First-in-human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors.

Clin Cancer Res. 2017 Mar 22;:

Authors: Stein MN, Bertino JR, Kaufman HL, Mayer T, Moss R, Silk A, Chan N, Malhotra J, Rodriguez-Rodriguez L, Aisner J, Aiken RD, Haffty BG, DiPaola RS, Saunders T, Zloza A, Damare S, Beckett Y, Yu B, Najmi S, Gabel C, Dickerson S, Zheng L, El-Deiry WS, Allen J, Stogniew M, Oster W, Mehnert JM

Abstract
Purpose ONC201 is a small molecule selective antagonist of the G protein-coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design This open-label study treated 10 patients during dose escalation with histologically-confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic (PK), and pharmacodynamic (PD) information. Results No Grade >1 drug-related adverse events occurred and the RP2D was defined as 625 mg. PK analysis revealed a Cmax of 1.5 - 7.5µg/mL (~3.9-19.4µM), mean half-life of 11.3 hours, and mean AUC of 37.7 h.ug/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved, however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (> 9 cycles) in prostate and endometrial cancer patients. Conclusion ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks.

PMID: 28331050 [PubMed - as supplied by publisher]

Dementia with Lewy bodies presenting marked tongue protrusion and bite due to lingual dystonia: A case report.

Rinsho Shinkeigaku. 2016 Jun 22;56(6):418-23

Authors: Shiga Y, Kanaya Y, Kono R, Takeshima S, Shimoe Y, Kuriyama M

Abstract
We report the patient of a 53-year-old woman who developed subacute-onset marked tonge protrusion and bite. She was diagnosed as dementia with Lewy bodies (DLB) from the clinical features including progressive cognitive decline, visual hallucinations, parkinsonism, and severe insomnia and depression, and the radiological finding of low dopamine transported uptake in basal ganglia by Dat SCAN and low blood circulation in occipital lobe of cerebrum. The patient received 600 mg doses of levodopa for over a year, followed by rotigotine and ropinirole with a rapid increase of dosage. It is believed that these treatments stimulated and sensitized dopamine D1 receptors, thereby inducing lingual dystonia. Furthermore, the patient demonstrated dyspnea and attacks of apnea caused by the closure of bilateral vocal cords due to laryngeal dyskinesia. After initiation of the neuroleptic, olanzapine, for a short duration, the high dose of levodopa overlapped with neuroleptic sensitivity, suggesting DOPA-induced dystonia and dyskinesia. This interaction can sometimes lead to lethal adverse events, and must be considered very important when treating patients with DLB.

PMID: 27212676 [PubMed - indexed for MEDLINE]

A combined in vitro approach to improve the prediction of mitochondrial toxicants.

Toxicol In Vitro. 2016 Aug;34:161-70

Authors: Eakins J, Bauch C, Woodhouse H, Park B, Bevan S, Dilworth C, Walker P

Abstract
Drug induced mitochondrial dysfunction has been implicated in organ toxicity and the withdrawal of drugs or black box warnings limiting their use. The development of highly specific and sensitive in vitro assays in early drug development would assist in detecting compounds which affect mitochondrial function. Here we report the combination of two in vitro assays for the detection of drug induced mitochondrial toxicity. The first assay measures cytotoxicity after 24h incubation of test compound in either glucose or galactose conditioned media (Glu/Gal assay). Compounds with a greater than 3-fold toxicity in galactose media compared to glucose media imply mitochondrial toxicity. The second assay measures mitochondrial respiration, glycolysis and a reserve capacity with mechanistic responses observed within one hour following exposure to test compound. In order to assess these assays a total of 72 known drugs and chemicals were used. Dose-response data was normalised to 100× Cmax giving a specificity, sensitivity and accuracy of 100%, 81% and 92% respectively for this combined approach.

PMID: 27083147 [PubMed - indexed for MEDLINE]

Adverse Effects of Plant Food Supplements and Plants Consumed as Food: Results from the Poisons Centres-Based PlantLIBRA Study.

Phytother Res. 2016 Jun;30(6):988-96

Authors: Lüde S, Vecchio S, Sinno-Tellier S, Dopter A, Mustonen H, Vucinic S, Jonsson B, Müller D, Veras Gimenez Fruchtengarten L, Hruby K, De Souza Nascimento E, Di Lorenzo C, Restani P, Kupferschmidt H, Ceschi A

Abstract
Plant food supplements (PFS) are products of increasing popularity and wide-spread distribution. Nevertheless, information about their risks is limited. To fill this gap, a poisons centres-based study was performed as part of the EU project PlantLIBRA. Multicentre retrospective review of data from selected European and Brazilian poisons centres, involving human cases of adverse effects due to plants consumed as food or as ingredients of food supplements recorded between 2006 and 2010. Ten poisons centres provided a total of 75 cases. In 57 cases (76%) a PFS was involved; in 18 (24%) a plant was ingested as food. The 10 most frequently reported plants were Valeriana officinalis, Camellia sinensis, Paullinia cupana, Melissa officinalis, Passiflora incarnata, Mentha piperita, Glycyrrhiza glabra, Ilex paraguariensis, Panax ginseng, and Citrus aurantium. The most frequently observed clinical effects were neurotoxicity and gastro-intestinal symptoms. Most cases showed a benign clinical course; however, five cases were severe. PFS-related adverse effects seem to be relatively infrequent issues for poisons centres. Most cases showed mild symptoms. Nevertheless, the occurrence of some severe adverse effects and the increasing popularity of PFS require continuous active surveillance, and further research is warranted. Copyright © 2016 John Wiley & Sons, Ltd.

PMID: 26948409 [PubMed - indexed for MEDLINE]

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[Cost-effectiveness analysis of octreotide long acting release and lanreotide slow release for the treatment of postoperative patients with active acromegaly in China].

Zhonghua Yi Xue Za Zhi. 2017 Mar 14;97(10):765-769

Authors: Xuan JW, Zhang ZY, Wang YF, Mao ZG, Lu YJ, Wang RZ

Abstract
Objective: To evaluate the cost-effectiveness of octreotide long acting release (LAR) vs lanreotide slow release (SR) for the treatment of postoperative acromegalic patients with elevated levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) in China. Methods: A decision tree model was constructed and the treatment impact was projected for one year in Chinese setting. The clinical efficacy measure used was the percentage of patients achieving normalization (control) of either IGF-1 or GH levels. Efficacy of octreotide LAR and lanreotide SR, incidence of comorbidities, impact of acromegaly on health-related quality of life, and drug-related side effects data were obtained from literature. The cost of medication was collected through a chart review from five hospitals in five cities of China. Clinical experts from these hospitals were requested to complete a questionnaire to document the utilization of medical resources, costs of comorbidities, side effects as well as cost of administration. One-way sensitivity analysis was performed to evaluate the robustness of the results. Results: Compared to lanreotied SR group, the percentage of patients achieving normalization of IGF-1 and GH levels of octreotide LAR group were 10% and 9% higher, respectively. When either IGF-1 or GH control were used as the efficacy measure, patients in the octreotide LAR group exhibit less comorbidities and need less continued treatment with a second operation and radiotherapy than those in lanreotide SR group. When IGF-1 was used as efficacy measure, octreotide LAR not only achieved better efficacy but resulted in overall cost-saving, with a total cost savings of ￥ 3 792 per patient for one year, which demonstrated that octreotide LAR was a dominant cost-saving strategy. When GH control was used as the efficacy measure, octreotide LAR achieved a better overall clinical efficacy with a slightly higher total costs (￥ 4 121 higher per patient per year). Sensitivity analysis didn't change the conclusion that octreotide LAR remains dominant over lanreotide SR, indicating the robustness of this model. Conclusion: Octreotide LAR achieved better overall biochemical control compared with lanreotide SR which result in less comorbidity rate, second operation and radiotherapy as well as related costs.

PMID: 28316158 [PubMed - in process]

Association of itraconazole and potassium iodide in the treatment of feline sporotrichosis: a prospective study.

Med Mycol. 2016 Oct 01;54(7):684-90

Authors: Reis ÉG, Schubach TM, Pereira SA, Silva JN, Carvalho BW, Quintana MS, Gremião ID

Abstract
Feline sporotrichosis is an endemic disease in Rio de Janeiro, Brazil, where zoonotic transmission of Sporothrix spp. has been reported since 1998. Itraconazole (ITZ) remains the first choice for treating this disease in cats. However, there have been reports of therapeutic failure and a long-term endeavor. Potassium iodide (KI), considered in the past as a drug with variable effectiveness in cats with sporotrichosis, arises as an important option in the treatment of cats from the endemic area of Rio de Janeiro. In order to evaluate the effectiveness of the association of ITZ and KI in naive cats with sporotrichosis, a prospective cohort study was conducted on 30 cats receiving ITZ 100 mg/day and KI 2.5 mg-20 mg/kg/day. Clinical and laboratory adverse effects were assessed once a month according to the standard care protocol. The cure rate was 96.15% within a median of 14 weeks of treatment. Adverse effects were observed in 50% of cats and were managed with a temporary drug suspension and/or a hepatoprotective therapy. The association of ITZ and KI emerges as an effective option for the treatment of feline sporotrichosis.

PMID: 27207412 [PubMed - indexed for MEDLINE]

[Adverse drug reactions in children: 10 years of pharmacovigilance].

Arch Pediatr. 2016 May;23(5):468-76

Authors: Damien S, Patural H, Trombert-Paviot B, Beyens MN

Abstract
BACKGROUND: Knowledge of drug tolerance and safety in children is limited. The study of spontaneous notifications of adverse events (AEs) can be an important source of information.
OBJECTIVE: Describe the characteristics of drug adverse effects (DAEs) in children 0-17 years of age reported to the pharmacovigilance center of Saint-Étienne in 2004-2013.
METHODS: This retrospective descriptive study was conducted based on DAE notifications, classified according to age, sex, severity of organ affected (using classification by the System organ class [SOC]) and by suspected drug (Anatomical therapeutic chemical [ATC] drugs).
RESULTS: A total of 371 notifications were analyzed. The male:female ratio was 1. Serious cases accounted for 36%, of which 73% resulted in hospitalization or prolongation of hospitalization. The most frequent DAEs were cutaneous (21.1%), infection (13.5%) and general (11.5%). The most frequently involved therapeutic classes were anti-infectives for systemic use (38.7%), mainly vaccines and antibiotics, as well as antineoplastic and immunomodulatory therapy (19.2%) and drugs acting on the nervous system (12.5%).
CONCLUSIONS: The analysis of notifications of adverse drug reactions is an important source of information and is underutilized in pediatrics. The data from this study confirm those of European databases with spontaneous reporting. The majority of anti-infectives including antibiotics raises the question of the proper use of this class in this population. Larger studies focused on the drugs at risk would improve the knowledge and safe use of medicines in children.

PMID: 27062190 [PubMed - indexed for MEDLINE]

Impressions of pharmacogenomic testing among Certified Registered Nurse Anesthetists: a mixed-method study.

Pharmacogenomics. 2016 04;17(6):593-602

Authors: Riddle D, Gregoski M, Baker K, Dumas B, Jenkins CH

Abstract
AIM: Pharmacogenomic testing is useful in helping to predict and explain patient responsiveness to medication. In clinical practice, the use of pharmacogenomic testing has been shown to help reduce adverse drugs events and increase patient satisfaction with their healthcare. Prior to a test being useful, it must have clinical utility. There is a gap in the literature about the perceived clinical utility of pharmacogenomic testing among anesthesia providers.
METHODS: This qualitative-quantitative sequential mixed-method study used focused interviews to formulate probes for a quantitative survey aimed at quantifying the perceptions of anesthesia providers about pharmacogenomic testing.
RESULTS: The results indicate anesthesia providers do not have enough knowledge about pharmacogenomic testing for it to be considered clinically useful in anesthesia practice.
CONCLUSION: Although outcomes data indicate pharmacogenomic testing can help predict outcomes, anesthesia providers do not have enough knowledge and have concerns about the ethical implications of pharmacogenomic testing.

PMID: 27023204 [PubMed - indexed for MEDLINE]

Thiopurine S-methyltransferase testing for averting drug toxicity in patients receiving thiopurines: a systematic review.

Pharmacogenomics. 2016 04;17(6):633-56

Authors: Roy LM, Zur RM, Uleryk E, Carew C, Ito S, Ungar WJ

Abstract
AIM: Thiopurine S-methyltransferase (TPMT) testing is used in patients receiving thiopurines to identify enzyme deficiencies and risk for adverse drug reactions. It is uncertain whether genotyping is superior to phenotyping. The objectives were to conduct a systematic review of TPMT-test performance studies.
MATERIALS & METHODS: Electronic and grey literature sources were searched for studies reporting test performance compared with a reference standard. Sixty-six eligible studies were appraised for quality.
RESULTS: Thirty phenotype-genotype and six phenotype-phenotype comparisons were of high quality. The calculated sensitivity and specificity for genotyping to identify a homozygous mutation ranged from 0.0-100.0% and from 97.8-100.0%, respectively.
CONCLUSION: Clinical decision-makers require high-quality evidence of clinical validity and clinical utility of TPMT genotyping to ensure appropriate use in patients.

PMID: 27020704 [PubMed - indexed for MEDLINE]

30-Day Potentially Avoidable Readmissions Due to Adverse Drug Events.

J Patient Saf. 2017 Mar 17;:

Authors: Dalleur O, Beeler PE, Schnipper JL, Donzé J

Abstract
OBJECTIVE: To analyze the patterns of potentially avoidable readmissions due to adverse drug events (ADEs) to identify the most appropriate risk reduction interventions.
METHODS: In this observational study, we analyzed a random sample of 534 potentially avoidable 30-day readmissions from 10,275 consecutive discharges from the medical department of an academic hospital. Readmissions due to ADEs were reviewed to identify the causative drugs and the severity and interventions to prevent them.
RESULTS: Seventy cases (13.1%) of readmission were partially or predominantly due to ADEs, of which, 58 (82.9%) were serious ADEs. Overall, 65 (92.9%) of the ADEs have been confirmed to be preventable. Inappropriate prescribing was identified as the cause of ADE in 34 cases (48.6%) mainly involving diuretics, analgesics, or antithrombotics: misprescribing n = 19 (27.1%), underprescribing n = 8 (11.4%), and overprescribing n = 7 (10.0%). The remaining half of preventable ADEs (n = 36; 51.4%) were related to suboptimal patient monitoring/education, such as adherence issues (n = 6; 8.6%) or lack of monitoring (n = 31; 44.3%). In 64 cases (91.4%), the readmission could have been potentially prevented by better monitoring for drug efficacy/disease control, or for predictable side effect. Thirty-three (97.1%) of the 34 ADEs due to inappropriate prescribing could have also been prevented by better monitoring.
CONCLUSIONS: Adverse drug events accounted for approximately 13% of 30-day preventable readmissions. A half were due to prescription errors involving mainly diuretics, analgesics, or antithrombotics, and the other half were due to suboptimal patient monitoring/education, most frequently with antineoplastics. Both these avoidable causes may represent opportunities to reduce the total drug-related adverse events.

PMID: 28306610 [PubMed - as supplied by publisher]

Adverse Effects of Statins-Reply.

JAMA. 2017 03 14;317(10):1080

Authors: Thompson PD

PMID: 28291889 [PubMed - indexed for MEDLINE]

Adverse Effects of Statins.

JAMA. 2017 03 14;317(10):1079-1080

Authors: Malachowski SJ, Quattlebaum AM, Miladinovic B

PMID: 28291886 [PubMed - indexed for MEDLINE]

Adverse Effects of Statins.

JAMA. 2017 03 14;317(10):1079

Authors: Goldstein LB

PMID: 28291885 [PubMed - indexed for MEDLINE]

Pharmaceuticals and Medical Devices: FDA Oversight.

Issue Brief Health Policy Track Serv. 2016 Dec 27;2016:1-74

Authors: White RS, Thomson Reuters Accelus

PMID: 28252887 [PubMed - indexed for MEDLINE]

Media coverage of statins may have led to 2000 cardiovascular events.

BMJ. 2016 Jun 30;353:i3630

Authors: Galliver M

PMID: 27364525 [PubMed - indexed for MEDLINE]

Authors' reply to Cunningham and Messerli and colleagues.

BMJ. 2016 Jun 07;353:i3141

Authors: Kotecha D, Altman DG, Collins PD, Flather MD

PMID: 27268202 [PubMed - indexed for MEDLINE]

Research into "real world" older patients is needed.

BMJ. 2016 Jun 07;353:i3136

Authors: Cunningham CJ

PMID: 27268071 [PubMed - indexed for MEDLINE]

Adverse effects and tolerability of β blockers.

BMJ. 2016 Jun 07;353:i3142

Authors: Messerli FH, Bangalore S, Grossman E

PMID: 27268029 [PubMed - indexed for MEDLINE]

Managing Infusion-Related Reactions for Patients With Chronic Lymphocytic Leukemia Receiving Obinutuzumab.

Clin J Oncol Nurs. 2016 Apr;20(2):E41-8

Authors: Dawson K, Moran M, Guindon K, Wan H

Abstract
BACKGROUND: In patients with previously untreated chronic lymphocytic leukemia (CLL) and comorbidities, treatment with the glycoengineered, type II anti-CD20 monoclonal antibody obinutuzumab (Gazyva®) (GA101) plus chlorambucil (Leukeran®) was associated with superior outcomes to rituximab (Rituxan®) plus chlorambucil, with a similar safety profile. However, a higher occurrence of infusion-related reactions (IRRs) was reported with obinutuzumab. These reactions typically require additional management.
OBJECTIVES: The focus of this article is to provide oncology nurses and physicians with advice for obinutuzumab IRR management based on clinical trial data and nursing experience.
METHODS: The authors reviewed the published management strategies for IRRs with obinutuzumab that were identified during the phase III CLL11 trial and an expanded access phase IIb study (ML28979). Practical advice for obinutuzumab IRR management was developed based on available clinical trial information and nursing experience.
FINDINGS: IRRs with obinutuzumab are generally manageable. Most IRRs (all grades), and all grade 3-4 IRRs, occurred during the first infusion. Therefore, IRR management could be improved substantially with extra vigilance at this early stage.

PMID: 26991722 [PubMed - indexed for MEDLINE]