Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer.

J Clin Oncol. 2018 Jan 20;:JCO2017769901

Authors: Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, Morse MA, Van Cutsem E, McDermott R, Hill A, Sawyer MB, Hendlisz A, Neyns B, Svrcek M, Moss RA, Ledeine JM, Cao ZA, Kamble S, Kopetz S, André T

Abstract
Purpose Nivolumab provides clinical benefit (objective response rate [ORR], 31%; 95% CI, 20.8 to 42.9; disease control rate, 69%; 12-month overall survival [OS], 73%) in previously treated patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC); nivolumab plus ipilimumab may improve these outcomes. Efficacy and safety results for the nivolumab plus ipilimumab cohort of CheckMate-142, the largest single-study report of an immunotherapy combination in dMMR/MSI-H mCRC, are reported. Patients and Methods Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks. Primary end point was investigator-assessed ORR. Results Of 119 patients, 76% had received ≥ two prior systemic therapies. At median follow-up of 13.4 months, investigator-assessed ORR was 55% (95% CI, 45.2 to 63.8), and disease control rate for ≥ 12 weeks was 80%. Median duration of response was not reached; most responses (94%) were ongoing at data cutoff. Progression-free survival rates were 76% (9 months) and 71% (12 months); respective OS rates were 87% and 85%. Statistically significant and clinically meaningful improvements were observed in patient-reported outcomes, including functioning, symptoms, and quality of life. Grade 3 to 4 treatment-related adverse events (AEs) occurred in 32% of patients and were manageable. Patients (13%) who discontinued treatment because of study drug-related AEs had an ORR (63%) consistent with that of the overall population. Conclusion Nivolumab plus ipilimumab demonstrated high response rates, encouraging progression-free survival and OS at 12 months, manageable safety, and meaningful improvements in key patient-reported outcomes. Indirect comparisons suggest combination therapy provides improved efficacy relative to anti-programmed death-1 monotherapy and has a favorable benefit-risk profile. Nivolumab plus ipilimumab provides a promising new treatment option for patients with dMMR/MSI-H mCRC.

PMID: 29355075 [PubMed - as supplied by publisher]

Estimating causal log-odds ratio using the case-control sample and its application in the pharmaco-epidemiology study.

Stat Methods Med Res. 2018 Jan 01;:962280217750175

Authors: Zhu A, Zeng D, Zhang P, Li L

Abstract
One important goal in pharmaco-epidemiology studies is to understand the causal relationship between drug exposures and their clinical outcomes, including adverse drug events. In order to achieve this goal, however, we need to resolve several challenges. Most of pharmaco-epidemiology data are observational and confounding is largely present due to many co-medications. The pharmaco-epidemiology study data set is often sampled from large medical record databases using a matched case-control design, and it may not be representative of the original patient population in the medical record databases. Data analysis method needs to handle a large sample size that cannot be handled using existing statistical analysis packages. In this paper, we tackle these challenges both methodologically and computationally. We propose a conditional causal log-odds ratio (OR) definition to characterize causal effects of drug exposures on a binary adverse drug event adjusting for individual level confounders. Using a case-control design, we present a propensity score estimation using only case samples and we provide sufficient conditions for the consistency of the estimation of the causal log-odds ratio using case-based propensity scores. Computationally, we implement a principle component analysis to reduce high-dimensional confounders. Extensive simulation studies are performed to demonstrate superior performance of our method to existing methods. Finally, we apply the proposed method to analyze drug-induced myopathy data sampled from a de-identified subset of medical record database (close to 5 million patient records), The Indiana Network for Patient Care. Our method identified 70 drug-induced myopathy ( p < 0.05) out 72 drugs, which have myoathy side effects on their FDA drug labels. These 70 drugs include three statins who are known for their myopathy side effects.

PMID: 29355073 [PubMed - as supplied by publisher]

Preventing drug-related adverse events following hospital discharge: the role of the pharmacist.

Integr Pharm Res Pract. 2017;6:61-69

Authors: Nicholls J, MacKenzie C, Braund R

Abstract
Transition of care (ToC) points, and in particular hospital admission and discharge, can be associated with an increased risk of adverse drug events (ADEs) and other drug-related problems (DRPs). The growing recognition of the pharmacist as an expert in medication management, patient education and communication makes them well placed to intervene. There is evidence to indicate that the inclusion of pharmacists in the health care team at ToC points reduces ADEs and DRPs and improves patient outcomes. The objectives of this paper are to outline the following using current literature: 1) the increased risk of medication-related problems at ToC points; 2) to highlight some strategies that have been successful in reducing these problems; and 3) to illustrate how the role of the pharmacist across all facets of care can contribute to the reduction of ADEs, particularly for patients at ToC points.

PMID: 29354552 [PubMed]

The effect of prescriber education on medication-related patient harm in the hospital: a systematic review.

Br J Clin Pharmacol. 2017 May;83(5):953-961

Authors: Bos JM, van den Bemt PMLA, de Smet PAGM, Kramers C

Abstract
AIMS: Educating prescribers is a strategy to reduce prescription errors in hospitals. The present systematic review gives an overview of original research papers on the education of prescribers and reporting outcomes on (potential) patient harm.
METHODS: A search of the databases Embase and Medline, using the Ovid interface, was performed. Research on the effect of physician education in order to prevent medication-related problems in inpatients, and on reporting original data and outcomes on prescribing errors and/or (potential) patient harm, was included. The assessment of methodological quality and risk of bias was performed using the Methodological Index for Non-Randomized studies (MINORS) checklist and the suggested risk of bias criteria for Effective Practice and Organization of Care (EPOC) reviews.
RESULTS: Eight studies investigated an intervention on education alone, and in seven studies education was the main part of a multifaceted intervention. All studies were small and had short follow-up periods. The educational programmes varied and were given to physicians of different specialties and levels of experience. Most studies reported intermediate process parameters as the outcome. The risk of performance and reporting bias were high.
CONCLUSION: All included studies suffered from poor methodology. The majority, especially studies in which education was part of a multifaceted intervention, reported effectiveness on intermediate outcome markers as prescription errors and potential adverse drug events. However, we found no firm evidence that educating prescribers in the hospital leads to a decrease in patient harm. Further work is needed to develop educational programmes, accompanied by more high-quality research with outcomes on the improvement of patient care.

PMID: 27918623 [PubMed - indexed for MEDLINE]

QT-interval prolongation due to medication found in the preoperative evaluation.

J Dent Anesth Pain Med. 2017 Dec;17(4):323-327

Authors: Seto M, Koga S, Kita R, Kikuta T

Abstract
QT prolongation is an electrocardiographic change that can lead to lethal arrhythmia. Acquired QT prolongation is known to be caused by drugs and electrolyte abnormalities. We report three cases in which the prolonged QT interval was improved at the time of operation by briefly discontinuing the drugs suspected to have caused the QT prolongation observed on preoperative electrocardiography. The QTc of cases 1, 2, and 3 improved from 518 to 429 ms, 463 to 441 ms, and 473 to 443 ms on discontinuing the use of a gastrointestinal prokinetic agent, a proton pump inhibitor, and a molecular targeted drug, respectively. These cases were considered to have drug-induced QT prolongation. We reaffirmed that even drugs administered for conditions unrelated to cardiac diseases can have adverse side effect of QT prolongation. In conclusion, our cases indicate that dental surgeons should be aware of the dangerous and even potentially lethal side effects of QT prolongation. For safe oral and maxillofacial surgery, cooperation with medical departments in various fields is important.

PMID: 29349356 [PubMed]

A Personalized and Learning Approach for Identifying Drugs with Adverse Events.

Yonsei Med J. 2017 Nov;58(6):1229-1236

Authors: Shin SK, Hur H, Cheon EK, Oh OH, Lee JS, Ko WJ, Kim BS, Kwon Y

Abstract
PURPOSE: Adverse drug events (ADEs) are associated with high health and financial costs and have increased as more elderly patients treated with multiple medications emerge in an aging society. It has thus become challenging for physicians to identify drugs causing adverse events. This study proposes a novel approach that can improve clinical decision making with recommendations on ADE causative drugs based on patient information, drug information, and previous ADE cases.
MATERIALS AND METHODS: We introduce a personalized and learning approach for detecting drugs with a specific adverse event, where recommendations tailored to each patient are generated using data mining techniques. Recommendations could be improved by learning the associations of patients and ADEs as more ADE cases are accumulated through iterations. After consulting the system-generated recommendations, a physician can alter prescriptions accordingly and report feedback, enabling the system to evolve with actual causal relationships.
RESULTS: A prototype system is developed using ADE cases reported over 1.5 years and recommendations obtained from decision tree analysis are validated by physicians. Two representative cases demonstrate that the personalized recommendations could contribute to more prompt and accurate responses to ADEs.
CONCLUSION: The current system where the information of individual drugs exists but is not organized in such a way that facilitates the extraction of relevant information together can be complemented with the proposed approach to enhance the treatment of patients with ADEs. Our illustrative results show the promise of the proposed system and further studies are expected to validate its performance with quantitative measures.

PMID: 29047249 [PubMed - indexed for MEDLINE]

Preventivt arbete kan minska läkemedelsbiverkningar.

Lakartidningen. 2017 Jul 14;114:

Authors: Hallberg P, Collin S, Wadelius M

PMID: 28718862 [PubMed - indexed for MEDLINE]

Consumer reporting of adverse drug reactions: Systems that allow patients to report side effects of the drugs they are taking have yielded valuable information for improving drugs safety and health care.

EMBO Rep. 2016 07;17(7):949-52

Authors: Weigmann K

PMID: 27198546 [PubMed - indexed for MEDLINE]

Bioinformatics Approaches to Predict Drug Responses from Genomic Sequencing.

Methods Mol Biol. 2018;1711:277-296

Authors: Madhukar NS, Elemento O

Abstract
Fulfilling the promises of precision medicine will depend on our ability to create patient-specific treatment regimens. Therefore, being able to translate genomic sequencing into predicting how a patient will respond to a given drug is critical. In this chapter, we review common bioinformatics approaches that aim to use sequencing data to predict sample-specific drug susceptibility. First, we explain the importance of customized drug regimens to the future of medical care. Second, we discuss the different public databases and community efforts that can be leveraged to develop new methods for identifying new predictive biomarkers. Third, we cover the basic methods that are currently used to identify markers or signatures of drug response, without any prior knowledge of the drug's mechanism of action. We further discuss how one can integrate knowledge about drug targets, mechanisms, and predictive markers to better estimate drug response in a diverse set of samples. We begin this section with a primer on popular methods to identify targets and mechanism of action for new small molecules. This discussion also includes a set of computational methods that incorporate other drug features, which do not relate to drug-induced genetic changes or sequencing data such as drug structures, side-effects, and efficacy profiles. Those additional drug properties can aid in gaining higher accuracy for the identification of drug target and mechanism of action. We then progress to discuss using these targets in combination with disease-specific expression patterns, known pathways, and genetic interaction networks to aid drug choice. Finally, we conclude this chapter with a general overview of machine learning methods that can integrate multiple pieces of sequencing data along with prior drug or biological knowledge to drastically improve response prediction.

PMID: 29344895 [PubMed - in process]

Levetiracetam-Induced Skin Hyperpigmentation: An Extremely Rare Undesirable Side Effect.

J Epilepsy Res. 2017 Dec;7(2):106-108

Authors: Algahtani H, Marghalani S, Satti M, Shirah B

Abstract
Levetiracetam is one of the newer second-generation antiepileptic drugs with multiple mechanisms of action. Cutaneous side effects due to levetiracetam are rarely reported in the literature. In this article, we describe a patient with skin hyperpigmentation due to the treatment with levetiracetam with complete resolution after discontinuation of the medication. In addition, we review the topic and hypothesize the mechanism behind this rare complication. To the best of our knowledge, this is the first report of skin hyperpigmentation as a side effect of levetiracetam in the literature. The prescribing physicians should inform the patients about all potential side effect of levetiracetam including skin hyperpigmentation. Similar to many undiagnosed conditions, increased awareness of their existence is the key to diagnosis. Early recognition and timely cessation of therapy are important to reverse this effect. Further studies should be conducted to explore the pathophysiology of this rare side effect.

PMID: 29344468 [PubMed]

Safety of yellow fever vaccine in Indian travellers: A prospective observational study.

Indian J Med Res. 2016 Nov;144(5):778-780

Authors: Tiwari P, Ahlawat R, Gupta G

PMID: 28361832 [PubMed - indexed for MEDLINE]

Serious adverse events reported for antiobesity medicines: postmarketing experiences from the EU adverse event reporting system EudraVigilance.

Int J Obes (Lond). 2016 Nov;40(11):1742-1747

Authors: Aagaard L, Hallgreen CE, Hansen EH

Abstract
BACKGROUND: Use of antiobesity medicines has been linked with serious cardiac and psychiatric adverse events (AEs). Spontaneous reports can provide information about serious, rare and unknown AEs occurring after the time of marketing. In Europe, information about AEs reported for antiobesity medicines can be accessed in the EudraVigilance (EV) database. Therefore, we aimed to identify and characterise AEs associated with the use of antiobesity medicines in Europe.
METHODS: AE reports submitted for antiobesity medicines (Anatomical Therapeutic Chemical (ATC) group A08A) from 2007 to 2014 and located in the EV database were analysed. AE data were categorised with respect to time, age and sex of patient/consumer, type of reporter, category and seriousness of reported AEs and medicines. Consumer AE reports were compared with reports from other types of reporters with respect to age and sex of consumer, seriousness, system organ class and medicine. The unit of analysis was one AE and one AE report, respectively.
RESULTS: We located 4941 AE reports corresponding to 13 957 AEs for antiobesity medicines in the EV database. More than 90% of all AE cases were serious, including 159 deaths. The majority of AE cases were reported for female adults. The majority of serious AEs was reported for orlistat (37%) and rimonabant (22%). The largest share of serious AEs was of the type 'cardiac disorders' (19%) and 'psychiatric disorders' (18%). Consumer AEs reporting differed from other sources with respect to share and seriousness of AEs, type of AEs (system organ class) and medicines (ATC level 5).
CONCLUSIONS: Many serious AEs were found for antiobesity medicines in EV, and consumers contributed with a relatively high share of reports. Although several products have been withdrawn from the market and new medicines are being marketed, the utilisation of antiobesity medicines is widespread, and therefore systematic monitoring of the safety of these medicines is necessary.

PMID: 27478924 [PubMed - indexed for MEDLINE]

33 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 2018/01/18

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.

33 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 2018/01/18

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.

27 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 2018/01/17

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.

Metabolic acidosis and anaemia associated with dorzolamide in a patient with impaired renal function.

Br J Clin Pharmacol. 2018 Jan 14;:

Authors: Hoffmanová I, Sánchez D

Abstract
Topical carbonic anhydrase inhibitors (CAI), used for treatment of glaucoma, are generally regarded as safe and unconnected with systemic side effects. We report an unusual case of fatigue, metabolic acidosis, and normocytic anaemia associated with ocular administration of the CAI, dorzolamide, in a patient with impaired renal function. In chronic kidney disease, where CAI elimination may be decreased, and patients prone to develop metabolic acidosis, systemic absorption of ocular administered CAI could lead to rare, but potentially serious adverse reaction, that are a consequence of inhibition of extraocular carbonic anhydrase isoenzymes.

PMID: 29333622 [PubMed - as supplied by publisher]

Toward Better-Quality Compounded Drugs - An Update from the FDA.

N Engl J Med. 2017 12 28;377(26):2509-2512

Authors: Woodcock J, Dohm J

PMID: 29281577 [PubMed - indexed for MEDLINE]

The Use of Rituximab in the Management of Refractory Dermatomyositis.

J Drugs Dermatol. 2017 Feb 01;16(2):162-166

Authors: Kuye IO, Smith GP

Abstract
There is growing adoption of rituximab in the treatment of dermatomyositis patients whose disease is refractory to steroids. However, the effects have not been extensively studied. This is a retrospective study of 25 patients with dermatomyositis who were treated with rituximab. Data from January 2000 to July 2014 was obtained from a clinical data repository, which yielded results from two tertiary centers in the United States. We analyzed information on muscle weakness, skin disease, enzyme levels, and immunosuppressive medication use before and after treatment with rituximab. The follow-up time was six months. Among the patients with skin disease before treatment with rituximab, 72.2% had a clinical improvement in their skin disease at the follow-up visit (P less than0.01). Among the patients with proximal muscle weakness before treatment with rituximab, 81.8% had clinical improvement in their symptoms at the follow-up visit (P less than0.01). The average prednisone dose before rituximab therapy was 18.9 mg, and this dropped to 11.0 mg at follow up (P less than 0.05). The average number of immunosuppressive medications taken by patients dropped from 2.04 to 1.74 (P less than0.05). These changes were less in magnitude and significance among the subset of patient that had an additional connective tissue autoimmune condition. <p><em>J Drugs Dermatol. 2017;16(2):162-166.</em></p>.

PMID: 28300859 [PubMed - indexed for MEDLINE]

Regression Analysis of Local Skin Reactions to Predict Clearance of Actinic Keratosis on the Face in Patients Treated With Ingenol Mebutate Gel: Experience from Randomized Controlled Trials.

J Drugs Dermatol. 2017 Feb 01;16(2):112-114

Authors: Jim On S, Knudsen KM, Skov T, Lebwohl M

Abstract
<p>Ingenol mebutate gel, a topical field treatment for actinic keratosis (AK), elicits inflammatory application-site reactions in most patients. This analysis explored the relationship between the intensity of local skin reactions (LSRs) and AK clearance, measured by the reduction in AK count from baseline in 218 patients who were treated for AK on the face in the pivotal Phase 3 studies. The analysis modeled the AK count at week 8, adjusted for baseline count, with the composite LSR score at 1 day after the last treatment application for each patient as a predictor to estimate the mean and 90% prediction interval for the percent reduction in AK count. The predicted mean percent reduction in AK count was higher in patients with higher composite LSR scores. Lower composite scores demonstrated a variable, less predictive percentage reduction in efficacy. Therefore, a large inflammatory reaction from ingenol mebutate gives a more reliable prognosis for improved AK clearance.</p> <p><em>J Drugs Dermatol. 2017;16(2):112-114.</em></p>.

PMID: 28300852 [PubMed - indexed for MEDLINE]

Classification of toxicity effects of biotransformed hepatic drugs using whale optimized support vector machines.

J Biomed Inform. 2017 Apr;68:132-149

Authors: Tharwat A, Moemen YS, Hassanien AE

Abstract
Measuring toxicity is an important step in drug development. Nevertheless, the current experimental methods used to estimate the drug toxicity are expensive and time-consuming, indicating that they are not suitable for large-scale evaluation of drug toxicity in the early stage of drug development. Hence, there is a high demand to develop computational models that can predict the drug toxicity risks. In this study, we used a dataset that consists of 553 drugs that biotransformed in liver. The toxic effects were calculated for the current data, namely, mutagenic, tumorigenic, irritant and reproductive effect. Each drug is represented by 31 chemical descriptors (features). The proposed model consists of three phases. In the first phase, the most discriminative subset of features is selected using rough set-based methods to reduce the classification time while improving the classification performance. In the second phase, different sampling methods such as Random Under-Sampling, Random Over-Sampling and Synthetic Minority Oversampling Technique (SMOTE), BorderLine SMOTE and Safe Level SMOTE are used to solve the problem of imbalanced dataset. In the third phase, the Support Vector Machines (SVM) classifier is used to classify an unknown drug into toxic or non-toxic. SVM parameters such as the penalty parameter and kernel parameter have a great impact on the classification accuracy of the model. In this paper, Whale Optimization Algorithm (WOA) has been proposed to optimize the parameters of SVM, so that the classification error can be reduced. The experimental results proved that the proposed model achieved high sensitivity to all toxic effects. Overall, the high sensitivity of the WOA+SVM model indicates that it could be used for the prediction of drug toxicity in the early stage of drug development.

PMID: 28286029 [PubMed - indexed for MEDLINE]