Background & Aims Use of dabigatran, an inhibitor of thrombin, increases the risk of gastrointestinal bleeding (GIB). However, it is not clear whether gastroprotective agents (GPAs) prevent GIB in ...dabigatran users. We investigated the risk of GIB and the role of gastroprotective agents (including proton pump inhibitors and histamine type-2–receptor antagonists) in patients using dabigatran. Methods We performed a retrospective cohort study using a population-wide database managed by the Hong Kong Hospital Authority. Patients newly prescribed dabigatran from 2010 through 2013 were included in the analysis. Poisson regression was used to assess the risk of GIB in dabigatran users by incidence rate ratio (IRR), adjusted for patient characteristics, comorbidities, and concurrent medications. Results Among the 5041 patients newly prescribed dabigatran, 124 (2.5%) developed GIB during follow-up evaluation (4.2/100 patient-years). The risk of GIB in this population increased among patients 75 years and older (IRR, 2.47; 95% confidence interval CI, 1.66–3.68), patients with a history of peptic ulcers or GIB (IRR, 2.31; 95% CI, 1.54–3.46), and patients who used aspirin (IRR, 1.52; 95% CI, 1.03–2.24). Concomitant use of gastroprotective agents was associated with a reduced risk of GIB (IRR, 0.52; 95% CI, 0.35–0.77). Subcategory analysis showed that use of proton pump inhibitors (IRR, 0.53; 95% CI, 0.31–0.91) or histamine type-2–receptor antagonists (IRR, 0.61; 95% CI, 0.40–0.94) were associated with a lower risk of GIB. Further analysis showed that the risk reduction by gastroprotective agents was significant for only upper GIB (IRR, 0.29; 95% CI, 0.15–0.54), and only for patients with a prior history of peptic ulcers or GIB (IRR, 0.14; 95% CI, 0.06–0.30). Conclusions In the Hong Kong population, use of gastroprotective agents was associated with a reduced risk of GIB in patients taking dabigatran. The association was stronger for upper GIB than lower GIB, and in patients with a prior history of peptic ulcers or GIB.
Abstract
Aims
Concern about the cardiovascular safety of coronavirus disease 2019 (COVID-19) vaccines among individuals with cardiovascular disease (CVD) may lead to vaccine hesitancy. We sought to ...assess the association between two COVID-19 vaccines, BNT162b2 and CoronaVac, and the risk of major adverse cardiovascular events (MACE) in individuals with established CVD.
Methods and results
We identified individuals with a history of CVD before 23 February 2021 and a diagnosis of MACE between 23 February 2021 and 31 January 2022 in Hong Kong. MACE was defined as a composite of myocardial infarction, stroke, revascularization, and cardiovascular death. Electronic health records from the Hong Kong Hospital Authority were linked to vaccination records from the Department of Health. A self-controlled case-series method was used to evaluate the risk of MACE for 0–13 and 14–27 days after two doses of COVID-19 vaccine. We estimated incidence rate ratios (IRRs) to compare the risk of MACE between each risk period and the baseline period. A total of 229 235 individuals with CVD were identified, of which 1764 were vaccinated and had a diagnosis of MACE during the observation period (BNT162b2 = 662; CoronaVac = 1102). For BNT162b2, IRRs were 0.48 95% confidence interval (CI) 0.23–1.02 for the first dose and 0.87 (95% CI 0.50–1.52) for the second dose during the 0–13 days risk period, 0.40 (95% CI 0.18–0.93) for the first dose and 1.13 (95% CI 0.70–1.84) for the second dose during the 14–27 days risk period. For CoronaVac, the IRRs were 0.43 (95% CI 0.24–0.75) for the first dose and, 0.73 (95% CI 0.46–1.16) for the second dose during the 0–13 days risk period, 0.54 (95% CI 0.33–0.90) for the first dose and 0.83 (95% CI 0.54–1.29) for the second dose during the 14–27 days risk period. Consistent results were found in subgroup analyses for different sexes, age groups and different underlying cardiovascular conditions.
Conclusion
Our findings showed no evidence of an increased risk of MACE after vaccination with BNT162b2 or CoronaVac in patients with CVD. Future research is required to monitor the risk after the third dose of each vaccine.
Individual case safety reports (ICSRs) are a cornerstone in drug safety surveillance. The knowledge on using these data specifically for children is limited. We studied characteristics of pediatric ...ICSRs reported to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Public available ICSRs reported in children (0-18 years) to FAERS were downloaded from the FDA-website for the period Jan 2004-Dec 2011. Characteristics of these ICSRs, including the reported drugs and events, were described and stratified by age-groups. We included 106,122 pediatric ICSRs (55% boys and 58% from United States) with a median of 1 drug range 1-3 and 1 event 1-2 per ICSR. Mean age was 9.1 years. 90% was submitted through expedited (15-days) (65%) or periodic reporting (25%) and 10% by non-manufacturers. The proportion and type of pediatric ICSRs reported were relatively stable over time. Most commonly reported drug classes by decreasing frequency were 'nervous system drugs' (58%), 'antineoplastics' (32%) and 'anti-infectives' (25%). Most commonly reported system organ classes were 'general' (13%), 'nervous system' (12%) and 'psychiatric' (11%) disorders. Duration of use could be calculated for 19.7% of the reported drugs, of which 14.5% concerned drugs being used long-term (>6 months). Knowledge on the distribution of the drug classes and events within FAERS is a key first step in developing pediatric specific methods for drug safety surveillance. Because of several differences in terms of drugs and events among age-categories, drug safety signal detection analysis in children needs to be stratified by each age group.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The formulation of medicines for children remains a challenge. An ideal pediatric formulation must allow accurate dose administration and be in a dosage form that can be handled by the target age ...group. It is also important to consider the choices and the amount of excipients used in the formulation for this vulnerable age group. Although oral formulations are generally acceptable to most pediatric patients, they are not suitable for drugs with poor oral bioavailability or when a rapid clinical effect is required. In recent years, oral transmucosal delivery has emerged as an attractive route of administration for pediatric patients. With this route of administration, a drug is absorbed through the oral mucosa, therefore bypassing hepatic first pass metabolism and thus avoiding drug degradation or metabolism in the gastrointestinal tract. The high blood flow and relatively high permeability of the oral mucosa allow a quick onset of action to be achieved. It is a simple and non-invasive route of drug administration. However, there are several barriers that need to be overcome in the development of oral transmucosal products. This article aims to provide a comprehensive review of the current development of oral transmucosal delivery specifically for the pediatric population in order to achieve systemic drug delivery. The anatomical and physiological properties of the oral mucosa of infants and young children are carefully examined. The different dosage forms and formulation strategies that are suitable for young patients are discussed.
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Three hundred million people living with rare diseases worldwide are disproportionately deprived of in-time diagnosis and treatment compared with other patients. This review provides an overview of ...global policies that optimize development, licensing, pricing, and reimbursement of orphan drugs.
Pharmaceutical legislation and policies related to access and regulation of orphan drugs were examined from 194 World Health Organization member countries and 6 areas. Orphan drug policies (ODPs) were identified through internet search, emails to national pharmacovigilance centers, and systematic academic literature search. Texts from selected publications were extracted for content analysis.
One hundred seventy-two drug regulation documents and 77 academic publications from 162 countries/areas were included. Ninety-two of 200 countries/areas (46.0%) had documentation on ODPs. Thirty-four subthemes from content analysis were categorized into 6 policy themes, namely, orphan drug designation, marketing authorization, safety and efficacy requirements, price regulation, incentives that encourage market availability, and incentives that encourage research and development. Countries/areas with ODPs were statistically wealthier (gross national income per capita = $10 875 vs $3950, P < .001). Country/area income was also positively correlated with the scope of the respective ODP (correlation coefficient = 0.57, P < .001).
Globally, the number of countries with an ODP has grown rapidly since 2013. Nevertheless, disparities in geographical distribution and income levels affect the establishment of ODPs. Furthermore, identified policy gaps in price regulation, incentives that encourage market availability, and incentives that encourage research and development should be addressed to improve access to available and affordable orphan drugs.
•Before undertaking this study, we searched academic databases for all English systematic reviews on global orphan drug policies published before July 2019. We identified 1 review on orphan drug policies published in 2015 and 2 reviews on laws and national strategies for rare diseases from selected countries that were published in 2017 and 2018, respectively. These 3 reviews uncovered a plethora of governmental efforts that facilitate the availability of and access to orphan drugs, with critical differences in scope and approaches among countries.•Vast areas worldwide were omitted from previous reviews, such as Africa, India, Latin America, and Russia. No studies attempted an overview of orphan drug policies in all countries with both governmental and academic evidence. The current global landscape of orphan drug policy (ODP) remains unclear. By systematically reviewing pharmaceutical policies and academic literature from 200 countries/areas, our study presents the most comprehensive review on global ODP to date.•Of the 200 countries or areas examined, 92 had ODPs alongside a notable increase in ODP establishment in non-high-income countries/areas over the last decade. Our findings highlight disparities in ODP establishment and scope in countries/areas with different income levels. This allows respective stakeholders to reference orphan drug regulatory standards of countries/areas with similar political realities while informing policy formulation and advocacy direction for treatment access of patients with rare diseases.
IMPORTANCE: Drug repurposing is potentially cost-effective, low risk, and necessary in psychiatric drug development. The availability of large, routine data sets provides the opportunity to evaluate ...the potential for currently used medication to benefit people with serious mental illness (SMI). OBJECTIVE: To determine whether hydroxylmethyl glutaryl coenzyme A reductase inhibitors (HMG-CoA RIs), L-type calcium channel (LTCC) antagonists, and biguanides are associated with reduced psychiatric hospitalization and self-harm in individuals with SMI. DESIGN, SETTING, AND PARTICIPANTS: These within-individual cohort studies of patients with SMI compared rates of psychiatric hospitalization and self-harm during periods of exposure and nonexposure to the study drugs, with adjusting for a number of time-varying covariates. Participants included 142 691 individuals from the entire population of Sweden with a diagnosis of bipolar disorder (BPD), schizophrenia, or nonaffective psychosis (NAP) who were 15 years or older and who were treated with psychiatric medication from October 1, 2005, through December 31, 2016. Data were analyzed from April 1 through August 31, 2018. INTERVENTIONS: Treatment with HMG-CoA RIs, LTCC antagonists, or biguanides. MAIN OUTCOMES AND MEASURES: Psychiatric hospitalizations and self-harm admissions. RESULTS: Among the 142 691 eligible participants, the HMG-CoA RI exposure periods were associated with reduced rates of psychiatric hospitalization in BPD (adjusted hazard ratio aHR, 0.86; 95% CI, 0.83-0.89; P < .001), schizophrenia (aHR, 0.75; 95% CI, 0.71-0.79; P < .001), and NAP (aHR, 0.80; 95% CI, 0.75-0.85; P < .001) and reduced self-harm rates in BPD (aHR, 0.76; 95% CI, 0.66-0.86; P < .001) and schizophrenia (aHR, 0.58; 95% CI, 0.45-0.74; P < .001). Exposure to LTCC antagonists was associated with reduced rates of psychiatric hospitalization and self-harm in subgroups with BPD (aHRs, 0.92 95% CI, 0.88-0.96; P < .001 and 0.81 95% CI, 0.68-0.95; P = .01, respectively), schizophrenia (aHRs, 0.80 95% CI, 0.74-0.85; P < .001 and 0.30 95% CI, 0.18-0.48; P < .001, respectively), and NAP (aHRs, 0.89 95% CI, 0.83-0.96; P = .002 and 0.56 95% CI, 0.42-0.74; P < .001, respectively). During biguanide exposure, psychiatric hospitalization rates were reduced in subgroups with BPD (aHR, 0.80; 95% CI, 0.77-0.84; P < .001), schizophrenia (aHR, 0.73; 95% CI, 0.69-0.77; P < .001), and NAP (aHR, 0.85; 95% CI, 0.79-0.92; P < .001), and self-harm was reduced in BPD (aHR, 0.73; 95% CI, 0.62-0.84; P < .001) and schizophrenia (aHR, 0.64; 95% CI, 0.48-0.85; P < .001). CONCLUSIONS AND RELEVANCE: This study provides additional evidence that exposure to HMG-CoA RIs, LTCC antagonists, and biguanides might lead to improved outcomes for individuals with SMI. Given the well-known adverse event profiles of these agents, they should be further investigated as repurposed agents for psychiatric symptoms.
Background
Behavioural interventions are recommended for use with children and young people with attention deficit hyperactivity disorder (ADHD); however, specific guidance for their implementation ...based on the best available evidence is currently lacking.
Methods
This review used an explicit question and answer format to address issues of clinical concern, based on expert interpretation of the evidence with precedence given to meta‐analyses of randomised controlled trials.
Results
On the basis of current evidence that takes into account whether outcomes are blinded, behavioural intervention cannot be supported as a front‐line treatment for core ADHD symptoms. There is, however, evidence from measures that are probably blinded that these interventions benefit parenting practices and improve conduct problems which commonly co‐occur with ADHD, and are often the main reason for referral. Initial positive results have also been found in relation to parental knowledge, children's emotional, social and academic functioning – although most studies have not used blinded outcomes. Generic and specialised ADHD parent training approaches – delivered either individually or in groups – have reported beneficial effects. High‐quality training, supervision of therapists and practice with the child, may improve outcomes but further evidence is required. Evidence for who benefits the most from behavioural interventions is scant. There is no evidence to limit behavioural treatments to parents with parenting difficulties or children with conduct problems. There are positive effects of additive school‐based intervention for the inattentive subtype. Targeting parental depression may enhance the effects of behavioural interventions.
Conclusions
Parent training is an important part of the multimodal treatment of children with ADHD, which improves parenting, reduces levels of oppositional and noncompliant behaviours and may improve other aspects of functioning. However, blinded evidence does not support it as a specific treatment for core ADHD symptoms. More research is required to understand how to optimise treatment effectiveness either in general or for individual patients and explore potential barriers to treatment uptake and engagement. In terms of selecting which intervention formats to use, it seems important to acknowledge and respond to parental treatment preferences.
Background COVID-19 vaccines have demonstrated effectiveness against SARS-CoV-2 infection, hospitalization, and mortality. The association between vaccination and risk of cardiovascular complications ...shortly after SARS-CoV-2 infection among patients with cardiovascular disease remains unknown. Methods and Results A case-control study was conducted with cases defined as patients who had myocardial infarction or stroke within 28 days after SARS-CoV-2 infection between January 1, 2022 and August 15, 2022. Controls were defined as all other patients who attended any health services and were not cases. Individuals without history of cardiovascular disease were excluded. Each case was randomly matched with 10 controls according to sex, age, Charlson comorbidity index, and date of hospital admission. Adjusted odds ratio with 95% CI was estimated using conditional logistic regression. We identified 808 cases matched with 7771 controls among all patients with cardiovascular disease. Results showed that vaccination with BNT162b2 or CoronaVac was associated with a lower risk of myocardial infarction or stroke after SARS-CoV-2 infection with a dose-response relationship. For BNT162b2, risk decreased from 0.49 (95% CI, 0.29-0.84) to 0.30 (95% CI, 0.20-0.44) and 0.17 (95% CI, 0.08-0.34) from 1 to 3 doses, respectively. Similar trends were observed for CoronaVac, with risk decreased from 0.69 (95% CI, 0.57-0.85) to 0.42 (95% CI, 0.34-0.52) and 0.32 (95% CI, 0.21-0.49) from 1 to 3 doses, respectively. Conclusions Vaccination with BNT162b2 or CoronaVac is associated with a lower risk of myocardial infarction or stroke after SARS-CoV-2 infection among patients with cardiovascular disease.
The goal was to investigate the epidemiologic features of antipsychotic prescribing to children and adolescents in general practice in the United Kingdom.
A total of 384 participating general ...practices from the United Kingdom General Practice Research Database were used to identify patients 0 to 18 years of age who were prescribed > or = 1 antipsychotic medication between January 1, 1992, and December 31, 2005. Annual age-specific prevalences and incidences of antipsychotic prescribing were calculated.
The overall prevalence of use of all antipsychotics increased from 1992 (0.39 users per 1000 patient-years) to 2005 (0.77 users per 1000 patient-years). The prescribing prevalence for patients 7 to 12 years of age almost tripled between 1992 (0.23 users per 1000 patient-years) and 2005 (0.61 users per 1000 patient-years). Atypical antipsychotic prescribing increased 60-fold from 1994 (0.01 users per 1000 patient-years) to 2005 (0.61 users per 1000 patient-years). However, typical antipsychotic prescribing decreased significantly from 2000 (0.44 users per 1000 patient-years) to 2005 (0.18 users per 1000 patient-years). The incidences for typical and atypical antipsychotics showed trends similar to those of the respective prevalences. However, the overall incidence (number of new starters) for all antipsychotics was relatively stable between 1992 and 2005, which suggests that patients remain on treatment longer.
The overall prevalence of antipsychotics almost doubled between 1992 and 2005; however, the rate of increase was much lower than the reported figures in the United States. The prescribing of atypical antipsychotic drugs has increased despite the lack of conclusive evidence showing their superiority over older conventional antipsychotics. Additional investigation is required to evaluate their efficacy and safety in children and adolescents.
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