The increasing challenge of the possible impact of ethnicity on psychopharmacology.

Ethnic differences may significantly influence the outcome of psychopharmacological treatment, in terms of prescription, adherence, clinical response, emergence of side effects, as well as pharmacokinetics and pharmacodynamics. The purpose of this review was to explore the available literature in order to provide general suggestions to help clinicians in choosing the best therapeutic option for patients, taking into account ethnicity. Although findings are sometimes controversial, the overall published studies suggest that ethnicities other than Caucasians tend to show a lower response to antidepressants and a reduced compliance. Africans tend to be more prescribed with antipsychotics, probably due to cultural stereotypes, except with clozapine, probably for their chronic benign neutropenia. Asians usually require less antipsychotic dosages than Caucasians. The differential response and side effect profile of antidepressants and antipsychotics have been related to individual intrinsic factors, to genetic make-up, but also to cultural and contextual variables. Interestingly, albeit limited data suggest ethnic-related genetic heterogeneity at the level of the serotonin transporters, the cytochromes and some neuroreceptors. Taken together, no conclusive findings are available about the role and impact of ethnicity in psychopharmacology. One of the main problems is that the majority of the studies in psychopharmacology have been conducted on Caucasians, so that there is an urgent need to have data in other populations. Furthermore, in the era of precision medicine, the role of ethnicity may be also supported by genetic analysis.

The Efficacy and Safety of Epicutaneous Immunotherapy for Allergic Diseases: A Systematic Review and Meta-Analysis.

OBJECTIVES: To systematically review the effect and safety of epicutaneous immunotherapy (EPIT) for allergic diseases. METHODS: We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, CQ VIP Database, Wanfang Data, and international trial register from their inception to July 29, 2019, without language restrictions, for randomized controlled trials (RCTs) that compared EPIT versus no EPIT for allergen-triggered allergic reactions. We assessed certainty of evidence by the GRADE approach. RESULTS: Ten RCTs with 1,085 participants (aged from 10 months to 65 years) comparing EPIT with placebo for peanut, cow milk, or grass-pollen allergy met the eligibility criteria. A substantial benefit in terms of desensitization in EPIT group was more likely for peanut or cow milk protein allergy (risk ratio [RR] 2.34, 95% CI 1.69-3.23; I2 = 0%; high certainty evidence). EPIT increased local-treatment-related adverse events (L-TRAE; RR 1.56, 95% CI 1.03-2.36; I2 = 82%; moderate certainty evidence). But there were no significantly increased risk of any TRAEs (low certainty evidence) or systemic-TRAEs (S-TRAEs; very low certainty evidence) in EPIT group. The incidence rate of serious AEs, the use of rescue medications, and anaphylactic reactions stratified by organ systems including skin and mucosa, eyes and upper respiratory, lower respiratory, and gastrointestinal system in EPIT group were similar to placebo group. In subgroup analysis, desensitization of EPIT was significantly effective in peanut allergy (RR 2.29, 95% CI 1.64-3.21; I2 = 0%) and children <12 years (RR 2.85, 95% CI 1.92-4.24; I2 = 0%) with high certainty evidence. Only epicutaneous grass-pollen immunotherapy significantly increased the risk of S-TRAE (RR 4.65, 95% CI 1.10-19.64; I2 = 0%). CONCLUSION: The systematic review suggests that EPIT might induce desensitization in peanut allergy and an increased risk of local AEs. These findings should be interpreted with caution owing to the limited study and heterogeneity. More data in the older (children ≥12 years and adults) and other allergic diseases are needed.

Opportunities and Challenges in Cardiovascular Pharmacogenomics: From Discovery to Implementation.

This review will provide an overview of the principles of pharmacogenomics from basic discovery to implementation, encompassing application of tools of contemporary genome science to the field (including areas of apparent divergence from disease-based genomics), a summary of lessons learned from the extensively studied drugs clopidogrel and warfarin, the current status of implementing pharmacogenetic testing in practice, the role of genomics and related tools in the drug development process, and a summary of future opportunities and challenges.

Ethnic inequality in non-steroidal anti-inflammatory drug-associated harm in New Zealand: A national population-based cohort study.

PURPOSE: Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with many serious complications and they are widely used in New Zealand (NZ). However, differences in NSAID-associated risk for these complications between ethnic groups are largely unknown. We assessed ethnic disparities in risk of hospital admission for upper gastrointestinal bleeding (UGIB), heart failure, and acute kidney failure (AKF) in NZ's primary care population prescribed and dispensed NSAIDs. METHODS: Retrospective cohort study utilising national pharmaceutical dispensing and hospital admissions data 2007 to 2015. Patient follow-up included 90-day periods following the dispensing of NSAIDs. Risk for each adverse outcome in Maori, Pacific, European, and Asian patients was estimated using multivariable Poisson regression adjusting for age, sex, deprivation, comorbidity and concurrent drug use. RESULTS: 3 023 067 patients were dispensed NSAIDs between 2008 and 2015. Their total intended duration of NSAID treatment encompassed 2 353 140 patient-years. Maori, Pacific and Asian patients were younger than European patients (all P < .001). After adjusting for other risk factors, Maori (rate ratio: 2.54, 95% confidence interval: 2.23-2.90) and Pacific patients (3.17, 2.69-3.74) were more likely to be hospitalised for UGIB than Europeans (reference), and heart failure (Maori: 2.48, 2.24-2.74; Pacific: 1.97, 1.69-2.30). Risk of AKF was higher in Maori (1.46, 1.23-1.74). Higher risk for UGIB and HF in Maori and Pacific patients was most pronounced in males and patients aged <60 years. CONCLUSIONS: Inequalities exist in the incidence of serious adverse outcomes experienced by different ethnic groups in NZ while using NSAIDs. Interventions to promote safer use of these medicines are required to reduce this inequity.

A personalized medicine approach for Asian Americans with the aldehyde dehydrogenase 2*2 variant.

Asian Americans are one of the fastest-growing populations in the United States. A relatively large subset of this population carries a unique loss-of-function point mutation in aldehyde dehydrogenase 2 (ALDH2), ALDH2*2. Found in approximately 560 million people of East Asian descent, ALDH2*2 reduces enzymatic activity by approximately 60% to 80% in heterozygotes. Furthermore, this variant is associated with a higher risk for several diseases affecting many organ systems, including a particularly high incidence relative to the general population of esophageal cancer, myocardial infarction, and osteoporosis. In this review, we discuss the pathophysiology associated with the ALDH2*2 variant, describe why this variant needs to be considered when selecting drug treatments, and suggest a personalized medicine approach for Asian American carriers of this variant. We also discuss future clinical and translational perspectives regarding ALDH2*2 research.

Ethnic differences in adverse drug reactions to asthma medications: a systematic review.

BACKGROUND: Information on ethnic diversity of adverse drug reactions (ADRs) to asthma medications is rare despite evidence suggesting higher risk for African Americans when using ß2-adrenergic receptor agonists. The objectives are to investigate how ethnic background was involved in ADR assessment and to examine the relationship between ethnic background and ADRs to asthma medications. METHODS: MEDLINE was searched until March 2014. All types of studies reporting ADRs to asthma medications involving more than one ethnic group were included. Extracted information includes study designs, ethnic backgrounds, intervention, and types and severities of ADRs. RESULTS: Among the selected 15 randomised clinical trials, six pooled analyses of randomized clinical trials, and five prospective observational studies, only six studies compared ADRs across different ethnic groups. The majority of the comparisons were either statistically insignificant or inconclusive. CONCLUSIONS: Ethnicity was largely overlooked. Most studies neglected to report ADRs by ethnicity. Lack of consistency in defining ethnicities complicated further pooled analyses. Despite the higher prevalence of asthma among specific ethnic minority groups, few studies disaggregated information by ethnic background, and reports of ADRs to asthma medications in different ethnic groups were rare. We suggest that the inclusion of ADR analysis by different ethnic backgrounds is desirable.

2015 Update on Acute Adverse Reactions to Gadolinium based Contrast Agents in Cardiovascular MR. Large Multi-National and Multi-Ethnical Population Experience With 37788 Patients From the EuroCMR Registry.

OBJECTIVES: Specifically we aim to demonstrate that the results of our earlier safety data hold true in this much larger multi-national and multi-ethnical population. BACKGROUND: We sought to re-evaluate the frequency, manifestations, and severity of acute adverse reactions associated with administration of several gadolinium- based contrast agents during routine CMR on a European level. METHODS: Multi-centre, multi-national, and multi-ethnical registry with consecutive enrolment of patients in 57 European centres. RESULTS: During the current observation 37,788 doses of Gadolinium based contrast agent were administered to 37,788 patients. The mean dose was 24.7 ml (range 5-80 ml), which is equivalent to 0.123 mmol/kg (range 0.01 - 0.3 mmol/kg). Forty-five acute adverse reactions due to contrast administration occurred (0.12%). Most reactions were classified as mild (43 of 45) according to the American College of Radiology definition. The most frequent complaints following contrast administration were rashes and hives (15 of 45), followed by nausea (10 of 45) and flushes (10 of 45). The event rate ranged from 0.05% (linear non-ionic agent gadodiamide) to 0.42% (linear ionic agent gadobenate dimeglumine). Interestingly, we also found different event rates between the three main indications for CMR ranging from 0.05% (risk stratification in suspected CAD) to 0.22% (viability in known CAD). CONCLUSIONS: The current data indicate that the results of the earlier safety data hold true in this much larger multi-national and multi-ethnical population. Thus, the "off-label" use of Gadolinium based contrast in cardiovascular MR should be regarded as safe concerning the frequency, manifestation and severity of acute events.

Livestock herding and Fulani ethnicity are a combined risk factor for development of early adverse reactions to antivenom treatment: Findings from a cross-sectional study in Nigeria.

BACKGROUND: Adverse reactions to antivenom considerably complicate the clinical management of snakebite envenomed patients because it necessitates a temporary suspension of life-saving antivenom, increases costs and can compromise patient outcomes. This study sought to explore the association between cattle-herding occupation and ethnic group and the occurrence of early adverse reactions to antivenom. METHODS: This cross-sectional study was conducted between the 25th April and 11th July 2011 at the Kaltungo General Hospital in north east Nigeria. The exposure variable of cattle-herding occupation showed a strong correlation with the ethnic group variable, thus these were combined into a new variable with three categories (Fulani and herder, either Fulani or herder, and neither Fulani nor herder). The outcome variable was the occurrence of early adverse reactions, defined as any new symptoms occurring within 6 hours of antivenom administration. Odds Ratios were estimated using multivariable logistic regression models controlling for potential confounders. RESULTS: Among 231 envenomed snakebite victims, the overall incidence of early adverse reactions was 11.9% (95% confidence intervals: 8.0-16.9%). Patients who were Fulani and herders had a higher incidence of early adverse reactions compared to patients who were neither Fulani nor herders (20% vs 5.7%). After adjusting for age and gender, victims who were Fulani and herders were 5.9 times more likely to have an early adverse reaction, compared to victims who were neither Fulani nor herders (95% CI: 1.88-18.59; p = 0.002). INTERPRETATION: To the best of our knowledge, this is the first study to provide evidence of higher odds of early adverse reactions among patients from a particular occupation and/or ethnic group. We recommend that snake envenomed patients of Fulani origin be especially closely monitored for adverse reactions, that hospitals receiving these patients be appropriately resourced to manage both envenoming and adverse reactions and that premedication with adrenaline should be considered. Our findings provide an argument for speculation on the influence of immunological or lifestyle-related differences on the occurrence of early adverse reactions to antivenom.

"It is through shared conversation, that I understand"-Maori older adults' experiences of medicines and related services in Aotearoa New Zealand.

AIM: An understanding of patients' healthcare experiences and perceptions is essential for developing new health services. In Aotearoa New Zealand, inequities in health outcomes exist, with Maori experiencing worse health outcomes than non-Maori. This includes poorer access to, and quality of, prescribed medicines. This study aims to explore kaumatua (Maori older adults') experiences of medicines and medicine-related services in New Zealand. METHOD: This qualitative research applied kaupapa Maori theory and explored Maori older adults' experiences of medicines and medicine-related services in New Zealand. Ten kaumatua from Auckland, New Zealand participated in semi-structured interviews. Reflexive thematic analysis was used to analyse data. RESULTS: Three themes were generated: 1. diverse, multi-dimensional realities of medicine-taking for Maori with ageing; 2. medicines supply as a business transaction; and 3. self-determined agency of kaumatua supported by authentic healthcare partnerships. Kaumatua expressed their ability to retain power and control over their medicine therapy and their desire for this to occur within a supportive, authentic partnership model that involves them and their multiple healthcare providers. CONCLUSION: Maori older adults have the ability, desire and right to control their medicines journey in a way that is relevant to their experiences of medicines. They value support from authentic healthcare partnerships in enabling this.

Informatics investigations into anti-thyroid drug induced agranulocytosis associated with multiple HLA-B alleles.

INTRODUCTION: Adverse drug reactions have been linked with HLA alleles in different studies. These HLA proteins play an essential role in the adaptive immune response for the presentation of self and non-self peptides. Anti-thyroid drugs methimazole and propylthiouracil have been associated with drug induced agranulocytosis (severe lower white blood cell count) in patients with B*27:05, B*38:02 and DRB1*08:03 alleles in different populations: Taiwanese, Vietnamese, Han Chinese and Caucasian. METHODS: In this study, informatics methods were used to investigate if any sequence or structural similarities exist between the two associated HLA-B alleles, compared with a set of "control" alleles assumed not be associated, which could help explain the molecular basis of the adverse drug reaction. We demonstrated using MHC Motif Viewer and MHCcluster that the two alleles do not have a propensity to bind similar peptides, and thus at a gross level the structure of the antigen presentation region of the two alleles are not similar. We also performed multiple sequence alignment to identify polymorphisms shared by the risk but not by the control alleles and molecular docking to compare the predicted binding poses of the drug-allele combinations. RESULTS: Two residues, Cys67 and Thr80, were identified from the multiple sequence alignments to be unique to these risk alleles alone. The molecular docking showed the poses of the risk alleles to favour the F-pocket of the peptide binding groove, close to the Thr80 residue, with the control alleles generally favouring a different pocket. The data are thus suggestive that Thr80 may be a critical residue in HLA-mediated anti-thyroid drug induced agranulocytosis, and thus can guide future research and risk assessment.

Impact of aging on immune-related adverse events generated by anti-programmed death (ligand)PD-(L)1 therapies.

BACKGROUND: Aging is an important risk factor for cancers and is associated with poor prognosis. Weakness of the immune system, also called immunosenescence may occur with older age. The impact of aging on efficacy and safety of immune checkpoint blockers, such as anti-programmed death (ligand) PD-(L)1, remains undetermined. This study aims to evaluate the incidence of immune-related adverse events (irAEs) in patients aged 70 years or older than their younger counterparts. METHODS: Patients with advanced solid tumors treated at Gustave Roussy with an anti-PD-(L)1 monotherapy between June 2014 and October 2017 were prospectively included within the dedicated irAEs pharmacovigilance registry REISAMIC (Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie). The incidence of irAEs of grade ≥II was compared between patients aged ≥70 (old patients, OP) versus patients aged < 70 years (young patients, YP) using a chi-squared test. Survivals were estimated using the Kaplan-Meier method. RESULTS: Among the 603 patients treated by anti-PD(L)1, 191 were ≥70 y.o (OP) and 424 < 70 y.o (YP). The median (range) age of OP and YP were respectively 77 (70-93) and 59 years old (17-69). A total of 165 irAEs occurred in these patients (103 grade II and 58 grade III-IV). The overall incidence of grade ≥II irAEs was higher in OP than in YP (33% versus 25%, p = 0.03). In addition, OP were more prone of having multiples irAEs compared with YP (p = 0.037). Skin toxicities were more frequent in OP than in YP (p = 0.007) but endocrine toxicities were less frequent in OP than in YP (p = 0.044). This higher level of irAEs seems to be responsible for a higher rate of treatment discontinuation in OP (p = 0.2). There was no statistical difference in median time to toxicity, exposure to steroids or survival between the two groups. CONCLUSION: Although anti-PD-(L)1 immunotherapies remain an acceptable treatment option for older patients, prescribers should be aware that irAEs are more frequent in the elderly. Further translational studies are warranted to better understand the relationship between aging and irAEs.

Drug-drug interactions in patients using tyrosine kinase inhibitors: A multicenter retrospective study.

PURPOSE: Tyrosine kinase inhibitors (TKIs) are frequently used drugs in oncology practice. Although oral administration is an advantage, long-term use increases potential drug-drug interaction risk. The purpose of this study was to assess the prevalence of potential TKI-drug interaction (PTDI) in patients who used TKIs and increase awareness of this subject. METHODS: We retrospectively evaluated the data of 310 patients collected from four different oncology centers, where TKIs were administered for solid organ cancer, between January 2007 and December 2017. The potential interaction between TKI and any other prescribed drug was determined using ''Lexicomp® Drug Interactions, App Version 1.1'' software. RESULTS: Overall, 310 patients were included; among those, 301 (97.1%) were using another drug with TKI and 147 (47.4%) experienced PTDI at least once. The median number of additional drugs was 4 (range 1-12). We detected 250 PTDIs, of which 30.8% were major interactions. The most frequently interacting TKI was imatinib (29.6%), and the additional drug group was antibiotics (21.2%). We observed that PTDIs caused the following effects: TKI concentration was increased or decreased owing to 14.4% or 22.8% PTDIs, respectively, and electrocardiographic QT prolongation occurred in 22% of all PTDIs. Multivariate analysis demonstrated that use of higher number of additional drugs (odds ratio/OR=1.63), pre-existing lung cancer (OR=8.82), and use of pazopanib (OR=9.22) were potential risk factors. CONCLUSION: The rate of PTDI is quite high in patients using TKIs. Effort must be made to increase awareness of this subject. Increasing awareness aids in lowering toxicity rates and providing efficient antitumor therapy.

Hypersensitivity and Cardiovascular Risks Related to Allopurinol and Febuxostat Therapy in Asians: A Population-Based Cohort Study and Meta-Analysis.

The safety of newer xanthine oxidase inhibitor febuxostat compared to allopurinol remains unclear. To compare the risks of allopurinol hypersensitivity and febuxostat hypersensitivity and cardiovascular diseases (CVDs) in Asians, we conducted a population-based cohort study enrolling patients receiving allopurinol or febuxostat from Chang Gung Memorial Hospital Health System across Taiwan during 2012-2016 and further performed a meta-analysis incorporating two recent studies. Among the 61,539 users, a corresponding 12,007 and 5,680 patients were identified as new users. The overall incidence of febuxostat hypersensitivity was significantly lower than allopurinol hypersensitivity (0.2 vs. 2.7 per 1,000 new users; P < 0.001). There were 33 allopurinol-hypersensitivity reactions (including 18 severe cutaneous adverse drug reactions), and only one patient developed febuxostat-maculopapular exanthema. Moreover, febuxostat did not statistically increase the risk of CVD (hazard ratio (HR), 1.16; P = 0.152) and related death (HR, 1.49; P = 0.496) compared to allopurinol. The result of the meta-analysis also showed a consistent result. In conclusion, the incidence and severity of febuxostat-hypersensitivity are lower than with allopurinol. Febuxostat did not show an increased risk of CVD and related death.

Pharmacovigilance in developing countries (part II): a path forward.

In recent years, attention to pharmacovigilance has gained momentum in developing countries, however awareness of, and policies or systems for pharmacovigilance in most developing countries still lags sharply behind developed countries. This article proposes different strategies to encourage the introduction and sustain the advancement of robust pharmacovigilance systems in developing countries. To this end, this article seeks to accomplish the ultimate goal of pharmacovigilance in a developing country context; ensuring patient safety and promoting safe and rational use of drugs.

Pharmacovigilance in developing countries (part I): importance and challenges.

The thalidomide disaster was the significant historical event that acted as a catalyst for pharmacovigilance activity. Following this event developed countries initiated drug monitoring systems that evolved and now extend their scope to broader drug-related safety issues; however, this was not the case in developing countries. Pharmacovigilance is still a relatively new concept with low priority in developing countries although various issues are raising concerns that magnify the need for systems to monitor post marketing drug safety in these countries. This article analyzes the barriers to introducing robust pharmacovigilance systems in developing countries.

Racial/ethnic disparities in magnesium sulfate neuroprotection: a subgroup analysis of a multicenter randomized controlled trial.

OBJECTIVE: Despite known racial disparities in obstetrics, as well as differences in magnesium pharmacodynamics according to race, the effect of race/ethnicity in magnesium sulfate (MgSO4) use during pregnancy has not been studied. Whether some mothers are at increased risk of side effects, or infants at decreased neuroprotective effects is unknown. We analyze the effect of race/ethnicity in maternal/infant outcomes after MgSO4 neuroprotection. STUDY DESIGN: Subgroup analysis of a multicenter clinical trial (BEAM trial) where pregnant women at risk of preterm birth were randomized to either MgSO4 or placebo. For this study, nonanomalous singleton pregnancies were studied. The effect of race in maternal/neonatal outcomes after MgSO4 was analyzed with Breslow-Day and multifactorial ANOVA. Logistic regression was used to calculate odds ratios (OR) of complications according to race. RESULTS: 922 MgSO4 and 972 placebo cases were included (45.0% African-American, 36.2% Caucasian, 17.8% Hispanics, and 1.0% Asians). Interaction analysis showed a significant effect of race/ethnicity (p = .043). Hispanics presented the highest frequency (88.3%, p < .001), as well as the highest odds of MgSO4 side effects [OR(95%CI) = 6.6 (1.3-33.8)]. CONCLUSION: Hispanics present increased risk of magnesium toxicity compared to other racial/ethnic groups. Whether specific racial/ethnic groups require closer surveillance for early signs of magnesium toxicity needs to be further explored.

Patient Reporting of Adverse Drug Reactions (ADRs): Survey of Public Awareness and Predictors of Confidence to Report.

BACKGROUND: Many countries incorporate direct patient reporting of adverse drug reactions (ADRs) into their pharmacovigilance systems as patients provide a different insight into drug safety compared to health care professionals. This study aimed to examine public awareness about ADR reporting in Malaysia and patients' confidence in reporting ADRs. METHODS: Using a cross-sectional design and convenient sampling, data were collected in public areas within Kuala Lumpur, Malaysia, via face-to-face interview with a structured questionnaire. Multivariate logistic regression analysis was used to identify the significant predictors of patients' confidence in ADR reporting. RESULTS: Out of 860 consented respondents achieving a response rate of 73.5%, only 69 (8%) were aware of the Malaysian ADR monitoring system. The majority (60%) of the respondents indicated they had the confidence to report ADRs. Multivariate logistic regression analysis revealed that ease in completing the ADR reporting form was the strongest variable predictive of confidence to report ADRs (odds ratio [OR], 18.45; 95% confidence interval [CI], 10.55-32.25). Increased confidence in ADR reporting was also associated with education level. Respondents with a higher education level were more likely to be confident to report ADRs compared to those with primary or no formal education (OR, 2.49; 95% CI, 0.77-8.1). CONCLUSIONS: Lack of awareness of the ADR monitoring system is still prevalent among Malaysian patients. The ease of completing the ADR form and education level are predictive of patient confidence to report ADRs. These factors should be considered in designing public promotional activities to encourage patient contributions to pharmacovigilance.

Safety of pazopanib and sunitinib in treatment-naive patients with metastatic renal cell carcinoma: Asian versus non-Asian subgroup analysis of the COMPARZ trial.

BACKGROUND: The international, phase 3 COMPARZ study demonstrated that pazopanib and sunitinib have comparable efficacy as first-line therapy in patients with advanced renal cell carcinoma, but that safety and quality-of-life profiles favor pazopanib. Our report analyzed pazopanib and sunitinib safety in Asian and non-Asian subpopulations. METHODS: Patients were randomized 1:1 to receive pazopanib 800 mg once daily (continuous dosing) or sunitinib 50 mg once daily in 6-week cycles (4 weeks on, 2 weeks off). RESULTS: Safety population was composed of 363 Asian patients and 703 non-Asian patients. Asian patients had similar duration of exposure to either drug compared with non-Asian patients, although Asian patients had a higher frequency of dose modifications. Overall, hematologic toxicities, cytopenias, increased AST/ALT, and palmar-plantar erythrodysesthesia (PPE) were more prevalent in Asian patients, whereas gastrointestinal toxicities were more prevalent in non-Asian patients. Among Asian patients, hematologic adverse events and most non-hematologic AEs were more common in sunitinib-treated versus pazopanib-treated patients. Among Asian patients, the most common grade 3/4 AEs with pazopanib were hypertension (grade 3, 22%) and alanine aminotransferase increased (grade 3, 12%; grade 4, 1%); the most common grade 3/4 AEs with sunitinib were thrombocytopenia/platelet count decreased (grade 3, 36%; grade 4, 10%), neutropenia/neutrophil count decreased (grade 3, 24%; grade 4, 3%) hypertension (grade 3, 20%), and PPE (grade 3, 15%). CONCLUSIONS: A distinct pattern and severity of adverse events was observed in Asians when compared with non-Asians with both pazopanib and sunitinib. However, the two drugs were well tolerated in both subpopulations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00720941 , Registered July 22, 2008 ClinicalTrials.gov, NCT01147822 , Registered June 22, 2010.

Genetic and ethnic modulation of cardiovascular toxicity of vascular endothelial growth factor inhibitors.

Vascular endothelial growth factor (VEGF) inhibitors, including monoclonal antibodies and tyrosine kinase inhibitors (TKIs), are important as anticancer treatments through curbing tumour angiogenesis and growth. VEGF inhibitors have significant cardiovascular effects. By blocking VEGF receptors, ligands, or signal pathways, VEGF inhibitors disturb the balance between vasodilation and vasoconstriction, undermine endothelial cell integrity, and activate cardiomyocyte apoptosis. VEGF inhibitors increase risks of hypertension, heart failure, thromboembolism and arrhythmia. Genetic and geographic studies showed that genetic polymorphisms likely play significant predictive or prognostic roles in cardiovascular toxicity associated with VEGF inhibitors. This review updates current understandings of VEGF inhibitors on cardiovascular toxicity, explores potential mechanisms, and clarifies whether genetic or ethnic factors contribute to their adverse effects. Key Messages VEGF inhibitors disturb the balance between vasodilation and vasoconstriction, undermine endothelial cell integrity and activate cardiomyocyte apoptosis. VEGF inhibitors increase risks of hypertension, heart failure, thromboembolism and arrhythmia. Genetic and geographic studies showed that genetic polymorphisms likely play significant predictive or prognostic roles in cardiovascular toxicity associated with VEGF inhibitors.

Post-marketing surveillance study to assess the safety and tolerability of an Inactivated Poliomyelitis Vaccine in Indian children.

OBJECTIVE: To evaluate the incidence of adverse events following administration of an Inactivated poliomyelitis vaccine (IPV) manufactured by Serum Institute of India Pvt. Ltd., Pune, India. METHODS: A single 0.5 ml dose of the IPV was administered intramuscularly to children attending private clinics or out-patient department of hospitals for routine immunization across different cities in India. They were observed over a period of 30 d for local or systemic adverse events and rare case of anaphylaxis, if any. RESULTS: A total of 2210 children were enrolled of which 2120 children received the vaccine within primary immunization series and 90 children received booster dose. The common adverse events reported were pain, erythema, swelling and fever. No serious adverse event was reported during the study period. CONCLUSIONS: Poliomyelitis vaccine (Inactivated) manufactured by Serum Institute of India Pvt. Ltd., Pune can be safely administered to children following the Expanded Programme on Immunization or World Health Organization recommended immunization schedule.