Evaluation of Harm Associated with High Dose-Range Clinical Decision Support Overrides in the Intensive Care Unit.

Drug Saf. 2019 04;42(4):573-579

Authors: Wong A, Rehr C, Seger DL, Amato MG, Beeler PE, Slight SP, Wright A, Bates DW

Abstract
INTRODUCTION: Medication-related clinical decision support (CDS) alerts have been shown to be effective at reducing adverse drug events (ADEs). However, these alerts are frequently overridden, with limited data linking these overrides to harm. Dose-range checking alerts are a type of CDS alert that could have a significant impact on morbidity and mortality, especially in the intensive care unit (ICU) setting.
METHODS: We performed a single-center, prospective, observational study of adult ICUs from September 2016 to April 2017. Targeted overridden alerts were triggered when doses greater than or equal to 5% over the maximum dose were prescribed. The primary outcome was the appropriateness of the override, determined by two independent reviewers, using pre-specified criteria formulated by a multidisciplinary group. Overrides which resulted in medication administration were then evaluated for ADEs by chart review.
RESULTS: The override rate of high dose-range alerts in the ICU was 93.0% (total n = 1525) during the study period. A total of 1418 overridden alerts from 755 unique patients were evaluated for appropriateness (appropriateness rate 88.8%). The most common medication associated with high dose-range alerts was insulin regular infusion (n = 262, 18.5%). The rates of ADEs for the appropriately and inappropriately overridden alerts per 100 overridden alerts were 1.3 and 5.0, respectively (p < 0.001).
CONCLUSIONS: Overriding high dose-range CDS alerts was found to be common and often appropriate, suggesting that more intelligent dose checking is needed. Some alerts were clearly inappropriately presented to the provider. Inappropriate overrides were associated with an increased risk of ADEs, compared to appropriately overridden alerts.

PMID: 30506472 [PubMed - indexed for MEDLINE]

Prevalence of Drug Prescriptions and Potential Safety in Patients with Cirrhosis: A Retrospective Real-World Study.

Drug Saf. 2019 04;42(4):539-546

Authors: Weersink RA, Taxis K, Drenth JPH, Houben E, Metselaar HJ, Borgsteede SD

Abstract
INTRODUCTION: Patients with cirrhosis are at risk for adverse drug reactions (ADRs) due to altered pharmacokinetics and pharmacodynamics. We aimed to determine the prevalence of drug prescriptions and the potential safety of these prescriptions in a real-world cohort of patients with cirrhosis.
METHODS: This was a retrospective cohort study based on linked real-world data from the Out-patient Pharmacy Database and the Hospitalisation Database of the PHARMO Database Network. Patients with a diagnosis of cirrhosis between January 1998 and December 2015 were included. Follow-up ended when the patient underwent a liver transplant, died, transferred out of the database, or on 31 December 2015. Prescription data were derived from a community pharmacy database and were compared with our previously developed safety recommendations for 209 drugs.
RESULTS: In total, 5618 patients were included and followed for a median of 3 years (interquartile range [IQR] 1-7). In the first year after the diagnosis, patients used a median of nine drugs (IQR 5-14), with proton pump inhibitors (prevalence 53.9%), aldosterone antagonists (43.6%), and sulfonamide diuretics (41.3%) being the most commonly used drug groups. Almost half (48.3%) of 102,927 prescriptions consisted of drugs with a safety recommendation. The prevalence of potentially unsafe drug use was 60.0% during the total follow-up. Three nonsteroidal anti-inflammatory drugs (NSAIDs) were among the five most commonly used potentially unsafe drugs.
CONCLUSIONS: Patients with cirrhosis use a large number of drugs. Almost two-thirds of patients in our cohort used potentially unsafe drugs. To prevent ADRs in these frail patients, personalised pharmacotherapy is necessary.

PMID: 30357649 [PubMed - indexed for MEDLINE]

The Role of European Patient Organizations in Pharmacovigilance.

Drug Saf. 2019 04;42(4):547-557

Authors: Matos C, Weits G, van Hunsel F

Abstract
INTRODUCTION: Patient organizations have a privileged position to be active agents for promoting pharmacovigilance and patient engagement, encouraging direct patient reporting and improving the awareness of pharmacovigilance.
AIM: The objective of this study was to understand the role of European patient organizations as stakeholders to optimize patient involvement in pharmacovigilance.
METHODS: A descriptive correlational study was conducted to investigate the opinions and attitudes of patient organizations regarding general patient involvement in pharmacovigilance, and their initiatives to support drug safety through a web-based questionnaire during the months of March and April 2018.
RESULTS: A total of 1898 patient organizations were invited to participate in the survey, including 89 pan-European organizations. In total, 337 questionnaires (17.76%) were collected from 31 countries, including 297 complete answers (88.31%). A large number of organizations stated that they would like to increase the awareness of patients regarding specific adverse drug reactions (ADRs) related to their medicines (43.19%, n  = 130); however, 38.54% (n  = 116) declared they do not have any pharmacovigilance goals. Barriers to supporting pharmacovigilance activities include low budget to promote pharmacovigilance among members (45.45%, n  = 135), lack of resources to participate in pharmacovigilance activities (43.77%, n  = 130), or lack of support from the National Competent Authorities (33.33%, n  = 99). Organizations inform patients to report ADRs (40.40%; n  = 120), information regarding new ADRs related to their medicines (40.07%; n  = 119), or when a new drug is marketed (30.98%; n  = 92); however, more than one-third indicated that they never had any involvement in pharmacovigilance (34.68%; n  = 103).
CONCLUSION: Bringing pharmacovigilance stakeholders and patient organizations together could create a more optimal reporting culture. Patient organizations appear to have an important role in encouraging patients to talk with their doctors/pharmacists about ADRs experienced, or to help him/her report the ADRs to the pharmacovigilance systems. Lack of resources, budget, and support from NCAs are seen as the main barriers to being involved in pharmacovigilance awareness.

PMID: 30357648 [PubMed - indexed for MEDLINE]

Artificial Intelligence and the Future of the Drug Safety Professional.

Drug Saf. 2019 04;42(4):491-497

Authors: Danysz K, Cicirello S, Mingle E, Assuncao B, Tetarenko N, Mockute R, Abatemarco D, Widdowson M, Desai S

Abstract
The healthcare industry, and specifically the pharmacovigilance industry, recognizes the need to support the increasing amount of data received from individual case safety reports (ICSRs). To cope with this increase, more healthcare and qualified professionals are required to capture and evaluate the data. To address the evolving landscape, it will be necessary to embrace assistive technologies such as artificial intelligence (AI) at scale. AI in the field of pharmacovigilance will possibly result in the transformation of the drug safety (DS) professional's daily work life and their career development. Celgene's Global Drug Safety and Risk Management (GDSRM) function has established a series of work activities to drive innovation across the pharmacovigilance value chain (Celgene Chrysalis Fact Sheet. https://www.celgene.com/newsroom/media-library/chrysalis-fact-sheet/, 2018). The development of AI in pharmacovigilance raises questions about the possible changes in DS professionals' lives, who may find themselves curious about their future roles in a workplace assisted by AI. We discuss the current state of pharmacovigilance and the DS professional, AI in pharmacovigilance and the potential skillsets a DS professional may require when working with AI. We also describe the results of research conducted at Celgene GDSRM. The objective of the research was to understand the thoughts of pharmacovigilance professionals about their jobs. These results are provided in the form of aggregated responses to interview questions based on a 12-part questionnaire [see the Electronic Supplementary Material (ESM)]. A sample of six DS professionals representing various areas of pharmacovigilance operations were asked a range of questions about their backgrounds, current roles and future expectations. The DS professionals interviewed were, overall, enthusiastic about their job roles potentially changing with AI enhancements. Interviewees suggested that AI would allow for pharmacovigilance resources, time, and skills to shift the work from a volume-based to a value-based focus. The results suggest that pharmacovigilance professionals wish to use their qualifications, skillsets and experience in work that provides more value for their efforts. Machine learning algorithms have the potential to enhance DS professionals' decision-making processes and support more efficient and accurate case processing.

PMID: 30343417 [PubMed - indexed for MEDLINE]

Safety of an extended-release injectable moxidectin suspension formulation (ProHeart® 12) in dogs.

Parasit Vectors. 2019 Sep 06;12(1):433

Authors: Krautmann MJ, Mahabir S, Fielder A, Collard W, Wolthuis TL, Esch K, Morton T, Alleman K, Luo L, McCandless E, Nederveld S, Kryda K, Carroll R, Boucher JF

Abstract
BACKGROUND: The safety of ProHeart® 12 (PH 12; extended-release injectable suspension; 10% moxidectin in glyceryl tristearate microspheres) was evaluated in four studies using Beagle dogs and one study using ivermectin-sensitive Collies. The recommended dose is 0.5 mg/kg subcutaneously once yearly.
METHODS: Study 1: safety margin was evaluated as 3 treatments of PH 12 (0× (control); 1× (recommended dose); 3× (3 times recommended dose) and 5× (5 times recommended dose) in 12 months via clinical observations, body weights, food consumption, injection site observations, physical examinations, moxidectin tissue assay, pharmacokinetics, and clinical and anatomic pathology. Study 2: safety in breeding-age males was demonstrated by semen testing at 14-day intervals from Day 7 to Day 91 post-treatment (0× or 3×). Study 3: reproductive safety in females was demonstrated by monitoring dams and litters following treatments (0× or 3×) administered during breeding, gestation, or lactation. Study 4: safety in dogs surgically implanted with adult heartworms was evaluated by clinical and laboratory monitoring following treatment with 0× or 3× administered 61 days post-implantation. Study 5: safety in ivermectin-sensitive dogs (120 µg/kg SC) was by clinical monitoring for 1 week after administering 1×, 3× or 5×.
RESULTS: Study 1: slight swelling clinically detectable at some 3× and 5× injection sites was characterized microscopically as granulomatous inflammation, like tissue responses to medical implants, interpreted as non-adverse. Pharmacokinetics were dose-proportional and there was little or no systemic accumulation. Residual moxidectin mean (range) at 1× injection sites after 1 year was 16.0% (0.045-37.6%) of the administered mass. Studies 2 and 3: no effects were identified in reproductive indices (females) or semen quality characteristics (males). Study 4: PH 12 produced marked reductions in circulating microfilariae and lower numbers of adult heartworms, but no adverse clinical signs were identified. Study 5: there were no abnormal clinical signs at 1×, 3× or 5× overdoses of PH 12 in ivermectin-sensitive dogs.
CONCLUSIONS: PH 12 has a > 5× safety margin in both normal and ivermectin-sensitive dogs, has no effects on canine reproduction, and is well tolerated in heartworm-positive dogs. The only treatment-related finding was non-adverse, granulomatous inflammation at the injection site.

PMID: 31492168 [PubMed - indexed for MEDLINE]

Drugs in renal disease and pregnancy.

Best Pract Res Clin Obstet Gynaecol. 2019 May;57:106-119

Authors: Sarwar A

Abstract
This review aims to summarise historic and the latest evidence of commonly used drugs in pregnant women with chronic kidney disease (CKD). Data regarding safety of drugs in breastfeeding are also described. Practical recommendations are made on the use of newer agents that have limited information of use in pregnant women with CKD. Pharmacokinetic and dynamic issues are outlined, and general principles for prescribing drugs in pregnant women with CKD are listed. Resources to investigate drug safety are presented.

PMID: 31031053 [PubMed - indexed for MEDLINE]

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2020/01/01

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Idiosyncratic Drug Reaction: A Rare Mechanism of Acute Tylenol Toxicity.

Cureus. 2019 Nov 08;11(11):e6099

Authors: Raza A, Chan V, Atiq MU

Abstract
Acetaminophen (APAP) is perhaps the most commonly used drug both inside and outside the hospital due to its relative safety and over-the-counter availability. Despite its safety, it can cause drug-related side effects, especially acute liver injury that can be unpredictable. Additionally, due to its variable, delayed and nonspecific symptomatology, it can pose a significant diagnostic challenge. Due to potential reversibility with an antidote and adverse outcome related to liver failure, timely recognition and treatment is key in suspected toxicity. Here we present a case of a young female who presented for the evaluation of seizure and found to have APAP-related liver failure with only 2 g of APAP taken over two days duration.

PMID: 31886040 [PubMed]

Drug-Interaction Between Febuxostat and Thiopurine Antimetabolites: A Review of the FDA Adverse Event Reporting System and Medical Literature.

Pharmacotherapy. 2019 Dec 29;:

Authors: Logan JK, Wickramaratne Senarath Yapa S, Harinstein L, Saluja B, Muñoz M, Sahajwalla C, Neuner R, Seymour S

Abstract
BACKGROUND: There is a known drug interaction (DI) between xanthine oxidase (XO) inhibitors and the thiopurine immunosuppressants, azathioprine (AZA) and mercaptopurine (6-MP). Xanthine Oxidase inhibition increases concentrations of AZA and 6-MP active metabolites, possibly resulting in myelosuppression. When allopurinol is used with AZA or 6-MP, dose reduction of AZA or 6-MP is recommended. Febuxostat is a newer XO inhibitor approved for the treatment of gout.
OBJECTIVE: To determine the clinical impact of the febuxostat-thiopurine DI.
DESIGN AND SETTING: Case series derived from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) and published medical literature.
PATIENTS: Nineteen patients who received concomitant febuxostat and either AZA or 6-MP.
MEASUREMENTS: Laboratory and clinical data.
RESULTS: Nineteen cases reporting myelosuppressive events were identified in patients receiving febuxostat with AZA or 6-MP. Eighteen cases were treated with the combination of AZA and febuxostat. A median of 1.6 months elapsed from initiation of the drug combination until discovery of the event. Sixteen cases required hospitalization and 15 reported administration of blood products. Most cases reported resolution of the event with discontinuation of both drugs (n=13), discontinuation of the thiopurine only (n=2), or discontinuation of febuxostat only (n=1).
LIMITATIONS: Thiopurine monotherapy may cause myelosuppression. Complications of immunosuppression that may contribute to the real-world morbidity and mortality associated with the febuxostat-thiopurine DI were not examined. Finally, FAERS data is limited by the voluntarily nature of reporting.
CONCLUSION: Current febuxostat labeling contraindicates concomitant administration of febuxostat with either AZA or 6-MP. This case series demonstrates that the DI can result in clinically significant adverse events and is supportive of current febuxostat labeling.

PMID: 31885095 [PubMed - as supplied by publisher]

Rate of adverse events and associated health care costs for the management of inflammatory bowel disease in Germany.

Clin Ther. 2019 Dec 26;:

Authors: Wilke T, Groth A, Long GH, Tatro AR, Sun D

Abstract
PURPOSE: Therapeutic management of inflammatory bowel disease (IBD) is challenging, and available therapies are associated with adverse events (AEs) that may lead to treatment discontinuation. This study evaluated the rate of drug-related AEs of special interest (AESIs) associated with IBD therapies and compare health care costs among patients with IBD who did and did not experience AESIs.
METHODS: A retrospective cohort analysis was conducted using claims data from a German Sickness Fund (Allgemeine Ortskrankenkasse PLUS). Patients were diagnosed with ulcerative colitis (UC) or Crohn's disease (CD) and newly initiating treatment with immunosuppressant, anti-tumor necrosis factor α, or anti-integrin therapies from January 1, 2011, to December 31, 2015. Patients were required to have continuous insurance coverage and no evidence of use of these IBD therapies for 12 months before the date of newly initiating therapy (index date). Rates of AESIs were based on 28 different events or chronic conditions associated with IBD treatment. Direct health care costs were reported separately for patients who did or did not experience AESIs. Only treatment periods lasting ≥60 days were considered. AESI rates related to all possible treatment patterns were calculated and reported as the number of events per 10,000 patient-years. Health care costs were calculated based on IBD-related health care resource use.
FINDINGS: A total of 1126 (CD, n = 676; UC, n = 450) patients met the inclusion criteria. Mean age was 36.5 years for patients with CD and 42.5 years for patients with UC; 60.5% and 47.6% were female, respectively. Median observed time since the index date was 1460 and 1552 days, for patients with CD and UC. The overall rate for any AESI was 1392.4 and 1917.9 events per 10,000 patient-years in patients with CD and those with UC. Severe infections and diabetes mellitus were the most common AESIs. Significant differences in mean total direct health care costs were found for CD patients with AESIs versus those without (€8920.08 and €6004.86; P < 0.001). A similar trend was observed with mean drug costs and mean medical costs. In UC, total direct health care costs, although generally higher in patients with AESIs, were not significantly different; however, medical costs were (€1946.93 vs €971.28; P < 0.001).
IMPLICATIONS: AEs are common in patients with IBD treated with current therapies and associated with substantial health care costs. An urgent need exists for development of IBD treatments that are associated with lower rates of AEs. (Clin Ther. 2019;41:XXX-XXX) © 2019 Elsevier HS Journals, Inc.

PMID: 31883702 [PubMed - as supplied by publisher]

Organizational implications of implementing a new adverse drug event reporting system for care providers and integrating it with provincial health information systems.

Healthc Manage Forum. 2019 Jul;32(4):208-212

Authors: Small SS, Hohl CM, Balka E

Abstract
Cross-sector collaborations between academia, government, and private industry, known as Triple Helix configurations, are increasingly common. In the health Information Technology (IT) sector, such configurations often also include health delivery organizations where technology is implemented and used. The complexity of collaborating within and between multiple organizations can present hurdles for innovators that are seldom discussed in the literature. We outline challenges we encountered in cross-sector collaboration and offer some guiding principles for decision-makers, academics, industry partners, and health delivery organizations to successfully negotiate divergent approaches to innovation and implementation. We discuss an innovative project that aims to implement a researcher-designed adverse drug event reporting system into clinical care and integrate it with provincial and health authority IT systems. Based on our experience, implementing an interoperable health IT system must extend beyond technical integration to encompass meaningful stakeholder engagement to ensure utility for end-users and beneficial impact for participating organizations.

PMID: 31091996 [PubMed - indexed for MEDLINE]

Methanol extract of Muntingia calabura leaves attenuates CCl4-induced liver injury: possible synergistic action of flavonoids and volatile bioactive compounds on endogenous defence system.

Pharm Biol. 2019 Dec;57(1):335-344

Authors: Zakaria ZA, Mahmood ND, Omar MH, Taher M, Basir R

Abstract
CONTEXT: Muntingia calabura L. (Muntingiaceae) exerts antioxidant and anti-inflammatory activities, thus, it might be a good hepatoprotective agent.
OBJECTIVE: This study investigates the effect of methanol extract of M. calabura leaves (MMCL) on hepatic antioxidant and anti-inflammatory activities in CCl4-induced hepatotoxic rat.
MATERIALS AND METHODS: Sprague Dawley rats (n = 6) were treated (p.o.) with 10% DMSO (Groups 1 and 2), 50 mg/kg N-acetylcysteine (Group 3) or, 50, 250, or 500 mg/kg MMCL (Groups 4-6) for 7 consecutive days followed by pretreatment (i.p.) with vehicle (Group 1) or 50% CCl4 in olive oil (v/v) (Groups 2-6) on day 7th. Plasma liver enzymes and hepatic antioxidant enzymes and pro-inflammatory cytokines concentrations were measured while liver histopathology was examined.
RESULTS: MMCL, at 500 mg/kg, significantly (p < 0.05) ameliorated CCl4-induced hepatotoxicity by decreasing the plasma level of alanine transaminase (429.1 versus 168.7 U/L) and aspartate transaminase (513.8 versus 438.1 U/L) as well as the tissue level of nitric oxide (62.7 versus 24.1 nmol/g tissue). At 50, 250, or 500 mg/kg, MMCL significantly (p < 0.05) reduced the tumour necrosis factor α (87.8 versus 32.7 pg/mg tissue), interleukin-1β (1474.4 versus 618.3 pg/mg tissue), and interleukin-6 (136.7 versus 30.8 pg/mg tissue) while increased the liver catalase (92.1 versus 114.4 U/g tissue) and superoxide dismutase (3.4 versus 5.5 U/g tissue). Additionally, qualitative phytochemicals analysis showed that MMCL contained gallic acid, ferulic acid, quercetin, and genistein.
DISCUSSION AND CONCLUSIONS: MMCL ability to attenuate CCl4-induced hepatotoxicity could be helpful in the development of hepatoprotective agents with fewer side effects.

PMID: 31068038 [PubMed - indexed for MEDLINE]

Systemic agents for psoriasis and their relevance to primary care.

Br J Gen Pract. 2019 Feb;69(679):96-97

Authors: Tso S, Hunt W, Frow H, Ilchyshyn A

PMID: 30705021 [PubMed - indexed for MEDLINE]

Molecular Docking for Prediction and Interpretation of Adverse Drug Reactions.

Comb Chem High Throughput Screen. 2018;21(5):314-322

Authors: Luo H, Fokoue-Nkoutche A, Singh N, Yang L, Hu J, Zhang P

Abstract
AIM AND OBJECTIVE: Adverse drug reactions (ADRs) present a major burden for patients and the healthcare industry. Various computational methods have been developed to predict ADRs for drug molecules. However, many of these methods require experimental or surveillance data and cannot be used when only structural information is available.
MATERIALS AND METHODS: We collected 1,231 small molecule drugs and 600 human proteins and utilized molecular docking to generate binding features among them. We developed machine learning models that use these docking features to make predictions for 1,533 ADRs.
RESULTS: These models obtain an overall area under the receiver operating characteristic curve (AUROC) of 0.843 and an overall area under the precision-recall curve (AUPR) of 0.395, outperforming seven structural fingerprint-based prediction models. Using the method, we predicted skin striae for fluticasone propionate, dermatitis acneiform for mometasone, and decreased libido for irinotecan, as demonstrations. Furthermore, we analyzed the top binding proteins associated with some of the ADRs, which can help to understand and/or generate hypotheses for underlying mechanisms of ADRs.
CONCLUSION: Machine learning combined with molecular docking can help to predict ADRs for drug molecules and provide possible explanations for the ADR mechanisms.

PMID: 29792141 [PubMed - indexed for MEDLINE]

Long-Term Safety and Efficacy of Blonanserin Transdermal Patches in Japanese Patients with Schizophrenia: A 52-Week Open-Label, Multicenter Study.

CNS Drugs. 2019 Dec 27;:

Authors: Iwata N, Ishigooka J, Naoi I, Matsumoto M, Kanamori Y, Nakamura H, Higuchi T

Abstract
BACKGROUND: Blonanserin transdermal patch therapy is now available in Japan for the treatment of schizophrenia and may provide several advantages over the tablet formulation.
OBJECTIVE: The aim was to evaluate the long-term safety and efficacy of blonanserin transdermal patches in Japanese patients with schizophrenia.
METHODS: An open-label study was conducted in adults with schizophrenia at 37 sites in Japan. Patients were enrolled in either cohort 1 or 2. Patients in cohort 1 received 8-16 mg/day blonanserin tablets for 6 weeks and then 40-80 mg/day blonanserin patches for 52 weeks. The dose of blonanserin patches was determined according to the dose of the tablets. In cohort 2, every patient started from 40 mg/day and then 40-80 mg/day blonanserin transdermal patches for 52 weeks. Both cohorts had 1-2 weeks of follow-up. Safety endpoints included the incidence of adverse events (AEs), treatment-related AEs, extrapyramidal AEs [also assessed using the change in Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) score], the use of any concomitant antiparkinsonian drugs, and skin-related AEs, including skin irritation. Patients also underwent assessment of laboratory values including for serum prolactin concentration, vital signs, body weight, electrocardiographic (ECG) changes, and the corrected QT (QTc) interval. Suicidal ideation was assessed via the Columbia-Suicide Severity Rating Scale (C-SSRS) score. Efficacy was assessed via duration of blonanserin transdermal patch treatment, Positive and Negative Syndrome Scale (PANSS) total and subscale scores, and Clinical Global Impression-Severity (CGI-S) scores. Other endpoints included total Drug Attitude Inventory 10 (DAI-10) scores, EuroQol-5 Dimension (EQ-5D) effect values, and a patient questionnaire about the dosage form.
RESULTS: A total of 223 patients with consents, 117 in cohort 1 and 106 in cohort 2 were included in the study. Of the 117 patients in cohort 1, 108 were treated with blonanserin tablets, and 97 received blonanserin patches and were included in the safety analysis set. In cohort 2, 103 of the 106 patients were treated with blonanserin transdermal patches and were included in the safety analysis set. In total, 91 patients were male (45.5%). The mean age was 43.8 years. Discontinuation occurred in 40 patients (41.2%) in cohort 1 and 44 patients (42.7%) in cohort 2. Discontinuation resulted from AEs in 18.6% (cohort 1) and 11.7% (cohort 2) and from withdrawal of consent in 13.4% (cohort 1) and 20.4% (cohort 2), and seven patients overall discontinued due to skin reactions. AEs were reported in 174 patients (87.0%), and 13 serious AEs occurred in 12 patients (6.0%), of which six patients were in cohort 1 and six patients were in cohort 2. Serious AEs were six schizophrenia (n = 6) and seven other AEs (n = 6), which included impulse-control disorder, fracture, epistaxis, asthma, pneumonia aspiration, pneumonia hemophilus, and pneumonia. The most common AEs were nasopharyngitis (n = 62, 31.0%), application site erythema (n = 45, 22.5%), application site pruritus (n = 23, 11.5%), and akathisia (n = 20, 10.0%). AE incidence was similar in cohort 1 (84.5%) and cohort 2 (89.3%). Extrapyramidal and skin-related AEs were reported in 51 patients (25.5%) and 83 patients (41.5%), respectively. None of these AEs were serious. The mean change from baseline in total DIEPSS score at Week 52 {last observation carried forward [LOCF] (standard deviation [SD])} was -0.1 (1.55), indicating no marked effect. In terms of concomitant medications used in cohort 1 and cohort 2, 33.0% (32/97) and 22.3% (23/103) used antiparkinsonian drugs, respectively. The majority of skin-related AEs occurred early in treatment and were appropriately managed with topical therapies. Of the patients who answered "No" to all C-SSRS categories at baseline (n = 129), 13 patients (10.1%) were evaluated as having emergence of suicidal ideation. Among patients who answered "No" to all C-SSRS suicidal behavior categories at baseline (n = 172), one (0.6%) was evaluated as having suicidal behavior during blonanserin transdermal patch treatment. There were no clinically significant changes in laboratory tests or examinations, including prolactin level, vital signs, body weight, ECG, metabolism-related parameters, and QTc interval. The mean (SD) change in body weight was - 0.04 (4.561) kg and - 0.67 (6.841) kg in cohort 1 and cohort 2, respectively. The mean changes from baseline in PANSS total score at Week 52 (LOCF [SD]) were - 0.1 [11.6] and - 3.4 [15.3] in cohort 1 and 2, respectively. PANSS scores did not change after switching from tablet to patch formulation in cohort 1 and decreased over the 52 weeks of treatment with the blonanserin patches. The mean change from baseline in CGI-S score at Week 52 (LOCF [SD]) was - 0.2 [1.03] in both cohorts combined. After 52 weeks of blonanserin patch treatment, the total DAI-10 score increased or remained unchanged compared with baseline in 82 of the 129 patients (63.6%) for whom these data were available. In the intention-to-treat population of the combined cohorts (n = 200), the mean (SD) change from baseline in EQ-5D score at the last assessment was - 0.0365 (0.17603). Patients' attitudes to the blonanserin transdermal patches were generally positive.
CONCLUSIONS: Blonanserin transdermal patches are safe and effective in the long-term treatment of schizophrenia. CLINICALTRIALS.
GOV REGISTRATION: NCT02335658.

PMID: 31883082 [PubMed - as supplied by publisher]

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2019/12/28

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2019/12/28

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Safety and Bioavailability of Complete and Half-Dose Intravitreal Ziv-Aflibercept in an Experimental Model: Contralateral Eye Study.

Ophthalmic Surg Lasers Imaging Retina. 2019 Dec 01;50(12):785-790

Authors: Lashay A, Delrish E, Ashrafi E, Movassat M, Asadi-Amoli F, Dinarvand R, Abrishami M

Abstract
BACKGROUND AND OBJECTIVE: To evaluate the safety and bioavailability of complete and half-dose of intravitreal ziv-aflibercept (IVZ) in an experimental model.
MATERIALS AND METHODS: Thirty-two eyes of 16 male rabbits received one IVZ injection under anesthesia and the operating microscope. All right and left eyes received 1,250 μg/0.05 mL and 625 μg/0.05 mL of ziv-aflibercept, respectively. Then, rabbits were randomly allocated to four groups (four rabbits in each group). The rabbits were euthanized at predesignated intervals (at 24, 168, 336, and 720 hours), and the eyes were enucleated. Indirect ophthalmoscopy, vitreous sampling, and electrophysiological recordings were obtained before euthanization. Histological examination was performed after enucleation. Vitreous samples were evaluated by enzyme-linked immunosorbent assay to measure the concentration of aflibercept.
RESULTS: No serious drug-related ocular inflammation and toxicity or systemic adverse events were identified. Electroretinogram findings showed no significant difference to the baseline measurements. Remaining vitreal concentrations of ziv-aflibercept injection for the 625 μg/mL group were 416 μg/mL, 349 μg/mL, 124 μg/mL, 41.2 μg/mL, and 18.1 μg/mL (± 10 μg/mL) and for the 1,250 μg/mL group were 833 μg/mL, 737 μg/mL, 284 μg/mL, 87.3 μg/mL, and 38.2 μg/mL (± 10 μg/mL), at zero, 24, 168, 336, and 720 hours after injection, respectively. The vitreous concentration of aflibercept was analyzed by one-compartment model. The area under curve from time 0 to the end point (AUC last) was 147,637 hours × μg/mL for the complete dose group (1,250 μg/0.05mL) and 68,498 hours × μg/mL for the half-dose group (625 μg/0.05 mL). The assessed vitreous half-life of ziv-aflibercept was 113 hours in both groups.
CONCLUSIONS: IVZ proved to be safe and well tolerated, even in the complete dose group. It seems to be a cost-effective therapeutic option for the treatment of retinal vascular diseases. However, the long-term safety and efficacy of intravitreal ziv-aflibercept remain unknown. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:785-790.].

PMID: 31877224 [PubMed - in process]

Advanced intrahepatic cholangiocarcinoma treated using anlotinib and microwave ablation: A case report.

Medicine (Baltimore). 2019 Dec;98(52):e18435

Authors: Zhang A, Liu B, Xu D, Sun Y

Abstract
INTRODUCTION: Intrahepatic cholangiocarcinoma (ICC) accounts for 10% to 15% of all primary hepatic carcinomas. However, there are no effective drug treatment strategies against ICC, and surgery is currently the only curative treatment. Here, we present a case of ICC successfully treated with anlotinib, a novel oral agent.
PATIENT CONCERNS: The patient was a 66-year-old Han Chinese woman, and she was a retired worker. The patient had no history of hepatitis B infection or hypertension. Physical examination showed no abnormalities, and the patient showed no conscious discomfort. However, ultrasound revealed liver occupation.
DIAGNOSIS: Liver ultrasound and enhanced computed tomography (CT) indicated liver cancer with intrahepatic metastasis. Serum carbohydrate antigen 199 and alpha fetoprotein levels were high at 4270 and 1561 ng/mL, respectively. Pathologic findings of CT-guided liver biopsy revealed an adenocarcinoma. Owing to further immunohistochemical staining and clinical results, a diagnosis of ICC was made.
INTERVENTIONS: The patient had received 5 cycles of transhepatic arterial chemotherapy and embolization and 1 cycle of microwave ablation. Due to rapid tumor progression and loss of liver function, systemic chemotherapy was contraindicated. As second-line therapy, she received anlotinib, a novel tyrosine kinase inhibitor that inhibits tumor angiogenesis and proliferative signaling and has been used to treat refractory advanced non-small-cell lung cancer that shows progression despite treatment with ≥2 chemotherapy regimens.
OUTCOMES: This patient showed a partial response after 2 cycles of treatment with anlotinib (12 mg daily, days 1-14 of a 21-day cycle). Drug-related side effects, such as hypertension and hand foot skin reaction, were observed. After 4 cycles of anlotinib, the efficacy appeared to be stable, and the patient showed a progression-free survival period of almost 4 months. However, the patient's condition worsened and she died of liver failure 6 months after treatment (overall survival, almost 6 months).
CONCLUSION: Some cases of ICC may be responsive to the antiangiogenic drug, anlotinib, when combined with microwave ablation. Randomized clinical studies are required to further confirm the efficacy and safety of anlotinib in the clinical treatment of ICC.

PMID: 31876723 [PubMed - in process]

Antipsychotic Medication Exposure, Clozapine, and Pneumonia: Results from a Self-controlled Study.

Acta Psychiatr Scand. 2019 Dec 25;:

Authors: Rohde C, Siskind D, de Leon J, Nielsen J

Abstract
OBJECTIVE: By using a self-controlled design, we investigated whether antipsychotic medication exposure was associated with increased pneumonia risk and whether patients receiving clozapine were more likely to develop pneumonia than patients receiving other antipsychotic medications.
METHODS: Through nationwide health registers, we identified all outpatients with schizophrenia initiating antipsychotic treatment. First, we estimated whether antipsychotic-naïve patients with schizophrenia increased their risk of pneumonia after initiation of either a first- or second-generation antipsychotic medication using a one-year mirror-image model. Afterwards, similar analyses were made for individual second-generation antipsychotics. Lastly, the rate of pneumonia for patients initiated on clozapine was compared to patients commenced on other second-generation antipsychotics.
RESULTS: In total, 8355 antipsychotic-naïve patients with schizophrenia were initiated on a first-generation antipsychotic medication; 0.95% of the patients had developed pneumonia before exposure, compared to 0.68% after exposure (p=0.057). Similar findings were made for the 8001 antipsychotic-naïve patients with schizophrenia initiated on second-generation antipsychotic medications, with 0.56% developing pneumonia before exposure compared to 0.55% after exposure (p=1.00). Second-generation antipsychotic medications did not increase the pneumonia risk, except for risperidone (increased by 0.32%; p=0.007) and clozapine, which gave the largest absolute increase in pneumonia risk although not significant (increased by 0.64 %; p=0.10). The rate of pneumonia was higher after initiation of clozapine than for other second-generation antipsychotic medications.
CONCLUSION: Most antipsychotic medications were not found to increase the risk of pneumonia. Clozapine exposure might be associated with increased risk of developing pneumonia.

PMID: 31875941 [PubMed - as supplied by publisher]