[Immunotherapy is cancer treatment with a novel side-effect profile].

Ugeskr Laeger. 2017 Oct 02;179(40):

Authors: Kondrup M, Raunkilde L, Svane IM, Schmidt H, Bastholt L

Abstract
Within the last few years we have treated still more types of cancer with immune checkpoint inhibitors - anti-cytotoxic T-lymphocyte-associated-4 antibodies and anti-program-med cell death 1/anti-programmed cell death ligand 1 antibodies. A unique set of side effects called immune related adverse events irAEs may occur during treatment. Although severe irAEs remain rare they can become life-threatening. Early detection of irAEs and initiation of relevant treatment are therefore crucial to reduce the risk of long-term seque-lae. We provide a detailed overview of irAEs and recommendations for treatment according to established guidelines.

PMID: 28992844 [PubMed - indexed for MEDLINE]

A single center retrospective analysis of a protocol for high-dose methotrexate and leucovorin rescue administration.

J Oncol Pharm Pract. 2019 Jan;25(1):76-84

Authors: Cerminara Z, Duffy A, Nishioka J, Trovato J, Gilmore S

Abstract
BACKGROUND: Methotrexate has a wide dosing range. High-dose methotrexate is a dose of 1000 mg/m2 or greater. In the 1970s, the incidence of mortality associated with High-dose methotrexate ranged from 4.6 to 6%. In 2012, the University of Maryland Medical Center implemented a standardized high-dose methotrexate protocol. The purpose of this study was to evaluate whether the institution followed recommendations based on the Bleyer nomogram for the administration of high-dose methotrexate more closely after the implementation of the protocol.
METHODS: In this retrospective chart review, 37 patients received 119 cycles of high-dose methotrexate before the protocol implementation (1 January 2009 through 31 December 2010) and 45 patients received 106 cycles of high-dose methotrexate after protocol implementation (1 January 2013 through 31 December 2014). Patient characteristics, protocol data, and complications were analyzed.
RESULTS: Protocol implementation significantly reduced the deviation of methotrexate level timing at 24, 48, and 72 h: median 7.47 vs. 1.46 h, 7.23 vs. 1.35 h, and 7.00 vs. 1.52 h before and after implementation, respectively (p < 0.0001 for each). The protocol significantly reduced deviation of the first dose of leucovorin administration: median 5.2 vs. 0.675 h before and after implementation, respectively (p<0.0001). After protocol implementation, there was an increase in the use of leucovorin prescriptions written appropriately for patients discharged before methotrexate levels reached a value of ≤0.05 µmol/L.
CONCLUSIONS: Implementation of a protocol for the administration of high-dose methotrexate improved the adherence to consensus recommendations. Further analysis is needed to assess clinical pharmacist involvement and the cost savings implications within this protocol.

PMID: 28942720 [PubMed - indexed for MEDLINE]

Implementation and evaluation of medicine and therapeutic information service by clinical pharmacists in oncology care setting.

J Oncol Pharm Pract. 2019 Jan;25(1):60-67

Authors: Patel H, Gurumurthy P

Abstract
BACKGROUND: This study was conducted to explore the role of clinical pharmacists in providing medicine and therapeutic information service in oncology care setting.
METHODS: It was a prospective study conducted for a period of three years after implementation of medicine and therapeutic information service as an integral part of oncology pharmacy services. The medicine and therapeutic information queries were received during ward rounds, at ambulatory care and via telephone by clinical pharmacists. All the medicine and therapeutic information requests were reviewed and answered to the concerned requester(s). Answered medicine and therapeutic information requests were electronically documented in the hospital drug information database and analyzed further.
RESULTS: A total of 484 medicine and therapeutic information requests were received by clinical pharmacists during period of August 2013 to June 2016. Majority of medicine and therapeutic information queries were requested by radiation oncologists (27.2%) followed by medical oncologists (26.4%), general physicians (14.04%), resident medical officers (11.7%), ambulatory care nurses (8.6%), in-patient nurses (5.1%) and patients and care takers (6.6%). Majority of the medicine and therapeutic information queries were asked for the purpose of improving patient care (48.3%) followed by to update knowledge (30.9%) and training sessions to nurses (6.6%). The most common categories of medicine and therapeutic information were adverse drug reactions and its management (21.4%) followed by dosage adjustments of chemotherapy and biologicals (15.5%), supportive care related (14.6%), contraindications (14%), drug-drug interactions (11.9%), management of co-morbidities (7.8%), chemotherapy selection in special populations (4.5%).
CONCLUSION: The provision of medicine and therapeutic information was found to be useful in providing medicine information to improve patient care and to update knowledge of health care professionals at the study hospital.

PMID: 28841101 [PubMed - indexed for MEDLINE]

[Vaccinovigilance: Reports of adverse reactions in the year 2017].

Schweiz Arch Tierheilkd. 2018 Oct;160(10):607-611

Authors: Albrecht N, Ottiger H

Abstract
INTRODUCTION: The aim of the Vaccinovigilance system is the identification of adverse reactions and rare events after the use of immunological veterinary medicinal products. In the year 2017, 128 reports of adverse reactions following the application of various authorized vaccines were received and evaluated. The notifications were submitted primarily by marketing authorization holders (96) or veterinarians (27) and private persons (5). As in previous years, dogs were involved in most of the adverse effects (55%), followed by cattle (18%) and swine (10%). Unlike the previous years, significantly fewer reports were submitted on cats (8%). The correlation between reaction and vaccination was considered probable in 43% of the - cases.

PMID: 30301714 [PubMed - indexed for MEDLINE]

Commentary: Improving Care through Innovations in Infusion Systems.

Biomed Instrum Technol. 2018 Sep/Oct;52(5):366-371

Authors: Gray G

PMID: 30260667 [PubMed - indexed for MEDLINE]

Consumer Healthcare Products Association response to Major et al., "Trends in rates of acetaminophen-related adverse events in the United States", Pharmacoepidemiology & Drug Safety, May 2016, 25: 590-8.

Pharmacoepidemiol Drug Saf. 2017 03;26(3):353-354

Authors: Sirois JE

PMID: 28247547 [PubMed - indexed for MEDLINE]

Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of ELX-02, a Potential Treatment for Genetic Disorders Caused by Nonsense Mutations, in Healthy Volunteers.

Clin Pharmacol Drug Dev. 2019 Jan 16;:

Authors: Leubitz A, Frydman-Marom A, Sharpe N, van Duzer J, Campbell KCM, Vanhoutte F

Abstract
ELX-02 is an investigational synthetic eukaryotic ribosome-selective glycoside optimized as a translational read-through molecule that induces read through of nonsense mutations, resulting in normally localized full-length functional proteins. ELX-02 is being developed as a therapy for genetic diseases caused by nonsense mutations. Two phase 1a, randomized, double-blind placebo-controlled, single-ascending-dose studies were conducted in healthy human subjects to evaluate the safety and pharmacokinetics of ELX-02. Single subcutaneously injected doses of ELX-02 between 0.3 mg/kg and 7.5 mg/kg showed an acceptable safety profile without severe or serious drug-related adverse events, including a lack of renal and ototoxicity events. Injection of ELX-02 resulted in a rapid time to peak concentration and elimination phase, with complete elimination from the vascular compartment within 10 hours. ELX-02 area under the concentration-time curve to infinity showed dose-exposure linearity (24-fold increase for a 25-fold dose increase), and the maximum concentration showed dose proportionality (17-fold increase for a 25-fold increase). The mean apparent volume of distribution was dose dependent, suggesting an increased distribution and tissue uptake of ELX-02 at higher doses. The primary route of excretion was in the urine, with the majority of the compound excreted unchanged. These results support the evaluation of the safety, pharmacokinetics, and efficacy of repeat dosing in future studies.

PMID: 30650260 [PubMed - as supplied by publisher]

Drug-induced diabetes type 2: In silico study involving class B GPCRs.

PLoS One. 2019;14(1):e0208892

Authors: Latek D, Rutkowska E, Niewieczerzal S, Cielecka-Piontek J

Abstract
A disturbance of glucose homeostasis leading to type 2 diabetes mellitus (T2DM) is one of the severe side effects that may occur during a prolonged use of many drugs currently available on the market. In this manuscript we describe the most common cases of drug-induced T2DM, discuss available pharmacotherapies and propose new ones. Among various pharmacotherapies of T2DM, incretin therapies have recently focused attention due to the newly determined crystal structure of incretin hormone receptor GLP1R. Incretin hormone receptors: GLP1R and GIPR together with the glucagon receptor GCGR regulate food intake and insulin and glucose secretion. Our study showed that incretin hormone receptors, named also gut hormone receptors as they are expressed in the gastrointestinal tract, could potentially act as unintended targets (off-targets) for orally administrated drugs. Such off-target interactions, depending on their effect on the receptor (stimulation or inhibition), could be beneficial, like in the case of incretin mimetics, or unwanted if they cause, e.g., decreased insulin secretion. In this in silico study we examined which well-known pharmaceuticals could potentially interact with gut hormone receptors in the off-target way. We observed that drugs with the strongest binding affinity for gut hormone receptors were also reported in the medical information resources as the least disturbing the glucose homeostasis among all drugs in their class. We suggested that those strongly binding molecules could potentially stimulate GIPR and GLP1R and/or inhibit GCGR which could lead to increased insulin secretion and decreased hepatic glucose production. Such positive effect on the glucose homeostasis could compensate for other, adverse effects of pharmacotherapy which lead to drug-induced T2DM. In addition, we also described several top hits as potential substitutes of peptidic incretin mimetics which were discovered in the drug repositioning screen using gut hormone receptors structures against the ZINC15 compounds subset.

PMID: 30650080 [PubMed - in process]

Enhanced passive surveillance of influenza vaccination in England, 2016-2017 - an observational study using an adverse events reporting card.

Hum Vaccin Immunother. 2019 Jan 16;:

Authors: de Lusignan S, Ferreira F, Damaso S, Byford R, Pathirannehelage S, Yeakey A, Yonova I, Schuind A, Dos Santos G

Abstract
Influenza is a major public health burden, mainly prevented by vaccination. Recommendations on influenza vaccine composition are updated annually and constant benefit-risk monitoring is therefore needed. We conducted near-real-time enhanced passive surveillance (EPS) for the influenza vaccine, Fluarix Tetra, according to European Medicines Agency guidance, in 10 volunteer general practices in England using Fluarix Tetra as their principal influenza vaccine brand, from 1-Sep to 30-Nov-2016. The EPS method used a combination of routinely collected data from electronic health records (EHR) and a customized adverse events reporting card (AERC) distributed to participants vaccinated with Fluarix Tetra. For participants vaccinated with a different influenza vaccine, data were derived exclusively from the EHR. We reported weekly and cumulative incidence of pre-defined adverse events of interest (AEI) occurring within 7 days post-vaccination, adjusted for clustering effect. Of the 97,754 eligible participants, 19,334 (19.8%) received influenza vaccination, of whom 13,861 (71.7%) received Fluarix Tetra. A total of 1,049 participants receiving Fluarix Tetra reported AEIs; 703 (67%) used the AERC (adjusted cumulative incidence rate 4.96% [95% CI: 3.92-6.25]). Analysis by individual pre-specified AEI categories identified no safety signal for Fluarix Tetra. A total of 62 individuals reported an AEI with a known brand of non-GSK influenza vaccine and 54 with an unknown brand (adjusted cumulative incidence rate 2.59% [1.93-3.47] and 1.77% [1.42-2.20], respectively). In conclusion, the study identified no safety signal for Fluarix Tetra and showed that the AERC was a useful tool that complemented routine pharmacovigilance by allowing more comprehensive capture of AEIs.

PMID: 30648923 [PubMed - as supplied by publisher]

Ameliorative and protective effects of ginger and its main constituents against natural, chemical and radiation-induced toxicities: A comprehensive review.

Food Chem Toxicol. 2019 Jan;123:72-97

Authors: Alsherbiny MA, Abd-Elsalam WH, El Badawy SA, Taher E, Fares M, Torres A, Chang D, Li CG

Abstract
Fatal unintentional poisoning is widespread upon human exposure to toxic agents such as pesticides, heavy metals, environmental pollutants, bacterial and fungal toxins or even some medications and cosmetic products. In this regards, the application of the natural dietary agents as antidotes has engrossed a substantial attention. One of the ancient known traditional medicines and spices with an arsenal of metabolites of several reported health benefits is ginger. This extended literature review serves to demonstrate the protective effects and mechanisms of ginger and its phytochemicals against natural, chemical and radiation-induced toxicities. Collected data obtained from the in-vivo and in-vitro experimental studies in this overview detail the designation of the protective effects to ginger's antioxidant, anti-inflammatory, and anti-apoptotic properties. Ginger's armoury of phytochemicals exerted its protective function via different mechanisms and cell signalling pathways, including Nrf2/ARE, MAPK, NF-ƙB, Wnt/β-catenin, TGF-β1/Smad3, and ERK/CREB. The outcomes of this review could encourage further clinical trials of ginger applications in radiotherapy and chemotherapy regime for cancer treatments or its implementation to counteract the chemical toxicity induced by industrial pollutants, alcohol, smoking or administered drugs.

PMID: 30352300 [PubMed - indexed for MEDLINE]

Factors associated with potentially harmful drug-drug interactions in older Korean people: A population-based study.

Geriatr Gerontol Int. 2018 Sep;18(9):1378-1382

Authors: Yoon SJ, Kim JS, Jung JG, Ahn SK, Song YS, Bae NK, Seon JY, Kim JH

Abstract
AIM: The present study investigated the status of potentially harmful drug-drug interactions (PHDI) in older adults, to obtain insight into factors that influence the risk of PHDI.
METHODS: The present study included Korean people aged ≥65 years who were prescribed one or more drugs included in the list of PHDI under the Beers Criteria 2015 from January to December, 2016 (n = 1 257 317). PHDI were defined based on the Beers Criteria 2015. Among 10 PHDI, a prevalence of >5% was taken to be clinically significant, and the relationships between multiple variables and PHDI were examined.
RESULTS: The most frequent PHDI was corticosteroids and non-steroidal anti-inflammatory drugs (n = 259 499, 20.64%), followed by a combination of two or more anticholinergic drugs (n = 139 622, 11.1%), and three or more drugs acting on the central nervous system (n = 86 023, 6.84%). These three types of PHDI were more frequent in women (OR 1.066-1.141) and medical aid beneficiaries (OR 1.095-1.510). The risk of PHDI increased in proportion to the number of healthcare institutions used by the participants and their outpatient visits during the year (OR 1.043-1.079, 1.008-1.010, respectively). The risk of PHDI was low when patients took no more than five medications in a single prescription (OR 0.017-0.791).
CONCLUSIONS: The findings of the present study highlight the three most frequent PHDI in Korea according to the Beers Criteria 2015. Healthcare providers should take PHDI into account when treating female patients, medical aid beneficiaries, patients using multiple healthcare institutions, frequent outpatient visitors and patients prescribed more than six medications in a single prescription. Geriatr Gerontol Int 2018; 18: 1378-1382.

PMID: 30094910 [PubMed - indexed for MEDLINE]

Tolerability of trivalent inactivated influenza vaccine among pregnant women, 2015.

BMC Pregnancy Childbirth. 2018 04 23;18(1):110

Authors: Asavapiriyanont S, Kittikraisak W, Suntarattiwong P, Ditsungnoen D, Kaoiean S, Phadungkiatwatana P, Srisantiroj N, Chotpitayasunondh T, Dawood FS, Lindblade KA

Abstract
BACKGROUND: Thailand recommends influenza vaccination among pregnant women. We conducted a cohort study to determine if the prevalence of adverse events following immunization (AEFIs) with influenza vaccine among Thai pregnant women was similar to that often cited among healthy adults.
METHODS: Women who were ≥17 gestational weeks and ≥18 years of age were recruited. Demographic and health history data were collected using structured questionnaires. Women were provided with symptom diary, ruler to measure local reaction(s), and thermometer to measure body temperature. AEFIs were defined as any new symptom/abnormality occurring within four weeks after vaccination. The diaries were abstracted for frequency, duration, and level of discomfort/inconvenience of the AEFIs. Serious adverse events (SAEs) and the likelihood of AEFIs being associated with vaccination were determined using standard definitions.
RESULTS: Among 305 women enrolled between July-November 2015, median age was 29 years. Of these, 223 (73%) were in their third trimester, 271 (89%) had completed secondary school or higher, and 20 (7%) reported ≥1 pre-existing conditions. AEFIs were reported in 134 women (44%; 95% confidence interval [CI] 38-50%). Soreness at the injection site (74, 24%; CI 19-29%), general weakness (50, 16%; CI 12-21%), muscle ache (49, 16%; CI 12-21%), and headache (45, 15%; CI 1-19%) were most common. Of those with AEFIs, 120 (89%) reported symptom/abnormality occurred on day 0 or day 1 following vaccination. Ten women (7%) reported the AEFIs affected daily activities. The AEFIs generally spontaneously resolved within 24 h of onset. There were two vaccine-unrelated SAEs. Of 294 women with complete follow-up, 279 (95%) had term deliveries, 12 (4%) had preterm deliveries, and 3 (1%) had miscarriage or stillbirth.
CONCLUSION: In our cohort, AEFIs with influenza vaccine occurred with similar frequency to those reported among healthy adults in other studies, and were generally mild and self-limited. No influenza vaccine-associated SAEs were identified.

PMID: 29685106 [PubMed - indexed for MEDLINE]

Efficacy and safety of taxane-based systemic chemotherapy of advanced gastric cancer: A systematic review and meta-analysis.

Sci Rep. 2017 07 13;7(1):5319

Authors: Shi J, Gao P, Song Y, Chen X, Li Y, Zhang C, Wang H, Wang Z

Abstract
Taxanes are chemotherapeutic agents commonly used to treat several cancers. However, the effects of taxanes on advanced gastric cancer (AGC) are still not clear, especially when used as a first-line treatment. This systematic review and meta-analysis aims to investigate the efficacy and safety of taxanes as a first-line treatment of AGC. The quality of our included studies was assessed using the Cochrane risk of bias tool for RCTs and NOS scale for nRCTs, and the data of the included studies was of satisfactory quality to analyze. The outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and toxicity. Taxanes significantly improved OS (HR = 0.84, 95% CI 0.76-0.92, P = 0.0004) and had a slight effect on ORR (RR = 1.23, 95% CI 1.00-1.51, P = 0.05). However, taxanes may also increase the risks of neutropenia and leucopenia, similar to effects observed in other conventional chemotherapeutic treatments such as oxaliplatin and epirubicin. Therefore, patient characteristics including concomitant diseases, physical condition, and prior therapies should be considered before selecting taxane-based treatments for AGC.

PMID: 28706257 [PubMed - indexed for MEDLINE]

Switching to anastrozole plus goserelin vs continued tamoxifen for adjuvant therapy of premenopausal early-stage breast cancer: preliminary results from a randomized trial.

Cancer Manag Res. 2019;11:299-307

Authors: Li JW, Liu GY, Ji YJ, Yan X, Pang D, Jiang ZF, Chen DD, Zhang B, Xu BH, Shao ZM

Abstract
Purpose: To assess the efficacy, safety, and quality-of-life impact of switching adjuvant treatment in hormone receptor-positive primary breast cancer patients who are still premenopausal after 2-3 years of tamoxifen therapy to anastrozole plus goserelin as compared with continuing tamoxifen over a total period of 5 years.
Patients and methods: Hormone receptor-positive, premenopausal, lymph node-positive, or tumor size ≥4 cm breast cancer patients who had received tamoxifen for 2-3 years were randomly assigned to continue tamoxifen treatment (TAM group) or switch to adjuvant anastrozole plus goserelin (ADD group) and continue treatment for another 2-3 years (total treatment duration 5 years). Endpoints evaluated were adverse events (AEs), changes in bone mineral density, quality of life, and disease-free survival-related events.
Results: A total of 62 patients (33 in the ADD group and 29 in the TAM group) were evaluated. Grade 3-4 drug-related AEs occurred in five patients (15.2%) in the ADD group vs none in the TAM group. In the ADD group, arthralgias were the most common AEs (5/33 patients; 15.2%), and three patients in this group were discontinued because of AEs. Treatment was temporarily suspended due to AEs in three patients (9.1%) in the ADD group and one patient (3.4%) in the TAM group. Compared with continuing TAM therapy, switching to anastrozole plus goserelin did not result in any worsening of bone mineral density or quality of life. During a median follow-up of 34 months, five patients (15.2%) in the ADD group had disease-free survival events vs four patients (13.8%) in the TAM group.
Conclusion: For early-stage breast cancer patients who remain premenopausal following 2-3 years of adjuvant tamoxifen therapy, switching to anastrozole plus goserelin therapy was safe with tolerable adverse effects. However, it did not show superior efficacy compared to remaining on tamoxifen treatment.
Trial Registration: ClinicalTrials.gov (identifier NCT01352091).

PMID: 30643455 [PubMed]

Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study.

Lancet Haematol. 2019 Jan 11;:

Authors: Younes A, Brody J, Carpio C, Lopez-Guillermo A, Ben-Yehuda D, Ferhanoglu B, Nagler A, Ozcan M, Avivi I, Bosch F, Caballero Barrigón MD, Hellmann A, Kuss B, Ma DDF, Demirkan F, Yağci M, Horowitz NA, Marlton P, Cordoba R, Wrobel T, Buglio D, Streit M, Hodkinson BP, Schaffer M, Alvarez J, Ceulemans R, Balasubramanian S, de Jong J, Wang SS, Fourneau N, Jurczak W

Abstract
BACKGROUND: Preclinical studies have shown synergistic antitumour effects between ibrutinib and immune-checkpoint blockade. The aim of this study was to assess the safety and activity of ibrutinib in combination with nivolumab in patients with relapsed or refractory B-cell malignant diseases.
METHODS: We did a two-part, open-label, phase 1/2a study at 21 hospitals in Australia, Israel, Poland, Spain, Turkey, and the USA. The primary objective of part A (dose escalation) was to assess the safety of daily oral ibrutinib (420 mg or 560 mg) in combination with intravenous nivolumab (3 mg/kg every 2 weeks) to ascertain a recommended phase 2 dose in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, or diffuse large B-cell lymphoma. Dose optimisation was investigated using a modified toxicity probability interval design. The primary objective of the part B expansion phase was to establish the preliminary activity (the proportion of patients who achieved an overall response) of the combination of ibrutinib and nivolumab in four cohorts: relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, diffuse large B-cell lymphoma, and Richter's transformation. All participants who received at least one dose of treatment were included in the primary analysis and analyses were done by disease cohort. This trial is registered with ClinicalTrials.gov, number NCT02329847. The trial is ongoing.
FINDINGS: Between March 12, 2015, and April 11, 2017, 144 patients were enrolled in the study. Three patients died before receiving study treatment; thus, 141 patients were included in the analysis, 14 in part A and 127 in part B. One dose-limiting toxicity (grade 3 hyperbilirubinaemia) was reported at the 420 mg dose in the diffuse large B-cell lymphoma cohort, which resolved after 5 days. The combination of ibrutinib and nivolumab led to overall responses in 22 (61%) of 36 patients with high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma, 13 (33%) of 40 patients with follicular lymphoma, 16 (36%) of 45 patients with diffuse large B-cell lymphoma, and 13 (65%) of 20 patients with Richter's transformation. The most common all-grade adverse events were diarrhoea (47 [33%] of 141 patients), neutropenia (44 [31%]), and fatigue (37 [26%]). 11 (8%) of 141 patients had adverse events leading to death; none were reported as drug-related. The most common grade 3-4 adverse events were neutropenia (40 [28%] of 141 patients) and anaemia (32 [23%]). The incidence of grade 3-4 neutropenia ranged from eight (18%) of 45 patients with diffuse large B-cell lymphoma to 19 (53%) of 36 patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma; incidence of grade 3-4 anaemia ranged from five (13%) of 40 patients with follicular lymphoma to seven (35%) of 20 patients with Richter's transformation. The most common serious adverse events included anaemia (six [4%] of 141 patients) and pneumonia (five [4%]). The most common grade 3-4 immune-related adverse events were rash (11 [8%] of 141 patients) and increased alanine aminotransferase (three [2%]).
INTERPRETATION: The combination of ibrutinib and nivolumab had an acceptable safety profile and preliminary activity was similar to that reported with single-agent ibrutinib in chronic lymphocytic leukaemia or small lymphocytic lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. The clinical response in patients with Richter's transformation was promising and supports further clinical assessment.
FUNDING: Janssen R&D.

PMID: 30642819 [PubMed - as supplied by publisher]

Pharmacokinetics and Safety of Enzalutamide in Healthy Chinese Male Volunteers.

Clin Ther. 2019 Jan 11;:

Authors: Liu YM, Wu P, Fukushi R, Yamada S, Chen Q

Abstract
PURPOSE: This open-label, single-dose study evaluated the pharmacokinetic profiles of enzalutamide and its major metabolites and the safety of enzalutamide in healthy, Chinese male volunteers.
METHODS: Fourteen volunteers (median age, 28.5 years) received a single oral dose of enzalutamide (160 mg) under fasting conditions on day 1 and were followed for 50 days. Pharmacokinetic profiles were obtained for enzalutamide and its major metabolites, carboxylic acid metabolite (M1; inactive metabolite) and N-desmethyl enzalutamide (M2; active metabolite), on day 1 up to 1176 hours (49 days). Safety data were also collected.
FINDINGS: Enzalutamide plasma concentration rapidly increased (median Tmax, 1.5 hours) followed by a slow decrease (mean t½, 90.7 hours). M1 and M2 plasma concentrations increased gradually with a median Tmax of 72.0 and 121 hours, respectively. M1 and M2 mean metabolite-to-parent ratios were 0.2 and 1.3, respectively. Mean AUC0-∞ of enzalutamide plus M2 was 828 μg h/mL versus 368 μg h/mL for enzalutamide alone. Mean t½, maximum concentration, and Tmax of enzalutamide plus M2 were comparable with those of enzalutamide. Drug-related treatment-emergent adverse events were reported in 4 men (28.6%): 1 each of upper respiratory tract infection, chest discomfort, increased blood bilirubin, and decreased white blood cell count. No deaths or serious treatment-emergent adverse events were observed.
IMPLICATIONS: The pharmacokinetic profiles of enzalutamide, M1, M2, and enzalutamide plus M2 in healthy Chinese men were generally consistent with those in white men. No new safety concerns were found. Chinese Clinical Trial Registration identifier: CTR20150635.

PMID: 30642613 [PubMed - as supplied by publisher]

Adverse drug reactions of anticancer drugs derived from natural sources.

Food Chem Toxicol. 2019 Jan;123:522-535

Authors: Tewari D, Rawat P, Singh PK

Abstract
Cancer, a life threatening disease adversely affects huge population worldwide. Naturally derived drug discovery has emerged as a potential pathway in search of anticancers. Natural products-based drugs are generally considered safe, compared to their synthetic counterparts. A systematic review on adverse drugs reactions (ADRs) of the anticancer natural products has not been performed till date. We reviewed anticancer drugs, derived from plants, microbes and marine sources with their mechanistic action and reported ADRs. PubMed, ScienceDirect and Scopus were searched through Boolean information retrieval method using keywords "natural products", "cancer", "herbal", "marine drugs" and "adverse drug reaction". We documented ADRs of natural products based anticancer agents, mechanisms of action and chemical structures. It was observed that majority of the natural products based anticancer drugs possess ample adverse effects, dominantly hematological toxicities, alopecia, neurotoxicity and cardiotoxicity. These findings deviate from the preconceived notion about safer nature of herbal drugs. We also came across some anti-cancer natural products with less/no reported adverse events like Cabazitaxel and Arglabin. Comprehensive pharmacovigilance studies are needed to report ADRs and thereby predicting safety of anti-cancer drugs, either originated from natural sources or chemically synthesized.

PMID: 30471312 [PubMed - indexed for MEDLINE]

Evaluating exposure using confidence intervals: implication in tiered quantitation of metabolites for safety risks.

Bioanalysis. 2018 Oct;10(19):1553-1556

Authors: Niwa M, Ishii T, Ono K, Kuriyama S, Nakai N, Hosaka S, Mayumi T, Yasuda Y, Yamakawa T

PMID: 30295549 [PubMed - indexed for MEDLINE]

[The analysis of the association of the polymorphic variants of the TPMT, COMT, and ABCC3 genes with the development of hearing disorders induced by the cisplatin treatment].

Vestn Otorinolaringol. 2018;83(4):60-66

Authors: Mironovich OL, Bliznetz EA, Garbaruk ES, Belogurova MB, Subora NV, Varfolomeeva SR, Kachanov DY, Shamanskaya TV, Markova TG, Polyakov AV

Abstract
Cisplatin and its derivatives are widely used chemotherapeutic agents for the treatment of many cancers, including hepatoblastoma, brain tumors, and germ-cell tumors. This therapy contributed to the dramatic increase in the survival rate. However, its use is restricted by the high incidence of irreversible ototoxicity associated with cisplatin application (in more than 60% of the children receiving it). Some studies have reported that genetic variants of TPMT (rs 12201199), COMT (rs4646316), and ABCC3 (rs 1051640) are conferring increased risk of developing cisplatin-induced hearing loss. However, in other studies the results were not replicated. In the present study, we replicated the previous studies based on an independent cohort of Russian patients. SNP genotypes for rs 12201199, rs4646316 and rs 1051640 were determined in DNA samples obtained from 16 patients who developed hearing loss and a group of 34 patients whose hearing was retained. The association between TPMT (rs 12201199), COMT (rs4646316), and ABCC3 (rs 1051640) variants and the hearing loss was not observed in our cohort.

PMID: 30113582 [PubMed - indexed for MEDLINE]

Potential Drug-Drug Interactions Among Critically Ill Pediatric Patients in a Tertiary Pulmonary Center.

J Clin Pharmacol. 2018 02;58(2):221-227

Authors: Hassanzad M, Arenas-Lopez S, Baniasadi S

Abstract
Patients in the pediatric intensive care unit (PICU) are at increased risk of potential drug-drug interactions (pDDIs) because of the complexity of pharmacotherapy. The current study aimed to assess the rate, pattern, risk factors, and management of pDDIs in the PICU of an academic pulmonary hospital. A prospective observational study was conducted for 6 months. Pharmacotherapy data of PICU-admitted patients were evaluated by a clinical pharmacologist. Interacting drugs, reliability, mechanism, potential outcome, and clinical management of pDDIs were identified using the Lexi-Interact database. Logistic regression was applied to analyze the risk factors that could be associated with the interactions. One hundred and twenty-three medication profiles were evaluated during the study period. Diseases of the respiratory system were the main diagnoses among intensive care unit (ICU)-admitted patients (56.1%). A total of 38.6% of the patients exposed to at least 1 major and/or contraindicated interaction during ICU admission. Most pDDIs occurred through metabolic (35.4%) and additive (34.8%) mechanisms. The existence of pDDIs was significantly associated with the number of prescribed medications. Exposure to pDDIs is frequent in critically ill pediatric patients and related to the number of medications. Daily and close cooperation between clinicians and clinical pharmacologists is recommended to prevent harmful outcomes of DDIs.

PMID: 28834562 [PubMed - indexed for MEDLINE]