Ophthalmic manifestations of coronavirus disease 2019 and ocular side effects of investigational pharmacologic agents.

Curr Opin Ophthalmol. 2020 Sep;31(5):403-415

Authors: Olson DJ, Ghosh A, Zhang AY

Abstract
PURPOSE OF REVIEW: To compile and report the ocular manifestations of coronavirus disease 2019 (COVID-19) infection and summarize the ocular side effects of investigational treatments of this disease.
RECENT FINDINGS: Conjunctivitis is by far the most common ocular manifestation of COVID-19 with viral particles being isolated from tears/secretions of infected individuals. Multiple therapeutic options are being explored across a variety of medication classes with diverse ocular side effects.
SUMMARY: Eye care professionals must exercise caution, as conjunctivitis may be the presenting or sole finding of an active COVID-19 infection. While no currently studied therapeutic agents have been found to reliably treat COVID-19, early vaccination trials are progressing and show promise. A video abstract is available for a more detailed summary. VIDEO ABSTRACT: http://links.lww.com/COOP/A36.

PMID: 32740062 [PubMed - indexed for MEDLINE]

Automatic Classification of Discharge Letters to Detect Adverse Drug Reactions.

Stud Health Technol Inform. 2020 Jun 16;270:48-52

Authors: Foufi V, Ing Lorenzini K, Goldman JP, Gaudet-Blavignac C, Lovis C, Samer C

Abstract
Adverse drug reactions (ADRs) are frequent and associated to significant morbidity, mortality and costs. Therefore, their early detection in the hospital context is vital. Automatic tools could be developed taking into account structured and textual data. In this paper, we present the methodology followed for the manual annotation and automatic classification of discharge letters from a tertiary hospital. The results show that ADRs and causal drugs are explicitly mentioned in the discharge letters and that machine learning algorithms are efficient for the automatic detection of documents containing mentions of ADRs.

PMID: 32570344 [PubMed - indexed for MEDLINE]

Mechanism-based integrated assay systems for the prediction of drug-induced liver injury.

Toxicol Appl Pharmacol. 2020 05 01;394:114958

Authors: Kawaguchi M, Nukaga T, Sekine S, Takemura A, Susukida T, Oeda S, Kodama A, Hirota M, Kouzuki H, Ito K

Abstract
Drug-induced liver injury (DILI) can cause hepatic failure and result in drug withdrawal from the market. It has host-related and compound-dependent mechanisms. Preclinical prediction of DILI risk is very challenging and safety assessments based on animals inadequately forecast human DILI risk. In contrast, human-derived in vitro cell culture-based models could improve DILI risk prediction accuracy. Here, we developed and validated an innovative method to assess DILI risk associated with various compounds. Fifty-four marketed and withdrawn drugs classified as DILI risks of "most concern", "less concern", and "no concern" were tested using a combination of four assays addressing mitochondrial injury, intrahepatic lipid accumulation, inhibition of bile canalicular network formation, and bile acid accumulation. Using the inhibitory potencies of the drugs evaluated in these in vitro tests, an algorithm with the highest available DILI risk prediction power was built by artificial neural network (ANN) analysis. It had an overall forecasting accuracy of 73%. We excluded the intrahepatic lipid accumulation assay to avoid overfitting. The accuracy of the algorithm in terms of predicting DILI risks was 62% when it was constructed by ANN but only 49% when it was built by the point-added scoring method. The final algorithm based on three assays made no DILI risk prediction errors such as "most concern " instead of "no concern" and vice-versa. Our mechanistic approach may accurately predict DILI risks associated with numerous candidate drugs.

PMID: 32198022 [PubMed - indexed for MEDLINE]

Screening for Adverse Drug Reactions in Dementia Patients on Cholinesterase Inhibitor Therapy.

J Am Geriatr Soc. 2020 01;68(1):216-218

Authors: Saraon SK, Bernick C, Wint D, McConnell E

PMID: 31617580 [PubMed - indexed for MEDLINE]

Physician Perspectives on Deprescribing Cardiovascular Medications for Older Adults.

J Am Geriatr Soc. 2020 01;68(1):78-86

Authors: Goyal P, Anderson TS, Bernacki GM, Marcum ZA, Orkaby AR, Kim D, Zullo A, Krishnaswami A, Weissman A, Steinman MA, Rich MW

Abstract
BACKGROUND/OBJECTIVES: Guideline-based management of cardiovascular disease often involves prescribing multiple medications, which contributes to polypharmacy and risk for adverse drug events in older adults. Deprescribing is a potential strategy to mitigate these risks. We sought to characterize and compare clinician perspectives regarding deprescribing cardiovascular medications across three specialties.
DESIGN: National cross-sectional survey.
SETTING: Ambulatory.
PARTICIPANTS: Random sample of geriatricians, general internists, and cardiologists from the American College of Physicians.
MEASUREMENTS: Electronic survey assessing clinical practice of deprescribing cardiovascular medications, reasons and barriers to deprescribing, and choice of medications to deprescribe in hypothetical clinical cases.
RESULTS: In each specialty, 750 physicians were surveyed, with a response rate of 26% for geriatricians, 26% for general internists, and 12% for cardiologists. Over 80% of respondents within each specialty reported that they had recently considered deprescribing a cardiovascular medication. Adverse drug reactions were the most common reason for deprescribing for all specialties. Geriatricians also commonly reported deprescribing in the setting of limited life expectancy. Barriers to deprescribing were shared across specialties and included concerns about interfering with other physicians' treatment plans and patient reluctance. In hypothetical cases, over 90% of physicians in each specialty chose to deprescribe when patients experienced adverse drug reactions. Geriatricians were most likely and cardiologists were least likely to consider deprescribing cardiovascular medications in cases of limited life expectancy (all P < .001), such as recurrent metastatic cancer (84% of geriatricians, 68% of general internists, and 45% of cardiologists), Alzheimer dementia (92% of geriatricians, 81% of general internists, and 59% of cardiologists), or significant functional impairment (83% of geriatricians, 68% of general internists, and 45% of cardiologists).
CONCLUSIONS: While barriers to deprescribing cardiovascular medications are shared across specialties, reasons for deprescribing, especially in the setting of limited life expectancy, varied. Implementing deprescribing will require improved processes for both physician-physician and physician-patient communication. J Am Geriatr Soc 68:78-86, 2019.

PMID: 31509233 [PubMed - indexed for MEDLINE]

Psychosis as an adverse effect of monoclonal antibody immunotherapy.

Brain Behav Immun. 2019 10;81:646-649

Authors: Essali N, Goldsmith DR, Carbone L, Miller BJ

Abstract
Immunotherapy is a "hot" area in schizophrenia research. Monoclonal antibodies (mAbs) target specific immune molecules, and therefore offer an unparalleled opportunity to directly test the hypothesis that immune dysfunction plays a causal role in psychopathology in schizophrenia. Cytokine-based immunotherapy for other disorders has been associated with a range of neuropsychiatric adverse effects, including psychosis. The purpose of the present study was to investigate the prevalence of spontaneously-reported adverse drug reactions of psychotic symptoms for mAbs, and to calculate odds of psychosis for individual mAbs, compared to bevacizumab, which does not directly target the immune system. We searched the publicly available VigiBase, a World Health Organization global individual case safety report database from inception through February 2019 for which a mAb was the suspected agent of an adverse drug reaction (ADR). We investigated 43 different mAbs, comprising 1,298,185 case reports and 2025 psychosis ADRs. For individual mAbs, the prevalence of psychosis ADRs ranged from 0.1 to 0.4%. Seven mAbs were associated with a significantly increased odds of psychosis (OR = 1.42-2.22), including two agents that target CD25. Eight mAbs were associated with a significantly decreased odds of psychosis (OR = 0.28-0.75), including 4 anti-TNF-α agents. Our results suggest that psychosis is a relatively rare adverse effect of mAb treatment, but risks vary by specific agents. Findings indicate that modulating the immune system may sometimes lead to the development of psychosis. Ongoing clinical trials of adjunctive mAb immunotherapy in schizophrenia will provide valuable insights into the role of the immune system in psychosis.

PMID: 31170448 [PubMed - indexed for MEDLINE]

Pharmacokinetic and Pharmacodynamic Equivalence of Pegfilgrastim-cbqv and Pegfilgrastim in Healthy Subjects.

Adv Ther. 2020 Aug 13;:

Authors: Finck B, Tang H, Civoli F, Hodge J, O'Kelly H, Vexler V

Abstract
INTRODUCTION: Pegfilgrastim-cbqv was developed as a biosimilar of pegfilgrastim, a pegylated form of recombinant human granulocyte colony-stimulating factor approved for decreasing febrile neutropenia-associated infection in patients receiving myelosuppressive drugs. This multicenter, randomized, single-blind, partial-reference-replicated, three-sequence crossover study assessed pharmacokinetic and pharmacodynamic bioequivalence of pegfilgrastim-cbqv and pegfilgrastim in healthy subjects.
METHODS: One hundred twenty-two subjects were randomized to one of three treatment sequences; each included one dose of pegfilgrastim-cbqv and two doses of pegfilgrastim separated by ≥ 28 days. The primary pharmacokinetic end points were area under the curve (AUC) from 0 to infinity (AUC0-∞) and maximum concentration (Cmax). The primary pharmacodynamic end points were maximum absolute neutrophil count (ANCmax) and ANC AUC from time 0 to the last measurable observation (ANC AUC0-last). Pharmacokinetic and pharmacodynamic bioequivalences were demonstrated if the 90% CI for the geometric mean ratio (GMR) of pegfilgrastim-cbqv to pegfilgrastim was within 80-125% for the primary end points.
RESULTS: Pharmacokinetic bioequivalence criteria were met for Cmax (GMR 105.0; 90% CI 95.5-115.4) and AUC0-∞ (GMR 97.5; 90% CI 88.6-107.2). Pharmacodynamic bioequivalence criteria were met for ANCmax (GMR 99.6; 90% CI 96.2-103.2) and ANC AUC0-last (GMR 96.7; 90% CI 92.2-101.4). Adverse events occurred in 76.0%, 76.6%, and 73.1% of subjects for pegfilgrastim-cbqv, first pegfilgrastim, and second pegfilgrastim dosing periods across treatment sequences, respectively. Investigators found no drug-related serious adverse events.
CONCLUSION: This study established pharmacokinetic and pharmacodynamic bioequivalence of pegfilgrastim-cbqv to pegfilgrastim. The treatments displayed similar safety profiles, including immunogenicity, with no unexpected safety findings.
CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov, NCT02650973, February 2016.

PMID: 32789809 [PubMed - as supplied by publisher]

A Case of Valproate-Induced Hyperammonemic Encephalopathy.

Cureus. 2020 Jul 10;12(7):e9114

Authors: Zafar F, Billadeau BM, Ahmed AU

Abstract
A 56-year-old Caucasian male with a history of seizure disorder on long-term prophylaxis with valproate presented with altered mental status, aggressive behavior, decreased oral intake, and frequent myoclonic jerking movements. Electrolyte and other basic metabolic lab testing, liver function testing, and imaging studies were negative for acute abnormalities or infection, though ammonia levels returned markedly elevated, and he also had a macrocytic anemia despite having normal folate and B12 levels. Following discussions with neurology, his valproate was felt to be the inducing factor for his hyperammonemic encephalopathy. After discontinuation of valproate and changing to a new anti-seizure medication, he soon returned to his neurologic baseline. This case report evaluates his presentation and current literature on hyperammonemic encephalopathy induced by valproate.

PMID: 32789057 [PubMed - as supplied by publisher]

Efficacy and Safety of Banxia XieXin Decoction, a Blended Traditional Chinese Medicine, as Monotherapy for Patients With Advanced Hepatocellular Carcinoma.

Integr Cancer Ther. 2020 Jan-Dec;19:1534735420942587

Authors: Wang L, Ke J, Wang C, Li Y, Wu G, Ding Q, Luo Q, Cai R, Lv P, Song T, Xiong S

Abstract
PURPOSE: To explore a new therapeutic option for patients with hepatocellular carcinoma (HCC), the efficacy and safety of a group of traditional Chinese medicines (Banxia XieXin recipe) as monotherapy for patients with advanced HCC was studied.
MATERIALS AND METHODS: The study included 68 patients with advanced HCC from August 16,2016 to August 15,2019 for analysis. These eligible patients received treatment with Banxia XieXin recipe for at least 1 month. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary efficacy endpoints included objective response rate (ORR) and disease control rate (DCR). In addition, safety was also assessed.
RESULTS: The median treatment duration of these 68 patients was 10.3 months (range = 1.6-33.5 months), and follow-up is still ongoing. The median PFS was 6.07 months (95% confidence interval [CI] = 3.748-8.392 months), and the median OS was 12.60 months (95% CI = 8.019-17.181 months). The ORR was 10.3% and the DCR was 41.2%. In the subgroup analysis, the median OS in the transcatheter arterial chemoembolization (TACE) group was not reached, and the median OS in the NO TACE group was 11.30 months (95% CI = 3.219-19.381 months). In addition, no drug-related serious adverse events were observed during the study.
CONCLUSION: This is the first clinical analysis of traditional Chinese medicine as a single treatment for advanced HCC. The obtained results are encouraging as they suggest that this panel of Chinese herbs is safe and it may be effective for patients with advanced HCC in a real-world clinical setting.

PMID: 32787468 [PubMed - as supplied by publisher]

Preliminary exploration on the role of clinical pharmacists in cancer pain pharmacotherapy.

Ann Palliat Med. 2020 Aug 04;:

Authors: Su YJ, Yan YD, Wang WJ, Xu T, Gu ZC, Bai YR, Lin HW

Abstract
BACKGROUND: More than half of cancer patients affected by cancer experience pain of moderate-tosevere intensity. Therefore, facilitating appropriate and safe administration of analgesics is crucial to the comprehensive management of cancer patients. In this article, we assessed medication adherence, pain relief, drug related problems (DRPs) and analgesics adverse events (AEs) in cancer pain patients based on a model of clinical pharmacy services.
METHODS: In this prospective, single-arm intervention study, cancer pain patients admitted to our institution were eligible. According to different adherence, heterogeneity of pain, and individual treatment strategy, clinical pharmacists (CPs) provided comprehensive pain assessment and medication education for patients, as well as provided consultation and recommendation for physicians. CPs' pharmacy services were assessed through medication adherence, numbers of DRPs, acceptance of recommendation, pain intensity (PI), daily interference and AEs.
RESULTS: A total of 42 patients were enrolled between November, 2018 and November, 2019. Compared to baseline, patients' medication adherence evaluated with a medication adherence scale showed a significantly improvement at 14 and at 28 days after receiving CPs' interventions (8 score vs. 7 score at 14 days and at 28 days, P<0.01). During the 28-day follow-up, a total of 63 interventions were put forward according to 57 identified DRPs in 33 patients (78.6%), and approximately 95% (60/63) of the interventions were accepted by physicians. PI and daily interference significantly improved on the third day after the interventions of CPs, and the improvement continued until day 28 (P<0.01). AEs caused by opioids occurred in 19 patients (45.2%), and the most common one was constipation (14 patients, 33.3%).
CONCLUSIONS: CPs' comprehensive interventions for cancer pain patients were efficacious in improving their medication adherence and pain relief, as well as reducing incidence of AEs. Therefore, this promising model should be replicated in other medical centers.

PMID: 32787363 [PubMed - as supplied by publisher]

Safety and Efficacy of Rifampin or Isoniazid Among People with Mycobacterium tuberculosis Infection and Living with HIV or Other Health Conditions: Post-Hoc Analysis of Two Randomized Trials.

Clin Infect Dis. 2020 Aug 12;:

Authors: Campbell JR, Al-Jahdali H, Bah B, Belo M, Cook VJ, Long R, Schwartzman K, Trajman A, Menzies D

Abstract
BACKGROUND: Data on the safety and efficacy of rifampin among people living with HIV or other health conditions has not been reported. We assessed completion, safety, and efficacy of four-months of rifampin vs nine-months of isoniazid among people living with HIV or other health conditions.
METHODS: We conducted post-hoc analysis of two randomized trials including 6859 adult participants with Mycobacterium tuberculosis infection. Participants were randomized 1:1 to 10 mg/kg/d rifampin or 5 mg/kg/d isoniazid. We report completion, drug-related adverse events, and active tuberculosis incidence among people 1) living with HIV; 2) with renal failure or receiving immunosuppressants; 3) using drugs or with hepatitis; 4) with diabetes mellitus; 5) consuming >1 alcoholic drink per week or current/former smokers; 6) with no health condition.
RESULTS: Overall, 270 (3.9%) people were living with HIV (135 receiving ART), 2012 (29.3%) had another health condition, and 4577 (66.8%) had no condition. Rifampin was more often or similarly completed to isoniazid in all populations. Drug-related adverse events were less common with rifampin than isoniazid among people living with HIV (risk difference: -2.1%, 95%CI -5.9 to 1.6). This was consistent for others except people with renal failure or on immunosuppressants (2.1%, 95%CI -7.2 to 11.3). Tuberculosis incidence was similar among people receiving rifampin or isoniazid. Among participants receiving rifampin living with HIV, incidence was comparable to those with no health condition (rate difference: 4.1 per 1000 person-years, 95%CI -6.4 to 14.7).
CONCLUSIONS: Rifampin appears to be safe and as effective as isoniazid across many populations with health conditions, including HIV.

PMID: 32785709 [PubMed - as supplied by publisher]

A Randomized, Double-blind, Multicenter Trial Comparing Efficacy and Safety of Imipenem/Cilastatin/Relebactam Versus Piperacillin/Tazobactam in Adults With Hospital-acquired or Ventilator-associated Bacterial Pneumonia (RESTORE-IMI 2 Study).

Clin Infect Dis. 2020 Aug 12;:

Authors: Titov I, Wunderink RG, Roquilly A, Rodríguez Gonzalez D, David-Wang A, Boucher HW, Kaye KS, Losada MC, Du J, Tipping R, Rizk ML, Patel M, Brown ML, Young K, Kartsonis NA, Butterton JR, Paschke A, Chen LF

Abstract
BACKGROUND: Imipenem combined with the β-lactamase inhibitor relebactam has broad antibacterial activity, including against carbapenem-resistant gram-negative pathogens. We evaluated efficacy and safety of imipenem/cilastatin/relebactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP).
METHODS: This was a randomized, controlled, double-blind phase 3 trial. Adults with HABP/VABP were randomized 1:1 to imipenem/cilastatin/relebactam 500 mg/500 mg/250 mg or piperacillin/tazobactam 4 g/500 mg, intravenously every 6 hours for 7-14 days. The primary endpoint was day 28 all-cause mortality in the modified intent-to-treat (MITT) population (patients who received study therapy, excluding those with only gram-positive cocci at baseline). The key secondary endpoint was clinical response 7-14 days after completing therapy in the MITT population.
RESULTS: Of 537 randomized patients (from 113 hospitals in 27 countries), the MITT population comprised 264 imipenem/cilastatin/relebactam and 267 piperacillin/tazobactam patients; 48.6% had ventilated HABP/VABP, 47.5% APACHE II score ≥15, 24.7% moderate/severe renal impairment, 42.9% were ≥65 years old, and 66.1% were in the intensive care unit. The most common baseline pathogens were Klebsiella pneumoniae (25.6%) and Pseudomonas aeruginosa (18.9%). Imipenem/cilastatin/relebactam was noninferior (P < .001) to piperacillin/tazobactam for both endpoints: day 28 all-cause mortality was 15.9% with imipenem/cilastatin/relebactam and 21.3% with piperacillin/tazobactam (difference, -5.3% [95% confidence interval {CI}, -11.9% to 1.2%]), and favorable clinical response at early follow-up was 61.0% and 55.8%, respectively (difference, 5.0% [95% CI, -3.2% to 13.2%]). Serious adverse events (AEs) occurred in 26.7% of imipenem/cilastatin/relebactam and 32.0% of piperacillin/tazobactam patients; AEs leading to treatment discontinuation in 5.6% and 8.2%, respectively; and drug-related AEs (none fatal) in 11.7% and 9.7%, respectively.
CONCLUSIONS: Imipenem/cilastatin/relebactam is an appropriate treatment option for gram-negative HABP/VABP, including in critically ill, high-risk patients.
CLINICAL TRIALS REGISTRATION: NCT02493764.

PMID: 32785589 [PubMed - as supplied by publisher]

COVID-19 and hydroxychloroquine: Is the wonder drug failing?

Eur J Intern Med. 2020 08;78:1-3

Authors: Paliani U, Cardona A

PMID: 32553587 [PubMed - indexed for MEDLINE]

"It is through shared conversation, that I understand"-Māori older adults' experiences of medicines and related services in Aotearoa New Zealand.

N Z Med J. 2020 06 12;133(1516):33-46

Authors: Hikaka J, Jones R, Hughes C, Martini N

Abstract
AIM: An understanding of patients' healthcare experiences and perceptions is essential for developing new health services. In Aotearoa New Zealand, inequities in health outcomes exist, with Māori experiencing worse health outcomes than non-Māori. This includes poorer access to, and quality of, prescribed medicines. This study aims to explore kaumātua (Māori older adults') experiences of medicines and medicine-related services in New Zealand.
METHOD: This qualitative research applied kaupapa Māori theory and explored Māori older adults' experiences of medicines and medicine-related services in New Zealand. Ten kaumātua from Auckland, New Zealand participated in semi-structured interviews. Reflexive thematic analysis was used to analyse data.
RESULTS: Three themes were generated: 1. diverse, multi-dimensional realities of medicine-taking for Māori with ageing; 2. medicines supply as a business transaction; and 3. self-determined agency of kaumātua supported by authentic healthcare partnerships. Kaumātua expressed their ability to retain power and control over their medicine therapy and their desire for this to occur within a supportive, authentic partnership model that involves them and their multiple healthcare providers.
CONCLUSION: Māori older adults have the ability, desire and right to control their medicines journey in a way that is relevant to their experiences of medicines. They value support from authentic healthcare partnerships in enabling this.

PMID: 32525860 [PubMed - indexed for MEDLINE]

A prospective pharmacovigilance study in the infectious diseases unit of a tertiary care hospital.

J Infect Dev Ctries. 2019 07 31;13(7):649-655

Authors: Karaismailoglu B, Saltoglu N, Balkan II, Mete B, Tabak F, Ozturk R

Abstract
INTRODUCTION: The frequency, causality, severity, preventability and risk factors of ADRs (adverse drug reactions) in infectious disease units are not well defined in the literature. Thus, the aim of this study was to determine the characteristics of the ADRs encountered in an infectious disease unit of a tertiary teaching hospital.
METHODOLOGY: The patients who were admitted to the infectious disease unit of a tertiary teaching hospital longer than 24 hours between January and December of 2016 were followed prospectively. Patients were observed and questioned for any sign of ADRs. The proportion of ADRs and patient characteristics were investigated. Causality was evaluated by the Naranjo algorithm, severity was determined using the Hartwig classification, and preventability was assessed using the Schumock and Thornton scale.
RESULTS: 210 patients were admitted to the unit during the study period, of whom 44 patients (20.9%) experienced 51 ADRs. 5.9% of ADRs were found to be serious according to the Hartwig severity classification. In addition, 88.1% of ADRs were not preventable. The most frequently detected ADR was skin and subcutaneous tissue reactions (33.3%), and systemic antimicrobials were the most common type of drugs that caused an ADR. Prolonged hospitalization (p < 0.001) and usage of an increased number of drugs (p < 0.001) were found to be significant risk factors for ADR development.
CONCLUSIONS: Prolonged hospital stay and polypharmacy are significant risk factors that increase the incidence of ADRs in infectious disease units. The likelihood of unavoidable ADRs should arouse the attention of clinicians when prescribing antimicrobials.

PMID: 32065823 [PubMed - indexed for MEDLINE]

Plasmafiltration as an effective method in the removal of circulating pegylated liposomal doxorubicin (PLD) and the reduction of mucocutaneous toxicity during the treatment of advanced platinum-resistant ovarian cancer.

Cancer Chemother Pharmacol. 2020 02;85(2):353-365

Authors: Kubeček O, Martínková J, Chládek J, Bláha M, Maláková J, Hodek M, Špaček J, Filip S

Abstract
PURPOSE: The present study evaluates the safety and efficacy of double-plasma filtration (PF) to remove the exceeding pegylated liposomal doxorubicin (PLD) in circulation, thus reducing mucocutaneous toxicity.
METHODS: A total of 16 patients with platinum-resistant ovarian cancer were treated with 50 mg/m2 PLD applied in 1-h IV infusion every 28 days. PF was scheduled at 44-46 h post-infusion. The concentration of plasma PLD and non-liposomal doxorubicin (NLD) was monitored with high-performance liquid chromatography at 116 h post-infusion. A non-linear method for mixed-effects was used in the population pharmacokinetic model. The dose fraction of PLD eliminated by the patient prior to PF was compared with the fraction removed by PF. PLD-related toxicity was recorded according to CTCAE v4.0 criteria and compared to historical data. Anticancer effects were evaluated according to RECIST 1.1 criteria.
RESULTS: The patients received a median of 3 (2-6) chemotherapy cycles. A total of 53 cycles with PF were evaluated, which removed 31% (10) of the dose; on the other hand, the fraction eliminated prior to PF was of 34% (7). Exposure to NLD reached only 10% of exposure to the parent PLD. PLD-related toxicity was low, finding only one case of grade 3 hand-foot syndrome (6.7%) and grade 1 mucositis (6.7%). Other adverse effects were also mild (grade 1-2). PF-related adverse effects were low (7%). Median progression-free survival (PFS) and overall survival (OS) was of 3.6 (1.5-8.1) and 7.5 (1.7-26.7) months, respectively. Furthermore, 33% of the patients achieved stable disease (SD), whereas that 67% progressed.
CONCLUSION: PF can be considered as safe and effective for the extracorporeal removal of PLD, resulting in a lower incidence of mucocutaneous toxicity.

PMID: 31728628 [PubMed - indexed for MEDLINE]

Shock From Twisting Peaks: A Rare Case of Recurrent Torsades de Pointes Secondary to Leuprolide-Induced Prolonged QT.

Cureus. 2020 Jul 07;12(7):e9041

Authors: Abbasi D, Faiek S, Shetty S, Khan E

Abstract
Leuprolide acetate is a synthetic nonpeptide analog that is a potent gonadotropin-releasing hormone receptor agonist. It is used in diverse clinical applications, including treatment for prostate cancer, endometriosis, and uterine fibroids as well as the in vitro fertilization technique. Prolonged QT interval leading to torsades de pointes (TdP) is one of the very rare side effects of leuprolide therapy. Herein, we report a 68-year-old male patient with a history of prostate cancer post-radiation and on androgen suppression therapy with leuprolide who suffered from out-of-hospital cardiac arrest. After initial resuscitation, the patient's electrocardiogram (ECG) showed a prolonged corrected QT interval (QTc), which subsequently progressed into a TdP rhythm, requiring lidocaine drip initially. The patient's symptoms improved, and his ECG rhythm was resolved after initiating mexiletine and propranolol treatment with no recurrent TdP episodes after discontinuation of leuprolide.

PMID: 32782861 [PubMed]

Immune-Related Adverse Events Requiring Hospitalization: Spectrum of Toxicity, Treatment, and Outcomes.

J Oncol Pract. 2019 09;15(9):e825-e834

Authors: Balaji A, Zhang J, Wills B, Marrone KA, Elmariah H, Yarchoan M, Zimmerman JW, Hajjir K, Venkatraman D, Armstrong DK, Laheru DA, Mehra R, Ho WJ, Reuss JE, Heng J, Vellanki P, Donehower RC, Holdhoff M, Naidoo J

Abstract
PURPOSE: Immune checkpoint inhibitors (ICIs) cause immune-related adverse events (irAEs). The proportion of patients who are hospitalized for irAEs and their spectrum, management, and outcomes are not well described.
METHODS: We report the proportion of hospitalized patients in an academic center who were treated with ICIs from May to December 2017. Patient characteristics, toxicities, management, and outcomes for confirmed irAE admissions are reported. Associations between patient features and irAE hospitalizations are examined.
RESULTS: Twenty-three percent (n = 100) of 443 patients who were admitted to an academic oncology center over 6 months had ever received ICIs. Of these patients, 41% were admitted for suspected irAEs and 23% were confirmed irAEs. IrAEs accounted for 5% of all oncology hospitalizations (n = 23). Ninety-one percent of patients with confirmed irAEs prompted a medicine subspecialist consultation, most commonly gastroenterology (22%). Fifteen patients (65%) had their irAEs improve/resolve, seven (30%) had worsening irAEs, and three (13%) died of their irAEs. The majority of patients (n = 20; 87%) discontinued ICIs after discharge. Among ICI-treated patients who required admission, an increased likelihood of irAE-related hospitalization was associated with patient age older than 65 years (odds ratio, 5.4; 95% CI, 1.6 to 17.8) and receipt of combination immunotherapy (OR, 6.8; 95% CI, 2.0 to 23.2).
CONCLUSION: A notable proportion of ICI-treated patients are hospitalized for irAEs, and these patients have a high demand for multidisciplinary management. Older age and combination ICI treatment were associated with an increased risk of irAE-related hospitalization. Whereas these data are from an academic center and include patients in clinical trials, with expanding use of ICIs, these data have important implications for inpatient service planning and risk stratification.

PMID: 31386608 [PubMed - indexed for MEDLINE]

Serial monitoring of isavuconazole blood levels during prolonged antifungal therapy.

J Antimicrob Chemother. 2019 08 01;74(8):2341-2346

Authors: Furfaro E, Signori A, Di Grazia C, Dominietto A, Raiola AM, Aquino S, Ghiggi C, Ghiso A, Ungaro R, Angelucci E, Viscoli C, Mikulska M

Abstract
BACKGROUND: Isavuconazole is the newest triazole antifungal approved for the treatment of invasive aspergillosis (IA) and invasive mucormycosis in adult patients.
OBJECTIVES: To characterize the assessment of the blood levels of isavuconazole and their association with efficacy and toxicity.
METHODS: From January 2017 to May 2018, blood samples obtained from patients receiving isavuconazole were analysed for therapeutic drug monitoring. Factors influencing the blood concentrations of isavuconazole, such as weight, length of treatment, route of administration and results of selected liver function tests, were analysed in univariate and multivariate models. The receiver operating characteristic (ROC) curve was analysed to detect the best cut-off for isavuconazole toxicity.
RESULTS: A total of 264 isavuconazole blood concentrations in 19 patients were analysed. The median value of isavuconazole concentration in all patients during the first 30 days of therapy was 3.69 mg/L (range 0.64-8.13 mg/L). A linear increase of 0.032 mg/L (range 0.023-0.041 mg/L) for each day of treatment (P = 0.002) was observed. In multivariate analysis the association between the length of treatment and higher levels of isavuconazole (P < 0.001) and higher serum GGT and lower isavuconazole levels (P = 0.001) was confirmed. Adverse events, mainly gastrointestinal, were reported in six patients (31.6%). Based on time-dependent and fixed-time ROC curve analysis, 4.87 mg/L and 5.13 mg/L, respectively, were the identified thresholds for toxicity.
CONCLUSIONS: Isavuconazole was efficacious and well tolerated. Side effects, mainly gastrointestinal, were associated with prolonged administration and high serum levels.

PMID: 31119272 [PubMed - indexed for MEDLINE]

Possible recurrent aseptic meningitis associated with nusinersen therapy.

Muscle Nerve. 2020 Aug 11;:

Authors: Moshe-Lilie O, Riccelli LP, Karam C

PMID: 32779205 [PubMed - as supplied by publisher]