IntroductionAlthough bacteria contribute significantly to acute exacerbations of chronic obstructive pulmonary disease (AECOPD), the added value of antibiotics remains controversial, especially in ...outpatient settings. Age may affect antibiotic effectiveness, but real-world evidence is lacking. We aimed to assess the influence of age on the effectiveness of doxycycline for AECOPD.MethodsA retrospective cohort study among outpatients with the first recorded AECOPD treated with oral corticosteroids was conducted using a large pharmacy dispensing database. The primary outcome was treatment failure within 15–31 days after treatment start. Secondary outcome was time to second exacerbation. All analyses were stratified by age groups.ResultsWe identified 6300 outpatients with the first AECOPD. 2261 (36%) received doxycycline and 4039 (64%) did not receive any antibiotic (reference group). Overall, there was no difference in treatment failure (adjusted OR: 0.97, 95% CI: 0.84 to 1.12) between two groups. Similarly, no difference in treatment failure was observed in younger groups. However, in patients with advanced age (≥75 years), treatment failure was significantly reduced by doxycycline compared with reference (16% vs 20%, adjusted OR: 0.77, 95% CI: 0.62 to 0.97). Overall, median time to second exacerbation was 169 days (95% CI: 158 to 182 days) in doxycycline group compared with 180 days (95% CI: 169 to 191 days) in reference group (adjusted HR: 1.06, 95% CI: 0.99 to 1.12). Although in older patients there was a trend within 3 months towards longer time of next exacerbation by doxycycline, it did not achieve statistical significance.ConclusionsOur findings showed short-term treatment benefit of doxycycline added to oral corticosteroids for chronic obstructive pulmonary disease patients with advanced age. This value remains unclear for persons aged under 75 years in current primary care. Long-term preventive benefits of doxycycline for the next exacerbation were not observed, irrespective of age.
Objectives:
An established theory for the pathogenesis of tardive dyskinesia is disturbed dopaminergic receptor sensitivity and/or dopaminergic intracellular signaling. We examined associations ...between genetic variants of neurotransmitter receptors and tardive dyskinesia.
Methods:
We assessed tardive dyskinesia in Caucasian psychiatric inpatients from Siberia (N = 431) and a long-stay population from the Netherlands (N = 168). These patients were genotyped for 43 tag single nucleotide polymorphisms in five neurotransmitter receptor genes, and the results for the two populations were compared.
Results:
Several significant associations with tardive dyskinesia were identified, but only GRIN2A (rs1345423) was found in both patient populations. This lack of agreement was probably due to the small effect size of the associations, the multiple testing and the small sample size of the Dutch patient population. After reviewing the literature, we propose that the constitutive stimulatory activity of serotonergic type 2 receptors may be relevant.
Conclusions:
Inactivity of the serotonergic, type 2C receptor or blockade of these receptors by atypical antipsychotic drugs may decrease the vulnerability to develop tardive dyskinesia.
Background: Although the misuse of ketamine constitutes a worldwide issue, ketamine is quickly taking its place as a therapeutic option in the management of several mental disorders. However, the use ...of ketamine and/or its analogues, as well as combinations with other drugs, can be fatal.
Objective: To outline the cases of overdoses and deaths related to the use of ketamine and/or its analogues, as reported in the scientific literature. To investigate if ketamine is safe in a therapeutic context, particularly in its use as an antidepressant.
Methods: Electronic searches were performed on three medical databases. Articles describing cases of overdose and/or death associated with ketamine and/or its analogues were included. After the removal of duplicates, title analysis and full-text analysis, 34 articles were included in this review.
Results: Eighteen articles described fatal cases and sixteen described overdoses. Poly-substance use was mentioned in 53% of the selected articles. Most cases were males and the ages varied from two to 65 years old. A total of 312 overdose cases and 138 deaths were reported. In both death reports and overdose cases, ketamine was preponderant: 89.1% and 79%, respectively. No cases of overdose or death related to the use of ketamine as an antidepressant in a therapeutic setting were found; most of the deaths occurred in the circumstances of polydrug use and overdoses left no sequelae.
Conclusion: There is legitimate concern about the risks involving the use of ketamine and its analogues, especially in recreational settings. On the other hand, ketamine as medicine is considered safe and it is listed as an essential medicine by the World Health Organization. Although clinicians must remain vigilant, this should not deter appropriate prescription.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IJS, NUK, SIK, UILJ, UKNU, UL, UM, UPUK
Aims
The aim of this study is to evaluate the potential association between N‐acetyltransferase type 2 (NAT2) polymorphisms and drug‐induced liver injury during anti‐TB treatment (AT‐DILI).
Methods
...We conducted a systematic review and performed a meta‐analysis to clarify the role of NAT2 polymorphism in AT‐DILI. PubMed, Medline and EMBASE databases were searched for studies published in English to December 31, 2017, on the association between the NAT2 polymorphism and AT‐DILI risk. Outcomes were pooled with random‐effects meta‐analysis. Details were registered in the PROSPERO register (number: CRD42016051722).
Results
Thirty‐seven studies involving 1527 cases and 7184 controls were included in this meta‐analysis. The overall odds ratio (OR) of AT‐DILI associated with NAT2 slow acetylator phenotype was 3.15 (95% CI 2.58–3.84, I2 = 51.3%, P = 0.000). The OR varied between different ethnic populations, ranging from 6.42 (95% CI 2.41–17.10, I2 = 2.3%) for the West Asian population to 2.32 (95% CI 0.58–9.24, I2 = 80.3%) for the European population. Within the slow NAT2 genotype, variation was also observed; NAT2*6/*7 was associated with the highest risk of AT‐DILI (OR = 1.68, 95% CI 1.09–2.59) compared to the other slow NAT2 acetylators combined.
Conclusions
NAT2 slow acetylation was observed to increase the risk of AT‐DILI in tuberculosis patients. Our results support the hypothesis that the slow NAT2 genotype is a risk factor for AT‐DILI.
Currently, Indonesia is in the fifth rank of highest TB prevalence over the world. One of the TB problem is low patients’ adherence due to the oral antituberculosis induced hepatotoxicity. ...Polymorphisms of NAT2 and CYP2E1 genes had important role in the isoniazid (INH)-induced hepatotoxicity. The aim of this study was to evaluate the polymorphisms profile of NAT2 and CYP2E1 genes associated with hepatotoxicity induced by INH. We used cohort design in Public Health Centers and Lung Clinics of Yogyakarta and Lampung. The inclusion criteria were adult subjects (> 18 yo), newly diagnosed TB and treated by oral antituberculosis, normal function of renal and live and willingness to participate in this study. Subjects were excluded when having positive reaction of HbsAg test, history of HIV and abnormality of renal and liver function. The SNPs of NAT2 and CYP2E1 were designed using IPlex method of DNA sequenom. Among 57 TB patients, we found 14 patients with higher INH serum concentration and experienced increase of ALT-AST. Subjects with SNPs of rs 2070676, rs 1329149, rs 3813867, rs 6413432, rs 8192772, rs 2031920, rs 2515641, rs 8192775, rs 915908 of CYP2E1 experienced increase of ALT and AST. Subjects with SNPs of rs 1799930, rs1799931, rs1801279, rs1801280, rs1799929 , rs1208, rs1041983 of NAT2 are associated with the increase of ALT and AST. The polymorphisms of CYP2E1 and NAT2 may have a role in the mechanisms of INH induced DILI.
Aim
Metoprolol (a CYP2D6 substrate) is often co‐prescribed with paroxetine/fluoxetine (a CYP2D6 inhibitor) because the clinical relevance of this drug–drug interaction (DDI) is still unclear. This ...review aimed to systematically evaluate the available evidence and quantify the clinical impact of the DDI.
Method
Pubmed, Web of Science, Cochrane Library and Embase were searched for studies reporting on the effect of the DDI among adults published until April 2018. Data on pharmacokinetics, pharmacodynamics and clinical outcomes from experimental, observational and case report studies were retrieved. The protocol of this study was registered in PROSPERO (CRD42018093087).
Results
We found nine eligible articles that consisted of four experimental and two observational studies as well as three case reports. Experimental studies reported that paroxetine increased the AUC of metoprolol three to five times, and significantly decreased systolic blood pressure and heart rate of patients. Case reports concerned bradycardia and atrioventricular block due to the DDI. Results from observational studies were conflicting. A cohort study indicated that the DDI was significantly associated with the incidence of early discontinuation of metoprolol as an indicator of the emergence of metoprolol‐related side effects. In a case–control study, the DDI was not significantly associated with bradycardia.
Conclusion
Despite the contradictory conclusions from the current literature, the majority of studies suggest that the DDI can lead to adverse clinical consequences. Since alternative antidepressants and beta‐blockers with comparable efficacy are available, such DDIs can be avoided. Nonetheless, if prescribing the combination is unavoidable, a dose adjustment or close monitoring of the metoprolol‐related side effects is necessary.
ObjectiveTo assess the pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents with tuberculous meningitis (TBM).DesignProspective observational ...pharmacokinetic study with an exploratory pharmacokinetic/pharmacodynamic analysis.SettingHasan Sadikin Hospital, Bandung, Indonesia.PatientsIndividuals aged 0–18 years clinically diagnosed with TBM and receiving first-line anti-tuberculosis drug dosages according to revised WHO-recommended treatment guidelines.InterventionsPlasma and cerebrospinal fluid (CSF) concentrations of isoniazid, rifampicin and pyrazinamide were assessed on days 2 and 10 of treatment.Main outcome measuresPlasma exposures during the daily dosing interval (AUC0–24), peak plasma concentrations (C max) and CSF concentrations.ResultsAmong 20 eligible patients, geometric mean AUC0–24 of isoniazid, rifampicin and pyrazinamide was 18.5, 66.9 and 315.5 hour∙mg/L on day 2; and 14.5, 71.8 and 328.4 hour∙mg/L on day 10, respectively. Large interindividual variabilities were observed in AUC0–24 and C max of all drugs. All patients had suboptimal rifampicin AUC0–24 for TBM treatment indication and very low rifampicin CSF concentrations. Four patients developed grade 2–3 drug-induced liver injury (DILI) within the first 4 weeks of treatment, in whom anti-tuberculosis drugs were temporarily stopped, and no DILI recurred after reintroduction of rifampicin and isoniazid. AUC0–24 of isoniazid, rifampicin and pyrazinamide along with C max of isoniazid and pyrazinamide on day 10 were higher in patients who developed DILI than those without DILI (p<0.05).ConclusionHigher rifampicin doses are strongly warranted in treatment of children and adolescents with TBM. The association between higher plasma concentrations of isoniazid, rifampicin and pyrazinamide and the development of DILI needs confirmatory studies.
Background: Scientific studies on cardiovascular disease (CVD) burden and risk factors are predominantly based on short-term risk in Westerner populations, and such information may not be applicable ...to Asian populations, especially over the longer term. This review aims to estimate the long-term (>10 years) CVD burden, including coronary heart disease (CHD) and stroke, as well as associated risk factors in Asian populations.
Methods: PubMed, Embase and Web of Science were systematically searched, and hits screened on: Asian adults, free of CVD at baseline; cohort study design (follow-up >10 years). Primary outcomes were fatal and non-fatal CVD events. Pooled estimates and between-study heterogeneity were calculated using random effects models, Q and I
2
statistics.
Results: Overall, 32 studies were eligible for inclusion (follow-up: 11-29 years). The average long-term rate of fatal CVD is 3.68 per 1000 person-years (95% CI 2.84-4.53), the long-term cumulative risk 6.35% (95% CI 4.69%-8.01%, mean 20.13 years) and the cumulative fatal stroke/CHD risk ratio 1.5:1. Important risk factors for long-term fatal CVD (RR, 95% CI) were male gender (1.49, 1.36-1.64), age over 60/65 years (7.55, 5.59-10.19) and current smoking (1.68, 1.26-2.24). High non-HDL-c, and β- and γ-tocopherol serum were associated only with CHD (HR 2.46 95% CI 1.29-4.71 and 2.47 1.10-5.61 respectively), while stage 1 and 2 hypertensions were associated only with fatal stroke (2.02 1.19-3.44 and 2.89 1.68-4.96 respectively).
Conclusions: Over a 10 year + follow-up period Asian subjects had a higher risk of stroke than CHD. Contrary to CVD prevention in Western countries, strategies should also consider stroke instead of CHD only.
As a vulnerable population, children and adolescents with tuberculosis (TB) are faced with many challenges, even those who live in low TB incidence countries. We aimed to evaluate factors associated ...with TB treatment outcomes allowing more focused interventions to support this population once diagnosed.
A retrospective cohort study using a nationwide surveillance database was performed in children and adolescents (aged 0-18 years) treated for TB in the Netherlands from 1993 to 2018. Logistic regression analyses were used to estimate adjusted odds ratios (aOR) for associated factors of mortality and loss to follow-up (LTFU).
Among 3253 eligible patients with known outcomes, 94.4% (95.9% children and 92.8% adolescents) were cured or completed treatment, 0.7% died during treatment and 4.9% were LTFU. There were no reported treatment failures. Risk factors of death included children aged 2-4 years (aOR 10.42), central nervous system TB (aOR 5.14), miliary TB (aOR 10.25), HIV co-infection (aOR 8.60), re-treated TB cases (aOR 10.12) and drug-induced liver injury (aOR 6.50). Active case-finding was a protective factor of death (aOR 0.13). Risk factors of LTFU were adolescents aged 15-18 years (aOR 1.91), illegal immigrants (aOR 4.28), urban domicile (aOR 1.59), unknown history of TB contact (aOR 1.99), drug-resistant TB (aOR 2.31), single adverse drug reaction (aOR 2.12), multiple adverse drug reactions (aOR 7.84) and treatment interruption >14 days (aOR 6.93). Treatment in recent years (aOR 0.94) and supervision by public health nurses (aOR 0.14) were protective factors of LTFU.
Highly successful treatment outcomes were demonstrated in children and adolescents routinely treated for TB. Special attention should be given to specific risk groups to improve treatment outcomes.
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