Improving drug safety with a systems pharmacology approach.

Eur J Pharm Sci. 2016 Oct 30;94:84-92

Authors: Schotland P, Bojunga N, Zien A, Trame MN, Lesko LJ

Abstract
Systems pharmacology is used to mechanistically analyze drug-adverse drug reaction (ADRs) pairs and is a promising solution to the complex problem of understanding mechanisms of toxicity. In this research, we have explored the feasibility of retrospectively mapping population-level adverse events from the FDA Adverse Event Reporting System (FAERS) to chemical and biological databases to identify drug safety signals and the underlying molecular mechanisms. We used an analytic platform - Molecular Analysis of Side Effects (MASE™). For this purpose, we selected the adverse event of severe and potentially fatal cutaneous reactions (SCARs) that are associated with acetaminophen (APAP). SCARs encompass the continuum between Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). We found a statistically significant association between APAP and TEN, the most severe form of SCARs. We also explored the influence of APAP on other classes of drugs commonly associated with SCARs. We found that APAP significantly reduced the risk of SCARs commonly associated with carbamazepine (CBZ). We used molecular docking simulations to propose a mechanism for APAP's reduction in CBZ-induced SCARs which is competitive inhibition of the binding of CBZ to HLA-B*15:02. We conclude that systems pharmacology can complement established surveillance methodologies by providing a means to undertake an independent investigation and review of the mechanisms by which drugs cause adverse events.

PMID: 27287422 [PubMed - indexed for MEDLINE]

Systems pharmacology to predict drug safety in drug development.

Eur J Pharm Sci. 2016 Oct 30;94:93-95

Authors: Trame MN, Biliouris K, Lesko LJ, Mettetal JT

Abstract
Ensuring that drugs are safe and effective is a very high priority for drug development and the US Food and Drug Administration review process. This is especially true today because of faster approval times and smaller clinical trials, especially in oncology and rare diseases. In light of these trends, systems pharmacology is seen as an essential strategy to understand and predict adverse drug events during drug development by analyzing interactions between drugs and multiple targets rather than the traditional "one-drug-one-target" approach. This commentary offers an overview of the current trends and challenges of using systems pharmacology to reduce the risks of unintended adverse events.

PMID: 27251780 [PubMed - indexed for MEDLINE]

A Systematic Approach to Assess the Burden of Drug Interactions in Adult Kidney Transplant Patients.

Curr Drug Saf. 2016;11(2):156-63

Authors: Bril F, Castro V, Centurion IG, Espinosa J, Keller GA, Gonzalez CD, Riera MC, Saubidet CL, Di Girolamo G, Pujol GS, Alvarez PA

Abstract
AIM: Renal transplant patients are frequently subject to polypharmacy and drug-drug interactions. However, no previous study has systematically assessed the risk of drug interactions and Adverse Drug Reactions (ADRs) in this population.
METHODS: A total of 138 consecutive adult kidney transplant recipients admitted to our hospital between August 2010 and February 2012 were prospectively and systematically assessed by our pharmacovigilance team, within 24 hours of admission, to identify potential drug-drug interactions and probable ADRs.
RESULTS: As a consequence of the high number of medications per patient (7.8±0.2 drugs), a considerable number of drugdrug interactions were observed in this population, with an average of 5.6±0.4 drug interactions per patient. Moreover, a significant percentage of admissions (~10%) of kidney transplant patients were related to probable ADRs. Almost all these patients had at least one drug interaction that could have potentially contributed to the probable ADR. Of note, clinically significant (i.e. severe) drug interactions were more frequent among patients with ADRs (29% vs. 15%, p<0.01). Also, patients with ADRs were more likely to have started a medication 30 days before admission (38.5% vs. 10.4%, p < 0.01). Non-immunosuppressive drugs most commonly involved in severe interactions were omeprazole, magnesium sulphate, and statins. The most commonly observed interactions were: tacrolimus and omeprazole, mycophenolate and omeprazole, sirolimus and enalapril, mycophenolate and antivirals, and mycophenolate and magnesium sulphate.
CONCLUSION: Drug interactions were extremely frequent among kidney transplant recipients, and responsible for potentially avoidable ADRs. They should be carefully considered when following kidney transplant recipients.

PMID: 27194037 [PubMed - indexed for MEDLINE]

Computed Biological Relations among Five Select Treatment-Related Organ/Tissue Toxicities.

Chem Res Toxicol. 2016 05 16;29(5):914-23

Authors: Sakellaropoulos T, Herod TJ, Alexopoulos LG, Bai JP

Abstract
Drug toxicity presents a major challenge in drug development and patient care. We set to build upon previous works regarding select drug-induced toxicities to find common patterns in the mode of action of the drugs associated with these toxicities. In particular, we focused on five disparate organ toxicities, peripheral neuropathy (PN), rhabdomyolysis (RM), Stevens-Johnson syndrome/toxic epidermal necrosis (SJS/TEN), lung injury (LI), and heart contraction-related cardiotoxicity (CT), and identified biological commonalities between and among the toxicities in terms of pharmacological targets and nearest neighbors (indirect effects) using the hyper-geometric test and a distance metric of Spearman correlation. There were 20 significant protein targets associated with two toxicities and 0 protein targets associated with three or more toxicities. Per Spearman distance, PN was closest to SJS/TEN compared to other pairs, whereas the pairs involving RM were more different than others excluding RM. The significant targets associated with RM outnumbered those associated with every one of the other four toxicities. Enrichment analysis of drug targets that are expressed in corresponding organ/tissues determined proteins that should be avoided in drug discovery. The identified biological patterns emerging from the mode of action of these drugs are statistically associated with these serious toxicities and could potentially be used as predictors for new drug candidates. The predictive power and usefulness of these biological patterns will increase with the database of these five toxicities. Furthermore, extension of our approach to all severe adverse reactions will produce useful biological commonalities for reference in drug discovery and development.

PMID: 27063352 [PubMed - indexed for MEDLINE]

Patterns of Adverse Drug Reaction in the Medical Wards of a Teaching Hospital: A Prospective Observational Cohort Study.

Curr Drug Saf. 2016;11(2):164-71

Authors: Peter JV, Varghese GH, Alexander H, Tom NR, Swethalekshmi V, Truman C, Kumar TR, Sivakumar T

Abstract
INTRODUCTION: According to the World Health Organization (WHO) definition, an Adverse Drug Reaction (ADR) is a response to a drug that is noxious and unintended and occurs at doses normally used in humans for the prophylaxis, diagnosis, and treatment of disease. The risk factors of ADR are multi-factorial and include poly-pharmacy, age, gender, race, genetics and inter-current disease.
PATIENTS AND METHODS: This was a hospital based, prospective, observational cohort study undertaken in a tertiary care hospital in south India to assess the different patterns of adverse drug reaction in medical wards over 6 months. The severity of ADR was assessed using Hartwig Siegel scale and causality by Naranjo and WHO UMC Scale. Preventability was assessed using Schumock and Thornton scale and other parameters such as incidence, onset, duration, management and outcome were also assessed. Risk factors were assessed by bi-variate logistic regression analysis and length of hospital stay by T test.
RESULTS: The incidence of ADR was 10.42% in medicine wards. The causality of ADR done by Naranjo scale showed that most of the ADRs were probable (7.38%). Anti-tubercular agents were the leading cause of ADR. Duration of hospitalization was significantly longer (7.18 ± 2.64 vs. 5.06 ± 2.13 days) in patients with ADR (Odds ratio 1.38, 95% Confidence interval 1.26 to 1.51). 7.28% of ADRs were moderately severe. Seriousness criteria assessment showed that 0.33% were serious reactions. Most of the ADRs were definitely preventable. Most of the ADRs were managed by discontinuing the suspected drug. The present study showed female gender predominance over males for ADRs and no relationship with age.
CONCLUSION: Adverse drug reactions impose significant burden on hospitals through prolonging patient stay and by increasing admission rates. The occurrence of ADR in this study was higher when compared to that reported in previous studies. This study highlights the importance of ADR reporting among ADR reporting among health care professionals in hospital.

PMID: 26916785 [PubMed - indexed for MEDLINE]

Incidence of Adverse Drug Reactions in Indian Hospitals: A Systematic Review of Prospective Studies.

Curr Drug Saf. 2016;11(2):128-36

Authors: Patel TK, Patel PB

Abstract
This systematic review estimated the incidence of ADRs that lead to hospitalization (ADRAd) and that developed during hospitalization (ADRIn) and factors affecting in Indian population. Two independent investigators searched the electronic databases describing ADRs. Due to high heterogeneity, incidence of ADRAd and ADRIn were presented as median (interquartile range-IQR). We performed the subgroup analysis of incidence based on characteristics of the included studies. The meta-analysis (generic inverse variance method with random effect model) was possible for the fatal ADR incidence. The risk factors for ADRs were also explored from the included studies. We used 'Review manager software version 5.0' and 'Graph Pad Prism version 6.0' for the analysis. Of 77 fully evaluated references, 21 prospective studies were selected. The median incidence of ADRAd and ADRIn were 2.85% (IOR: 1.25 - 3.93%) and 6.34% (IQR: 3.36 - 16.37%), respectively. The subgroup analysis found high incidence rate with studies conducted in intensive care units, elderly age groups, with intensive monitoring, duration of > 1 year and multidisciplinary team. The fatal ADR incidence was 0.08% (95% CI: 0.00-0.15%). Important risk factors for ADRs included elderly, female sex and polypharmacy. The hospitalized patients have a significant burden of ADRs. The multiple factors may have affected their occurrence.

PMID: 26391424 [PubMed - indexed for MEDLINE]

Comparison of antipseudomonal beta-lactams for febrile neutropenia empiric therapy: systematic review and network meta-analysis.

Clin Microbiol Infect. 2017 Apr 01;:

Authors: Horita N, Shibata Y, Watanabe H, Namkoong H, Kaneko T

Abstract
OBJECTIVES: Compare the effectiveness and safety of antipseudomonal beta-lactam empiric monotherapy for febrile neutropenia by network meta-analysis.
METHODS: The searches using Pubmed, Cochrane CENTRAL, EMBASE, and Web of Science Core Collection were carried out in June 2016. English articles, non-English articles, full-length articles, short articles, and conference abstracts were allowed. Eligible trial design was a parallel-group individual randomization. We included febrile neutropenia adult and pediatric patients undergoing chemotherapy for either solid tumors or hematological malignanciesand treated with intravenous antipseudomonal beta-lactams for initial empiric therapy. Protocol was registered with PROSPERO ID 42016043377.
RESULTS: Of 1275 articles detected by the search, 50 studies with 10872 patients were finally included. Among guideline-recommended Cefepime, Meropenem, Imipenem/Cilastatin, Piperacillin/Tazobactam, and Ceftazidime; Imipenem/Cilastatin showed the highest odds of treatment success without modification, which was the primary endpoint, based on the random-effect model network analysis. Ceftazidime was related to lower treatment success rate without modification compared to Imipenem/Cilastatin with odds ratio (OR) of 0.71 (95%CI 0.57-0.89, P = 0.006). Imipenem/Cilastatin showed the lowest odds of all-cause death. Patients treated by Cefepime had higher risk for all-cause death compared to those treated by Imipenem/Cilastatin (OR 2.05, 95%CI 1.11-3.78, P = 0.029). Any adverse event was significantly more prevalent in Imipenem/Cilastatin arm; however, there was no difference concerning adverse event leading to discontinuation.
CONCLUSIONS: Imipenem/Cilastatin, Piperacillin/Tazobactam, and Meropenem may be reasonable first-choice medications for empiric therapy of febrile neutropenia.

PMID: 28377312 [PubMed - as supplied by publisher]

Adverse drug reactions among patients admitted with infectious diseases at a Brazilian hospital.

Rev Soc Bras Med Trop. 2016 Nov-Dec;49(6):763-767

Authors: Saavedra PA, Meiners MM, Lopes LC, Silva EV, Silva DL, Noronha EF, Toledo MI

Abstract
INTRODUCTION: : Despite the therapeutic benefits of drugs, adverse drug reactions (ADRs) occur. Method: We assessed a series of suspected ADRs identified from notifications and intensive monitoring of inpatients from March 2013 to March 2014.
RESULTS:: Skin reactions predominated (31%). Systemic anti-infective agents were implicated in 16 (72%) reactions. Fifteen (68%) ADRs were classified as possible. The implicated drug was not correctly identified by the healthcare team in 12 cases.
CONCLUSIONS: : Some reactions were not correctly attributed to the causative drug(s), suggesting that the use of a validated evaluation method can promote successful identification of causal links between ADRs and drugs.

PMID: 28001225 [PubMed - indexed for MEDLINE]

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Development of an automated assessment tool for MedWatch reports in the FDA adverse event reporting system.

J Am Med Inform Assoc. 2017 Mar 21;:

Authors: Han L, Ball R, Pamer CA, Altman RB, Proestel S

Abstract
Objective: As the US Food and Drug Administration (FDA) receives over a million adverse event reports associated with medication use every year, a system is needed to aid FDA safety evaluators in identifying reports most likely to demonstrate causal relationships to the suspect medications. We combined text mining with machine learning to construct and evaluate such a system to identify medication-related adverse event reports.
Methods: FDA safety evaluators assessed 326 reports for medication-related causality. We engineered features from these reports and constructed random forest, L1 regularized logistic regression, and support vector machine models. We evaluated model accuracy and further assessed utility by generating report rankings that represented a prioritized report review process.
Results: Our random forest model showed the best performance in report ranking and accuracy, with an area under the receiver operating characteristic curve of 0.66. The generated report ordering assigns reports with a higher probability of medication-related causality a higher rank and is significantly correlated to a perfect report ordering, with a Kendall's tau of 0.24 ( P  = .002).
Conclusion: Our models produced prioritized report orderings that enable FDA safety evaluators to focus on reports that are more likely to contain valuable medication-related adverse event information. Applying our models to all FDA adverse event reports has the potential to streamline the manual review process and greatly reduce reviewer workload.

PMID: 28371826 [PubMed - as supplied by publisher]

Current Status of Parkinsonism-Related Adverse Events and Associated Drugs in Korea.

J Patient Saf. 2017 Apr 01;:

Authors: Kim S, Suh HS

Abstract
OBJECTIVE: The aim of the study was to explore the current status of drug-induced parkinsonism and drugs possibly related to drug-induced parkinsonism in Korea.
METHODS: We conducted a cross-sectional study using the Korea Adverse Event Reporting System database between July 1, 2010, and June 30, 2015. We identified all adverse event reports associated with parkinsonism.
RESULTS: There were 1402 adverse event reports associated with parkinsonism. The number of adverse event reports has increased annually. Among the 1499 drugs associated with parkinsonism, the most common were metoclopramide (49.77%) and paliperidone (16.14%). The major therapeutic groups (the third level of the Anatomical Therapeutic Chemical code) were propulsives (53.87%) and antipsychotics (35.58%). The mean time of onset of parkinsonism was 34.9 days. However, the time of onset of parkinsonism varied by drug, for example, it was 4.6 days for metoclopramide and 37.2 days for paliperidone.
CONCLUSIONS: Metoclopramide and antipsychotics were reported in most adverse event reports associated with parkinsonism in Korea.

PMID: 28368965 [PubMed - as supplied by publisher]

Natural Compounds As Modulators of Non-apoptotic Cell Death in Cancer Cells.

Curr Genomics. 2017 Apr;18(2):132-155

Authors: Guamán-Ortiz LM, Orellana MI, Ratovitski EA

Abstract
Cell death is an innate capability of cells to be removed from microenvironment, if and when they are damaged by multiple stresses. Cell death is often regulated by multiple molecular pathways and mechanism, including apoptosis, autophagy, and necroptosis. The molecular network underlying these processes is often intertwined and one pathway can dynamically shift to another one acquiring certain protein components, in particular upon treatment with various drugs. The strategy to treat human cancer ultimately relies on the ability of anticancer therapeutics to induce tumor-specific cell death, while leaving normal adjacent cells undamaged. However, tumor cells often develop the resistance to the drug-induced cell death, thus representing a great challenge for the anticancer approaches. Numerous compounds originated from the natural sources and biopharmaceutical industries are applied today in clinics showing advantageous results. However, some exhibit serious toxic side effects. Thus, novel effective therapeutic approaches in treating cancers are continued to be developed. Natural compounds with anticancer activity have gained a great interest among researchers and clinicians alike since they have shown more favorable safety and efficacy then the synthetic marketed drugs. Numerous studies in vitro and in vivo have found that several natural compounds display promising anticancer potentials. This review underlines certain information regarding the role of natural compounds from plants, microorganisms and sea life forms, which are able to induce non-apoptotic cell death in tumor cells, namely autophagy and necroptosis.

PMID: 28367073 [PubMed - in process]

Evaluation of the efficacy and safety of Tribulus terrestris in male sexual dysfunction-A prospective, randomized, double-blind, placebo-controlled clinical trial.

Maturitas. 2017 May;99:20-26

Authors: Kamenov Z, Fileva S, Kalinov K, Jannini EA

Abstract
OBJECTIVE: The primary objectives were to compare the efficacy of extracts of the plant Tribulus terrestris (TT; marketed as Tribestan), in comparison with placebo, for the treatment of men with erectile dysfunction (ED) and with or without hypoactive sexual desire disorder (HSDD), as well as to monitor the safety profile of the drug. The secondary objective was to evaluate the level of lipids in blood during treatment.
PARTICIPANTS AND DESIGN: Phase IV, prospective, randomized, double-blind, placebo-controlled clinical trial in parallel groups. This study included 180 males aged between 18 and 65 years with mild or moderate ED and with or without HSDD: 90 were randomized to TT and 90 to placebo. Patients with ED and hypertension, diabetes mellitus, and metabolic syndrome were included in the study. In the trial, an herbal medicine intervention of Bulgarian origin was used (Tribestan(®), Sopharma AD). Each Tribestan film-coated tablet contains the active substance Tribulus terrestris, herba extractum siccum (35-45:1) 250mg which is standardized to furostanol saponins (not less than 112.5mg). Each patient received orally 3×2 film-coated tablets daily after meals, during the 12-week treatment period. At the end of each month, participants' sexual function, including ED, was assessed by International Index of Erectile Function (IIEF) Questionnaire and Global Efficacy Question (GEQ). Several biochemical parameters were also determined. The primary outcome measure was the change in IIEF score after 12 weeks of treatment. Complete randomization (random sorting using maximum allowable% deviation) with an equal number of patients in each sequence was used. This randomization algorithm has the restriction that unequal treatment allocation is not allowed; that is, all groups must have the same target sample size. Patients, investigational staff, and data collectors were blinded to treatment. All outcome assessors were also blinded to group allocation.
RESULTS: 86 patients in each group completed the study. The IIEF score improved significantly in the TT group compared with the placebo group (Р<0.0001). For intention-to-treat (ITT) there was a statistically significant difference in change from baseline of IIEF scores. The difference between TT and placebo was 2.70 (95% CI 1.40, 4.01) for the ITT population. A statistically significant difference between TT and placebo was found for Intercourse Satisfaction (p=0.0005), Orgasmic Function (p=0.0325), Sexual Desire (p=0.0038), Overall Satisfaction (p=0.0028) as well as in GEQ responses (p<0.0001), in favour of TT. There were no differences in the incidence of adverse events (AEs) between the two groups and the therapy was well tolerated. There were no drug-related serious AEs. Following the 12-week treatment period, significant improvement in sexual function was observed with TT compared with placebo in men with mild to moderate ED. TT was generally well tolerated for the treatment of ED.

PMID: 28364864 [PubMed - in process]

Safety of Denosumab Versus Zoledronic Acid in Patients with Bone Metastases: A Meta-Analysis of Randomized Controlled Trials.

Oncol Res Treat. 2016;39(7-8):453-9

Authors: Chen F, Pu F

Abstract
INTRODUCTION: Bone metastases lead to local bone destruction and skeletal complications. Bisphosphonates, particlulaly zoledronic acid (ZA), play a central role in the treatment of bone metastases. Some studies have shown that denosumab may delay and prevent SREs in metastatic bone disease more effectively than ZA; therefore, we systematically reviewed and assessed the safety of denosumab and ZA.
METHODS: The PubMed, EMBASE, Cochrane Library, Web of Science with Conference Proceedings, Elsevier, and China National Knowledge Infrastructure (CNKI) databases were searched up to October 2015. 2 independent reviewers extracted data from each eligible study using a standard protocol, and both fixed-effects and random-effects models were used to analyze and evaluate the data extracted from eligible articles.
RESULTS: 6 randomized controlled trials enrolling 13,733 patients were included. Occurrences of adverse events were generally similar between the denosumab and ZA groups except anemia and anorexia in patients with bone metastases and back pain and bone pain. However, occurrences of serious adverse events such as hypocalcaemia , renal adverse events , and new primary malignancy were significantly different between the denosumab and ZA groups. Only the occurrence of osteonecrosis of the jaw showed no significant difference between the denosumab and ZA groups in patients with bone metastases.
CONCLUSION: Denosumab was safer in delaying or preventing skeletal-related events in patients with bone metastases and prevented pain progression compared to ZA in this meta-analysis.

PMID: 27487236 [PubMed - indexed for MEDLINE]

[Pharmacokinetic and pharmacodynamic effects of psychotropic medications: Differences between sexes].

Psychiatriki. 2016 Apr-Jun;27(2):118-26

Authors: Bergiannaki JD, Kostaras P

Abstract
The gender based or gender sensitive pharmacology is a new research area. Differences among sexes are observed in several parameters of their pharmacokinetic which may relate to alteration of their pharmacodynamic as well. Most psychotropics are given per os, and the greater part of their absorption takes place in the small intestine. Premenopausal women have slower gastric emptying times and lower gastrointestinal blood flow which probably reduces the extent of drug absorption. The distribution of drugs is influenced by the relative lower body mass index, the lower blood volume and flow and the greater percentage of body fat of women. Further, the elimination and renal clearance is reduced in women and the hepatic metabolism differ between sexes. Besides, women differ from men in physiological conditions which may have an impact on the psychotropic medication and dosage required for efficacy and response. Women are exposed to monthly hormonal fluctuations (menstruation), pregnancy, puerperium, menopause and use of contraceptives or synthetic hormonal replacement therapies. Throughout of these conditions changes may occur in total body water, in renal clearance, cardiovascular and autoimmune system, which may cause fluctuations in the activity of the psychotropics, changes in the central neurotransmitters, in the number and sensitivity of the receptors, and the general metabolism as well. Despite the fact that women are the primer consumers of psychotropic medication, taking more psychotropics as well as more multiple medications than men, little attention has been paid to sex differences in psychopharmacology. Till recently women were under-represented or excluded from most of the pharmacological clinical trials. The treatment guidelines for psychotropic medication are based on studies verified and investigated almost exclusively in men. Results from such studies were generalized and recommended for use in the clinical practice without any critique and justification between the sexes. In conclusion, women compared to men, tend to have a greater bioavailability and slower elimination of drugs leading to higher concentrations of free circulating drugs in serum and causing more side effects and adverse reactions to the psychotropic medication than men do. In general, women require lower doses of antidepressants, antipsychotics and benzodiazepines than men. For safety and efficacy reasons and despite the fact that research is still being carried out to determine the exact differences in pharmacodynamic of several psychotropics between genders, the clinician must be aware of the reported effect of the recommended medications on serum levels and organ tissues both for men and women.

PMID: 27467032 [PubMed - indexed for MEDLINE]

Improving Care in Older Patients with Diabetes: A Focus on Glycemic Control.

Perm J. Summer 2016;20(3):51-6

Authors: Lee EA, Gibbs NE, Martin J, Ziel F, Polzin JK, Palmer-Toy D

Abstract
Diabetes affects more than 25% of Americans older than age 65 years. The medical care of older patients must differ from the care of their younger counterparts. Older patients are at high risk of drug toxicity. A hemoglobin A1c (HbA1c) level less than 7.0% has historically been the goal of all patients with diabetes, regardless of age. Recent research has demonstrated that using medications to achieve such tight glycemic control is not necessary and is often not safe.This article discusses the seminal research findings that strongly suggest that HbA1c goals should be relaxed in older patients. The authors then recommend an age-specific and functionally appropriate HbA1c reference range for patients receiving medications to improve glycemic control. Other interventions are suggested that should make diabetes care safer in older patients receiving hypoglycemic medications.

PMID: 27352408 [PubMed - indexed for MEDLINE]

A Questionnaire Study to Assess the Value of the Vulnerable Elders Survey, G8, and Predictors of Toxicity as Screening Tools for Frailty and Toxicity in Geriatric Cancer Patients.

Oncol Res Treat. 2016;39(4):210-6

Authors: Hentschel L, Rentsch A, Lenz F, Hornemann B, Schmitt J, Baumann M, Ehninger G, Schuler M

Abstract
BACKGROUND: The aim of this study was to identify an appropriate screening instrument for the identification of frail elderly patients in a tertiary cancer center. In order to improve cancer care for older patients, the use of a geriatric assessment (GA) has been proposed to identify frail patients or those who are at a higher risk for chemotherapy-related toxicities. In busy clinical routine, an appropriate screening instrument could be used to spare time- and resource-consuming application of GA.
PATIENTS AND METHODS: We administered the Vulnerable Elders Survey (VES-13), G8 questionnaire, and Predictors of Toxicity (POT) as well as a GA at the first visit of 84 consecutive patients at a single Comprehensive Cancer Center. Analysis for patients' characteristics as well as sensitivity, specificity, and positive and negative predictive value (npv) was conducted.
RESULTS: The median age of the patients was 73 years (range 63-93 years), 61.9% were male, most (63%) suffered from gastrointestinal tumors, 39.3% had a multiple cancer diagnosis, and 53.6% had metastasis. 30 (35.7%) individuals were classified as 'frail' by the GA. Sensitivity of G8 was 38.3%, and the npv was 63.8%. Sensitivity for VES-13 was 57.1%, and npv was 76.3%. Sensitivity of POT was 72.7%, and the npv was 80.6%.
CONCLUSION: For the first time, the VES-13, G8, and POT are compared in a sample of older German patients. The POT seems to be a sufficient screening tool to identify frail patients in a tertiary referral cancer center and helps to save time and resources compared with a complete GA.

PMID: 27160741 [PubMed - indexed for MEDLINE]

Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study.

Lancet Infect Dis. 2017 Mar 28;:

Authors: McCarthy JS, Lotharius J, Rückle T, Chalon S, Phillips MA, Elliott S, Sekuloski S, Griffin P, Ng CL, Fidock DA, Marquart L, Williams NS, Gobeau N, Bebrevska L, Rosario M, Marsh K, Möhrle JJ

Abstract
BACKGROUND: DSM265 is a novel antimalarial that inhibits plasmodial dihydroorotate dehydrogenase, an enzyme essential for pyrimidine biosynthesis. We investigated the safety, tolerability, and pharmacokinetics of DSM265, and tested its antimalarial activity.
METHODS: Healthy participants aged 18-55 years were enrolled in a two-part study: part 1, a single ascending dose (25-1200 mg), double-blind, randomised, placebo-controlled study, and part 2, an open-label, randomised, active-comparator controlled study, in which participants were inoculated with Plasmodium falciparum induced blood-stage malaria (IBSM) and treated with DSM265 (150 mg) or mefloquine (10 mg/kg). Primary endpoints were DSM265 safety, tolerability, and pharmacokinetics. Randomisation lists were created using a validated, automated system. Both parts were registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000522718 (part 1) and number ACTRN12613000527763 (part 2).
FINDINGS: In part 1, 73 participants were enrolled between April 12, 2013, and July 14, 2015 (DSM265, n=55; placebo, n=18). In part 2, nine participants were enrolled between Sept 30 and Nov 25, 2013 (150 mg DSM265, n=7; 10 mg/kg mefloquine, n=2). In part 1, 117 adverse events were reported; no drug-related serious or severe events were reported. The most common drug-related adverse event was headache. The mean DSM265 peak plasma concentration (Cmax) ranged between 1310 ng/mL and 34 800 ng/mL and was reached in a median time (tmax) between 1·5 h and 4 h, with a mean elimination half-life between 86 h and 118 h. In part 2, the log10 parasite reduction ratio at 48 h in the DSM265 (150 mg) group was 1·55 (95% CI 1·42-1·67) and in the mefloquine (10 mg/kg) group was 2·34 (2·17-2·52), corresponding to a parasite clearance half-life of 9·4 h (8·7-10·2) and 6·2 h (5·7-6·7), respectively. The median minimum inhibitory concentration of DSM265 in blood was estimated as 1040 ng/mL (range 552-1500), resulting in a predicted single efficacious dose of 340 mg. Parasite clearance was significantly faster in participants who received mefloquine than in participants who received DSM265 (p<0·0001).
INTERPRETATION: The good safety profile, long elimination half-life, and antimalarial effect of DSM265 supports its development as a partner drug in a single-dose antimalarial combination treatment.
FUNDING: Wellcome Trust, UK Department for International Development, Global Health Innovative Technology Fund, Bill & Melinda Gates Foundation.

PMID: 28363636 [PubMed - as supplied by publisher]

Anabolic steroid use.

BMJ. 2016 Oct 13;355:i5023

Authors: Brooks JH, Ahmad I, Easton G

PMID: 27737851 [PubMed - indexed for MEDLINE]

Adverse effects of nephrectomy.

Pediatr Nephrol. 2016 07;31(7):1195

Authors: Cozzi DA, Ceccanti S, Cozzi F

PMID: 27025374 [PubMed - indexed for MEDLINE]