Evaluation of prescription along three health-care periods in the elderly.

Geriatr Psychol Neuropsychiatr Vieil. 2017 Jun 01;15(2):153-162

Authors: Santoni F, Antoine V, di Castri A, Viala M, Geronimi-Robelin L, LeGuillou C, de Taddeo C, Bastide S, Jeandel C, de Wazieres B

Abstract
Polypharmacy, potentially inappropriate prescriptions and inadequate coordination between prescribers are among main factors explaining the occurrence of adverse drug events in elderly patients. Prospective and descriptive study of medication prescriptions for elderly patients during a continuous period of health-care: entry in an acute geriatric unit (T1), at discharge (T2) and two months after hospitalization (T3). A global iatrogenic risk was defined: presence of poly-pharmacy and/or PPI (Laroche criteria) and/or absence of quality indicators for prescription according to the French health authority. For the 79 patients (mean age 87), mean number of medication decreased from 7.33 (T1) to 6 (T2) (p=0.0018) and 6 (T3). Number of quality indicators for prescription improved from 6.67 (T1) to 6.92 (T2) (p=0.001) then decreased to 6.84 (T3). Number of PPI decreased from 1.16 to 0.42 between T1 and T2 (p=0.001) then increased to 0.59 at T3. The global iatrogenic risk indicator fluctuated from 80% (T1) to 64% (T2) and 75% (T3). Selected interventions were developed to prevent adverse drug events during hospitalization and ambulatory follow-up. If geriatric intervention can enhance quality of prescription, iatrogenic risk remains frequent all along health-care follow-up. A local study of prescriptions can be a first step to develop an adequate program for adverse drug events prevention.

PMID: 28625935 [PubMed - indexed for MEDLINE]

Letters to the Editor.

AACN Adv Crit Care. 2017;28(2):133-134

Authors: Gosselin S, Lavergne V, Stork C, Hoffman RS

PMID: 28592470 [PubMed - indexed for MEDLINE]

Overview of systematic reviews of therapeutic ranges: methodologies and recommendations for practice.

BMC Med Res Methodol. 2017 Jun 02;17(1):84

Authors: Cooney L, Loke YK, Golder S, Kirkham J, Jorgensen A, Sinha I, Hawcutt D

Abstract
BACKGROUND: Many medicines are dosed to achieve a particular therapeutic range, and monitored using therapeutic drug monitoring (TDM). The evidence base for a therapeutic range can be evaluated using systematic reviews, to ensure it continues to reflect current indications, doses, routes and formulations, as well as updated adverse effect data. There is no consensus on the optimal methodology for systematic reviews of therapeutic ranges.
METHODS: An overview of systematic reviews of therapeutic ranges was undertaken. The following databases were used: Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts and Reviews of Effects (DARE) and MEDLINE. The published methodologies used when systematically reviewing the therapeutic range of a drug were analyzed. Step by step recommendations to optimize such systematic reviews are proposed.
RESULTS: Ten systematic reviews that investigated the correlation between serum concentrations and clinical outcomes encompassing a variety of medicines and indications were assessed. There were significant variations in the methodologies used (including the search terms used, data extraction methods, assessment of bias, and statistical analyses undertaken). Therapeutic ranges should be population and indication specific and based on clinically relevant outcomes. Recommendations for future systematic reviews based on these findings have been developed.
CONCLUSION: Evidence based therapeutic ranges have the potential to improve TDM practice. Current systematic reviews investigating therapeutic ranges have highly variable methodologies and there is no consensus of best practice when undertaking systematic reviews in this field. These recommendations meet a need not addressed by standard protocols.

PMID: 28577540 [PubMed - indexed for MEDLINE]

Efficacy and Safety of Panobinostat in Relapsed or/and Refractory Multiple Myeloma: Meta Analyses of Clinical Trials and Systematic Review.

Sci Rep. 2016 06 07;6:27361

Authors: Liu JD, Sun CY, Tang L, Wu YY, Wang QY, Hu B, Hu Y

Abstract
During the past decades, many novel agents have improved response and survival of patients with multiple myeloma. Nevertheless, it remains challenging when they suffer relapsing. Thus, novel therapeutic agents are needed. We aimed to assess the efficacy and safety of a novel agent panobinostat for patients with relapsed or/and refractory MM. A systematic literature review identified studies for clinical trials about panobinostat in patients with relapsed or/and refractory MM. We searched studies published between January 2000 and December 2015 in Pubmed, Ovid, EBSCO and the Cochrane library. Random-effect pooled estimates were calculated for overall response rate and rates of common adverse effects. The results showed 11 clinical trials including 700 patients with relapsed or/and refractory MM treated with panobinostat were identified. The ORR varied between 0.08 and 0.67. Pooled analyses showed the results that the ORR was 0.45 (95% CI: 0.31-0.59, I(2) = 90.5%, P = 0.000) for panobinostat combined with any other kind of drugs. The most common Grade3/4 adverse effects were thrombocytopenia, neutropenia, lymphopenia, anemia, diarrhea, fatigue, nausea and so on. In conclusion, based on our analyses, the regimen of panobinostat combining with other agents seems to be well tolerated and efficacious in patients with relapsed or/and refractory MM.

PMID: 27270478 [PubMed - indexed for MEDLINE]

Pharmacokinetic and pharmacodynamic profile of the sodium-glucose co-transporter-2 inhibitor empagliflozin in young people with Type 2 diabetes: a randomized trial.

Diabet Med. 2018 Apr 14;:

Authors: Laffel LMB, Tamborlane WV, Yver A, Simons G, Wu J, Nock V, Hobson D, Hughan KS, Kaspers S, Marquard J

Abstract
AIMS: To assess the pharmacokinetic and pharmacodynamic profile of a single dose of empagliflozin in young people with Type 2 diabetes to identify the appropriate doses for further paediatric development.
METHODS: We conducted a single-dose, open-label, randomized, parallel-group study with empagliflozin 5 mg, 10 mg and 25 mg in young people with Type 2 diabetes aged 10-17 years.
RESULTS: Of 39 participants screened, 27 were randomized and completed the study; their mean (± sd) age was 14.1±2.0 years and body weight was 96.7±23.5 kg. Compared with similar studies in adults with Type 2 diabetes, the maximum observed plasma concentrations were slightly lower with the 10-mg and 25-mg doses, and the area under the plasma concentration-time curve was slightly lower with the 10-mg but slightly higher with the 25-mg dose. The adjusted mean increases in urinary glucose excretion were 53 g/24 h (95% CI 32,74), 73 g/24 h (95% CI 52,94) and 87 g/24 h (95% CI 68,107), and the adjusted mean decreases in fasting plasma glucose were 0.9 mmol/l (95% CI -1.6,-0.1), 0.9 mmol/l (95% CI -1.7,-0.2) and 1.1 mmol/l (95% CI -1.8,-0.5) for the 5- 10- and 25-mg doses, respectively. There were no serious adverse events and one investigator-reported drug-related event (dehydration).
CONCLUSIONS: After a single oral dose of empagliflozin, adults and young people with Type 2 diabetes had similar exposure-response relationships after adjusting for significant covariates. These data support testing 10-mg and/or 25-mg doses of empagliflozin in an upcoming paediatric phase III Type 2 diabetes trial. This article is protected by copyright. All rights reserved.

PMID: 29655290 [PubMed - as supplied by publisher]

Cardiovascular safety signals with dipeptidyl peptidase-4 inhibitors: A disproportionality analysis among high-risk patients.

Pharmacoepidemiol Drug Saf. 2018 Apr 14;:

Authors: Baksh SN, McAdams-DeMarco M, Segal JB, Alexander GC

Abstract
PURPOSE: In 2008, the US Food and Drug Administration (FDA) issued Draft Guidance on investigating cardiovascular risk with oral diabetic drugs, including dipeptidyl peptidase-4 inhibitors (DPP-4i). In 2014, underpowered, post hoc analyses of clinical trials suggested an increased risk of heart failure with the use of these products. As such, we assessed disproportionate reporting of major adverse cardiac events (MACE) among reports for DPP-4i submitted to the FDA Adverse Event Reporting System (FAERS) from 2006 to 2015.
METHODS: We assessed the empirical Bayes geometric mean (EBGM) and its lower bound (EB05) of the relative reporting ratio for MACE among DPP-4i reports in the full FAERS database and in a subset of reports limited to cardiovascular and diabetic drugs. We then compared the EB05 in these 2 analyses and calculated the percent positive agreement for signals of disproportional reporting (SDRs) involving MACE.
RESULTS: Of 180.3 million adverse event reports, 13.4 million were for diabetic and cardiovascular drugs. In the cardiovascular subset, there was an SDR for heart failure with linagliptin (EB05 = 2782.47) and saxagliptin (EB05 = 2.40), myocardial infarction with alogliptin (EB05 = 290.11), and cerebral infarction with sitagliptin (EB05 = 2.80). Of the 14 MACE, 8 had a percent positive agreement ≥50% for an SDR in both analyses. Overall, the cardiovascular subset elicited 11 more SDRs for DPP-4i than the full dataset.
CONCLUSIONS: Postmarketing surveillance of DPP-4i through FAERS suggest increased reporting of MACE, supporting the current FDA warning of heart failure risk. This suggests the need for additional longitudinal, observational research into the association of DPP-4i and other MACE.

PMID: 29655237 [PubMed - as supplied by publisher]

Factors affecting adherence to antiretroviral therapy among pregnant women in the Eastern Cape, South Africa.

BMC Infect Dis. 2018 Apr 13;18(1):175

Authors: Adeniyi OV, Ajayi AI, Ter Goon D, Owolabi EO, Eboh A, Lambert J

Abstract
BACKGROUND: Context-specific factors influence adherence to antiretroviral therapy (ART) among pregnant women living with HIV. Gaps exist in the understanding of the reasons for the variable outcomes of the prevention of mother-to-child transmission (PMTCT) programme at the health facility level in South Africa. This study examined adherence levels and reasons for non-adherence during pregnancy in a cohort of parturient women enrolled in the PMTCT programme in the Eastern Cape, South Africa.
METHODS: This was a mixed-methods study involving 1709 parturient women in the Eastern Cape, South Africa. We conducted a multi-centre retrospective analysis of the mother-infant pair in the PMTCT electronic database in 2016. Semi-structured interviews of purposively selected parturient women with self-reported poor adherence (n = 177) were conducted to gain understanding of the main barriers to adherence. Binary logistic regression was used to determine the independent predictors of ART non-adherence.
RESULTS: A high proportion (69.0%) of women reported perfect adherence. In the logistic regression analysis, after adjusting for confounding factors, marital status, cigarette smoking, alcohol use and non-disclosure to a family member were the independent predictors of non-adherence. Analysis of the qualitative data revealed that drug-related side-effects, being away from home, forgetfulness, non-disclosure, stigma and work-related demand were among the main reasons for non-adherence to ART.
CONCLUSIONS: Non-adherence to the antiretroviral therapy among pregnant women in this setting is associated with lifestyle behaviours, HIV-related stigma and ART side-effects. In order to eliminate mother-to-child transmission of HIV, clinicians need to screen for these factors at every antenatal clinic visit.

PMID: 29653510 [PubMed - in process]

Nanomedicine formulations for the delivery of antiviral drugs: a promising solution for the treatment of viral infections.

Expert Opin Drug Deliv. 2018 Jan;15(1):93-114

Authors: Lembo D, Donalisio M, Civra A, Argenziano M, Cavalli R

Abstract
INTRODUCTION: Viral infections represent a public health problem and one of the leading causes of global mortality. Nanomedicine strategies can be considered a powerful tool to enhance the effectiveness of antiviral drugs, often associated with solubility and bioavailability issues. Consequently, high doses and frequent administrations are required, resulting in adverse side effects. To overcome these limitations, various nanomedicine platforms have been designed. Areas covered: This review focuses on the state of the art of organic-based nanoparticles for the delivery of approved antivirals. A brief description of the main characteristics of nanocarriers is followed by an overview of the most promising research addressing the treatment of most important viral infections. Expert opinion: The activity of antiviral drugs could be improved with nanomedicine formulations. Indeed, nanoparticles can affect the fate of the encapsulated drugs, allowing controlled release kinetics, enhanced bioavailability, modified pharmacokinetics, and reduced side effects. In addition, the physicochemical properties of nanocarriers can enable their capability to target specific sites and to interact with virus structures. In this regard, nanomedicines can be considered an opportunity to enhance the therapeutic index of antivirals. Efficacy, safety, and manufacturing issues need to be carefully assessed to bring this promising approach to the clinic.

PMID: 28749739 [PubMed - indexed for MEDLINE]

Implementing exercise in cancer care: study protocol to evaluate a community-based exercise program for people with cancer.

BMC Cancer. 2017 Feb 06;17(1):103

Authors: Cormie P, Lamb S, Newton RU, Valentine L, McKiernan S, Spry N, Joseph D, Taaffe DR, Doran CM, Galvão DA

Abstract
BACKGROUND: Clinical research has established the efficacy of exercise in reducing treatment-related side-effects and increasing wellbeing in people with cancer. Major oncology organisations have identified the importance of incorporating exercise in comprehensive cancer care but information regarding effective approaches to translating evidence into practice is lacking. This paper describes the implementation of a community-based exercise program for people with cancer and the protocol for program evaluation.
METHODS/DESIGN: The Life Now Exercise program is a community-based exercise intervention designed to mitigate and rehabilitate the adverse effects of cancer and its treatment and improve physical and psychosocial wellbeing in people with cancer. Involvement in the program is open to people with any diagnosis of cancer who are currently receiving treatment or within 2 years of completing treatment. The 3-month intervention consists of twice weekly group-based exercise sessions administered in community exercise clinics under the supervision of exercise physiologists trained to deliver the program. Evaluation of the program involves measures of uptake, safety, adherence and effectiveness (including cost effectiveness) as assessed at the completion of the program and 6 months follow-up.
DISCUSSION: To bridge the gap between research and practice, the Life Now Exercise program was designed and implemented to provide people with cancer access to evidence-based exercise medicine. The framework for program implementation and evaluation offers insight into the development of feasible, generalizable and sustainable supportive care services involving exercise. Community-based exercise programs specifically designed for people with cancer are necessary to facilitate adherence to international guidelines advising patients to participate in high-quality exercise.
TRIAL REGISTRATION: ACTRN12616001669482 (retrospectively registered 5 Dec 2016).

PMID: 28166766 [PubMed - indexed for MEDLINE]

Slow infusion of low{\hyphen}dose ketamine reduces bothersome side effects compared to IV push: a double{\hyphen}blind, double dummy, randomized controlled trial.

Acad Emerg Med. 2018 Apr 12;:

Authors: Clattenburg EJ, Hailozian C, Haro D, Yoo T, Flores S, Louie D, Herring AA

Abstract
STUDY OBJECTIVE: We compared the analgesic efficacy and incidence of side effects when low{\hyphen}dose (0.3 mg{\sol}kg) ketamine (LDK) is administered as a slow infusion (SI) over 15 minutes versus an intravenous push (IVP) over one minute.
METHODS: This was a prospective, randomized, double blind, double dummy, placebo{\hyphen}controlled trial of adult ED patients presenting with moderate to severe pain (numerical rating score ≥ 5). Patients received ketamine 0.3mg{\sol}kg administered either as a SI or IVP. Our primary outcome was the proportion of patients experiencing any psychoperceptual side effect over 60 minutes. A secondary outcome was incidence of moderate or greater psychoperceptual side effects. Additional outcomes included reduction in pain NRS scores at 60 minutes and percent maximum summed pain intensity difference ({\percnt}SPID).
RESULTS: Fifty{\hyphen}nine participants completed the study. 86.2{\percnt} of the IVP arm and 70.0{\percnt} of the SI arm experienced any side effect (difference 16.2{\percnt}, 95{\percnt}CI {\hyphen}5.4 - 37.8). We found a large reduction in moderate or greater psychoperceptual side effects with SI administration-75.9{\percnt} reported moderate or greater side effects versus 43.4{\percnt} in the SI arm (difference 32.5{\percnt}, 95{\percnt}CI 7.9 - 57.1). Additionally, the IVP arm experienced more hallucinations (n{\equal}8, 27.6{\percnt}) than the SI arm (SI n{\equal}2, 6.7{\percnt}; difference 20.9{\percnt}, 95{\percnt}CI 1.8 - 43.4). We found no significant differences in analgesic efficacy. At 60 minutes, the mean {\percnt}SPID in the IVP and SI arms was 39.9{\percnt} and 33.5{\percnt}, respectively, with a difference of 6.5{\percnt} (95{\percnt}CI {\hyphen}5.8 - 18.7).
CONCLUSION: Most patients who are administered LDK experience a psychoperceptual side effect regardless of administration via SI or IVP. However, patients receiving LDK as a SI reported significantly fewer moderate or greater psychoperceptual side effects and hallucinations with equivalent analgesia. This article is protected by copyright. All rights reserved.

PMID: 29645317 [PubMed - as supplied by publisher]

[Pharmacological treatment of osteoarthritis-related pain].

Schmerz. 2018 Apr 11;:

Authors: Nees TA, Schiltenwolf M

Abstract
Joint pain due to osteoarthritis (OA) is often severe and disabling and affects a large proportion of the aging population impairing daily living and quality of life. Numerous pharmacological treatment approaches are available. Including major OA guidelines this review presents the current evidence of pharmacological therapies in OA-related pain and covers topical, oral and intraarticular treatment approaches. In patients with mild OA topical nonsteroidal antiinflammatory drugs (NSAIDs) can be recommended. Topical capsaicin can be used when other treatments are ineffective or contraindicated. In patients with moderate to severe OA oral NSAIDs are suggested at the lowest effective dose for the shortest possible duration to control symptoms. Importantly, drug-related side effects and gastrointestinal, cardiovascular and renal comorbidities need to be taken into account. In patients with multiple-joint OA and high risk of NSAID-induced adverse events duloxetine can be considered. The evidence of metamizole, symptomatic slow-acting drugs in osteoarthritis and other nutritional supplements in the treatment of OA pain is uncertain and the use of opioids is not routinely recommended. In patients suffering from severe OA-related pain intraarticular injections with glucocorticoids can be suggested to achieve short-term pain relief. Evidence for interventional approaches using hyaluronic acid or platelet-rich plasma is uncertain. Yet, the efficacy of pharmacological therapies in OA-related pain is often inconsistent and severe adverse events might occur. Thus, critical use of the different treatment options considering patient-related comorbidities and nonpharmacological therapies is of major importance.

PMID: 29644468 [PubMed - as supplied by publisher]

Beneficial Effects of Bioactive Compounds in Mulberry Fruits against Cisplatin-Induced Nephrotoxicity.

Int J Mol Sci. 2018 Apr 09;19(4):

Authors: Lee D, Yu JS, Lee SR, Hwang GS, Kang KS, Park JG, Kim HY, Kim KH, Yamabe N

Abstract
Mulberry, the fruit of white mulberry tree (Morus alba L., Moraceae), is commonly used in traditional Chinese medicines as a sedative, tonic, laxative, and emetic. In our continuing research of the bioactive metabolites from mulberry, chemical analysis of the fruits led to the isolation of five compounds, 1-5. The compounds were identified as butyl pyroglutamate (1), quercetin 3-O-β-d-glucoside (2), kaempferol 3-O-β-d-rutinoside (3), rutin (4), and 2-phenylethyl d-rutinoside (5) by spectroscopic data analysis, comparing their nuclear magnetic resonance (NMR) data with those in published literature, and liquid chromatography-mass spectrometry analysis. The isolated compounds 1-5 were evaluated for their effects on anticancer drug-induced side effects by cell-based assays. Compound 1 exerted the highest protective effect against cisplatin-induced kidney cell damage. This effect was found to be mediated through the attenuation of phosphorylation of c-Jun N-terminal kinase, extracellular signal-regulated kinase, p38, mitogen-activated protein kinase, and caspase-3 in cisplatin-induced kidney cell damage.

PMID: 29642519 [PubMed - in process]

Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury.

Arch Toxicol. 2017 Aug;91(8):2849-2863

Authors: Proctor WR, Foster AJ, Vogt J, Summers C, Middleton B, Pilling MA, Shienson D, Kijanska M, Ströbel S, Kelm JM, Morgan P, Messner S, Williams D

Abstract
Drug-induced liver injury (DILI) continues to be a major source of clinical attrition, precautionary warnings, and post-market withdrawal of drugs. Accordingly, there is a need for more predictive tools to assess hepatotoxicity risk in drug discovery. Three-dimensional (3D) spheroid hepatic cultures have emerged as promising tools to assess mechanisms of hepatotoxicity, as they demonstrate enhanced liver phenotype, metabolic activity, and stability in culture not attainable with conventional two-dimensional hepatic models. Increased sensitivity of these models to drug-induced cytotoxicity has been demonstrated with relatively small panels of hepatotoxicants. However, a comprehensive evaluation of these models is lacking. Here, the predictive value of 3D human liver microtissues (hLiMT) to identify known hepatotoxicants using a panel of 110 drugs with and without clinical DILI has been assessed in comparison to plated two-dimensional primary human hepatocytes (PHH). Compounds were treated long-term (14 days) in hLiMT and acutely (2 days) in PHH to assess drug-induced cytotoxicity over an 8-point concentration range to generate IC50 values. Regardless of comparing IC50 values or exposure-corrected margin of safety values, hLiMT demonstrated increased sensitivity in identifying known hepatotoxicants than PHH, while specificity was consistent across both assays. In addition, hLiMT out performed PHH in correctly classifying hepatotoxicants from different pharmacological classes of molecules. The hLiMT demonstrated sufficient capability to warrant exploratory liver injury biomarker investigation (miR-122, HMGB1, α-GST) in the cell-culture media. Taken together, this study represents the most comprehensive evaluation of 3D spheroid hepatic cultures up to now and supports their utility for hepatotoxicity risk assessment in drug discovery.

PMID: 28612260 [PubMed - indexed for MEDLINE]

Editorial.

Rev Med Brux. 2016;37(6):459

Authors: Berghmans T

PMID: 28525172 [PubMed - indexed for MEDLINE]

Treatment of giant-cell arteritis, a literature review.

Mod Rheumatol. 2017 Sep;27(5):747-754

Authors: Watelet B, Samson M, de Boysson H, Bienvenu B

Abstract
Giant-cell arteritis (GCA) is the most common vasculitis in people aged more than 50 years. Despite the frequency of this disease, there is currently no international consensus on its therapeutic modalities. The aim of this study was to conduct a review on an international literature about the treatment of GCA, whatever the clinical pattern might be. Oral corticosteroids remain the cornerstone treatment, possibly preceded by intravenous bolus in complicated forms. In cases of glucocorticoid (GC) dependence or GC-related side effects, a GC-sparing agent may be necessary. Methotrexate is one of the most used treatments despite its low level of evidence and mild efficacy. Cyclophosphamide and tocilizumab look promising but require validation in further studies. The results for TNF-α blockers and azathioprine are disappointing. Preventing complications of prolonged corticosteroid therapy is a world challenge and the management of GC-induced osteoporosis is not the same from one country to another. There is a significant risk of arterial thrombosis, mainly at treatment onset, which may encourage to associate an antiplatelet therapy, especially in patients with other cardiovascular risk factors. Place of statins in the treatment of the disease is uncertain.

PMID: 27919193 [PubMed - indexed for MEDLINE]

11 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 2018/04/11

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.

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 2018/04/10

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.

11 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 2018/04/10

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.

DPD functional tests in plasma, fresh saliva and dried saliva samples as predictors of 5-fluorouracil exposure and occurrence of drug-related severe toxicity.

Clin Biochem. 2018 Apr 03;:

Authors: Neto OV, Raymundo S, Franzoi MA, do Carmo Artmann A, Tegner M, Müller VV, Hahn RZ, Alves GV, Schwartsmann G, Linden R, Antunes MV

Abstract
OBJECTIVE: to evaluate plasma and salivary uracil (U) to dihydrouracil (UH2) ratios as tools for predicting 5-fluorouracil systemic exposure and drug-related severe toxicity, and clinically validate the use of dried saliva spots (DSS) as an alternative sampling strategy for dihydropyrimidine dehydrogenase (DPD) deficiency assessment.
METHODS: Pre-chemotherapy plasma, fresh saliva and DSS samples were obtained from gastrointestinal patients (N = 40) for measurement of endogenous U and UH2 concentrations by LC-MS/MS. A second plasma sample collected during 5FU infusion was used for 5FU area under the curve (AUC) determination by HPLC-DAD. Data on toxicity was reported according to CTCAE.
RESULTS: 15% of the patients developed severe 5FU-related toxicity, with neutropenia accounting for 67% of the cases. U, UH2 and [UH2,]/[U] were highly correlated between fresh and dried saliva samples (rs = 0.960; rs = 0.828; rs = 0.910, respectively). 5FU AUC ranged from 11.3 to 37.31 mg h L-1, with 46.2% of under-dosed and 10.3% over-dosed patients. The [UH2]/[U] ratios in plasma, fresh saliva and dried saliva samples were moderately correlated with 5FU AUC and adverse events grade, indicating a partial contribution of the variables to drug exposure (r = -0.412, rs = -0.373, rs = 0.377) and toxicity (r = -0.363, rs = -0.523, rs = 0.542). Metabolic ratios were lower in patients with severe toxicity (P < .01 salivary ratios, and P < .5 plasma ratios), and 5FU AUC were in average 47% higher in this group than in moderate toxicity. The diagnostic performance of [UH2]/[U] ratios in fresh saliva and DSS for the identification of patients with severe toxicity were comparable.
CONCLUSIONS: The [UH2]/[U] metabolic ratios in plasma, fresh saliva and DSS were significantly associated with 5FU systemic exposure and toxicity degree. This study also demonstrated the applicability of DSS as alternative sampling for evaluating DPD activity.

PMID: 29625079 [PubMed - as supplied by publisher]

Trabectedin plus pegylated liposomal doxorubicin (PLD) for patients with platinum-sensitive recurrent ovarian cancer: a prospective, observational, multicenter study.

J Cancer Res Clin Oncol. 2018 Apr 06;:

Authors: Runnebaum IB, Reichert D, Ringsdorf U, Kuther M, Hesse T, Sehouli J, Wimberger P

Abstract
PURPOSE: The OVA-YOND study is the first prospective, non-interventional trial designed to evaluate trabectedin (1.1 mg/m2) plus PLD (30 mg/m2) in patients with platinum-sensitive recurrent ovarian cancer (ROC), given according to the marketing authorization in real-life clinical practice across Germany.
METHODS: Eligible patients were adults with platinum-sensitive ROC, pretreated with ≥ 1 platinum-containing regimen/s. The primary endpoint was to assess safety/tolerability of the combination.
RESULTS: Seventy-seven patients with platinum-sensitive relapse from 31 sites were evaluated. Patients received a median of 6 cycles (range 1-21) with 39 patients (50.6%) receiving ≥ 6 cycles. Median treatment duration was 4.2 months (range 0.7-18.8), mostly on an outpatient basis (88.3% of patients). Most common grade 3/4 trabectedin-related adverse events (AEs) were leukopenia (18.2%), neutropenia (15.6%), thrombocytopenia (9.1%), alanine (7.8%) and aspartate aminotransferase (6.5%) increase, and nausea/vomiting (5.2% each). Neutropenia (18.2%), leukopenia (15.6%), thrombocytopenia (10.4%), and nausea/vomiting (5.2% each) were the most frequent grade 3/4 PLD-related AEs. No deaths attributed to drug-related AEs or unexpected AEs occurred. Five patients (6.5%) had a complete response and 19 patients (24.7%) achieved a partial response for an objective response rate of 31.2% with median response duration of 6.25 months. Sixteen patients (20.8%) had disease stabilization for a disease control rate of 51.9%. Median progression-free survival was 6.3 months and median overall survival was 16.4 months.
CONCLUSION: Trabectedin plus PLD confer clinically meaningful benefit to pre-treated patients with platinum-sensitive ROC, being comparable to those previously observed in selected populations from clinical trials and with a manageable safety profile.

PMID: 29623421 [PubMed - as supplied by publisher]