Anticancer Drugs. 2022 Nov 21. doi: 10.1097/CAD.0000000000001456. Online ahead of print.

ABSTRACT

SHR-A1201 is an antibody-drug conjugate (ADC) that combines trastuzumab with DM1 (a chemotherapeutic agent) using a chemical connector. This phase I study investigated the safety, tolerability and pharmacokinetics of SHR-A1201 in patients with human epidermal growth factor receptor 2-positive advanced breast cancer. This phase I study enrolled patients in a traditional 3 + 3 dose-escalation design to receive a single dose of SHR-A1201 (1.2 mg/kg, 2.4 mg/kg, 3.6 mg/kg or 4.8 mg/kg). The observation period of dose-limiting toxicity (DLT) was 21 days. A total of 12 patients were enrolled and received SHR-A1201. Most treatment-emergent adverse events (TEAEs) were grade 1 or 2 in severity, with elevated aspartate aminotransferase (75%), thrombocytopenia (75%), and nausea (66.7%) being reported most frequently. The common grade 3 TEAEs were thrombocytopenia and decreased lymphocyte count, and there were no grade 4 or above TEAEs. There were no serious adverse events or drug-related deaths. One DLT occurred in one patient treated with SHR-A1201 4.8 mg/kg (asymptomatic grade 3 increased γ-glutamyltransferase). The maximum tolerated dose of SHR-A1201 was not lower than that of T-DM1 (3.6 mg/kg). A total of 8.3% (1/12) of patients had ADA-positive reactions 504 h after administration, but no differences were observed in the type, incidence, or severity of TEAEs between patients with and without ADA. SHR-A1201 exhibited the pharmacokinetics characteristics of typical ADCs. An encouraging antitumor effect was observed in the 4.8 mg/kg dose group. SHR-A1201 was well tolerated and safe in patients with advanced HER2-positive breast cancer. The pharmacokinetics parameters showed a linear trend, and the immunogenicity results met the clinical expectations.

PMID:36730296 | DOI:10.1097/CAD.0000000000001456

J Cancer Surviv. 2023 Feb 2. doi: 10.1007/s11764-022-01316-7. Online ahead of print.

ABSTRACT

PURPOSE: Platinum-based chemotherapies used to treat many types of cancers are ototoxic. Ototoxicity management (OtoM) to mitigate the ototoxic outcomes of cancer survivors is recommended practice yet it is not a standard part of oncologic care. Although more than 10,000 patients each year are treated with platinum-based chemotherapies at the US Veterans Health Administration (VA), the current state of OtoM in VA is not well-defined. This study reports on a national survey of VA audiologists' perceptions regarding OtoM in cancer patients.

METHODS: A 26-item online survey was administered to VA audiologists and service chiefs across the VA's 18 regional systems of care. Descriptive statistics and deductive thematic analysis were used to analyze the data.

RESULTS: The 61 respondents included at least one from each VA region. All reported they felt some form of OtoM was necessary for at-risk cancer patients. A pre-treatment baseline, the ability to detect ototoxicity early, and management of ototoxic effects both during and after treatment were considered high value objectives of OtoM by respondents. Roughly half reported routinely providing these services for patients receiving cisplatin and carboplatin. Respondents disagreed regarding appropriate hearing testing schedules and how to co-manage OtoM responsibilities with oncology. They identified barriers to care that conformed to three themes: care and referral coordination with oncology, audiology workload, and lack of protocols.

CONCLUSIONS: Although VA audiologists value providing OtoM for cancer patients, only about half perform OtoM for highly ototoxic treatment regimens. The OtoMIC survey provides clinician perspectives to benchmark and address OtoM care gaps.

IMPLICATIONS FOR CANCER SURVIVORS: Collaboration between oncology and audiology is needed to improve current OtoM processes, so that cancer survivors can have more control over their long term hearing health.

PMID:36729345 | DOI:10.1007/s11764-022-01316-7

Clin Ophthalmol. 2023 Jan 26;17:385-390. doi: 10.2147/OPTH.S393519. eCollection 2023.

ABSTRACT

PURPOSE: To determine the reported rates of intraocular inflammation (IOI) in patients treated with intravitreal aflibercept (IVT-AFL) 2 mg in routine clinical practice (ie, outside interventional studies), across all indications and within all countries (excluding the United States), with access to either the vial presentation or pre-filled syringe (PFS).

PATIENTS AND METHODS: A search was conducted using the Bayer EYLEA® Global Safety Pharmacovigilance Database for reported cases of IOI and IVT-AFL use between October 2012 and March 31, 2022.

RESULTS: With more than 10 years of post-marketing experience with the IVT-AFL vial presentation (>25 million sold units), and over 2 years of experience with the PFS of IVT-AFL (>6.7 million sold units) the rate of any IOI, including endophthalmitis, outside the United States was 0.3 events per 10,000 units for the PFS and 1.2 events per 10,000 units for the vial presentation. The event rates specifically for endophthalmitis were 0.1 per 10,000 units for the IVT-AFL PFS and 0.6 per 10,000 units for the IVT-AFL vial presentation.

CONCLUSION: In patients with retinal diseases treated in routine clinical practice with IVT-AFL either from a vial or the PFS, medically important adverse events of IOI, and in particular, endophthalmitis, are infrequently reported events. Numerically, reported rates of IOI and endophthalmitis are low for the vial presentation and even lower for the PFS.

PMID:36726365 | PMC:PMC9886133 | DOI:10.2147/OPTH.S393519

Cutis. 2023 Feb;111(2):80-81. doi: 10.12788/cutis.0700.

NO ABSTRACT

PMID:37075187 | DOI:10.12788/cutis.0700

Indian J Pharmacol. 2022 Nov-Dec;54(6):417-422. doi: 10.4103/ijp.ijp_474_22.

ABSTRACT

BACKGROUND: Mucormycosis is a rare but serious fungal infection which has dramatically increased in post-COVID patients. There is a paucity of safety data on amphotericin B (amphoB) used for mucormycosis treatment.

OBJECTIVES: The objective of this prospective, observational, active safety surveillance study was to evaluate the safety profile of amphoB in a cohort of hospitalized patients who were on the drug for suspected mucormycosis.

MATERIALS AND METHODS: All suspected adverse drug reactions (ADRs) in hospitalized mucormycosis patients who had received amphoB were analyzed. The nature, severity, outcome of the ADRs were recorded and analyzed.

RESULTS: Of the 77 patients enrolled, 70% had documented history of prior COVID-19 infection. 96% had comorbidities, the most common being diabetes. Majority received conventional amphotericin B deoxycholate formulation. 97% experienced at least one suspected ADR and the median ADR/patient was 3. Out of 214 ADRs, 91 were serious but there were no ADR-related deaths. The most common ADRs were hypokalemia (31.78%), infusion-related reactions (22.43%), and anemia (17.29%). Thirty-three patients had serum potassium <2.5 mEq/L, while 11 had serum magnesium <1.25 mg/dL. Doubling of pretreatment creatinine level was noted in 15 patients. Seventy percent ADRs were of "possible" category as per the World Health Organization Uppsala Monitoring Centre categorization.

CONCLUSION: AmphoB deoxycholate use in mucormycosis patients was associated with a high incidence of electrolyte abnormalities and infusion-related reactions. All ADRs subsided with medical management and none were fatal. The safety data generated from this study may be useful in resource-limited settings where the far more expensive liposomal formulation is not being used.

PMID:36722553 | DOI:10.4103/ijp.ijp_474_22

Longit Life Course Stud. 2022 Oct 11;14(1):22-47. doi: 10.1332/175795921X16615892091105.

ABSTRACT

Considerable evidence demonstrates that perceiving oneself as an object of discrimination has negative consequences for mental health. However, little is known about whether this experience is more or less harmful in distinct phases of the life course, consistent with the life course principle of timing; or whether, in accord with the principle of lifespan development, it has long-term implications. We draw on longitudinal data addressing perceived workplace discrimination based on race/ethnicity and gender from the prospective Youth Development Study, covering early adulthood to midlife. Hierarchical linear modelling of the effects of discrimination on depressed mood indicates that both forms of discrimination have short-term (within life stages) and long-term (across stages) adverse effects on adult mental health. The impacts of perceived discrimination within stages on depressed mood appear to be greatest in the mid-30s and to weaken by midlife. Lingering effects of discrimination are more pronounced early on. These patterns are observed with controls for key time-varying negative experiences at work and personal socio-economic status, as well as invariant background characteristics (gender, race and parental socio-economic status). We consider these findings in relation to the dynamics of personal change in the context of occupational careers.

PMID:36722305 | DOI:10.1332/175795921X16615892091105

Drug Ther Bull. 2023 Feb 1:dtb-2023-000005. doi: 10.1136/dtb.2023.000005. Online ahead of print.

ABSTRACT

Overview of: van Dyck CH, Swanson CJ, Aisen P, et al Lecanemab in Early Alzheimer's Disease. N Engl J Med 2023;388:9-21.

PMID:36725282 | DOI:10.1136/dtb.2023.000005

Sci Transl Med. 2023 Feb;15(681):eabq5241. doi: 10.1126/scitranslmed.abq5241. Epub 2023 Feb 1.

ABSTRACT

In October 2019, Novartis launched brolucizumab, a single-chain variable fragment molecule targeting vascular endothelial growth factor A, for the treatment of neovascular age-related macular degeneration. In 2020, rare cases of retinal vasculitis and/or retinal vascular occlusion (RV/RO) were reported, often during the first few months after treatment initiation, consistent with a possible immunologic pathobiology. This finding was inconsistent with preclinical studies in cynomolgus monkeys that demonstrated no drug-related intraocular inflammation, or RV/RO, despite the presence of preexisting and treatment-emergent antidrug antibodies (ADAs) in some animals. In this study, the immune response against brolucizumab in humans was assessed using samples from clinical trials and clinical practice. In the brolucizumab-naïve population, anti-brolucizumab ADA responses were detected before any treatment, which was supported by the finding that healthy donors can harbor brolucizumab-specific B cells. This suggested prior exposure of the immune system to proteins with structural similarity. Experiments on samples showed that naïve and brolucizumab-treated ADA-positive patients developed a class-switched, high-affinity immune response, with several linear epitopes being recognized by ADAs. Only patients with RV/RO showed a meaningful T cell response upon recall with brolucizumab. Further studies in cynomolgus monkeys preimmunized against brolucizumab with adjuvant followed by intravitreal brolucizumab challenge demonstrated that high ADA titers were required to generate ocular inflammation and vasculitis/vascular thrombosis, comparable to RV/RO in humans. Immunogenicity therefore seems to be a prerequisite to develop RV/RO. However, because only 2.1% of patients with ADA develop RV/RO, additional factors must play a role in the development of RV/RO.

PMID:36724238 | DOI:10.1126/scitranslmed.abq5241

Curr Opin Oncol. 2023 Mar 1;35(2):132-144. doi: 10.1097/CCO.0000000000000924. Epub 2022 Dec 28.

ABSTRACT

PURPOSE OF REVIEW: Because the high risk of death and poor prognosis of patients with refractory thyroid cancer (TC), studies related to tyrosine kinase inhibitors (TKIs) in treating different types of refractory TC have gradually attracted attention. Thus, we conducted a meta-analysis of published randomized controlled trials and single-arm trials to evaluate tyrosine kinase inhibitors' efficacy and safety profile treatment in TC patients.

RECENT FINDINGS: The studies of 29 in 287 met the criteria, 9 were randomized controlled trials and 20 were single-arm trials, involving 11 TKIs (Apatinib, Anlotinib, Cabozantinib, Imatinib, Lenvatinib, Motesanib, Pazopanib, Sorafenib, Sunitinib, Vandetanib, Vemurafenib). Treatment with TKIs significantly improved progression-free survival [hazard ratio [HR] 0.34 (95% confidence interval [CI]: 0.24, 0.48), P < 0.00001] and overall survival [OS] [HR 0.76, (95% CI: 0.64, 0.91), P = 0.003] in randomized controlled trials, but adverse events (AEs) were higher than those in the control group (P < 0.00001). The result of the objective response rate (ORR) in single-arm trials was statistically significant [odds ratio [OR] 0.49 (95% CI: 0.32, 0.75), P = 0.001].

SUMMARY: TKIs significantly prolonged progression-free survival and OS or improved ORR in patients with different types of TC (P < 0.01). Our recommendation is to select appropriate TKIs to treat different types of TC patients, and to prevent and manage drug-related AEs after using TKIs.

PMID:36721897 | DOI:10.1097/CCO.0000000000000924

Cureus. 2022 Dec 28;14(12):e33064. doi: 10.7759/cureus.33064. eCollection 2022 Dec.

ABSTRACT

Infliximab belongs to the family of tumor necrosis factor (TNF) alpha inhibitors and since its development, it has revolutionized treatment for both rheumatological diseases and inflammatory bowel disease (IBD). In IBD specifically, it has shown to result in symptomatic, endoscopic, and histological remission which is why it is one of the most widely used treatments for moderate to severe IBD. While common side effects include infections due to immunosuppression, cytopenias and hepatotoxicity, interstitial lung disease (ILD) has been infrequently reported to result from inflixiamb use. We present the case of a patient with ulcerative colitis (UC) who achieved remission with infliximab, however, after about two years of infusions, developed evidence of non-specific interstitial pneumonitis (NSIP). Extensive work up was done to rule out infections, mixed connective tissue disorders, and hypersensitivity pneumonitis. Although lung biopsy remains the gold standard for diagnosing NSIP; clinical, laboratory, and radiographic findings were sufficient in establishing this diagnosis. Initiation of empiric high dose steroids, and cessation of infliximab infusions showed improvement in respiratory status and resolution of lung findings. This case highlights the importance of recognizing adverse effects of infliximab on the pulmonary status of an IBD patient given that infliximab mediated ILD does not adhere to a specific timeline. Considering that respiratory function may be compromised post any number of infusions, it is imperative to acknowledge patients' respiratory complaints and initiate prompt investigation and evaluation for this rare complication.

PMID:36721597 | PMC:PMC9883057 | DOI:10.7759/cureus.33064

Pediatr Rev. 2023 Feb 1;44(2):68-80. doi: 10.1542/pir.2022-005641.

ABSTRACT

Food-drug interactions should be suspected when a patient is taking their medications as directed and doses are optimized yet therapy is still not optimal (increased adverse effects, decreased efficacy, new adverse effects, etc). In all individuals with suspected food-drug interactions, diet history, baseline laboratory values, drug concentrations, and prescription history are recommended to assess the patient for a possible food-drug interaction. The 3 types of food-drug interactions are pharmaceutical, pharmacokinetic, and pharmacodynamic. Pharmaceutical interactions occur with delivery devices or enteral feeding products. Pharmacokinetic interactions include the processes of a drug's release, absorption, distribution, metabolism, and/or elimination, ultimately affecting the effectiveness and safety of therapy. Pharmacodynamic interactions occur when food alters a drug's clinical effect on the body. The most common food-drug interactions exist with fruits (especially grapefruit), dairy, vitamin K, tyramine-containing foods, and alcohol. Patient counseling and collaboration between health-care teams can help patients avoid food-drug interactions. As a result, medication therapy can be optimized and adverse effects can be avoided.

PMID:36720679 | DOI:10.1542/pir.2022-005641

Antioxid Redox Signal. 2023 Jan 31. doi: 10.1089/ars.2023.0006. Online ahead of print.

ABSTRACT

SIGNIFICANCE: Cardiovascular disease and drug-induced health side effects are frequently associated with - or even caused by - an imbalance between the concentrations of reactive oxygen and nitrogen species (RONS) and antioxidants respectively determining the metabolism of these harmful oxidants.

RECENT ADVANCES: According to the "kindling radical" hypothesis, initial formation of RONS may further trigger the additional activation of RONS formation under certain pathological conditions. The present review will specifically focus on a dysfunctional, uncoupled endothelial nitric oxide synthase (eNOS) caused by RONS in the setting of transportation noise exposure or chronic treatment with organic nitrates, especially nitroglycerin. We will further describe the various "redox switches" that are proposed to be involved in the uncoupling process of eNOS.

CRITICAL ISSUES: In particular, the oxidative depletion of tetrahydrobiopterin (BH4), and S-glutathionylation of the eNOS reductase domain will be highlighted as major pathways for eNOS uncoupling upon noise exposure or nitroglycerin treatment. In addition, oxidative disruption of the eNOS dimer, inhibitory phosphorylation of eNOS at threonine or tyrosine residues, redox-triggered accumulation of asymmetric dimethylarginine (ADMA) and L-arginine deficiency will be discussed as alternative mechanisms of eNOS uncoupling.

FUTURE DIRECTIONS: The clinical consequences of eNOS dysfunction due to uncoupling on cardiovascular disease will be summarized also providing a template for future clinical studies on endothelial dysfunction caused by pharmacological or environmental risk factors.

PMID:36719770 | DOI:10.1089/ars.2023.0006

Clin J Am Soc Nephrol. 2023 Jan 1;18(1):36-46. doi: 10.2215/CJN.0000000000000022.

ABSTRACT

BACKGROUND: Tolvaptan slows expansion of kidney volume and kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD). Progression during childhood could be treated before irreversible kidney damage occurs, but trial data are lacking. We evaluated the safety and efficacy of tolvaptan in children/adolescents with ADPKD.

METHODS: This was the 1-year, randomized, double-blind, portion of a phase 3b, two-part trial being conducted at 20 academic pediatric nephrology centers. Key eligibility criteria were ADPKD and eGFR ≥60 ml/min per 1.73 m2. Participants aged 12-17 years were the target group (group 1, enrollment goal n≥60); participants aged 4-11 years could additionally enroll (group 2, anticipated enrollment approximately 40). Treatments were tolvaptan or placebo titrated by body weight and tolerability. Coprimary end points, change from baseline in spot urine osmolality and specific gravity at week 1, assessed inhibition of antidiuretic hormone activity. The key secondary end point was change in height-adjusted total kidney volume (htTKV) to month 12 in group 1. Additional end points were safety/tolerability and quality of life. Statistical comparisons were exploratory and post hoc.

RESULTS: Among the 91 randomized (group 1, n=66; group 2, n=25), least squares (LS) mean reduction (±SEM) in spot urine osmolality at week 1 was greater with tolvaptan (-390 [28] mOsm/kg) than placebo (-90 [29] mOsm/kg; P<0.001), as was LS mean reduction in specific gravity (-0.009 [0.001] versus -0.002 [0.001]; P<0.001). In group 1, the 12-month htTKV increase was 2.6% with tolvaptan and 5.8% with placebo (P>0.05). For tolvaptan and placebo, respectively, 65% and 16% of subjects experienced aquaretic adverse events, and 2% and 0% experienced hypernatremia. There were no elevated transaminases or drug-induced liver injuries. Four participants discontinued tolvaptan, and three discontinued placebo. Quality-of-life assessments remained stable.

CONCLUSIONS: Tolvaptan exhibited pharmacodynamic activity in pediatric ADPKD. Aquaretic effects were manageable, with few discontinuations.

CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Safety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children and Adolescents With ADPKD (Autosomal Dominant Polycystic Kidney Disease) NCT02964273.

PMID:36719158 | DOI:10.2215/CJN.0000000000000022

Int J Clin Pract. 2023 Jan 14;2023:3336736. doi: 10.1155/2023/3336736. eCollection 2023.

ABSTRACT

BACKGROUND: Pharmaceutical care services offered by pharmacists rationalize drug therapy, improve patient quality of life, and save patients' lives. This study was designed to optimize patient drug therapy through pharmaceutical care services offered by a pharmacist in consultation with other health care providers (HCPs) at a tertiary care hospital.

METHODS: This descriptive study was conducted to assess the role and effectiveness of pharmacists in optimizing drug therapy outcomes. The study was carried out at an internal and pulmonary medicine unit of a tertiary care hospital in Srinagar, Jammu and Kashmir, India, with a total of 50 health care providers (HCPs) (24 doctors, 16 nurses, and 10 pharmacists). A total of 182 patients (males and females) of all age groups were recruited into the study over a period of nine months. Patient-specific pharmaceutical care plans initiated by the pharmacist based on drug therapy-related needs and problems were used to address and optimize drug therapy outcomes in consultation with other HCPs.

RESULTS: A total of 388 drug-related problems (DRPs) with an average of 2.29 DRPs per patient were identified, for which 258 pharmaceutical care plans as interventions were proposed, out of which 233 (90.31%) were accepted and implemented. Preassessment and postassessment by HCPs on services rendered by the pharmacist showed a positive change in attitude among HCPs with respect to their endorsement and acceptance of the pharmacist's services in providing direct patient care.

CONCLUSIONS: Pharmaceutical care services offered by pharmacists helped in optimizing drug therapy and patient care.

PMID:36713950 | PMC:PMC9867584 | DOI:10.1155/2023/3336736

Drug Ther Bull. 2023 Jan 30:dtb-2023-000003. doi: 10.1136/dtb.2023.000003. Online ahead of print.

ABSTRACT

Overview of: Baunwall SMD, Andreasen SE, Hansen MM, et al Faecal microbiota transplantation for first or second Clostridioides difficile infection (EarlyFMT): a randomised, double-blind, placebo-controlled trial. Lancet Gastroenterol Hepatol 2022;7:1083-91.

PMID:36717202 | DOI:10.1136/dtb.2023.000003

Z Orthop Unfall. 2023 Jan 30. doi: 10.1055/a-1994-7500. Online ahead of print.

ABSTRACT

BACKGROUND: Venous thromboembolism (VTE) is one of the major and potentially life-threatening complications following major orthopedic surgeries. Research evidence comparing the effectiveness of rivaroxaban and enoxaparin for thromboprophylaxis specific to total hip arthroplasty (THA) has been limited. Hence, this review was done to compare the efficacy and safety of rivaroxaban against enoxaparin for thromboprophylaxis after THA.

MATERIALS AND METHODS: We conducted a search in databases including Medline, EMBASE, ScienceDirect, Google Scholar, and Cochrane Library from inception until May 2021. Randomized controlled trials directly comparing the effectiveness of rivaroxaban and enoxaparin for thromboprophylaxis among patients undergoing THA were eligible for inclusion. Outcome parameters assessed were efficacy in terms of total VTE and all-cause mortality, major VTE, deep vein thrombosis, symptomatic VTE, and safety in terms of major bleeding events, clinically relevant nonmajor bleeding events, minor bleeding events, total bleeding events, drug-related adverse events, and wound infection. We performed a meta-analysis with a random effects model and reported a pooled risk ratio (RR) with a 95% confidence interval (CI).

RESULTS: Eleven studies, including 9057 participants, were analyzed. Amongst efficacy outcomes, VTE and all-cause mortality pooled an RR of 0.58 (95% CI: 0.34-0.99), major VTE pooled an RR of 0.37 (95% CI: 0.15-0.90), deep vein thrombosis pooled an RR of 0.57 (95% CI: 0.32-1.02), and symptomatic VTE pooled an RR of 0.51 (95% CI: 0.30-0.87). Amongst safety outcomes, major bleeding events pooled an RR of 1.18 (95% CI: 0.77-1.80), total bleeding events pooled an RR of 1.12 (95% CI: 0.93-1.34), drug-related adverse event pooled an RR of 0.99 (95% CI: 0.87-1.12), and wound infection pooled an RR of 1.11 (95% CI: 0.58-2.14).

CONCLUSION: Rivaroxaban is a more efficacious drug in terms of VTE and all-cause mortality compared to enoxaparin following THA, and rivaroxaban was non-inferior in terms of safety profiles such as wound infection, bleeding, and drug-related adverse events.

PMID:36716770 | DOI:10.1055/a-1994-7500

Livers. 2023 Mar;3(1):33-53. doi: 10.3390/livers3010003. Epub 2023 Jan 12.

ABSTRACT

The epidemic of obesity, type 2 diabetes and nonalcoholic liver disease (NAFLD) favors drug consumption, which augments the risk of adverse events including liver injury. For more than 30 years, a series of experimental and clinical investigations reported or suggested that the common pain reliever acetaminophen (APAP) could be more hepatotoxic in obesity and related metabolic diseases, at least after an overdose. Nonetheless, several investigations did not reproduce these data. This discrepancy might come from the extent of obesity and steatosis, accumulation of specific lipid species, mitochondrial dysfunction and diabetes-related parameters such as ketonemia and hyperglycemia. Among these factors, some of them seem pivotal for the induction of cytochrome P450 2E1 (CYP2E1), which favors the conversion of APAP to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). In contrast, other factors might explain why obesity and NAFLD are not always associated with more frequent or more severe APAP-induced acute hepatotoxicity, such as increased volume of distribution in the body, higher hepatic glucuronidation and reduced CYP3A4 activity. Accordingly, the occurrence and outcome of APAP-induced liver injury in an obese individual with NAFLD would depend on a delicate balance between metabolic factors that augment the generation of NAPQI and others that can mitigate hepatotoxicity.

PMID:36713231 | PMC:PMC9879315 | DOI:10.3390/livers3010003

bioRxiv. 2023 Jan 4:2023.01.04.522664. doi: 10.1101/2023.01.04.522664. Preprint.

ABSTRACT

An increasing number of preclinical and clinical studies are exploring the use of receptor-engineered cells that can respond to disease states for the treatment of cancer, infectious disease, autoimmunity, and regeneration. However, receptor-based cell therapies, including chimeric antigen receptor (CAR), face many critical issues including target recognition escape, adverse side effects, and lack of in vivo control. Drug-controllable receptors offer a promising solution to overcome these issues through precise in vivo tuning of cells via enhanced sensing and therapeutic efficacy. Here we develop a novel class of modular and tunable receptors, termed valency-controlled receptors (VCRs), which can leverage customized small molecules to mediate cell signaling strength via controlled spatial clustering. We first develop DNA origami activated VCRs to demonstrate that receptor valency is a core mechanism that modulates immune cell activation. We design a series of customized valency-control ligands (VCLs) by transforming small molecule drugs into a multivalency format and modularly fusing VCR onto the CAR architecture. We demonstrate that VCL induction allows enhanced target sensitivity of engineered cells. Using medicinal chemistry, we develop programmable bioavailable VCL drugs to demonstrate that the VCR system enables drug-induced highly potent responses towards low antigen cancers in vitro and in vivo . Valency controlled receptors and customizable drug ligands provide a new synthetic biology platform to precisely tune engineered cell therapeutic potency, which can address existing safety and efficacy barriers in cell therapy.

PMID:36712002 | PMC:PMC9881924 | DOI:10.1101/2023.01.04.522664

Eur J Gastroenterol Hepatol. 2023 Mar 1;35(3):261-269. doi: 10.1097/MEG.0000000000002506. Epub 2022 Dec 22.

ABSTRACT

BACKGROUND: Real-world data showed that ustekinumab is an effective treatment for Crohn's disease for up to 52 weeks. Yet, long-term effectiveness and safety outcomes beyond 52 weeks are limited. This study aimed to evaluate the corticosteroid-free clinical remission for up to 104 weeks. Secondary aims were focused on biochemical disease, dosing adjustments and safety outcomes.

METHODS: This multicentre prospective cohort study enrolled Crohn's disease patients who started ustekinumab between May 2016 and September 2019. Participants had scheduled outpatient visits at week 0, 13, 26, 52 and 104. Data on clinical disease [Harvey Bradshaw Index (HBI) = 4 points = remission], biochemical disease (faecal calprotectin = 200 µg/g or C-reactive protein = 10 mg/l = remission), dose adjustments and adverse drug reactions (ADRs) were recorded.

RESULTS: We included 101 Crohn's disease patients. In all patients, the proportion of patients in corticosteroid-free clinical remission was 35 and 36% at week 52 and 104. Of patients achieving corticosteroid-free remission at week 52, more than half maintained corticosteroid-free remission throughout week 104. Biochemical remission rates were 25 and 30% at week 52 and 104, respectively. In the first year of treatment, 33% required their first dose escalation, and 15% in the second year. Overall, 7% of patients discontinued ustekinumab due to ADRs. Ustekinumab persistency rates were 68% at week 52 and 59% at week 104.

CONCLUSION: Ustekinumab is an effective and well-tolerated treatment for Crohn's disease. More than half of all patients continued ustekinumab treatment after 104 weeks whereas one-third achieved corticosteroid-free remission.

PMID:36708296 | DOI:10.1097/MEG.0000000000002506

Alzheimers Res Ther. 2023 Jan 28;15(1):24. doi: 10.1186/s13195-023-01163-3.

ABSTRACT

BACKGROUND: This phase II proof-of-concept study assessed the efficacy and safety of BI 425809, a novel selective glycine transporter-1 inhibitor, for the treatment of cognitive impairment associated with probable Alzheimer's disease dementia.

METHODS: This 12-week, multicenter, double-blind, placebo-controlled, parallel-group study randomized (1:1:1:1:1) patients with mild-to-moderate probable Alzheimer's disease dementia to BI 425809 2, 5, 10, and 25 mg or placebo once daily. The primary efficacy endpoint was the change from baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale 11-item total score after 12 weeks of treatment. Safety was also assessed.

RESULTS: Six hundred and ten male and female patients were randomized to BI 425809 2 mg (n = 123), 5 mg (n = 122), 10 mg (n = 122), and 25 mg (n = 123) or placebo (n = 120). Approximately 47% (n = 286) were male; the mean (standard deviation) age was 72.9 (7.7) years. Treatment compliance was above 97% for all dose groups. The Mini-Mental State Examination category on the median score was < 22 in 47% (n = 287) of patients and ≥ 22 in 53% (n = 322) of patients. No significant, non-flat dose-response relationship was detected for the primary endpoint (adjusted p-value > 0.76 for all models). BI 425809 was generally well-tolerated. Overall, 47.9% (n = 292) of patients reported at least one adverse event during the trial; the frequency of patients with investigator-defined drug-related adverse events was similar in all treatment groups, ranging from 15.4 to 19.5% across the BI 425809 treatment groups and 15.8% for placebo.

CONCLUSIONS: No clinically meaningful changes from baseline were observed following treatment with BI 425809 in patients with mild-to-moderate probable Alzheimer's disease dementia.

TRIAL REGISTRATION: ClinicalTrials.gov NCT02788513 (1346-0023). Registered on June 2, 2016. EU Clinical Trials Register 2015-005438-24. Registered on May 6, 2016.

PMID:36709275 | DOI:10.1186/s13195-023-01163-3