[Medicaments and oral healthcare 4. Pharmacotherapy in (frail and care dependent) older people].

Ned Tijdschr Tandheelkd. 2017 May;124(5):265-270

Authors: de Baat C, van der Putten GJ, Visser A, Vissink A

Abstract
Polypharmacy is the consequence of multimorbidity. Both phenomena may cause functional limitations and/or frailty and/or care dependency in older people. In the human body, a medicament undergoes at least 3 important actions: absorption, distribution and elimination. These actions may proceed aberrantly in older people. Following interaction with receptors, a medicament triggers a chain reaction in the human body. The receptors and each link of the chain reaction may be subject to changes due to diseases as well as ageing. This, particularly, is the case with regard to medications directed towards the central nervous system and the cardiovascular system. Furthermore, interactions may occur between various medications mutually and between medications on the one hand and on the other hand food and water intake, self-medication with herbs, and diseases. Moreover, older people usually experience more adverse effects of medications when compared to younger people. This is due to altered body actions and reactions, polypharmacy and the many possible interactions. In older people, utilisation and intake of medications often give rise to problems that can be divided into medicament-related, patient-related, care- and care provider-related and other problems.

PMID: 28501881 [PubMed - indexed for MEDLINE]

Clinical research: Inequality in medicine.

Nature. 2017 10 04;550(7674):S18-S19

Authors: Nowogrodzki A

PMID: 28976953 [PubMed - indexed for MEDLINE]

Integrating natural language processing expertise with patient safety event review committees to improve the analysis of medication events.

Int J Med Inform. 2017 Aug;104:120-125

Authors: Fong A, Harriott N, Walters DM, Foley H, Morrissey R, Ratwani RR

Abstract
OBJECTIVES: Many healthcare providers have implemented patient safety event reporting systems to better understand and improve patient safety. Reviewing and analyzing these reports is often time consuming and resource intensive because of both the quantity of reports and length of free-text descriptions in the reports.
METHODS: Natural language processing (NLP) experts collaborated with clinical experts on a patient safety committee to assist in the identification and analysis of medication related patient safety events. Different NLP algorithmic approaches were developed to identify four types of medication related patient safety events and the models were compared.
RESULTS: Well performing NLP models were generated to categorize medication related events into pharmacy delivery delays, dispensing errors, Pyxis discrepancies, and prescriber errors with receiver operating characteristic areas under the curve of 0.96, 0.87, 0.96, and 0.81 respectively. We also found that modeling the brief without the resolution text generally improved model performance. These models were integrated into a dashboard visualization to support the patient safety committee review process.
CONCLUSIONS: We demonstrate the capabilities of various NLP models and the use of two text inclusion strategies at categorizing medication related patient safety events. The NLP models and visualization could be used to improve the efficiency of patient safety event data review and analysis.

PMID: 28529113 [PubMed - indexed for MEDLINE]

Efficacy and safety of weekly intravenous nanoparticle albumin-bound paclitaxel for non-small cell lung cancer patients who have failed at least two prior systemic treatments.

Thorac Cancer. 2017 May;8(3):138-146

Authors: Duan J, Hao Y, Wan R, Yu S, Bai H, An T, Zhao J, Wang Z, Zhuo M, Wang J

Abstract
BACKGROUND: The study was conducted to evaluate the efficacy and safety of weekly intravenous nanoparticle albumin-bound paclitaxel (NAB-paclitaxel) treatment in patients with advanced non-small-cell lung cancer (NSCLC) who have undergone multi-line therapy, and to investigate the association of secreted protein acidic and rich in cysteine (SPARC) expression status with clinical outcome.
METHODS: Sixty-four patients who received NAB-paclitaxel treatment (130 mg/m2 on days 1 and 8 of a 21 day cycle) as third line or further systemic treatment from 1 May 2011 to 30 June 2014 were included in this retrospective analysis. Tumor tissue was available in 28 patients for analysis of SPARC expression by immunohistochemistry.
RESULTS: Sixty-two patients had response evaluation and complete survival follow-up data; 83.9% received the weekly NAB-paclitaxel as fourth-line treatment or beyond. The objective response and disease control rates (n = 62) were 16.1% (10/62) and 64.5% (40/62), respectively. The median progression-free and overall survival rates were 3.7 (95% confidence interval 2.6-4.8) and 9.8 months (95% confidence interval 6.9-12.8), respectively. Previous treatment with taxane did not affect the response to NAB-paclitaxel. The main grade 3-4 toxicities experienced were neutropenia (9.4%) and leukopenia (7.8%). Patients with SPARC expression in tumor stroma but not in cancer cells had poorer progression-free survival compared with those with negative SPARC expression in tumor stroma cells (3.3 vs. 5.0 months, P = 0.036).
CONCLUSION: Weekly NAB-paclitaxel might be effective for heavily pretreated NSCLC patients. SPARC expression in tumor stroma cells might be a potential negative predictor of NAB-paclitaxel.

PMID: 28304139 [PubMed - indexed for MEDLINE]

Comparing the adverse effects of platinum in combination with etoposide or irinotecan in previously untreated small-cell lung cancer patients with extensive disease: A network meta-analyses.

Thorac Cancer. 2017 May;8(3):170-180

Authors: Chen Y, Chen L, Zhong D

Abstract
BACKGROUND: The safety of front-line chemotherapies for the treatment of extensive stage small-cell lung cancer (ED-SCLC) is uncertain. We carried out a network meta-analysis to compare the toxicity of different therapies for ED-SCLC.
METHODS: We searched EMBASE, PubMed, CENTRAL and clinicaltrials.gov. We performed network meta-analysis on hematological (anemia, leukopenia, neutropenia, and thrombocytopenia) and non-hematological toxicities (diarrhea, infection, and nausea and vomiting).
RESULTS: Nine studies with 2317 patients were included. Etoposide with carboplatin (EC) was associated with a higher incidence of anemia (odds ratio [OR] 2.02, 95% confidence interval [CI] 1.13-3.63), leukopenia (OR 2.67, 95% CI 1.25-5.72), neutropenia (OR 12.08, 95% CI 2.13-68.66), and thrombocytopenia (OR 2.73, 95% CI 1.27-5.85) compared with irinotecan with carboplatin (IC). Similarly, etoposide with cisplatin (EP) was associated with a higher incidence of anemia (OR 1.70, 95% CI 1.13-2.56), leukopenia (OR 2.65, 95% CI 1.34-5.28), neutropenia (OR 5.70, 95% CI 2.93-11.10), and thrombocytopenia (OR 3.26, 95% CI 1.66-6.38) compared with irinotecan with cisplatin (IP). EC was associated with a lower incidence of diarrhea (OR 0.26, 95% CI 0.10-0.68) compared with IC, and EP was associated with a lower incidence of diarrhea (OR 0.09, 95% CI 0.03-0.25) and nausea and vomiting (OR 0.53, 95% CI 0.33-0.84) than IP.
CONCLUSIONS: Hematological toxicities were most common in EC-treated patients, while the lowest incidence occurred with IP treatment. The IP regimen was associated with the highest incidence of toxicities of the digestive tract, while the lowest incidence occurred with EC treatment.

PMID: 28263036 [PubMed - indexed for MEDLINE]

Randomized Phase II Study of Ramucirumab or Icrucumab in Combination with Capecitabine in Patients with Previously Treated Locally Advanced or Metastatic Breast Cancer.

Oncologist. 2017 03;22(3):245-254

Authors: Vahdat LT, Layman R, Yardley DA, Gradishar W, Salkeni MA, Joy AA, Garcia AA, Ward P, Khatcheressian J, Sparano J, Rodriguez G, Tang S, Gao L, Dalal RP, Kauh J, Miller K

Abstract
BACKGROUND: Icrucumab (ICR) and ramucirumab (RAM) bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. This open-label, randomized phase II study evaluated their efficacy and safety in combination with capecitabine (CAP) in patients with previously treated unresectable, locally advanced or metastatic breast cancer.
METHODS: Patients were randomly assigned (1:1:1) to receive CAP (1,000 mg/m2 orally twice daily, days 1-14) alone or in combination with RAM (10 mg/kg intravenously [IV], days 1 and 8) (RAM + CAP) or ICR (12 mg/kg IV, days 1 and 8) (ICR + CAP) every 21 days. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), tumor response, safety, and pharmacokinetics.
RESULTS: Of 153 patients randomized, 150 received treatment. Median PFS (95% confidence interval) was 22.1 (12.1-36.1) weeks on RAM + CAP, 7.3 (6.3-13.0) weeks on ICR + CAP, and 19.0 (12.1-24.3) weeks on CAP (hazard ratios [HRs]: 0.691, p = .1315, RAM + CAP versus CAP; 1.480, p = .0851, ICR + CAP versus CAP). Median OS was 67.4 weeks on RAM + CAP, 62.1 weeks on ICR + CAP, and 71.6 weeks on CAP (HRs: 1.833, p = .0283, RAM + CAP versus CAP; 1.468, p = .1550, ICR + CAP versus CAP). There was no statistically significant difference in PFS or OS between either combination arm and CAP. Treatment-related adverse events more frequent (by ≥10%) on RAM + CAP than on CAP were constipation, decreased appetite, headache, epistaxis, and hypertension. Those more frequent (by ≥10%) on ICR + CAP than CAP were anemia, increased lacrimation, periorbital edema, nausea, vomiting, peripheral edema, facial edema, dehydration, and dyspnea.
CONCLUSION: Combining RAM or ICR with CAP did not improve PFS in the targeted study population. The Oncologist 2017;22:245-254 IMPLICATIONS FOR PRACTICE: Icrucumab and ramucirumab are recombinant human IgG1 monoclonal antibodies that bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. VEGFR-1 activation on endothelial and tumor cell surfaces increases tumor vascularization and growth and supports tumor growth via multiple mechanisms, including contributions to angiogenesis and direct promotion of cancer cell proliferation. Strong preclinical and clinical evidence suggests key roles for VEGF and angiogenesis in breast cancer growth, invasion, and metastasis. This randomized phase II study evaluated the efficacy and safety of each antibody in combination with capecitabine in patients with previously treated unresectable, locally advanced or metastatic breast cancer.

PMID: 28220020 [PubMed - indexed for MEDLINE]

Efficacy and Safety of FOLFIRI Regimen in Elderly Versus Nonelderly Patients with Metastatic Colorectal or Gastric Cancer.

Oncologist. 2017 Mar;22(3):293-303

Authors: Kim JW, Lee KW, Kim KP, Lee JH, Hong YS, Kim JE, Kim SY, Park SR, Nam BH, Cho SH, Chung IJ, Park YS, Oh HS, Lee MA, Kang HJ, Park YI, Song EK, Han HS, Lee KT, Shin DB, Kang JH, Zang DY, Kim JH, Kim TW

Abstract
BACKGROUND: Irinotecan-based chemotherapy is a standard backbone of therapy in patients with metastatic colorectal cancer (CRC) or gastric cancer (GC). However, there is still a paucity of information concerning the efficacy and safety of irinotecan-based regimens in elderly patients.
PATIENTS AND METHODS: Using the patient cohort (n = 1,545) from the UGT1A1 genotype study, we compared the efficacy and safety between elderly and nonelderly patients with metastatic CRC (n = 934) or GC (n = 611) who received first- or second-line FOLFIRI (irinotecan, leucovorin, and 5-fluorouracil) chemotherapy.
RESULTS: Despite lower relative dose intensity in elderly patients, progression-free survival and overall survival were similar between elderly (age ≥70 years) and nonelderly (<70 years) patients in the CRC cohort (hazard ratio [HR], 1.117; 95% confidence interval [CI], 0.927-1.345; p = .244, and HR, 0.989; 95% CI, 0.774-1.264; p = .931, respectively) and the GC cohort (HR, 1.093; 95% CI, 0.854-1.400; p = .479, and HR, 1.188; 95% CI, 0.891-1.585; p = .241, respectively). In both cohorts, febrile neutropenia (22.1% vs. 14.6% in CRC cohort and 35.2% vs. 22.5% in GC cohort) and asthenia (grade 3: 8.4% vs. 1.7% in CRC cohort and 5.5% vs. 2.9% in GC cohort) were more frequent in elderly patients. In the CRC cohort, mucositis and anorexia were more frequent in elderly patients. In the GC cohort, nausea and vomiting were less frequent in elderly patients.
CONCLUSION: The efficacy of the FOLFIRI regimen was similar between elderly and nonelderly patients in both the CRC and the GC cohorts. However, special attention should be paid to elderly patients because of increased risk for febrile neutropenia and asthenia. The Oncologist 2017;22:293-303 IMPLICATIONS FOR PRACTICE: The efficacy of FOLFIRI (irinotecan, leucovorin, and 5-fluorouracil) chemotherapy in elderly patients with metastatic colorectal cancer or gastric cancer was similar to that in nonelderly patients. However, special attention should be paid to elderly patients because of the increased risk for febrile neutropenia and asthenia. These data suggest that the FOLFIRI regimen could be considered as a standard backbone of therapy in elderly patients with metastatic colorectal cancer or gastric cancer and that the clinical decision between doublet and singlet chemotherapy may not be based solely on age. However, the data require further assessment of frailty and performance status.

PMID: 28209749 [PubMed - indexed for MEDLINE]

OntoADR a semantic resource describing adverse drug reactions to support searching, coding, and information retrieval.

J Biomed Inform. 2016 Oct;63:100-107

Authors: Souvignet J, Declerck G, Asfari H, Jaulent MC, Bousquet C

Abstract
INTRODUCTION: Efficient searching and coding in databases that use terminological resources requires that they support efficient data retrieval. The Medical Dictionary for Regulatory Activities (MedDRA) is a reference terminology for several countries and organizations to code adverse drug reactions (ADRs) for pharmacovigilance. Ontologies that are available in the medical domain provide several advantages such as reasoning to improve data retrieval. The field of pharmacovigilance does not yet benefit from a fully operational ontology to formally represent the MedDRA terms. Our objective was to build a semantic resource based on formal description logic to improve MedDRA term retrieval and aid the generation of on-demand custom groupings by appropriately and efficiently selecting terms: OntoADR.
METHODS: The method consists of the following steps: (1) mapping between MedDRA terms and SNOMED-CT, (2) generation of semantic definitions using semi-automatic methods, (3) storage of the resource and (4) manual curation by pharmacovigilance experts.
RESULTS: We built a semantic resource for ADRs enabling a new type of semantics-based term search. OntoADR adds new search capabilities relative to previous approaches, overcoming the usual limitations of computation using lightweight description logic, such as the intractability of unions or negation queries, bringing it closer to user needs. Our automated approach for defining MedDRA terms enabled the association of at least one defining relationship with 67% of preferred terms. The curation work performed on our sample showed an error level of 14% for this automated approach. We tested OntoADR in practice, which allowed us to build custom groupings for several medical topics of interest.
DISCUSSION: The methods we describe in this article could be adapted and extended to other terminologies which do not benefit from a formal semantic representation, thus enabling better data retrieval performance. Our custom groupings of MedDRA terms were used while performing signal detection, which suggests that the graphical user interface we are currently implementing to process OntoADR could be usefully integrated into specialized pharmacovigilance software that rely on MedDRA.

PMID: 27369567 [PubMed - indexed for MEDLINE]

Differences in reproductive toxicology between alopecia drugs: an analysis on adverse events among female and male cases.

Oncotarget. 2016 Dec 13;7(50):82074-82084

Authors: Wu M, Yu Q, Li Q

Abstract
Alopecia is a dermatological condition with limited therapeutic options. Only two drugs, finasteride and minoxidil, are approved by FDA for alopecia treatment. However, little is known about the differences in adverse effects between these two drugs. We examined the clinical reports submitted to the FDA Adverse Event Reporting System (FAERS) from 2004 to 2014. For both female and males, finasteride was found to be more associated with reproductive toxicity as compared to minoxidil. Among male alopecia cases, finasteride was significantly more concurrent with several forms of sexual dysfunction. Among female alopecia cases, finasteride was significantly more concurrent with harm to fetus and disorder of uterus. In addition, drug-gene network analysis indicated that finasteride could profoundly disturb pathways related to sex hormone signaling and oocyte maturation. These findings could provide clues for subsequent toxicological research. Taken together, this analysis suggested that finasteride could be more liable to various reproductive adverse effects. Some of these adverse effects have yet to be warned in FDA-approved drug label. This information can help improve the treatment regimen of alopecia and post-marketing regulation of drug products.

PMID: 27738338 [PubMed - indexed for MEDLINE]

Safety and tolerability of intravenous regadenoson in healthy subjects: A randomized, repeat-dose, placebo-controlled study.

J Nucl Cardiol. 2017 Feb;24(1):57-65

Authors: Townsend R, Desai A, Rammelsberg D, Kowalski D, Simmons N, Kitt TM

Abstract
BACKGROUND: Regadenoson is a selective A2A adenosine receptor agonist indicated for radionuclide myocardial perfusion imaging in patients unable to undergo adequate exercise stress. However, the safety, tolerability, and plasma concentrations associated with repeated doses have not previously been assessed.
METHOD AND RESULTS: Healthy males and females were randomized to receive intravenous regadenoson [100 μg (3 doses), 200 μg (3 doses), or 400 μg (2 doses)], or placebo (2 or 3 doses; 0.9% sodium chloride); all doses 10 minutes apart. The primary endpoint was vital sign measurements (blood pressure and heart rate). Secondary endpoints included 12-lead electrocardiogram measurements, clinical laboratory evaluations (hematology, chemistry, and urinalysis), and adverse events. Thirty-six subjects were randomized and completed the study. Plasma concentrations of regadenoson increased in a dose-related manner and with successive doses. No consistent effect was observed for systolic blood pressure, although diastolic blood pressure was slightly lower than placebo for all regadenoson groups. Transient, dose-dependent increases in heart rate were observed in all regadenoson groups. There were no serious adverse events; 27 adverse events occurred in 14 regadenoson-treated subjects vs two events in two placebo-treated subjects.
CONCLUSION: Repeated doses of regadenoson appeared to be safe and well tolerated in healthy subjects.

PMID: 26607361 [PubMed - indexed for MEDLINE]

Preventable ADRs leading to hospitalization - results of a long-term prospective safety study with 6,427 ADR cases focusing on elderly patients.

Expert Opin Drug Saf. 2018 Feb;17(2):125-137

Authors: Schmiedl S, Rottenkolber M, Szymanski J, Drewelow B, Siegmund W, Hippius M, Farker K, Guenther IR, Hasford J, Thuermann PA, German Net of Regional Pharmacovigilance Centers (NRPC)

Abstract
BACKGROUND: Studies evaluating the impact of age and potentially inappropriate medication (PIM) on avoidable adverse drug reactions (ADRs) are scarce.
METHODS: In this prospective, multi-center, long-term (8.5 years) observational study, we analysed ADRs leading to hospitalization in departments of internal medicine. ADRs causality and preventability were assessed using standardised algorithms. PIM was defined based on the PRISCUS-list. Multivariate analyses and estimation of ADR incidence rates were conducted.
RESULTS: Of all 6,427 ADR patients, a preventable ADR was present in 1,253 (19.5%) patients (elderly patients ≥70 years: 828). Risk factors for preventable ADRs in elderly patients were multimorbidity, two to four ADR-causative drugs, and intake of particular compounds (e.g. spironolactone) but not sex, PIM usage, or the total number of drugs. Regarding particular compounds associated with preventable ADRs, highest incidence rates for preventable ADRs were found for patients aged ≥70 years for spironolactone (3.3 per 1,000 exposed persons (95% CI: 1.4-6.6)) and intermediate-acting insulin (3.3 per 1,000 exposed persons (95% CI: 1.6-6.1)).
CONCLUSION: Avoiding PIM usage seems to be of limited value in increasing safety in elderly patients whereas our results underline the importance of an individualized medication review of the most commonly implicated drugs in preventable ADRs (supported by BfArM FoNr: V-11337/68605/2008-2010).

PMID: 29258401 [PubMed - indexed for MEDLINE]

New and incremental FDA black box warnings from 2008 to 2015.

Expert Opin Drug Saf. 2018 Feb;17(2):117-123

Authors: Solotke MT, Dhruva SS, Downing NS, Shah ND, Ross JS

Abstract
BACKGROUND: The boxed warning (also known as 'black box warning [BBW]') is one of the strongest drug safety actions that the U.S. Food & Drug Administration (FDA) can implement, and often warns of serious risks. The objective of this study was to comprehensively characterize BBWs issued for drugs after FDA approval.
METHODS: We identified all post-marketing BBWs from January 2008 through June 2015 listed on FDA's MedWatch and Drug Safety Communications websites. We used each drug's prescribing information to classify its BBW as new, major update to a preexisting BBW, or minor update. We then characterized these BBWs with respect to pre-specified BBW-specific and drug-specific features.
RESULTS: There were 111 BBWs issued to drugs on the US market, of which 29% (n = 32) were new BBWs, 32% (n = 35) were major updates, and 40% (n = 44) were minor updates. New BBWs and major updates were most commonly issued for death (51%) and cardiovascular risk (27%). The new BBWs and major updates impacted 200 drug formulations over the study period, of which 64% were expected to be used chronically and 58% had available alternatives without a BBW.
CONCLUSIONS: New BBWs and incremental updates to existing BBWs are frequently added to drug labels after regulatory approval.

PMID: 29215916 [PubMed - indexed for MEDLINE]

First experiences with a tool to measure the level of clinical information present in adverse drug reaction reports.

Expert Opin Drug Saf. 2018 Feb;17(2):111-115

Authors: Oosterhuis I, Rolfes L, Ekhart C, Muller-Hansma A, Härmark L

Abstract
BACKGROUND: To make a proper causality assessment of an adverse drug reaction (ADR) report, a certain level of clinical information is necessary. A tool was developed to measure the level of clinical information present in ADR reports. The aim of this study was to test the validity and reliability of the clinical documentation tool (ClinDoc) in an international setting.
METHODS: The tool was developed by a panel of pharmacovigilance experts. It includes four domains: ADR, chronology of the ADR, suspected drug and patient characteristics. The final score categorizes reports into: excellent, well, moderately or poorly documented. In two rounds, eight pharmacovigilance assessors of different countries made a total of 224 assessments using the tool, with the expert panels judgement as a standard. Sensitivity and specificity were calculated.
RESULTS: The tool with four outcome-categories demonstrated low sensitivity. A lack of distinctiveness was demonstrated between the categories moderate and well. Results for the second round were re-analysed using three categories. This demonstrated a better validity.
CONCLUSION: This is the first tool to give insight in the level of relevant clinical information present in ADR reports. It can be used internationally to compare reports coming from different reporting methods and different types of reporters in pharmacovigilance.

PMID: 29157026 [PubMed - indexed for MEDLINE]

Immunotherapeutic strategies in non-small-cell lung cancer: the present and the future.

Immunotherapy. 2017 05;9(6):507-520

Authors: Steendam CM, Dammeijer F, Aerts JGJV, Cornelissen R

Abstract
Non-small cell lung cancer (NSCLC) is still the leading cause of cancer death worldwide, with a poor prognosis. In the era of immunotherapies, the field is rapidly changing, and the clinician needs to be aware of the current state and future perspectives of immunotherapeutic strategies. In this review, we discuss the current status of immune checkpoint inhibitors, cancer vaccines and cellular therapies specifically in NSCLC. Last but not least, we will discuss rational combination strategies that are promising for the near future.

PMID: 28472903 [PubMed - indexed for MEDLINE]

Risk Factors for Adverse Drug Reactions in Older Subjects Hospitalized in a Dedicated Dementia Unit.

Am J Geriatr Psychiatry. 2017 Mar;25(3):290-296

Authors: Kanagaratnam L, Dramé M, Novella JL, Trenque T, Joachim C, Nazeyrollas P, Jolly D, Mahmoudi R

Abstract
OBJECTIVE: To identify risk factors for the occurrence of adverse drug reactions (ADRs) based on geriatric evaluation.
DESIGN: Longitudinal prospective study from May 2010 to November 2011.
SETTING: Dedicated acute geriatric care unit specializing in the management of patients with dementia syndrome (Alzheimer disease or related syndromes) at the University Hospital of Reims, France.
PARTICIPANTS: Older patients with dementia syndrome (Alzheimer disease or related syndromes).
MEASUREMENTS: Sociodemographic variables and comprehensive geriatric assessment were recorded. Occurrence of ADRs was noted. Risk factors for ADR were identified by multivariate logistic regression.
RESULTS: During the study period, 293 patients were included; average age was 82 ± 8 years; the majority were women (61.4%). Average Mini-Mental State Examination score was 13 ± 8; average activities of daily living (ADL) score was 3.6 ± 2.1. Independent risk factors for occurrence of at least one ADR were polypharmacy (≥5 drugs/day) (OR: 4.0, 95% CI: 1.1-14.1) and dependence on at least 1 ADL (OR: 2.6, 95% CI: 1.1-6.5).
CONCLUSIONS: Risk factors for ADRs were polypharmacy and dependence on at least one ADL. Our findings underline the importance of taking into consideration the characteristics of the patients when prescribing drugs in this specific population. Prescriptions should be re-evaluated at each follow-up.

PMID: 27742527 [PubMed - indexed for MEDLINE]

Imatinib and polypharmacy in very old patients with chronic myeloid leukemia: effects on response rate, toxicity and outcome.

Oncotarget. 2016 Nov 29;7(48):80083-80090

Authors: Iurlo A, Nobili A, Latagliata R, Bucelli C, Castagnetti F, Breccia M, Abruzzese E, Cattaneo D, Fava C, Ferrero D, Gozzini A, Bonifacio M, Tiribelli M, Pregno P, Stagno F, Vigneri P, Annunziata M, Cavazzini F, Binotto G, Mansueto G, Russo S, Falzetti F, Montefusco E, Gugliotta G, Storti S, D'Addosio AM, Scaffidi L, Cortesi L, Cedrone M, Rossi AR, Avanzini P, Mauro E, Spadea A, Celesti F, Giglio G, Isidori A, Crugnola M, Calistri E, Sorà F, Rege-Cambrin G, Sica S, Luciano L, Galimberti S, Orlandi EM, Bocchia M, Tettamanti M, Alimena G, Saglio G, Rosti G, Mannucci PM, Cortelezzi A

Abstract
BACKGROUND: About 40% of all patients with chronic myeloid leukemia are currently old or very old. They are effectively treated with imatinib, even though underrepresented in clinical studies. Furthermore, as it happens in the general population, they often receive multiple drugs for associated chronic illnesses. Aim of this study was to assess whether or not in imatinib-treated patients aged >75 years the exposure to polypharmacy (5 drugs or more) had an impact on cytogenetic and molecular response rates, event-free and overall survival, as well as on hematological or extra-hematological toxicity.
METHODS: 296 patients at 35 Italian hematological institutions were evaluated.
RESULTS: Polypharmacy was reported in 107 patients (36.1%), and drugs more frequently used were antiplatelets, diuretics, proton pump inhibitors, ACE-inhibitors, beta-blockers, calcium channel blockers, angiotensin II receptors blockers, statins, oral hypoglycemic drugs and alpha blockers. Complete cytogenetic response was obtained in 174 patients (58.8%), 78 (26.4%) within 6 month, 63 (21.3%) between 7 and 12 months. Major molecular response was obtained in 153 patients (51.7%), 64 (21.6%) within the 12 month. One hundred and twenty-eight cases (43.2%) of hematological toxicity were recorded, together with 167 cases (56.4%) of extra-hematological toxicity. Comparing patients exposed to polypharmacy to those without, no difference was observed pertaining to the dosage of imatinib, cytogenetic and molecular responses and hematological and extra-hematological toxicity.
CONCLUSION: Notwithstanding the several interactions reported in the literature between imatinib and some of the medications considered herewith, this fact does not seem to have a clinical impact on response rate and outcome.

PMID: 27579540 [PubMed - indexed for MEDLINE]

Asian perspectives on the recognition and management of levodopa 'wearing-off' in Parkinson's disease.

Expert Rev Neurother. 2015;15(11):1285-97

Authors: Bhidayasiri R, Hattori N, Jeon B, Chen RS, Lee MK, Bajwa JA, Mok VC, Zhang B, Syamsudin T, Tan LC, Jamora RD, Pisarnpong A, Poewe W

Abstract
Most Parkinson's disease patients will receive levodopa therapy, and of these, the majority will develop some levodopa-induced complications. For many patients, the first complication to develop is the decline in the duration of therapeutic benefit of each levodopa dose, a phenomenon commonly termed 'wearing-off'. There is already extensive literature documenting the epidemiology and management of wearing-off in Parkinson's disease patients of western descent. However, data derived from these studies might not always apply to patients of Asian descent due to genetic variations, differences in co-morbidities or non-availability of certain drugs. This review summarizes the current literature regarding the epidemiology of wearing-off in Asian (including Arab) patients and discusses the management issues in the context of drug availability in Asia.

PMID: 26390066 [PubMed - indexed for MEDLINE]

Propylthiouracil-induced ANCA-negative cutaneous small vessel vasculitis.

J Community Hosp Intern Med Perspect. 2018;8(1):35-37

Authors: Trusau A, Brit ML

Abstract
Propylthiouracil (PTU) is a commonly used medication for the treatment of hyperthyroidism. PTU is known to cause different adverse reactions including autoimmune syndromes. PTU-induced autoimmune syndromes can be classified into drug-induced lupus or drug-induced vasculitis. Differential diagnoses could be very challenging. PTU-induced vasculitis is more common than PTU-induced lupus, and has a higher risk of morbidity and mortality. Usually it is limited to the skin in a form of cutaneous leukocytoclastic vasculitis, but may also affect organs including kidneys and lungs. Discontinuation of PTU should be a first step in the treatment and could lead to complete resolution of symptoms. Typically, lesions resolve spontaneously within 2-4 weeks, but chronic or recurrent disease may occur in up to 10% of patients. In cases without improvement after drug discontinuation, cases refractory to glucocorticosteroids, with necrotizing skin lesions or extracutaneous organ involvement referral to rheumatologist for more aggressive immunosuppressive treatment is indicated. Optimal duration of immunosuppressive therapy is unknown, but it is reasonable to gradually taper mediations and monitor clinical response. Frequent monitoring for side effects is mandatory for patients on PTU therapy. Treatment should be stopped immediately, if patient develops any of autoimmune syndromes. An accurate and prompt diagnosis is essential, because it determines further management. We report a rare case of antineutrophil cytoplasm antibody-negative cutaneous small vessel vasculitis as a result of longstanding exposure to PTU.

PMID: 29441165 [PubMed]

Know your medicine: A novel student-led community service learning program.

Curr Pharm Teach Learn. 2017 May;9(3):353-359

Authors: Howell CK, Reveles KR, Knodel LC, Pattyn NR, Frei CR

Abstract
INTRODUCTION: The objective of this article is to describe the efforts of the student pharmacist organization called Know Your Medicine (KYM) as they conduct medication therapy management (MTM) for older adults and underserved communities.
METHODS: Patients brought medications, immunization records, and health concerns to KYM events during academic years 2012-2013 and 2013-2014. Student pharmacists performed health screenings, created personalized medication records (PMR), made recommendations, created personal action plans (PAP), and conducted follow-up phone calls.
RESULTS: Student pharmacists provided MTM services for a total of 107 patients. The mean duration of a KYM appointment was 62±21min, and student pharmacists provided a mean of 3.5±2.1 recommendations per patient. Patients had a mean age of 78±11 years, 4.5±3.2 disease states, 6.9±4.6 prescriptions, 1.9±1.9 OTC medications, and 2.8±2.6 vitamins or herbals. At the time of the follow-up phone call, a mean of 2.6±1.9 recommendations per patient had been followed.
DISCUSSION AND CONCLUSIONS: Student pharmacists successfully implemented a new MTM program for older adults and underserved communities. This program can serve as an example of how other pharmacy colleges and schools might implement MTM training and real-world MTM experience for their student pharmacists.

PMID: 29233271 [PubMed - indexed for MEDLINE]

Phase I Dose-Escalation Study of Pilaralisib (SAR245408, XL147) in Combination with Paclitaxel and Carboplatin in Patients with Solid Tumors.

Oncologist. 2017 Apr;22(4):377-e37

Authors: Wheler J, Mutch D, Lager J, Castell C, Liu L, Jiang J, Traynor AM

Abstract
LESSONS LEARNED: Despite involvement of PI3K pathway activation in tumorigenesis of solid tumors, single-agent PI3K inhibitors have shown modest clinical activity.Preclinical evidence suggests that combining PI3K pathway inhibitors and chemotherapy can enhance antitumor effects.In patients with solid tumors, the PI3K inhibitor pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin.Further clinical evaluation is warranted to identify effective combination strategies with PI3K pathway inhibitors.
BACKGROUND: Pilaralisib (SAR245408) is an oral, pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I dose-escalation study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of pilaralisib in capsule and tablet formulations, administered in combination with paclitaxel and carboplatin in patients with advanced solid tumors.
METHODS: A 3 + 3 design was used. Pilaralisib was administered once daily (QD); paclitaxel (up to 175 mg/m2) and carboplatin (up to area under the curve [AUC] of 6) were administered on day 1 of 21-day cycles. An MTD expansion cohort of patients with endometrial carcinoma was included.
RESULTS: Fifty-eight patients were enrolled. Six patients (10.3%) had dose-limiting toxicities, of which only rash (two patients, 3.4%) occurred in more than one patient. The MTD of pilaralisib tablets in combination with paclitaxel and carboplatin was determined to be 200 mg QD. The most frequently reported adverse events (AEs) of any grade were neutropenia (67.2%) and thrombocytopenia (67.2%). PK data showed no interaction between pilaralisib and paclitaxel/carboplatin. Tumor tissue showed moderate inhibition of PI3K and mitogen-activated protein kinase (MAPK) pathways. Seven of 52 evaluable patients had a partial response (PR; 13.5%).
CONCLUSION: Pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin in solid tumors. The Oncologist 2017;22:377-378.

PMID: 28275119 [PubMed - indexed for MEDLINE]