A Phase I Clinical Trial and Independent Patient-Derived Xenograft Study of Combined Targeted Treatment with Dacomitinib and Figitumumab in Advanced Solid Tumors.

Clin Cancer Res. 2017 Mar 01;23(5):1177-1185

Authors: Calvo E, Soria JC, Ma WW, Wang T, Bahleda R, Tolcher AW, Gernhardt D, O'Connell J, Millham R, Giri N, Wick MJ, Adjei AA, Hidalgo M

Abstract
Purpose: This phase I, open-label, single-arm trial assessed the safety and tolerability of dacomitinib-figitumumab combination therapy in patients with advanced solid tumors.Experimental Design: A standard 3 + 3 dose escalation/de-escalation design was utilized. Starting doses were figitumumab 20 mg/kg administered intravenously once every 3 weeks and dacomitinib 30 mg administered orally once daily. We also performed an independent study of the combination in patient-derived xenograft (avatar mouse) models of adenoid cystic carcinoma.Results: Of the 74 patients enrolled, the most common malignancies were non-small cell lung cancer (24.3%) and colorectal cancer (14.9%). The most common treatment-related adverse events in the 71 patients who received treatment across five dose levels were diarrhea (59.2%), mucosal inflammation (47.9%), and fatigue and acneiform dermatitis (45.1% each). The most common dose-limiting toxicity was mucosal inflammation. Dosing schedules of dacomitinib 10 or 15 mg daily plus figitumumab 20 mg/kg every 3 weeks after a figitumumab loading dose were tolerated by patients over multiple cycles and considered recommended doses for further evaluation. Objective responses were seen in patients with adenoid cystic carcinoma, ovarian carcinoma, and salivary gland cancer. Pharmacokinetic analysis did not show any significant drug-drug interaction. In the adenoid cystic carcinoma xenograft model, figitumumab exerted significant antitumor activity, whereas dacomitinib did not. Figitumumab-sensitive tumors showed downregulation of genes in the insulin-like growth factor receptor 1 pathway.Conclusions: Dacomitinib-figitumumab combination therapy was tolerable with significant dose reductions of both agents to less than the recommended single-agent phase II dose of each drug. Preliminary clinical activity was demonstrated in the potential target tumor adenoid cystic carcinoma. Clin Cancer Res; 23(5); 1177-85. ©2016 AACRSee related commentary by Sundar et al., p. 1123.

PMID: 27733479 [PubMed - indexed for MEDLINE]

Safety and Pharmacodynamics of the PDE4 Inhibitor Roflumilast in Advanced B-cell Malignancies.

Clin Cancer Res. 2017 Mar 01;23(5):1186-1192

Authors: Kelly K, Mejia A, Suhasini AN, Lin AP, Kuhn J, Karnad AB, Weitman S, Aguiar RC

Abstract
Purpose: In this study, we aimed to validate our extensive preclinical data on phosphodiesterase 4 (PDE4) as actionable target in B-cell malignancies. Our specific objectives were to determine the safety, pharmacokinetics, and pharmacodynamics (PI3K/AKT activity), as well as to capture any potential antitumor activity of the PDE4 inhibitor roflumilast in combination with prednisone in patients with advanced B-cell malignancies.Experimental Design: Single-center, exploratory phase Ib open-label, nonrandomized study. Roflumilast (500 mcg PO) was given daily for 21 days with prednisone on days 8 to 14. Additional 21-day cycles were started if patients tolerated cycle 1 and had at least stable disease.Results: Ten patients, median age 65 years with an average of three prior therapies, were enrolled. The median number of cycles administered was 4 (range, 1-13). Treatment was well tolerated; the most common ≥grade 2 treatment-related adverse events were fatigue, anorexia (≥25%), and transient ≥ grade 2 neutropenia (30%). Treatment with roflumilast as a single agent significantly suppressed PI3K activity in the 77% of patients evaluated; on average, patients with PI3K/AKT suppression stayed in trial for 156 days (49-315) versus 91 days (28-139 days) for those without this biomarker response. Six of the nine evaluable patients (66%) had partial response or stable disease. The median number of days in trial was 105 days (range, 28-315).Conclusions: Repurposing the PDE4 inhibitor roflumilast for treatment of B-cell malignancies is safe, suppresses the oncogenic PI3K/AKT kinases, and may be clinically active. Clin Cancer Res; 23(5); 1186-92. ©2016 AACR.

PMID: 27542768 [PubMed - indexed for MEDLINE]

Divergent roles for antigenic drive in the aetiology of primary versus dasatinib-associated CD8+ TCR-Vβ+ expansions.

Sci Rep. 2018 Feb 07;8(1):2534

Authors: Lissina A, McLaren JE, Ilander M, Andersson EI, Lewis CS, Clement M, Herman A, Ladell K, Llewellyn-Lacey S, Miners KL, Gostick E, Melenhorst JJ, Barrett AJ, Price DA, Mustjoki S, Wooldridge L

Abstract
CD8+ T-cell expansions are the primary manifestation of T-cell large granular lymphocytic leukemia (T-LGLL), which is frequently accompanied by neutropenia and rheumatoid arthritis, and also occur as a secondary phenomenon in leukemia patients treated with dasatinib, notably in association with various drug-induced side-effects. However, the mechanisms that underlie the genesis and maintenance of expanded CD8+ T-cell receptor (TCR)-Vβ+ populations in these patient groups have yet to be fully defined. In this study, we performed a comprehensive phenotypic and clonotypic assessment of expanded (TCR-Vβ+) and residual (TCR-Vβ-) CD8+ T-cell populations in T-LGLL and dasatinib-treated chronic myelogenous leukemia (CML) patients. The dominant CD8+ TCR-Vβ+ expansions in T-LGLL patients were largely monoclonal and highly differentiated, whereas the dominant CD8+ TCR-Vβ+ expansions in dasatinib-treated CML patients were oligoclonal or polyclonal, and displayed a broad range of memory phenotypes. These contrasting features suggest divergent roles for antigenic drive in the immunopathogenesis of primary versus dasatinib-associated CD8+ TCR-Vβ+ expansions.

PMID: 29416058 [PubMed - in process]

Imaging spectrum of immunomodulating, chemotherapeutic and radiation therapy-related intracranial effects.

Br J Radiol. 2018 Feb;91(1082):20170553

Authors: Lincoln CM, Fata P, Sotardi S, Pohlen M, Uribe T, Bello JA

Abstract
OBJECTIVE: A wide range of treatment-related side effects result in specific neurologic symptoms and signs and neuroimaging features. Even to the most seasoned neuroradiologist, elucidating therapy-related side effects from other common mimics can be challenging. We provide a pictorial survey of some common and uncommon medication-induced and therapy-related neuroimaging manifestations, discuss pathophysiology and common pitfalls in imaging and diagnosis.
METHODS: A case-based review is utilized to depict scenarios on a routine basis in a general radiology or neuroradiology practice such as medication-induced posterior reversible encephalopathy syndrome to the more challenging cases of pseudoprogression and pseudoregression in temozolmide and bevacizumab therapy in gliobastoma treatment protocols.
CONCLUSION: Knowledge of the treatment-induced imaging abnormalities is essential in the accurate interpretation and diagnosis from the most routine to most challenging of clinical situations. We provide a pictorial review for the radiologist to employ in order to be an invaluable provider to our clinical colleagues and patients.

PMID: 29039692 [PubMed - indexed for MEDLINE]

Sequence-Specific Pharmacokinetic and Pharmacodynamic Phase I/Ib Study of Olaparib Tablets and Carboplatin in Women's Cancer.

Clin Cancer Res. 2017 Mar 15;23(6):1397-1406

Authors: Lee JM, Peer CJ, Yu M, Amable L, Gordon N, Annunziata CM, Houston N, Goey AK, Sissung TM, Parker B, Minasian L, Chiou VL, Murphy RF, Widemann BC, Figg WD, Kohn EC

Abstract
Purpose: Our preclinical studies showed that the PARP inhibitor, olaparib, prior to carboplatin attenuated carboplatin cytotoxicity. We evaluated sequence-specific pharmacokinetic and pharmacodynamic effects, safety, and activity of the combination.Experimental Design: Eligible patients had metastatic or recurrent women's cancer. Olaparib tablets were introduced (100 or 200 mg twice daily, days 1-7) in a 3 + 3 dose escalation with carboplatin AUC4 or 5 every 21 days, up to eight cycles, followed by olaparib 300 mg twice daily maintenance. Patients were randomly assigned to starting schedule: cohort A (olaparib days 1-7, carboplatin on day 8) or B (carboplatin on day 1, olaparib days 2-8) during cycle 1. Patients received the reversed scheme in cycle 2. Blood was collected for olaparib pharmacokinetics, platinum-DNA adducts, comet assay, and PAR concentrations. The primary objectives were to examine schedule-dependent effects on olaparib pharmacokinetics and platinum-DNA adducts.Results: A total of 77 (60 ovarian, 14 breast, and 3 uterine cancer) patients were treated. Dose-limiting toxicity was thrombocytopenia and neutropenia, defining olaparib 200 mg twice daily + carboplatin AUC4 as the MTD. Olaparib clearance was increased approximately 50% when carboplatin was given 24 hours before olaparib. In vitro experiments demonstrated carboplatin preexposure increased olaparib clearance due to intracellular olaparib uptake. Quantities of platinum-DNA adducts were not different as a function of the order of drug administration. Responses included 2 CRs and 31 PRs (46%) with a higher RR in BRCA mutation carriers compared with nonmutation carriers (68% vs. 19%).Conclusions: Tablet olaparib with carboplatin is a safe and active combination. Carboplatin preexposure causes intracellular olaparib accumulation reducing bioavailable olaparib, suggesting carboplatin should be administered prior to olaparib. Clin Cancer Res; 23(6); 1397-406. ©2016 AACR.

PMID: 27663600 [PubMed - indexed for MEDLINE]

The need for educating patients with schizophrenia about the adverse effects of medications.

Australas Psychiatry. 2016 Aug;24(4):352-5

Authors: Hashimoto Y, Tensho M

Abstract
OBJECTIVE: Medication non-adherence is observed in many patients with schizophrenia. We investigated the effects of educational intervention on patient awareness of the adverse effects of their medication for patients with schizophrenia.
METHODS: Inpatients with schizophrenia (N=87) in two Japanese hospitals were allocated to two groups, one that was aware of the adverse effects of medications and one that was unaware, according to their responses to the question 'In the past month, have you experienced any adverse effects from your medications?' Then, they were questioned about adverse effects.
RESULTS: Only 27.6% of patients recognized the adverse effects of their medications. After pharmacists educated them and showed them a list of adverse effects, the prevalence of recognition increased dramatically (≤96.6%). Most patients with schizophrenia clearly did not recognize the adverse effects of their medications. When patients experienced discomfort they tended to stop taking their medications.
CONCLUSIONS: Adverse effects are a common risk factor for discontinuation of medication, so early detection and reporting of such effects may result in them being addressed sooner. Considering the risks of relapse caused by discontinuation of medication, healthcare professionals should actively educate patients with schizophrenia about dysphoria and manage adverse effects.

PMID: 26912469 [PubMed - indexed for MEDLINE]

The Drug-Drug Interaction Profile of Presatovir.

J Clin Pharmacol. 2018 Feb 07;:

Authors: Xin Y, Weng W, Murray BP, Eisenberg EJ, Chien JW, Ling J, Silverman JA

Abstract
Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in young children. Presatovir (previously GS-5806) is a novel, orally administered RSV fusion inhibitor with a favorable safety profile and proven antiviral efficacy in preclinical and clinical studies. In vitro, presatovir is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 and is slowly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5. This study enrolled 64 healthy subjects to evaluate the effect of cyclosporine, a P-gp, BCRP, and OATP1B1/1B3 inhibitor; rifampin, a strong CYP3A4 and P-gp inducer; efavirenz, a moderate CYP3A4 inducer; and cobicistat, a potent CYP3A inhibitor, on presatovir pharmacokinetics. Presatovir plasma exposures (maximum observed plasma concentration [Cmax ] and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUCinf ]) were not affected by coadministration of cyclosporine, suggesting presatovir is not a sensitive substrate of P-gp, BCRP, or OATP1B1/1B3. As expected, based on the role of CYP3A in presatovir metabolism, presatovir exposure was increased by cobicistat (122% in AUCinf ), and decreased by rifampin (40.3% in Cmax and 82.5% in AUCinf ) and efavirenz (55.7% in AUCinf ). These data support coadministration of presatovir with inhibitors of P-gp, BCRP, OATP1B1/1B3, or CYP3A, but not with moderate or strong CYP3A4 inducers. Presatovir was well-tolerated with the most common drug-related adverse events of dizziness (n = 12) and somnolence (n = 4) reported during efavirenz treatment.

PMID: 29412463 [PubMed - as supplied by publisher]

Fimasartan-induced liver injury in a patient with no adverse reactions on other types of angiotensin II receptor blockers: A case report.

Medicine (Baltimore). 2017 Nov;96(47):e8905

Authors: Park DH, Yun GY, Eun HS, Joo JS, Kim JS, Kang SH, Moon HS, Lee ES, Lee BS, Kim KH, Kim SH

Abstract
RATIONALE: Angiotensin II receptor blockers (ARBs) are widely used for patients with hypertension, and fimasartan is a recently approved ARBs. Fimasartan can cause headache, dizziness, itching, and coughing. There have been several reports of hepatotoxicity in ARBs. However, there have not yet been published reports of the hepatotoxicity of fimasartan.
PATIENT CONCERNS: A 73-year-old man with hypertension experienced liver injury after fimasartan administration. He had a previous history of taking 3 types of ARBs each for more than 2 years before taking fimasartan, and there were no side effects on ARBs except for fimasartan.
DIAGNOSES: Other factors that could cause liver injury were excluded in diagnostic tests, and fimasartan was suspected to be the causative agent.
INTERVENTION: Fimasartan was immediately discontinued and the patient was managed with supportive care via hepatotonics.
DIAGNOSES: Other factors that could cause liver injury were excluded in diagnostic tests, and fimasartan was suspected to be the causative agent.
OUTCOME: The liver injury due to fimasartan was confirmed by histology and accidental redosing.
LESSONS: We emphasize that liver function should be monitored during fimasartan administration because fimasartan may cause hepatotoxicity in patients who have no side effects with other types of ARBs. And fimasartan-induced liver injury may appear later than other ARBs.

PMID: 29382024 [PubMed - indexed for MEDLINE]

Magnitude of Antiretroviral Drug Toxicity in Adult HIV Patients in Ethiopia: A cohort study at seven teaching hospitals.

Ethiop J Health Sci. 2017 Feb;27(Suppl 1):39-52

Authors: Gudina EK, Teklu AM, Berhan A, Gebreegziabhier A, Seyoum T, Nega A, Medhin G, Kebede A, Assefa Y

Abstract
BACKGROUND: The introduction of antiretroviral therapy (ART) has resulted in significant mortality reduction and improvement in the quality of life. However, this has come at a cost of increased drug toxicity. The objective of this study was to assess the patterns and predictors of ART toxicity in adult HIV patients in Ethiopia.
METHODS: This is a prospective cohort study conducted at seven teaching hospitals between September 2009 and December 2013 involving 3921 HIV patients on ART. Adverse drug reactions (ADR) due to ART were identified based on clinical assessment and/or laboratory parameters. Multivariable random effects Poisson regression analysis was used to identify factors independently associated with toxicity.
RESULT: ADR due to ART drugs was reported in 867 (22.1 %) of the participants; 374 (9.5%) had severe forms. About 87% of reported toxicities were limited to three organ systems - the skin, nervous system and blood. The overall incidence of ADR was 9 per 100 person years. About a third of toxicities occurred during the first six months after ART initiation with the incidence rate of 22.4 per 100 person years. Concomitant anti-tuberculosis treatment was the strongest independent predictor of toxicity.
CONCLUSION: ADR was found to be highly prevalent in HIV patients on ART at tertiary hospitals in Ethiopia. Most of these conditions occurred early after ART initiation and in those with concomitant anti-tuberculosis treatment. Thus, routine monitoring of patients on ART should be strengthened with particular emphasis in the first 6 months. Strategies should also be devised to replace older and more toxic agents with newer and safer drugs available.

PMID: 28465652 [PubMed - indexed for MEDLINE]

Adverse events in hospitalised cancer patients: a comparison to a general hospital population.

Acta Oncol. 2017 Sep;56(9):1218-1223

Authors: Haukland EC, von Plessen C, Nieder C, Vonen B

Abstract
BACKGROUND: Patients with cancer are often treated by many healthcare providers, receive complex and potentially toxic treatments that can increase the risk for iatrogenic harm. The aim of this study is to investigate whether hospitalised cancer patients are at higher risk of adverse events (AEs) compared to a general hospital population.
MATERIAL AND METHODS: A total of 6720 patient records were retrospectively reviewed comparing AEs in hospitalised cancer patients to a general hospital population in Norway, using the IHI Global Trigger Tool method.
RESULTS: 24.2 percent of admissions for cancer patients had an AE compared to 17.4% of admissions of other patients (p < .001, rr 1.39, 95% CI 1.19-1.62). However, cancer patients did not have a higher rate of AEs per 1000 patient days compared to other patients, 37.1 vs. 36.0 (p = .65, rr 0.94, 95% CI 0.90-1.18). No particular cancer category is at higher risk. The rate of AEs increases by 1.05 times for each day spent in hospital. For every year increase in age, the risk for AEs increases by 1.3%. Cancer patients more often have hospital-acquired infections, other surgical complications and AEs related to medications.
CONCLUSIONS: Because of higher age, longer length of stay and surgical treatment, hospitalised cancer patients experience AEs more often than other patients.

PMID: 28379721 [PubMed - indexed for MEDLINE]

Immunogenicity and safety of an adjuvanted herpes zoster subunit candidate vaccine in adults ≥ 50 years of age with a prior history of herpes zoster: A phase III, non-randomized, open-label clinical trial.

Hum Vaccin Immunother. 2017 May 04;13(5):1051-1058

Authors: Godeaux O, Kovac M, Shu D, Grupping K, Campora L, Douha M, Heineman TC, Lal H

Abstract
This phase III, non-randomized, open-label, multi-center study (NCT01827839) evaluated the immunogenicity and safety of an adjuvanted recombinant subunit herpes zoster (HZ) vaccine (HZ/su) in adults aged ≥ 50 y with prior physician-documented history of HZ. Participants (stratified by age: 50-59, 60-69 and ≥ 70 y) received 2 doses of HZ/su 2 months apart and were followed-up for another 12 months. Anti-glycoprotein E (gE) antibodies were measured by enzyme-linked immunosorbent assay before vaccination and 1 month after the second dose (Month 3). Solicited local and general adverse events (AEs) were recorded for 7 d and unsolicited AEs for 30 d after each vaccination. Serious AEs were recorded until study end. The primary immunogenicity objective was met if the lower limit of the 95% confidence interval (CI) of the vaccine response rate (VRR), defined as a 4-fold increase in anti-gE over baseline, at Month 3 was ≥ 60%. 96 participants (32/age group) were enrolled. The primary immunogenicity objective was met, as the VRR at Month 3 was 90.2% (95% CI: 81.7-95.7). Geometric mean anti-gE antibody concentrations at Month 3 were similar across age groups. 77.9% and 71.6% of participants reported local and general solicited AEs, respectively. The most frequent solicited AEs were pain at injection site, fatigue, headache, myalgia and shivering. The HZ/su vaccine was immunogenic in adults aged ≥ 50 y with a physician-documented history of HZ, and no safety concerns were identified.

PMID: 28068212 [PubMed - indexed for MEDLINE]

Nivolumab in the Treatment of Hodgkin Lymphoma.

Clin Cancer Res. 2017 Apr 01;23(7):1623-1626

Authors: Ansell SM

Abstract
Despite an extensive immune infiltrate that is recruited to the tumor by malignant Reed-Sternberg cells in Hodgkin lymphoma, the antitumor immune response is ineffective and unable to eradicate the malignant cells. The ineffective immune response is in part due to PD-1 signaling that renders intratumoral immune cells anergic. Reed-Sternberg cells have been shown to upregulate expression of the PD-1 ligands, PD-L1 and PD-L2, due to either genetic alterations at chromosome 9p24.1 or Epstein-Barr virus infection, and these ligands suppress the function of PD-1+ intratumoral T cells. Blockade of PD-1 signaling has proven to be a highly successful therapeutic approach, and the use of the anti-PD-1 mAb nivolumab recently received accelerated approval by the FDA for patients with classical Hodgkin lymphoma that has relapsed or progressed after autologous stem cell transplant and posttransplantation brentuximab vedotin. Initial clinical trials using nivolumab in this patient population resulted in high response rates that were durable. Adverse events associated with nivolumab included immune-mediated adverse reactions and infusion reactions, but these were well tolerated, allowing for continued nivolumab administration. Clinical trials are now in progress to test the use of nivolumab in combination with standard chemotherapy or with novel agents with a goal of improving the outcome of patients with Hodgkin lymphoma. Clin Cancer Res; 23(7); 1623-6. ©2016 AACR.

PMID: 27881581 [PubMed - indexed for MEDLINE]

Monitoring potential adverse event rate differences using data from blinded trials: the canary in the coal mine.

Stat Med. 2017 Jan 15;36(1):92-104

Authors: Gould AL, Wang WB

Abstract
The development of drugs and biologicals whose mechanisms of action may extend beyond their target indications has led to a need to identify unexpected potential toxicities promptly even while blinded clinical trials are under way. One component of recently issued FDA rules regarding safety reporting requirements raises the possibility of breaking the blind for pre-identified serious adverse events that are not the clinical endpoints of a blinded study. Concern has been expressed that unblinding individual cases of frequently occurring adverse events could compromise the overall validity of the study. However, if external information is available about adverse event rates among patients not receiving the test product in populations similar to the study population, then it may be possible to address the potential for elevated risk without unblinding the trial. This article describes a Bayesian approach for determining the likelihood of elevated risk suitable binomial or Poisson likelihoods that applies regardless of the metric used to express the difference. The method appears to be particularly appropriate for routine monitoring of safety information for project development programs that include large blinded trials. Copyright © 2016 John Wiley & Sons, Ltd.

PMID: 27666940 [PubMed - indexed for MEDLINE]

Randomized Multicenter Study Comparing Safety and Efficacy of Daptomycin Versus Standard of Care in Pediatric Patients with Staphylococcal Bacteremia.

Pediatr Infect Dis J. 2018 Feb 03;:

Authors: Arrieta AC, Bradley JS, Popejoy MW, Bensaci M, Grandhi A, Bokesch P, Glasser C, Du L, Kartsonis NA

Abstract
BACKGROUND: Staphylococcus aureus, including community-associated methicillin-resistant S. aureus, is an important cause of pediatric bacteremia. Daptomycin is a well-established treatment option for gram-positive bacteremia in adults, but its safety and efficacy in children require confirmation.
METHODS: This was a randomized (2:1), evaluator-blinded, multi-center, phase 4 clinical trial comparing intravenous daptomycin with standard-of-care (SOC) for treatment of S. aureus bacteremia in 1-17 year-old patients. Total treatment duration (intravenous followed by oral step-down therapy) was 5-42 days. Daptomycin was dosed once daily by patient age: 12-17 years, 7 mg/kg; 7-11 years, 9 mg/kg; 1-6 years, 12 mg/kg. The primary objective was to evaluate daptomycin safety in children who received ≥1 dose; secondary objectives included comparing daptomycin efficacy with SOC (the trial was not designed to confirm non-inferiority), and pharmacokinetic analysis.
RESULTS: 55 children were randomized to daptomycin and 27 to SOC (primarily vancomycin or cefazolin); 90% had S. aureus. In both groups, 15% of patients had drug-related adverse events, primarily diarrhea (4% daptomycin, 8% SOC) and increased creatine phosphokinase (4% daptomycin, 0% SOC). Clinical success (blinded evaluator-assessed complete/partial resolution of bacteremia signs and symptoms 7-14 days after end-of-treatment) rates were similar for daptomycin (88%) and SOC (77%; 95% CI for difference: -9% to 31%). Daptomycin plasma levels across age groups were comparable to those in adults receiving daptomycin at 6 mg/kg.
CONCLUSIONS: Once-daily, age-appropriate daptomycin was well tolerated in children with staphylococcal bacteremia; efficacy was comparable to SOC. Daptomycin in age-adjusted doses is a safe treatment alternative in this setting.(clinicaltrials.gov NCT01728376).

PMID: 29406465 [PubMed - as supplied by publisher]

Drug-Induced Ototoxicity: Diagnosis and Monitoring.

Drug Saf. 2018 Feb 06;:

Authors: Campbell KCM, Le Prell CG

Abstract
Ototoxicity diagnosis and management has historically been approached using a variety of methods. However, in recent years a consensus on useful and practical approaches has been developed through clinical guidelines of the American Speech Language Hearing Association, the American Academy of Audiology, and multiple clinical trials published in peer-reviewed literature. Some of the guidelines and approaches are used to detect and monitor ototoxicity, while others are used to grade adverse events. Some of the audiologic measures are primary, while others are adjunct measures and may be tailored to the specific needs of the patient or clinical trial. For some types of monitoring, such as drug-induced tinnitus or dizziness, validated paper survey instruments can be both sensitive and easy for fragile patients. This review addresses the characteristics of some of the most common clinical ototoxins and the most common methods for detecting and monitoring ototoxicity in clinical practice and clinical trials.

PMID: 29404977 [PubMed - as supplied by publisher]

Ketamine for Pain Management-Side Effects & Potential Adverse Events.

Pain Manag Nurs. 2017 Dec;18(6):372-377

Authors: Allen CA, Ivester JR

Abstract
An old anesthetic agent, ketamine is finding new use in lower doses for analgesic purposes. There are concerns stemming from its potential side effects-specifically psychomimetic effects. These side effects are directly related to dose amount. The doses used for analgesic purposes are much lower than those used for anesthesia purposes. A literature review was performed to ascertain potential side effects and/or adverse events when using ketamine for analgesia purposes. The search included CINAHL, PubMed, and Ovid using the search terms "ketamine," "ketamine infusion," "pain," "adverse events," "practice guideline," and "randomized controlled trial." Searches were limited to full-text, peer-reviewed articles and systematic reviews. Initially 1,068 articles were retrieved. The search was then narrowed by using the Boolean connector AND with various search term combinations. After adjusting for duplication, article titles and abstracts were reviewed, leaving 25 articles for an in-depth analysis. Specific exclusion criteria were then applied. The literature supports the use of ketamine for analgesic purposes, and ketamine offers a nonopioid option for the management of some pain conditions. Because ketamine is still classified as an anesthetic agent, health care institutions should develop their own set of policies and protocols for the administration of ketamine. By using forethought and understanding of the properties of ketamine, appropriate care may be planned to mitigate potential side effects and adverse events so that patients are appropriately cared for and their pain effectively managed.

PMID: 28743507 [PubMed - indexed for MEDLINE]

Psychiatric side effects and antiepileptic drugs: Observations from prospective audits.

Epilepsy Behav. 2017 Jun;71(Pt A):73-78

Authors: Stephen LJ, Wishart A, Brodie MJ

Abstract
Psychiatric comorbidities are common in people with epilepsy. A retrospective study of characteristics associated with withdrawal due to psychiatric side effects was undertaken in patients with treated epilepsy participating in prospective audits with new antiepileptic drugs (AEDs). A total of 1058 treated patients with uncontrolled seizures (942 focal-onset seizures, 116 generalized genetic epilepsies [GGEs]) participated in eight prospective, observational audits from 1996 to 2014. These patients were prescribed adjunctive topiramate (n=170), levetiracetam (n=220), pregabalin (n=135), zonisamide (n=203), lacosamide (n=160), eslicarbazepine acetate (n=52), retigabine (n=64), or perampanel (n=54). Doses were titrated according to efficacy and tolerability to optimize zeizure outcomes and reduce side effects. Psychiatric comorbidities were recorded prior to and after the addition of each AED. At baseline, patients with focal-onset seizures (189 of 942; 20.1%) were statistically more likely to have psychiatric diagnoses compared to patients with GGEs (14 of 116, 12.1%; p=0.039). Following adjunctive AED treatment, neuropsychiatric adverse effects led to AED withdrawal in 1.9-16.7% of patients. Patients with a pre-treatment psychiatric history (22 of 209; 10.5%) were statistically more likely to discontinue their new AED due to psychiatric issues compared to patients with no previous psychiatric diagnosis (50 of 849; 5.9%; p=0.017). Patients receiving sodium channel blocking AEDs (4 of 212, 1.9%) were statistically less likely to develop intolerable psychiatric problems, compared to those on AEDs possessing other mechanisms of action (68 of 846, 8.0%; p=0.012). Depression was the commonest problem, leading to discontinuation of AEDs in 2.8% (n=30) patients. Aggression was statistically more common in men (11 of 527, 2.1%) compared to women (1 of 531, 0.2%; p=0.004). Patients with learning disability (12 of 122, 9.8%; p=0.0015) were statistically less likely to have psychiatric issues prior to adjunctive AED treatment compared to other patients (208 of 936, 22.2%), but there were no statistically significant differences once the new AEDs were added (8 of 122 patients with learning disability, 6.6%; 64 of 936 other patients, 6.8%). Awareness of these issues may assist clinicians in avoiding, identifying and treating psychiatric comorbidities in people with epilepsy.

PMID: 28551500 [PubMed - indexed for MEDLINE]

Potential drug-drug interactions and adverse drug reactions in dermatological inpatients.

J Dtsch Dermatol Ges. 2016 Nov;14(11):1122-1129

Authors: Koch L, Kränke B, Aberer W

Abstract
OBJECTIVES: To present information on the frequency of drug-drug interactions and adverse drug reactions, and to provide assistance on how to minimize these major problems in the pharmacological treatment of dermatological inpatients.
PATIENTS AND METHODS: The medications given to 1,099 dermatological inpatients were retrospectively analyzed for drug-drug interactions and adverse drug reactions using web-based drug interaction software (Diagnosia® Check).
RESULTS: We report an overall frequency of relevant drug-drug interactions of 51.7 %, with an average of 3.2 interactions per affected inpatient. Drug combinations that should have been avoided were found in 5.7 % of the study population. Total drug count was the most important risk factor. Drug groups involved in the majority of interactions were analgesics, cardiovascular and antithrombotic agents, as well as antidepressants. The risk of developing adverse drug reactions was rated as "high" in 53.1 % of inpatients. The top five adverse reactions in this patient group were bleeding, constipation, anticholinergic effects, sedation, and orthostatic effects.
CONCLUSIONS: Potential drug-drug interactions as well as adverse drug reactions are alarmingly common in dermatological inpatients. Every other patient is at risk of experiencing such interactions or adverse reactions, and every twentieth patient receives a drug combination that should not be administered. Increased alertness is a must in order to identify patients at risk.

PMID: 27879085 [PubMed - indexed for MEDLINE]

Drug survival rates and reasons for drug discontinuation in psoriasis.

J Dtsch Dermatol Ges. 2016 Nov;14(11):1089-1099

Authors: Arnold T, Schaarschmidt ML, Herr R, Fischer JE, Goerdt S, Peitsch WK

Abstract
BACKGROUND AND OBJECTIVES: Moderate-to-severe psoriasis frequently requires long-term systemic therapy. Reflecting efficacy, safety, and treatment satisfaction, drug survival is an indicator of therapeutic success. The objective of the present study was to assess drug survival rates and reasons for discontinuation of fumaric acid esters (FAE), methotrexate (MTX), acitretin (ACI), cyclosporine A (CyA), adalimumab (ADA), etanercept (ETA), infliximab (INF), and ustekinumab (UST) in patients with moderate-to-severe psoriasis.
PATIENTS AND METHODS: We performed a retrospective analysis of 373 patients who had received a total of 696 treatment courses at a German university hospital in the period 1/2003-5/2014.
RESULTS: The crude probability of survival was highest for UST, followed by ADA, ETA, INF, FAE, MTX, ACI, and CyA. In multivariate regression analysis using FAE as reference, hazard ratios (HR) for discontinuation were 0.14 (95 % confidence interval: 0.06-0.35) for UST, 0.43 (0.26-0.73) for ADA, 2.11 (1.14-3.91) for ACI, and 3.26 (1.44-7.39) for CyA. INF showed longer survival when combined with MTX (HR 2.87, 1.21-6.81). Traditional systemic antipsoriatic agents as well as INF were most frequently discontinued due to adverse events; all other biologics, due to inefficacy with respect to cutaneous lesions.
CONCLUSIONS: Drug survival rates should be integrated into therapeutic decisions in order to provide patients with an optimal long-term strategy.

PMID: 27879076 [PubMed - indexed for MEDLINE]

U.S. Food and Drug Administration Approval: Cabozantinib for the Treatment of Advanced Renal Cell Carcinoma.

Clin Cancer Res. 2017 Jan 15;23(2):330-335

Authors: Singh H, Brave M, Beaver JA, Cheng J, Tang S, Zahalka E, Palmby TR, Venugopal R, Song P, Liu Q, Liu C, Yu J, Chen XH, Wang X, Wang Y, Kluetz PG, Daniels SR, Papadopoulos EJ, Sridhara R, McKee AE, Ibrahim A, Kim G, Pazdur R

Abstract
On April 25, 2016, the FDA approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of advanced renal cell carcinoma (RCC) in patients who have received prior antiangiogenic therapy. The approval was based on data from one randomized, open-label, multicenter study in which patients with RCC who had received prior antiangiogenic therapy were treated with either cabozantinib 60 mg orally once daily (n = 330) or everolimus 10 mg orally once daily (n = 328). The major efficacy outcome measure was progression-free survival (PFS) as assessed by a blinded independent radiology review committee in the first 375 randomized patients. A statistically significant improvement in PFS was seen, with a median PFS of 7.4 and 3.8 months in the cabozantinib and everolimus arms, respectively [hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.45-0.74; P < 0.0001]. At a second interim analysis, a statistically significant improvement in overall survival (OS) in the intent-to-treat population was also demonstrated, with a median OS of 21.4 and 16.5 months in the cabozantinib and everolimus arms, respectively (HR, 0.66; 95% CI, 0.53-0.83; P = 0.0003). The most common (greater than or equal to 25%) adverse reactions included diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia syndrome, hypertension, vomiting, weight loss, and constipation. Clin Cancer Res; 23(2); 330-5. ©2016 AACR.

PMID: 27793960 [PubMed - indexed for MEDLINE]