Capsaicin 8% Patch Repeat Treatment in Nondiabetic Peripheral Neuropathic Pain: A 52-Week, Open-Label, Single-Arm, Safety Study.

Clin J Pain. 2017 Oct;33(10):921-931

Authors: Gálvez R, Navez ML, Moyle G, Maihöfner C, Stoker M, Ernault E, Nurmikko TJ, Attal N

Abstract
OBJECTIVES: To investigate the long-term safety and tolerability of capsaicin 8% patch repeat treatment in nondiabetic patients with peripheral neuropathic pain.
METHODS: A prospective, open-label, observational study in patients with postherpetic neuralgia, posttraumatic or postsurgical nerve injury, HIV-associated distal sensory polyneuropathy, or other peripheral neuropathic pain, and average daily pain score ≥4, who received ≤6 capsaicin 8% patch treatments over 52 weeks according to clinical need (retreatment at 9 to 12 wk intervals). Sensory testing and analgesic effectiveness were assessed using "bedside tests" and Brief Pain Inventory (question 5).
RESULTS: Overall, 306 patients received treatment. Treatment-emergent adverse events (TEAEs) and drug-related TEAEs were reported by 252 (82.4%) and 207 (67.6%) patients. Application site pain was the most common drug-related TEAE (n=112, 36.6%); no drug-related serious TEAEs were reported. Sensory category shift analyses from baseline to end of study (EoS) in patients attending at least 2 sensory visits (n=278 for all tests except warm, n=277) found sensory deterioration/loss in at least 1 modality in 50.4% (n=140); deterioration/loss in 1, 2, 3, 4, or 5 modalities occurred in 26.6% (n=74), 14.0% (n=39), 5.8% (n=16), 2.5% (n=7), and 1.4% (n=4) cases. Newly emergent hyperesthesia or allodynia was apparent in 1.1% to 3.6% of the cases (depending on modality) by EoS. Between 25.2% and 32.0% of patients reported improvement in a sensory modality by EoS. Average daily pain was 6.6 and 4.7 at baseline and month 12.
CONCLUSIONS: Generally, capsaicin 8% patch repeat treatment over 52 weeks was well tolerated, with variable alteration in sensory function and minimal chance of complete sensory loss.

PMID: 28872473 [PubMed - in process]

Evaluation of the adverse drug reaction surveillance system Kadoma City, Zimbabwe 2015.

Pan Afr Med J. 2017;27:55

Authors: Muringazuva C, Chirundu D, Mungati M, Shambira G, Gombe N, Bangure D, Juru T, Tshimanga M

Abstract
INTRODUCTION: Medicines have the potential to cause adverse drug reactions and because of this Zimbabwe monitor reactions to medicines through the Adverse Drug Reaction Surveillance System. The Medicines Control Authority of Zimbabwe monitors reactions to medicines through the Adverse Drugs Reactions Surveillance System. The system relies on health professionals to report adverse drug reactions to maximize patient safety. We report results of an evaluation of the Adverse Drugs Reactions Surveillance System in Kadoma District.
METHODS: A descriptive cross-sectional study was conducted using the updated CDC guidelines in six health facilities in Kadoma City. Data were collected using a pretested interviewer administered questionnaire, checklists and records review. Data was analyzed using Epi Info(TM) to calculate frequencies and means. Qualitative data were analyzed manually. Written informed consent was obtained from all study participants.
RESULTS: The surveillance system did not meet up to its objectives as it failed to detect the adverse drug reactions and there was no monitoring of increases in known events. Fewer than half (43%) of the participants were aware of at least 2 objectives of the surveillance system but 83% of health workers willing to participate. However the system was not acceptable, 79% did not perceive the system to be necessary with the majority saying ''why should we fill in the forms when the reactions were already known or minor''. Though the system was supposed to identify potential patient risk factors for particular types of events health workers were reluctant to participate as evidenced by only one form filled out of 20 reactions experienced in the district. The system was simple as the notification form has 16 fields which require easily obtainable information from the patient records.
CONCLUSION: The surveillance system was not useful and was not acceptable to health workers but was simple and stable. Health workers lacked knowledge. Sharing of results with the Medicines Control Authority of Zimbabwe through the Matrons facilitated training of health workers in Kadoma City. Health workers were encouraged to notify any drug reaction and to completely fill in the notification forms. Patients were also encouraged to report any drug reaction to health care workers.

PMID: 28819477 [PubMed - indexed for MEDLINE]

[A prospective multi-center trial of non-interventional and observational study of lenalidomide in Chinese patients with multiple myeloma].

Zhonghua Nei Ke Za Zhi. 2017 Jul 01;56(7):500-506

Authors: Wang GM, Yang GZ, Huang ZX, Zhong YP, Jin FY, Liao AJ, Wang XM, Fu ZZ, Liu H, Li XL, Zhou JF, Zhang X, Hu Y, Meng FY, Huang XJ, Chen WM, Lu J

Abstract
Objective: To evaluate the efficacy and safety of lenalidomide in a real-world clinical practice in Chinese patients with multiple myeloma (MM). Methods: It was a prospective, multi-center, observational study. A total of 165 consecutive patients with MM treated with lenalidomide-based regimens were enrolled in 12 hospitals from June 2013 to November 2015. Relevant information was recorded, such as baseline clinical data, cytogenetic abnormalities, treatment regimens, and duration of treatment, safety, and survival. Results: (1)There were 126 relapsed and refractory MM (RRMM) patients, 25 newly diagnosed patients and 19 maintenance patients. The evaluable RRMM patients accounted for 120 cases, among which 74 cases(61.7%) reached the partial response (PR) or above, and a very good partial response (VGPR) in 16 patients (13.3%), a complete response (CR) in 14 cases (11.7%), a strictly complete response (sCR) in 4 cases (3.3%). Thus, a VGPR or above in 34 patients accounted for 28.3%. (2)The median follow-up was 13 months, the median time to progression 12 months. The median survival after receiving lenalidomide was 19 months, and the median overall survival (OS) was 62 months. (3) The univariate analysis in 120 RRMM patients suggested that prognostic factors for significant improvement in PFS included normal karyotype, international staging system (ISS) Ⅰ-Ⅱ, t(4; 14) negative (detected by fluorescence in situ hybridization), non-bortezomib resistance and response to previous regimens. As to OS, non-bortezomib resistance, response to previous regimens and non-primary refractoriness were positive factors. Multivariate analysis showed that the response to previous regimens (PR or better) was an independent good prognostic factor for progress-free survival(PFS), non-bortezomib resistance and non-primary refractoriness for OS. (4) Grade 3 or 4 adverse events that occurred in more than 10% of all enrolled patients were neutropenia (12.7%), leukocytosis(11.5%) and thrombocytopenia (12.7%). Owing to intolerance of toxic side effects, 7 cases withdrew lenalidomide. Conclusions: No matter what combination, regimens containing lenalidomide are effective to RRMM patients with overall response rate 61.7%, a time to progression 12 months and an overall survival 62 months.The toxicity is quite tolerable and manageable. In addition, the response to previous treatment (reached PR or above) is the independent good prognostic factor for PFS, non-bortezomib resistance and non-primary refractoriness for OS. Clinical trail registration: Clinicaltrials.gov, NCT01947309.

PMID: 28693058 [PubMed - indexed for MEDLINE]

[Adverse reaction caused by rabies vaccine in China: a Meta-analysis].

Zhonghua Liu Xing Bing Xue Za Zhi. 2017 Jun 10;38(6):821-827

Authors: Zhang XR, Wu ZG, Zhang WS

Abstract
Objective: To conduct a Meta-analysis on the rate of adverse reaction related to rabies vaccine, so as to provide reference for rabies vaccine immunization in China. Methods: We electronically searched databases including CNKI, VIP information resource integration service platform, WanFang Data, CBM, PubMed and The Cochrane Library, to collect studies on Chinese people who had received full rabies vaccination and recording all the adverse reactions, from January 2000 to July 2016. Inclusion and exclusion criteria were strictly followed. Meta-analysis for the adverse reaction rate was performed using the R software. Results: A total of 29 related papers had met the inclusion criteria, with no publication bias noticed. A total number of 11 020 cases had adverse reactions, among all the 94 222 respondents, with an incidence of adverse reactions as 1.04%-47.78%. The overall incidence rate of adverse reaction was 9.82% (95%CI: 7.58%-12.72%). A combined local adverse reaction rate appeared as 12.05% (95% CI: 9.26%-15.69%). The systemic adverse reaction rate was 9.06% (95%CI: 7.07%-11.61%). The overall adverse reaction rate on aqueous vaccine was 32.39% (95%CI: 21.88%-47.94%). Combined adverse reaction rate of freeze dried vaccine appeared as 8.65% (95%CI: 4.54%-16.51%). Significant differences were seen between both groups (P<0.05). Conclusions: The local adverse reaction rate caused by rabies vaccination was higher than the systemic adverse reaction rate. The adverse reaction rate of aqueous rabies vaccine was higher than that of freeze dried rabies vaccine. Our results suggested that the aqueous vaccine should gradually be eliminated.

PMID: 28647990 [PubMed - indexed for MEDLINE]

Characterization of Guideline Evidence for Off-label Medication Use in the Intensive Care Unit.

Ann Pharmacother. 2017 Jul;51(7):529-542

Authors: Shoulders BR, Smithburger PL, Tchen S, Buckley M, Lat I, Kane-Gill SL

Abstract
BACKGROUND: Non-Food and Drug Administration (FDA) or off-label medication prescribing occurs commonly in the intensive care unit (ICU). Off-label medication use creates a concern for untoward adverse effects; however, this worry may be alleviated by supportive literature.
OBJECTIVE: To evaluate the evidence behind off-label medication use by determining the presence of guideline support and compare graded recommendations to an online tertiary resource, DRUGDEX.
METHODS: Off-label medication use was identified prospectively over 3 months in medical ICUs in 3 academic medical centers. Literature searches were conducted in PubMed and the national guideline clearinghouse website to determine the presence of guideline support. DRUGDEX was also searched for strength-of-evidence ratings to serve as a comparator.
RESULTS: A total of 287 off-label medication indication searches resulted in 44% (126/287) without identified evidence; 253 guidelines were identified for 56% (161/287) of indications. Of the published guidelines, 89% (226/253) supported the off-label indication. In the DRUGDEX comparison, 67% (97/144) of guideline gradings disagree with DRUGDEX, whereas 33% (47/144) of the gradings matched the online database.
CONCLUSION: Because more than half of off-label medication use has the benefit of supportive guidelines recommendations and a majority of gradings are inconsistent with DRUGDEX, clinicians should consider utilizing guidelines to inform off-label medication use in the ICU. Still, there is a considerable amount of off-label medication use in the ICU that lacks supporting evidence, and use remains concerning because it may lead to inappropriate treatment and adverse events.

PMID: 28622741 [PubMed - indexed for MEDLINE]

[Promoting translational research on drug-induced liver injury].

Zhonghua Gan Zang Bing Za Zhi. 2016 Nov 20;24(11):807-809

Authors: Mao YM

Abstract
Drug-induced liver injury (DILI) is one of the most important drug-induced diseases and an important reason for failure to obtain approval, an increase in warnings, and withdrawal from market. DILI has a complex clinical phenotype and can cause almost all types of acute, subacute, and chronic liver injury, and it may cause liver failure and even death in patients with severe conditions. The diversity of drugs involved and heterogeneity of populations are the main reasons for unpredictability of most DILI cases in clinical practice. Therefore, the prediction, diagnosis, and treatment of DILI become challenging issues in the field of liver disease, and it is of great significance to strengthen clinical translational research in this aspect, so as to transform more achievements into actual diagnostic and treatment methods.

PMID: 27978924 [PubMed - indexed for MEDLINE]

Evaluating the effectiveness of a patient storytelling DVD intervention to encourage physician-patient communication about nonsteroidal anti-inflammatory drug (NSAID) use.

Patient Educ Couns. 2016 Nov;99(11):1837-1844

Authors: Miller MJ, Weech-Maldonado R, Outman RC, Ray MN, Gary LC, Chen L, Cobaugh DJ, Allison JJ, Saag KG

Abstract
OBJECTIVE: To evaluate the effectiveness of a culturally-sensitive, patient storytelling intervention to enhance physician-patient communication about NSAID risk.
METHODS: A group randomized trial of 40 medical practices in Alabama was conducted. Patients within intervention practices received a 13-minute DVD that included patient stories related to their experiences with NSAIDs, adverse effects, and importance of communication with their physicians. The proportion of patients who: (1) spoke with their physician about NSAID risk; and (2) used both prescription and over-the-counter (OTC) NSAIDS were primary outcomes. Generalized estimating equations for panel data were used for analysis.
RESULTS: Intention-to-treat analyses revealed no significant differences between intervention (n=102) and control (n=106) groups for patients speaking with their physician about NSAID risk or concomitant use of prescription/OTC NSAIDs (Odds Ratio [OR]=1.11, p=0.670; OR=0.87, p=0.632, respectively). For 54% of patients who watched the DVD, per-protocol (PP) analyses trended toward increased odds of patients speaking with their physician about prescription NSAID risk compared to the control group [OR=1.37, p=0.354] and lower odds of concomitant prescription/OTC NSAIDs use [OR=0.79, p=0.486].
CONCLUSIONS: A patient storytelling intervention in DVD format alone may not increase patient-physician interaction.
PRACTICE IMPLICATIONS: Strategies that facilitate use of patient educational materials delivered by DVD are needed.

PMID: 27380647 [PubMed - indexed for MEDLINE]

Drug therapy problems and medication discrepancies during care transitions in super-utilizers.

J Am Pharm Assoc (2003). 2016 Nov - Dec;56(6):633-642.e1

Authors: Surbhi S, Munshi KD, Bell PC, Bailey JE

Abstract
OBJECTIVES: First, to investigate the prevalence and types of drug therapy problems and medication discrepancies among super-utilizers, and associated patient characteristics. Second, to examine the outcomes of pharmacist recommendations and estimated cost avoidance through care transitions support focused on medication management.
DESIGN: Retrospective analysis of the pharmacist-led interventions as part of the SafeMed Program.
SETTING: A large nonprofit health care system serving the major medically underserved areas in Memphis, Tennessee.
PARTICIPANTS: Three hundred seventy-four super-utilizing SafeMed participants with multiple chronic conditions and polypharmacy.
INTERVENTION: Comprehensive medication review, medication therapy management, enhanced discharge planning, home visits, telephone follow-up, postdischarge medication reconciliation, and care coordination with physicians.
MAIN OUTCOME MEASURES: Types of drug therapy problems, outcomes of pharmacist recommendations, estimated cost avoided, medication discrepancies, and self-reported medication adherence.
RESULTS: Prevalence of drug therapy problems and postdischarge medication discrepancies was 80.7% and 75.4%, respectively. The most frequently occurring drug therapy problems were enrollee not receiving needed medications (33.4%), underuse of medications (16.9%), and insufficient dose or duration (11.2%). Overall 50.8% of the pharmacist recommendations were accepted by physicians and patients, resulting in an estimated cost avoidance of $293.30 per drug therapy problem identified. Multivariate analysis indicated that participants with a higher number of comorbidities were more likely to have medication discrepancies (odds ratio 1.23 [95% CI 1.05-1.44]). Additional contributors to postdischarge medication discrepancies were difficulty picking up and paying for medications and not being given necessary prescriptions before discharge.
CONCLUSION: Drug therapy problems and medication discrepancies are common in super-utilizers with multiple chronic conditions and polypharmacy during transitions of care, and greater levels of comorbidity magnify risk. Pharmacist-led interventions in the SafeMed Program have demonstrated success in resolving enrollees' medication-related issues, resulting in substantial estimated cost savings. Preliminary evidence suggests that the SafeMed model's focus on medication management has great potential to improve outcomes while reducing costs for vulnerable super-utilizing populations nationwide.

PMID: 27720595 [PubMed - indexed for MEDLINE]

Association of anticholinergic burden with adverse effects in older people with intellectual disabilities: an observational cross-sectional study.

Br J Psychiatry. 2016 Dec;209(6):504-510

Authors: O'Dwyer M, Maidment ID, Bennett K, Peklar J, Mulryan N, McCallion P, McCarron M, Henman MC

Abstract
BACKGROUND: No studies to date have investigated cumulative anticholinergic exposure and its effects in adults with intellectual disabilities.
AIMS: To determine the cumulative exposure to anticholinergics and the factors associated with high exposure.
METHOD: A modified Anticholinergic Cognitive Burden (ACB) scale score was calculated for a representative cohort of 736 people over 40 years old with intellectual disabilities, and associations with demographic and clinical factors assessed.
RESULTS: Age over 65 years was associated with higher exposure (ACB 1-4 odds ratio (OR) = 3.28, 95% CI 1.49-7.28, ACB 5+ OR = 3.08, 95% CI 1.20-7.63), as was a mental health condition (ACB 1-4 OR = 9.79, 95% CI 5.63-17.02, ACB 5+ OR = 23.74, 95% CI 12.29-45.83). Daytime drowsiness was associated with higher ACB (P<0.001) and chronic constipation reported more frequently (26.6% ACB 5+ v. 7.5% ACB 0, P<0.001).
CONCLUSIONS: Older people with intellectual disabilities and with mental health conditions were exposed to high anticholinergic burden. This was associated with daytime dozing and constipation.

PMID: 27660331 [PubMed - indexed for MEDLINE]

Communicating information concerning potential medication harms and benefits: What gist do numbers convey?

Patient Educ Couns. 2016 Dec;99(12):1964-1970

Authors: Blalock SJ, Sage A, Bitonti M, Patel P, Dickinson R, Knapp P

Abstract
OBJECTIVES: Fuzzy trace theory was used to examine the effect of information concerning medication benefits and side-effects on willingness to use a hypothetical medication.
METHODS: Participants (N=999) were recruited via Amazon Mechanical Turk. Using 3×5 experimental research design, each participant viewed information about medication side effects in 1 of 3 formats and information about medication benefits in 1 of 5 formats. For both side-effects and benefits, one format presented only non-numeric information and the remaining formats presented numeric information.
RESULTS: Individuals in the non-numeric side-effect condition were less likely to take the medication than those in the numeric conditions (p<0.0001). In contrast, individuals in the non-numeric benefit condition were more likely to take the medication than those in the numeric conditions (p<0.0001).
CONCLUSIONS: Our findings suggest that non-numeric side-effect information conveys the gist that the medication can cause harm, decreasing willingness to use the medication; whereas non-numeric benefit information has the opposite effect.
PRACTICE IMPLICATIONS: Presenting side-effect and benefit information in non-numeric format appears to bias decision-making in opposite directions. Providing numeric information for both benefits and side-effects may enhance decision-making. However, providing numeric benefit information may decrease adherence, creating ethical dilemmas for providers.

PMID: 27444232 [PubMed - indexed for MEDLINE]

Drugs as Possible Triggers of Takotsubo Cardiomyopathy: A Comprehensive Literature Search - Update 2015.

Curr Clin Pharmacol. 2016;11(2):95-109

Authors: Amariles P, Cifuentes L

Abstract
BACKGROUND: In 2011 a list of 20 drugs linked to drug-induced Tako-Tsubo cardiomyopathy (TCM) was published. Thus, the objectives were both to identify cases of drug-induced TCM, and update the 2011 list of drugs as possible triggers of this cardiomyopathy.
METHOD: As the 2011 report of drug-induced TCM, case reports of drug-induced TCM were identified by a comprehensive search in Medline/PubMed database. From December 2010 to March 2015 search terms were Takotsubo cardiomyopathy, Takotsubo cardiomyopathy, stress cardiomyopathy, transient-left-ventricular ballooning syndrome, ampulla cardiomyopathy, apical ballooning syndrome, OR broken heart syndrome; together with "iatrogenic", "drug-induced", OR "induced by". Publications limited to English, Spanish, and French, in humans, and with full texts were retrieved. Articles that recognized any drug as a possible trigger of TCM were selected.
RESULTS: Overall, 405 different references were retrieved and 67 were selected (62 case reports and 5 case series) involving 78 patient cases with TCM possibly associated to drugs were reviewed. At total of 44 drugs were recognized as possible drug-induced TCM, mainly with sympathetic effect, and 37 (84.1%) were different to those 20 identified in the 2011 review; therefore, a list of 57 drugs associated to TCM was obtained.
CONCLUSION: There are new case reports that linked drug-use with the development of TCM. The list of 57 drugs obtained is principally integrated by drugs that generate sympathetic overstimulation. Consequently, the recommendation "drug-induced TCM would be considered in patients with TCM, particularly those in which no clear emotional or stress trigger could be identified" is endorsed.

PMID: 27049039 [PubMed - indexed for MEDLINE]

Dose-dependent acute liver injury with hypersensitivity features in humans due to a novel microsomal prostaglandin E synthase 1 inhibitor.

Br J Clin Pharmacol. 2017 Sep 02;:

Authors: Jin Y, Regev A, Kam J, Phipps K, Smith C, Henck J, Campanale K, Hu L, Hall DG, Yang XY, Nakano M, McNearney TA, Uetrecht J, Landschulz W

Abstract
AIM: LY3031207, a novel microsomal prostaglandin E synthase 1 inhibitor, was evaluated in a multiple ascending dose study after nonclinical toxicology studies and a single ascending dose study demonstrated an acceptable toxicity, safety, and tolerability profile.
METHODS: Healthy subjects were randomised to receive LY3031207 (25, 75, and 275 mg), placebo, or celecoxib (400 mg) once daily for 28 days. The safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of LY3031207 were evaluated.
RESULTS: The study was terminated when two subjects experienced drug-induced liver injury (DILI) after they had received 225 mg LY3031207 for 19 days. Liver biopsy from these subjects revealed acute liver injury with eosinophilic infiltration. Four additional DILI cases were identified after LY3031207 dosing had been stopped. All six DILI cases shared unique presentations of hepatocellular injury with hypersensitivity features and demonstrated a steep dose-dependent trend. Prompt discontinuation of the study drug and supportive medical care resulted in full recovery. Metabolites from metabolic activation of the imidazole ring were observed in plasma and urine samples from all subjects randomized to LY3031207 dosing.
CONCLUSIONS: This study emphasised the importance of careful safety monitoring and serious adverse events management in phase I trials. Metabolic activation of the imidazole ring may be involved in the development of hepatotoxicity of LY3031207.

PMID: 28865237 [PubMed - as supplied by publisher]

The efficacy of (+)-Naltrexone on alcohol preference and seeking behaviour is dependent on light-cycle.

Brain Behav Immun. 2017 Aug 29;:

Authors: Jacobsen JHW, Buisman-Pijlman FT, Mustafa S, Rice KC, Hutchinson MR

Abstract
Circadian rhythm affects drug-induced reward behaviour and the innate immune system. Peaks in reward-associated behaviour and immune responses typically occur during the active (dark) phase of rodents. While the role of the immune system, specifically, Toll-like receptor 4 (TLR4, an innate immune receptor) in drug-induced reward is becoming increasingly appreciated, it is unclear whether its effects vary according to light-cycle. Therefore, the aim of this study was to characterise the effects of the phase of the light-cycle and the state of the innate immune system on alcohol reward behaviour and subsequently determine whether the efficacy of targeting the immune component of drug reward depends upon the light-cycle. This study demonstrates that mice exhibit greater alcohol-induced conditioned place preference and alcohol two-bottle choice preference during the dark cycle. This effect overlapped with elevations in reward-, thirst- and immune-related genes. Administration of (+)-Naltrexone, a biased TLR4 antagonist, reduced immune-related gene mRNA expression and alcohol preference with its effects most pronounced during the dark cycle. However, (+)-Naltrexone, like other TLR4 antagonists exhibited off-target side effects, with a significant reduction in overall saccharin intake - an effect likely attributable to a reduction in tyrosine hydroxylase (Th) mRNA expression levels. Collectively, the study highlights a link between a time-of-day dependent influence of TLR4 on natural and alcohol reward-like behaviour in mice.

PMID: 28864261 [PubMed - as supplied by publisher]

Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors.

Cancer Res Treat. 2017 Aug 29;:

Authors: Kim TM, Lee KW, Oh DY, Lee JS, Im SA, Kim DW, Han SW, Kim YJ, Kim TY, Kim JH, Han H, Kim WH, Bang YJ

Abstract
Purpose: Poziotinib, a pan-HER tyrosine kinase inhibitor (TKI), has shown potent activity against wild type of epidermal growth factor receptor (EGFR) family kinases including EGFR, HER-2 and HER-4 and EGFR-mutant cells in vitro. Two phase I studies were conducted to determine the maximum tolerated dose (MTD), pharmacokinetics, safety and antitumor activity against advanced solid tumors.
Materials and Methods: Standard 3+3 dose escalation scheme using two different dosing schedules were studied: once daily, 14-day on and 7-day off (intermittent schedule); and once daily continuous dosing with food effect. Additional patients were enrolled in an expansion cohort.
Results: A total of 75 patients were enrolled in the 2 studies. The most common drug-related treatment-emergent adverse events were diarrhea, rash, stomatitis, pruritus, and anorexia. Dose-limiting toxicities were Grade 3 diarrhea in the intermittent schedule and Grade 3 anorexia and diarrhea in the continuous dosing schedule. The MTDs were determined as 24mg/day in the intermittent dosing schedule and 18mg/day in the continuous dosing schedule. Eight (16%) and twenty-four (47%) of 51 evaluable patients in the intermittent schedule achieved partial response (PR) and stable disease (SD), respectively. Four (21%) and six (32%) of 19 evaluable patients in continuous dosing schedule achieved PR and SD, respectively. Patients with PR (n=7) or SD ≥ 12 weeks (n=7) had HER2 amplification (n=7; breast cancer, 5; and stomach cancer, 2) and EGFR amplification (n=1, squamous cell lung cancer).
Conclusions: Poziotinib was safe and well tolerated in patients with advanced solid tumors. It showed an encouraging activity against EGFR-mutant and HER2-amplified cancers.

PMID: 28859471 [PubMed - as supplied by publisher]

Morbidity in Pregnant Women Associated with Unverified Penicillin Allergies, Antibiotic Use, and Group B Streptococcus Infections.

Perm J. 2017;21:

Authors: Desai SH, Kaplan MS, Chen Q, Macy EM

Abstract
CONTEXT: The morbidity potentially associated with unverified penicillin allergy in pregnant women, with and without group B streptococcus (GBS) infections, is unknown. Penicillin allergy testing is safe during pregnancy but is done infrequently.
OBJECTIVE: To determine morbidity associated with antibiotic use in a large cohort of pregnant women, with and without an unverified history of penicillin allergy, and with and without GBS.
DESIGN: Retrospective. All pregnant women who delivered live infants in Kaiser Permanente Southern California between January 1, 2009, and December 31, 2014, were identified.
MAIN OUTCOME MEASURES: Penicillin allergy status at delivery, delivery method, maternal and infant hospital utilization, peripartum antibiotic exposures, new antibiotic-associated adverse drug reactions, and new Clostridium difficile infections.
RESULTS: There were 170,379 unique women who had 201,316 pregnancies during the study period. There were 16,084 pregnancies in women with an active, but unverified, penicillin allergy at delivery. There were 42,524 pregnancies in GBS-positive women, and 3500 also had a penicillin allergy. Women with a penicillin allergy, with or without GBS, had significantly (about 10%) higher cesarean section rates and spent significantly more (about 0.1) days in the hospital after delivery. Among GBS-positive women, those with an unverified penicillin allergy were exposed to significantly more cefazolin, clindamycin, vancomycin, and gentamicin and had significantly higher rates of adverse drug reactions associated with all antibiotic use.
CONCLUSIONS: Unverified penicillin allergy is associated with more hospital utilization and additional morbidity. Penicillin allergy testing of pregnant women with a history of penicillin allergy may help reduce these unwanted outcomes.

PMID: 28333608 [PubMed - indexed for MEDLINE]

Context as a drug: some consequences of placebo research for primary care.

Scand J Prim Health Care. 2016 Dec;34(4):428-433

Authors: Lucassen P, Olesen F

Abstract
OBJECTIVE: On the basis of emerging research evidence, this review aims to discuss the importance of the context surrounding the doctor-patient encounter for the success of treatment.
DESIGN AND SETTING: Discussion paper based on placebo-nocebo and pain studies conducted in the western world.
MAIN OUTCOME MEASURES: Literature-based theory about impact of communication elements on seriousness of symptoms in clinical practice.
RESULTS: The therapeutic outcome seems to be impacted by rituals around a clinical encounter and by the doctor patient communication and relation. A warm, friendly and empathic attitude is crucial in the first contact with the practice and during the consultation as it influences the patient's perceived outcome. It is important to raise positive expectations when discussing the prognosis, conducting treatment and prescribing medications as the effect may be reduced if the physician expresses doubt about the effectiveness of the medication. Additionally, overly focus on side effects in the doctor-patient conversation about proposed treatments seems to influence the magnitude of perceived side effects in the patient. Thus, shared decision-making might be a desirable tool for ensuring better expectations in the patient and successful symptom relief.
CONCLUSIONS: The context of the doctor-patient interplay matters. Placebo-nocebo research provides strong evidence for this link. The therapeutic context induces biomedical processes in the patient's brain that may enhance or reduce the effects of chosen interventions. The context thus works as a drug, with real effects and side effects. KEY POINTS Increased awareness of the context drug may help GPs alleviate symptoms and better motivate patients for treatment. Treatment is affected by multiple types of context, as also confirmed by placebo-nocebo research. The therapeutic context influences the biomedical processes, which may enhance or reduce intervention effects on symptoms. The impact of context should be considered in daily general practice as it may serve as a drug, with real effects and side effects.

PMID: 27978780 [PubMed - indexed for MEDLINE]

Does dual HER-2 blockade treatment increase the risk of severe toxicities of special interests in breast cancer patients: A meta-analysis of randomized controlled trials.

Oncotarget. 2017 Mar 21;8(12):19923-19933

Authors: Hao S, Tian W, Gao B, Jiang Y, Zhang X, Zhang S, Guo L, Zhao J, Zhang G, Hu C, Yan J, Luo D

Abstract
Although dual HER-2 blockade treatment could offer greater clinical efficacy in breast cancer, the risk of severe toxicities of special interest related to this combined regimen in breast cancer remained unknown. We systematically searched public databases (MEDLINE, EMBASE, Cochrane library) to identify relevant studies that comparing anti-HER2 monotherapy (lapatinib or trastuzumab or pertuzumab) with dual HER-2 blockade treatment (pertuzumab plus trastuzumab or trastuzumab plus lapatinib) in breast cancer. A total of 11,941 breast cancer patients from 9 trials were included for analysis. Meta-analysis showed that dual HER2 blockade treatment significantly increased the risk of severe diarrhea (OR 2.52, p<0.001) and treatment discontinuation (OR 1.52, p=0.014), but not for severe rash (OR 1.06, p=0.81), liver toxicities (OR 1.16, p=0.28), CHF (OR 1.46, p=0.09), LVEF decline (OR 1.09, p=0.40) and FAEs (OR 0.97, p=0.91). Similar results were observed in sub-group analysis according to anti-HER2 regimens in terms of severe diarrhea and treatment discontinuation. Additionally, trastuzumab plus lapatinib significantly increased the risk of LVEF decline in comparison with lapatinib alone (OR 1.48, p=0.002). Our analysis indicated that dual anti-HER2 blockade treatment significantly increased the risk of developing severe diarrhea and treatment discontinuation in comparison with anti-HER2 monotherapy. These were no evidence of an increased risk of fatal adverse events with dual-HER2 blockade treatment.

PMID: 28199966 [PubMed - indexed for MEDLINE]

Prognosis and treatment of FOLFOX therapy related interstitial pneumonia: a plea for multimodal immune modulating therapy in the respiratory insufficient patient.

BMC Cancer. 2017 Aug 29;17(1):586

Authors: De Weerdt A, Dendooven A, Snoeckx A, Pen J, Lammens M, Jorens PG

Abstract
BACKGROUND: The FOLFOX regimen, i.e., folinic acid (FOL), fluorouracil (F) and oxaliplatin (OX), is a drug cocktail that is used to treat gastric and colorectal cancers. Despite the concomitant improvements in response rate, duration of response and patient survival, reports of serious toxic pulmonary side effects have progressively emerged.
CASE PRESENTATION: We describe a patient who was treated with FOLFOX as an adjuvant to a rectosigmoidal resection of a rectosigmoidal carcinoma and who developed respiratory insufficiency requiring mechanical ventilation. Computed tomography (CT) imaging and open lung biopsy findings were compatible with interstitial pneumonia (IP). She received multimodal combination treatment (acetylcysteine, corticosteroids, immune globulins and cyclophosphamide) and survived. We performed a systematic literature search and reviewed all 45 reported cases of FOLFOX-related lung toxicity and/or pulmonary fibrosis for their clinical characteristics and their outcomes related to therapy.
CONCLUSIONS: We found that for the 45 cases with available data, the median age was 70 years, and the male-female ratio was 3.5: 1. In the patients exhibiting only mild respiratory symptoms, discontinuation of the culprit drug (oxaliplatin) resulted in a 100% regression of the symptoms. However the prognosis of the respiratory insufficient patient proved to be grim: death occurred in 76.9% of the cases despite conventional treatment with corticosteroids. We therefore urge oncologists and critical care specialists not to limit their interventions to the discontinuation of chemotherapy, artificial ventilation, corticosteroids and glutathione replenishment and to consider the gradual introduction of additional immune-modulating agents whenever life-threatening respiratory symptoms in oxaliplatin-treated patients do not subside; all the more so considering the fact that our analysis showed that every patient who survived intubation and mechanical ventilation experienced a full clinical recovery.

PMID: 28851379 [PubMed - in process]

Adherence and feasibility of 2 treatment schedules of S-1 as adjuvant chemotherapy for patients with completely resected advanced lung cancer: a multicenter randomized controlled trial.

BMC Cancer. 2017 Aug 29;17(1):581

Authors: Hata Y, Kiribayashi T, Kishi K, Nagashima M, Nakayama T, Ikeda S, Kadokura M, Ozeki Y, Otsuka H, Murakami Y, Takagi K, Iyoda A

Abstract
BACKGROUND: We conducted a multicenter randomized study of adjuvant S-1 administration schedules for surgically treated pathological stage IB-IIIA non-small cell lung cancer patients.
METHODS: Patients receiving curative surgical resection were centrally randomized to arm A (4 weeks of oral S-1 and a 2-week rest over 12 months) or arm B (2 weeks of S-1 and a 1-week rest over 12 months). The primary endpoints were completion of the scheduled adjuvant chemotherapy over 12 months, and the secondary endpoints were relative total administration dose, toxicity, and 3-year disease-free survival.
RESULTS: From April 2005 to January 2012, 80 patients were enrolled, of whom 78 patients were eligible and assessable. The planned S-1 administration over 12 months was accomplished to 28 patients in 38 arm A patients (73.7%) and to 18 patients in 40 arm B patients (45.0%, p = 0.01). The average relative dose intensity was 77.2% for arm A and 58.4% for arm B (p = 0.01). Drug-related grade 3 adverse events were recorded for 11% of arm A and 5% of arm B (p = 0.43). Grade 1-3 elevation of bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine transaminase were more frequently recorded in arm A than in arm B. The 3-year disease-free survival rate was 79.0% for arm A and 79.3% for arm B (p = 0.94).
CONCLUSIONS: The superiority of feasibility of the shorter schedule was not recognized in the present study. The conventional schedule showed higher completion rates over 12 months (p = 0.01) and relative dose intensity of S-1 (p = 0.01). Toxicity showed no significant difference among the shorter schedule and the conventional schedule, except for grade 1-3 elevation of bilirubin.
TRIAL REGISTRATION: This randomized multicenter study was retrospectively registered with the UMIN-CTR (UMIN000016086, registration date December 30, 2014).

PMID: 28851314 [PubMed - in process]

Blood Pressure, Antihypertensive Polypharmacy, Frailty, and Risk for Serious Fall Injuries Among Older Treated Adults With Hypertension.

Hypertension. 2017 Aug;70(2):259-266

Authors: Bromfield SG, Ngameni CA, Colantonio LD, Bowling CB, Shimbo D, Reynolds K, Safford MM, Banach M, Toth PP, Muntner P

Abstract
Antihypertensive medication and low systolic blood pressure (BP) and diastolic BP have been associated with an increased falls risk in some studies. Many older adults have indicators of frailty, which may increase their risk for falls. We contrasted the association of systolic BP, diastolic BP, number of antihypertensive medication classes taken, and indicators of frailty with risk for serious fall injuries among 5236 REGARDS study (Reasons for Geographic and Racial Difference in Stroke) participants ≥65 years taking antihypertensive medication at baseline with Medicare fee-for-service coverage. Systolic BP and diastolic BP were measured, and antihypertensive medication classes being taken assessed through a pill bottle review during a study visit. Indicators of frailty included low body mass index, cognitive impairment, depressive symptoms, exhaustion, impaired mobility, and history of falls. Serious fall injuries were defined as fall-related fractures, brain injuries, or joint dislocations using Medicare claims through December 31, 2014. Over a median of 6.4 years, 802 (15.3%) participants had a serious fall injury. The multivariable-adjusted hazard ratio for a serious fall injury among participants with 1, 2, or ≥3 indicators of frailty versus no frailty indicators was 1.18 (95% confidence interval, 0.99-1.40), 1.49 (95% confidence interval, 1.19-1.87), and 2.04 (95% confidence interval, 1.56-2.67), respectively. Systolic BP, diastolic BP, and number of antihypertensive medication classes being taken at baseline were not associated with risk for serious fall injuries after multivariable adjustment. In conclusion, indicators of frailty, but not BP or number of antihypertensive medication classes, were associated with increased risk for serious fall injuries among older adults taking antihypertensive medication.

PMID: 28652459 [PubMed - indexed for MEDLINE]