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]

Spleen Dose-Volume Parameters as a Predictor of Treatment-related Lymphopenia During Definitive Chemoradiotherapy for Esophageal Cancer.

In Vivo. 2018 Nov-Dec;32(6):1519-1525

Authors: Saito T, Toya R, Yoshida N, Shono T, Matsuyama T, Ninomura S, Watakabe T, Sasaki Y, Baba H, Oya N

Abstract
AIM: Our study sought to identify dosimetric predictors of treatment-related lymphopenia during chemoradiotherapy for esophageal cancer.
MATERIALS AND METHODS: Patients with esophageal cancer who had received definitive chemoradiotherapy at our Institution were retrospectively assessed. The absolute volume of the spleen, body, and bone marrow that had received 5, 10, 20, and 30 Gy and the mean splenic dose were recorded.
RESULTS: Multivariate linear regression analysis revealed that docetaxel use and spleen dose-volume parameters (V5, V10, V20, V30, and mean splenic dose) were significant independent factors negatively influencing the absolute lymphocyte count at nadir. An increase of 1 Gy in mean splenic dose predicted a 2.9% decrease in nadir absolute lymphocyte count. Univariable logistic regression analysis showed that the mean splenic dose was a significant predictor of grade 4 lymphopenia. None of the body or bone marrow dose-volume parameters significantly predicted lymphopenia.
CONCLUSION: Higher spleen dose-volume parameters were associated with severe lymphopenia during chemoradiotherapy.

PMID: 30348711 [PubMed - indexed for MEDLINE]

Post-mortem analysis of suicide victims shows ABCB1 haplotype 1236T-2677T-3435T as a candidate predisposing factor behind adverse drug reactions in females.

Pharmacogenet Genomics. 2018 04;28(4):99-106

Authors: Rahikainen AL, Palo JU, Haukka J, Sajantila A

Abstract
BACKGROUND: Genetic variation in efflux transporter, permeability glycoprotein (P-gp), has recently been associated with completed violent suicides and also violent suicide attempts. As depression is known to be a risk factor for suicide and many antidepressants are P-gp substrates, it has been speculated that inadequate antidepressant treatment response or adverse side effects could be involved.
OBJECTIVES: The aim of this study was to investigate whether there is an association between the P-gp coding ABCB1 gene and completed suicides in citalopram users. Also, the effect of sex and suicide method used (violent vs. non-violent) was evaluated.
MATERIALS AND METHODS: All cases included in the study population, 349 completed suicide victims and 284 controls, were shown to be positive for antidepressant citalopram in a post-mortem toxicological drug screen. ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms were determined by TaqMan genotyping assays. Haplotypes were constructed from genotype data using the PHASE software. The association between the manner of death and the ABCB1 haplotype was tested with logistic regression analysis.
RESULTS: No statistically significant differences were observed in the ABCB1 allele or genotype frequencies between the suicide and control groups. However, the ABCB1 1236T-2677T-3435T haplotype was associated with completed suicides of female citalopram users (odds ratio: 2.23; 95% confidence interval: 1.22-4.07; P=0.009). After stratification by the method used for suicide, the association emerged in fatal intoxications (odds ratio: 2.51; 95% confidence interval: 1.29-4.87; P=0.007). In other groups, no statistically significant associations were observed.
CONCLUSION: Our results suggest that female citalopram users with ABCB1 1236T-2677T-3435T are more vulnerable to adverse effects of the drugs as this haplotype was enriched in non-violent suicides of female citalopram users. Even though the biological mechanism behind this observation is unknown, the results provide another example of the importance of sex-based segregation in pharmacogenetics studies.

PMID: 29481489 [PubMed - indexed for MEDLINE]

Safety Reporting: It Can Enter the 21st Century-If We Let It.

Ther Innov Regul Sci. 2018 05;52(3):354-361

Authors: Seltzer J, Bhattacharyya A

Abstract
This is a commentary about the evolution of safety reporting, the new FDA Draft Guidance on Safety Reporting and possible paths forward.

PMID: 29714542 [PubMed - indexed for MEDLINE]

Comparison of Serious Adverse Event Profiles Among Antirheumatic Agents Using Japanese Adverse Drug Event Report Database.

Ther Innov Regul Sci. 2018 05;52(3):339-347

Authors: Matsuoka Y, Narukawa M

Abstract
BACKGROUND: The association between drugs and adverse events (AEs) has been investigated using various AE databases. The aim of this study was to provide useful information for risk minimization of antirheumatic agents by investigating the safety profiles of antirheumatic agents using the Japanese Adverse Drug Event Report database (JADER), focusing on some important serious AEs (SAEs) and their relation to time.
METHODS: Tumor necrosis factor-alpha inhibitors (TNF-Is), interleukin-6 inhibitors (IL-6-Is), and methotrexate (MTX) were selected as antirheumatic agents. Tuberculosis, malignant tumors, and bone marrow disorders were focused as typical SAEs. Disproportionate reporting of these SAEs was evaluated using the reporting odds ratio. Time to onset of each SAE was calculated using date information.
RESULTS: Increased reporting odds ratios were observed in tuberculosis and malignant tumors associated with TNF-I, in tuberculosis and malignant tumors associated with IL-6-I, and in tuberculosis, malignant tumors, and bone marrow disorders associated with MTX. The median time to onset of the focused SAEs associated with TNF-I were 501, 681, and 254 days, respectively; those associated with IL-6-I were 387, 636, and 116 days; and those associated with MTX were 537, 1125, and 328 days. These results suggested different profiles for the focused SAEs.
CONCLUSION: The time-to-onset profiles of the SAEs for TNF-I, IL-6-I, and MTX as antirheumatic agent were different among different SAEs, which suggests that they should be monitored carefully based on the profiles. The information from JADER is expected to contribute to the risk minimization of drugs in the actual clinical practice.

PMID: 29714536 [PubMed - indexed for MEDLINE]

Statistical Signal Process in R Language in the Pharmacovigilance Programme of India.

Ther Innov Regul Sci. 2018 05;52(3):329-333

Authors: Kumar A, Ahuja J, Shrivastava TP, Kumar V, Kalaiselvan V

Abstract
BACKGROUND: The Ministry of Health & Family Welfare, Government of India, initiated the Pharmacovigilance Programme of India (PvPI) in July 2010. The purpose of the PvPI is to collect data on adverse reactions due to medications, analyze it, and use the reference to recommend informed regulatory intervention, besides communicating the risk to health care professionals and the public. The goal of the present study was to apply statistical tools to find the relationship between drugs and ADRs for signal detection by R programming.
METHODS: Four statistical parameters were proposed for quantitative signal detection. These 4 parameters are IC025, PRR and PRRlb, chi-square, and N11; we calculated these 4 values using R programming. We analyzed 78,983 drug-ADR combinations, and the total count of drug-ADR combination was 4,20,060. During the calculation of the statistical parameter, we use 3 variables: (1) N11 (number of counts), (2) N1. (Drug margin), and (3) N.1 (ADR margin).
RESULTS: The structure and calculation of these 4 statistical parameters in R language are easily understandable. On the basis of the IC value (IC value >0), out of the 78,983 drug-ADR combination (drug-ADR combination), we found the 8,667 combinations to be significantly associated.
CONCLUSIONS: The calculation of statistical parameters in R language is time saving and allows to easily identify new signals in the Indian ICSR (Individual Case Safety Reports) database.

PMID: 29714534 [PubMed - indexed for MEDLINE]

Unique Populations with Episodic Migraine: Pregnant and Lactating Women.

Curr Pain Headache Rep. 2018 Oct 05;22(12):80

Authors: Parikh SK

Abstract
PURPOSE OF REVIEW: Migraine is a disabling and prevalent neurological disease, commonly affecting women during their reproductive years. It is crucial for providers to be able to adequately counsel women who are pregnant, planning pregnancy, or nursing, regarding preventive and abortive treatment options for episodic migraine. This review will discuss (1) the expected course of migraine during pregnancy and the post-partum period, (2) recommended preventive therapies for migraine during pregnancy and lactation, and (3) recommended abortive medications for migraine during pregnancy and lactation.
RECENT FINDINGS: Recent research has indicated safety for triptan use during pregnancy and ibuprofen use during the first trimester of pregnancy. Considerations for use of emerging migraine-preventive treatment, such as non-invasive neurostimulators, are discussed. For clinical decision-making and patient counseling, it is important to understand both the limitations in determining teratogenic effects in humans and the principles affecting medication transmission from mother to breast milk.

PMID: 30291521 [PubMed - indexed for MEDLINE]

International Group for Reducing Inappropriate Medication Use & Polypharmacy (IGRIMUP): Position Statement and 10 Recommendations for Action.

Drugs Aging. 2018 07;35(7):575-587

Authors: Mangin D, Bahat G, Golomb BA, Mallery LH, Moorhouse P, Onder G, Petrovic M, Garfinkel D

Abstract
Globally, the number of drug prescriptions is increasing causing more adverse drug events, which is now a significant cause of mortality, morbidity, and disability that has reached epidemic proportions. The risk of adverse drug events is correlated to very old age, multiple co-morbidities, dementia, frailty, and limited life expectancy, with the major contributor being polypharmacy. Each characteristic alters the risk-benefit balance of medications, typically reducing anticipated benefits and amplifying risk. Current clinical guidelines are based on evidence proven in younger/healthier adult populations using a single disease model and their application to older adults with multimorbidity, in whom testing has not been conducted, yields a different risk-benefit prospect and makes inappropriate medication use and polypharmacy inevitable. Applying inappropriate clinical practice guidelines to older adults is antithetical to good healthcare, is likely to increase health inequity, and is associated with substantial negative clinical, economic, and social implications for health systems. The casualties are on the scale of a war or epidemic, yet are usually invisible in measures of healthcare quality and formal recommendations. Radical and rapid action is required to achieve a better quality of life for older populations and to remain true to the principles of medical professionalism and evidence-based medicine that place patients' interests and autonomy at the fore. This first International Group for Reducing Inappropriate Medication Use & Polypharmacy position statement briefly details the causes, consequences, and extent of inappropriate medication use and polypharmacy. This article outlines current strategies to reduce inappropriate medication use, provides evidence for their effect, and then proposes recommendations for moving forward with 10 recommendations for action and 12 recommendations for research. We conclude that an urgent integrated effort to reduce inappropriate medication use and polypharmacy should be a leading global target of the highest priority. The cornerstone of this position statement from the International Group for Reducing Inappropriate Medication Use & Polypharmacy is the understanding that without evidence of definite relevant benefit, when it comes to prescribing, for many older patients 'less is more'. This approach differs from most other current recommendations and guidance in medical care, as the focus is on what, when, and how to stop, rather than on when to start medications/interventions. Disrupting the framework that indiscriminately applies standard guidelines to older adults requires a new approach that better serves patients with multimorbidity. This transition requires a shift in medical education, research, and diagnostic frameworks, and re-examination of the measures used as quality indicators. In achieving this objective, we promote a return to some of the original concepts of evidence-based medicine: which considers scientific data (where it exists), clinical judgment, patient/family preference, and context. A shift is needed: from the current model that focuses on single conditions to one that simultaneously considers multiple conditions and patient priorities. This approach reframes the clinician's role as a professional providing care, rather than a disease technician.

PMID: 30006810 [PubMed - indexed for MEDLINE]

Contribution of Patient Interviews as Part of a Comprehensive Approach to the Identification of Drug-Related Problems on Geriatric Wards.

Drugs Aging. 2018 07;35(7):665-675

Authors: Stämpfli D, Boeni F, Gerber A, Bättig VAD, Hersberger KE, Lampert ML

Abstract
BACKGROUND: Inappropriate prescribing is linked to increased risks for adverse drug reactions and hospitalisation. Combining explicit and implicit criteria of inappropriate prescribing with the information obtained in patient interviews seems beneficial with regard to the identification of drug-related problems (DRPs) in hospitalised patients.
OBJECTIVE: We aimed to investigate the inclusion of pharmacist interviews as part of medication reviews (including the use of explicit and implicit criteria of inappropriate prescribing) to identify DRPs in older inpatients.
METHODS: Clinical medication reviews were performed on geriatric and associated physical and neurological rehabilitation wards in a regional secondary care hospital. Data from electronic medical records, laboratory data, and current treatment regimens were complemented with a novel structured patient interview performed by a clinical pharmacist. The structured interview questioned patients on administration issues, prescribed medication, self-medication, and allergies. The reviews included the use of current treatment guidelines, the Medication Appropriateness Index, the Screening Tool of Older People's Prescriptions (STOPP, v2), and the Screening Tool to Alert to Right Treatment (START, v2). The potential relevance of the DRPs was estimated using the German version of the CLEO tool.
RESULTS: In 110 patients, 595 DRPs were identified, averaging 5.4 per patient (range 0-17). The structured interviews identified 249 DRPs (41.8%), of which 227 were not identified by any other source of information. The majority of DRPs (213/249, i.e. 85.5%) identified by patient interview were estimated to be of minor clinical relevance (i.e. limited adherence, knowledge, quality of life, or satisfaction).
CONCLUSION: We demonstrated that structured patient interviews identified additional DRPs that other sources did not identify. Embedded within a comprehensive approach, the structured patient interviews were needed as data resource for over one-third of all DRPs.

PMID: 29916139 [PubMed - indexed for MEDLINE]

Adverse drug events related to mood and emotion in paediatric patients treated for ADHD: A meta-analysis.

J Affect Disord. 2018 10 01;238:161-178

Authors: Pozzi M, Carnovale C, Peeters GGAM, Gentili M, Antoniazzi S, Radice S, Clementi E, Nobile M

Abstract
BACKGROUND: ADHD is frequently comorbid with anxiety and mood disorders, which may increase the severity of inattention and hyperactivity symptoms. Emotional symptoms (anxiety, irritability, mood lability) also affect patients without comorbidity or emerge as adverse drug events. The influence of ADHD drugs on emotional symptoms demands investigation to improve therapies.
METHODS: Systematic review of trials reporting adverse events in patients pharmacologically treated for ADHD. Meta-analysis of the occurrence of irritability, anxiety, apathy, reduced talk, sadness, crying, emotional lability, biting nails, staring, perseveration, euphoria. Meta-regression analysis.
RESULTS: Forty-five trials were meta-analysed. The most frequently reported outcomes were irritability, anxiety, sadness, and apathy. Methylphenidates, especially immediate-release formulations, were most studied; amphetamines were half as studied and were predominantly mixed amphetamine salts. Reports on atomoxetine were scant. Meta-analysis showed that methylphenidates reduced the risk of irritability, anxiety, euphoria, whereas they worsened the risk of apathy and reduced talk; amphetamines worsened the risk of emotional lability. Factors influencing risks were study year and design, patients' sex and age, drug dose and release formulation.
LIMITATIONS: Possible discrepancy between adverse events as indicated in clinical trials and as summarised herein. Confounding due to the aggregation of drugs into groups; uninvestigated sources of bias; incomplete lists of adverse events; lack of observations on self-injury.
CONCLUSIONS: Methylphenidates appeared safer than amphetamines, although younger patients and females may incur higher risks, especially with high-dose, immediate-release methylphenidates. Only atomoxetine holds a black-box warning, but amphetamines and methylphenidates also did not show a safe profile regarding mood and emotional symptoms.

PMID: 29883938 [PubMed - indexed for MEDLINE]

Differential misclassification between self-reported status and official HPV vaccination records in Japan: Implications for evaluating vaccine safety and effectiveness.

Papillomavirus Res. 2018 12;6:6-10

Authors: Yamaguchi M, Sekine M, Kudo R, Adachi S, Ueda Y, Miyagi E, Hara M, Hanley SJB, Enomoto T

Abstract
Japan has no national vaccine registry and approximately 1700 municipalities manage the immunization records independently. In June 2013, proactive recommendations for the human papillomavirus (HPV) vaccine were suspended after unconfirmed reports of adverse events following immunization in the media, despite no vaccine safety signal having been raised. Furthermore, studies assessing HPV vaccine safety and effectiveness published post suspension are predominantly based on self-reported information. Our aim was to examine the accuracy of self-reported vaccination status compared with official municipal records. Participants were women aged 20-22 yrs, who were attending for cervical screening in Niigata city. Among the 1230 eligible registrants, vaccine uptake, defined as any dose, was 75.0% and 77.2% according to a self-reported questionnaire and municipal records, respectively. The accuracy rate of self-reported information was as follows: positive predictive value (PPV) was 87.7%; negative predictive value (NPV) was 54.5%; sensitivity was 85.2%; and specificity was 59.8%. The validity of self-reported information was only moderate (Kappa statistic = 0.44, 95% confidence interval 0.37-0.50). This combined with the low NPV may lead to reduced estimation of effectiveness and safety. A more reliable method, such as a national HPV vaccine registry, needs to be established for assessing HPV immunization status in Japan.

PMID: 29807210 [PubMed - indexed for MEDLINE]

Daclizumab in multiple sclerosis.

Rev Neurol. 2018 Apr 16;66(8):271-282

Authors: Perez-Miralles FC

Abstract
INTRODUCTION: Daclizumab is a monoclonal antibody directed against the CD25 subunit of the interleukin-2 receptor, investigated as a disease-modifying therapy in relapsing-remitting multiple sclerosis. The present review addresses how the drug was developed, the known mechanism of action of the drug and the up-to-date data of efficacy and safety.
DEVELOPMENT: Daclizumab has shown superiority in prevention of relapses against placebo and low-dose interferon beta-1a at a level that puts it on par with the rest of current first-line drugs. The effect on the progression of the disease and on neurodegeneration parameters, however, is not clear. On the other hand, it presents safety problems (mainly risk of autoimmunity phenomena including fulminant hepatopathy and encephalitis) that have supposed eventually its withdrawn from marketing. Daclizumab introduces a new mechanism of action through the blocking of a key interleukin in immune regulation and its effect on a population of cells with regulatory ability, such as the NK CD56(bright) cells.
CONCLUSIONS: Daclizumab has shown efficacy in slowing the inflammatory process of multiple sclerosis, although the appearance of potentially serious side effects has not allowed its use to significantly impact current clinical practice. The development of new drugs in multiple sclerosis must be contingent on maintaining or improving the risk-benefit profile with respect to those already in use.

PMID: 29645071 [PubMed - indexed for MEDLINE]

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Severe Cutaneous Adverse Reactions in Korean Pediatric Patients: A Study From the Korea SCAR Registry.

Allergy Asthma Immunol Res. 2019 Mar;11(2):241-253

Authors: Oh HL, Kang DY, Kang HR, Kim S, Koh YI, Kim SH, Kim MH, Suh DI, Korean Severe Cutaneous Adverse Reactions Consortium

Abstract
PURPOSE: Although severe cutaneous adverse drug reactions (SCARs) are rare, they are associated with high morbidity and mortality, and thus early diagnosis and treatment are critical for improving prognoses. However, few studies have reported the characteristics of SCARs in children. Thus, we aimed to evaluate the clinical characteristics, current management and prognosis of pediatric SCARs.
METHODS: We analyzed pediatric data in the Korean SCARs registry, which was built retrospectively in 2016 with SCAR cases treated in 34 tertiary referral university hospitals during 2010-2015. Using these cases, we descriptively analyzed detailed data regarding etiology, clinical and laboratory features, treatment strategies, and prognosis.
RESULTS: Forty-seven pediatric SCAR cases from 15 tertiary referral hospitals were included. The median patient age was 10 (interquartile range, 3-15.5) years and 68.1% (n = 32) were males. The culprit drug was identified in 95.7% (n = 45) of the patients; antibiotics (44.7%) and antiepileptic drugs (19.1%) were the most common and second most common culprits, respectively. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) cases presented with the largest area of skin involvement without permanent sequelae. Stevens-Johnson syndrome (SJS) cases involved relatively small areas of skin but serious sequelae in two children. Of 4 patients with toxic epidermal necrolysis (TEN), 1 died. Of all patients assessed, 36 (76.6%) received systemic steroids and 21 (44.7%) received intravenous immunoglobulin (IVIG). Thirteen (27.7%) received both systemic steroids and IVIG. Cyclosporine was administered to only 1 patient along with a systemic steroid.
CONCLUSIONS: In patients with pediatric SCARs, including those with DRESS, SJS and TEN, clinical presentations were variable. Thus, there was no clear continuous disease spectrum. Although the mortality rate was low (2.1%), clinical suspicion may be the best tool for proactive SCAR management.

PMID: 30661316 [PubMed]

Treatment of acute hepatitis C genotypes 1 and 4 with 8 weeks of grazoprevir plus elbasvir (DAHHS2): an open-label, multicentre, single-arm, phase 3b trial.

Lancet Gastroenterol Hepatol. 2019 Jan 16;:

Authors: Boerekamps A, De Weggheleire A, van den Berk GE, Lauw FN, Claassen MAA, Posthouwer D, Bierman WF, Hullegie SJ, Popping S, van de Vijver DACM, Dofferhoff ASM, Kootstra GJ, Leyten EM, den Hollander J, van Kasteren ME, Soetekouw R, Ammerlaan HSM, Schinkel J, Florence E, Arends JE, Rijnders BJA

Abstract
BACKGROUND: Direct-acting antivirals effectively treat chronic hepatitis C virus (HCV) infection but there is a paucity of data on their efficacy for acute HCV, when immediate treatment could prevent onward transmission. We assessed the efficacy of grazoprevir plus elbasvir treatment in acute HCV infection and investigated whether treatment can be shortened during the acute phase of HCV infection.
METHODS: The Dutch Acute HCV in HIV study number 2 (DAHHS2) study was a single-arm, open-label, multicentre, phase 3b trial. Adult patients (≥18 years) with acute HCV genotype 1 or 4 infection (duration of infection 26 weeks or less, according to presumed day of infection) were recruited at 15 HIV outpatient clinics in the Netherlands and Belgium. All patients were treated with 8 weeks of grazoprevir 100 mg plus elbasvir 50 mg administered as one oral fixed drug combination tablet once daily. The primary efficacy endpoint was sustained virological response at 12 weeks after the end of treatment (SVR12; HCV RNA <15 IU/mL) in all patients who started treatment. Reinfection with a different HCV virus was not considered treatment failure in the primary analysis. This trial is registered with ClinicalTrials.gov, number NCT02600325.
FINDINGS: Between Feb 15, 2016, and March 2, 2018, we assessed 146 patients with a recently acquired HCV infection for eligibility, of whom 86 were enrolled and 80 initiated therapy, all within 6 months after infection. All patients who initiated treatment completed treatment and no patients were lost to follow-up. 79 (99%, 95% CI 93-100) of 80 patients achieved SVR12. All 14 patients who were infected with a virus carrying a clinically significant polymorphism in NS5A were cured. If reinfections were considered treatment failures, 75 (94%, 86-98) of 80 patients achieved SVR12. Two serious adverse events not considered related to the treatment were reported (traumatic rectal bleeding and low back surgery). The most common adverse event was a new sexually transmitted infection (19 [24%] of 80 patients). The most common reported possibly drug-related adverse events were fatigue (11 [14%] patients), headache (seven [9%] patients), insomnia (seven [9%] patients), mood changes (five [6%] patients), dyspepsia (five [6%] patients), concentration impairment (four [5%] patients), and dizziness (4 [5%] patients), all of which were regarded as mild by the treating physician. No adverse events led to study drug discontinuation.
INTERPRETATION: 8 weeks of grazoprevir plus elbasvir was highly effective for the treatment of acute HCV genotype 1 or 4 infection. The ability to treat acute HCV immediately after diagnosis might help physicians to reach the WHO goal of HCV elimination by 2030.
FUNDING: Merck Sharp and Dohme and Health-Holland.

PMID: 30660617 [PubMed - as supplied by publisher]

Assessment of drug related problems among type 2 diabetes mellitus patients with hypertension in Hiwot Fana Specialized University Hospital, Harar, Eastern Ethiopia.

BMC Res Notes. 2018 Oct 12;11(1):728

Authors: Ayele Y, Melaku K, Dechasa M, Ayalew MB, Horsa BA

Abstract
OBJECTIVE: This study was conducted to assess magnitude and pattern of drug related problems among patients with type 2 diabetes mellitus (T2DM) and hypertension.
RESULTS: This study identified 364 drug related problems (DRPs) across the three categories of drug related problems, giving an average of 1.8 DRPs per patient. The effect of drug treatment being not optimal 179 (49.2%), untreated indication and symptoms 77 (21.1%), unnecessary drug-treatment 39 (10.7%) and adverse drug reactions 69 (19%) were the most frequent categories of DRPs identified. In general, high prevalence of drug-related problems was identified among patients with T2DM hypertension. The effect of drug treatment being not optimal, untreated indication and symptoms, unnecessary drug-treatment and adverse drug reactions were the most frequent categories of drug related problems identified. Therefore, the clinicians should work to improve patient care through prevention and resolving drug related problems since it can affect the quality of the care significantly.

PMID: 30314443 [PubMed - indexed for MEDLINE]