Stevens-Johnson syndrome and toxic epidermal necrolysis with antiepileptic drugs: An analysis of the US Food and Drug Administration Adverse Event Reporting System.

Epilepsia. 2018 12;59(12):2318-2324

Authors: Borrelli EP, Lee EY, Descoteaux AM, Kogut SJ, Caffrey AR

Abstract
OBJECTIVE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and potentially fatal adverse skin reactions that are most commonly triggered by certain medications. One class of medications that has been highly associated with SJS/TEN reactions is antiepileptic drugs (AEDs). We sought to quantify the risk of SJS/TEN associated with AEDs as a class, as well as individual AEDs, in the United States.
METHODS: An analysis was performed of the US Food and Drug Administration Adverse Event Reporting System (FAERS) from July 2014 through December 2017. Rates of SJS/TEN were calculated for each AED compared with all other non-AEDs. Reporting odds ratios (RORs), proportional reporting ratios (PRRs), and 95% confidence intervals (CIs) were calculated using OpenEpi.
RESULTS: With 198 reports, AEDs had more reports of SJS/TEN than any other medication class. AEDs as a class had an ROR of 8.7 (95% CI 7.5-10.2) and a PRR of 8.7 (95% CI 7.5-10.2) compared with all other non-AEDs. The AEDs with the highest risk estimates were zonisamide (ROR 70.2, 95% CI 33.1-148.7; PRR 68.7, 95% CI 32.9-143.5), rufinamide (ROR 60.0, 95% CI 8.3-433.5; PRR 58.9, 95% CI 8.4-411.5), clorazepate (ROR 56.0, 95% CI 7.8-404.1; PRR 55.1, 95% CI 7.8-385.0), lamotrigine (ROR 53.0, 95% CI 43.2-64.9; PRR 52.2, 95% CI 42.7-63.7), phenytoin (ROR 26.3, 95% CI 15.5-44.7; PRR 26.1, 95% CI 15.4-44.2), and carbamazepine (ROR 24.5, 95% CI 16.0-37.5; PRR 24.3, 95% CI 16.0-37.1).
SIGNIFICANCE: Although AEDs as a class were associated with 9 times the risk of SJS/TEN compared with non-AEDs, there were 6 AEDs with risk estimates greater than 20. Increased awareness of this risk among both prescribers and patients, particularly variations in risk among different AEDs, along with education on early recognition of SJS/TEN signs/symptoms, may help mitigate the number and severity of these adverse events.

PMID: 30395352 [PubMed - indexed for MEDLINE]

Effects of a Public Subsidy Program for Mumps Vaccine on Reducing the Disease Burden in Nagoya City, Japan.

Jpn J Infect Dis. 2019 Mar 25;72(2):106-111

Authors: Ozaki T, Goto Y, Nishimura N, Nakano T, Kumihashi H, Kano M, Ohfuji S

Abstract
Nagoya City initiated a public subsidy program for mumps vaccination using either the Torii or Hoshino strains in August 2010. To determine the effects of the program, we used publicly available information from Nagoya City to investigate the changes in immunization rates and numbers of patients who developed post-immunization adverse reactions, including post-vaccinal aseptic meningitis, in the 7 years since its initiation. We also investigated the numbers of mumps patients reported by sentinel sites in a national database during this period. The immunization rate in one-year-old children increased from 24.3% before the program to 91.0% after 7 years. The mean numbers of reported mumps cases per sentinel site in one-year-old to preschool children-the age groups targeted by the program- were 12.9 in the 7 years before the program and 4.93 in the 7 years after initiation of the program, showing a significant decrease of 1/2.6 (p = 0.01). The number of vaccinations during the 6.5-year period was 140,316, with only one case of aseptic meningitis reported (0.7 cases/100,000 vaccinations). No other serious adverse reactions were observed. The present findings demonstrate that the public subsidy program in Nagoya City is an effective and safe measure against mumps in children.

PMID: 30381683 [PubMed - indexed for MEDLINE]

Current trends in pharmacovigilance: value and gaps of patient reporting.

Int J Clin Pharm. 2018 Aug;40(4):754-757

Authors: Inácio P, Cavaco A, Airaksinen M

Abstract

PMID: 30006734 [PubMed - indexed for MEDLINE]

Reporting adverse drug reactions: contribution, knowledge and perception of German pharmacy professionals.

Int J Clin Pharm. 2018 Aug;40(4):842-851

Authors: Laven A, Schmitz K, Franzen WH

Abstract
Background The detection, assessment and prevention of adverse drug reactions along the product's life cycle is known as pharmacovigilance. German pharmacists are obliged by law to conduct pharmacovigilance measures, a specific training is not required. Objectives To assess the knowledge, contribution and perception of German pharmacy professionals regarding pharmacovigilance activities, in order to identify their needs to report better on the issue. Setting A semi-quantitative survey among German pharmacy professionals was conducted in November 2017. Method A questionnaire with 20 questions was developed and distributed to pharmacy professionals in four different German regions. Main outcome measures To assess the knowledge the number of right answered questions were examined; for perception a six-point-Likert was used and for contribution, yes or no questions. Results The participation ratio was 64.5% (n = 127). Nearly half of the participants (47.2%, n = 60) stated that they had already reported adverse drug reactions. Regarding the knowledge questions, there was neither a statistically significant difference between the correct answers of pharmacists and pharmacy technical assistents (p = 0.7209), nor between the different regions (p > 0.5054). For better reporting, the participants recommended better training, shorter forms to fill in and/or a contact person to call. Conclusion For the successful integration of pharmacovigilance reporting in daily practice, we suggest the following: (1) A structured, mandatory training of the pharmacy team. (2) The preparation of a standard operating procedure for the pharmacy or its integration into the pharmacy software.

PMID: 29909562 [PubMed - indexed for MEDLINE]

Acute liver injury following Garcinia cambogia weight-loss supplementation: case series and literature review.

Intern Emerg Med. 2018 Sep;13(6):857-872

Authors: Crescioli G, Lombardi N, Bettiol A, Marconi E, Risaliti F, Bertoni M, Menniti Ippolito F, Maggini V, Gallo E, Firenzuoli F, Vannacci A

Abstract
Herbal weight-loss supplements are sold as self-medication products, and are often used under the misconception that their natural origin guarantees their safety. Food supplements are not required to provide any benefit/risk profile evaluation before marketing; however, possible risks associated with use of herbal extracts in food supplements are becoming more and more documented in the literature. Some herbs are listed as the leading cause of herb-induced liver injury, with a severe or potentially lethal clinical course, and unpredictable herb-drug interactions. Garcinia cambogia (GC) extract and GC-containing products are some of the most popular dietary supplements currently marketed for weight loss. Here, we present four cases of acute liver failure in women taking GC extract for weight loss, and a literature review of clinical evidences about hepatic toxicity in patients taking dietary supplements containing GC extract.

PMID: 29802521 [PubMed - indexed for MEDLINE]

A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture.

Calcif Tissue Int. 2019 Apr 20;:

Authors: Kharazmi M, Michaëlsson K, Schilcher J, Eriksson N, Melhus H, Wadelius M, Hallberg P

Abstract
Atypical femoral fracture is a well-documented adverse reaction to bisphosphonates. It is strongly related to duration of bisphosphonate use, and the risk declines rapidly after drug withdrawal. The mechanism behind bisphosphonate-associated atypical femoral fracture is unclear, but a genetic predisposition has been suggested. With the aim to identify common genetic variants that could be used for preemptive genetic testing, we performed a genome-wide association study. Cases were recruited mainly through reports of adverse drug reactions sent to the Swedish Medical Products Agency on a nation-wide basis. We compared atypical femoral fracture cases (n = 51) with population-based controls (n = 4891), and to reduce the possibility of confounding by indication, we also compared with bisphosphonate-treated controls without a current diagnosis of cancer (n = 324). The total number of single-nucleotide polymorphisms after imputation was 7,585,874. A genome-wide significance threshold of p < 5 × 10-8 was used to correct for multiple testing. In addition, we performed candidate gene analyses for a panel of 29 genes previously implicated in atypical femoral fractures (significance threshold of p < 5.7 × 10-6). Compared with population controls, bisphosphonate-associated atypical femoral fracture was associated with four isolated, uncommon single-nucleotide polymorphisms. When cases were compared with bisphosphonate-treated controls, no statistically significant genome-wide association remained. We conclude that the detected associations were either false positives or related to the underlying disease, i.e., treatment indication. Furthermore, there was no significant association with single-nucleotide polymorphisms in the 29 candidate genes. In conclusion, this study found no evidence of a common genetic predisposition for bisphosphonate-associated atypical femoral fracture. Further studies of larger sample size to identify possible weakly associated genetic traits, as well as whole exome or whole-genome sequencing studies to identify possible rare genetic variation conferring a risk are warranted.

PMID: 31006051 [PubMed - as supplied by publisher]

Pharmacokinetics of Single Doses of BI 425809 in Healthy Chinese and Japanese Subjects: A Randomized Study.

Clin Ther. 2019 Apr 17;:

Authors: Tsuda Y, Ugai H, Wunderlich G, Shin JG

Abstract
PURPOSE: This study's primary goal was to evaluate the safety profile, tolerability, pharmacokinetics, and dose proportionality of BI 425809, a potent and selective inhibitor of glycine transporter 1, in healthy Chinese and Japanese subjects.
METHODS: This single center, double-blind, single-rising dose study conducted in Korea randomly assigned (3:1) subjects within each ethnic subgroup (Chinese and Japanese) to receive a single dose of BI 425809 (10, 25, or 50 mg) or placebo. The primary end point was number (%) of subjects with drug-related adverse events (AEs). Secondary end points included AUC, Cmax, tmax, and t½ for BI 425809 in plasma. The CL/F and volume of distribution (Vz/F) were also measured.
FINDINGS: Of the 49 subjects enrolled into the study (24 Chinese, 25 Japanese), 36 were randomly assigned to receive BI 425809 (12 per dose group) and 13 to receive placebo. All subjects were analyzed for the primary end point and completed the study. Overall, 4 of 49 subjects (8.2%) reported ≥1 AE (placebo: n = 1, BI 425809: n = 3). One drug-related AE of moderate somnolence was reported by a Japanese subject who received placebo. In both subgroups, slightly lower than dose-proportional increases in exposure (AUC and Cmax) were observed with increasing dose. In addition, median tmax was 3.5-4.0 h, with a geometric mean t½ of 29.0-41.2 h. CL/F was similar between Chinese and Japanese subjects and increased with increasing dose (10-50 mg: 68.1-111 mL/min). Vz/F was 209-315 mL/min and similar between the subgroups.
IMPLICATIONS: BI 425809 was generally well tolerated in healthy Chinese and Japanese subjects with no significant findings for tolerability. No apparent difference in the pharmacokinetic variables of BI 425809 was observed between Chinese and Japanese subjects. The safety profile results and pharmacokinetic exposure levels are consistent with previous trials in Caucasian subjects. ClinicalTrials.gov identifier: NCT02383888.

PMID: 31005336 [PubMed - as supplied by publisher]

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Severe rhabdomyolysis related to oxaliplatin adjuvant therapy for colorectal cancer.

BMJ Case Rep. 2019 Apr 16;12(4):

Authors: Pissarra A, Malheiro M, Matos LV, Plácido AN

Abstract
Colorectal cancer is the third most common cancer in men and the second in women. The standard chemotherapy regiment in stage III colon cancer is based in oxaliplatin. The most common side effects include neutropenia, peripheral neuropathy, vomiting and diarrhoea. Rhabdomyolysis due to oxaliplatin is rare, and there are no established guidelines for managing this adverse event. This report describes a case of a 52-year-old man, with a resected stage III colon cancer that started postoperative adjuvant chemotherapy with capecitabine plus oxaliplatin. After the second cycle, the patient developed distal muscle pain and weakness, with a total inability to walk. Blood tests showed an elevated creatine kinase and renal injury. Severe drug-related rhabdomyolysis was diagnosed. The goal of this case report is to discuss the side effect of adjuvant chemotherapy, given its rarity and severity.

PMID: 30996068 [PubMed - in process]

Rapid assessment of enhanced safety surveillance for influenza vaccine.

Public Health. 2019 Mar;168:137-141

Authors: Alguacil-Ramos AM, Portero-Alonso A, Pastor-Villalba E, Muelas-Tirado J, Díez-Domingo J, Sanchis-Ferrer A, Lluch-Rodrigo JA

Abstract
OBJECTIVES: The enhanced safety surveillance for seasonal influenza vaccines established by the European Medicines Agency is required each season. Therefore, a registry capable of rapidly detecting and evaluating potential new safety concerns is needed. The aim of the study is to demonstrate the effectiveness of the vaccine information system of the Valencia region to make a rapid assessment of the influenza vaccine safety and describe the safety of the two vaccine types used in the 2017/2018 season.
STUDY DESIGN: It is a population-based descriptive study.
METHODS: Adverse events following immunization reports collected from 23rd October 2017 to 15th March 2018 were analyzed.
RESULTS: A total of 55 adverse events for influenza vaccine were reported in season 2017/2018 with a reporting rate (RR) of 0.77 per 10,000 administered doses. Injection site reactions had a RR of 0.30 and 0.47 per 10,000 for subunit and adjuvanted vaccines, respectively. Differences per vaccine, sex, and risk group did not reach statistical significance.
CONCLUSIONS: Reported events of the two influenza vaccine types used were similar than in other seasons and consistent with their safety profiles.

PMID: 30769245 [PubMed - indexed for MEDLINE]

Safety and Efficacy of Reduced Prolonged-release Tacrolimus Exposure in De Novo Kidney Transplantation: A Randomized, Open-label, Pilot Study in Asia-OPTIMIZE Study.

Transplant Direct. 2019 Apr;5(4):e340

Authors: Kim YH, Chiang YJ, Kim SJ, Kim MS, Park SB, Wu ST, Horita K, Nakashima Y, Jiang H, Han DJ

Abstract
Background: A multicenter, randomized, open-label, parallel group, pilot, 52-week study in Asian countries that assessed the renal function, efficacy, and safety of reduced-exposure versus standard-exposure prolonged-release tacrolimus (PR-T) in adult kidney transplant recipients (KTRs).
Methods: Posttransplantation, KTRs received PR-T from weeks 0 to 4 (initial dose, 0.2-0.3 mg/kg; target trough level, 6-10 ng/mL). At week 4, KTRs were randomized (1:1) to receive reduced-exposure PR-T (target 4-6 ng/mL, weeks 4-12; 3-5 ng/mL, weeks 12-52) or standard-exposure PR-T (target: 6-10 ng/mL, weeks 4-52). Primary end point: estimated glomerular filtration rate (eGFR) over 52 weeks. Secondary end points (week 52) included creatinine clearance, serum creatinine, graft/patient survival, biopsy-confirmed acute rejection (AR), composite of graft loss/patient death/biopsy-confirmed AR, and steroid-resistant AR. Treatment-emergent adverse events were recorded.
Results: Sixty-six KTRs received PR-T (reduced-exposure, n = 32; standard-exposure, n = 34) and were analyzed. After per-protocol dose adjustment, mean ± standard deviation tacrolimus trough level was lower with reduced- versus standard-exposure PR-T (week 52, 4.5 ± 1.1 ng/mL vs 8.0 ± 2.2 ng/mL). In the reduced- versus standard-exposure group, eGFR was similar at weeks 8 to 52 (overall least-square mean difference, -2.82; 95% confidence interval, -7.91 to 2.27; P = 0.272). At week 52, there was no significant difference in creatinine clearance (P = 0.375) or serum creatinine (P = 0.547) between groups. All grafts/patients survived, no steroid-resistant AR was reported, and 4 and 3 patients had AR in reduced- and standard-exposure groups, respectively. Drug-related treatment-emergent adverse events were reported in 34.4% and 38.2% of patients, respectively.
Conclusions: Reducing exposure to PR-T resulted in a clinically acceptable short-term safety profile and was generally as effective as standard tacrolimus exposure for Asian patients.

PMID: 30993185 [PubMed]

Albuminuria-lowering effect of dapagliflozin alone and in combination with saxagliptin and effect of dapagliflozin and saxagliptin on glycaemic control in patients with type 2 diabetes and chronic kidney disease (DELIGHT): a randomised, double-blind, placebo-controlled trial.

Lancet Diabetes Endocrinol. 2019 Apr 12;:

Authors: Pollock C, Stefánsson B, Reyner D, Rossing P, Sjöström CD, Wheeler DC, Langkilde AM, Heerspink HJL

Abstract
BACKGROUND: In patients with type 2 diabetes, intensive glucose control can be renoprotective and albuminuria-lowering treatments can slow the deterioration of kidney function. We assessed the albuminuria-lowering effect of the sodium-glucose co-transporter-2 inhibitor dapagliflozin with and without the dipeptidyl peptidase-4 inhibitor saxagliptin, and the effect of dapagliflozin-saxagliptin on glycaemic control in patients with type 2 diabetes and moderate-to-severe chronic kidney disease.
METHODS: In this double-blind, placebo-controlled trial (DELIGHT), we enrolled patients at 116 research centres in Australia, Canada, Japan, South Korea, Mexico, South Africa, Spain, Taiwan, and the USA. We included patients with a known history of type 2 diabetes, increased albuminuria (urine albumin-to-creatinine ratio [UACR] 30-3500 mg/g), an estimated glomerular filtration rate of 25-75 mL/min per 1·73 m2, and an HbA1c of 7·0-11·0% (53-97 mmol/mol), who had been receiving stable doses of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker therapy and glucose-lowering treatment for at least 12 weeks. After a 4-week, single-blind placebo run-in period, participants were randomly assigned (1:1:1; via an interactive voice-web response system) to receive dapagliflozin (10 mg) only, dapagliflozin (10 mg) and saxagliptin (2·5 mg), or placebo once-daily for 24 weeks. Primary endpoints were change from baseline in UACR (dapagliflozin and dapagliflozin-saxagliptin groups) and HbA1c (dapagliflozin-saxagliptin group) at week 24 in all randomly allocated patients with available data (full analysis set). This study is registered with ClinicalTrials.gov, number NCT02547935 and is completed.
FINDINGS: The study took place between July 14, 2015, and May 18, 2018. 1187 patients were screened, of whom 461 were randomly assigned: 145 to the dapagliflozin group, 155 to the dapagliflozin-saxagliptin group, and 148 to the placebo group (13 patients were excluded because of data integrity issues). Dapagliflozin and dapagliflozin-saxagliptin reduced UACR versus placebo throughout the study period. At week 24, the difference (vs placebo; n=134 patients with available data) in mean UACR change from baseline was -21·0% (95% CI -34·1 to -5·2; p=0·011) for dapagliflozin (n=132) and -38·0% (-48·2 to -25·8; p<0·0001) for dapagliflozin-saxagliptin (n=139). HbA1c was reduced in the dapagliflozin-saxagliptin group (n=137) compared with the placebo group (n=118) at week 24 (-0·58% [-0·80 to -0·37; p<0·0001]). The numbers of patients with adverse events (79 [54%] in the dapagliflozin group, 104 [68%] in the dapagliflozin-saxagliptin group, and 81 [55%] in the placebo group) or serious adverse events (12 [8%], 12 [8%], and 16 [11%], respectively) were similar across groups. There were no new drug-related safety signals.
INTERPRETATION: Dapagliflozin with or without saxagliptin, given in addition to angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment, is a potentially attractive option to slow the progression of kidney disease in patients with type 2 diabetes and moderate-to-severe chronic kidney disease.
FUNDING: AstraZeneca.

PMID: 30992195 [PubMed - as supplied by publisher]

Micafungin prophylaxis for acute leukemia patients undergoing induction chemotherapy.

BMC Cancer. 2019 Apr 16;19(1):358

Authors: Park H, Youk J, Shin DY, Hong J, Kim I, Kim NJ, Lee JO, Bang SM, Yoon SS, Park WB, Koh Y

Abstract
BACKGROUND: Micafungin is a well-tolerated and effective prophylactic antifungal agent used in hematologic diseases. In this prospective trial, we evaluated the efficacy and safety of prophylactic micafungin during first induction chemotherapy in patients with acute leukemia. We also compared outcomes of prophylactic micafungin with those of prophylactic posaconazole in acute myeloid leukemia (AML).
METHODS: Medically fit patients with newly diagnosed acute leukemia received 50 mg micafungin intravenously once daily from the initiation of first induction chemotherapy to recovery of neutrophil count, suspected fungal infection, or unacceptable drug-related toxicity ( Clinicaltrials.gov number, NCT02440178). The primary end point was incidence of invasive fungal infection, and the secondary end points were adverse events of prophylactic micafungin and mortality during induction therapy.
RESULTS: The 65 patients (median age = 51 years, male:female = 34:31) enrolled in this study had diagnoses of AML (33, 50.8%), acute lymphoblastic leukemia (31, 47.7%), and acute biphenotypic leukemia (1, 1.5%). Median duration of micafungin treatment was 24 days (range 1-68), with proven invasive fungal disease in one patient (1.5%) and possible fungal infection in two patients (3.1%). Three of the patients (4.6%) experienced the following adverse events, but all events were tolerable: liver function abnormality (Grade 2, n = 1; Grade 3, n = 1) and allergic reaction (Grade 2, n = 1). Three patients died during induction therapy, and invasive aspergillosis pneumonia was the cause of death for one of those patients. Overall, 19 patients (29.2%) discontinued prophylactic micafungin, and 18 (27.7%) patients switched to another antifungal agent. We observed no fungal infections caused by amphotericin B-resistant organisms. In AML patients, outcomes of prophylactic micafungin during induction chemotherapy did not differ significantly with those of prophylactic posaconazole with regard to incidence of fungal infections, rate of discontinuation, or safety.
CONCLUSIONS: Our study demonstrates that prophylactic micafungin is safe and effective in patients with acute leukemia undergoing induction chemotherapy. Outcomes in patients with AML were similar to those of prophylactic posaconazole, indicating the usefulness of micafungin as a prophylactic antifungal agent during induction chemotherapy for AML.
TRIAL REGISTRATION: Clinicaltrials.gov NCT02440178, registered May 12th 2015.

PMID: 30991992 [PubMed - in process]

The clinical characteristics and related factors of tremor in patients with epilepsy.

Seizure. 2019 Mar;66:70-75

Authors: Xiao Y, Xiong W, Lu L, Chen J, Zhang Y, Jiang X, Zhou D

Abstract
PURPOSE: Tremor is frequently observed in patients with epilepsy (PWE), which is generally attributed to the side-effect of antiepileptic drugs (AEDs) particularly valproate (VPA) with largely unknown mechanisms. The study aimed to assess the clinical features and related factors of tremor in PWE with tremor.
METHODS: PWE with tremor and a control group of age- and sex-matched PWE without tremor were enrolled. Detailed demographic and clinical information for each individual was recorded. PWE with tremor were evaluated by The Clinical Rating Scale for Tremor (CRST) and Tremor Related Activities of Daily Living (TRADL) questionnaire.
RESULTS: 132 individuals were enrolled, which including sixty-six (36 males) PWE with tremor with mean age of 33 years and epilepsy duration of 12.5 years. Tremor was postural in all, with median duration of four and one year from diagnosis and AED treatment to the onset of tremor respectively. The upper limbs were predominantly affected. VPA had been used in 62 (93.9%) PWE with tremor compared to 31 (47.0%) PWE without tremor (P < 0.001). The total CRST score was significantly associated with epilepsy duration and maximum VPA dosage (B = 0.30, p < 0.001; B = 0.32, p = 0.013). Patients with VPA dosage over 17.05 mg/kg/d might be more vulnerable to develop tremor.
CONCLUSIONS: PWE with tremor were more frequently treated with VPA, however, tremor was mild in most without any functional impairment. Epilepsy duration and maximum VPA dosage were important factors of tremor severity, suggesting mechanisms underlying tremor in PWE may be an elaborate interplay of AEDs and disease itself.

PMID: 30807902 [PubMed - indexed for MEDLINE]

The Harvard medical practice study trigger system performance in deceased patients.

BMC Health Serv Res. 2019 Jan 08;19(1):16

Authors: Klein DO, Rennenberg RJMW, Koopmans RP, Prins MH

Abstract
BACKGROUND: To detect possible threats to quality and safety, multiple systems have been developed. One of them is retrospective chart review. A team of experts scrutinizes medical records, selected by trigger systems, to detect possible adverse events (AEs). The most important AEs and more hints for possible improvement of care appear in deceased patients. Using triggers in a sample of these patients might increase the performance and lower the burden of scrutinizing records without possible preventable AEs. The aim of this study was therefore to determine the performance of the trigger system in a sample of deceased patients and to calculate the specificity and the sensitivity of this trigger system for predicting AEs.
METHODS: We performed a study in which the records of deceased patients were screened for triggers by a team of trained nurses. A sample of 100 medical records was randomly selected out of records which had been screened between 2012 and 2015 for the first time, prior to the study in 2016. For the determination of significant differences between the first and second screening, McNemar's test of symmetry was used. Also, observed agreement, Cohen's Kappa and prevalence-adjusted and-bias-adjusted-kappa (PABAK) statistics were calculated. This was done for the two trigger rounds on both any trigger present and for every trigger separately.
RESULTS: The observed agreement for any given trigger was 75% with a Kappa and PABAK of 0.5. For the individual triggers, the observed agreement was on average 90%. The corresponding Kappa was on average 0.42 (range: - 0.03-0.78) and the average PABAK was 0.8 (range: 0.44-0.92). Two adverse events were found in cases without triggers previously. The recalculated specificity and sensitivity for the original population were 58 and 92% respectively.
CONCLUSIONS: For the reproducibility of triggers it seems that some perform better than others, but on average this is to our opinion suboptimal. The low specificity implies that many records are selected without AEs. This leads to a high false-positive rate making this labour-intensive record review process costly. Therefore, research for better and more expedient systems is required.

PMID: 30621689 [PubMed - indexed for MEDLINE]

Prescription and non-prescription antibiotic dispensing practices in part I and part II pharmacies in Moshi Municipality, Kilimanjaro Region in Tanzania: A simulated clients approach.

PLoS One. 2018;13(11):e0207465

Authors: Horumpende PG, Sonda TB, van Zwetselaar M, Antony ML, Tenu FF, Mwanziva CE, Shao ER, Mshana SE, Mmbaga BT, Chilongola JO

Abstract
Antibiotic dispensing without a prescription poses a threat to public health as it leads to excessive antibiotic consumption. Inappropriate antibiotic availability to the community has been documented to be amongst drivers of antimicrobial resistance emergence. Community pharmacies are a source of antibiotics in low and middle-income countries (LMICs). We aimed at assessing antibiotic dispensing practices by community pharmacy retailers in Moshi urban, Kilimanjaro, Tanzania and recommend interventions to improve practice. Using a Simulated Client (SC) Method, an observational cross-sectional survey of antibiotic dispensing practices was conducted from 10th June to 10th July 2017. Data analysis was done using Stata 13 (StataCorp, College Station, TX, USA). A total of 82 pharmacies were visited. Part I pharmacies were 26 (31.71%) and 56 (68.29%) were part II. Overall 92.3% (95% CI 77.8-97.6) of retailers dispensed antibiotics without prescriptions. The antibiotics most commonly dispensed without a prescription were ampiclox for cough (3 encounters) and azithromycin for painful urination (3 encounters). An oral third generation cephalosporin (cefixime) was dispensed once for painful urination without prescription by a part I pharmacy retailer. Out of 21, 15(71.43%) prescriptions with incomplete doses were accepted and had antibiotics dispensed. Out of 68, 4(5.9%) retailers gave instructions for medicine use voluntarily. None of the retailers voluntarily explained drug side-effects. In Moshi pharmacies, a high proportion of antibiotics are sold and dispensed without prescriptions. Instructions for medicine use are rarely given and none of the retailers explain side effects. These findings support the need for a legislative enforcement of prescription-only antibiotic dispensing rules and regulations. Initiation of clinician and community antibiotic stewardship and educational programs on proper antibiotic use to both pharmacists and public by the regulatory bodies are highly needed.

PMID: 30462700 [PubMed - indexed for MEDLINE]

On estimands and the analysis of adverse events in the presence of varying follow-up times within the benefit assessment of therapies.

Pharm Stat. 2019 03;18(2):166-183

Authors: Unkel S, Amiri M, Benda N, Beyersmann J, Knoerzer D, Kupas K, Langer F, Leverkus F, Loos A, Ose C, Proctor T, Schmoor C, Schwenke C, Skipka G, Unnebrink K, Voss F, Friede T

Abstract
The analysis of adverse events (AEs) is a key component in the assessment of a drug's safety profile. Inappropriate analysis methods may result in misleading conclusions about a therapy's safety and consequently its benefit-risk ratio. The statistical analysis of AEs is complicated by the fact that the follow-up times can vary between the patients included in a clinical trial. This paper takes as its focus the analysis of AE data in the presence of varying follow-up times within the benefit assessment of therapeutic interventions. Instead of approaching this issue directly and solely from an analysis point of view, we first discuss what should be estimated in the context of safety data, leading to the concept of estimands. Although the current discussion on estimands is mainly related to efficacy evaluation, the concept is applicable to safety endpoints as well. Within the framework of estimands, we present statistical methods for analysing AEs with the focus being on the time to the occurrence of the first AE of a specific type. We give recommendations which estimators should be used for the estimands described. Furthermore, we state practical implications of the analysis of AEs in clinical trials and give an overview of examples across different indications. We also provide a review of current practices of health technology assessment (HTA) agencies with respect to the evaluation of safety data. Finally, we describe problems with meta-analyses of AE data and sketch possible solutions.

PMID: 30458579 [PubMed - indexed for MEDLINE]

Pharmacogenetic and clinical predictors of response to clopidogrel plus aspirin after acute coronary syndrome in Egyptians.

Pharmacogenet Genomics. 2018 09;28(9):207-213

Authors: Fathy S, Shahin MH, Langaee T, Khalil BM, Saleh A, Sabry NA, Schaalan MF, El Wakeel LL, Cavallari LH

Abstract
OBJECTIVES: Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduces the risk for recurrent cardiovascular events after acute coronary syndrome (ACS). However, there is significant variation in response to DAPT that may be influenced by both genetic and nongenetic factors. This study aimed to assess the effect of genetic polymorphisms in PON-1, PEAR-1, P2Y12, CES1, and CYP2C19, along with clinical, demographic, and social factors, on variation in response to DAPT in Egyptians.
PARTICIPANTS AND METHODS: This study included 230 Egyptians treated with clopidogrel 75 mg/day and aspirin 81 mg/day for at least 12 months following their first ACS. Simple and multivariable logistic regression analyses were carried out to identify factors associated with major adverse cardiovascular events (MACE), defined as the occurrence of recurrent ACS, ischemic stroke, stent-related revascularization, or death, in clopidogrel-treated participants.
RESULTS: Using multivariable logistic regression analysis, the CYP2C19*2 polymorphism was the only genetic predictor of MACE [odds ratio (OR): 2.23, 95% confidence interval (CI): 1.15-4.33, P=0.01]. In addition, proton pump inhibitor use (OR: 4.77, 95% CI: 1.47-15.54, P=0.009) and diabetes (OR: 1.83, 95% CI: 1.03-3.26, P=0.03) were associated with higher cardiovascular risk, whereas statin use was associated with lower risk (OR: 0.43, 95% CI: 0.25-0.76, P=0.003). The contribution of these four genetic and nongenetic factors explained 19% of the variability in risk for MACE in Egyptians treated with DAPT.
CONCLUSION: These results highlight that CYP2C19*2, along with diabetes, and use of proton pump inhibitor and statin are important factors jointly associated with variability in clinical response to DAPT following ACS in Egyptians.

PMID: 30188374 [PubMed - indexed for MEDLINE]

Study Design Parameters Affecting Exposure Response Analysis of QT Data: Results From Simulation Studies.

J Clin Pharmacol. 2018 05;58(5):674-685

Authors: Ferber G, Sun Y, Darpo B, Garnett C, Liu J

Abstract
The operating characteristics of dose-escalating studies in terms of false-negative predictions of the QT effect and the power to exclude clinically relevant QT effects are not quantitatively established. One thousand single-ascending-dose (SAD) studies with 7 dose groups with 6/2 subjects on active drug/placebo were generated through simulation for each of 32 scenarios with (1) 8 different QT effects of the study drug and (2) achieved plasma concentration 2- or 4-fold above therapeutic levels. For each subject, drug-free QT data from a thorough QT study were subsampled to capture the circadian profile, on which a drug effect was added. The percentage of false-negative studies was between 4% and 9% when the drug's QT effect was set to 10 milliseconds. If a somewhat lower effect of 6.7 milliseconds was set at therapeutic concentrations, the fraction of negative studies was higher, 40% to 60% when the variability of the QT data was well controlled. When the QT effect was set to 5 milliseconds at therapeutic plasma concentrations, the power of SAD studies to exclude 10 milliseconds QT effect was generally above 70% (74% to 94%) with well-controlled QT variability, whereas the power was reduced to 36% to 69% if supratherapeutic plasma concentrations were not achieved. The rate of false-negative studies was acceptably low in placebo-controlled SAD studies. With a drug with no or a small QT effect, supratherapeutic plasma concentrations, and well-controlled variability of QT data, the power of SAD studies to exclude a relevant effect was above 70%.

PMID: 29420838 [PubMed - indexed for MEDLINE]

In vivo biodistribution and toxicity of intravesical administration of quantum dots for optical molecular imaging of bladder cancer.

Sci Rep. 2017 08 24;7(1):9309

Authors: Pan Y, Chang T, Marcq G, Liu C, Kiss B, Rouse R, Mach KE, Cheng Z, Liao JC

Abstract
Optical molecular imaging holds the potential to improve cancer diagnosis. Fluorescent nanoparticles such as quantum dots (QD) offer superior optical characteristics compared to organic dyes, but their in vivo application is limited by potential toxicity from systemic administration. Topical administration provides an attractive route for targeted nanoparticles with the possibility of minimizing exposure and reduced dose. Previously, we demonstrated successful ex vivo endoscopic imaging of human bladder cancer by topical (i.e. intravesical) administration of QD-conjugated anti-CD47. Herein we investigate in vivo biodistribution and toxicity of intravesically instilled free QD and anti-CD47-QD in mice. In vivo biodistribution of anti-CD47-QD was assessed with inductively coupled plasma mass spectrometry. Local and systemic toxicity was assessed using blood tests, organ weights, and histology. On average, there was no significant accumulation of QD outside of the bladder, although in some mice we detected extravesical biodistribution of QD suggesting a route for systemic exposure under some conditions. There were no indications of acute toxicity up to 7 days after instillation. Intravesical administration of targeted nanoparticles can reduce systemic exposure, but for clinical use, nanoparticles with established biosafety profiles should be used to decrease long-term toxicity in cases where systemic exposure occurs.

PMID: 28839158 [PubMed - indexed for MEDLINE]