CNS Toxicity Research Articles

High-Dose Methotrexate-Related Toxicity in Children with Acute Lymphoblastic Leukemia

Introduction: High-dose methotrexate (HD-MTX) is a key component in treatment of acute lymphoblastic leukemia (ALL) but associates with several toxicities. In addition to myelosuppression and emesis, HD-MTX has specific adverse effects such as oral mucositis, nephrotoxicity, hepatotoxicity, dermatitis, and methotrexate-related stroke like syndrome. Toxicity during prior courses of HD-MTX, delayed MTX elimination and pre-existing nephropathy are associated with toxicity, but information on other risk factors is scarce. Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol included an intensive consolidation with HD-MTX for non-high risk patients. We aimed to describe the incidence of and risk factors for HD-MTX induced toxicity during consolidation therapy. Method: This is a retrospective study, including patients aged 2-<18 years with ALL, treated according to the non-high risk arm of the NOPHO ALL2008 protocol in Stockholm and Uppsala, Sweden, during 2008-2019. Data on toxicities during the consolidation was collected after the three HD-MTX courses (5 g/m2) during consolidation. Concomitant chemotherapeutic agents were pegylated asparaginase, vincristine and oral mercaptopurine. The registered toxicities included hematological toxicity (transfusions and/or neutropenia), infections or mucositis requiring hospitalization, administration of intravenous antibiotics or parenteral nutrition, liver toxicity, dermatitis, increased creatinine and CNS toxicity (definitions in Table). Clinical variables included age, immunophenotype, renal ultrasound at diagnosis, blood cell count and creatinine at diagnosis and at start of HD-MTX, BMI standard deviation scores (BMI-SDS), and weight change during induction. Results: The study cohort comprised 143 patients with 426 high-dose HD-MTX courses in total. The median age at diagnosis was 5.1 years (IQR 5.09). Toxicity was common, especially after the first HD-MTX course (Figure). Every fifth patient was hospitalized due to mucositis after the first HD-MTX and 79% of those needed parenteral nutrition. Infections were frequent; 49.7% were admitted to in-patient care with infection after the first HD-MTX, of whom all but one (70/71) were treated with intravenous antibiotics and 15% had a positive blood culture. Hematological toxicity, whilst most frequent after the first HD-MTX, was common after all three HD-MTX courses. A significantly higher risk of recurrent toxicity after the first HD-MTX was found for mucositis (Odds ratio (OR) 5.4; 95% confidence interval (CI) 1.1- 26.1; p=0.034), dermatitis (OR 32.8; 95% CI 5.5-197; p=<0.001), delayed nephrotoxicity (OR 59.0; 95% CI 11.2-307; p=<0.001). Liver toxicity and acute nephrotoxicity were not associated with an increased risk of recurrence after subsequent HD-MTX courses. When risk factors were analyzed separately for the first HD-MTX course, mucositis was more frequent in patients with weight loss (> 5%) during induction (p=0.007). The median BMI-SDS at diagnosis was also lower in patients with mucositis than those without (p=0.081). High MTX concentration (MTX >1 µM at hour 42) at first HD-MTX was associated with an increased need of thrombocyte- (p=0.021) and erythrocyte transfusion (p=0.041). Mildly (42-hour plasma MTX ≥1.0-3.9 µM), moderately (42-hour plasma MTX ≥4.0-9.9 µM) or severely delayed (42-hour plasma MTX ≥10 µM) elimination was seen in 38.0% (moderate; 5.6%; severe; 1.4%), 17.6% (moderate 2.1%) and 19.9% (moderate; 1.4%; severe; 0.7%) after first, second and third HD-MTX courses, respectively. Higher MTX concentration and slower clearance to non-toxic levels was associated with acute and delayed nephrotoxicity after the first HD-MTX (p=0.001). Conclusion: Our study demonstrated that severe toxicities that warrant hospitalization are very common, especially after the first HD-MTX. Low BMI at diagnosis and weight loss during induction was related to higher risk for mucositis and high MTX concentration and delayed excretion predicted nephrotoxicity after the first HD-MTX. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pharmacogenetic effects of single nucleotide polymorphisms commonly associated with antiretroviral therapy metabolism

Introduction. Identification of pharmacogenetic effects on antiretroviral therapy (ART) has become an important milestone to reach in the advancement of personalised treatment for HIV-positive patients. The therapy schemes are accompanied by multiple side effects. Therapy effectiveness and adverse reactions can be dictated by individual genetic predisposition factors, which should be taken into account for an optimal prescription. Some genetic markers (HLA-B*57:01 and UGT1A1*28), were already proven to improve discontinuation rates, and efforts are allocated to expand the range of clinically-relevant genetic tests.Objective. In this review, an updated summary of genetic polymorphisms and their effects defining patients’ tolerability to ART is presented. The aim of this research is to assess single nucleotide polymorphisms (SNPs) present in the genes that encode proteins involved in ART metabolism and transport. This review will be used to develop a PCR-based testing methodology for the detection and confirmation of risk alleles in the Caucasian population.Materials and methods. Data from 46 original research papers and reviews was analysed. Allele frequencies of the most relevant polymorphisms were checked against the data for European population.Results. As an outcome of this review, a few most promising SNPs were selected for future research. Firstly, ABCC4 rs1751034 and rs3742106 and ABCC10 rs9349256 and rs2125739 were associated with an increased risk of renal impairment, higher plasma concentration, and toxicity when treated with tenofovir. Parallel analysis of ABCC4 and ABCC10 SNP effects on renal impairment together with CYP24A1 rs2248359 that was recently reported as a potential renal toxicity marker might be more informative. Secondly, CYP2B6 rs3745274 that was associated with an increased efavirenz plasma concentration, and increased risk of liver and CNS toxicity should be evaluated. SNPs in CYP2B6, CYP2A6 (rs28399433), and CYP3A4 (rs4646437) should be evaluated in parallel since possession of all three variants might put patients at a much higher risk.Conclusion. Identified alleles could become new markers used in drug prescription protocols if significant effect in Caucasian population will be found. The most relevant SNPs should be tested in in supporting future studies to evaluate the significance for patients with HIV in Russia.

HyperArc Planning for Benign Intracranial Pathologies: A Prospective Analysis on Plan Quality, Delivery, Control and Toxicity

<h3>Purpose/Objective(s)</h3> This study reviews a treatment planning system (TPS) that automates both treatment planning and delivery of single-isocenter VMAT radiosurgery (SRS). The TPS was intended for complex multi-metastasis cases, for which it generates high quality, rapidly-deliverable plans. The effectiveness of treating benign intracranial pathologies (BIP) with TPS was unknown. Under an IRB-approved prospective registry, we collected data on the treatment planning and delivery as well as clinical outcomes of BIP managed with SRS since deployment of TPS. <h3>Materials/Methods</h3> Patients included received SRS between October 2017 and November 2021 using TPS. Patients with less than 3 months follow-up (FU) were censored. For all targets, full prescription dose was normalized to ≥ 99% of target volume without additional PTV expansion. All treatments were delivered on a linear accelerator with 10MV flattening-filter free beam at 2400 MU/min with high-definition (2.5mm) multi-leaf collimator. Descriptive statistics related to SRS treatment, pathology, and prior therapy determined at the time of or prior to treatment were analyzed. Post-treatment imaging, toxicities, and standard pathology-specific outcomes were assessed during FU visits. Significant toxicity was defined as ≥ Grade 3 by CTCAE. <h3>Results</h3> 245 targets (min=0.1cc, max=58.9cc) in 235 patients (53.5% female, median age=59) were treated with TPS. The most common pathologies were meningiomas (134), AVMs (43), pituitary adenomas (30), and acoustic schwannomas (23). 45% of patients were treated due to recurrent, residual, or persistent disease after prior treatment with 15% having prior radiation. A majority (53.5%) were treated in a single fraction (12-22Gy), and 46.5% were treated with fractionated SRS (24-35Gy). A majority (74%) were treated with 3 arcs with median (MED) total treatment and beam-on time lasting 10.4 and 2.3 minutes, respectively. MED RTOG CI and Paddick GI were 1.12 and 3.28, respectively. MED FU was 1.1 years. Excluding AVMs, 11 of 202 (5.4%) benign tumors progressed on FU imaging. Among those that progressed, MED time to failure was 1.14 years. Of those, 9 were WHO grade 2+ meningiomas with prior surgery. Of all patients, significant CNS toxicity was reported in 13 (5.6%, G3=9, G4=4), most of whom had persistent cerebral edema after steroids. Of those with BIP near cochlea (> 3 Gy dose max) without severe hearing loss prior to SRS (n=65), 14% subjectively reported decreased hearing after SRS and 3.5% did not preserve hearing. Of those with BIP near the optics (> 3 Gy dose max, n=81), visual preservation was 100%. <h3>Conclusion</h3> Although developed for multi-metastasis SRS, TPS is capable of generating and efficiently delivering high quality plans characterized by excellent conformality and rapid fall-off. Early clinical outcomes appear congruent with historical controls.

Implementation of a Special Medical Physics Consult Process for Re-Irradiation in Patients with Brain Tumors: Planning and Toxicity Outcomes

<h3>Purpose/Objective(s)</h3> We hypothesized that implementation of a systematic approach to re-irradiation (ReRT) using a special medical physics consult (SMPC) process would lead to acceptably low rates of high-grade toxicity associated with planning parameters impacting clinical management. <h3>Materials/Methods</h3> Consecutive patients treated using the ReRT-SMPC process during the first 18 months of its implementation were included. Accuracy of data set registration in the region of treatment was assessed by physics and verified by physician to generate cumulative physical and biologically corrected dose maps (equivalent dose in 2 Gy fractions EQD₂, alpha/beta 2.5 for normal tissue). Standardized dose discounts based on time interval from prior treatment and consistent guidelines for acceptable EQD₂ dose-limits per organ-at-risk (OAR) were used in all cases to provide allowable dose constraints prior to planning. Post-planning physics evaluation highlighted exceeded limits to assist clinical management. Comparison of planning parameters among patients with and without high-grade toxicity (grade 3 or higher) per CTCAE v5.0 was performed using 2-sided t-test and significance level 0.05. <h3>Results</h3> From April 2017 to September 2018, 261 consecutive patients underwent ReRT using this workflow, of whom 55 (21%) had brain tumors. ReRT with conventional fractionation (CFRT) was given to 47% primarily for gliomas (median EQD₂ 47 Gy (IQR, 41-56)), and with single or multi-fraction stereotactic radiosurgery in 53% primarily for brain metastases (median EQD₂ 100 Gy (IQR 57-120)). Median follow-up after ReRT among patients alive at time of analysis was 6.9 months (IQR, 5.3-10.8). No high-grade toxicity was observed in any delineated OAR including brainstem or optic structures. No specific normal brain constraint was employed in the SMPC process, and 5 (9%) patients experienced high-grade toxicity both early (cerebral edema, n=3) and late (necrosis, n=2). Cumulative EQD₂ was lower among patients with vs without toxicity (D0.03cc 87 vs 155 Gy, p=0.047), as 80% of patients with toxicity underwent ReRT with CFRT to larger volumes (39 vs 14 cc). While no constraints were applied for normal brain, recovery factors based on interval from index treatment were applied for all patients. However, no association with time interval was observed in patients with vs without toxicity (p=0.4). In two instances, the ReRT-SMPC analysis resulted in physician decision not to treat due to potential toxicity concerns. <h3>Conclusion</h3> Re-irradiation of primary and metastatic brain tumors using a standardized SMPC process yields low rates of high-grade CNS toxicity and meaningfully impacts physician decision-making. Future planning parameters including normal brain dose will be refined using this systematic process to improve the therapeutic ratio among patients undergoing re-irradiation.

Induced pluripotent stem cell-derived brain organoids as potential human model system for chemotherapy induced CNS toxicity.

Neurotoxic phenomena are among the most common side effects of cytotoxic agents. The development of chemotherapy-induced polyneuropathy (CIPN) is a well-recognized adverse reaction in the peripheral nervous system, while changes of cognitive functions (post-chemotherapy cognitive impairment (PCCI)) are more diffuse and have only recently drawn scientific interest. PCCI in patients most often displays as short-term memory loss, reduced multitasking ability or deficits in language. Not least, due to a lack of preclinical human model systems, the underlying molecular mechanisms are poorly understood, and treatments are missing. We thus investigated whether induced pluripotent stem cell (iPSC)-derived brain organoids can serve as a human model system for the study of chemotherapy induced central nervous system toxicity. We robustly generated mature brain organoids from iPSC-derived neuronal precursor cells (NPC), which showed a typical composition with 1) dividing NPCs forming ventricle like structures 2) matured neurons and 3) supporting glial cells closer to the surface. Furthermore, upon stimulation the brain organoids showed functional signaling. When exposed to increasing concentrations of paclitaxel, a frequently used chemotherapy drug, we observed time dependent neurotoxicity with an EC50 of 153 nM, comparable to a published murine model system. Histological analysis after paclitaxel exposure demonstrated dose dependent apoptosis induction and reduced proliferation in the organoids with further Western blot analyses indicating the degradation of neuronal calcium sensor one protein (NCS-1) and activation of Caspase-3. We could also provide evidence that paclitaxel treatment negatively affects the pool of neuronal and astrocyte precursor cells as well as mature neurons. In summary our data suggests that human iPSC derived brain organoids are a promising preclinical model system to investigate molecular mechanisms underlying PCCI and to develop novel prevention and treatment strategies.

S-03-04 Update on fluidic biomarkers of CNS toxicity – current approach and development

S-03-04 Update on fluidic biomarkers of CNS toxicity – current approach and development

Pitfalls of Antiretroviral Therapy: Current Status and Long-Term CNS Toxicity.

HIV can traverse the BBB using a Trojan horse-like mechanism. Hidden within infected immune cells, HIV can infiltrate the highly safeguarded CNS and propagate disease. Once integrated within the host genome, HIV becomes a stable provirus, which can remain dormant, evade detection by the immune system or antiretroviral therapy (ART), and result in rebound viraemia. As ART targets actively replicating HIV, has low BBB penetrance, and exposes patients to long-term toxicity, further investigation into novel therapeutic approaches is required. Viral proteins can be produced by latent HIV, which may play a synergistic role alongside ART in promoting neuroinflammatory pathophysiology. It is believed that the ability to specifically target these proviral reservoirs would be a vital driving force towards a cure for HIV infection. A novel drug design platform, using the in-tandem administration of several therapeutic approaches, can be used to precisely target the various components of HIV infection, ultimately leading to the eradication of active and latent HIV and a functional cure for HIV. The aim of this review is to explore the pitfalls of ART and potential novel therapeutic alternatives.

S180: RG6234, A NOVEL GPRC5D T-CELL ENGAGING BISPECIFIC ANTIBODY, INDUCES RAPID RESPONSES IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA: PRELIMINARY RESULTS FROM A FIRST-IN-HUMAN TRIAL

Background: Patients (pts) with relapsed/refractory multiple myeloma (RRMM) are in need of effective treatment options. RG6234 is a T-cell engaging bispecific antibody targeting GPRC5D with a novel 2:1 format. NCT04557150 is an ongoing first-in-human Phase 1 trial. We present initial results from the dose-escalation part using intravenous (IV) administration. Aims: To characterize the safety of RG6234 and to identify a recommended Phase 2 dose (RP2D), and to characterize the pharmacokinetics, pharmacodynamics, and preliminary clinical activity. Methods: Eligible pts with RRMM received RG6234 in escalating weekly step-up doses followed by a q2w regimen at a peak ‘target dose’ for up to 1 year. A mCRM model was used for overdose control. Adverse events (AEs) were graded per CTCAE v5.0 and cytokine release syndrome (CRS) per ASTCT criteria (Lee et al. 2019). Response was assessed by the investigator according to IMWG criteria. All pts provided informed consent. Results: As of January 31, 2022, 41 pts had received RG6234 IV (0.006mg to 10mg). Median age was 63 years (range: 27 to 78) and 61% had R-ISS stage II or III at study entry. High-risk cytogenetics (t(4;14), t(14;16), del(17p), 1q21 gain) were present in 17/29 (58%) evaluable cases. Median number of prior therapies was 5 (range: 2 to 15). Pts were triple-class refractory in 67% of cases and penta-class refractory in 36%. Six pts (14.6%) had prior BCMA-directed therapy. CRS occurred in 85.4% of pts (G1 56.1%, G2 24.4%, G3 2.4%). CRS was generally confined to the first cycle, with a median time to onset of 4.2 hours (range: 0 to 64.2), and 14 pts (34%) requiring tocilizumab. Three pts (7.3%) experienced CNS toxicity related to RG6234 (G1 and G3 headache; G1 confusion). G3/4 neutropenia, thrombocytopenia, and anemia occurred in 9.8%, 19.5%, and 12.2% of pts, respectively. Infections were reported in 46.3% of pts (≥G3 14.6%). One patient died of an E. coli sepsis not considered related to RG6234. AEs probably related to target expression included skin-related AEs in 66% of pts (G3 7.3%), dysgeusia/ageusia (36.6%, all G1/2), dry mouth (36.6%, all G1/2), dysphagia (17.1%, all G1/2), and nail changes (12.2%, all G1/2). No discontinuations due to RG6234-related AEs occurred. The maximum tolerated dose (MTD) was not reached. Within the tested target-dose range, RG6234 serum exposure generally showed a dose-proportional increase, with a preliminary IV terminal T½ of ～5 days (mean value, n=22). At the predicted active-dose range (>0.162mg), RG6234 induced profound and rapid reductions in serum free light chains (FLC) and sBCMA. After the first treatment cycle, 93% of evaluable pts (14/15) had <1% of multiple myeloma cells in bone marrow based on flow cytometry. Overall response rate in 34 efficacy evaluable pts across all doses was 68%, and 50% achieved a VGPR or better response, including 2/6 BCMA pre-treated pts. Responses occurred rapidly, with a median time to first response of 1.3 months (95% CI: 1.1, 1.6). Median follow-up was 3.5 months (range: 0.03 to 11.7). Treatment was ongoing for 58.5% of pts at the time of the data cut. Duration of response was not mature. Response was ongoing in 18/23 (78.3%) responding pts, with a longest duration of response of 10 months. Summary/Conclusion: RG6234, a novel T-cell engaging bispecific antibody targeting GPRC5D, demonstrates compelling clinical activity with manageable safety in heavily pretreated pts with RRMM. Dose escalation via IV and subcutaneous routes continues, and data will be updated.

Tisagenlecleucel for secondary CNS lymphoma, a case series.

e19507 Background: Secondary CNS lymphoma (SCNSL) in setting of relapsed, refractory (R/R) B cell lymphoma has unmet needs as this disease state has a poor prognosis with a reported median survival of 2 to 5 months. Historically, the mainstay of treatment for SCNSL in setting of R/R B cell lymphoma included high dose methotrexate, whole brain radiation (WBRT), and/or chemotherapy followed by autologous stem cell transplant. More recently, chimeric antigen receptor (CAR)-T cell therapy has gained attention as a new modality of therapy for patients with R/R SCNSL. The first two CAR-T cell products to gain FDA approval for R/R B cell lymphoma were Axicabtagene ciloleucel and Tisagenlecleucel. In the initial studies for these products, patients with SCNSL were excluded due to concerns for immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS). Retrospective data has shown that patients with R/R SCNSL treated with Axicabtagene ciloleucel or Tisagenlecleucel could achieve high response rates; however, the data on the durability of response remains unclear. Recently, Lisocabtagene maraleucel, another CAR-T cell product, was approved for the treatment of R/R B cell lymphoma. The TRANSCEND trial which led to Lisocabtagene maraleucel’s approval did not exclude patients with SCNSL; however, only 3% of the patients had SCNSL. As such, literature on the durability of response of CAR-T cell therapy in R/R SCNSL still remains sparse. Here, we share our single institution experience of patients with R/R SCNSL treated with Tisagenlecleucel, an anti- CD19CAR-T cell therapy. Methods: For this observational study, patients with R/R SCNSL were identified and placed on a follow up list. Data was collected from May 2021 till December 2021. Data was analyzed for incidence of ICANS, CRS, and for duration of response. Results: A total of 3 patients with SCNSL were identified and treated at our center with Tisagelecleucel. One patient achieved complete response 30 days post CAR-T therapy but the day +100 imaging revealed progression of disease and was placed on subsequent line of therapy. One patient had partial response with progression of disease noted on day +60 imaging and died from complications of disease progression. One patient died from complications of CNS toxicity after receiving CAR-T therapy. Two patients had ICANS grade 4 and CRS grade 1 toxicities. One patient had no CNS or CRS toxicity. Conclusions: Our series is limited by the number of patients; however, suggests that though CAR-T therapy may result in disease response in R/R SCNSL the duration of response may be limited and that such patients may require other therapies such as autologous stem cell transplant to improve long term prognosis.

Recent Synergy of Nanodiamonds: Role in Brain-Targeted Drug Delivery for the Management of Neurological Disorders.

The aim of the present review article is to summarize the role of nanodiamonds in various neurological diseases. We have taken related literature of making this review article from ScienceDirect, springer, Research gate, PubMed, Sci-finder, etc. The current approaches for treating neurological conditions such as glioblastoma includes chemotherapy or combination anti-retro viral therapy for HIV (human immunodeficiency virus) or use of anti-Alzheimer drugs during cognitive impairment. These approaches can provide only symptomatic relief as they do not target the cause of the disease due to their inability to penetrate the blood brain barrier. On long-term use, they may cause CNS toxicity due to accumulation in the brain. So nanodiamonds could prove as a promising approach in the brain targeting of the bioactive and to treat many neurological disorders such as Alzheimer's disease, Parkinson's disease, brain tumor (glioblastoma), HIV, amyotrophic multiple sclerosis, Huntington disease, stroke (cerebrovascular attack), batten disease, schizophrenia, epilepsy, and bacterial infections (encephalitis, sepsis, and meningitis) due to their ability to penetrate the blood-brain barrier and owing to their excellent surface properties, i.e., nano size and high surface area, ease of functionalization, multiple drug binding, and biocompatibility; they can be useful for brain targeted drug delivery with minimal side effects.

Universal Accessible Biomarkers of Drug-Induced Tissue Injury and Systemic Inflammation in Rat: Performance Assessment of TIMP-1, A2M, AGP, NGAL, and Albumin.

The ability to monitor for general drug-induced tissue injury (DITI) or systemic inflammation in any tissue using blood-based accessible biomarkers would provide a valuable tool in early exploratory animal studies to understand potential drug liabilities. Here we describe the evaluation of 4 biomarkers of tissue remodeling and inflammation (α2-macroglobulin [A2M], α1-acid glycoprotein [AGP], neutrophil gelatinase-associated lipocalin [NGAL], and tissue inhibitor of metalloproteinases [TIMP-1]) as well as the traditional serum parameter albumin as potential blood-based biomarkers of DITI and systemic inflammatory response (SIR). Biomarker performance was assessed in 51 short-term rat in vivo studies with various end-organ toxicities or SIR and receiver operating characteristic curves were generated to compare relative performances. All 4 biomarkers performed well in their ability to detect DITI and SIR with an area under the curve (AUC) of 0.82-0.78, however TIMP-1 achieved the best sensitivity (at 95% specificity) of 61%; AGP, NGAL, and A2M sensitivity was 51%-52%. AUC for albumin was 0.72 with sensitivity of 39%. A2M was the best performer in studies with only SIR (AUC 0.91). In the subset of studies with drug-induced vascular injury, TIMP-1 performed best with an AUC of 0.96. Poor performance of all tested biomarkers was observed in samples with CNS toxicity. In summary, TIMP-1, A2M, AGP, and NGAL demonstrated performance as sensitive accessible biomarkers of DITI and SIR, supporting their potential application as universal accessible tissue toxicity biomarkers to quickly identify dose levels associated with drug-induced injury in early exploratory rat safety and other studies.

ABCB1 limits brain exposure of the KRASG12C inhibitor sotorasib, whereas ABCB1, CYP3A, and possibly OATP1a/1b restrict its oral availability

Sotorasib (Lumakras™) is the first FDA-approved KRASG12C inhibitor for treatment of patients with non-small cell lung cancer (NSCLC) carrying this mutation. Using genetically modified mouse models, we studied the influence of the efflux transporters ABCB1 and ABCG2, the OATP1a/1b uptake transporters, and the CYP3A drug-metabolizing enzyme complex on the plasma pharmacokinetics and tissue distribution of oral sotorasib. In vitro, sotorasib was a potent substrate for human ABCB1 and a modest substrate for mouse Abcg2, but not for human ABCG2. In vivo, the brain-to-plasma ratio of sotorasib (40 mg/kg) was highly increased in Abcb1a/1b-/- (5.9-fold) and Abcb1a/1b;Abcg2-/- (7.6-fold) compared to wild-type mice, but not in single Abcg2-/- mice. Upon coadministering elacridar, an ABCB1/ABCG2 inhibitor, sotorasib brain accumulation increased 7.5-fold, approaching the levels observed in Abcb1a/1b-deficient mice. No acute CNS toxicity emerged upon boosting of the sotorasib exposure. In Oatp1a/1b-deficient mice, we observed a 2-fold reduction in liver disposition compared to wild-type mice, although these uptake transporters had no noticeable impact on sotorasib plasma exposure. However, plasma exposure was limited by mouse Cyp3a and human CYP3A4, as the AUC0–4 h in Cyp3a-/- mice was increased by 2.5-fold compared to wild-type mice, and subsequently strongly decreased (by 3.9-fold) in Cyp3aXAV mice transgenically overexpressing human CYP3A4 in liver and intestine. Collectively, the oral availability of sotorasib was markedly limited by CYP3A and possibly also by ABCB1 and OATP1a/b, whereas its brain accumulation was strongly restricted by ABCB1. The obtained results may help to further optimize the safety and efficacy of sotorasib in clinical use.

High-content analysis and Kinetic Image Cytometry identify toxicity and epigenetic effects of HIV antiretrovirals on human iPSC-neurons and primary neural precursor cells

IntroductionDespite viral suppression due to combination antiretroviral therapy (cART), HIV-associated neurocognitive disorders (HAND) continue to affect half of people with HIV, suggesting that certain antiretrovirals (ARVs) may contribute to HAND. MethodsWe examined the effects of nucleoside/nucleotide reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) and the integrase inhibitors dolutegravir (DTG) and elvitegravir (EVG) on viability, structure, and function of glutamatergic neurons (a subtype of CNS neuron involved in cognition) derived from human induced pluripotent stem cells (hiPSC-neurons), and primary human neural precursor cells (hNPCs), which are responsible for neurogenesis. ResultsUsing automated digital microscopy and image analysis (high content analysis, HCA), we found that DTG, EVG, and TDF decreased hiPSC-neuron viability, neurites, and synapses after 7 days of treatment. Analysis of hiPSC-neuron calcium activity using Kinetic Image Cytometry (KIC) demonstrated that DTG and EVG also decreased the frequency and magnitude of intracellular calcium transients. Longer ARV exposures and simultaneous exposure to multiple ARVs increased the magnitude of these neurotoxic effects. Using the Microscopic Imaging of Epigenetic Landscapes (MIEL) assay, we found that TDF decreased hNPC viability and changed the distribution of histone modifications that regulate chromatin packing, suggesting that TDF may reduce neuroprogenitor pools important for CNS development and maintenance of cognition in adults. ConclusionThis study establishes human preclinical assays that can screen potential ARVs for CNS toxicity to develop safer cART regimens and HAND therapeutics.

Synthesis and Biological Evaluation of Some Newer 1h-Benzo[b][1,5]diazepin-2(3h)-One Derivatives as Potential Anticonvulsant Agents

Background: Regardless of the availability of all novel and earlier treatments, seizure control is notoriously complicated. In the hopes of discovering the latest and ultimate therapy, medicinal chemists will keep on to hunt for new antiepileptic compounds with high specificity and low CNS toxicity. The biological effects of benzodiazepine compounds have been examined. Benzene and a diazepine ring are fused together to form the chemical structure. Diverse combinations of moieties attached to the innermost structure in positions 1, 2, 5, and 7 the pharmacological qualities, effect potency, and pharmacokinetic conditions are all influenced by the various side groups. Method: This paper describes the synthesis of several 1H-benzo[b][1,5]diazepin-2(3H)-one derivatives. The substituents at N1 are benzoyl, 5-substituted-1,3,4-thiadiazoles-2-yl-aminoacetyl. Condensation of orthophenylene diamine with ethyl acetoacetate gave 7-substituted-4-methyl-1H-benzo[b][1,5]diazepin-2(3H)-ones, which were then linked to benzoyl chloride and chloroacetyl chloride to yield N1-benzoyl and N1-chloroacetyl derivatives. N1- chloroacetyl derivatives were further linked with 5-substituted-1,3,4-thiadiazoles amines using microwave irradiation. Result: IR, 1H-NMR, and mass spectroscopy were used to authenticate the synthesized compounds. The PTZ produced convulsions method was used to test the compounds for anticonvulsant activity. Compounds 4a and 4c gave 80% protection at 0.4 mg/kg, whereas Compounds 2a and 2c offered 80% protection at 20 and 30 mg/kg, respectively, when compared to the Control. Conclusion: When compared to a control, the experimental synthesis and pharmacological assessment of the 1,5-benzodiazepin-2-one moiety replaced with 1,3,4-thiadiazole yields a potentially active anticonvulsant drug.

Real-Life Impact of Drug Toxicity on Dolutegravir Tolerability: Clinical Practice Data from a Multicenter Italian Cohort.

Dolutegravir (DTG) is currently one of the most used Integrase inhibitors (INI) in antiretroviral therapies (ARV) in both naïve and experienced people living with HIV (PLWHIV). We analyzed a multicenter cohort of PLWHIV, both naïve and experienced, starting an ARV including DTG. We enrolled 3775 PLWHIV: 2763 (73.2%) were males, with a median age of 50 years. During 9890.7 PYFU, we observed 930 discontinuations (9.4 per 100 PYFU). Estimated probabilities of maintaining DTG at three and five years were 75.1% and 67.2%, respectively. Treatment-naïve pts showed a lower probability of maintaining DTG at three and five years compared to treatment-experienced PLWHIV (log-rank p < 0.001). At a multivariate analysis, a longer time of virological suppression (aHR 0.994, p < 0.001) and having experienced a previous virological failure (aHR 0.788, p = 0.016) resulted protective against DTG discontinuation. Most discontinuations (84.0%) happened within the first 12 months of DTG initiation, in particular, 92.2% of discontinuations due to neuropsychiatric toxicity were observed in the first year. Our data confirm the overall good tolerability of DTG in clinical practice, with a low rate of discontinuations. CNS toxicity resulted the main reason for DTG discontinuation, with most related interruptions happening in the first year from DTG introduction.

Cerebellar ataxia: a rare toxicity of commonly used drug

Background and Aim: Metronidazole is commonly prescribed drug for amoebiasis and is usually well tolerated, and safe but can cause serious neurological adverse events including peripheral neuropathy which is relatively common but CNS toxicity is rare. We report a case of cerebellar ataxia who had taken metronidazole inadvertently for amoebic liver abscess.

Assessment of glufosinate-containing herbicide exposure: A multi-center retrospective study.

Exposure to glufosinate ammonium, an herbicide used worldwide, can cause CNS and respiratory toxicities. This study aimed to analyze acute human glufosinate ammonium poisoning. This multicenter retrospective cohort study involved five medical institutes affiliated with the Chang Gung Memorial Hospital system. Patients with glufosinate ammonium exposure visiting the emergency department (ED) between January 2008 and December 2020 were included. In total, 95 patients were enrolled. Compared to exposure via the non-oral route, patients exposed orally (n = 61) had lower GCS scores, higher mortality rates, and longer hospital lengths of stay (P-value: <0.001, 0.002, and < 0.001, respectively). In the subgroup analysis among oral exposure patients, the survival group had a lower amount of estimated glufosinate ingestion than the non-survival group (10.5 [3.4-27] vs. 40.5 [27-47.3] g, P-value: 0.022), lower rate of substance co-exposure (9 [19.6%] vs. 10 [66.7%] P-value: 0.001), and lower rate of paraquat co-exposure (0 [0%] vs. 7 [46.7%] P < 0.001) compared with the mortality group. In the orally-exposed and non-paraquat co-exposure patients (n = 54), age > 70 years and GCS score < 9 at triage presented a high sensitivity (100.00%, 95% CI: 63.06-100.00%) and medium specificity (58.70%, 95% CI: 43.23-73.00%) in predicting mortality. Old age, change in consciousness, and paraquat co-exposure were associated with higher mortality in human glufosinate poisoning. Age > 70 years and GCS score < 9 at triage could be predictors of mortality in patients with acute oral glufosinate poisoning.

The Utility of Ecmo and Intraaortic Balloon Pumps in Lipophilic Beta Blocker and Bupropion Overdose

Patient: Female, 21 year old Final Diagnosis: Cardiogenic shock due to ingestion Symptoms: Encephalopathy, seizures Medication: Propranolol, Bupropion Clinical Procedure: ECMO, Intraaortic Balloon Pump Specialty: Critical Care, Toxicology Background Combined massive ingestion of Beta Adrenergic Blocking Medications (BBs), Calcium Channel Blockers (CCBs), and behavioral modulators can be dangerous due to their cardiotoxicity leading to hypotension and severe refractory cardiogenic shock. Beta blockers can cause serious myocardial depression by decreasing calcium influx into cells. Some beta blockers exhibit sodium channel blockade, while others cross the blood brain barrier due to their lipophilicity causing CNS toxicity. Behavioral modulators, specifically Bupropion, cause significant cardiac depression as well by acting as a potential cardiac gap junctions blocker and therefore decreasing intercellular communication. Case Report We present a case of combined massive drug ingestion leading to severe refractory cardiogenic shock where invasive mechanical support was implemented. Patient was a 21-year-old female who presented after polyingestion in a suicide attempt. Patient took a large amount of propranolol and bupropion. She initially presented in cardiogenic shock, and seizing. She was intubated for airway protection, started multiple vasopressors, and high - dose insulin. Despite multiple therapies, she continued to deteriorate and her ejection fraction continued to worsen, at which point she was cannulated for Extracorporeal Membrane Oxygenation (ECMO) and an Intraaortic Balloon Pump (IABP) for refractory cardiogenic shock. She was in the intensive care unit for multiple weeks. Her cardiac function improved and she was able to be weaned off the mechanical support devices and vasopressors. She was discharged to a rehab facility with a good neurological outcome. Conclusion The use of ECMO contributed to the overall outcome of our patient. ECMO has a direct impact on drug pharmacokinetics. ECMO can be used to alter drug levels based on altering clearance as well as direct extraction from the circuit. Based on these results, implementation of early ECMO should be considered in patients with massive overdoses in refractory cardiogenic shock.

A Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Advanced Systemic Mastocytosis (AdvSM)

A Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Advanced Systemic Mastocytosis (AdvSM)

A 3-Part, Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Nonadvanced Systemic Mastocytosis (NonAdvSM)

A 3-Part, Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Nonadvanced Systemic Mastocytosis (NonAdvSM)