Broad Dose Range Research Articles

Optimizing Pediatric Sedation: Evaluating Remimazolam and Dexmedetomidine for Safety and Efficacy in Clinical Practice.

Daily, children undergo countless investigations and interventions, which require sedation and immobilization to ensure safety and accuracy. This remains associated with a persistent risk of sedation-induced life-threatening events as children are particularly vulnerable to adverse medical events and complications. Consequently, there is an urgent need to increase the safety of pediatric sedation and anesthesia. An ideal approach involves the use of drugs with fewer intrinsic side effects. In this context, on the basis of their pharmacokinetic properties, remimazolam (RMZ) and dexmedetomidine (DEX) were evaluated for their suitability as ideal sedatives. RMZ and DEX, both of which are currently available in pediatric medicine, have shown great promise in initial publications. To date, only very limited data concerning RMZ in small children are available. RMZ is a novel, ultrashort-acting benzodiazepine that is metabolized by tissue esterase, largely independent of organ function. It has a context-sensitive half-life of approximately 10 min, with minimal accumulation even with prolonged use. Its effects can be completely reversed with flumazenil. DEX, an isomer of medetomidine, is a potent α2-receptor-agonist with multiple indications in anesthesia and intensive care medicine. It has coanalgesic potential, allows for 'arousal sedations' and has a low profile for cardiorespiratory side effects. DEX is metabolized in the liver and is predominantly excreted renally. Both drugs show potential in the prevention and treatment of delirium, with DEX having additional neuroprotective effects. DEX and RMZ possess several properties of an optimal sedative, including clinically insignificant main metabolites and a broad dosage range, indicating their potential to reduce the incidence of sedation-related life-threatening events in children. However, further clinical research is necessary to better evaluate their potential risks.

In vivo and Laboratory Studies of Tetracycline Prevention of Foulbrood disease of Apis cerana indica Fab. and its Effects on Honey

Laboratory and field studies were carried out to assess the efficacy of the antibiotic tetracycline in preventing and managing American foulbrood (AFB) and European foulbrood (EFB) diseases in honey bees. Experiments with immature worker bees in the laboratory demonstrated that honey bee larvae could endure a broad range of antibiotic doses in their diet. The recommended dose of tetracycline (100 μg/ml) effectively protected young larvae from infection. However, once the dose exceeded this recommended level, it reached a point where it became lethal.

The Impact of Cannabidiol Treatment on Anxiety Disorders: A Systematic Review of Randomized Controlled Clinical Trials.

Generalized Anxiety Disorder (GAD) is a common psychiatric condition characterized by persistent and excessive worry, often accompanied by dysautonomic symptoms that significantly impact patients' well-being. Cannabidiol (CBD), a non-psychoactive compound derived from cannabis, has shown potential as an anxiolytic through its partial agonism of the 5HT-1A receptor and its negative allosteric modulation of CB1 receptors, which may help mitigate the anxiogenic effects of tetrahydrocannabinol (THC). This study evaluates the impact of CBD on individuals diagnosed with various anxiety disorders, comparing its effects to placebo and conventional pharmaceutical treatments through a systematic review of randomized controlled trials (RCTs). A systematic search of RCTs published between 2013 and 2023 was conducted across three databases using the terms "cannabidiol" and "anxiety". Out of the 284 articles identified, 11 met the eligibility criteria. The studies reviewed varied widely in terms of the types of anxiety disorders and CBD dosages examined, leading to results that were often contradictory. Despite these conflicting outcomes, the data suggest that CBD may reduce anxiety with minimal adverse effects when compared to a placebo. However, further RCTs with improved methodologies, encompassing a broad range of doses and continuous CBD administration across specific anxiety disorders, are needed. Unlike previous studies and meta-analyses, this review encompasses a broader spectrum of anxiety disorders and a variety of study designs and dosages, providing a more nuanced understanding of CBD's potential efficacy across different conditions.

Dose-escalation of second-line and first-line asciminib in chronic myeloid leukemia in chronic phase: the ASC2ESCALATE Phase IItrial.

Up to 40% of newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) discontinue treatment by 5 years, primarily due to resistance or intolerance. Rates of resistance to second-line (2L) treatment are also high. Some patients with resistance respond with dose escalation of tyrosine kinase inhibitors (TKIs). Asciminib demonstrated safety and efficacy across a broad dosage range. ASC2ESCALATE is an ongoing, Phase II, multicenter, single-arm, dose-escalation study of asciminib in 2L and first-line treatment of CML-CP. The primary end point is major molecular response at 12months in 2L. Secondary end points include molecular responses at and by scheduled time points, survival, and safety. ASC2ESCALATE is the first study investigating asciminib in CML-CP following failure of one prior TKI.Clinical Trial Registration: NCT05384587 (ClinicalTrials.gov).

Examination of the antiallodynic effect of rosmarinic acid in neuropathic pain and possible mechanisms of action

This study aimed to explore the potential antiallodynic effects of rosmarinic acid, a natural antioxidant with a demonstrated safety profile across a broad dose range. Using a chronic constriction injury-induced neuropathic pain model, the impact of rosmarinic acid on allodynia was investigated. Furthermore, the involvement of adrenergic and opioidergic mechanisms in its activity was assessed. To evaluate rosmarinic acid’s efficacy, doses of 10, 20, and 40 mg/kg were administered and the electronic von Frey test was utilized along with an activity cage apparatus. % MPE values were calculated to gauge the extent of pain relief. Mechanistic insights were obtained by pretreating animals with the β-adrenergic receptor antagonist propranolol, the α1-adrenergic receptor antagonist prazosin, α2-adrenergic receptor antagonist yohimbine, and the opioid receptor antagonist naloxone. Rosmarinic acid demonstrated a statistically significant antiallodynic effect that was independent of locomotor activity. This effect was noteworthy as it resembled both the level and duration of relief provided by pregabalin. Additionally, the %MPE value of the group treated with 40 mg/kg rosmarinic acid showed a significant difference compared to the value of the pregabalin-treated group (P<0.001). Pre-administration of the antagonists revealed that the antiallodynic activity was shown to be mediated by the stimulation of opioid and adrenergic receptors, with a primary contribution from α2-adrenergic receptor stimulation. Our findings suggest that rosmarinic acid may hold promise as a potential therapeutic agent for neuropathic pain. By elucidating the involvement of adrenergic and opioidergic mechanisms, we have provided valuable preclinical data that could inform novel treatment approaches.

First-in-human study (FIH) of FS222, a next-generation tetravalent PD-L1/CD137 bispecific antibody: Safety, pharmacodynamics (PD), and antitumor activity in patients (pts) with advanced solid tumors including PD-1 refractory melanoma.

2505 Background: Most pts receiving immune checkpoint inhibitors do not respond to treatment or relapse. FS222 is a novel affinity optimized, tetravalent bispecific PD-L1/CD137 antibody. FS222’s structure allows for potent, PD-L1-dependent, CD137 activation across a wide range of dose levels, and is designed to provide selective CD137 agonism in the tumor. We present data from the ongoing, FIH, open-label, phase I trial of FS222 in advanced solid tumors. Methods: Pts with pretreated advanced solid tumors received increasing doses of FS222 in an accelerated dose titration and 3+3 design intravenously every 3 or 4 weeks (Q4W) until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary and exploratory endpoints included pharmacokinetics, PD and antitumor activity (by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1). Results: As of data cut off (DCO) on 05Dec2023, a total of 104 pts had been treated across a range of doses and schedules in the FIH study (NCT04740424). We report interim results from the Q4W cohorts (N=90). Patients had a median age of 61 years (31-88 years) and had received a median of 2 (1-7) regimens of prior treatments. The median duration of exposure to FS222 was 82.5 days (24 – 529 days). The most common treatment-related AEs (TRAEs; &gt;20% of pts) were increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT), pyrexia, thrombocytopenia, asthenia, and neutropenia. The most common TRAEs grade ≥3 (≥10% of pts) were increased AST (13.3%) and ALT (11.1%). The most common treatment related serious AEs (≥3 pts) were febrile neutropenia (5 pts, 5.6%); and pyrexia, cytokine release syndrome, increased ALT, increased AST (all in 3 pts, 3.3%). On-target FS222 pharmacology was confirmed by the presence of dose-dependent target engagement, significant peripheral CD8+ T cell modulation and increased tumor CD3+ CD8+ T cells at multiple dose levels. At the DCO, 20 (22.2%) pts remained on treatment. Objective responses (CR, PR) were observed in pts with melanoma, NSCLC, ovarian cancer, TNBC, liposarcoma and colon cancer, for an ORR of 15.7% with evidence of further enrichment by dose. In post-PD-1 treated metastatic/advanced cutaneous melanoma the ORR was 60% (9/15, all PRs - 7 confirmed) and the disease control rate was 86.7% (13/15). Conclusions: The novel PD-L1/CD137 bispecific antibody FS222 demonstrated PD activity across a broad range of doses. The safety profile was acceptable and manageable. Encouraging anti-tumor activity was observed, including in patients with PD-1 refractory cutaneous melanoma. Next steps include further dose optimization and further evaluation of FS222 in patients with melanoma and other tumor types. Clinical trial information: NCT04740424 .

Clinical update related to the first-in-human trial of SYS6002 (CRB-701), a next-generation nectin-4 targeting antibody drug conjugate.

3151 Background: SYS6002 (CRB-701) is a novel, nectin-4 targeting antibody drug conjugate (ADC) that take advantage of a third generation, site-specific cleavable linker with novel conjugation chemistry. This technology is designed to establish a stable linker across antibody and payload, to produce an ADC with a homogenous drug antibody ratio of 2.0, with the additional aim to reduce the concentration of free-MMAE and thereby improve known payload related toxicities. SYS6002 (CRB-701) also contains a novel monoclonal antibody with a prolonged half-life that can support Q3W dosing. Methods: This is a multicenter, open-label, single-arm, phase I study using Bayesian optimal interval design. Eligible patients were aged ≥18 years with histologically confirmed Nectin-4 positive solid tumors (no Nectin-4 testing was required for urothelial carcinoma [UC]) who had failed or were intolerant to standard of care options. In the dose escalation, patients were given SYS6002 (dose level 0.2, 0.6, 1.2, 1.8, 2.7, 3.6, and 4.5 mg/kg) administered Q3W by intravenous infusion. The primary endpoints were safety, tolerability, and the recommended phase 2 dose. Results: As of January 2024, SYS6002 (CRB-701) has established a differentiated safety profile across a broad dose range (0.2-3.6 mg/kg) with no dose limiting toxicities and the majority of adverse events representing grade 1 or 2. No low-grade peripheral neuropathy, skin rash or fatigue, known toxicities that rate limit the usage of enfortumab vedotin (EV) have occurred. Herein, we report the anti-tumor activity of SYS6002 (CRB-701) in patients with nectin-4 positive solid tumors with a median of 4 prior therapies. The first confirmed stable disease was observed at 0.6 mg/kg and the first confirmed partial response was at 1.2 mg/kg. Anti-tumor activity in nectin-4 positive patients at doses ≥ 2.7 mg/kg ( n=6) would suggest an overall unconfirmed objective response rate of 50%, and among them, the ORR of patients with UC was 50% (1/2), and that of patients with cervical cancer reached 67% (2/3). Across this group of patients, 4/6 had moderate to high nectin-4 expression (H-score ≥ 150) and 3 achieved a partial response, suggesting SYS6002 (CRB-701) could achieve a highly differentiated ORR of 75% in patients with moderate to high Nectin-4 expression. After single IV infusion of SYS6002 0.2-3.6 mg/kg, the exposure of TAb, ADC and MMAE generally increased in a dose proportional manner. The half-lives of TAb, ADC and MMAE were 4-6 days, 4-5 days and 5-10 days, respectively. SYS6002 (CRB-701) exhibited a longer ADC half-life and lower free-MMAE exposures relative to EV at comparable dose levels. Conclusions: SYS6002 (CRB-701) demonstrates promising anti-tumor activity with a well-tolerated safety profile in patients with advanced nectin-4 positive solid tumors. Dose escalation at 4.5 mg/kg Q3W and dose expansion at 3.6 mg/kg Q3W are ongoing. Clinical trial information: ChiCTR2200066256.

Synthetic and Natural Radioprotective Agents: Recent Status and their Underlying Mechanism of Action.

Various substances possessing radiation scavenging properties, known as radioprotectors, play a crucial role in shielding organisms from the harmful effects of ionizing radiation (IR) by preventing cellular damage caused by free radicals. Initially, synthetic radioprotectors were developed using thiol synthetic compounds. However, among these, only amifostine (WR-2721) underwent clinical testing as a radioprotector. Various composites with different chemical structures other than thiol compounds were also investigated. However, synthetic radioprotectors are known to be associated with severe side effects, which lead to an inclination towards natural substances. Plants and natural products have emerged as promising sources of radioprotectors, renowned for their non-toxic nature across a broad range of doses and their cost-effectiveness. Radioprotectors are employed in diverse pharmaceutical approaches to mitigate the toxicities induced by radiation. The present review encompasses a detailed account of various synthetic and naturally occurring compounds possessing radioprotective properties, and different investigations related to their radioprotective action, ranging from free radicals scavenging to gene therapy, have also been precisely covered. Numerous radioprotectors have different mechanisms of action, and have proven benefits of naturally occurring compounds over chemically synthesized ones.

Pharmacokinetics and pharmacodynamics of standard nerve agent medical countermeasures in Göttingen Minipigs

Animal research continues to serve a critical role in the testing and development of medical countermeasures. The Göttingen minipig, developed for laboratory research, may provide many benefits for addressing research questions within chemical defense. Targeted development of the Göttingen minipig model could reduce reliance upon non-human primates, and improve study design, statistical power, and throughput to advance medical countermeasures for regulatory approval and fielding. In this vein, we completed foundational pharmacokinetics and physiological safety studies of intramuscularly administered atropine sulfate, pralidoxime chloride (2-PAM), and diazepam across a broad range of doses (1–6 autoinjector equivalent) using adult male Göttingen minipigs (n=11; n=4–8/study) surgically implanted with vascular access ports and telemetric devices to monitor cardiovascular, respiratory, arterial pressure, and temperature signals. Pharmacokinetic data were orderly and the concentration maximum mirrored available human data at comparably scaled doses clearly for atropine, moderately for 2-PAM, and poorly for diazepam. Time to peak concentration approximated 2, 7, and 20 min for atropine, 2-PAM, and diazepam, respectively, and the elimination half-life of these drugs approximated 2 hr (atropine), 3 hr (2-PAM), and 8 hr (diazepam). Atropine sulfate dose-dependently increased the magnitude and duration of tachycardia and decreased the PR and ST intervals (consistent with findings obtained from other species). Mild hypothermia was observed at the highest diazepam dose. Göttingen minipigs appear to provide a ready and appropriate large animal alternative to non-human primates, and further development and evaluation of novel nerve agent medical countermeasures and treatment strategies in this model are justified.

The balance of evidence on 100% juice &amp; health: A systematic umbrella review of meta-analyses

Fruit and vegetable intakes are major modifiable determinants of risk for non-communicable disease(1), yet intake levels remain low(2) and multiple barriers (cost, access, perishability, preparation skills) exist(3,4). 100% fruit and vegetable juices contain key micronutrients and bioactive compounds (5–7) and may help circumvent these barriers to consumption(6,7). However, their role in dietary guidelines and models of healthy eating remains controversial due to their free sugars and reduced dietary fibre content, relative to whole fruits and vegetables(6,7). Therefore, we conducted a systematic umbrella review of systematic literature reviews (SLRs) with meta-analyses assessing the relationships between 100% juice consumption and human health outcomes. Four databases (Medline, Cochrane Library, EMBASE, and CINAHL) were systematically searched for SLRs with meta-analyses of human prospective cohort, case-control, and intervention studies examining the relationship between 100% juice and any health outcome through to 20th October 2022. Screening (Covidence), quality (GRADE)(8), risk of bias (ROBIS)(9) and content overlap (corrected covered area(10)) tools were applied, and extracted data were narratively synthesised. The protocol was pre-registered (PROSPERO) and conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklists. 15 SLRs on 100% fruit juice including 51 primary meta-analyses, 6 dose-response analyses, and 87 sub-analyses were eligible for inclusion. No eligible studies on vegetable juice were found. Included studies represented data from almost 2 million subjects with a range of doses (50-1200mL/day) and timeframes (hours to years). Significant improvements in health outcomes were found in 19.6% of included meta-analyses (blood pressure, flow-mediated dilation, IL-6, c-reactive protein, and stroke mortality), and increased disease risks were found in 5.9% of included meta-analyses (CVD mortality, prostate cancer, and type II diabetes). The remainder (74.5%) found no significant difference (blood lipids, weight, liver function, metabolic markers, colorectal and breast cancers, and multiple inflammatory markers). The ROBIS quality assessment rated nine SLRs as low risk of bias, three as unclear and three as high. Using GRADE, confidence in the body of evidence ranged from very low (27 primary and 79 secondary meta-analyses) to low (19 primary and 13 secondary meta-analyses), and medium (4 primary and one secondary meta-analyses.) Findings show 100% juice consumption has limited risks of harm and some potential benefits, over a broad range of doses, including some that are relatively high, and time periods. The positive associations between 100% juice consumption and specific health outcomes relevant to population health may be explained by multiple mechanisms, including the vitamin, mineral, and bioactive contents. The balance of evidence suggests that 100% may have a neutral or beneficial place in general, population-level dietary guidelines.

Beta irradiation-induced thermoluminescence: Glow curve analysis and kinetic parameters in combustion-synthesized undoped Ca4YO(BO3)3

This study examines the thermoluminescent (TL) properties of undoped Ca4YO(BO3)3 phosphor, focusing on how it behaves under a variety of experimental conditions. The IRSL-TL 565 nm was chosen as the appropriate detection filter among various optical detection filter combinations. During the preheating trials conducted at a rate of 2 °C/s, the TL peak exhibited increased intensity, particularly around 200 °C. The experimental outcomes demonstrated a reliable linear relationship (R2 = 0.996 and b = 1.015) in the dose response of undoped preheated Ca4YO(BO3)3 within the range of 1–200 Gy. The investigation encompasses a range of techniques, including the TM-Tstop method, computerized glow curve deconvolution (CGCD) analysis, and theoretical modelling. The application of the TM-Tstop method to samples irradiated with a 5 Gy dose revealed distinct zones on the TM versus Tstop diagram, signifying the presence of at least two discernible components within the TL glow curve, specifically, a single general order kinetics peak and a continuous distribution. The analysis of activation energy versus preheated temperature exhibited a stepwise curve, indicating five trap levels with depths ranging between 1.13 eV and 1.40 eV. The CGCD method also revealed the superposition of at least five distinct TL glow peaks. It was observed that their activation energies were consistent with the Tm-Tstop experiment. Furthermore, the low Figure of Merit (FOM) value of 1.18% indicates high reliability in the goodness-of-fit measure. These findings affirm the reliability and effectiveness of the employed methods in characterizing the TL properties of the Ca4YO(BO3)3 phosphor under investigation. Theoretical models, including the semi-localized transition model, were introduced to explain anomalous observations in TL glow peak intensities and heating rate patterns. While providing a conceptual framework, these models may require adjustments to accurately capture the specific characteristics uncovered through CGCD analysis. As a potential application, the study suggests that the characterized TL properties of Ca4YO(BO3)3 phosphor could be utilized in dosimetric applications, such as radiation dose measurements, owing to its reliable linear response within a broad dose range.

Dosimetric properties of Cr–La, Cr–Cu, and Cu–La ions codoped Ca9 Al (PO4)7 nanostructure

In the present work, Cr–La, Cr–Cu, and Cu–La ions codoped Ca9Al (PO4)7 nanostructures (symbolized as Cr–La, Cr–Cu, and Cu–La) were prepared using the sol-gel method for their dosimetric properties. X-ray diffraction (XRD) and transmission electron microscopy (TEM) results reflected the existence of the nanoparticle structure. This confirmed the successful sol-gel preparation method used. The surface morphological properties of the prepared samples were scrutinized by scanning electron microscopy (SEM). The presence and distribution of the constituent elements of the samples were determined using energy-dispersive X-ray (EDX) spectroscopy. The thermoluminescence (TL) sensitivity enhancement and homogenous properties of the prepared samples were assessed using a γ-radiation dose of 5 Gy. TL sensitivity of the Cr–Cu sample was found to be optimum. The relative standard deviations (RSD) of the homogenous study were found to be 6.5, 5.7, and 3.9% for Cr–La, Cr–Cu, and Cu–La, respectively, which were acceptable according to the ISO requirements (<10%). The dose-linearity response was investigated in 0.5 up to 20 Gy γ-dose ranges. The sample Cr–Cu had a good dose-linearity of up to 20 Gy while the others (Cr–La and Cu–La samples) had a dose-linearity of up to 13 Gy. The threshold doses (MDD) of the Cr–La, Cr–Cu, and Cu–La samples were computed and found to be approximately 110, 32, and 134 μGy, respectively. The photon attenuation parameters of the prepared samples were computed using the Phy-X PSD program, and the acquired data showed that the Ca9Al (PO4)7 composition had bone-equivalent material characteristics. Results of the dosimetric properties of Cr–La, Cr–Cu, and Cu–La co-doped Ca9Al (PO4)7 samples suggested that these compositions had potentially excellent TL characteristics to be used in various dosimetric applications across a broad range of gamma doses.

Synthesis and thermoluminescence behavior of novel Sm3+ doped YCa4O(BO3)3 under beta irradiation

This study investigates the luminescent properties and dosimetric potential of YCa4O(BO3)3:0.5%Sm3+ phosphor synthesized via the combustion method. Dose-response investigations unveil a noteworthy linear increment in thermoluminescence (TL) intensity, emphasizing a remarkable linearity spanning a broad dose range from 0.1 to 300 Gy. Unusual heating rate effects are explored, revealing a shift in TL glow curve peak temperature (i.e 200 °C) towards higher temperatures with increasing heating rate. Speculative models, including Kinetic Trapping Effect, Thermal Quenching Compensation, and Defect Activation Energy Changes, are proposed. The study employs the Tmax-Tstop method to identify characterize glow curve peaks, and the Initial Rise method for the low-temperature segment analysis, revealing seven distinct trap levels at various depths within the bandgap. Glow curve deconvolution using the Complex Glow Curve Deconvolution (CGCD) method delineates a multi-peak structure, offering valuable insights into luminescent mechanisms. The model exhibits a Figure of Merit (FOM) of 1.71%, within an acceptable range, affirming its reliability. However, interpretation of the activation energy and frequency factor values suggests intricate site processes, necessitating a nuanced analysis to understand the material's luminescent characteristics. The YCa4O(BO3)3:0.5%Sm3+ phosphor demonstrates promising characteristics for precise dosimetry, with linear dose response, absence of saturation effects, and intriguing heating rate behavior.

Radiation response properties of Ce-doped CaF2 transparent ceramics

We report on the luminescence properties of CaF2 transparent ceramics having various concentrations of CeF3 (0.1 %, 0.5 %, and 1 %). Scintillation emissions centered at approximately 318, 345, and 386 nm derived from the 5d→4f transition of Ce3+ were detected, and scintillation light yields were determined to be 8600 photons/MeV (0.1 % CeF3), 1930 photons/MeV (0.5 % CeF3), and 1850 photons/MeV (1 % CeF3) under gamma-ray irradiation from 241Am. The Ce-doped CaF2 transparent ceramics showed thermally stimulated luminescence (TSL) with a broad glow peak at around 115–145 °C, and their dose response curves were determined over a broad dose range (0.01–3 mGy). Moreover, optically stimulated luminescence (OSL) exponential decay curves were obtained under 500 nm stimulation light, and dose response curves were obtained in the dose range of 0.1–100 mGy. The minimum detectable dose was estimated to be 0.1 mGy. A direct correlation between scintillation light yields under gamma-ray irradiation and TSL/OSL intensities was demonstrated.

Daily methocinnamox treatment dose-dependently attenuates fentanyl self-administration in rhesus monkeys

Opioid use disorder and opioid overdose continue to be significant public health challenges despite the availability of effective treatments. Methocinnamox (MCAM) is a novel, long-acting opioid receptor antagonist that might be an effective treatment for opioid use disorder (i.e., preventing relapse and overdose). In nonhuman primates, MCAM selectively blocks the positive reinforcing effects of mu opioid receptor agonists, including heroin, fentanyl, and its ultra-potent analogs (e.g., carfentanil) with a single administration of MCAM being effective for up to two weeks. Because treatment of opioid use disorder would involve repeated administration of a medication, MCAM was studied in rhesus monkeys (3 males and 2 females) responding under a fixed-ratio self-administration procedure for a range of doses of fentanyl (0.000032–0.1 mg/kg/infusion). The fentanyl self-administration dose-effect curve was determined before and during treatment with progressively increasing daily doses of MCAM (0.001–0.1 mg/kg) given subcutaneously 1 h before the session. MCAM dose-dependently shifted the fentanyl dose-effect curve rightward and then, at larger doses, downward. The largest treatment dose of MCAM (0.1 mg/kg/day) shifted the curve more than 120-fold rightward with monkeys receiving doses much larger than the likely lethal dose of fentanyl with no adverse effect or observable change in behavior. This study demonstrates that MCAM reliably and dose-dependently decreases fentanyl self-administration and prevents opioid overdose, with no evidence of adverse effects over a broad dose range, further supporting the potential therapeutic utility of this novel antagonist.

ASC2ESCALATE: A US Phase 2, Open-Label, Single-Arm, Dose-Escalation Study of Asciminib (ASC) Monotherapy in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) As Second-Line (2L) and First-Line (1L) Treatment

CONCLUSIONS Adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) have increased survival in CML, although resistance and intolerance remain challenges, which often necessitate switch to another TKI. Many pts discontinue 1L treatment due to resistance/intolerance and switch to 2L therapy, to which resistance is typically higher. A need exists for effective, safe treatment options for pts in 1L and 2L. ASC is thefirst approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), with activity against most BCR::ABL1 kinase domain mutations conferring resistance to ATP-competitive TKIs, potentially providing a new early-line treatment option. ASC was first approved in the United States for pts with CML-CP after ≥2 TKIs at 80 mg once daily (QD) or 40 mg twice daily (BID) and for pts with CML-CP with the T315I mutation at 200 mg BID. A large, phase 1, dose-escalation trial (NCT02081378) demonstrated efficacy and tolerability of ASC across a broad range of dosages. Also, with &amp;gt;2 years of follow-up, ASC demonstrated superior efficacy and better safety and tolerability compared with bosutinib in pts with CML-CP without the T315I mutation after ≥2 prior TKIs in the phase 3 ASCEMBL study (NCT03106779). We describe the phase 2 ASC2ESCALATE trial investigating efficacy and safety of ASC with dose escalation in pts with CML-CP receiving ASC as their 2L or 1L therapy. This is a phase 2, open-label, multicenter, single-arm, dose-escalation study with sites in the United States (NCT05384587) (Figure). Pts receiving ASC as their 2L TKI must be adults with non-T315I CML-CP who discontinued their first ATP-competitive TKI for warning response ( BCR::ABL1IS &amp;gt;1%-10% after 6 months or &amp;gt;0.1%-1% after 12 months of 1L treatment), resistance ( BCR::ABL1IS &amp;gt;10% after 6-12 months or &amp;gt;1% or loss of major molecular response [MMR] after &amp;gt;12 months of 1L treatment), or intolerance (with BCR::ABL1IS &amp;gt;0.1% at screening). In addition to pts receiving ASC as their 2L TKI, a separate cohort of newly diagnosed pts will be included, and these pts may receive up to 4 weeks of prior treatment with imatinib or an approved second-generation TKI (Table). All pts will start treatment with ASC 80 mg QD. Pts achieving BCR::ABL1IS ≤1% at 6 months will continue at the same dose; pts not achieving BCR::ABL1IS ≤1% at 6 months will have their dose escalated to 200 mg QD. In pts not achieving MMR at 12 months, dose escalation from 80 to 200 mg QD or from 200 mg QD to 200 mg BID will occur or the pt will be taken off the study. If pts have grade ≥3 or persistent grade 2 toxicity refractory to optimal management, no dose escalation will occur, and pts will remain on ASC at their most current dose. This dose-escalation strategy applies to both the 2L and 1L cohorts. The primary endpoint is MMR rate at 12 months in pts using ASC as their 2L TKI. As all primary and secondary endpoints for the 2L cohort will be measured for the 1L cohort as secondary endpoints, the MMR rate at 12 months in pts receiving ASC as their 1L TKI is a secondary endpoint. Additional secondary endpoints are the same for both 2L and 1L cohorts and include MMR rates at 3, 6, 18, and 24 months; MMR rates by all scheduled time points; MR 2 ( BCR::ABL1IS ≤1%), MR 4 ( BCR::ABL1IS ≤0.01%), and MR 4.5 ( BCR::ABL1IS ≤0.0032%) at and by scheduled time points; time to and duration of MMR; time to treatment failure; progression-free survival; overall survival; and safety/tolerability. Exploratory endpoints include assessment of BCR::ABL1 mutations. ASC2ESCALATE is the first clinical trial designed to assess pts with CML-CP using ASC as their 2L TKI and will provide critical information on efficacy and safety of dose escalation in pts for whom certain response milestones are not met in 2L and 1L. Dose escalation of ASC in 2L and 1L is another treatment strategy and results from ASC2ESCALATE will add to the growing body of evidence for using ASC to treat pts with CML-CP. Recruitment for pts using ASC as their 2L TKI began November 2022, and as of July 10, 2023, 5 pts have been enrolled in this cohort; Up to 92 and 90 pts are estimated to enroll in the 2L and 1L cohorts, respectively, across 90 sites.

Product development and quality of pharmacy compounded chenodeoxycholic acid capsules for Dutch cerebrotendinous xanthomatosis patients.

Introduction: In 2017 the drug chenodeoxycholic acid (CDCA) became unavailable to Dutch patients with the rare inborn error of metabolism cerebrotendinous xanthomatosis (CTX). This was a direct result of a steep price increase after CDCA was authorized in the EU as an orphan drug. As a result, Dutch health insurance companies were unable to reimburse this drug and the availability of CDCA to patients with CTX was directly at risk creating an unmet medical need. CTX is characterized by juvenile cataract, tendon xanthomas, infantile-onset diarrhea, psychomotor retardation and progressive cerebellar ataxia. Treatment with CDCA, when initiated before neurological symptoms are present, can prevent the onset of neurological complications. Methods: To assure continuation of patient treatment with a high quality product, the hospital pharmacy of the Amsterdam UMC developed CDCA capsules as a pharmacy preparation. A simple and robust formulation was developed for capsules in a broad dose range of 35-250mg, ensuring that both pediatric and adult patients can receive an exact dose tailored to their specific needs. Capsules are prepared manually on a small scale for the individual patient. To assure the quality of the product, product validation and stability studies were performed. Results: The results show that the product complies with all specifications based on the requirements of the European Pharmacopoeia. The capsules contain the declared amount of CDCA, no degradation product or other (microbiological) impurities are formed during the production process and the capsules show a quick dissolution profile. Stability studies indicate that it is a stable product and no impurities increase or arise over time. These results show that these pharmacy preparations are of high quality and comply to Good Manufacturing Practice (GMP) requirements. Discussion: Through our research, we have demonstrated that pharmacy compounding can be a viable alternative in situations where immediate access to essential medication is crucial or when certain drugs are temporarily inaccessible. The purpose of this paper is to offer comprehensive guidance to other pharmacies to improve the availability of currently inaccessible drugs through the practice of pharmacy compounding, thereby facilitating improved patient care.

SAT595 A Successful Long-time Experience Of A Dose-finding Approach For The Treatment Of Central Adrenal Insufficiency (CAI) With Prednisone

Abstract Disclosure: P.F. Santos-Neto: None. S.R. Correa-Silva: None. B.M. Mascarenhas Nakano: None. J. Abucham: None. Introduction: In patients with CAI, hydrocortisone (HC) is considered the preferred treatment. Recommended daily doses are based on estimates of daily cortisol production which have recently been decreased. Doses in the upper part of the previously suggested range have been associated with higher cardiovascular morbimortality. Currently recommended HC replacement doses have been reduced. In our country, HC has never been commercially available in tablets, but prednisone, an intermediate action glucocorticoid available in 5mg and 20mg tablets (lower doses are available elsewhere) is easily found, at low cost, and doesn't need prescription. Aim: To analyze our experience with prednisone in patients with CAI using the same dose-finding protocol established four decades ago. Patients: Data were extracted from electronic files. After applying inclusion/exclusion criteria, 72 out of 96 patients entered the study. Inclusion criteria: &amp;gt;18y, last consultation &amp;lt;2y, stable and same daily doses of prednisone, stable replacement of thyroid and sex hormone deficits in the last year. Exclusion criteria: Cushing´s disease, alternating prednisone doses, non-controlled acromegaly, intestinal malabsortion, other diseases requiring glucocorticoid, hepatic insufficiency. Dose-finding Protocol: Starting doses of prednisone in outpatients are usually 2.5mg or 5.0mg. Thereafter, dose adjustments are done according to clinical signs and symptoms and a pre-defined minimal dose of 2.5mg is attempted in all patients. Patients requiring &amp;gt;2.5mg are changed to 5.0mg, and then suggested to decrease to 3.75mg (3/4 of a 5.0mg tablet). If 3.75mg doses are judged insufficient, we return to 5.0mg; if unpractical, we suggest to alternate doses or to return to 5.0mg. Statistical Analysis: Patients were divided in two groups according to the prednisone daily dose. Group comparisons: Student´s t-test and Fisher´s exact test. P&amp;lt;0.05 was set as significant. Results: Fifty-four patients were on 2.5mg (75%) and 18 patients were on 5.0mg (25%) of prednisone. None was on GH replacement. The 5mg group tended to be younger (P=0.06). No significant differences (0.10&amp;lt;P&amp;lt;1.0) were found in relation to sex, treatment duration, BMI (both at diagnosis and last visit), other hormone deficiencies, IGF-1 levels, diabetes mellitus, dyslipidemia, and hypertension between the two groups. Conclusions: Adult patients with CAI are successfully treated with a single daily morning dose of prednisone determined by a dose-finding approach. In the absence of GH replacement, most patients stay at 2.5mg and the remaining ones at 5.0mg. The lack of difference between doses in parameters of excessive glucocorticoid exposure indicates that our approach is able to adjust prednisone doses close to individual requirements. A broader range of doses from &amp;lt;2.5mg including intermediate doses &amp;lt;5mg should be tried if low dose tablets are available. Presentation: Saturday, June 17, 2023

Nonviral In Vivo Delivery of CRISPR-Cas9 Using Protein-Agnostic, High-Loading Porous Silicon and Polymer Nanoparticles.

The complexity of CRISPR machinery is a challenge to its application for nonviral in vivo therapeutic gene editing. Here, we demonstrate that proteins, regardless of size or charge, efficiently load into porous silicon nanoparticles (PSiNPs). Optimizing the loading strategy yields formulations that are ultrahigh loading─>40% cargo by volume─and highly active. Further tuning of a polymeric coating on the loaded PSiNPs yields nanocomposites that achieve colloidal stability under cryopreservation, endosome escape, and gene editing efficiencies twice that of the commercial standard Lipofectamine CRISPRMAX. In a mouse model of arthritis, PSiNPs edit cells in both the cartilage and synovium of knee joints, and achieve 60% reduction in expression of the therapeutically relevant MMP13 gene. Administered intramuscularly, they are active over a broad dose range, with the highest tested dose yielding nearly 100% muscle fiber editing at the injection site. The nanocomposite PSiNPs are also amenable to systemic delivery. Administered intravenously in a model that mimics muscular dystrophy, they edit sites of inflamed muscle. Collectively, the results demonstrate that the PSiNP nanocomposites are a versatile system that can achieve high loading of diverse cargoes and can be applied for gene editing in both local and systemic delivery applications.

Micro/nanoplastics contamination of the terrestrial environment: exposure routes, dose, and co-contaminants complicate the risk calculus

As xenobiotics in the environment, microplastics and nanoplastics have become ever-present in the environment, especially in terrestrial environment. However, a critical issue is that these anthropogenic contaminants are toxic to some terrestrial microorganisms, and the results of that toxic interaction over time can significantly impact microbial community structure and function, with unknown ramifications for ecosystem health. This viewpoint highlights the fact that, considering the diverse array of MPs/NPs, the broad dose range, and the presence of co-contaminants (e.g., retained organic and elemental pollutants, polymer additives) associated with these materials, their risk calculus to microbiome in terrestrial environment is incredibly complex. Short- and long-term dose-response that spans environmentally relevant concentrations and includes appropriate levels of analyte complexity (additives, co-contaminants). This should include microcosm studies that enable assessment of 'omic' parameters over the long term, as well as detailed assessment of impacts on soil microbiome function. We also need to understand impacts on eukaryotic microbes. In conclusion, for both toxicity and benefit, we should focus more on the dynamics of impacts on the microbiome. As some populations are inhibited, others increase. It is not because the plastics are conveying benefit directly but because more sensitive species are decreasing, which frees up resources from less competition. Those changes then have additional consequences, such as shifts in predator species and nutrient cycling and redox conditions.Graphical