J Thorac Oncol. 2021 Jul 12:S1556-0864(21)02291-7. doi: 10.1016/j.jtho.2021.06.024. Online ahead of print.

ABSTRACT

INTRODUCTION: The optimal management for immune related adverse events (irAEs) in patients who do not respond or become intolerant to steroids is unclear. Guidelines suggest additional immunosuppressants based on case reports and expert opinion.

METHODS: We examined patients with lung cancers at MSK treated with immune checkpoint blockade (ICB) from 2011-2020. Pharmacy records were queried to identify patients who received systemic steroids as well as an additional immunosuppressant (eg TNFα inhibitor, mycophenolate mofetil). Patient records were manually reviewed to examine baseline characteristics, management, and outcomes.

RESULTS: Among 2,750 patients with lung cancers treated with ICB, 51 (2%) received both steroids and an additional immunosuppressant for a severe irAE (TNFα inhibitor (73%), mycophenolate mofetil (20%)). The most common events were colitis (53%), pneumonitis (20%), hepatitis (12%), and neuromuscular (10%). At 90 days after start of an additional immunosuppressant, 57% were improved from their irAE, 18% were unchanged, and 25% were deceased. Improvement was more common in hepatitis (5/6) and colitis (18/27) but less common in neuromuscular (1/5) and pneumonitis (3/10). Of patients who died, 8/13 were attributable directly to the irAE and 4/13 were related to toxicity from immunosuppression (3, infection-related deaths; 1, drug-induced liver injury leading to acute liver failure).

CONCLUSIONS: Steroid-refractory/resistant immune related adverse events are rare. While existing treatments help patients with hepatitis and colitis, many patients with other irAEs remain refractory and/or experience toxicities from immunosuppression. A more precise understanding of the pathophysiology of specific irAEs is needed to guide biologically-informed treatments for severe irAEs.

PMID:34265432 | DOI:10.1016/j.jtho.2021.06.024

Epilepsia Open. 2021 Jul 15. doi: 10.1002/epi4.12522. Online ahead of print.

ABSTRACT

The primary objective of this trial (SP1042; NCT02582866) was to assess long-term safety and tolerability of lacosamide monotherapy (200-600 mg/day) in adults with focal (partial-onset) seizures or generalized tonic-clonic seizures (without clear focal origin). This Phase III, long-term, open-label, multicenter, follow-up trial enrolled patients with epilepsy who were taking lacosamide in, and completed, the previous double-blind trial (SP0994; NCT01465997). Primary safety outcomes were treatment-emergent adverse events (TEAEs), discontinuations due to TEAEs, and serious TEAEs. One hundred and six patients were enrolled and received lacosamide; 84 (79.2%) completed the trial, and 22 (20.8%) discontinued. The median duration of exposure was 854.0 days, with a median modal dose of 200 mg/day. Ninety-six (90.6%), 64 (60.4%), and 44 (41.5%) patients had ≥12, ≥24, and ≥36 months of lacosamide exposure, respectively. At least one TEAE was reported by 61 (57.5%) patients. The most common (≥4%) TEAEs were headache (10 [9.4%]), nasopharyngitis (eight [7.5%]), and back pain (five [4.7%]). One (0.9%) patient discontinued due to a TEAE (sudden unexpected death in epilepsy; not considered drug-related), 14 (13.2%) patients reported serious TEAEs, and seven (6.6%) patients reported TEAEs that were considered drug-related. Overall, long-term lacosamide monotherapy was generally well tolerated up to 600 mg/day, with no new safety signals identified.

PMID:34265173 | DOI:10.1002/epi4.12522

Blood. 2021 Jul 15:blood.2021012021. doi: 10.1182/blood.2021012021. Online ahead of print.

ABSTRACT

Belumosudil, an investigational oral selective inhibitor of rho-associated coiled-coil-containing protein kinase-2 (ROCK2), reduces type 17 and follicular helper T cells via downregulation of signal transducer and activator of transcription 3 (STAT3) and enhances regulatory T cells via upregulation of signal transducer and activator of transcription 5 (STAT5). Belumosudil may effectively treat patients with cGVHD, a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2, randomized, multicenter registration study evaluated belumosudil 200 mg QD (n=66) and 200 mg BID (n=66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR (95% CI) of belumosudil 200 mg QD and 200 mg BID was 74% (62%-84%) and 77% (65%-87%), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg QD and 200 mg BID was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil due to possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. (Funded by Kadmon Corporation, LLC; ClinicalTrials.gov number, NCT03640481.).

PMID:34265047 | DOI:10.1182/blood.2021012021

Therap Adv Gastroenterol. 2021 Jun 28;14:17562848211024458. doi: 10.1177/17562848211024458. eCollection 2021.

ABSTRACT

BACKGROUND: Selecting a bowel preparation for patients with renal impairment or diabetes requires special consideration. We aimed to describe the effect of baseline renal impairment or diabetes on the safety, efficacy, and tolerability of low-volume sodium picosulfate, magnesium oxide, and citric acid (SPMC) ready-to-drink oral solution bowel preparation.

METHODS: A post hoc secondary analysis was performed from a randomized, assessor-blinded study of SPMC oral solution bowel preparation in participants with mild or moderate baseline renal impairment or diabetes. Primary efficacy endpoint ('responders') was the proportion of participants with 'excellent' or 'good' ratings on a modified Aronchick Scale (AS). Secondary efficacy outcomes were the quality of ascending colon cleansing from the Boston Bowel Preparation Scale (BBPS), and selected results from the Mayo Clinic Bowel Prep Tolerability Questionnaire. Safety assessments included adverse events (AEs), adenoma detection, and laboratory evaluations.

RESULTS: Similar overall colon cleansing was demonstrated in the subgroups, with >85% of participants in any subgroup rated as responders by the AS, and >92% of participant responders by the BBPS. Most participants reported a tolerable bowel preparation, regardless of baseline renal impairment or diabetes history. Safety of SPMC oral solution was similar between all subgroups and the overall cohort. For the mild renal impairment, moderate renal impairment, and diabetes subgroups, respectively, commonly reported, drug-related AEs were nausea (2.6%, 5.3%, 1.4%) and headache (2.2%, 2.6%, 4.3%).

CONCLUSIONS: Ready-to-drink SPMC oral solution demonstrated efficacious colon cleansing in patients with baseline mild/moderate renal impairment or diabetes, with a tolerable bowel preparation reported by most.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03017235.

PMID:34262611 | PMC:PMC8243104 | DOI:10.1177/17562848211024458

Medicine (Baltimore). 2021 Jul 16;100(28):e25002. doi: 10.1097/MD.0000000000025002.

ABSTRACT

BACKGROUND: Lung cancer is the main cause of cancer-related death in the world, and non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Cisplatin and its derivatives are the first-line chemotherapeutic drugs for patients with advanced lung cancer, but the chemotherapy-related adverse reactions greatly impact the quality of life (QOL) of patients and limit their use. Jinfukang is a commonly used traditional Chinese medicine preparation with anti-tumor effect in China, which has been approved by China Food and Drug Administration against NSCLC. At present, there is a lack of strict randomized controlled trials to study whether Jinfukang could alleviate the chemotherapy-related adverse effects in the treatment of advanced NSCLC. Therefore, we intend to perform a double-blind, placebo controlled, randomized trial to evaluate the effect of Jinfukang in alleviating the chemotherapy-related adverse effects of patients with advanced NSCLC.

METHODS: This is a prospective, double-blind, randomized, placebo controlled trial. According to the randomized control principle, 168 patients will be divided into treatment group and control group at 1:1 ratio. The patients in the two groups will be treated continuously for 3 cycles and followed up for 3 years. Outcome indicators include: the incidence of chemotherapy-related adverse effects, the progression-free survival (PFS), total effective rate, and QOL evaluation. We will use SPSS19.0 to analyze the results.

CONCLUSIONS: This study will help to evaluate the effect of Jinfukang alleviating chemotherapy-related adverse effects in the treatment of advanced NSCLC.

TRIAL REGISTRATION: DOI 10.17605/OSF.IO/YWBSC.

PMID:34260519 | PMC:PMC8284706 | DOI:10.1097/MD.0000000000025002

BMC Infect Dis. 2021 Jul 13;21(1):680. doi: 10.1186/s12879-021-06364-5.

ABSTRACT

BACKGROUND: Campylobacter fetus is an uncommon Campylobacter species, and its infections mainly cause infective endocarditis, aortic aneurysm, and meningitis rather than enteritis. It is more likely to be detected in blood than Campylobacter jejuni or Campylobacter coli, specifically reported in 53% of patients. In our case, C. fetus was detected in both blood and cerebrospinal fluid (CSF) cultures.

CASE PRESENTATION: A 33-year-old woman, who was on maintenance chemotherapy for acute lymphoblastic leukemia (ALL), presented to our clinic with chief complaints of severe headache and nausea. Blood and CSF cultures revealed C. fetus. We administrated meropenem 2 g intravenously (IV) every 8 h for 3 weeks, and she was discharged without neurological sequelae.

CONCLUSION: We encountered a case of C. fetus meningitis without gastrointestinal symptoms, neck stiffness or jolt accentuation in a patient with ALL. Undercooked beef was considered the source of C. fetus infection in this case, suggesting that the need for a neutropenic diet and safe food handling be considered.

PMID:34256709 | PMC:PMC8278592 | DOI:10.1186/s12879-021-06364-5

Clin Toxicol (Phila). 2021 Jul 14:1-8. doi: 10.1080/15563650.2021.1945081. Online ahead of print.

ABSTRACT

INTRODUCTION: Valproic acid is a carboxylic acid derivative commonly prescribed for several types of seizure disorders or for acute manic episodes in patients with bipolar disorder. Several cases of valproate-induced pleural effusion have been reported, although the precise pathophysiological mechanism remains unknown.

OBJECTIVE: To describe the presentation of pleural effusion associated with valproate use and to categorize published case reports according to clinical, immunological, and pleural effusion cell type.

METHODS: PubMed/MEDLINE and Embase databases were systematically searched from January 1970 until November 2020 using the following search terms: "valproic acid" OR "valproate" OR "pleural fluid" OR "exudative effusion" OR "transudative effusion" OR "valproic lung adverse events". These searches yielded 171 references of which 135 articles were considered irrelevant, leaving 36 potentially relevant references which were carefully scrutinized. Twenty-eight cases of valproate-induced pleural effusion were identified after excluding two articles reporting five patients with lung parenchymal adverse reactions to treatment with valproic acid; two articles reporting three patients in whom the pleural effusion could not be attributed to valproic acid alone; one case discussing valproate therapy and fungal pleural effusion; and one describing a patient who suffered from severe cardiac failure. There were also two cases, in an abstract form, with pericardial and pleural effusion, but without any further informative details, and, thus, they were also excluded from this survey.

EXUDATIVE EOSINOPHILIC PLEURAL EFFUSION: This was the most common type of valproate-induced pleural effusion reported in 17 out of 28 cases (60.7%), with concurrent peripheral eosinophilia in ten. Acute hypersensitivity reaction, inflammation of the pleural cavity induced by the drug, drug toxicity, and damage to mesothelial cells due to oxidants, comprise the possible pivotal mechanisms.

EXUDATIVE LYMPHOCYTIC PLEURAL EFFUSION: This was reported in two cases, with concurrent pericardial effusion in one. Discontinuation of valproate led to resolution of the effusion, although the underlying pathophysiological mechanisms remain abstruse. Interestingly, a patient presented with recurrent pleural effusion characterized by transition from eosinophilic to lymphocytic predominance after readministration of valproate.

TRANSUDATIVE PLEURAL EFFUSION: Three out of 28 cases (10.7%) were characterized by neutrophilic transudative pleural effusion after long-term therapy with valproate, while concurrent pericardial effusion was also noted in two.

VALPROATE-INDUCED LUPUS ERYTHEMATOSUS WITH PLEURAL EFFUSION: Five patients receiving valproate therapy (17.9% out of the 28 cases) developed drug-induced lupus erythematosus with concurrent pleural effusion that was eosinophilic in three. All patients had positive antinuclear antibodies; anti-histone antibodies were positive in two.

CONCLUSIONS: Valproate-induced pleural effusion is rare, but patients receiving treatment with valproic acid who develop respiratory symptoms should be examined for valproate-induced pleural effusion.

PMID:34259092 | DOI:10.1080/15563650.2021.1945081

Cureus. 2021 Jun 4;13(6):e15441. doi: 10.7759/cureus.15441. eCollection 2021 Jun.

ABSTRACT

With the rapid development and adoption of novel anti-cancer therapeutics, physicians commonly encounter cancer patients on regimens with recently approved drugs for which information about rare or long-term side effects may not be available. In this case, we present a young woman with cholangiocarcinoma who was treated with the rearranged during transfection (RET)-selective tyrosine kinase inhibitor (TKI), pralsetinib, and presented to the hospital with shortness of breath. We review her diagnosis of new-onset systolic dysfunction as a possible sequela of her TKI therapy to encourage ongoing efforts to enhance provider familiarity with the side effects of this important and increasingly prescribed drug class.

PMID:34258110 | PMC:PMC8255035 | DOI:10.7759/cureus.15441

Genet Med. 2021 Jul 13. doi: 10.1038/s41436-021-01259-x. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate the safety and efficacy of N-acetylmannosamine (ManNAc) in GNE myopathy, a genetic muscle disease caused by deficiency of the rate-limiting enzyme in N-acetylneuraminic acid (Neu5Ac) biosynthesis.

METHODS: We conducted an open-label, phase 2, single-center (NIH, USA) study to evaluate oral ManNAc in 12 patients with GNE myopathy (ClinicalTrials.gov NCT02346461). Primary endpoints were safety and biochemical efficacy as determined by change in plasma Neu5Ac and sarcolemmal sialylation. Clinical efficacy was evaluated using secondary outcome measures as part of study extensions, and a disease progression model (GNE-DPM) was tested as an efficacy analysis method.

RESULTS: Most drug-related adverse events were gastrointestinal, and there were no serious adverse events. Increased plasma Neu5Ac (+2,159 nmol/L, p < 0.0001) and sarcolemmal sialylation (p = 0.0090) were observed at day 90 compared to baseline. A slower rate of decline was observed for upper extremity strength (p = 0.0139), lower extremity strength (p = 0.0006), and the Adult Myopathy Assessment Tool (p = 0.0453), compared to natural history. Decreased disease progression was estimated at 12 (γ = 0.61 [95% CI: 0.09, 1.27]) and 18 months (γ = 0.55 [95% CI: 0.12, 1.02]) using the GNE-DPM.

CONCLUSION: ManNAc showed long-term safety, biochemical efficacy consistent with the intended mechanism of action, and preliminary evidence clinical efficacy in patients with GNE myopathy.

PMID:34257421 | DOI:10.1038/s41436-021-01259-x

J Neurol. 2021 Jul 13. doi: 10.1007/s00415-021-10664-w. Online ahead of print.

ABSTRACT

BACKGROUND: Alemtuzumab is an effective disease-modifying therapy (DMT) for highly active multiple sclerosis (MS). However, safety concerns limit its use in clinical practice.

OBJECTIVES: To evaluate the safety of alemtuzumab in a nationwide cohort of Finnish MS patients.

METHODS: In this retrospective case series study, we analyzed the data of all but two MS patients who had received alemtuzumab in Finland until 2019. Data were systematically collected from patient files.

RESULTS: Altogether 121 patients were identified, most of whom had received previous DMTs (82.6%). Median follow-up time after treatment initiation was 30.3 months and exceeded 24 months in 78 patients. Infusion-associated reactions (IARs) were observed in 84.3%, 57.3%, and 57.1% of patients during alemtuzumab courses 1-3, respectively. Serious adverse events (SAEs) were observed in 32.2% of patients, serious IARs in 12.4% of patients, and SAEs other than IARs in 23.1% of patients. Autoimmune adverse events were observed in 30.6% of patients. One patient died of hemophagocytic lymphohistiocytosis, and one patient died of pneumonia. A previously unreported case of thrombotic thrombocytopenic purpura was documented.

CONCLUSIONS: SAEs were more frequent in the present cohort than in previous studies. Even though alemtuzumab is a highly effective therapy for MS, vigorous monitoring with a long enough follow-up time is advised.

PMID:34255182 | DOI:10.1007/s00415-021-10664-w

Gynecol Oncol. 2021 Jul 10:S0090-8258(21)00538-2. doi: 10.1016/j.ygyno.2021.07.008. Online ahead of print.

ABSTRACT

OBJECTIVE: To determine the clinical benefit of monotherapy with PI3K/AKT/mTOR inhibitors in patients diagnosed with advanced or recurrent ovarian cancer and to investigate the predictive value of current PI3K/AKT/mTOR biomarkers on therapy response.

METHODS: A systematic search was conducted in PubMed, Embase and the Cochrane Library for articles reporting on treatment with PI3K/AKT/mTOR inhibitors in ovarian cancer. The primary endpoint was defined as the clinical benefit rate (CBR), including the proportion of patients with complete (CR) and partial response (PR) and stable disease (SD). Secondary endpoints included the overall response rate (ORR, including CR and PR) and drug-related grade 3 and 4 adverse events.

RESULTS: We included 233 patients from 19 studies and observed a pooled CBR of 32% (95% CI 20-44%) and ORR of 3% (95% CI 0-6%) in advanced or recurrent ovarian cancer patients treated with PI3K/AKT/mTOR inhibitors. Subgroup analysis tended to favor the studies who selected patients based on current PI3K/AKT/mTOR biomarker criteria (e.g. genomic alterations or loss of PTEN protein expression), but the difference in CBR was not statistically significant from studies with unselected populations (respectively, CBR of 42% (95% CI 23-62%) and 27% (95% CI 14-42%), P = 0.217). To better reflect true patient benefit, we excluded SD <6 months as a beneficial outcome which resulted in a pooled CBR of 7% (95% CI 2-13%). The overall proportion of patients with drug-related grade 3 and 4 adverse events was 36%.

CONCLUSIONS: The efficacy of monotherapy with PI3K/AKT/mTOR inhibitors in advanced recurrent ovarian cancer patients is limited to a small subgroup and selection of patients with the use of current biomarkers did not improved the CBR significantly. Given the toxicity profile, we suggest that current treatment with PI3K/AKT/mTOR inhibitors should not be initiated unless in clinical trials. Furthermore, improved biomarkers to measure functional PI3K/AKT/mTOR pathway activity are needed to optimize patient selection.

PMID:34253390 | DOI:10.1016/j.ygyno.2021.07.008

Asia Ocean J Nucl Med Biol. 2021 Spring;9(2):86-100. doi: 10.22038/AOJNMB.2021.55600.1386.

ABSTRACT

OBJECTIVES: Miltuximab® is a chimeric antibody targeting Glypican-1 (GPC-1), a cell surface antigen which is overexpressed in solid cancers. Miltuximab® has shown promising safety and efficacy in radioimmunotherapy models of prostate cancer. This first in human study used Miltuximab® radiolabelled with Gallium-67 ([67Ga]Ga-DOTA-Miltuximab®). The primary study endpoint was to establish safety and tolerability of Miltuximab®. Secondary endpoints were biodistribution, tumour targeting and pharmacokinetic analysis.

METHODS: Four cohorts of three patients (9 with advanced prostate cancer, 2 with pancreatic and 1 with bladder cancer) were dosed with 1 mg, ~250 MBq of [67Ga]Ga-DOTA-Miltuximab®. Cohort 1 received [67Ga]Ga-DOTA-Miltuximab® alone, while cohorts 2-4 were pre-infused with increasing doses (3.5, 11.5 and 24 mg, respectively) of unlabelled Miltuximab®-DOTA 1 hour prior to [67Ga]Ga-DOTA-Miltuximab®. Safety and tolerability were assessed by clinical and standard laboratory assessments. Patients underwent whole body gamma-camera scans and SPECT/CT scans up to 144 h post-infusion. Total organ radiation exposure was determined by dosimetry of whole-body gamma scans.

RESULTS: The dosing regimen was well tolerated, with no drug-related adverse events observed. Liver and spleen uptake of [67Ga]Ga-DOTA-Miltuximab® was observed. Liver uptake was reduced by pre-infusion of unlabelled Miltuximab®-DOTA. Dosimetry analysis showed a favorable exposure profile. [67Ga]Ga-DOTA-Miltuximab® targeting to tumour sites was observed in two prostate cancer patients who had failed enzalutamide treatment. Higher doses of unlabelled antibody achieved lower liver uptake and increased antibody serum half life.

CONCLUSIONS: This study is the first in human for Miltuximab® a first in class antibody targeting GPC-1. The trial met its primary endpoint of safety, demonstrating its potential as a safe and tolerable monoclonal antibody. This safety data, together with targeting to tumour lesions and biodistribution information supports the further clinical development of Miltuximab® as a theranostic agent in a planned Phase I human trial.

PMID:34250138 | PMC:PMC8255523 | DOI:10.22038/AOJNMB.2021.55600.1386

Cureus. 2021 Jun 2;13(6):e15385. doi: 10.7759/cureus.15385. eCollection 2021 Jun.

ABSTRACT

Enteric fever is a multisystem illness caused by Salmonella Typhi and Salmonella Paratyphi, and it is associated with a spectrum of conditions ranging from minor cases of diarrhea and low-grade fever to a potentially fatal illness that can lead to gastrointestinal (GI) perforation, hemorrhage, central nervous system (CNS) involvement. Neuroleptic malignant syndrome (NMS) is predominantly described as an idiosyncratic reaction to neuroleptic medications. However, it has also been associated with a variety of drugs that reduce dopaminergic activity. In this report, we present the case of a young woman who had enteric fever and was prescribed IV ceftriaxone and domperidone. She subsequently developed NMS secondary to domperidone. We highlight the challenges faced when dealing with two potentially lethal medical conditions presenting concurrently and their overlapping symptoms. The patient was treated for both of the conditions and recovered completely.

PMID:34249537 | PMC:PMC8252910 | DOI:10.7759/cureus.15385

Front Pharmacol. 2021 Jun 24;12:631293. doi: 10.3389/fphar.2021.631293. eCollection 2021.

ABSTRACT

Objective: The aim of the study was to observe the clinical efficacy and safety of intravenous and oral sequential treatment with voriconazole for Candida central nervous system (CNS) infection in premature infants. Methods: The study included retrospective analysis of the clinical data of six premature infants with Candida CNS infection admitted to the neonatology department in Shanghai Children's Hospital between November 2016 and November 2019. By reviewing the characteristics of voriconazole based on the literature, it showed that infants without gastrointestinal dysfunction could be effectively treated by intravenous and oral sequential therapy with voriconazole (both 7 mg/kg/dose, every 12 h). Clinical manifestations, the time required for the cerebrospinal fluid (CSF), blood culture, nonspecific infection markers such as platelets and C-reactive protein (CRP) to turn normal, and drug-related side effects were observed and recorded in the process of treatment. All data were statistically analyzed by T test and Mann-Whitney U test. Results: A total of six premature infants were diagnosed with Candida CNS infection, two cases were diagnosed by a positive CSF culture and four cases were clinically diagnosed. Blood culture was positive for Candida in five cases. Among the 6 patients, 4 cases were Candida albicans and 2 cases were Candida parapsilosis. All the six cases were cured. After 3-5 days of treatment, symptoms such as lethargy, apnea, and feeding intolerance were improved and disappeared; a repeated blood culture turned negative in 3-7 days; CSF returned to normal in 15 ± 9 days on an average. Brain abscess, meningeal inflammation, and other infectious lesions were cleared on cranial magnetic resonance imaging (MRI) after treatment. The average total course of voriconazole was 61 ± 29 days, and the average oral treatment was 28 ± 15 days. No Candida recurrence was found during the treatment, and no drug-related side effects such as skin rash, liver and kidney function impairment, or visual abnormalities were found. The white blood cells, CSF glucose/plasma glucose ratio, and protein in CSF were significantly improved after the treatment (p < 0.05). No statistically significant difference was identified in the liver and kidney function indexes (p > 0.05). Conclusion: Voriconazole is a relatively safe and effective alternative treatment for Candida CNS infection in preterm infants. No severe drug-related side effects were detected.

PMID:34248616 | PMC:PMC8263898 | DOI:10.3389/fphar.2021.631293

Can J Hosp Pharm. 2021 Summer;74(3):211-218. doi: 10.4212/cjhp.v74i3.3148. Epub 2021 Jul 1.

ABSTRACT

BACKGROUND: Pharmaceutical interventions aim to correct or prevent a drug-related problem (DRP) that might lead to negative clinical consequences and increase health care costs.

OBJECTIVE: To identify variables associated with the provision of pharmaceutical interventions by clinical pharmacists during hospitalization.

METHODS: In this retrospective cohort study, adult inpatients of the medical ward of the University Hospital of the University of São Paulo in São Paulo, Brazil, were followed from admission to discharge. Logistic regression models were used to evaluate the association between occurrence of at least 1 pharmaceutical intervention and the following baseline characteristics: sex, age, Charlson comorbidity index, renal failure, electrolyte imbalance, hemoglobin, platelet count, and use of a nasoenteric tube, as well as the number, second-level Anatomical Therapeutic Chemical (ATC) code, and administration route of prescribed medications.

RESULTS: A total of 148 patients were included in the study, of whom 75 (50.7%) were men. The mean age was 62.8 (95% confidence interval [CI] 59.9-65.8) years, and the mean length of the hospital stay was 10.7 (95% CI 8.4-13.1) days. Analgesics (ATC code N02), the most common type of medication, were prescribed to 144 (97.3%) of the patients. Pharmaceutical interventions were performed for only 49 (33.1%) of the patients. One out of every 4 of these interventions was intended to obtain information not provided in the prescription, to allow the prescription to be completed and dispensing to proceed. According to the multivariate analysis, the odds ratio (OR) of occurrence of at least 1 pharmaceutical intervention increased for patients with electrolyte imbalance (OR 2.68, 95% CI 1.09-6.63; p = 0.033), patients using 5 to 8 medications (OR 8.73, 95% CI 1.07-71.36; p = 0.043), patients using 9 or more medications (OR 10.39, 95% CI 1.28-84.05; p = 0.028), and patients using at least 1 systemic antibacterial (ATC code J01; OR 2.76, 95% CI 1.30-5.84; p = 0.008).

CONCLUSIONS: The findings of this study could allow the identification, at the time of admission and possibly before the occurrence of a DRP, of patients at higher risk of requiring a pharmaceutical intervention later during their hospital stay. To optimize patient care, clinical pharmacists should closely follow inpatients with electrolyte imbalance, polypharmacy, and/or use of systemic antibacterials.

PMID:34248161 | PMC:PMC8237951 | DOI:10.4212/cjhp.v74i3.3148

Aliment Pharmacol Ther. 2021 Jul 11. doi: 10.1111/apt.16518. Online ahead of print.

ABSTRACT

BACKGROUND: With the advent of biological therapy in IBD, it is uncertain to what extent 5aminosalicylates (5ASA) are used.

AIMS: To explore whether or not 5ASA is continued once biological or immunomodulator therapy is initiated, and the outcomes in those who continued the 5ASAs.

METHODS: We conducted a retrospective cohort study using the population-based University of Manitoba IBD Epidemiologic Database which includes prescription drug dispensation from 1996 through 2018. We assessed outcomes among 5ASA users who continued versus discontinued 5ASA after initiation of anti-TNF therapy or immunomodulators.

RESULTS: In all, 8379 (77%) of persons with IBD received at least one 5ASA dispensation (85% of ulcerative colitis, UC and 68% of Crohn's disease, CD). There was a reduction in later years, particularly for CD. The most common pattern of 5ASA use was intermittent at 65.1% (stopping and restarting use) versus one-time (4.1%), previous continuous (13.8%) and persistent (17%). Among the total IBD population use was 59% oral, 3% rectal and 14% combination. Of all 5ASA starts, only 25% were continued longer than 20 months. After immunomodulator or anti-TNF initiation, there was no difference in either UC or CD for negative outcomes (hospitalisation, surgery, corticosteroid starts, colorectal cancers or drug-related adverse events) between those who continued 5ASA versus those who discontinued.

CONCLUSIONS: 5ASA remains commonly prescribed in UC and CD. Rates of persistent use in UC are low. Once an anti-TNF or immunomodulator is initiated, continuation of 5ASA seems to add no benefit.

PMID:34247410 | DOI:10.1111/apt.16518

Epilepsy Res. 2021 Jun 29;176:106705. doi: 10.1016/j.eplepsyres.2021.106705. Online ahead of print.

ABSTRACT

This Phase III, long-term, open-label extension (OLE) trial (EP0009; NCT01832038) was conducted to evaluate the long-term safety, tolerability, and efficacy of adjunctive lacosamide (100-400 mg/day) in Chinese and Japanese people with epilepsy (PWE) (16-70 years) who had completed a double-blind, randomized, placebo-controlled trial of adjunctive lacosamide (EP0008; NCT01710657). PWE entered the OLE trial on 200 mg/day lacosamide and up to 3 concomitant antiseizure medications. Dose adjustments were permitted to optimize tolerability and seizure reduction. Safety variables were treatment-emergent adverse events (TEAEs) and discontinuations due to TEAEs. Efficacy variables were percent change in focal seizure frequency per 28 days from Baseline of the double-blind trial, ≥50 % and ≥75 % responder rates, seizure-freedom, and proportion of PWE on lacosamide monotherapy. Overall, 473 PWE (74.0 % Chinese and 26.0 % Japanese) were enrolled; 238 (50.3 %) PWE completed the trial and 235 (49.7 %) discontinued, most commonly due to lack of efficacy (81 [17.1 %]), adverse events (55 [11.6 %]), and consent withdrawn (49 [10.4 %]). During the trial, PWE received lacosamide for a median of 1016.0 days (∼3 years), with a total exposure of 1454.8 person-years; 321 (67.9 %) PWE received lacosamide for >24 months, and 246 (52.0 %) for >36 months. The median modal dose of lacosamide was 300 mg/day. Overall, 410/473 (86.7 %) PWE reported TEAEs, 244 (51.6 %) had a TEAE that was considered drug-related, and 49 (10.4 %) discontinued due to a TEAE. The most common TEAEs (≥20 % of PWE) were nasopharyngitis, dizziness, and upper respiratory tract infection. The median reduction in focal seizure frequency per 28 days from Baseline was 57.1 %, and the ≥50 % and ≥75 % responder rates were 57.1 % (269/471) and 29.7 % (140/471), respectively. Among PWE who completed 12, 24, and 36 months of treatment, the 12-, 24-, and 36-month seizure-freedom rates were 3.5 % (13/375), 3.4 % (11/321), and 2.0 % (5/247), respectively. Among PWE exposed to lacosamide for ≥6 months and ≥12 months, the proportions of PWE that maintained continuous monotherapy for ≥6 months and ≥12 months were 5.0 % (21/421) and 5.0 % (19/378), respectively. Overall, lacosamide was well-tolerated as long-term adjunctive therapy in Chinese and Japanese PWE and uncontrolled focal seizures, with improvements in seizure reduction maintained over 36 months of treatment.

PMID:34246118 | DOI:10.1016/j.eplepsyres.2021.106705

Int J Pharm Pract. 2021 Jul 9:riab035. doi: 10.1093/ijpp/riab035. Online ahead of print.

ABSTRACT

OBJECTIVES: This study aimed to retrospectively assess whether community pharmacy customers accepted the pharmacist's recommendations for the selection of an antihistamine based on medicine optimization guidelines.

METHODS: A retrospective study was conducted on the implementation of an antihistamine use optimization guide for patients who were seeking first-generation antihistamines between July and December 2019 across forty-five community pharmacies in Singapore. The primary outcome measure was the acceptance rate of ceasing or substituting first-generation antihistamine with a second-generation antihistamine. Secondary measures included the reduction in types of first-generation antihistamines used, adverse drug-related events reported, intended use of antihistamines and the types of recommendations.

KEY FINDINGS: During the study period, 2328 patients fulfilled the inclusion criteria, out of which 523 patients agreed to optimize their use of sedating first-generation antihistamines. Chlorpheniramine (95.2%) was the most widely accepted first-generation antihistamine for optimization, with 59.6% of the users experiencing adverse events, the most common being drowsiness (53.2%). The main indication of use was allergic conditions (allergic rhinitis or atopic dermatitis) (70.3%). After implementation of the guide, most interventions were direct substitution (72.8%) with a less-sedating antihistamine, followed by gradual tapering (22.6%). Loratadine, a second-generation antihistamine, was most frequently (51.4%) used to substitute first-generation antihistamines. The optimization guide can potentially reduce adverse effects in 59.6% (297 patients) of chlorpheniramine users, which were mainly drowsiness (265 patients; 53.2%) and dry mouth (14 patients; 2.8%).

CONCLUSIONS: This study highlighted the importance of assessing and reducing potentially inappropriate first-generation antihistamine self-use and that a guided approach and substitution with less-sedating antihistamines can be employed in the community pharmacy setting.

PMID:34244771 | DOI:10.1093/ijpp/riab035

Clin J Am Soc Nephrol. 2021 Jul 9:CJN.00920121. doi: 10.2215/CJN.00920121. Online ahead of print.

ABSTRACT

Background and objectives: Immune checkpoint inhibitors are increasingly used to treat various malignancies but their application in kidney transplant patients is complicated by high allograft rejection rates. Immune checkpoint inhibitor-associated rejection is a novel, poorly understood entity demonstrating overlapping histopathological features with immune checkpoint inhibitor-associated acute interstitial nephritis, which poses a challenge for diagnosis and clinical management. We sought to improve the understanding of these entities through biopsy-based gene expression analysis. Design, setting, participants, and measurements: NanoString was used to measure and compare the expression of 725 immune-related genes in 75 archival kidney biopsies, including a 25-sample discovery cohort comprising pure T-cell mediated rejection (TCMR) and immune checkpoint inhibitor-associated acute interstitial nephritis (ICI-AIN), and an independent 50-sample validation cohort comprising ICI-AIN, immune checkpoint inhibitor-associated T-cell mediated rejection (ICI-TCMR), immune checkpoint inhibitor-associated crescentic glomerulonephritis, drug-induced acute interstitial nephritis (Drug-AIN), BK virus nephropathy, and normal biopsies. Results: Significant molecular overlap was observed between ICI-AIN and TCMR. Nevertheless, IFI27, an interferon-alpha induced transcript, was identified and validated as a novel biomarker for differentiating ICI-TCMR from ICI-AIN (validation cohort: P<0.001, AUC=100%, accuracy=86%). Principal component analysis revealed heterogeneity in inflammatory gene expression patterns within sample groups; however, ICI-TCMR and ICI-AIN both demonstrated relatively more molecular overlap with Drug-AIN than TCMR, suggesting potential dominance of hypersensitivity mechanisms in these entities. Conclusions: These results indicate that, although there is significant molecular similarity between immune checkpoint inhibitor-associated rejection and AIN, biopsy-based measurement of IFI27 gene expression represents a potential biomarker for differentiating these entities.

PMID:34244334 | DOI:10.2215/CJN.00920121

BMC Public Health. 2021 Jul 9;21(1):1363. doi: 10.1186/s12889-021-11259-w.

ABSTRACT

BACKGROUND: Assessment health literacy in people with cardiovascular health problems would facilitate the development of appropriate health strategies for the care and reduction of complications associated with oral anticoagulation therapy.

AIM: To evaluate the relationship between health literacy and health and treatment outcomes (concordance with oral anticoagulants, Normalized Ratio control and occurrence of complications) in patients with cardiovascular pathology.

METHODS: Observational, analytic and cross-sectional study carried out on 252 patients with cardiovascular pathology (atrial fibrillation, flutter or valve prosthesis), aged 50-85 years, accessing primary care services in Valencia (Spain) in 2018-2019. Variables referring to anticoagulant treatment with vitamin K antagonists (years of treatment, adequate control, polypharmacy and occurrence of complications, among others) and health literacy (Health Literacy Questionnaire) were analysed.

RESULTS: All dimensions of health literacy were significantly related to the level of education (p < 0.02), social class (p < 0.02), an adequate control of acenocoumarol (p < 0.001), frequentation of health services (p < 0.001), information by patients to health professionals about anticoagulant treatment (p < 0.03), emergency care visits (p < 0.001) and unscheduled hospital admissions (p < 0.001).

CONCLUSION: Health literacy has a relevant influence on the adequate self-management of anticoagulation treatment and the frequency of complications. The different dimensions that comprise health literacy play an important role, but the "social health support" dimension seems to be essential for such optimal self-management.

TRIAL REGISTRATION: ACC-ACE-2016-01. Registration date: December 2015.

PMID:34243749 | DOI:10.1186/s12889-021-11259-w