Genome-wide and Phenome-wide Approaches to Understand Variable Drug Actions in Electronic Health Records.

Clin Transl Sci. 2018 03;11(2):112-122

Authors: Robinson JR, Denny JC, Roden DM, Van Driest SL

PMID: 29148204 [PubMed - indexed for MEDLINE]

Factors associated with polypharmacy in elderly home-care patients.

Geriatr Gerontol Int. 2018 Jan;18(1):33-41

Authors: Komiya H, Umegaki H, Asai A, Kanda S, Maeda K, Shimojima T, Nomura H, Kuzuya M

Abstract
AIM: Polypharmacy, which is often observed in elderly patients, has been associated with several unfavorable outcomes, including an increased risk of potentially inappropriate medications, medication non-adherence, drug duplication, drug-drug interactions, higher healthcare costs and adverse drug reactions. A significant association between polypharmacy and adverse outcomes among older people living in the community has also been confirmed. A reduction in the number of medications should thus be pursued for many older individuals. Nevertheless, the factors associated with polypharmacy in elderly home-care patients have not been reported. Here, we investigated those factors in elderly home-care patients in Japan.
METHODS: We used the data of the participants in the Observational Study of Nagoya Elderly with Home Medical investigation. Polypharmacy was defined as the current use of six or more different medications. We carried out univariate and multivariate logistic regression analyses to assess the associations between polypharmacy and each of several factors.
RESULTS: A total of 153 home-care patients were registered. The mean number of medications used per patient was 5.9, and 51.5% of the patients belonged to the polypharmacy group. The multivariate model showed that the patients' scores on the Charlson Comorbidity Index and the Mini-Nutrition Assessment Short Form were inversely associated with polypharmacy, and potentially inappropriate medication was most strongly associated with polypharmacy (odds ratio 4.992).
CONCLUSIONS: The present findings showed that polypharmacy was quite common among the elderly home-care patients, and they suggest that home-care physicians should prescribe fewer medications in accord with the deterioration of home-care patients' general condition. Geriatr Gerontol Int 2018; 18: 33-41.

PMID: 28786554 [PubMed - indexed for MEDLINE]

Cyclophosphamide and the taste system: Effects of dose fractionation and amifostine on taste cell renewal.

PLoS One. 2019;14(4):e0214890

Authors: Delay ER, Socia SH, Girardin JL, Jewkes BC, King JH, Delay RJ

Abstract
Chemotherapy often causes side effects that include disturbances in taste functions. Cyclophosphamide (CYP) is a chemotherapy drug that, after a single dose, elevates murine taste thresholds at times related to drug-induced losses of taste sensory cells and disruptions of proliferating cells that renew taste sensory cells. Pretreatment with amifostine can protect the taste system from many of these effects. This study compared the effects of a single dose (75 mg/kg) of CYP with effects generated by fractionated dosing of CYP (5 doses of 15 mg/kg), a dosing approach often used during chemotherapy, on the taste system of mice using immunohistochemistry. Dose fractionation prolonged the suppressive effects of CYP on cell proliferation responsible for renewal of taste sensory cells. Fractionation also reduced the total number of cells and the proportion of Type II cells within taste buds. The post-injection time of these losses coincided with the life span of Type I and II taste cells combined with lack of replacement cells. Fractionated dosing also decreased Type III cells more than a single dose, but loss of these cells may be due to factors related to the general health and/or cell renewal of taste buds rather than the life span of Type III cells. In general, pretreatment with amifostine appeared to protect taste cell renewal and the population of cells within taste buds from the cytotoxic effects of CYP with few observable adverse effects due to repeated administration. These findings may have important implications for patients undergoing chemotherapy.

PMID: 30947285 [PubMed - in process]

Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program.

J Immunother Cancer. 2019 Apr 03;7(1):99

Authors: Verzoni E, Cartenì G, Cortesi E, Giannarelli D, De Giglio A, Sabbatini R, Buti S, Rossetti S, Cognetti F, Rastelli F, Sobrero A, Turci D, Sternberg CN, Porta C, Cappuzzo F, Tortora G, Tassinari D, Panni S, Pazzola A, Surico G, Raimondi A, De Giorgi U, Procopio G, Italian Nivolumab Renal Cell Cancer Early Access Program group

Abstract
BACKGROUND: The Italian Renal Cell Cancer Early Access Program was an expanded access program that allowed access to nivolumab, for patients (pts) with metastatic renal cell carcinoma (mRCC) prior to regulatory approval.
METHODS: Pts with previously treated advanced or mRCC were eligible to receive nivolumab 3 mg/kg every 2 weeks. Pts included in the analysis had received ≥1 dose of nivolumab and were monitored for drug-related adverse events (drAEs) using CTCAE v.4.0. Immune-related (ir) AEs were defined as AEs displaying a certain, likely or possible correlation with immunotherapy (cutaneous, endocrine, hepatic, gastro-intestinal and pulmonary). The association between overall survival (OS) and irAEs was assessed, and associations between variables were evaluated with a logistic regression model.
RESULTS: A total of 389 pts were enrolled between July 2015 and April 2016. Overall, the objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% CI 3.7-6.2) and the 12-month overall survival rate was 63%. Any grade and grade 3-4 drAEs were reported in 124 (32%) and 27 (7%) of pts, respectively, and there were no treatment-related deaths. Any grade irAEs occurred in 76 (20%) of patients, 8% cutaneous, 4% endocrine, 2% hepatic, 5% gastro-intestinal and 1% pulmonary. Of the 22 drAEs inducing treatment discontinuation, 10 (45%) were irAEs. Pts with drAEs had a significantly longer survival than those without drAEs (median OS 22.5 versus 16.4 months, p = 0.01). Pts with irAEs versus without irAEs had a more significant survival benefit (median OS not reached versus 16.8 months, p = 0.002), confirmed at the landmark analysis at 6 weeks. The occurrence of irAEs displayed a strong association with OS in univariable (HR 0.48, p = 0.003) and multivariable (HR 0.57, p = 0.02) analysis.
CONCLUSIONS: The appearance of irAEs strongly correlates with survival benefit in a real-life population of mRCC pts treated with nivolumab.

PMID: 30944023 [PubMed - in process]

Hepatobiliary and pancreatic manifestations in inflammatory bowel diseases: a referral center study.

BMC Gastroenterol. 2019 Apr 03;19(1):48

Authors: Fousekis FS, Katsanos KH, Theopistos VI, Baltayiannis G, Kosmidou M, Glantzounis G, Christou L, Tsianos EV, Christodoulou DK

Abstract
BACKGROUND: Hepatobiliary and pancreatic manifestations have been reported in patients with Crohn's disease or ulcerative colitis. Our aim was to describe the prevalence of hepatobiliary and pancreatic manifestations in inflammatory bowel disease and their association with the disease itself and the medications used.
METHODS: Data were retrospectively extracted from the clinical records of patients followed up at our tertiary IBD referral Center.
RESULTS: Our study included 602 IBD patients, with liver function tests at regular intervals. The mean follow-up was 5.8 years (Std. Dev.: 6.72). Abdominal imaging examinations were present in 220 patients and revealed findings from the liver, biliary tract and pancreas in 55% of examined patients (120/220). The most frequent findings or manifestations from the liver, biliary tract and pancreas were fatty liver (20%, 44/220), cholelithiasis (14.5%, 32/220) and acute pancreatitis (0.6%, 4/602), respectively. There were 7 patients with primary sclerosing cholangitis. Regarding hepatitis viruses, one-third of the patients had been tested for hepatitis B and C. 5% (12/225) of them had positive hepatitis B surface antigen and 13.4% had past infection with hepatitis B virus (positive anti-HBcore). In addition, most of the patients were not immune against hepatitis B (negative anti-HBs), while 3% of patients were anti-HCV positive and only one patient had active hepatitis C. Furthermore, 24 patients had drug-related side effects from the liver and pancreas. The side effects included 21 cases of hepatotoxicity and 3 cases of acute pancreatitis. Moreover, there were two cases of HBV reactivation and one case of chronic hepatitis C, which were successfully treated.
CONCLUSION: In our study, approximately one out of four patients had some kind by a hepatobiliary or pancreatic manifestation. Therefore, it is essential to monitor liver function at regular intervals and differential diagnosis should range from benign diseases and various drug related side effects to severe disorders, such as primary sclerosing cholangitis.

PMID: 30943899 [PubMed - in process]

A Qualitative Analysis of the Impact of Carboplatin AUC 10 on Physical, Work Functioning and Bone Marrow Toxicity Among Seminoma Patients - A Single-centre Experience.

In Vivo. 2019 Jan-Feb;33(1):233-237

Authors: Milic M, Hall M, Hawkins A, Gogbashian A, Rustin G, Sharma A

Abstract
BACKGROUND: Single-agent carboplatin at area under the curve 10 (AUC10) is an effective treatment for metastatic seminoma. As far as we are aware of, there have been no studies reporting its effects on short-term quality of life. The objective was to study the efficacy, safety and tolerability, using health-related quality of life, of carboplatin AUC10 chemotherapy in patients with metastatic seminoma.
PATIENTS AND METHODS: Forty-four patients with metastatic seminoma treated at Mount Vernon Cancer Centre with carboplatin AUC10 were included in this study. Response to treatment was determined by radiological imaging (Response Evaluation Criteria in Solid Tumors v 1.1) and serum tumour markers. Toxicities were evaluated using the Common Terminology Criteria for Adverse Events Version 4.0. Quality of life treatment-related toxicities were assessed during treatment at pre-chemotherapy assessments. After treatment, toxicity was assessed using a defined telephone questionnaire consisting of four questions relating to hair loss, hearing impairment, days absent from work, and neuropathy.
RESULTS: At a median follow-up of 27.5 (range=4-84) months, no patient had experienced relapse. Grade 3/4 neutropenia was seen in 15 (35%) patients, nine (21%) required prophylactic granulocyte colony-stimulating factor, 13 (30%) patients had grade 3/4 thrombocytopenia. Commonest non-haematological toxicities were fatigue in 28 (65%) and nausea 14 (33%) patients. They were grade 1 in 82% and 92% of cases, respectively. Six out of 44 (14%) had residual tinnitus. One patient had residual grade 1 peripheral neuropathy. Ten patients continued to work throughout treatment and two patients were retired. Of the remaining patients, 16 (37%), took fewer than 5 days off work.
CONCLUSION: Carboplatin AUC10 is a safe and effective treatment for stage II/III seminoma with better health-related quality of life than experienced with combination cisplatin-based chemotherapy.

PMID: 30587629 [PubMed - indexed for MEDLINE]

Chiral pharmaceuticals: Environment sources, potential human health impacts, remediation technologies and future perspective.

Environ Int. 2018 12;121(Pt 1):523-537

Authors: Zhou Y, Wu S, Zhou H, Huang H, Zhao J, Deng Y, Wang H, Yang Y, Yang J, Luo L

Abstract
Chiral pharmaceuticals (CPs), including non-steroid anti-inflammatory drugs (NSAIDs), β-blockers and some herbicide and pesticides, are widely used in aquaculture, clinical treatment and many other fields. However, people are increasingly concerned about such ubiquitous pollutants, which can frequently be detected in contaminated soil and water. In large part, the significant sources of chiral pharmaceuticals stem from industrial processes, such as the direct discharge of untreated or incompletely treated wastewaters containing chiral pharmaceuticals, incorrect storage and use, animal wastes and biosolids. The main ways for human exposure to chiral pharmaceuticals are the disease treatment process and chiral pharmaceuticals contaminants. According to the results of a series of toxic studies, some diseases, even cancers, may be associated with exposure to certain chiral pharmaceuticals. Therefore, the treatment of chiral pharmaceuticals has become an important issue. The current advanced remediation techniques for chiral pharmaceuticals include the conventional method (sorption and sonolysis), biotransformation (an aerobic granular sludge-sequencing batch reactor and constructed wetland system) and advanced oxidation processes (ozonation and photocatalysis). Herein, in this review, we summarize the current status and sources of chiral pharmaceuticals, potential effects on human health, as well as the superiority, disadvantages and prospects of current advanced remediation technologies. Moreover, we also anticipate the prospect of the future research needed for chiral pharmaceuticals pollutant remediation.

PMID: 30292145 [PubMed - indexed for MEDLINE]

Impact of clinical pharmacist engagement in ward teams on the number of drug-related readmissions among older patients with dementia or cognitive impairment: An economic evaluation.

Res Social Adm Pharm. 2019 03;15(3):287-291

Authors: Sjölander M, Lindholm L, Pfister B, Jonsson J, Schneede J, Lövheim H, Gustafsson M

Abstract
BACKGROUND: Clinical pharmacists play an increasing role in the pharmacological treatment of hospital-admitted older patients with dementia or cognitive impairment. In an earlier randomised controlled trial, clinical pharmacist involvement in the ward team could significantly reduce drug-related readmissions in patient subgroups. However, the economic impact of the intervention has not been addressed so far.
OBJECTIVES: To evaluate the economic impact of clinical pharmacist engagement in hospital ward teams for medication therapy management in older patients with dementia or cognitive impairments.
METHODS: Economic evaluation of a randomised controlled trial conducted in two hospitals in Northern Sweden between January 2012 and December 2014. Participants included 460 hospital-admitted older patients with dementia or cognitive impairments. Patients were randomly assigned to usual care, or usual care with pharmacist intervention; the intervention consisted of medication reconciliation, medication review, and participation in ward rounds. The outcomes were measured as drug-related readmissions to hospital as assessed by a group of external experts, 180 and 30 days after discharge. Costs included pharmacists' direct labour costs for the interventions, average costs for drug-related readmissions, and from this the total cost per person was calculated.
RESULTS: The effect of the intervention on drug-related readmissions within 180 days was significant in patients without heart failure (subgroup analysis), and the intervention resulted in cost savings of €950 per person in this subgroup. Drug-related readmissions within 30 days were reduced in the total sample (post-hoc analysis), and the cost-savings in this intervention group were €460 per person.
CONCLUSIONS: Post-hoc and subgroup analyses indicate that engagement of pharmacists in hospital ward teams reduced the number of drug-related readmissions, and that the cost per person was lower in the intervention group compared to the control group. Including clinical pharmacists created savings in the subgroups of older patients with dementia or cognitive impairments.

PMID: 29778344 [PubMed - indexed for MEDLINE]

Beliefs influencing community pharmacists' interventions with chronic kidney disease patients: A theory-based qualitative study.

Res Social Adm Pharm. 2019 02;15(2):145-153

Authors: Quintana-Bárcena P, Lalonde L, Lauzier S

Abstract
BACKGROUND: Drug-related problems (DRPs) are highly prevalent in chronic kidney disease (CKD) patients. Community pharmacists are ideally positioned to manage these DRPs. However, little is known about the factors influencing their interventions with CKD patients.
OBJECTIVES: Using the theory of planned behavior (TPB), this qualitative study sought to: (1) explore the behavioral beliefs (perceived advantages and disadvantages), normative beliefs (perceived expectations of significant others) and control beliefs (perceived barriers and facilitators) influencing community pharmacists' interventions related to identifying and managing DRPs in CKD; and (2) compare these beliefs among three DRPs prevalent in CKD patients.
METHODS: Community pharmacists in Quebec, Canada participated in face-to-face individual semi-structured interviews. The topic guide was based on the TPB. Three vignettes were presented to stimulate community pharmacists' thoughts about their interventions regarding: (1) the use of an inappropriate over-the-counter laxative; (2) prescriptions of anti-inflammatory medications; and (3) non-adherence to antihypertensive medication. Integral transcripts of audio recordings were analyzed using thematic analysis. The findings on each of the three DRPs were systematically compared.
RESULTS: Fifteen community pharmacists participated in the study. All expressed a positive attitude toward DRP management, mentioning advantages such as gaining the patient's loyalty as a client and avoiding CKD complications. Participants mentioned that patients and physicians generally approve their interventions, but the dynamics of these relationships may vary depending on the DRP. Common barriers in the management of the three DRPs were the pharmacists' limited time and heavy workloads. The pharmacists felt that the main disadvantage is that these interventions interrupt the workflow in the pharmacy.
CONCLUSION: Community pharmacists hold positive views of their interventions in CKD. However, enhancing community pharmacists' involvement in CKD care may require measures to facilitate pharmacists' proactivity, inter-professional collaboration and a work organization adapted to clinical activities.

PMID: 29709530 [PubMed - indexed for MEDLINE]

Pharmacists in humanitarian crisis settings: Assessing the impact of pharmacist-delivered home medication management review service to Syrian refugees in Jordan.

Res Social Adm Pharm. 2019 02;15(2):164-172

Authors: Al Alawneh M, Nuaimi N, Basheti IA

Abstract
BACKGROUND: Refugees all over the world are facing several health-related problems. Chronic diseases among Syrian refugees in Jordan are high. The Home Medication Management Review (HMMR) service could be ideal to optimize refugees' health management.
OBJECTIVES: To assess the impact of the HMMR service on the type and frequency of Treatment Related Problems (TRPs) among Syrian refugees living in Jordan.
METHODS: This prospective randomized single blinded intervention-control study was conducted in three main cities in Jordan, between May and October 2016. Syrian refugees with chronic conditions were recruited and randomized into intervention and control groups. The HMMR service was conducted for all patients to identify TRPs at baseline. Data were collected via two home visits for all study participants. Clinical pharmacist's recommendations were written in a letter format to the physicians managing the patients in the intervention group only. Physicians' approved recommendations were conveyed to the patients via the pharmacist. Interventions at the patient level were delivered by the pharmacist directly. Patients were reassessed for their TRPs and satisfaction 3 months after baseline.
RESULTS: Syrian refugees (n = 106) were recruited with no significant differences between the intervention (n = 53) and control groups (n = 53). A total of 1141 TRPs were identified for both groups at baseline, with a mean number of 10.8 ± 4.2 TRPs per patient. At follow-up, there was a significant decrease in the number of TRPs among the intervention group (P < 0.001, paired sample t-test) but not among the control group (P = 0.116). Physicians' approval rate of the pharmacist's recommendations was high (82.9%), and more than 70.0% of refugees in the intervention group reported high satisfaction with the HMMR service.
CONCLUSION: Identified TRPs are high amongst Syrian refugees living in Jordan. The HMMR service significantly reduced the number of TRPs, and was highly accepted by the physicians. Refugees reported high satisfaction with this service.

PMID: 29661563 [PubMed - indexed for MEDLINE]

Safety and Efficacy of Atazanavir Powder and Ritonavir in HIV-1-Infected Infants and Children From 3 Months to <11 Years of Age: The PRINCE-2 Study.

Pediatr Infect Dis J. 2018 06;37(6):e149-e156

Authors: Cotton MF, Liberty A, Torres-Escobar I, Gonzalez-Tome MI, Lissens J, Zaru L, Klauck I, Cambilargiu D, Pikora C, Correll TA

Abstract
BACKGROUND: Novel antiretroviral formulations that are palatable, safe, and effective are needed for infants and children.
METHODS: PRINCE-2 is an ongoing clinical trial assessing safety, efficacy, and palatability of once-daily atazanavir powder formulation boosted with ritonavir (ATV + RTV) plus optimized dual nucleos(t)ide reverse transcriptase inhibitors therapy in antiretroviral-naïve/experienced children with screening HIV-1 RNA ≥1000 copies/mL. Children 3 months to <11 years received ATV + RTV by 5 baseline weight bands: 5 to <10 kg = 150/80 mg; 5 to <10 kg = 200/80 mg; 10 to <15 kg = 200/80 mg; 15 to <25 kg = 250/80 mg; and 25 to <35 kg = 300/100 mg.
RESULTS: Of 99 treated children, 83.8% and 59.6% remained on ATV powder until 24 and 48 weeks, respectively. Through 48 weeks, the most common adverse events were upper respiratory tract infections (33.3%), gastroenteritis (28.3%), vomiting (21.2%) and hyperbilirubinemia (18.2%; none leading to treatment discontinuation). Serious adverse events occurred in 20.2% of patients. Laboratory grade 3-4 hyperbilirubinemia occurred in 9.2% and elevated total/pancreatic amylase in 33.7%/3.1%. At week 24, proportions with virologic suppression (HIV-1 RNA <50 copies/mL; intention-to-treat analysis) across weight bands were 10/23 (43.5%), 2/12 (16.5%), 10/21 (47.6%), 19/35 (54.3%) and 5/8 (62.5%), respectively. Virologic suppression was similar in antiretroviral-naïve/experienced patients and lowest in the 5 to <10 kg = 200/80 mg group, likely because of higher baseline HIV-1 RNA and discontinuation (66.7%). Overall, virologic suppression at weeks 24 (46.5%) and 48 (43.0%) was comparable. At week 48, 83.3% and 74.1% of caregivers reported no trouble giving ATV powder and RTV, respectively.
CONCLUSIONS: ATV powder palatability, efficacy and lack of unexpected safety findings support its use for HIV-1-infected children ≥3 months to <11 years.

PMID: 29206747 [PubMed - indexed for MEDLINE]

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2019/04/04

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2019/04/04

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Phase II Study of Lenvatinib in Patients With Progressive, Recurrent or Metastatic Adenoid Cystic Carcinoma.

J Clin Oncol. 2019 Apr 02;:JCO1801859

Authors: Tchekmedyian V, Sherman EJ, Dunn L, Tran C, Baxi S, Katabi N, Antonescu CR, Ostrovnaya I, Haque SS, Pfister DG, Ho AL

Abstract
PURPOSE: Recurrent or metastatic adenoid cystic carcinoma (R/M ACC) is a malignant neoplasm of predominantly salivary gland origin for which effective therapies are lacking. We conducted a phase II trial evaluating the multitargeted tyrosine kinase inhibitor lenvatinib in patients with R/M ACC.
PATIENTS AND METHODS: This study was conducted with a two-stage minimax design. Patients with histologically confirmed R/M ACC of any primary site with radiographic and/or symptomatic progression were eligible. Any prior therapy was allowed except previous lenvatinib. Patients received lenvatinib 24 mg orally per day. The primary end point was overall response rate. Secondary end points were progression-free survival and safety. An exploratory analysis of how MYB expression and genomic alterations relate to outcomes was conducted.
RESULTS: Thirty-three patients were enrolled; 32 were evaluable for the primary end point. Five patients (15.6%) had a confirmed partial response, 24 patients (75%) had stable disease, two patients (6.3%) discontinued treatment as a result of toxicity before the first scan, and one patient (3.1%) had progression of disease as best response. Median progression-free survival time was 17.5 months (95% CI, 7.2 months to not reached), although only eight progression events were observed. Patients otherwise were removed for toxicity (n = 5), as a result of withdrawal of consent (n = 9), or at the treating physician's discretion (n = 6). Twenty-three patients required at least one dose modification, and 18 of 32 patients discontinued lenvatinib for drug-related issues. The most common grade 3 or 4 adverse events were hypertension (n = 9; 28.1%) and oral pain (n = 3; 9.4%). Three grade 4 adverse events were observed (myocardial infarction, n = 1; posterior reversible encephalopathy syndrome, n = 1; and intracranial hemorrhage, n = 1).
CONCLUSION: This trial met the prespecified overall response rate primary end point, demonstrating antitumor activity with lenvatinib in R/M ACC patients. Toxicity was comparable to previous studies, requiring monitoring and management.

PMID: 30939095 [PubMed - as supplied by publisher]

Butorphanol-Azaperone-Medetomidine for the Immobilization of Rhesus Macaques (Macaca mulatta).

J Am Assoc Lab Anim Sci. 2019 Apr 01;:

Authors: Malinowski CM, Cameron AI, Burnside WM, West SE, Nunamaker EA

Abstract
Maximizing animal wellbeing by minimizing drug-related side effects is a key consideration when choosing pharmaceuticalagents for chemical restraint in nonhuman primates. One drug combination that may promote this ideology is butorphanol(27.3 mg/mL), azaperone (9.1 mg/mL), and medetomidine (10.9 mg/mL; BAM). Based on results from a pilot study, 2 doses ofBAM (16 and 24 μL/kg IM) were compared in healthy, 3-y-old rhesus macaques. Physiologic parameters and anesthetic quality were assessed and recorded every 5 min. Experimental endpoints were established for hypoxemia (85% or less peripheral oxygen saturation with oxygen supplementation), pulse rate (80 bpm or less for 2 consecutive readings), mean arterial pressure(MAP; 50 mm Hg or less), and hypothermia (97 °F or less); if any endpoint was achieved, medetomidine was reversed by using atipamezole (0.22 mg/kg IM). Both BAM doses resulted in immobilization of all animals with no clinically significantdifferences between groups. All animals initially exhibited hypoxemia that resolved with oxygen supplementation. Regardlessof dose, most macaques (71%) reached established experimental endpoints for bradycardia (62 to 80 bpm) or hypotension(44 to 50 mm Hg MAP). Given the results of this study, our recommendation regarding the use of 16- or 24-μL/kg BAM forimmobilizing rhesus macaques is dependent on caution regarding cardiopulmonary parameters and the provision of supplementaloxygen.

PMID: 30935442 [PubMed - as supplied by publisher]

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2019/04/02

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

A first-in-human study of the novel metabolism-based anti-cancer agent SM-88 in subjects with advanced metastatic cancer.

Invest New Drugs. 2019 Mar 30;:

Authors: Stega J, Noel MS, Vandell AG, Stega D, Del Priore G, Hoffman S

Abstract
Purpose SM-88 (D,L-alpha-metyrosine; racemetyrosine) is a novel anti-cancer agent, used with melanin, phenytoin, and sirolimus (SMK Therapy). This pilot first-in-human study characterized the safety, tolerability, and efficacy of SMK Therapy in subjects with advanced metastatic cancer. Methods All subjects (n = 30) received SMK Therapy for an initial 6 week Cycle (5 days on, 2 off per week) and continued if well tolerated. Safety signals, clinical response, overall survival, progression free survival (PFS), and quality of life changes were assessed. Results The most common drug related adverse events were hyperpigmentation and rash. All drug related adverse events were mild to moderate in intensity. Following treatment with SMK Therapy, 4 subjects achieved complete response, 6 partial response, and 17 stable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (total clinical benefit 90%). Responses were observed within 6 weeks, and continued to improve, with 3 complete and 3 partial responders achieving best response after at least 3.2 months. Durable stable disease was observed, lasting a median duration of 11 months (range 1-31 months). Median overall survival for all subjects was 29.8 months, and median PFS was 13 months. Following 6 weeks of treatment, most (83.3%) subjects showed an improvement in Eastern Cooperative Oncology Group (ECOG) score and an improvement in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ 30) global health status (baseline 61.2 ± 25.0; end of Cycle 1 80.7 ± 14.7; n = 29; p < 0.001). Conclusions The results of this study support continued development of SM-88.

PMID: 30929156 [PubMed - as supplied by publisher]

Toxicities with Immune Checkpoint Inhibitors: Emerging Priorities From Disproportionality Analysis of the FDA Adverse Event Reporting System.

Target Oncol. 2019 Mar 29;:

Authors: Raschi E, Mazzarella A, Antonazzo IC, Bendinelli N, Forcesi E, Tuccori M, Moretti U, Poluzzi E, De Ponti F

Abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs), including antibodies targeting cytotoxic T-lymphocyte associated protein 4 (CTLA4) and programmed cell death 1 or its ligand (PD1/PDL1), elicit different immune-related adverse events (irAEs), but their global safety is incompletely characterized.
OBJECTIVE: The aim of this study was to characterize the spectrum, frequency, and clinical features of ICI-related adverse events (AEs) reported to the FDA Adverse Event Reporting System (FAERS).
PATIENTS AND METHODS: AEs from FAERS (up to June 2018) recording ICIs (ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab) as suspect were extracted. Comprehensive disproportionality analyses were performed through the reporting odds ratio (ROR) with 95% confidence interval (95% CI), using other oncological drugs as comparison. An overview of systematic reviews (OoSRs) was also undertaken to identify irAEs with consistent positive associations.
RESULTS: ICIs were recorded in 47,266 reports, submitted mainly by consumers receiving monotherapy with anti-PD1/PDL1 drugs. Three areas of toxicity emerged from both disproportionality analysis and the OoSRs (32 studies): endocrine (N = 2863; ROR = 6.91; 95% CI 6.60-7.23), hepatobiliary (2632; 1.33; 1.28-1.39), and respiratory disorders (7240; 1.04; 1.01-1.06). Different reporting patterns emerged for anti-CTLA4 drugs (e.g., hypophysitis, adrenal insufficiency, hypopituitarism, and prescribed overdose) and anti-PD1/PDL1 agents (e.g., pneumonitis, cholangitis, vanishing bile duct syndrome, tumor pseudoprogression, and inappropriate schedule of drug administration). No increased reporting emerged when comparing combination with monotherapy regimens, but multiple hepatobiliary/endocrine/respiratory irAEs were recorded.
CONCLUSIONS: This parallel approach through contemporary post-marketing analysis and OoSRs confirmed that ICIs are associated with a multitude of irAEs, with different reporting patterns between anti-CTLA4 and anti-PD1/PDL1 medications. Close clinical monitoring is warranted to early diagnose and timely manage irAEs, especially respiratory, endocrine, and hepatic toxicities, which warrant further characterization; patient- and drug-related risk factors should be assessed through analytical pharmaco-epidemiological studies and prospective multicenter registries.

PMID: 30927173 [PubMed - as supplied by publisher]

The Efficacy of Antivenin Latrodectus (Black Widow) Equine Immune F(ab')2 Versus Placebo in the Treatment of Latrodectism: A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial.

Ann Emerg Med. 2019 Mar 26;:

Authors: Dart RC, Bush SP, Heard K, Arnold TC, Sutter M, Campagne D, Holstege CP, Seifert SA, Lo JCY, Quan D, Borron S, Meurer DA, Burnham RI, McNally J, Garcia-Ubbelohde W, Anderson VE

Abstract
STUDY OBJECTIVE: The antivenom currently available for treatment of systemic black widow envenomation (latrodectism) is composed of equine whole immunoglobin. Although considered effective, it has been associated with anaphylaxis and 2 reported fatalities. We test the efficacy and safety of new equine antivenom composed of purified F(ab')2 antibody fragments.
METHODS: A randomized, double-blind, placebo-controlled trial was conducted at 16 sites across the United States. Subjects aged 10 years or older with moderate to severe pain because of black widow spider envenomation received F(ab')2 antivenom or placebo. The primary outcome measure was treatment failure, which was defined as failure to achieve and maintain clinically significant reduction in pain for 48 hours posttreatment. Secondary measures of pain intensity differences and summed pain intensity difference were computed. Adverse events were recorded.
RESULTS: Sixty patients were treated (29 antivenom and 31 placebo). The mean age was 39 years and 68% were male. There were 15 treatment failures in the antivenom group and 24 in the placebo group (P=.019). Differences in pain intensity difference between groups were lower at each postbaseline point, and the mean summed pain intensity difference was greater for the antivenom group (difference 2,133; 95% confidence interval 177 to 4,090). No deaths or serious drug-related adverse events were detected.
CONCLUSION: The F(ab')2 antivenom met the predefined primary outcome of reduced treatment failures. Secondary outcomes of pain intensity difference and summed pain intensity difference also supported efficacy. The rate of symptom improvement in the placebo group was higher than expected, which may be related to enrollment criteria or placebo effect.

PMID: 30926190 [PubMed - as supplied by publisher]

An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study.

Lancet Haematol. 2019 Apr;6(4):e194-e203

Authors: Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC, Faderl S, Harb W, Kantarjian H, Lowder J, Oganesian A, Azab M, Garcia-Manero G

Abstract
BACKGROUND: Decitabine, a DNA methyltransferase 1 inhibitor or DNA hypomethylating compound, is not readily orally bioavailable because of rapid clearance by cytidine deaminase (CDA) in the gut and liver. This dose-escalation study, guided by pharmacokinetic and pharmacodynamic observations, evaluated whether simultaneous oral administration with the novel CDA inhibitor cedazuridine increases decitabine bioavailability for the treatment of myelodysplastic syndromes.
METHODS: In this phase 1 study, we enrolled patients aged 18 years or older with myelodysplastic syndromes or chronic myelomonocytic leukaemia. Eligible patients were assigned to cohorts to receive escalating oral doses of decitabine and cedazuridine. The starting dose was decitabine 20 mg and cedazuridine 40 mg. Treatment cycles lasted 28 days, with 5 days of drug administration. In cycle 1, each patient received a cohort-defined dose of oral decitabine on day -3, a 1-h intravenous infusion of decitabine 20 mg/m2 on day 1, and cohort-defined doses of oral decitabine plus cedazuridine on days 2-5. In cycles 2 and beyond, the oral decitabine and cedazuridine were given on days 1-5. The dose of cedazuridine was escalated first and decitabine was escalated once CDA inhibition by cedazuridine approached the maximum effect. The drug dose was escalated if mean decitabine area under the curve (AUC) of the oral drug was less than 90% of that for intravenous decitabine in the cohort and if no dose-limiting toxicity was observed. Dose-limiting toxicity was defined as a grade 3 or greater non-haematologic toxicity or grade 4 haematologic toxicity lasting more than 14 days and unrelated to the underlying disease. Once the decitabine AUC target range set as the primary endpoint, and established with intravenous decitabine, was reached at a dose deemed to be safe, the cohort that most closely approximated intravenous decitabine exposure was expanded to 18 evaluable patients. The primary objectives were to assess the safety of decitabine plus cedazuridine, and to determine the dose of each drug needed to achieve a mean AUC for decitabine exposure similar to that for intravenous decitabine exposure. This study is registered with ClinicalTrials.gov, number NCT02103478.
FINDINGS: Between Oct 28, 2014, and Nov 13, 2015, we enrolled 44 eligible patients (of 75 screened) with previously treated or newly diagnosed myelodysplastic syndromes or chronic myelomonocytic leukaemia; 43 of the enrolled patients were evaluable. Participants were treated in five cohorts: cohorts 1-4 included six evaluable patients each; cohort 5 included 19 patients in a 13-patient expansion. Dose-dependent increases in decitabine AUC and peak plasma concentration occurred with each cohort dose escalation. There was no evident increase in toxicity compared with that reported for intravenous decitabine. Decitabine 30 mg and 40 mg plus cedazuridine 100 mg produced mean day-5 decitabine AUCs (146 ng × h/mL for decitabine 30 mg, and 221 ng × h/mL for decitabine 40 mg) closest to the mean intravenous-decitabine AUC (164 ng × h/mL). The most common grade 3 or more adverse events were thrombocytopenia (18 [41%] of 44 patients), neutropenia (13 [30%]), anaemia (11 [25%]), leukopenia (seven [16%]), febrile neutropenia (seven [16%]), and pneumonia (seven [16%]). Four (9%) patients died because of adverse events, none of which was considered drug related, and three (7%) patients died more than 30 days after discontinuing treatment because of progressive disease (two [5%]) and respiratory failure (one [2%]).
INTERPRETATION: Oral decitabine plus cedazuridine emulated the pharmacokinetics of intravenous decitabine, with a similar safety profile and dose-dependent demethylation. Clinical responses were similar to intravenous decitabine treatment for 5 days. Further study of decitabine plus cedazuridine as an alternative to parenteral therapy or in combination with other new oral agents for myeloid disorders is warranted.
FUNDING: Astex Pharmaceuticals, Inc.

PMID: 30926081 [PubMed - in process]