High-dose Tolerance Research Articles

Simultaneous integrated boost-intensity modulated radiation therapy (SIBIMRT) planning for pelvic tumours: dose coverage to target volume and normal tissue sparing.

To evaluate the better radiotherapy plan for pelvic tumours that may achieve a high target coverage dose and low normal tissue tolerance dose using simultaneous integrated boost-intensity-modulated radiation therapy technique. The analytical, cross-sectional, descriptive study was conducted from October 2020 to March 2021 at Al- Amal National Hospital for Cancer Treatment, Baghdad, Iraq, and comprised male pelvic cancer patients aged 50-80 years. Computed tomography scans were randomly selected. For each patient, 4 treatment plans (phases Ι and Π) were generated using the simultaneous integrated boost-intensity-modulated radiation therapy technique while keeping all parameters constant except the number of beams, which were 5, 7, 9 and 11. The optimal and safe dose was defined as the one to cover 95% planning target volume. Homogeneity and conformity indices were used to assess the uniformity of dose distribution in the target volume, and various treatment plans in the same patient were compared. Data was analysed using SPSS 24. There were 15 males with mean age 67.12±2.84 years. There was a significant variance in the target volume dose and organ at risk in the 4 different plans generated using the simultaneous integrated boost-intensitymodulated radiation therapy technique (p<0.05). The 9-beam treatment plan was the best for coverage of tumours and protection of healthy organs assessed through homogeneity and conformity indices (p<0.05). The 9-beam treatment plan showed significant tumour coverage, homogeneity and conformity values, and sparing dose for organs at risk.

A single-chain fab derived drug conjugate for HER2 specific delivery

Despite the development of antibody-drug conjugates, the fragment Fab-based drug conjugates offer some unique capabilities in terms of safety, clearance, penetration and others. Current methods for preparing Fab drug conjugates are limited by the availability and stability of Fab proteins, leaving reports on this rare. Here, we found that a single-chain scaffold of Fab enables stabilization of the paired structure and supports high-yield expression in bacteria cytoplasm. Furthermore, we conjugated anti-neoplastic agent SN38 to the C-terminus by sortase A ligation and generated a homogenous Fab conjugate with the drug-to-Fab ratio of 1. The resulting anti-HER2 Fab-SN38 conjugate demonstrated potent and antigen-dependent cell-killing ability with the aid of its special cathepsin-triggered cyclization-promoted release mechanism. In vivo, Fab-SN38 can prevent growths of HER2-positive tumors in athymic mice and be well tolerated to the treatment at 7 mg/kg per dose. Anti-tumor activity, high dose tolerance and penetration advantage observed in this study would merit Fab conjugate investigation in target chemotherapy.

Theories of immune recognition: Is anybody right?

The clonal selection theory (CST) is the centrepiece of the current paradigm used to explain immune recognition and memory. Throughout the past decades, the original CST had been expanded and modified to explain new experimental evidences since its original publication by Burnet. This gave origin to new paradigms that govern experimental immunology nowadays, such as the associative recognition of antigen model and the stranger/danger signal model. However, these new theories also do not fully explain experimental findings such as natural autoimmune immunoglobulins, idiotypic networks, low and high dose tolerance, and dual-receptor T and B cells. To make sense of these empirical data, some authors have been trying to change the paradigm of immune cognition using a systemic approach, analogies with brain processing and concepts from second-order cybernetics. In the present paper, we review the CST and some of the theories/hypotheses derived from it, focusing on immune recognition. We point out their main weaknesses and highlight arguments made by their opponents and believers. We conclude that, until now, none of the proposed theories can fully explain the totality of immune phenomena and that a theory of everything is needed in immunology.

Oral administration of coenzyme Q10 ameliorates memory impairment induced by nicotine-ethanol abstinence through restoration of biochemical changes in male rat hippocampal tissues

Substance abuse among adolescents has become a growing issue throughout the world. The significance of research on this life period is based on the occurrence of neurobiological changes in adolescent brain which makes the individual more susceptible for risk-taking and impulsive behaviors. Alcohol and nicotine are among the most available drugs of abuse in adolescents. Prolonged consumption of nicotine and alcohol leads to drug dependence and withdrawal which induce various dysfunctions such as memory loss. Coenzyme Q10 (CoQ10) is known to improve learning and memory deficits induced by various pathological conditions such as Diabetes mellitus and Alzheimer's disease. In the present study we investigated whether CoQ10 treatment ameliorates memory loss following a nicotine-ethanol abstinence. Morris water maze and novel object recognition tests were done in male Wistar rats undergone nicotine-ethanol abstinence and the effect of CoQ10 was assessed on at behavioral and biochemical levels. Results indicated that nicotine-ethanol abstinence induces memory dysfunction which is associated with increased oxidative and inflammatory response, reduced cholinergic and neurotrophic function plus elevated Amyloid-B levels in hippocampi. CoQ10 treatment prevented memory deficits and biochemical alterations. Interestingly, this ameliorative effect of CoQ10 was found to be dose-dependent in most experiments and almost equipotential to that of bupropion and naloxone co-administration. CoQ10 treatment could effectively improve memory defects induced by nicotine-ethanol consumption through attenuation of oxidative damage, inflammation, amyloid-B level and enhancement of cholinergic and neurotrophic drive. Further studies are required to assess the unknown side effects and high dose tolerability of the drug in human subjects.

Abstract 591: Discovery of ZM-2322, a highly selective, potent inhibitor of membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase (PKMYT1)

Abstract The genome DNA is consistently threatened by a variety of intrinsic and exogenous DNA damage factors. Cell cycle checkpoint is one important mechanism in response to DNA damage and maintaining genome stability. In tumor cells, gene alterations, such as CCNE1 amplification (encoding for Cyclin E1), result in G1/S checkpoint loss and replication stress, leading to high dependency on the G2/M checkpoint. PKMYT1 inhibits crucial checkpoint protein CDK1 activity by phosphorylating CDK1 at the residues of Thr-14 and Tyr-15 in the G2/M phase. In CCNE1 amplification cells, the inhibition of PKMYT1 leads to the reduction of pCDK1 and loss of G2/M checkpoint, consequently results in premature mitosis and the accumulation of DNA damage, then finally induces cell death. Here we identify a novel small molecular ZM-2322, which displays robust intracellular binding to PKMYT1 and inhibits the specific downstream phosphorylation of CDK1 Thr-14 with IC50 values of 14 nM and 29 nM, respectively. ZM-2322 strongly inhibits the proliferation of the HCC1569 cell line with CCNE1 high-level amplification and shows a &amp;gt;400 × selectivity folds over a CCNE1 wildtype cell line SKOV3. ZM-2322 also shows significant inhibition of tumor growth in a dose-dependent manner in the HCC1569 xenograft model, and the efficacy correlates well with PK and target inhibition. There is evidence showing that loss-of-function mutations of FBXW7, a cyclin E E3 ligase, lead to cyclin E accumulation and are synthetic-lethal with PKMYT1 inhibition. Consistently, a potent anti-proliferation of ZM-2322 is observed in DLD-1 FBXW7 -/- cells, but not DLD-1 parental cells. These data suggest a high potency of ZM-2322 on PKMYT1 inhibition and a potential good kinase selectivity which is further confirmed by using a kinase panel biochemical assay. As expected, when compared head-to-head with another clinical PKMYT1 inhibitor RP-6306 which shows inhibitory effect on 27 of 217 human kinases with inhibition rates &amp;gt;90% at 1 μM, ZM-2322 is found to be a much more PKMYT1-selective inhibitor and hits only several individual kinases under the same assay condition, suggesting a potentiality in better safety profile and higher dose tolerance. Furthermore, our data illustrates that in combination with gemcitabine, ZM-2322 elicits strong synergetic anti-proliferation activities on HCC1569 cells in vitro and results in tumor regression with a minor effect on body weight in vivo. Besides, a strong synergy effect is also observed in the combo of ZM-2322 and ATR inhibitor in HCC1569 in vitro. These data indicate that ZM-2322 has the potential of application expansion and good tolerance under continuous administration. Taken together, our data suggest that ZM-2322 is a potent and highly selective PKMYT1 inhibitor. Citation Format: Feng Zhou, Lu Liu, Lei Jiang, Baoying Cheng, Zhentao Li, Dongxing Zhu, Jianbin Xue, Liting Xue, Renhong Tang. Discovery of ZM-2322, a highly selective, potent inhibitor of membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase (PKMYT1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 591.

Methodology of botulinum therapy in the treatment of dystonic scoliosis in generalized dystonia (clinical case)

Dystonic scoliosis as one of the forms of generalized dystonia is a highly disabling form of dystonia, which can lead to damage to internal organs (lungs, heart) and the peripheral nervous system, including the spinal cord. Almost always, those muscles that are involved in the formation of a dystonic posture in generalized dystonia have not been studied in terms of the effectiveness of treatment with botulinum toxin type A and are not reflected in the instructions. As a result, there is no understanding of the general motor interaction with differentiation into targeted and non-targeted muscles, administration doses and control methods.The aim of the work was to evaluate the efficacy and tolerability of high doses of botulinum toxin type A in dystonic scoliosis, as well as to present the introduction of botulinum toxin type A using ultrasound and electromyographic control. We have described a clinical case of a 19-year-old patient suffering from generalized dystonia with S-shaped dystonic scoliosis of the III degree. Deep brain stimulation was recommended as a treatment for the patient. During the waiting period for the timing of the operation, we attempted symptomatic therapy using the drug incobotulotoxin A. Over the next year and a half, 700 units of botulinum toxin type A were administered under ultrasound and electromyographic control every 3–4 months. As a result, treatment of trunk dystonia in the patient during the observation period led to a clinically significant decrease in the degree of curvature (from 37° to 27°, from III to II degree of scoliosis) in the absence of undesirable effects of the drug, including generalized muscle weakness. According to the repeated conclusion of the council of neurosurgeons, surgical intervention is not indicated for the patient due to the positive effect of the introduction of botulinum toxin type A.

Fulminant acne induced by simultaneous taking of isotretinoin and anabolic steroids

Acne fulminans is a rare disease characterized by the sudden appearance of painful nodules with a pronounced tendency to ulceration, accompanied by general symptoms, including fever, arthralgia, hepatomegaly and impaired blood parameters. Among its most frequent triggers are anabolic steroids and isotretinoin.&#x0D; The article describes a patient whose disease was caused by the sequential administration of anabolic steroids and systemic isotretinoin. The clinical picture of acne fulminans in the patient was represented by typical skin rashes, changes in blood parameters, arthralgia and myalgia, as well as nodular erythema. Systemic antibacterial therapy with doxycycline was ineffective. The patient was hospitalized in the Saint Petersburg State Budgetary Healthcare Institution "City Dermatovenerological Dispensary", where he was treated with prednisone and then with systemic isotretinoin. Due to the severe course of the process, the cumulative dose of isotretinoin achieved 240 mg/kg. Against the background of treatment, studies of aspartate aminotransferases, alanine aminotransferases, bilirubin, cholesterol, triglyceride indicators were regularly conducted, the values of which did not exceed the limits of reference indicators. The remission of the disease was 3 years, there are residual phenomena in the form of scars. Scar correction is carried out using a fractional CO2 laser (SmartXide Touch), no more than 3% of the skin is treated in one procedure.&#x0D; The peculiarity of the observation presented by us is the association of fulminant acne with simultaneous administration of steroid hormones and isotretinoin, the combination of fulminant acne with erythema nodosum, as well as good tolerance of high doses of isotretinoin.&#x0D; The literature review discusses data on etiopathogenesis, features of clinical manifestations, approaches to the treatment of fulminant acne. Modern approaches to the classification of the disease are also presented.

Study of the tolerance of high doses of drugs for external use based on fipronil, praziquantel, moxidectin and pyriproxyfen

The purpose of the researchis to study the tolerance of increased doses of topical preparations based on fipronil, praziquantel, moxidectin and pyriproxyfen in dogs and cats at increased therapeutic doses.Materials and methods.In the laboratory of ectoparasitoses on the basis of VNIIP, a branch of the Federal State Budget Scientific Institution of the Federal Scientific Center of VIEV RAS, two preparations were developed in the form of a solution for external use for dogs and cats based on praziquantel, pyriproxyfen, imidacloprid and moxidectin. Work on the study of tolerance to high doses was carried out on 15 kittens and 15 puppies under the age of one year, 15 adult cats and 15 adult dogs. Animals were divided into 8 experimental and 4 control groups according to the principle of analogues, 5 animals each. The drugs were used at 1.5 and 2 times the increased therapeutic dose four times with an interval of 7 days. The animals were observed for 30 days; noted the general condition, behavior, appetite, controlled weight and body temperature. Before the start of the experiment and 30 days after the start of the use of the drugs, blood was taken for general clinical and biochemical studies.Results and discussion.It was found that drugs in 1.5 and 2 times increased therapeutic doses, applied four times with an interval of 7 days, did not have a negative effect on carnivores. There were no changes in behavior, body temperature and weight, physical condition, clinical status, hematological and biochemical parameters of blood and functions of internal organs. The drug was well tolerated by dogs and cats of different breeds of different age groups, as well as by puppies and kittens. Manifestations of any allergic reactions were not observed. The obtained results of the studies confirm the safety of the use of drugs in practice in the recommended dosing regimen.

Safety and efficacy of high-dose clobetasol propionate 0.05% in cutaneous lichen planus.

Cutaneous lichen planus is a highly pruritic dermatosis with an unmet need in its management. The aim of this study was to evaluate the short-term effect and tolerance of high doses of clobetasol propionate 0.05% in cutaneous lichen planus. We conducted a single-center retrospective cohort study from 2017 to 2021. All adults treated with high-dose (>5g/day) clobetasol propionate 0.05% for cutaneous lichen planus were included. Patients with less than 10% affected body surface area at initial presentation or who received concomitant systemic therapy were excluded. The primary endpoint was the rate of complete remission by week 16. Secondary endpoints included maximum daily and median cumulative doses, reduction in pruritus and occurrence of adverse events. Fifty-seven patients, 60% female, with a mean age of 48 years (min-max,18-83) were included. Cutaneous lichen planus had been present for a median duration of 2months at initial presentation (min-max, 1-4) and involved a median body surface area of 27%. Pruritus was reported by 55/57 (96%) patients. At week 16, 41/57 (72%) patients had achieved complete remission without treatment modification, among whom 25/41 (61%) had achieved it at week 6. The median daily and cumulative doses were, respectively, 20 g/day (IQR, 10-20) and 560 g (IQR, 320-925). Three patients experienced mild adverse events. No statistical association was demonstrated between the duration of the disease before treatment initiation and clinical response. In conclusion, high-dose clobetasol propionate 0.05% seems to be an effective, well-tolerated, and easy-to-implement treatment for cutaneous lichen planus.

On the tolerability of high doses of tubazid in patients with pulmonary tuberculosis

In an effort to improve the effectiveness of treatment of tuberculosis patients, clinicians have been increasingly using increased therapeutic doses of GINK drugs in recent years. Many researchers, both in experimental and clinical observations, have found the advantage of high doses of tubazide over low ones [8, 10, 11], In this regard, there has been a tendency to use tubazide 0.3 three times, i.e. 15-20 mg/kg, even in broad clinical practice. Meanwhile, such a dose in the world literature is considered high, often leading to toxic reactions. Based on the materials of Biehl and co. (1954), Costelletos and co. (1954), Benda and co. (1954), a side effect when using isoniazid at a dose of 16-24 mg / kg is observed in 28-44% of cases. At the same time, the data on the therapeutic advantage of high doses cannot yet be considered indisputable, since there is a message about the absence of an additional effect with an increase in the amount of the drug administered [7]. The purpose of this study was to study the nature and frequency of side effects of tubazide, used 0.3 3 times a day, compared with average doses and the possibility of preventing toxic-allergic reactions with pyridoxine. There were 807 patients with fresh and chronic forms of pulmonary tuberculosis under observation (age - from 18 to 68 years). 210 people received tubazid 0.15 3 times a day and 597 - 0.3 3 times a day in combination with other tuberculostatic agents of the I or II series. Some patients receiving high doses of tubazide were given pyridoxine to prevent side effects.

Feasibility, Tolerance, and Quality of Life for Hypofractionation Versus Conventional Fractionation for Post-mastectomy Radiotherapy in Indian Patients.

Introduction: The international standard for post-operative radiotherapy for breast cancer delivers hypofractionated radiotherapy. However, many centers in India still follow the longer conventional schedule probably because of paucity of large prospective trials in Indian patients on the same and apprehension regarding tolerance of high dose per fraction in the said population. We aimed to test the feasibility of hypofractionation in our setting and compared the toxicities and the quality of life in patients receiving conventional and hypofractionated radiotherapy.Materials and methods: Eighty histopathologically proven women of non-metastatic carcinoma breast who underwent modified radical mastectomy were assigned to receive 50 Gray/25 fractions/five weeks or 40 Gray/15 fractions/three weeks. Patients were assessed for the following toxicities - radiation dermatitis, radiation pneumonitis, dysphagia, skin fibrosis, lymphedema, shoulder stiffness, and brachial plexopathy, during radiation and at treatment completion and then at first, third, and sixth-month follow-up. Health-related quality of life was assessed using the European Organisation for Research and Treatment of Cancer core quality of life questionnaire (EORTC QLQ-C30) and breast cancer-specific quality of life questionnaire (QLQ-BR23) at treatment completion and then at first, third, and sixth-month follow-up.Results and conclusion: We had a mean follow-up of 12.78 months. All the assessed toxicities and quality of life scores were comparable between the two arms at all time points of evaluation (p>0.05); 40 Gray in 15 fractions over three weeks is feasible and as safe as the five-week schedule with comparable quality of life. Hypofractionation can be practiced as a routine for post-mastectomy breast cancer patients as this shorter radiotherapy schedule is convenient and cheaper for the patients with no compromise on normal tissue toxicity or quality of life.

Abstract TP234: Delayed Administration Of A Repurposed Drug With Sigma 1 Receptor Activity Improves Stroke Outcomes In Male Rats

Sigma-1 receptor ligands including agonists and antagonists have been shown to improve outcomes from experimental stroke when administered at delayed time points. However, clinical trials for one such agonist, cutamesine, failed to demonstrate benefit. In the present study, we sought to identify approved drugs that could be repurposed for Sigma-1 activity and the delayed treatment of stroke. High-throughput screening was used to identify Sigma-1 receptor selective binding and stimulation of brain-derived neurotrophic factor (BDNF) release for several potential ligands that are already approved for other indications. Two lead compounds, promethazine (an antihistamine) and oxeladin (a cough suppressant), were advance to in vivo studies. Both compounds displayed favorable oral absorption into the brain and high dose tolerance in rats. Neither compound significantly altered thrombosis in an in vitro blood coagulation assay. Daily oral administration of oxeladin (3 doses) or vehicle was started 48 hours after 90-minute transient middle cerebral artery occlusion in adult male Sprague-Dawley rats (n=12/group) and continued for 10 days in a treatment-blind manner. Rats receiving the two highest doses showed significant (P&lt;0.05, 2-way ANOVA and Dunnett’s test) improvements in Bederson scores (0.4±0.1 vs 1.5±0.2), an 11 point Neurological assessment (1.2±0.1 vs 3.9±0.2) , and the elevated body swing test (60% vs 90% bias) 1, 4, and 10 days after dosing compared to vehicle controls. A subset of rats was administered BrdU (50 mg/kg ip) every other day. However, there were no significant differences among groups in BrdU incorporation observed in the subventricular zone at 14 days after stroke. Additional studies are being performed to assess the mechanisms of neuroprotection. These data suggest that repurposing of approved/safe drugs with Sigma-1 receptor activity is a promising avenue for the treatment of chronic stroke.

Tumor suppression, dose-limiting toxicity and wellbeing with the fetal estrogen estetrol in patients with advanced breast cancer

PurposeThe aim of this study (the ABCE4 study) was to assess dose-limiting toxicity (DLT), safety, tolerability and preliminary efficacy of high doses of the fetal estrogen estetrol (E4) in postmenopausal patients with heavily pretreated, locally advanced and/or metastatic ER+/HER2−breast cancer, resistant to anti-estrogens.MethodsThis was a multicenter, open-label, phase IB/IIA, dose-escalation study with a 3 + 3 cohort design, whereby successive cohorts of three patients received 20 mg, 40 mg or 60 mg E4 per day for 12 weeks by oral administration. DLTs, safety and wellbeing were evaluated after 4, 8 and 12 weeks of treatment. Anti-tumor effects were investigated by computer tomography scanning and evaluated according to RECIST criteria before and after 12 weeks of treatment. Wellbeing was judged weekly by the investigator and by quality-of-life questionnaires by the patients. In view of the small number of patients, no statistical testing was performed.ResultsAll 12 patients enrolled had progressive, heavily pre-treated advanced breast cancer. No treatment-related serious adverse events or DLTs occurred during the first 4 weeks of E4 treatment allowing the investigation of all three doses. Five of nine patients completing 12 weeks of E4 treatment showed objective anti-tumor effects and six of nine patients reported improved wellbeing.ConclusionHigh doses of estetrol seem to be safe and are well tolerated during 12 weeks of treatment without dose-limiting toxicity and with anti-tumor effects in five of nine heavily treated patients with progressive, anti-estrogen resistant, advanced breast cancer.

Identification of Potent Paracaspase MALT1 Inhibitors for Hematological Malignancies

Introduction: MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1), was identified as a translocation protein fused with cIAP2 in mucosa-associated lymphoid tissue (MALT) B cell lymphomas. MALT1, a key mediator of NF-κB signaling and the main driver of a subset of B-cell lymphomas, functions via formation of a complex with CARMA1 and BCL10 to mediate antigen receptor-induced lymphocyte activation. MALT1 has been considered as a potential therapeutic target for several non-Hodgkin B cell lymphomas as well as chronic lymphocytic leukemia (CLL). Here, we describe the discovery of novel, potent MALT1 inhibitors that result in antiproliferative effects in non-Hodgkin B-cell lymphoma cells. Results: We have identified novel small molecule MALT1 inhibitors using our proprietary physics-based Free Energy Perturbation (FEP+) modeling technology. Our compounds show potent (sub nM) inhibition of MALT1 enzymatic activity, as well as high binding affinity (sub nM) to MALT1 protein measured by Surface Plasmon Resonance (SPR). BCL10 is a binding partner of MALT1 that is cleaved by MALT1 at the C-terminus. Our inhibitors were efficacious in a target engagement assay showing prevention of BCL10 cleavage in Activated B-cell (ABC) subtype of diffuse large B cell lymphoma (DLBCL) cell lines OCI-LY3 and OCI-LY10, which are Bruton tyrosine kinase (BTK) inhibitor ibrutinib-resistant and -responsive respectively. Our compounds are potent inhibitors of IL10 secretion in both OCI-LY3 and OCI-LY10 cells, which is consistent with the inhibition of NF-κB signaling. We also examined the effect of our MALT1 inhibitors on ABC-DLBCL cell proliferation. Our inhibitors demonstrated potent anti-proliferative effects in both OCI-LY3 and OCI-LY10 cell lines, as well as synergistic effects with ibrutinib in a BTKi sensitive ABC-DLBCL cell panel. Examinations of a protease panel and off-target safety screening panel, as well as in vivo high dose tolerability study showed our compound had excellent selectivity and significant safety margin. Plasma IL10 and tumor BCL10 have been identified as robust PD markers in PK/PD studies in both OCI-LY3 and OCI-LY10 tumor bearing mice. Dose-dependent tumor growth inhibition was observed after 3 weeks of treatment in OCI-LY3 xenograft model, with efficacy also observed in combination with venetoclax. Ongoing work: We are continuing to explore the synergistic effects of our compounds with BTK inhibitors in B-cell lymphoma mouse models. Preliminary data showed potent inhibition of IL-2 secretion in Jurkat cells from our compound treatment. Additional studies are ongoing to elucidate the role of MALT1 inhibition in Treg as well as Teffector cells in vitro and in vivo. Refinement of the current inhibitor series, using co-crystal structures, is in progress in preparation for further development of optimized molecules. Conclusion and Future Plans: We have identified novel potent MALT1 protease small molecule inhibitors that are efficacious in the in vitro B-cell lymphoma cell proliferation assays and in the in vivo B-cell lymphoma xenograft model. Our data suggest that targeting MALT1 may expand therapy options for patients with selected B-cell lymphomas, such as ABC-DLBCL. Our work provided insight into the anti-tumor efficacy of our inhibitors in B-cell lymphomas as single agent, and ongoing work will continue to assess the potential combination with BTKi to overcome drug-induced resistance in patients with relapsed/refractory B-cell lymphoma. Disclosures Yin: Schrodinger: Current Employment, Current equity holder in publicly-traded company. Zhe:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Placzek:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Trzoss:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Krilov:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Feng:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Lawrenz:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Pelletier:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Lai:Triplet Therapeutics: Current Employment, Current equity holder in private company. Bell:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Calkins:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Grimes:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Tang:Schrodinger: Current Employment, Current equity holder in publicly-traded company. McRobb:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Gerasyuto:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Feher:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Mondal:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Jensen:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Wright:Schrodinger: Current Employment, Current equity holder in publicly-traded company. Akinsanya:Schrodinger: Current Employment, Current equity holder in publicly-traded company.

Patients with acute heart failure treated with the CARRESS-HF diuretic protocol in association with canrenoate potassium: Tolerance of high doses of canrenoate potassium

Oral mineralocorticoid receptor antagonists have failed to prove their efficacy for decongestion and potassium homeostasis in acute heart failure. Intravenous mineralocorticoid receptor antagonists have yet to be studied. The aim of this study was to confirm the safety of high-dose potassium canrenoate in association with classic diuretics in acute heart failure. This retrospective single-centre study included consecutive patients who were hospitalized with acute heart failure between 2013 and 2018. One hundred patients with overload treated with the standardized diuretic protocol from the CARRESS-HF trial were included. There were no exclusion criteria relating to creatinine or kalaemia at the time of admission. Two groups were constituted on the basis of potassium canrenoate posology: a low-dose group (<300mg/day) and a high-dose group (≥300mg/day); the groups were similar in terms of baseline characteristics. Mean daily potassium canrenoate doses were 198mg/day (range 100-280mg/day) in the low-dose group and 360mg/day (range 300-600mg/day) in the high-dose group. There was no significant difference between the high-dose and low-dose groups in terms of mortality, dialysis, renal function, hyperkalaemia, haemorrhage, sepsis or confusion. Potassium canrenoate at high doses can be used safely in association with standard diuretics in acute heart failure, even in patients with altered renal function. A prospective study is required to evaluate the efficacy of high-dose potassium canrenoate in preventing hypokalaemia and improving decongestion.

P1753EFFECTIVENESS AND TOLERABILITY OF 500 MG-I.V. FERRIC CARBOXYMALTOSE FOR THE TREATMENT OF IRON DEFICIENCY IN PATIENTS WITH KIDNEY TRANSPLANT

Abstract Background and Aims Post transplantation anaemia (PTA) is a common finding in kidney transplant patients, with reported prevalence ranging from 25 to 40%, and it is associated with adverse outcomes for the kidney allograft and the recipient. The pathogenesis of PTA is multifactorial, including iron deficiency, reduced graft function, untoward effects of drugs (immunosuppressants, ACE-I and ARB), folic acid and vitamin B12 deficiency, inflammatory states. Ferric carboxymaltose (FCM) reportedly improved haemoglobin (Hb) levels and replenished depleted iron stores in various populations of patients with iron-deficiency anaemia, but there are few data about its use in PTA. In this study we evaluated the effectiveness and tolerability of high intravenous doses of FCM (500 mg) for the treatment of iron deficiency and anaemia in patients with kidney transplant. Method Absolute iron deficiency was considered as transferrin saturation (TSAT) less than 20% with ferritin levels below 100 µg/L. Anaemia was defined as Hb&amp;lt;13 g/dL in males and Hb&amp;lt;12 g/dL in females. Out of 101 patients with kidney transplant, 56 presented with absolute iron deficiency (59±13 years old, M/F=0.95, 8±4.6 years of transplantation; serum creatinine 1.45±0.64 mg/dL): of these, 40 patients had anaemia (7 were also taking ESAs) and 16 had normal Hb levels. The 16 patients with absolute iron deficiency and normal Hb were not prescribed iron supplements, fearing of causing erythrocytosis, whereas 36 of 40 patients with anaemia and iron deficiency were given FCM 500 mg, as i.v. infusion for 30 minutes. Hb, ferritin and TSAT were assayed either before and 45-60 days after FCM supplementation, which was repeated if Hb levels were less than 0.5 g/dL below the normal value. Data were reported as mean±SD. Results Among the 56 patients with absolute iron deficiency, there were not any significant differences in serum levels of folic acid and vitamin B12 between those with and without anaemia (p=ns). After the first dose of FCM, in 36 patients with iron deficiency and anaemia, ferritin levels increased from 55±69 ng/mL to 111±107 ng/mL (p&amp;lt;0.01), TSAT increased from 12.2±5.9% to 20.4±10.3% (p&amp;lt;0.01) and Hb increased from 10.9±0.9 g/dL to 12.3±1.3 g/dL (p&amp;lt;0.01). Furthermore, 24/36 patients (67%) no longer had absolute iron deficiency and 19/36 (53%) were not anaemic anymore. Out of the 17 patients still showing anaemia after the first FCM dose, 10 had Hb levels less than 0.5 g/dL below the normal value and were given a second dose of FCM. In this subset, Hb level increased on average from 11.4±0.5 g/dL to 12±0.9 g/dL (p&amp;lt;0.01) and became normal in 3 patients. After the FCM course, in 2 out of 7 patients ESAs were discontinued, whereas in 3 patients their doses were reduced and in 2 patients remained unchanged. Only one patient had an adverse effect during FCM infusion, namely, a transient skin flushing on her face during the second dose, which immediately remitted when the infusion was interrupted. Conclusion In patients with PTA and absolute iron deficiency, single or repeated doses of 500 mg of i.v. FCM were effective in improving Hb levels, well tolerated and reduced the need for ESAs. Of 56 patients with kidney transplant and absolute iron deficiency, 16 (28%) had normal Hb levels. We did not treat such subjects, fearing of causing erythrocytosis. However, given that iron deficiency may affect negatively both heart and muscle metabolism, what is the best management of iron deficiency in transplanted patients without anaemia is still an open question.

New regulations regarding e-prescriptions may increase the risk of acute withdrawal syndromes in patients dependent on benzodiazepines or non-benzodiazepine hypnotics.

The implementation of solutions in the area of e-health and use of electronically issued prescription obligations meets the modern requirements of the healthcare system. Adigital record of theissued prescriptions aims atpreventing prescriptions from being traded without a physician's name in patient medical records. Access to the system may in turn reveal doctors' bad practices, and fear of the professional and legal consequences may force achange in the prescription of benzodiazepines or non-benzodiazepine hypnotics. The effect of these activities may be the disclosure of many cases of 'hidden' dependence and adverse phenomena and increase in the number of effects of cases of sudden dose reduction or discontinuation of benzodiazepines or non-benzodiazepine hypnotics. It is recommended to develop integrated, central information and train Emergency Department staff. Awareness of the phenomenon and appropriate diagnostic and therapeutic procedures can significantly increase the chance of improving the quality and safety of services provided in the acute intervention mode (Emergency Department). Arational solution may be to urgently develop standards of conduct in cases of acute withdrawal syndromes from benzodiazepines or non-benzodiazepine hypnotics. Itseems reasonable to introduce preventative programs enabling early recognition and treatment of cases where large and very large doses of drugs have been taken (high dose tolerance). Under no circumstances should medication be stopped abruptly. An information campaign, raising awareness also among the personnel of psychiatric wards, may increase the chances of systemic preparation for admission of the currently unknown population of patients at risk.

Effect of physostigmine on recovery from septic shock following intra-abdominal infection – Results from a randomized, double-blind, placebo-controlled, monocentric pilot trial (Anticholium® per Se)

PurposeThe cholinergic anti-inflammatory pathway has been shown to be accessible by physostigmine salicylate in animal models. However, the cholinesterase inhibitor is not approved for adjunctive therapy in sepsis, and tolerability and safety of high initial doses followed by continuous infusion have not been investigated. Materials and methodsIn this trial, 20 patients with perioperative septic shock due to intra-abdominal infection were eligible. The physostigmine group received an initial dose of 0.04 mg/kg physostigmine salicylate, followed by continuous infusion of 1 mg/h for 120 h; the placebo group was treated with 0.9% sodium chloride. Primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score during treatment and up to 14 days. ResultsAdministration of physostigmine salicylate was well tolerated. Mean SOFA scores were 8.9 ± 2.5 and 11.3 ± 3.6 (mean ± SD) for physostigmine and placebo group, respectively. Adjusted for age, difference between means was not statistically significant (−2.37, 95% CI: −5.43 to 0.70, p = 0.121). Norepinephrine doses required only appeared lower in the physostigmine group (p = 0.064), along with a more rapid reduction from an elevated heart rate possibly indicating less hemodynamic instability. ConclusionsTreatment with physostigmine salicylate was feasible and safe. Further studies are justified to assess the effect on recovery from septic shock. Trial registrationEudraCT Number 2012-001650-26, ClinicalTrials.gov identifier NCT03013322.

Redox Responsive Polymersomes for Enhanced Doxorubicin Delivery.

In the present investigation, the potential of a novel, self-assembled, biocompatible, and redox-sensitive copolymer system with disulfide bond was explored for doxorubicin (DOX) delivery through polymersome nanostructures of ∼120 nm. The polymer system was synthesized with less steps, providing a high yield of 86%. The developed polymersomes showed admirable biocompatibility with high dose tolerability in vitro and in vivo. The colloidal stability of DOX-loaded polymersomes depicted a stable and uniform particle size over a period of 72 h. The cellular internalization of polymersomes was assessed in HeLa and MDA-MB-231 cell lines, where enhanced cellular internalization was observed. The dose-dependent cytotoxicity was observed for DOX-loaded polymersomes by MTT cytotoxicity assay in the above cell lines. The tumor suppression studies were assessed in Ehrlich ascites tumor (EAT) carrying Swiss albino mice, where polymersomes exhibited a 7.16-fold reduction in tumor volume correlated with control and 5.39-fold higher tumor inhibition capacity compared to conventional chemotherapy (free DOX treatment). The developed polymersomes gave safer insights concerning DOX associated toxicities by histopathology and serum biochemistry analysis. Thus, results focus on the potential of redox responsive polymersomes for efficacious and improved DOX therapy with enhanced antitumor activity and insignificant cardiotoxicity which can be translated to clinical settings.

Use of high doses of the methotrexate in children suffering from some form of cancer: specificities of the accompanying therapy, assessing the toxicity

Introduction. Methotrexate (MTX) is one of the most commonly used anti-tumor preparations which confirm it effectiveness against the large spectrum of the oncological diseases in children. Today the use of high doses of the MTX (g/m2 ) in the monotherapy or in combination with other chemotherapeutic agent is a standard of treatment of such nosology as osteosarcoma, tumors of the central nervous system (CNS), lymphomas, acute lymphoblastic leukemia. Despite of the developed recommendations on the fluid therapy, therapeutic monitoring, use of leukovorin which allowed to reduce the expected toxicity among some patients it is not always possible to prevent the development of complications. Ex post evaluation of different doses of schedule of the high-dose MTX is necessary in order to formulate new and effective treatment strategies with respect to the individual specifics of the patients. Materials and methods . During the period from October 2015 to February 2018, a patient cohort (n = 26) who received high-dose MTX therapy with the following nosology: osteosarcoma – 4, hemoblastosis – 11, and CNS – 11 tumors was evaluated. The average age of the patients was 7.3 years old; ratio of boys:girls – 2.25: 1. The used doses were ranged from 1 to 12 g/m 2 , the doses schedules ranged from 4 to 36 hours; the total number of courses during the observation period was 94; the average number of courses per patient was 3. In all cases, the level of MTX in the blood serum was monitored with correction of the dose of leucovorin according to international recommendations. Estimated toxicity parameters were the following: allergic reactions, skin and mucous membrane damage, neurologic disorders, myelosuppression, hepatic transaminase and creatinine growth. Results. Transitory toxicity was noted for 100 % of patients, of which clinically significant was in 62.7 % of cases. The development of complications that had required the use of antibacterial and blood transfusion therapy occurred after 36 courses of therapy (38.2 %), of wich in 24 cases (66.6 %) MTX was performed in combination with other antitumor agents. No cases of acute kidney injury were presented, there was no significant difference in creatinine level before and after high-dose MTX courses. The highest frequency of episodes of hepatotoxicity was noted in the group of patients diagnosed with “osteosarcoma”. After reduction the episodes of toxicity with the use of high-dose MTX, all patients continued programmed chemotherapy. Conclusions. Against the background of an adequate accompanying therapy (infusion therapy with alkalization of urine, pharmacodynamic monitoring, correction of the leucovorin dose), it is possible to achieve satisfactory tolerability of high doses of MTX. The combination of high doses of MTX with other antitumor drugs leads to a significant increase in the toxicity. Despite of the noted complications of therapy, continuation of treatment with the use of previous doses of MTX (does not require reduction) is possible, and a decrease in the rate of MTX removal is not always a predictor of episodes of the toxicity.