most promising clinical application of ADM is the use of the plasma level of mid-regional proadrenomedullin as a biomarker in cardiovascular diseases. It is a good marker of prognosis and survival in patients with coronary aretery disease or heart failure.