Utility of a trigger tool (TRIGGER-CHRON) to detect adverse events associated with high-alert medications in patients with multimorbidity.

Eur J Hosp Pharm. 2020 May 08;:

Authors: Otero MJ, Toscano Guzmán MD, Galván-Banqueri M, Martinez-Sotelo J, Santos-Rubio MD

Abstract
OBJECTIVE: To determine the utility of a tool (TRIGGER-CHRON) for identifying adverse drug events (ADEs) associated with the administration of high-alert medications in elderly patients with multimorbidity and to determine the medications most frequently implicated.
METHODS: A retrospective observational study was conducted at 12 Spanish hospitals. A random sample of five medical records from each hospital was selected weekly for review over a 12-week period. We included patients aged 65 and over with multimorbidities, hospitalised for >48 hours. ADEs detected by the 32 TRIGGER-CHRON signals and caused by high-alert medications included on the Spanish HAMC list for chronic patients were selected for analysis. Triggers identified and ADEs detected were recorded. The severity and preventability of the ADEs were evaluated. The positive predictive value (PPV) of each trigger was calculated.
RESULTS: On 720 charts reviewed, 908 positive triggers were identified that led to the detection of 158 ADEs caused by at least one high-alert medication on the HAMC list. These ADEs occurred in 139 patients (prevalence 19.3/100 admissions). The majority of ADEs were mild and 59.5% were deemed preventable. The drugs most frequently associated with ADEs were corticosteroids, loop diuretics, opioid analgesics and oral anticoagulants. Fifteen triggers had PPVs ≥20%. Six triggers (serum glucose >110 mg/dL, abrupt cessation of medication, oversedation/lethargy, hypotension, adverse reaction recorded and constipation) accounted for 69.8% of the ADEs identified.
CONCLUSIONS: Applying the TRIGGER-CHRON to hospitalised patients with multimorbidity in 12 Spanish centres allowed detection of one adverse event caused by a high-alert drug for every four patients, which were preventable in a large proportion of patients. This confirms the need to establish interventions that reduce harm with these medications. We believe that TRIGGER-CHRON can be a useful tool to measure this harm and to determine the effects of medication safety improvement programmes as they are implemented.

PMID: 32385069 [PubMed - as supplied by publisher]

Novel β-Lactam/β-Lactamase inhibitor combinations vs alternative antibiotics in the treatment of complicated urinary tract infections: A meta-analysis of randomized controlled trials.

Medicine (Baltimore). 2020 May;99(19):e19960

Authors: Lu LC, Lai CC, Chang SP, Lan SH, Hung SH, Lin WT

Abstract
OBJECTIVES: This meta-analysis assessed the efficacy and safety of novel β-lactam/β-lactamase inhibitor combinations in the treatment of complicated urinary tract infection (cUTI)/acute pyelonephritis (APN).
METHODS: PubMed, Web of Science, EBSCO (Elton B. Stephens Co.), Cochrane Library, Ovid MEDLINE, and Embase databases were accessed until November 21, 2019. In this meta-analysis, only randomized controlled trials comparing the treatment efficacy of novel β-lactam/β-lactamase inhibitor combinations with other antibiotics for cUTI/APN in adult patients were included. The outcomes included the clinical and microbiological responses, and risk of adverse events (AEs).
RESULTS: Overall, the experimental group treated with a novel β-lactam/β-lactamase inhibitor combination and the control group comprised 1346 and 1376 patients, respectively. No significant difference in the clinical response rate at test-of-cure was observed between the novel β-lactam/β-lactamase inhibitor combination and comparators among the microbiological modified intent-to-treat population (89.1% vs 88.3%, OR, 1.04; 95% confidence interval [CI], 0.76-1.42; I = 28%) and the microbiologically evaluable population (95.2% vs 94.7%, OR, 1.12; 95% CI, 0.68-1.84; I = 0%). Additionally, the novel β-lactam/β-lactamase inhibitor combination was associated with a better microbiological response at test-of-cure than the comparators among the microbiological modified intent-to-treat population (74.4% vs 68.5%, OR, 1.34; 95% CI, 1.04-1.72; I = 45%) and microbiologically evaluable population (80.1% vs 72.5%, OR, 1.49; 95% CI, 1.06-2.10; I = 58%). Finally, the risk of AEs associated with the novel β-lactam/β-lactamase inhibitor combination was similar to that associated with the comparators (treatment-emergent adverse events [TEAE], OR, 1.04; 95% CI, 0.87-1.23; I = 19%; serious AEs, OR, 1.21; 95% CI, 0.82-1.76; I = 0%; treatment discontinuation for drug-related TEAE, OR, 077; 95% CI, 0.38-1.56, I = 5%). The all-cause mortality did not differ between the novel β-lactam/β-lactamase inhibitor combination and comparators (OR, 1.19; 95% CI, 0.37-3.81; I = 0%).
CONCLUSIONS: The clinical and microbiological responses of novel β-lactam/β-lactamase inhibitor combinations in the treatment of cUTI/APN are similar to those of other available antibiotics. These combinations also share a safety profile similar to that of other antibiotics.

PMID: 32384444 [PubMed - as supplied by publisher]

[Immune Checkpoint Inhibitor Induced Pneumonitis and Its Management].

Gan To Kagaku Ryoho. 2020 Feb;47(2):207-213

Authors: Kodama H, Kenmotsu H

Abstract
Immune checkpoint inhibitors(ICIs)made a drastic change in treatment of various types of advanced tumors since its approval, showing improvement of survival. The use of ICIs however has revealed unique adverse events that are quite different from the conventional chemotherapies, and there still remains several unknown factors such as its onset time or risk factors. Drug-induced interstitial lung disease, one of the important immune-related adverse events, is a rare but sometimes lethal adverse event that often confuses physician of its diagnosis. Unspecific changes like dyspnea, cough, and radiographic changes would be the main findings, thus close and comprehensive diagnosis is needed for accurate treatment. Cessation of ICI and induction of corticosteroid is the fundamental treatment for drug-induced lung disease, and treatment with immunosuppressive drug may be required according to the severity of adverse events. Previous reports have shown that most cases of this entity are treatable if diagnosed and managed appropriately, so it is important to cooperate with pulmonologist and radiologist for better comprehension and proper treatment.

PMID: 32381948 [PubMed - in process]

[Investigation of Anti-Cancer Drugs Suspected as Causative Agents of Allergy by Drug-Induced Lymphocyte Stimulation Test and Subsequent Re-Administration].

Gan To Kagaku Ryoho. 2020 Jan;47(1):55-59

Authors: Sakurada H, Kawase Y, Asano H, Naito K

Abstract
Twenty-one patients underwent a drug-induced lymphocyte stimulation test(DLST)withanti -cancer drugs suspected as causative agents of allergy between January 1, 2013, and December 31, 2017, at Ichinomiya Municipal Hospital, and 7 (33.3%)and 14 patients were positive and negative, respectively. Moreover, only 2 out of 21 people had a low value in lymphocyte blast transformation test induced by phytohemagglutinin, and their immune ability was maintained. Two patients suspected of drug eruption were re-administered after a positive determination. Letrozole was re-administered in 1 patient, but exemestane was administered after the patient relapsed. The other patient received lenalidomide in combination with dose-reduction and prednisolone(PSL), and the patient did not relapse. Seven patients were re-administered after negative determination, and none of them relapsed. These results confirmed that re-administration was possible depending on the type of side effects even in DLST positive cases; however, it was necessary to take various precautions. Moreover, DLST results were an index for finding the cause, and it is important to consider other diagnostic methods carefully during re-administration.

PMID: 32381863 [PubMed - in process]

Significant association between tumor mutational burden and immune-related adverse events during immune checkpoint inhibition therapies.

Cancer Immunol Immunother. 2020 May;69(5):683-687

Authors: Kerepesi C, Bakacs T, Moss RW, Slavin S, Anderson CC

Abstract
More than 2000 immuno-oncology agents are being tested or are in use as a result of the cancer immunotherapy revolution. Manipulation of co-inhibitory receptors has achieved tumor eradication in a minority of patients, but widespread immune-related adverse events (irAEs) compromised tolerance to healthy self-tissues in the majority. We have proposed that a major mechanism of irAEs is similar to a graft-versus-malignancy effect of graft-versus-host disease. To verify our hypothesis, we retrieved post-marketing data of adverse events from the U.S. Food and Drug Administration Adverse Event Reporting System. A significant positive correlation was revealed in 7677 patients between the reporting odds ratio of irAEs during immune checkpoint inhibitor therapy and the corresponding tumor mutational burden across 19 cancer types. These results can be interpreted to mean that the ICI drugs unleashed T cells against "altered-self," self, and tumors resulting in better overall survival.

PMID: 32152702 [PubMed - indexed for MEDLINE]

The efficacy and safety of sunitinib given on an individualised schedule as first-line therapy for metastatic renal cell carcinoma: A phase 2 clinical trial.

Eur J Cancer. 2019 02;108:69-77

Authors: Bjarnason GA, Knox JJ, Kollmannsberger CK, Soulieres D, Ernst DS, Zalewski P, Canil CM, Winquist E, Hotte SJ, North SA, Heng DYC, Macfarlane RJ, Venner PM, Kapoor A, Hansen AR, Eigl BJ, Czaykowski P, Boyd B, Wang L, Basappa NS

Abstract
BACKGROUND: Sunitinib is administered on a rigid schedule that may not be optimal for all patients. We hypothesised that toxicity-driven dose and schedule changes would optimise drug exposure and outcome for each patient.
MATERIALS AND METHODS: In a phase 2 trial, 117 patients with metastatic clear cell renal cell cancer were started on sunitinib 50 mg/day with the aim to treat for 28 days. Treatment breaks were reduced to 7 days. Sunitinib dose and the number of days on therapy were individualised based on toxicity aiming for ≤ grade II toxicity with dose escalation in patients with minimal toxicity. The null hypothesis for the primary end-point was a progression-free survival (PFS) of 8.5 months based on a study with similar eligibility criteria.
RESULTS: The null hypothesis was rejected (p < 0.001) with a median PFS of 12.5 months (95% confidence interval [CI]: 9.6-16.5). The median overall survival was 38.5 months (95% CI: 28.3-not reached). The objective response rate (46.1%) and stable disease rate (38.5%) translated into a clinical benefit for 84.6% of patients with no decline in quality of life scores during therapy. Fewer patients were dose reduced (26.5% vs. 50%) or discontinued due to toxicity (7.7 vs. 18-20%) compared to standard sunitinib dosing, and 20 (18.4%) patients were dose escalated to 62.5 mg (12) and 75 mg (8) with a wide individual variation in the optimal dose and treatment duration.
CONCLUSIONS: Individualised sunitinib therapy is feasible, safe and an effective method to manage toxicity with one of the best efficacy seen for oral vascular endothelial growth factor inhibitors in metastatic renal cell carcinoma. CLINICALTRIALS.
GOV IDENTIFIER: NCT01499121.

PMID: 30648632 [PubMed - indexed for MEDLINE]

The Missing Record of Mental Status in Written Sign-Outs.

J Patient Saf. 2019 12;15(4):e40-e43

Authors: Croix M, Miller D, Whittle J, Singh S, Schapira MM, Carnahan J, Kuester J, Kallio C, Framberg S, Fletcher KE

Abstract
OBJECTIVE: The aim of the study was to determine how frequently mental status and mental status changes are documented in the written patient summary ("sign-out") provided to covering physicians.
PATIENTS AND METHODS: This was a retrospective cohort study of general medical patients hospitalized between March 16, 2009, and March 15, 2010, conducted at 2 teaching hospitals. Participants included patients with mental status change adverse events (MSAEs) and their providers. Chart review was performed to identify patients with MSAEs and details about these events. Sign-outs were reviewed for documentation of mental status. Main outcome measures were (1) proportion of patients with MSAEs who had mental status ever recorded in sign-out entries and (2) the proportion of patients with MSAEs whose change in mental status was recorded in the sign-out.
RESULTS: Sixty-eight patients had MSAEs and were included in the sample. Fifty percent of MSAEs were attributed to medications; 75% of these events were first detected by nurses. Only 25% of patients with MSAEs had their change in mental status recorded in sign-outs.
CONCLUSIONS: Recording mental status in written sign-outs is uncommon. Particularly concerning is that patients with MSAEs identified by chart review seldom had sign-outs that reflected those events. Interventions should be designed to increase the recording of this information in sign-outs.

PMID: 28098585 [PubMed - indexed for MEDLINE]

Measuring Patients' Knowledge About Adverse Effects of Angiotensin-Converting Enzyme Inhibitors.

J Patient Saf. 2019 12;15(4):e28-e31

Authors: Jankovic SM, Dajic M, Jacovic S, Markovic S, Papic T, Petrusic T, Radojkovic M, Rankovic A, Tanaskovic M, Vasic M, Vukicevic D, Zaric RZ, Kostic M

Abstract
BACKGROUND: Knowledge about adverse effects of medications is an important part of proper medication use and prerequisite for good treatment adherence.
OBJECTIVE: The aim of our study was to construct, develop, and test a new questionnaire for the measurement of patients' knowledge about adverse drug reactions of angiotensin-converting enzyme (ACE) inhibitors.
METHODS: The 8-item questionnaire was constructed to measure adverse reactions to ACE inhibitors. The questions were closed, with 7 offered answers, in the form of a Likert scale. It was tested for psychometric properties on patients who visited their general practitioners at state-owned health facilities in 5 Serbian cities: Belgrade, Kragujevac, Banja Luka, Gracanica, and Despotovac.
RESULTS: The questionnaire was tested on 259 patients from general practice, taking an ACE inhibitor for more than 3 months. Experience with at least 1 adverse effect of ACE inhibitor was reported in 64 patients (24.7%), only 94 patients (36.3%) previously received any form of information about at least 1 adverse effect of ACE inhibitors from health workers, and only 42% expressed knowledge of any adverse events. The patients who were informed knew about the following adverse events as phrased in the official patient information leaflets: severe dizziness or light-headedness (44%); cough (37%); swelling of the hands, face, lips, or tongue (32%); indigestion (22%); headache (51%); and difficulty in breathing (15%). The questionnaire showed satisfactory internal consistency, with Cronbach α of 0.767, and individual scores correlated with general education of the patients. Factorial analysis revealed 2 domains (subscales): the first one with 5 questions is directed to adverse effects the patients may physically experience directly, whereas the second with 3 questions measures knowledge about adverse effects that could be experienced only indirectly, through conditions caused by the adverse effects.
CONCLUSIONS: The questionnaire about knowledge of ACE inhibitors' adverse effects is a reliable and probably valid instrument for measuring patients' knowledge about adverse effects of ACE inhibitors.

PMID: 26741787 [PubMed - indexed for MEDLINE]

Multiparametric Mechanistic Profiling of Inotropic Drugs in Adult Human Primary Cardiomyocytes.

Sci Rep. 2020 May 06;10(1):7692

Authors: Abi-Gerges N, Indersmitten T, Truong K, Nguyen W, Ratchada P, Nguyen N, Page G, Miller PE, Ghetti A

Abstract
Effects of non-cardiac drugs on cardiac contractility can lead to serious adverse events. Furthermore, programs aimed at treating heart failure have had limited success and this therapeutic area remains a major unmet medical need. The challenges in assessing drug effect on cardiac contractility point to the fundamental translational value of the current preclinical models. Therefore, we sought to develop an adult human primary cardiomyocyte contractility model that has the potential to provide a predictive preclinical approach for simultaneously predicting drug-induced inotropic effect (sarcomere shortening) and generating multi-parameter data to profile different mechanisms of action based on cluster analysis of a set of 12 contractility parameters. We report that 17 positive and 9 negative inotropes covering diverse mechanisms of action exerted concentration-dependent increases and decreases in sarcomere shortening, respectively. Interestingly, the multiparametric readout allowed for the differentiation of inotropes operating via distinct mechanisms. Hierarchical clustering of contractility transient parameters, coupled with principal component analysis, enabled the classification of subsets of both positive as well as negative inotropes, in a mechanism-related mode. Thus, human cardiomyocyte contractility model could accurately facilitate informed mechanistic-based decision making, risk management and discovery of molecules with the most desirable pharmacological profile for the correction of heart failure.

PMID: 32376974 [PubMed - in process]

Revisited: Therapeutic and toxic blood concentrations of more than 1100 drugs and other xenobiotics.

Crit Care. 2020 May 06;24(1):195

Authors: Schulz M, Schmoldt A, Andresen-Streichert H, Iwersen-Bergmann S

Abstract
In order to assess the significance of drug/substance levels measured in intensive care medicine and clinical and forensic toxicology as well as for therapeutic drug monitoring, it is essential that a comprehensive collection of data is readily available. We revisited and expanded our 2012 compilation of therapeutic and toxic plasma concentration ranges as well as half-lives of now more than 1100 drugs and other xenobiotics.Data have been abstracted from original papers, text books, and previous compilations and have been completed with data collected in our own forensic and clinical toxicology laboratories. We compiled the data presented in the table and the corresponding annotations over the past 30+ years. A previous compilation was completely double-checked, revised, and updated, if necessary. In addition, more than 200 substances, especially drugs who have been introduced since 2012 to the market as well as illegal drugs and other xenobiotics which became known to cause intoxications were added. We carefully referenced all data. Moreover, the annotations providing details were updated and revised, when necessary.For more than 1100 drugs and other xenobiotics, therapeutic ("normal") and, if data was available, toxic, and comatose-fatal plasma/blood concentrations as well as elimination half-lives were compiled in a table.In case of intoxications, the blood concentration of the substance and/or metabolite better predicts the clinical severity of the case when compared to the assumed amount and time of ingestion. Comparing and contrasting the clinical case against the data provided, including the half-life, may support the decision for or against further intensive care. In addition, the data provided are useful for the therapeutic monitoring of pharmacotherapies, to facilitate the diagnostic assessment and monitoring of acute and chronic intoxications as well as to support forensic and clinical expert opinions.

PMID: 32375836 [PubMed - in process]

Kratom Use and Toxicities in the United States.

Pharmacotherapy. 2019 07;39(7):775-777

Authors: Eggleston W, Stoppacher R, Suen K, Marraffa JM, Nelson LS

Abstract
BACKGROUND: Kratom is an herbal supplement containing alkaloids with opioid properties. This review was conducted to determine toxicities associated with kratom use in the United States in order to provide insight into its safety as a dietary supplement.
METHODS: We conducted a retrospective review of kratom exposures reported to the National Poison Data System to determine the toxicities associated with kratom use. We also reviewed records from a county medical examiner's office in New York State to identify kratom-associated fatalities.
RESULTS: A total of 2312 kratom exposures were reported, with 935 cases involving kratom as the only substance. Kratom most commonly caused agitation (18.6%), tachycardia (16.9%), drowsiness (13.6%), vomiting (11.2%), and confusion (8.1%). Serious effects of seizure (6.1%), withdrawal (6.1%), hallucinations (4.8%), respiratory depression (2.8%), coma (2.3%), and cardiac or respiratory arrest (0.6%) were also reported. Kratom was listed as a cause or contributing factor in the death of four decedents identified by the county medical examiner's office.
CONCLUSIONS: Kratom use is increasing and is associated with significant toxicities. Our findings suggest kratom is not reasonably expected to be safe and poses a public health threat due to its availability as an herbal supplement.

PMID: 31099038 [PubMed - indexed for MEDLINE]

HLA- and immune-mediated adverse drug reactions: Another hit with vancomycin.

J Allergy Clin Immunol. 2019 07;144(1):44-45

Authors: Pirmohamed M

PMID: 31029771 [PubMed - indexed for MEDLINE]

Letter in response to 'Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors'.

Eur J Cancer. 2019 05;112:47-48

Authors: Leclair V, Landon-Cardinal O, Hudson M

PMID: 30913530 [PubMed - indexed for MEDLINE]

Predicting Drug-Disease Associations via Multi-Task Learning Based on Collective Matrix Factorization.

Front Bioeng Biotechnol. 2020;8:218

Authors: Huang F, Qiu Y, Li Q, Liu S, Ni F

Abstract
Identifying drug-disease associations is integral to drug development. Computationally prioritizing candidate drug-disease associations has attracted growing attention due to its contribution to reducing the cost of laboratory screening. Drug-disease associations involve different association types, such as drug indications and drug side effects. However, the existing models for predicting drug-disease associations merely concentrate on independent tasks: recommending novel indications to benefit drug repositioning, predicting potential side effects to prevent drug-induced risk, or only determining the existence of drug-disease association. They ignore crucial prior knowledge of the correlations between different association types. Since the Comparative Toxicogenomics Database (CTD) annotates the drug-disease associations as therapeutic or marker/mechanism, we consider predicting the two types of association. To this end, we propose a collective matrix factorization-based multi-task learning method (CMFMTL) in this paper. CMFMTL handles the problem as multi-task learning where each task is to predict one type of association, and two tasks complement and improve each other by capturing the relatedness between them. First, drug-disease associations are represented as a bipartite network with two types of links representing therapeutic effects and non-therapeutic effects. Then, CMFMTL, respectively, approximates the association matrix regarding each link type by matrix tri-factorization, and shares the low-dimensional latent representations for drugs and diseases in the two related tasks for the goal of collective learning. Finally, CMFMTL puts the two tasks into a unified framework and an efficient algorithm is developed to solve our proposed optimization problem. In the computational experiments, CMFMTL outperforms several state-of-the-art methods both in the two tasks. Moreover, case studies show that CMFMTL helps to find out novel drug-disease associations that are not included in CTD, and simultaneously predicts their association types.

PMID: 32373595 [PubMed]

A Rare Case of Statin-induced Immune-mediated Necrotizing Myopathy.

Cureus. 2020 Apr 01;12(4):e7500

Authors: Madgula AS, Gadela NV, Singh M, Chen K

Abstract
Statin-associated myopathy comprises of a spectrum of conditions ranging from benign myalgias to statin-induced immune-mediated necrotizing myopathy. Statin-induced immune-mediated necrotizing myopathy is an autoimmune condition wherein there is a destruction of normal skeletal muscular architecture that can be severely debilitating if not recognized promptly. Given its rarity, management is a challenge. We present one such case that was managed with aggressive immunosuppression.

PMID: 32373404 [PubMed]

Drug-Drug-Induced Akathisia: Two Case Reports.

Case Rep Psychiatry. 2020;2020:9649483

Authors: Owusu Aboagye G, Ankrah D

Abstract
Extrapyramidal side effects of psychotropic medicines are usually experienced by patients in the first few weeks of initiating therapy. Patients stabilized on these medications who present with distressing complaints akin to akathisia may be triggered by other factors. This report presents two cases of drug-drug-induced akathisia. Case A is a patient with schizophrenia who was being managed with risperidone 2 mg tablet daily for the past 3 years. She fell ill and reported to a nearby clinic where she was prescribed ciprofloxacin and artemether/lumefantrine tablets for the treatment of an infection and malaria. She presented 7 days later to her psychiatrist with complaints of restlessness, tremor, palpitations, insomnia, and resurgence of obsessive thoughts. Case B is a patient who was diagnosed with first-episode psychotic depression and admitted for 10 days. Her medications on admission were fluphenazine decanoate 25 mg depot injection once, olanzapine 10 mg tablet daily, and fluoxetine 20 mg capsule daily. On discharge, ciprofloxacin 500 mg tablet every 12 hours for 5 days and fluconazole 150 mg capsule once were added to her medications for the treatment of a urinary tract infection. She reported back to the hospital a day after discharge with complaints of restlessness, "seizures," tremor, abdominal discomfort, and weight gain. Both patients were diagnosed with akathisia using ICD-10 classification and the Barnes akathisia rating scale and managed with anticholinergics, benzodiazepines, and beta blockers. Other measures employed in managing the akathisia included reducing the dose of the antipsychotic and/or switching antipsychotics. Despite these management measures, the symptoms of akathisia persisted and only resolved after 4weeks. Upon the resolution of symptoms, Case A continued treatment on olanzapine 5 mg tablet daily and fluoxetine 20 mg capsule daily while Case B continued treatment on risperidone 2 mg tablet daily and fluoxetine 20 mg capsule daily. Using Naranjo's adverse drug reaction causality assessment scale, Medscape drug interaction checker, and literature review, a possible and probable case of drug-drug-induced akathisia was made for Case A and Case B. This report is to create more awareness about psychotropic-antimicrobial-induced akathisia. The information underpins the need for health professionals to consider adverse drug-drug interactions as the probable cause of extrapyramidal side effects experienced by patients on antipsychotics.

PMID: 32373382 [PubMed]

Traditional Chinese Medicine Combined With Chemotherapy and Cetuximab or Bevacizumab for Metastatic Colorectal Cancer: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Front Pharmacol. 2020;11:478

Authors: Liu N, Wu C, Jia R, Cai G, Wang Y, Zhou L, Ji Q, Sui H, Zeng P, Xiao H, Liu H, Huo J, Feng Y, Deng W, Li Q

Abstract
Background: Huangci Granule is a traditional Chinese medicine for treating metastatic colorectal cancer (mCRC).
Objective: To evaluate the efficacy and safety of Huangci Granule combination with chemotherapy and cetuximab (CET) or bevacizumab (BV) for treating mCRC.
Methods: We performed a randomized, controlled, and double-blind trial and recruited patients with mCRC who were planned to undergo chemotherapy combined with CET or BV. The treatment group was treated with Huangci Granule, while the control group was treated with placebo. Continuous treatment until disease progression, death, intolerable toxicity or up to 6 months. The primary endpoint was progression-free survival (PFS), and the secondary endpoint was quality of life and safety.
Result: 320 patients were randomly assigned to receive treatment, including 200 first-line patients and 120 second-line patients. In the first-line treatment, the median PFS was 9.59 months (95% CI, 6.94-13.25) vs 6.89 months (95% CI, 4.99-9.52) in treatment group and control group (HR, 0.69; 95% CI, 0.50-0.97; P = 0.027). Chinese medicine was an independent factor affecting the PFS. In the second-line treatment, the median PFS was 6.51 months (95% CI, 4.49-9.44) vs 4.53 months (95% CI, 3.12-6.57) in the treatment group and control group (HR, 0.65; 95% CI, 0.45-0.95; P = 0.020). Compared with the control group, "role function," "social function," "fatigue," and "appetite loss" were significantly improved in the treatment (P < 0.05) and drug related grades 3 to 4 adverse events were less.
Conclusion: Huangci Granule combined with chemotherapy and CET or BV can prolong the PFS of mCRC, improve the quality of life, reduce adverse reactions, and have good safety.

PMID: 32372960 [PubMed]

Quantification of observable behaviors induced by typical and atypical kappa-opioid receptor agonists in male rhesus monkeys.

Psychopharmacology (Berl). 2020 May 06;:

Authors: Huskinson SL, Platt DM, Brasfield M, Follett ME, Prisinzano TE, Blough BE, Freeman KB

Abstract
RATIONALE: Kappa-opioid receptor (KOR) agonists are antinociceptive but have side effects that limit their therapeutic utility. New KOR agonists have been developed that are fully efficacious at the KOR but may produce fewer or reduced side effects that are typical of KOR agonists.
OBJECTIVES: We determined behavioral profiles for typical and atypical KOR agonists purported to differ in intracellular-signaling profiles as well as a mu-opioid receptor (MOR) agonist, oxycodone, using a behavioral scoring system based on Novak et al. (Am J Primatol 28:124-138, 1992, Am J Primatol 46:213-227, 1998) and modified to quantify drug-induced effects (e.g., Duke et al. J Pharmacol Exp Ther 366:145-157, 2018).
METHODS: Six adult male rhesus monkeys were administered a range of doses of the typical KOR agonists, U50-488H (0.0032-0.1 mg/kg) and salvinorin A (0.00032-0.01 mg/kg); the atypical KOR agonists, nalfurafine (0.0001-0.001 mg/kg) and triazole 1.1 (0.01-0.32 mg/kg); the MOR agonist, oxycodone (0.0032-0.32 mg/kg); and as controls, cocaine (0.032-0.32 mg/kg) and ketamine (0.32-10 mg/kg). For time-course determinations, the largest dose of each KOR agonist or MOR agonist was administered across timepoints (10-320 min). In mixture conditions, oxycodone (0.1 mg/kg) was followed by KOR-agonist administration.
RESULTS: Typical KOR agonists produced sedative-like and motor-impairing effects. Nalfurafine was similar to typical KOR agonists on most outcomes, and triazole 1.1 produced no effects on its own except for reducing scratch during time-course determinations. In the mixture, all KOR agonists reduced oxycodone-induced scratching, U50-488H and nalfurafine reduced species-typical activity, and U50-488H increased rest/sleep posture.
CONCLUSIONS: Atypical "biased" KOR agonists produce side-effect profiles that are relatively benign (triazole 1.1) or reduced (nalfurafine) compared to typical KOR agonists.

PMID: 32372348 [PubMed - as supplied by publisher]

Financial toxicity: An adverse effect worthy of a black box warning?

Gynecol Oncol. 2020 02;156(2):263-264

Authors: Dottino JA, Rauh-Hain JA

PMID: 32046838 [PubMed - indexed for MEDLINE]

[First-episode psychosis as primary manifestation of medical disease: An update].

Rev Med Interne. 2019 Nov;40(11):742-749

Authors: Goutte J, Killian M, Antoine JC, Massoubre C, Fakra E, Cathébras P

Abstract
A huge variety of medical diseases may potentially present with isolated psychotic symptoms, and disease-specific treatment or management is available for a significant part of them. The initial medical work-up of a first-episode psychosis (FEP) is of crucial importance. This literature review aimed to identify medical conditions potentially revealed by FEP, to list the warning signs of secondary psychosis, and to discuss a screening strategy. Underlying organic conditions may be drugs and medications, neurologic diseases, infections, inflammatory and/or autoimmune pathologies, and metabolic disorders whether of hereditary origin. Each patient presenting with a first-episode psychosis should be evaluated with a precise anamnesis, a careful clinical examination, and routine laboratory tests. Brain imaging and tests (depending on the context) should be performed in the presence of atypical clinical features or "red flags", leading to suspect an organic disease.

PMID: 31421899 [PubMed - indexed for MEDLINE]