SGLT-2 inhibitors and the risk of infections: a systematic review and meta-analysis of randomized controlled trials.

Acta Diabetol. 2018 May;55(5):503-514

Authors: Puckrin R, Saltiel MP, Reynier P, Azoulay L, Yu OHY, Filion KB

Abstract
AIMS: There is concern about the infection-related safety profile of sodium-glucose co-transporter 2 (SGLT-2) inhibitors. We aimed to determine the effect of SGLT-2 inhibitors on genitourinary and other infections via systematic review and meta-analysis of randomized controlled trials (RCTs).
METHODS: We conducted a systematic search of Medline, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov to identify double-blinded RCTs enrolling ≥ 50 patients with type 2 diabetes which compared an SGLT-2 inhibitor to placebo or active comparator. Two independent reviewers extracted data and appraised study quality. Data were pooled using random-effects models.
RESULTS: Eighty-six RCTs enrolling 50,880 patients were included. SGLT-2 inhibitors increased the risk of genital infections compared to placebo (relative risk [RR] 3.37, 95% CI 2.89-3.93, I2 0%) and active comparator (RR 3.89, 95% CI 3.14-4.82, I2 0.3%). The risk of urinary tract infection (UTI) was not increased with SGLT-2 inhibitors compared to placebo (RR 1.03, 95% CI 0.96-1.11, I2 0%) or active comparator (RR 1.08, 95% CI 0.93-1.25, I2 22%). In drug-specific analyses, only dapagliflozin 10 mg daily was associated with a significantly increased risk of UTI compared to placebo (RR 1.33, 95% CI 1.10-1.61, I2 0%). SGLT-2 inhibitors were associated with a reduced risk of gastroenteritis (RR 0.38, 95% CI 0.20-0.72, I2 0%) but did not affect the risk of respiratory tract infections.
CONCLUSIONS/INTERPRETATION: SGLT-2 inhibitors are associated with an increased risk of genital tract infections. Although there is no association overall between SGLT-2 inhibitors and UTI, higher doses of dapagliflozin are associated with an increased risk.

PMID: 29484489 [PubMed - indexed for MEDLINE]

Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers.

PLoS Negl Trop Dis. 2018 01;12(1):e0006020

Authors: Muñoz J, Ballester MR, Antonijoan RM, Gich I, Rodríguez M, Colli E, Gold S, Krolewiecki AJ

Abstract
Ivermectin is a pivotal drug for the control of onchocerciasis and lymphatic filariasis, which is increasingly identified as a useful drug for the control of other Neglected Tropical Diseases. Its role in the treatment of soil transmitted helminthiasis through improved efficacy against Trichuris trichiura in combination with other anthelmintics might accelerate the progress towards breaking transmission. Ivermectin is a derivative of Avermectin B1, and consists of an 80:20 mixture of the equipotent homologous 22,23 dehydro B1a and B1b. Pharmacokinetic characteristics and safety profile of ivermectin allow to explore innovative uses to further expand its utilization through mass drug administration campaigns to improve coverage rates. We conducted a phase I clinical trial with 54 healthy adult volunteers who sequentially received 2 experimental treatments using a new 18 mg ivermectin tablet in a fixed-dose strategy of 18 and 36 mg single dose regimens, compared to the standard, weight based 150–200 μg/kg, regimen. Volunteers were recruited in 3 groups based on body weight. Plasma concentrations of ivermectin were measured through HPLC up to 168 hours post treatment. Safety data showed no significant differences between groups and no serious adverse events: headache was the most frequent adverse event in all treatment groups, none of them severe. Pharmacokinetic parameters showed a half-life between 81 and 91 h in the different treatment groups. When comparing the systemic bioavailability (AUC0t and Cmax) of the reference product (WA-ref) with the other two study groups using fixed doses, we observed an overall increase in AUC0t and Cmax for the two experimental treatments of 18 mg and 36 mg. Body mass index (BMI) and weight were associated with t1/2 and V/F, probably reflecting the high liposolubility of IVM with longer retention times proportional to the presence of more adipose tissue. Systemic exposure to ivermectin (AUC0t or Cmax) was not associated with BMI or weight in our study. These findings contribute to further understand the pharmacokinetic characteristics of ivermectin, highlighting its safety across different dosing regimens. They also correlate with known pharmacokinetic parameters showing stable levels of AUC and Cmax across a wide range of body weights, which justifies the strategy of fix dosing from a pharmacokinetic perspective.
TRIAL REGISTRATION: ClinicalTrials.gov NCT03173742.

PMID: 29346388 [PubMed - indexed for MEDLINE]

Positive Kappa-Deleting Recombination Excision Circles (KREC) Newborn Screening in a Neonate With Intrauterine Exposure to Rituximab.

Scand J Immunol. 2018 01;87(1):54-56

Authors: Krüger R, Borte S, von Weizsäcker K, Wahn V, Feiterna-Sperling C

PMID: 29106704 [PubMed - indexed for MEDLINE]

Drug-related problems in community-dwelling primary care patients screened positive for dementia.

Int Psychogeriatr. 2017 Nov;29(11):1857-1868

Authors: Wucherer D, Thyrian JR, Eichler T, Hertel J, Kilimann I, Richter S, Michalowsky B, Zwingmann I, Dreier-Wolfgramm A, Ritter CA, Teipel S, Hoffmann W

Abstract
BACKGROUND: Older people have a higher risk of drug-related problems (DRPs). However, little is known about the prevalence of DRPs in community-dwelling people who screened positive for dementia. Our study aimed to determine (1) the prevalence and types of DRPs and (2) the socio-demographic and clinical variables associated with DRPs in people screened positive for dementia in primary care.
METHODS: The Dementia: life- and person-centered help in Mecklenburg-Western Pomerania (DelpHi-MV) study is a general practitioner (GP)-based cluster-randomized controlled intervention study to implement and evaluate an innovative concept of collaborative dementia care management in the primary care setting in Germany. Medication reviews of 446 study participants were conducted by pharmacists based on a comprehensive baseline assessment that included a computer-based home medication assessment. ClinicalTrials.gov Identifier: NCT01401582.
RESULTS: A total of 1,077 DRPs were documented. In 414 study participants (93%), at least one DRP was detected by a pharmacist. The most frequent DRPs were administration and compliance problems (60%), drug interactions (17%), and problems with inappropriate drug choice (15%). The number of DRPs was significantly associated with the total number of drugs taken and with a formal diagnosis of a mental or behavioral disorder.
CONCLUSIONS: Degree of cognitive impairment (MMSE defined) and formal diagnosis of dementia were not risk factors for an increased number of DRPs. However, the total number of drug taken and the presence of a diagnosis of mental and behavioral disorders were associated with an increased total number of DRPs.

PMID: 28780910 [PubMed - indexed for MEDLINE]

The safety profile of subcutaneous allergen immunotherapy in children with asthma in Hangzhou, East China.

Allergol Immunopathol (Madr). 2017 Nov - Dec;45(6):541-548

Authors: Liu JL, Ning WX, Li SX, Xu YC, Wu L, Wang YS, Xu XF, Jiang Y, Sheng YJ, Zhou YL, Wang JH, Tang LF, Chen ZM

Abstract
BACKGROUND: The aim of the current study is to evaluate the prevalence, severity and possible risk factors of systemic reactions (SRs) to subcutaneous allergen immunotherapy (SCIT) in children and adolescents with asthma in Hangzhou, east China's Zhejiang province.
METHODS: From January 2011 to December 2016, this survey analysed the SCIT-related SRs involving 429 patients (265 children and 134 adolescents) affected by allergic asthma. Recorded data included demographics, diagnosis, patient statuses, pulmonary function testing results before and after each injection, allergen dosage, and details of SRs.
RESULTS: All patients finished the initial phase and six patients withdrew during the maintenance phase. There were 2.59% (328/12,655) SRs in all injections (3.28% in children and 1.47% in adolescents); 15.62% (67/429) patients experienced SRs (18.49% children and 10.98% adolescents). There were 54.57% SRs of grade 1; 42.37% SRs of grade 2; 3.05% SRs of grade 3; and no grades 4 or grade 5 SRs occurred in patients. Most reactions were mild, and were readily controlled by immediate emergency treatment. There was no need for hospitalisation. The occurrence of SRs was significantly higher in children than that in adolescents (p<0.01). A higher ratio of SRs was found among patients with moderate asthma.
CONCLUSION: This retrospective survey showed that properly-conducted SCIT was a safe treatment for children and adolescents with asthma in Hangzhou, East China. Children and patients with moderate asthma may be prone to develop SRs.

PMID: 28629672 [PubMed - indexed for MEDLINE]

Safety of sitagliptin in patients with type 2 diabetes and chronic kidney disease: outcomes from TECOS.

Diabetes Obes Metab. 2017 Nov;19(11):1587-1593

Authors: Engel SS, Suryawanshi S, Stevens SR, Josse RG, Cornel JH, Jakuboniene N, Riefflin A, Tankova T, Wainstein J, Peterson ED, Holman RR, TECOS Study Group

Abstract
AIMS: To characterize the incidence of diabetes-associated complications and assess the safety of sitagliptin in participants with chronic kidney disease (CKD) in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS).
MATERIALS AND METHODS: For participants with baseline eGFR measurements (n = 14 528), baseline characteristics and safety outcomes were compared for the CKD cohort (eGFR < 60 mL/min per 1.73 m2 ) vs those without CKD. Within the CKD cohort, the same analyses were performed, comparing sitagliptin- and placebo-assigned participants. Baseline characteristics were summarized for all participants, and serious adverse events were analysed in those who received at least 1 dose of study medication. Adverse events of interest and diabetes complications were summarized for the intention-to-treat population.
RESULTS: CKD was present in 3324 (23%) participants at entry into TECOS. The mean (SD) age for this CKD cohort was 68.8 (7.9) years, mean diabetes duration was 13.7 (9.0) years, and 62% were men. Incidences of serious adverse events, malignancy, bone fracture, severe hypoglycaemia and most categories of diabetes complications were higher in the CKD cohort compared with those without CKD. Over ~2.8 median years of follow-up, CKD participants assigned to sitagliptin had rates of diabetic eye disease, diabetic neuropathy, renal failure, malignancy, bone fracture, pancreatitis and severe hypoglycaemia similar to those of placebo-assigned participants.
CONCLUSIONS: Participants in TECOS with CKD had higher incidences of serious adverse events and diabetes complications than those without CKD. Treatment with sitagliptin was generally well tolerated, with no meaningful differences in safety outcomes observed between those with CKD assigned to sitagliptin or placebo.

PMID: 28432745 [PubMed - indexed for MEDLINE]

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Mining Patients' Narratives in Social Media for Pharmacovigilance: Adverse Effects and Misuse of Methylphenidate.

Front Pharmacol. 2018;9:541

Authors: Chen X, Faviez C, Schuck S, Lillo-Le-Louët A, Texier N, Dahamna B, Huot C, Foulquié P, Pereira S, Leroux V, Karapetiantz P, Guenegou-Arnoux A, Katsahian S, Bousquet C, Burgun A

Abstract
Background: The Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMA) have recognized social media as a new data source to strengthen their activities regarding drug safety. Objective: Our objective in the ADR-PRISM project was to provide text mining and visualization tools to explore a corpus of posts extracted from social media. We evaluated this approach on a corpus of 21 million posts from five patient forums, and conducted a qualitative analysis of the data available on methylphenidate in this corpus. Methods: We applied text mining methods based on named entity recognition and relation extraction in the corpus, followed by signal detection using proportional reporting ratio (PRR). We also used topic modeling based on the Correlated Topic Model to obtain the list of the matics in the corpus and classify the messages based on their topics. Results: We automatically identified 3443 posts about methylphenidate published between 2007 and 2016, among which 61 adverse drug reactions (ADR) were automatically detected. Two pharmacovigilance experts evaluated manually the quality of automatic identification, and a f-measure of 0.57 was reached. Patient's reports were mainly neuro-psychiatric effects. Applying PRR, 67% of the ADRs were signals, including most of the neuro-psychiatric symptoms but also palpitations. Topic modeling showed that the most represented topics were related to Childhood and Treatment initiation, but also Side effects. Cases of misuse were also identified in this corpus, including recreational use and abuse. Conclusion: Named entity recognition combined with signal detection and topic modeling have demonstrated their complementarity in mining social media data. An in-depth analysis focused on methylphenidate showed that this approach was able to detect potential signals and to provide better understanding of patients' behaviors regarding drugs, including misuse.

PMID: 29881351 [PubMed]

Memantine induces manic episode in a 73-year-old patient with vascular neurocognitive disorder: a case report.

Neuropsychiatr Dis Treat. 2018;14:1395-1398

Authors: Duan J, Lao C, Chen J, Pan F, Zhang C, Xu W, Zhou W, Hu J, Shang D, Huang M, Xu Y

Abstract
Memantine, an N-methyl-d-aspartate receptor antagonist, is a well-established treatment option for moderate-to-severe cognitive impairment related to Alzheimer disease. Recently, growing evidence has indicated memantine might also be effective in treatment of affective disorders. The common drug-induced adverse events of memantine include confusion, dizziness, drowsiness, headache, insomnia, and agitation. Herein, we presented a case of a 73-year-old female patient with vascular neurocognitive disorder, who developed a manic episode after taking memantine.

PMID: 29881276 [PubMed]

Enteral versus parenteral nutrition and enteral versus a combination of enteral and parenteral nutrition for adults in the intensive care unit.

Cochrane Database Syst Rev. 2018 Jun 08;6:CD012276

Authors: Lewis SR, Schofield-Robinson OJ, Alderson P, Smith AF

Abstract
BACKGROUND: Critically ill people are at increased risk of malnutrition. Acute and chronic illness, trauma and inflammation induce stress-related catabolism, and drug-induced adverse effects may reduce appetite or increase nausea and vomiting. In addition, patient management in the intensive care unit (ICU) may also interrupt feeding routines. Methods to deliver nutritional requirements include provision of enteral nutrition (EN), or parenteral nutrition (PN), or a combination of both (EN and PN). However, each method is problematic. This review aimed to determine the route of delivery that optimizes uptake of nutrition.
OBJECTIVES: To compare the effects of enteral versus parenteral methods of nutrition, and the effects of enteral versus a combination of enteral and parenteral methods of nutrition, among critically ill adults, in terms of mortality, number of ICU-free days up to day 28, and adverse events.
SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase on 3 October 2017. We searched clinical trials registries and grey literature, and handsearched reference lists of included studies and related reviews.
SELECTION CRITERIA: We included randomized controlled studies (RCTs) and quasi-randomized studies comparing EN given to adults in the ICU versus PN or versus EN and PN. We included participants that were trauma, emergency, and postsurgical patients in the ICU.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We assessed the certainty of evidence with GRADE.
MAIN RESULTS: We included 25 studies with 8816 participants; 23 studies were RCTs and two were quasi-randomized studies. All included participants were critically ill in the ICU with a wide range of diagnoses; mechanical ventilation status between study participants varied. We identified 11 studies awaiting classification for which we were unable to assess eligibility, and two ongoing studies.Seventeen studies compared EN versus PN, six compared EN versus EN and PN, two were multi-arm studies comparing EN versus PN versus EN and PN. Most studies reported randomization and allocation concealment inadequately. Most studies reported no methods to blind personnel or outcome assessors to nutrition groups; one study used adequate methods to reduce risk of performance bias.Enteral nutrition versus parenteral nutritionWe found that one feeding route rather than the other (EN or PN) may make little or no difference to mortality in hospital (risk ratio (RR) 1.19, 95% confidence interval (CI) 0.80 to 1.77; 361 participants; 6 studies; low-certainty evidence), or mortality within 30 days (RR 1.02, 95% CI 0.92 to 1.13; 3148 participants; 11 studies; low-certainty evidence). It is uncertain whether one feeding route rather than the other reduces mortality within 90 days because the certainty of the evidence is very low (RR 1.06, 95% CI 0.95 to 1.17; 2461 participants; 3 studies). One study reported mortality at one to four months and we did not combine this in the analysis; we reported this data as mortality within 180 days and it is uncertain whether EN or PN affects the number of deaths within 180 days because the certainty of the evidence is very low (RR 0.33, 95% CI 0.04 to 2.97; 46 participants).No studies reported number of ICU-free days up to day 28, and one study reported number of ventilator-free days up to day 28 and it is uncertain whether one feeding route rather than the other reduces the number of ventilator-free days up to day 28 because the certainty of the evidence is very low (mean difference, inverse variance, 0.00, 95% CI -0.97 to 0.97; 2388 participants).We combined data for adverse events reported by more than one study. It is uncertain whether EN or PN affects aspiration because the certainty of the evidence is very low (RR 1.53, 95% CI 0.46 to 5.03; 2437 participants; 2 studies), and we found that one feeding route rather than the other may make little or no difference to pneumonia (RR 1.10, 95% CI 0.82 to 1.48; 415 participants; 7 studies; low-certainty evidence). We found that EN may reduce sepsis (RR 0.59, 95% CI 0.37 to 0.95; 361 participants; 7 studies; low-certainty evidence), and it is uncertain whether PN reduces vomiting because the certainty of the evidence is very low (RR 3.42, 95% CI 1.15 to 10.16; 2525 participants; 3 studies).Enteral nutrition versus enteral nutrition and parenteral nutritionWe found that one feeding regimen rather than another (EN or combined EN or PN) may make little or no difference to mortality in hospital (RR 0.99, 95% CI 0.84 to 1.16; 5111 participants; 5 studies; low-certainty evidence), and at 90 days (RR 1.00, 95% CI 0.86 to 1.18; 4760 participants; 2 studies; low-certainty evidence). It is uncertain whether combined EN and PN leads to fewer deaths at 30 days because the certainty of the evidence is very low (RR 1.64, 95% CI 1.06 to 2.54; 409 participants; 3 studies). It is uncertain whether one feeding regimen rather than another reduces mortality within 180 days because the certainty of the evidence is very low (RR 1.00, 95% CI 0.65 to 1.55; 120 participants; 1 study).No studies reported number of ICU-free days or ventilator-free days up to day 28. It is uncertain whether either feeding method reduces pneumonia because the certainty of the evidence is very low (RR 1.40, 95% CI 0.91 to 2.15; 205 participants; 2 studies). No studies reported aspiration, sepsis, or vomiting.
AUTHORS' CONCLUSIONS: We found insufficient evidence to determine whether EN is better or worse than PN, or than combined EN and PN for mortality in hospital, at 90 days and at 180 days, and on the number of ventilator-free days and adverse events. We found fewer deaths at 30 days when studies gave combined EN and PN, and reduced sepsis for EN rather than PN. We found no studies that reported number of ICU-free days up to day 28. Certainty of the evidence for all outcomes is either low or very low. The 11 studies awaiting classification may alter the conclusions of the review once assessed.

PMID: 29883514 [PubMed - as supplied by publisher]

Pilot study on the occurrence of multiple cancers following cancer-related therapy at the University of Florida, Jacksonville (2011-2016).

J Investig Med. 2018 Jun 06;:

Authors: Seegobin K, Staggs E, Khawaja R, Maharaj S, Gautam S, Smotherman C, Rana F

Abstract
New primary cancers can occur in patients with a previous cancer. Among the risk factors, therapies such as chemotherapy, radiotherapy, and hormonal therapy have been associated with the development of neoplasms. Second cancers most commonly develop 5-10 years after the initial tumor. We observe the implications of cancer-related therapy in the development of a new tumor. We looked at 602 patients who had their first cancer diagnosed in 2011 and calculated the number of different primary cancers between 2011 and 2016 for each patient. Twenty-four patients had a second cancer within 5 years from the first diagnosis and there were no patients with a third cancer. There was no statically significant difference in the rates of second cancers after exposure to chemotherapy, radiotherapy, hormonal therapy, or any combination of these (p=0.738). Of the second cancers reported after 2011, renal, uterine, cervical, and lung cancers were the most frequently reported. Additionally, there was no statically significant difference among the rates of second cancers in men versus women (p=0.467), as well as among whites versus blacks (p=0.318). We conclude that while new primaries can occur after one cancer, there was no increased risk after exposure to different cancer-related therapies. With increased focus on the primary disease, there is a higher likelihood of missing another primary lesion. This is important as the practical implications of managing multiple primaries are rarely discussed.

PMID: 29880535 [PubMed - as supplied by publisher]

Ontology-based literature mining and class effect analysis of adverse drug reactions associated with neuropathy-inducing drugs.

J Biomed Semantics. 2018 Jun 07;9(1):17

Authors: Hur J, Özgür A, He Y

Abstract
BACKGROUND: Adverse drug reactions (ADRs), also called as drug adverse events (AEs), are reported in the FDA drug labels; however, it is a big challenge to properly retrieve and analyze the ADRs and their potential relationships from textual data. Previously, we identified and ontologically modeled over 240 drugs that can induce peripheral neuropathy through mining public drug-related databases and drug labels. However, the ADR mechanisms of these drugs are still unclear. In this study, we aimed to develop an ontology-based literature mining system to identify ADRs from drug labels and to elucidate potential mechanisms of the neuropathy-inducing drugs (NIDs).
RESULTS: We developed and applied an ontology-based SciMiner literature mining strategy to mine ADRs from the drug labels provided in the Text Analysis Conference (TAC) 2017, which included drug labels for 53 neuropathy-inducing drugs (NIDs). We identified an average of 243 ADRs per NID and constructed an ADR-ADR network, which consists of 29 ADR nodes and 149 edges, including only those ADR-ADR pairs found in at least 50% of NIDs. Comparison to the ADR-ADR network of non-NIDs revealed that the ADRs such as pruritus, pyrexia, thrombocytopenia, nervousness, asthenia, acute lymphocytic leukaemia were highly enriched in the NID network. Our ChEBI-based ontology analysis identified three benzimidazole NIDs (i.e., lansoprazole, omeprazole, and pantoprazole), which were associated with 43 ADRs. Based on ontology-based drug class effect definition, the benzimidazole drug group has a drug class effect on all of these 43 ADRs. Many of these 43 ADRs also exist in the enriched NID ADR network. Our Ontology of Adverse Events (OAE) classification further found that these 43 benzimidazole-related ADRs were distributed in many systems, primarily in behavioral and neurological, digestive, skin, and immune systems.
CONCLUSIONS: Our study demonstrates that ontology-based literature mining and network analysis can efficiently identify and study specific group of drugs and their associated ADRs. Furthermore, our analysis of drug class effects identified 3 benzimidazole drugs sharing 43 ADRs, leading to new hypothesis generation and possible mechanism understanding of drug-induced peripheral neuropathy.

PMID: 29880031 [PubMed - in process]

Peginterferon is preferable to entecavir for prevention of unfavourable events in patients with HBeAg-positive chronic hepatitis B: A five-year observational cohort study.

J Viral Hepat. 2017 Nov;24 Suppl 1:12-20

Authors: Li SY, Li H, Xiong YL, Liu F, Peng ML, Zhang DZ, Ren H, Hu P

Abstract
At present, the long-term effects of pegylated interferon-α (PEG-IFN-α) and entecavir (ETV) are controversial. Studies directly compared the long-term outcomes of these two drugs have not been completed. This study was designed to compare the clinical outcomes of PEG-IFN-α vs ETV therapy in Chinese patients with chronic HBV infection. From September 2008 to December 2016, a large, observational, open-label, prospective cohort study of HBeAg-positive patients with CHB who received PEG-IFN-α or ETV therapy was carried out at the Second Affiliated Hospital of Chongqing Medical University. Cumulative incidences of unfavourable events were calculated with respect to treatment type. Based on the REACH-B model, we compared the observed incidence of hepatocellular carcinoma (HCC) with the expected incidence in each group. PEG-IFN-α-treated patients showed a lower cumulative incidences of unfavourable events and cirrhosis than those treated with ETV (P = .031; P = .044, respectively). Impact factor exploration indicated that treatment type and platelet count are significantly associated with the occurrence of unfavourable events. Based on the REACH-B model, a lower observed cumulative incidence of HCC was observed in PEG-IFN-α-treated patients than predicted (P = .038). However, there was no significant difference of the cumulative HCC incidence between the observed and the predicted cases for ETV-experienced patients (P = .36). Treatment with PEG-INF-α leads to a lower incidence of unfavourable events including cirrhosis and HCC than ETV in patients with HBV. Treatment type and baseline platelet count may be two important factors associated with the long-term clinical outcomes of patients with CHB.

PMID: 29082649 [PubMed - indexed for MEDLINE]

Drugs and life-threatening ventricular arrhythmia risk: results from the DARE study cohort.

BMJ Open. 2017 Oct 16;7(10):e016627

Authors: Coughtrie AL, Behr ER, Layton D, Marshall V, Camm AJ, Shakir SAW

Abstract
OBJECTIVES: To establish a unique sample of proarrhythmia cases, determine the characteristics of cases and estimate the contribution of individual drugs to the incidence of proarrhythmia within these cases.
SETTING: Suspected proarrhythmia cases were referred by cardiologists across England between 2003 and 2011. Information on demography, symptoms, prior medical and drug histories and data from hospital notes were collected.
PARTICIPANTS: Two expert cardiologists reviewed data for 293 referred cases: 130 were included. Inclusion criteria were new onset or exacerbation of pre-existing ventricular arrhythmias, QTc >500 ms, QTc >450 ms (men) or >470 ms (women) with cardiac syncope, all secondary to drug administration. Exclusion criteria were acute ischaemia and ischaemic polymorphic ventricular tachycardia at presentation, structural heart disease, consent withdrawn or deceased prior to study. Descriptive analysis of Caucasian cases (95% of included cases, n=124) and culpable drug exposures was performed.
RESULTS: Of the 124 Caucasian cases, 95 (77%) were QTc interval prolongation-related; mean age was 62 years (SD 15), and 63% were female. Cardiovascular comorbidities included hypertension (53%) and patient-reported 'heart rhythm problems' (73%). Family history of sudden death (36%) and hypokalaemia at presentation (27%) were common. 165 culpable drug exposures were reported, including antiarrhythmics (42%), of which amiodarone and flecainide were the most common. Sotalol, a beta-blocking agent with antiarrhythmic activity, was also common (15%). 26% reported multiple drugs, of which 84% reported at least one cytochrome (CYP) P450 inhibitor. Potential pharmacodynamics interactions identified were mainly QT prolongation (59%).
CONCLUSIONS: Antiarrhythmics, non-cardiac drugs and drug combinations were found to be culpable in a large cohort of 124 clinically validated proarrhythmia cases. Potential clinical factors that may warn the prescriber of potential proarrhythmia include older women, underlying cardiovascular comorbidity, family history of sudden death and hypokalaemia.

PMID: 29042382 [PubMed - indexed for MEDLINE]

Potentially inappropriate prescribing and its association with health outcomes in middle-aged people: a prospective cohort study in Ireland.

BMJ Open. 2017 Oct 16;7(10):e016562

Authors: Moriarty F, Cahir C, Bennett K, Hughes CM, Kenny RA, Fahey T

Abstract
OBJECTIVES: To determine the prevalence of potentially inappropriate prescribing (PIP) in a cohort of community-dwelling middle-aged people and assess the relationship between PIP and emergency department (ED) visits, general practitioner (GP) visits and quality of life (QoL).
DESIGN: Prospective cohort study.
SETTING: The Irish Longitudinal Study on Ageing (TILDA), a nationally representative cohort study of ageing.
PARTICIPANTS: Individuals aged 45-64 years recruited to TILDA who were eligible for the means-tested General Medical Services scheme and followed up after 2 years.
EXPOSURE: PIP was determined in the 12 months preceding baseline and follow-up TILDA data collection by applying the PRescribing Optimally in Middle-aged People's Treatments (PROMPT) criteria to participants' medication dispensing data.
OUTCOME MEASURES: At follow-up, the reported rates of ED and GP visits over 12 months (primary outcome) and the CASP-R12 (Control Autonomy Self-realisation Pleasure) measure of QoL (secondary outcome).
ANALYSIS: Multivariate negative binomial (rates) and linear regression (CASP-R12) models controlling for potential confounders.
RESULTS: At 2-year follow-up (n=808), PIP was detected in 42.9% by the PROMPT criteria. An ED visit was reported by 18.7% and 94.4% visited a GP (median 4 visits, IQR 2-6). Exposure to ≥2 PROMPT criteria was associated with higher rates of healthcare utilisation and lower QoL in unadjusted regression. However, in multivariate analysis, the associations between PIP and rates of ED visits (adjusted incidence rate ratio (IRR) 0.92, 95% CI 0.53 to 1.58), and GP visits (IRR 1.06, 95% CI 0.87 to 1.28), and CASP-R12 score (adjusted β coefficient 0.35, 95% CI -0.93 to 1.64) were not statistically significant. Numbers of medicines and comorbidities were associated with higher healthcare utilisation.
CONCLUSIONS: Although PIP was prevalent in this study population, there was no evidence of a relationship with ED and GP visits and QoL. Further research should evaluate whether the PROMPT criteria are related to these and other adverse outcomes in the general middle-aged population.

PMID: 29042380 [PubMed - indexed for MEDLINE]

Prospects and Frontiers of Stem Cell Toxicology.

Stem Cells Dev. 2017 Nov 01;26(21):1528-1539

Authors: Liu S, Yin N, Faiola F

Abstract
The development of stem cell biology has revolutionized regenerative medicine and its clinical applications. Another aspect through which stem cells would benefit human health is their use in toxicology. In fact, owing to their ability to differentiate into all the lineages of the human body, including germ cells, stem cells, and, in particular, pluripotent stem cells, can be utilized for the assessment, in vitro, of embryonic, developmental, reproductive, organ, and functional toxicities, relevant to human physiology, without employing live animal tests and with the possibility of high throughput applications. Thus, stem cell toxicology would tremendously assist in the toxicological evaluation of the increasing number of synthetic chemicals that we are exposed to, of which toxicity information is limited. In this review, we introduce stem cell toxicology, as an emerging branch of in vitro toxicology, which offers quick and efficient alternatives to traditional toxicology assessments. We first discuss the development of stem cell toxicology, and we then emphasize its advantages and highlight the achievements of human pluripotent stem cell-based toxicity research.

PMID: 28874109 [PubMed - indexed for MEDLINE]

Investigation on the incidence of adverse reactions, viraemia and haematological changes following field immunization of cattle using a live attenuated vaccine against lumpy skin disease.

Transbound Emerg Dis. 2018 Feb;65(1):174-185

Authors: Katsoulos PD, Chaintoutis SC, Dovas CI, Polizopoulou ZS, Brellou GD, Agianniotaki EI, Tasioudi KE, Chondrokouki E, Papadopoulos O, Karatzias H, Boscos C

Abstract
The present study was performed to investigate the clinical impact and certain virological and haematological parameters following immunization of cattle against lumpy skin disease (LSD). The study was conducted in a dairy cattle farm (215 animals), immunized with a Neethling strain-based live vaccine. Twenty-seven animals (14 lactating cows, four dry cows and nine calves) were randomly selected for repetitive blood and saliva samplings. An EvaGreen-based real-time PCR was designed to differentiate vaccine from field LSDVs. Vaccinated animals underwent examination for adverse reactions. Nodule samples were collected from two representative cases for histopathological testing and virus identification. Milk yield was calculated based on bulk-tank measurements of all lactating cows (79). Viral DNA was detected between days 6-15 post-vaccination (p.v.) at 63% of the sampled animals (17/27). Saliva and bulk-tank milk samples were LSDV-negative. Pronounced swelling was observed at injection sites of 12% of the immunized animals (26/215), starting at day 6 p.v., and was resolved after 2-4 days. Small-sized (<0.5 cm) cutaneous lumps were developed between days 8-18 p.v. at 9% of the vaccinated animals (19/215). These were observed in adult cows and not in calves/heifers. Resolution was observable 10 days post-development. The vaccine virus was also identified in nodules and injection-site aspirates. Haematological changes (e.g., lower leucocyte counts) were observed in cows and not in calves. Daily milk production was being reduced during the first 12 days p.v. LSD immunization of cows resulted in nodules and low viraemia levels. The fact that nodules and haematological changes were not observed in calves, along with the low viraemia, supports the reduced virulence of the Neethling vaccine strain. The characteristic nodules in vaccinated animals could allow clinical differentiation from those observed in LSD. The developed real-time PCR efficiently differentiates infected from vaccinated cattle, and should be further validated as a tool in LSD surveillance.

PMID: 28391652 [PubMed - indexed for MEDLINE]

Patients' concerns regarding biological agents in rheumatology.

Int J Rheum Dis. 2018 Jun;21(6):1219-1226

Authors: Pehlivan Y, Orucoglu N, Pehlivan S, Kimyon G, Zengin O, Kucuk A, Sahin A, Tomas N, Oksuz MF, Kisacik B, Akar S, Onat AM, Dalkilic E

Abstract
OBJECTIVE: The potential side effects of biological agents may increase the anxiety levels of patients and influence not only their desire to use these therapies but also their concordance to treatment. This study aimed to determine the level and prevalence of drug-related concern in patients treated with biological agents and to acquire additional information regarding the related causes.
MATERIALS AND METHODS: A total of 1134 patients who were using biological agents for at least 3 months with a diagnosis of rheumatic diseases were enrolled. General anxiety levels were evaluated using the State-Trait Anxiety Inventory (STAI).
RESULTS: The most common cause for drug-related concerns was the potential side effects of the drugs (59.5%). Among the potential side effects, cancer risk was the most common cause for concern (40.1%), followed by the risk of tuberculosis activation (30.7%). Anxiety levels were higher in patients who experienced side effects than in other patients, and this difference was statistically significant (P < 0.05). STAI trait and state scores were moderately correlated with anxiety levels related to the drug (P < 0.001).
CONCLUSION: Anxiety related to biological agents may significantly affect the patients' anxiety levels. Awareness regarding the patients' concerns and expectations related to the drug is important to ensure drug adherence and concordance to treatment.

PMID: 29879318 [PubMed - in process]

Safe use of vasopressin and angiotensin II for patients with circulatory shock.

Pharmacotherapy. 2018 Jun 07;:

Authors: Bauer SR, Sacha GL, Lam SW

Abstract
Circulatory shock is a medical emergency that requires rapid intervention to optimize patient outcomes. Although catecholamine vasopressors are considered life-sustaining therapy they are associated with adverse reactions and vasopressin and angiotensin II may be utilized to minimize these adverse effects. However, vasopressin and angiotensin II are also associated with adverse reactions that must be known to the clinician in order to mitigate risk for patients. This review focuses on the known adverse drug effects of vasopressin and angiotensin II while offering potential solutions to minimize harm with these agents. Future directions with vasoactive medication safety, including optimization of the electronic medical record, clinical decision support, prediction analytics, and precision medicine for patients with circulatory shock are also discussed. This article is protected by copyright. All rights reserved.

PMID: 29878459 [PubMed - as supplied by publisher]

Cardiovascular Safety of Psychiatric Agents: A Cautionary Tale.

Angiology. 2018 Jan 01;:3319718780145

Authors: Manolis TA, Manolis AA, Manolis AS

Abstract
Psychiatric agents are among the most commonly prescribed medications. Despite the advent of newer generation agents, patients receiving them still experience cardiovascular (CV) side effects. However, these agents may have heterogeneous properties, calling for an individualized approach based on efficacy and also on the particular side effect profile of each specific agent. Proarrhythmic effects arising from drug-induced long-QT syndrome and consequent potentially life-threatening polymorphic ventricular arrhythmias in the form of torsade de pointes, the metabolic syndrome contributing to atherosclerosis and acute coronary syndromes, and drug-induced orthostatic hypotension raise major concerns. Of course, it is also crucial that fear of potential CV adverse effects does not deprive psychiatric patients of appropriate drug therapy. Modification of CV risk factors in psychiatric patients together with optimal management of their CV diseases and appropriate selection of psychotropic agents with greater efficacy and least CV toxicity are of paramount importance in mitigating CV risks and enhancing safety. Identifying patients at high risk of CV complications and close monitoring of all patients receiving these agents are crucial steps to prevent and manage such complications. All these issues are herein reviewed, relevant guidelines are discussed, and schemas are depicted that illustrate the interrelated connections among the psychotropic agents and their CV effects.

PMID: 29874922 [PubMed - as supplied by publisher]