PCNE definition of medication review: reaching agreement.

Int J Clin Pharm. 2018 Oct;40(5):1199-1208

Authors: Griese-Mammen N, Hersberger KE, Messerli M, Leikola S, Horvat N, van Mil JWF, Kos M

Abstract
Background Medication review is important in an era, in which polypharmacy is increasing. To date, no agreed international definition of medication review exists. Objective The aim was to reach agreement on an internationally applicable definition of medication review. Setting An international group of experts in medication review. Methods A working group of the Pharmaceutical Care Network Europe (PCNE) was established to agree on a definition including a classification of medication review. First, a survey with the aim of systematically gathering viewpoints on a definition of medication review was conducted. Second, a workshop was held to achieve an agreement. Finally, during the General Assembly of PCNE, the definition was approved. To ensure a better understanding of the scope and the considerations behind the definition, a position paper was created. Main outcome measure An internationally agreed definition of medication review. Results 58 PCNE members from 20 different countries completed the online survey. Then, 22 participants from 11 different countries (not only PCNE members) elaborated the final definition during a workshop. The final PCNE version agreed was: "Medication review is a structured evaluation of a patient's medicines with the aim of optimising medicines use and improving health outcomes. This entails detecting drug-related problems and recommending interventions". Overall, the consensus process included 225 people from 35 countries and resulted also in a classification of medication review taking into account the type and source of available information. Conclusion Involvement of an international community from research and practice and the use of a systematic process led to an agreement on the term medication review and on a classification valid for all settings and professions.

PMID: 30073611 [PubMed - indexed for MEDLINE]

Development of a risk model for predicting QTc interval prolongation in patients using QTc-prolonging drugs.

Int J Clin Pharm. 2018 Oct;40(5):1372-1379

Authors: Bindraban AN, Rolvink J, Berger FA, van den Bemt PMLA, Kuijper AFM, van der Hoeven RTM, Mantel-Teeuwisse AK, Becker ML

Abstract
Background Numerous drugs prolong the QTc interval on the ECG and potentially increase the risk of cardiac arrhythmia. This risk is clinically relevant in patients with additional risk factors. Objective The objective was to develop and validate a risk model to predict QTc interval prolongation of eligible ECGs. Setting Spaarne Gasthuis (Haarlem/Hoofddorp, The Netherlands). Method A dataset was created from ECGs recorded in patients using one or more QTc prolonging drugs, in the period January 2013 and October 2016. In the development set, independent risk factors for QTc interval prolongation were determined using binary logistic regression. Risk scores were assigned based on the beta coefficient. In the risk-score validation set, the area under the ROC-curve, sensitivity and specificity were calculated. Main outcome measure QTc interval prolongation, defined as a QTc interval > 500 ms. Results In the development set 12,949 ECGs were included and in the risk-score validation set 6391 ECGs. The proportion of ECGs with a prolonged QTc interval in patients with no risk factors in the risk-score validation set was 2.7%, while in patients with a high risk score the proportion was 26.1%. The area under the ROC curve was 0.71 (95% CI 0.68-0.73). The sensitivity and specificity were 0.81 and 0.48, respectively. Conclusion A risk model was developed and validated for the prediction of QTc interval prolongation. This risk model can be implemented in a clinical decision support system, supporting the management of the risks involved with QTc interval prolonging drugs.

PMID: 30051227 [PubMed - indexed for MEDLINE]

A dual intervention in geriatric patients to prevent drug-related problems and improve discharge management.

Int J Clin Pharm. 2018 Oct;40(5):1189-1198

Authors: Freyer J, Kasprick L, Sultzer R, Schiek S, Bertsche T

Abstract
Background Drug-related problems (DRPs) endanger geriatric patients' safety. Especially a follow-up treatment with increased number of care transitions is a critical time for patients. Objective This study aimed at optimising medication therapy and the transfer of medication-related information to ambulatory care in geriatric rehabilitation patients. Setting German geriatric rehabilitation centre (GRC). Method A prospective, controlled intervention study was performed. Patients in the control group (CG) received standard care, those in the intervention group (IG) an additional dual pharmaceutical intervention: (i) medication review to optimise in-hospital medication and (ii) improvement of discharge letters for optimising transfer of medication-related information. Main outcome measure (i) Number of patients with at least one DRP at discharge and (ii) predefined quality criteria for the discharge letters. Results 150 patients were enrolled in CG and 163 in IG. (i) At discharge, 126 (84%) patients in the CG were affected by at least one DRP. In the IG, the number of affected patients decreased to 64 (39%, P < 0.05). (ii) In comparison to discharge letters in the CG, predefined quality criteria were improved in the IG. Following differences were measured (CG vs. IG, each P < 0.05): active ingredient indicated (60 vs. 99%), brand name indicated (60 vs. 96%), explanation of medication changes (47 vs. 68%), visualisation of explanations next to the discharge medication (26 vs. 91%) and recommended therapy duration for short-term medications (49 vs. 84%). Conclusion DRPs and incomplete discharge letters affected many patients. The dual intervention improved in-hospital medication therapy and optimised the transfer of medication-related information.

PMID: 30051223 [PubMed - indexed for MEDLINE]

Impact of medication reconciliation and review and counselling, on adverse drug events and healthcare resource use.

Int J Clin Pharm. 2018 Oct;40(5):1154-1164

Authors: Al-Hashar A, Al-Zakwani I, Eriksson T, Sarakbi A, Al-Zadjali B, Al Mubaihsi S, Al Za'abi M

Abstract
Background Adverse drug events from preventable medication errors can result in patient morbidity and mortality, and in cost to the healthcare system. Medication reconciliation can improve communication and reduce medication errors at transitions in care. Objective Evaluate the impact of medication reconciliation and counselling intervention delivered by a pharmacist for medical patients on clinical outcomes 30 days after discharge. Setting Sultan Qaboos University Hospital, Muscat, Oman. Methods A randomized controlled study comparing standard care with an intervention delivered by a pharmacist and comprising medication reconciliation on admission and discharge, a medication review, a bedside medication counselling, and a take-home medication list. Medication discrepancies during hospitalization were identified and reconciled. Clinical outcomes were evaluated by reviewing electronic health records and telephone interviews. Main outcome measures Rates of preventable adverse drug events as primary outcome and healthcare resource utilization as secondary outcome at 30 days post discharge. Results A total of 587 patients were recruited (56 ± 17 years, 57% female); 286 randomized to intervention; 301 in the standard care group. In intervention arm, 74 (26%) patients had at least one discrepancy on admission and 100 (35%) on discharge. Rates of preventable adverse drug events were significantly lower in intervention arm compared to standard care arm (9.1 vs. 16%, p = 0.009). No significant difference was found in healthcare resource use. Conclusion The implementation of an intervention comprising medication reconciliation and counselling by a pharmacist has significantly reduced the rate of preventable ADEs 30 days post discharge, compared to the standard care. The effect of the intervention on healthcare resource use was insignificant. Pharmacists should be included in decentralized, patient-centred roles. The findings should be interpreted in the context of the study's limitations.

PMID: 29754251 [PubMed - indexed for MEDLINE]

Epidemiology of drug hypersensitivity reactions using 6-year national health insurance claim data from Korea.

Int J Clin Pharm. 2018 Oct;40(5):1359-1371

Authors: Han J, Ye YM, Lee S

Abstract
Background Drug hypersensitivity reactions (DHRs) constitute a large portion of adverse drug reactions (ADRs), but studies for DHR incidence based on national data are scarce. Objective This study aimed to estimate the incidence and patterns of DHRs in a Korean population and the associated utilization of medical resources using the national claims data. Setting The retrospective cohort study performed using the national insurance claim database of the Health Insurance Review and Assessment (HIRA) in Korea. Methods The International Classification of Disease 10th revision code was used to identify DHRs with 20 drug induced DHR codes. The claim data with a diagnosis of DHR in the 2009-2014 periods were analyzed. Main outcome and measure The annual incidence and the 6-year incidence rates were calculated. Incidence rate coefficients were analyzed by sex, age, and year. DHRs following with visits of emergency department (ED) or intensive care unit (ICU) were assessed for utilization of medical resources and risk of ER or ICU visits by sex and age Results A total of 535,049 patients with 1,083,507 claims were assessed in the HIRA database for 6 years. DHR incidence was high in the elderly. The risk of ED and ICU visit with DHR was also higher in the elderly than in the young [highest relative risk, RR of ED 2.59 (1.65-4.07), ICU 5.04 (2.50-10.18)]. DHRs related to blood were high in the young age. Conclusion Incidence of DHRs in the real-world clinical practice was higher in the elderly and female. Clinical consequence was more severe in the elderly.

PMID: 29611015 [PubMed - indexed for MEDLINE]

Rapid changes in serum cytokines and chemokines in response to inactivated influenza vaccination.

Influenza Other Respir Viruses. 2018 03;12(2):202-210

Authors: Talaat KR, Halsey NA, Cox AB, Coles CL, Durbin AP, Ramakrishnan A, Bream JH

Abstract
BACKGROUND: The timing of host cytokine responses to influenza vaccination is poorly understood.
OBJECTIVES: We examined serum cytokine kinetics following inactivated trivalent influenza vaccine (TIV) to better understand potential relationships between markers of inflammation and TIV-related side effects.
PATIENTS/METHODS: Twenty healthy adult subjects received TIV. Cytokines/chemokines were assessed in intervals from 3 hours to 14 days. Antibody titers were measured at baseline and Day 14.
RESULTS: Serum cytokine responses to TIV were evident as early as 3 hours post-immunization. Compared to baseline, IFN-γ and IP-10 were significantly elevated 7 hours after TIV administration. Both remained elevated and peaked between 16 and 24 hours before returning to baseline by 44 hours post-vaccination. Although IL-8 levels were variable between subjects during the first 24 hours after TIV, by 44 hours, IL-8 was significantly lower compared to baseline. Interestingly, IL-8 levels remained significantly lower for up to 2 weeks after receiving TIV. Fifteen of 20 subjects reported mild adverse events. The one subject who reported moderate myalgias and injection site pain after vaccination displayed a distinctive, early cytokine response profile which included IL-6, IL-2, IL-8, IP-10, MCP-1, TNF-α, TARC, and MCP-4.
CONCLUSIONS: Serum cytokines changed rapidly following TIV and generally peaked at 24 hours. Trivalent influenza vaccine-induced reductions in IL-8 occurred later (44 hours) and were sustained for 2 weeks. An outlier response coincided with the only moderate side effects to the vaccine. These data suggest that early cytokine/chemokine responses may provide additional insight into the pathogenesis of adverse events and immune reactivity to vaccination.

PMID: 28991404 [PubMed - indexed for MEDLINE]

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Serious central nervous system side effects of cephalosporins: A national analysis of serious reports registered in the French Pharmacovigilance Database.

J Neurol Sci. 2019 Jan 16;:

Authors: Lacroix C, Kheloufi F, Montastruc F, Bennis Y, Pizzoglio V, Micallef J

Abstract
INTRODUCTION: Among antibiotics, Central Nervous System (CNS) adverse drug reactions (ADRs) are often under-suspected and overlooked. Cephalosporins are an important cause of drug-induced CNS ADRs but the characteristics of such ADR have not been fully explored. We aimed to characterize the profile of cephalosporins serious CNS ADRs.
METHOD: We performed an analysis of serious reports recorded in the French Pharmacovigilance database from 1987 to 2017.
RESULTS: A total of 511 serious ADRs reports was analyzed. Patients had a mean age of 67.1 years and were mainly men (52.5%), with a mean creatinine clearance of 32.9 ml/min. The most involved molecules were cefepime (33.1%), ceftriaxone (29.7%), ceftazidime (19.6%), cefotaxime (9%) and cefazoline (2.9%), mostly administered intravenously (87.3%). A CNS history was observed in 25% of the reports (n = 128). Patients exhibited encephalopathy (30.3%), confusional state (19.4%), convulsion (15.1%), myoclonia (9.4%), status epilepticus (9.2%), coma (6.3%) and hallucination (4.3%). The mean time of onset was 7.7 days and the mean duration was 6 days. Cephalosporin plasma levels were recorded for 153 patients (29.9%) and 107 were above the standards including 62 (57.9%) related to renal impairment. Electroencephalograms were performed in 38.2% (n = 195) of the patients and 81% (n = 158) were abnormal.
CONCLUSION: This study characterizes an off-target CNS ADRs of several cephalosporins. Ceftriaxone represented a large part of our reports after cefepime and it would be relevant to warn healthcare professionals. Investigations (EEG, though plasma levels and renal function) can be precious tools for clinicians to make a prompt diagnosis and improve patients' outcomes.

PMID: 30683462 [PubMed - as supplied by publisher]

Avelumab Immunotherapy: Management of Adverse Events Associated With New Treatment for Merkel Cell Carcinoma.

Clin J Oncol Nurs. 2019 Feb 01;23(1):E1-E9

Authors: Ugolini H, Bryan J, Hennessy M, Kaufman HL, D'Angelo S

Abstract
BACKGROUND: Metastatic Merkel cell carcinoma (mMCC) is a rare skin cancer with poor prognosis. Avelumab is the first approved treatment option for patients with mMCC. Immune checkpoint inhibitors, such as avelumab, are associated with unique toxicities that can be effectively addressed with prompt recognition and appropriate management.
OBJECTIVES: This article discusses the use of avelumab for the treatment of mMCC and management of associated toxicities.
METHODS: Literature on mMCC disease state and clinical trial data for avelumab were reviewed.
FINDINGS: Avelumab has been investigated in patients with mMCC either following disease progression after one or more prior lines of chemotherapy or no prior systemic therapy. These patients experience clinically meaningful benefit. About 70% of patients receiving avelumab experience treatment-related adverse events. Given the limited benefit of chemotherapy, managing symptoms related to avelumab is key to administering this effective treatment to patients with mMCC.

PMID: 30682006 [PubMed - in process]

Karnofsky Performance Status as A Predictive Factor for Cancer-Related Fatigue Treatment with Astragalus Polysaccharides (PG2) Injection-A Double Blind, Multi-Center, Randomized Phase IV Study.

Cancers (Basel). 2019 Jan 22;11(2):

Authors: Wang CH, Lin CY, Chen JS, Ho CL, Rau KM, Tsai JT, Chang CS, Yeh SP, Cheng CF, Lai YL

Abstract
Fatigue is a common and debilitating symptom in patients with advanced cancer, resulting in poor quality of life and reduced treatment efficacy. Phytotherapeutic agents have shown potential effects to relieve cancer-related fatigue in these patients. The aim of this study was to evaluate the efficacy and safety of Astragalus Polysaccharides injection and identify predictive factors associated with this treatment. Patients with advanced cancer receiving palliative care with moderate to severe cancer-related fatigue were enrolled in this study for two treatment cycles. Fatigue improvement response rates were analyzed as the primary endpoint at the end of the first cycle to determine treatment efficacy. The drug safety profile was evaluated by the reporting of adverse events. Three hundred and ten patients were enrolled in this study and 214 patients were included ITT population. Improvement in fatigue scores by at least 10% was observed in greater than 65% of subjects after one treatment cycle compared to scores at baseline. Patients with higher Karnofsky Performance Status (KPS) responded better to the Astragalus Polysaccharides injection. Drug-related adverse event rates were less than 9%. This study identified KPS as a promising predictive factor for the therapeutic efficacy of Astragalus Polysaccharides injection.

PMID: 30678249 [PubMed]

American Geriatrics Society-Beers Criteria and adverse drug reactions: a comparative cross-sectional study of Nigerian and South African older inpatients.

Clin Interv Aging. 2018;13:2375-2387

Authors: Saka SA, Nlooto M, Oosthuizen F

Abstract
Background: The Beers Criteria were developed with the aim of improving the safety of medicines among older persons. While the association between the Beers' list of potentially inappropriate medicines (PIMs) and adverse drug reactions (ADRs) among older Caucasians is contentious, the ability of the Criteria to predict ADRs among older persons in Africa remains unexplored.
Objectives: This study aimed to compare the prevalence of PIMs and ADRs among hospitalized older persons in Nigeria and South Africa, and to determine the association between the 2015 American Geriatrics Society-Beers (AGS-Beers) PIMs and ADRs.
Methods: The medical records of older persons aged ≥60 years who were hospitalized in teaching hospitals in Nigeria and South Africa were randomly selected, and retrospectively evaluated for ADRs by two clinical pharmacists using the Naranjo algorithm. The PIMs were assessed using the 2015 AGS-Beers Criteria. A multivariate logistic regression was used to determine the associated factors for ADRs among the hospitalized older persons, with P<0.05 being considered significant.
Results: The samples which comprised 268 and 339 hospitalized older persons (mean age 70.53±8.22; 95% CI -0.21 to 2.32 vs mean age 69.49±7.64; 95% CI -0.25 to 2.34, P=0.11) were evaluated in Nigeria and South Africa, respectively. The PIMs among the older persons in Nigeria were 32.1% (86/268) and 30.1% (102/339, OR=0.91, 95% CI 0.64-1.29, P=0.6) for South Africa; 13.8% (37/268) of the hospitalized older persons in Nigeria experienced 43 cases of ADRs compared to 9.1% (31/339) in South Africa (95% CI 0.38-1.04, P=0.07). The multivariate analysis showed no association between PIMs and ADRs among the hospitalized older persons in Nigeria (OR=1.48 95% CI 0.70-3.17, P=0.31) and South Africa (OR=1.09, 95% CI 0.48-2.49, P=0.83).
Conclusion: The 2015 AGS-Beers PIMs were not associated with ADRs among the hospitalized older persons in Nigeria and South Africa. However, physicians should be cautious when prescribing certain medications in the AGS-Beers list.

PMID: 30538434 [PubMed - indexed for MEDLINE]

Rhabdomyolysis observed at forensic autopsy: a series of 52 cases.

Forensic Sci Med Pathol. 2018 12;14(4):424-431

Authors: Hu HY, Wei SY, Pan CH

Abstract
Rhabdomyolysis is characterized by skeletal muscle injury resulting in the release of intracellular proteins (such as myoglobin) and electrolytes into the blood circulation, which cause acute kidney injury, myoglobinuria and electrolyte imbalances. Clinical diagnosis of rhabdomyolysis is made on the basis of biochemical analysis; however, for forensic autopsies, biochemical data are often not available, and it is necessary to diagnose rhabdomyolysis via histopathological examinations. This study analyzed 52 cases with rhabdomyolysis and applied myoglobin immunohistochemistry to kidney, urine and blood samples. We found that blunt force injuries were the most common cause of rhabdomyolysis across all age groups, and drugs were the second most common cause. The drugs included ketamines, amphetamines, synthetic cathinones, entheogens, benzodiazepines, opioid analgesics, and anesthesia. Less than 60% of our cases had biochemical data, including myoglobin (92.5~416,978 ng/mL), creatine kinase (220~774,015 U/L), potassium (1.6~10.3 meq/L), calcium (2.7~29.2 mg/dL), and phosphorus (2.6~14.2 mg/dL). In the kidney tissue sections, we found that 95% of the rhabdomyolysis cases were positive for myoglobin immunohistochemistry and that 96% were associated with acute tubular necrosis. Our findings describe the features of fatal rhabdomyolysis in a large series and suggest that myoglobin immunohistochemistry can be used in post-mortem blood and urine cell blocks to detect myoglobin.

PMID: 30056625 [PubMed - indexed for MEDLINE]

A wearable remote monitoring system for the identification of subjects with a prolonged QT interval or at risk for drug-induced long QT syndrome.

Int J Cardiol. 2018 Sep 01;266:89-94

Authors: Castelletti S, Dagradi F, Goulene K, Danza AI, Baldi E, Stramba-Badiale M, Schwartz PJ

Abstract
BACKGROUND: A correct measurement of the QT interval in the out-of-hospital setting is important whenever the long QT syndrome (LQTS) is suspected or a therapy might lead to drug-induced LQTS (diLQTS) because QT interval monitoring in the initial days of therapy could alert to dangerous QT prolongation. We explored whether automated QTc measurements (BGM) by BodyGuardian™ (BG), a wearable remote monitoring system, are sufficiently reliable compared to our own manual measurements (MM) performed on the same beats during 12‑lead Holter recordings in LQTS patients (pts) and in healthy controls.
METHODS: We performed 351 measurements in 20 LQTS pts and 16 controls. MM and BGM were compared by a Bland-Altman plot (BAp). High values of BAp indicate large differences between measurements.
RESULTS: In all 36 subjects QTc was 446 ± 41 and 445 ± 47 ms in MM and BGM, respectively. The mean ± SE BAp was -1.4 ± 1.8 ms for QTc in all subjects, 8.3 ± 2.3 and -7.2 ± 2.5 ms respectively in controls and LQTS. The disagreement between BGM and MM <15 ms in all, in controls, and in LQTS was respectively 57%, 63% and 54%. Among controls, there were only 3/132 false positive measurements (BGM QTc >470 ms when MM QTc <440 ms) in 3 different subjects. Among LQTS, there were 10/219 false negative measurements (BGM QTc <440 ms when MM QTc >470 ms) in 6 pts, but only two had multiple false negative values.
CONCLUSIONS: This wearable monitoring system reliably identifies a prolonged QT interval and probably also subjects at risk for diLQTS.

PMID: 29887480 [PubMed - indexed for MEDLINE]

Hepatotoxicity induced by immune checkpoint inhibitors: a comprehensive review including current and alternative management strategies.

Expert Opin Drug Metab Toxicol. 2019 Jan 24;:

Authors: Jennings JJ, Mandaliya R, Nakshabandi A, Lewis JH

Abstract
INTRODUCTION: Immune checkpoint inhibitors (ICIs) block cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) receptors that control antitumor activities of lymphocytes. While highly efficacious, these drugs have been associated with several immune-related adverse events (irAEs) due to the disruption of self-tolerance. Immune-mediated hepatitis (IMH) usually presents as mild elevations of liver enzymes though it can rarely be associated with life-threatening hepatic injury. Areas covered: A comprehensive review was performed to define the clinicopathologic forms of liver injury associated with ICIs, comparing the various ICI classes as well as comparing this form of IMH with idiopathic autoimmune hepatitis and drug induced autoimmune hepatitis. Liver biopsy has proven very useful in selected patients. A specific form of fibrin ring granulomatous hepatitis appears to be associated with IMH. The current societal treatment algorithms and emerging data was reviewed to determine when to utilize corticosteroids. Expert opinion: Monitoring for severe ICI-IMH is recommended although acute liver failure remains rare. Most patients with grade 3-4 hepatotoxicity respond to corticosteroids, but a subset of patients with mild hepatitis on liver biopsy resolve without steroids and need to be carefully selected in concert with consultation of a hepatologist.

PMID: 30677306 [PubMed - as supplied by publisher]

Interventions to Improve Antimicrobial Stewardship for Older People in Care Homes: A Systematic Review.

Drugs Aging. 2019 Jan 24;:

Authors: Nguyen HQ, Tunney MM, Hughes CM

Abstract
BACKGROUND: Inappropriate antimicrobial prescribing has been reported in care homes. This may result in serious drug-related adverse events, Clostridium difficile colonization, and the development of antimicrobial resistance among care home residents. Interventions to improve antibiotic prescribing in nursing homes have been reported through clinical trials, but whether antifungal and antiviral prescribing and residential homes have been considered, or how outcomes were measured and reported in such interventions, remains unclear.
OBJECTIVES: Our aims were to evaluate the effect of interventions to improve antimicrobial stewardship in care homes and to report the outcomes used in these trials.
METHODS: We searched 11 electronic databases and five trial registries for studies published until 30 November 2018. Inclusion criteria for the review were randomized controlled trials, targeting care home residents and healthcare professionals, providing interventions to improve antimicrobial prescribing compared with usual care or other interventions. The Cochrane tools for assessing risk of bias were used for quality assessment. A narrative approach was taken because of heterogeneity across the studies.
RESULTS: Five studies met the inclusion criteria. The studies varied in terms of types of infection, key targets, delivery of interventions, and reported outcomes. In total, 27 outcomes were reported across the studies, with seven not prespecified in the methods. The interventions had little impact on adherence to guidelines and prevalence of antimicrobial prescribing; they appeared to decrease total antimicrobial consumption but were unlikely to have affected overall hospital admissions and mortality. The overall quality of evidence was low because the risk of bias was high across the studies.
CONCLUSION: The interventions had limited effect on improving antimicrobial prescribing but did not appear to cause harm to care home residents. The low quality of evidence and heterogeneity in outcome measurement suggest the need for future well-designed studies and the development of a core outcome set to best evaluate the effectiveness of antimicrobial stewardship in care homes.

PMID: 30675682 [PubMed - as supplied by publisher]

The complexation of steroid hormones into cyclodextrin alters the toxic effects on the biological parameters of zebrafish (Danio rerio).

Chemosphere. 2019 Jan;214:330-340

Authors: Silva MCGD, Silva JFD, Santos TP, Silva NPCD, Santos ARD, Andrade ALC, Souza EHLDS, Sales Cadena MR, Sá FB, Silva Junior VAD, Cadena PG

Abstract
The objective of this study was to evaluate the toxic effects of progesterone (P4F) and estradiol (E2F) and the effect of these steroid hormones complexed into cyclodextrins, commercially available drugs, such as micronized progesterone (P4M) and transdermal estradiol (E2T), and evaluate them as endocrine disruptors through biological parameters of Danio rerio. An acute toxicity test was performed with hormones using D. rerio embryos according to OECD 236 guidelines. The heart rate, mortality, and teratogenic effects were evaluated. In addition, a chronic toxicity test was assayed with adult animals for evaluation of animal behavior, reproductive capacity, and electrophysiological responses of the retina. Analysis of the results of the acute toxicity test with embryos exposed to progestins and estrogens showed that free hormones caused a higher percentage of teratogenic effects such as pericardial edema, yolk sac edema, and spinal deformation. Behavioral evaluation (30-60 days) of adult animals exposed to P4M, E2F, and E2T demonstrated higher frequencies of aggressive behaviors such as Chase away, Persecution, Escape, and Attack. Analysis of reproductive capacity did not show significant differences in the number of viable eggs, and no significant changes were observed in the electrophysiological responses of the retina. According to these results, there is a higher toxicity effect of hormones in the free form when compared to the commercial forms and inclusion complexes. This indicates that complexation into cyclodextrin reduced the toxicity of the hormones according to the parameters studied.

PMID: 30267906 [PubMed - indexed for MEDLINE]

Prediction of clinically relevant adverse drug events in surgical patients.

PLoS One. 2018;13(8):e0201645

Authors: Bos JM, Kalkman GA, Groenewoud H, van den Bemt PMLA, De Smet PAGM, Nagtegaal JE, Wieringa A, van der Wilt GJ, Kramers C

Abstract
BACKGROUND: Risk stratification of hospital patients for adverse drug events would enable targeting patients who may benefit from interventions aimed at reducing drug-related morbidity. It would support clinicians and hospital pharmacists in selecting patients to deliver a more efficient health care service. This study aimed to develop a prediction model that helps to identify patients on the day of hospital admission who are at increased risk of developing a clinically relevant, preventable adverse drug event during their stay on a surgical ward.
METHODS: Data of the pre-intervention measurement period of the P-REVIEW study were used. This study was designed to assess the impact of a multifaceted educational intervention on clinically relevant, preventable adverse drug events in surgical patients. Thirty-nine variables were evaluated in a univariate and multivariate logistic regression analysis, respectively. Model performance was expressed in the Area Under the Receiver Operating Characteristics. Bootstrapping was used for model validation.
RESULTS: 6780 admissions of patients at surgical wards were included during the pre-intervention period of the PREVIEW trial. 102 patients experienced a clinically relevant, adverse drug event during their hospital stay. The prediction model comprised five variables: age, number of biochemical tests ordered, heparin/LMWH in therapeutic dose, use of opioids, and use of cardiovascular drugs. The AUROC was 0.86 (95% CI 0.83-0.88). The model had a sensitivity of 80.4% and a specificity of 73.4%. The positive and negative predictive values were 4.5% and 99.6%, respectively. Bootstrapping generated parameters in the same boundaries.
CONCLUSIONS: The combined use of a limited set of easily ascertainable patient characteristics can help physicians and pharmacists to identify, at the time of admission, surgical patients who are at increased risk of developing ADEs during their hospital stay. This may serve as a basis for taking extra precautions to ensure medication safety in those patients.

PMID: 30138343 [PubMed - indexed for MEDLINE]

Tools to investigate and avoid drug-hypersensitivity in drug development.

Expert Opin Drug Discov. 2018 05;13(5):425-433

Authors: Corsini E, Casula M, Tragni E, Galbiati V, Pallardy M

Abstract
INTRODUCTION: Drug hypersensitivity reactions (DHRs) are common adverse effects of pharmaceuticals that clinically resemble allergies, and which are becoming an important burden to healthcare systems. Alongside accurate diagnostic techniques, tools which can predict potential drug-inducing hypersensitivity reactions in the pre-clinical phase are critical. Despite the important adverse reactions linked to immune-mediated hypersensitivity, at present, there are no validated or required in vivo or in vitro methods to screen the sensitizing potential of drugs and their metabolites in the pre-clinical phase. Areas covered: Enhanced prediction in preclinical safety evaluation is extremely important. The purpose of this review is to assess the state of the art of tools available to assess the allergenic potential of drugs and to highlight our current understanding of the molecular mechanisms underlying inappropriate immune activation. Expert opinion: The knowledge that allergenic drugs share common mechanisms of immune cell activation with chemical allergens, and of the definition of the mechanistic pathway to adverse outcomes, can enhance targeting toxicity testing in drug development and hazard assessment of hypersensitivity. Additional efforts and extensive resources are necessary to improve preclinical testing methodologies, including optimization, better design and interpretation of data.

PMID: 29405076 [PubMed - indexed for MEDLINE]

Antipsychotics for patients with pain.

Korean J Pain. 2019 Jan;32(1):3-11

Authors: Shin SW, Lee JS, Abdi S, Lee SJ, Kim KH

Abstract
Going back to basics prior to mentioning the use of antipsychotics in patients with pain, the International Association for the Study of Pain (IASP) definition of pain can be summarized as an unpleasant experience, composed of sensory experience caused by actual tissue damage and/or emotional experience caused by potential tissue damage. Less used than antidepressants, antipsychotics have also been used for treating this unpleasant experience as adjuvant analgesics without sufficient evidence from research. Because recently developed atypical antipsychotics reduce the adverse reactions of extrapyramidal symptoms, such as acute dystonia, pseudo-parkinsonism, akathisia, and tardive dyskinesia caused by typical antipsychotics, they are expected to be used more frequently in various painful conditions, while increasing the risk of metabolic syndromes (weight gain, diabetes, and dyslipidemia). Various antipsychotics have different neurotransmitter receptor affinities for dopamine (D), 5-hydroxytryptamine (5-HT), adrenergic (α), histamine (H), and muscarinic (M) receptors. Atypical antipsychotics antagonize transient, weak D2 receptor bindings with strong binding to the 5-HT2A receptor, while typical antipsychotics block long-lasting, tight D2 receptor binding. On the contrary, antidepressants in the field of pain management also block the reuptake of similar receptors, mainly on the 5-HT and, next, on the norepinephrine, but rarely on the D receptors. Antipsychotics have been used for treating positive symptoms, such as delusion, hallucination, disorganized thought and behavior, perception disturbance, and inappropriate emotion, rather than the negative, cognitive, and affective symptoms of psychosis. Therefore, an antipsychotic may be prescribed in pain patients with positive symptoms of psychosis during or after controlling all sensory components.

PMID: 30671198 [PubMed]

Rikkunshito for upper gastrointestinal symptoms: A systematic review and meta-analysis.

Complement Ther Med. 2019 Feb;42:255-263

Authors: Hoshino N, Nishizaki D, Hida K, Obama K, Sakai Y

Abstract
BACKGROUND: Upper gastrointestinal symptoms are major issues in various diseases such as postgastrectomy syndrome and functional dyspepsia. These symptoms cannot be fully controlled in such conditions and result in poorer quality of life. Rikkunshito has been traditionally used in Japan to relieve these symptoms. This systematic review assessed the efficacy and safety of rikkunshito for relieving upper gastrointestinal symptoms.
METHODS: A systematic literature search was conducted using Ovid MEDLINE, Scopus, the Cochrane Central Register of Controlled Trials, and ICHUSHI. Randomized controlled trials comparing rikkunshito to alternative drugs for the treatment of upper gastrointestinal symptoms were searched without language restriction. Two review authors independently assessed the literature and extracted data from identified studies. The risk of bias in each study was assessed.
RESULTS: Twenty-four studies with a combined total of 2175 participants were included in this review. Rikkunshito did not significantly relieve upper gastrointestinal symptoms when compared with other treatments via the Gastrointestinal Symptom Rating Scale (standardized mean difference, -0.07; 95% confidence interval [CI], -0.31 to 0.17; P =  0.59), while it significantly relieved the symptoms on a 5-point scale (mean difference, -0.38; 95% CI, -0.55 to -0.21; P <  0.001). No drug-related severe adverse events were reported. Most of the included studies had high or unclear overall risk of bias.
CONCLUSIONS: It remains still unclear whether rikkunshito is effective for the relief of upper gastrointestinal symptoms. Further high-quality studies are needed.

PMID: 30670250 [PubMed - in process]