Low-dose Regimen Research Articles

Efficacy and Safety of Low-Dose Protamine in Reducing Bleeding Complications during TAVI: A Propensity-Matched Comparison

Objectives: We aimed to evaluate the efficacy and safety of low-dose protamine in reducing access site-related complications during Transcatheter Aortic Valve Implantation (TAVI) as compared to full-dose protamine. Background: Access site-related complications represent an independent predictor of poor outcomes of TAVI. Data regarding heparin reversal with protamine and the dosage needed to prevent bleeding complications are scarce among patients undergoing TAVI. Methods: A total of 897 patients were retrospectively included in the study. Patients who underwent percutaneous coronary intervention within 4 weeks before or concomitantly with TAVI (n = 191) were given 0.5 mg protamine for each 100 units of unfractionated heparin. All other patients (n = 706) were considered as a control group and 1 mg protamine for each 100 units of heparin was administered. Results: The combined intra-hospital endpoint of death, life-threatening major bleeding, and major vascular complications were significantly more frequent in patients receiving low-dose protamine [29 (15.2%) vs. 50 (7.1%), p < 0.001]. After propensity matching (n = 130 for each group) for relevant clinical characteristics including anti-platelet therapy [19 (14.6%) vs. 6 (4.6%), p = 0.006], low-dose protamine predicted the combined endpoint (OR 3.54, 95%-CI 1.36–9.17, p = 0.009), and even in multivariable analysis, low-dose protamine continued to be a predictor of the combined endpoint in the matched model (OR 3.07, 95%-CI 1.17–8.08, p = 0.023) alongside baseline hemoglobin. Conclusions: In this propensity-matched retrospective analysis, a low-dose protamine regime is associated with a higher rate of major adverse events compared to a full-dose protamine regime following transfemoral TAVI.

P-661 Therapeutic management in women with a diminished ovarian reserve (DOR): a systematic review and meta-analysis of randomized control trials

Abstract Study question Unlike previous reviews, our meta-analysis investigated protocols involving only women with diminished ovarian reserve (DOR) identified by antral follicle count and/or AMH (POSEIDON criteria). Summary answer Testosterone, GH and delayed antagonist starting protocol are associated with better IVF outcomes comparing with respective control groups. What is known already The clinical management of women with diminished ovarian reserve (DOR) is a challenge in the field of medically assisted reproduction. Several therapeutic strategies have been proposed, however, with mixed results. This issue is probably linked to the fact that the definition of diminished ovarian reserve used was inconsistent among trials. The POSEIDON criteria define women with DOR, based on antral follicle count and levels of antimullerian hormone (AFC <5 or AMH <1.2 ng/ml). Study design, size, duration We conducted a systematic search using the MEDLINE, EMBASE, and ISI WEB OF KNOWLEDGE, to identify relevant studies published up to July 2022. The reference lists were also hand-searched to implement the systematic search. We selected only RCTs in which the study population was affected by DOR with basal levels of AMH and AFC consistent with Poseidon criteria. The primary outcome was live birth rate or ongoing pregnancy when data on live birth was unavailable. Participants/materials, setting, methods A total of 14,386 articles were identified through the search, and duplications were removed using the EndNote library and manually (n = 6,945). The titles and abstracts of 7,441 articles were scrutinized, and 117 full-text articles were assessed for eligibility. In total, forty-seven RCTs were included. The following interventions were evaluated: DHEA, testosterone; GH high versus low gonadotropin dose regimen, delayed started protocol, letrozole, clomiphene citrate, luteal phase stimulation, dual triggering, LH supplementation, corifollitropin alfa. Main results and the role of chance Testosterone, high-dose gonadotropin regimen, and delayed antagonist starting protocol significantly improved the total number of eggs collected. In addition, GH and delayed starting protocol significantly increased the number of metaphase II oocytes. Testosterone, GH, and delayed antagonist starting protocol were associated with improved clinical pregnancy rates among all interventions evaluated. Testosterone and GH were also associated with higher live birth rates comparing with no supplemented women. Limitations, reasons for caution The main limitation of the present review relates to the minimal number of studies reporting live birth rates. Another relevant issue is the heterogeneity in women involved and the IVF protocols' diversity. More trials are demanding to corroborate our findings. Wider implications of the findings Our study's results might help clinicians to identify the most appropriate approach to managing women with DOR. Furthermore, our findings may stimulate researchers to develop more specific trials centred on specific categories of low-prognosis women, for example, those with a standardized diagnosis of DOR. Trial registration number The review protocol was registered at http://www.crd.york.ac.uk/PROSPERO/ (registration number CRD42022346117O).

Leveraging CD16 fusion receptors to remodel the immune response for enhancing anti-tumor immunotherapy in iPSC-derived NK cells

BackgroundThe cytotoxicity of NK cells is largely dependent on IgG Fc receptor CD16a, which mediates antibody-dependent cell-mediated cytotoxicity (ADCC). The high-affinity and non-cleavable CD16 (hnCD16) is developed and demonstrated a multi-tumor killing potential. However, the hnCD16 receptor activates a single CD16 signal and provides limited tumor suppression. How to exploit the properties of hnCD16 and incorporate NK cell-specific activation domains is a promising development direction to further improve the anti-tumor activity of NK cells.MethodsTo expand the applications of hnCD16-mediated ADCC for NK cell-based immunotherapy in cancer, we designed the hnCD16 Fusion Receptor (FR) constructs with the ectodomain of hnCD16 fused with NK cell-specific activating domains in the cytoplasm. FR constructs were transduced into CD16-negative NK cell line and human iPSC-derived NK (iNK) cells and effective FR constructs were screened. The up-regulation of immune activation- and cytokine-releasing-related pathways in FR-transduced NK cells was screened and validated by RNA sequencing and multiplex cytokines release assay, respectively. The tumor-killing efficiency was tested in vitro and in vivo via co-culture with tumor cell lines and xenograft mice-bearing human B-cell lymphoma, respectively.ResultsWe screened the most effective combination to kill B cell lymphoma, which was fused with the ectodomain of hnCD16a, NK-specific co-stimulators (2B4 and DAP10) and CD3ζ in cytoplasmic domains. The screened construct showed excellent cytotoxicity effects and sharp multiple cytokines releasing both in the NK cell line and iNK cells. The transcriptomic analysis and validation assays of hnCD16- and hnCD16FR-transduced NK cells showed that hnCD16FR transduction remodeled immune-related transcriptome in NK cells, where significant upregulation of genes related to cytotoxicity, high cytokines releasing, induced tumor cell apoptosis, and ADCC in comparison with hnCD16 transduction were highlighted. In vivo xenograft studies demonstrated that a single low-dose regimen of engineered hnCD16FR iPSC-derived NK cells co-administered with anti-CD20 mAb treatment mediated potent activity and significantly improved survival.ConclusionWe developed a novel hnCD16FR construct that exhibits more potent cytotoxicity than reported hnCD16, which is a promising approach to treat malignancies with improved ADCC properties. We also offer a rationale for NK activation domains that remodel immune response to enhance CD16 signaling in NK cells.

#5801 EXTENDED LOW DOSE RITUXIMAB REGIMEN FOR THE TREATMENT OF ADULT PATIENTS WITH STEROID-DEPENDENT AND FREQUENTLY RELAPSING MINIMAL CHANGE DISEASE

Abstract Background and Aims Patients with frequently relapsing and steroid-dependent minimal change disease (MCD) imply a therapeutic challenge for nephrologists. The use of steroid sparing agents such as cyclosporine, rituximab and mycophenolate, allows minimization of steroids exposure among these patients. In children and adults, Rituximab has demonstrated safety and efficacy in some studies although there is no established treatment regimen. This study aims to demonstrate that a low dose extended regimen of rituximab is an effective alternative for preventing relapses among these patients. Method This is a single-centre retrospective descriptive study of a case series of adult MCD patients from Ramón y Cajal’ Hospital in Madrid, Spain. Since 2019, patients with steroids-dependent or frequently relapsing MCD were treated with a low dose extended protocol of Rituximab as follows; 500 mg of rituximab once remission is achieved with steroid therapy, and four additional doses at month +6, +18 and +30 during the follow-up. Relapse free survival was analyzed after rituximab therapy. Results Eight patients with a median age of 42 years (22–70 years) who received at least one dose of intravenous rituximab were included. Four of the patients (50%) had previously received additional immunosuppressive regimens (including cyclophosphamide, chlorambucil cyclosporine, mycophenolate or ACTH). Two of them (25%) had frequent relapses and the remaining six (75%) had steroid-dependent behaviour. After a median of 2 years (IQR, 1,4-3,3) of follow-up, 6 out of 8 (75%) patients stayed under remission, experiencing the remaining two one relapse at one month and at one year, respectively, after the first rituximab dose. Comparing relapses during the two years-period before and after rituximab use, the median relapse rate per patient dropped from 2.8 (IQR, 2-4) to 0.5 (IQR, 0-1; P = 0.001) (Fig. 1). No patient experienced rituximab related side effects nor infections during the study period. Conclusion In MCD patients, the administration of rituximab in an extended low-dose regimen as corticosteroid-sparing therapy appears to be safe and effective in most of the patients for preventing relapses. This regimen allows minimization exposure to rituximab as well as disease remission during a longer period of time.

Inability of Dirofilaria immitis infective larvae from mosquitoes fed on blood from microfilaremic dogs during low-dose and short-treatment regimens of doxycycline and ivermectin to complete normal development in heartworm naïve dogs

BackgroundThis study was conducted to determine whether heartworm infective larvae (L3) collected from mosquitoes fed on dogs during low-dose, short-treatment-regimen doxycycline and ivermectin could develop normally in dogs.MethodsTwelve Beagles in a separate study were infected with 10 pairs of adult male and female Dirofilaria immitis by IV transplantation and randomly allocated to three groups of four dogs. Starting on Day 0, Group 1 received doxycycline orally at 10 mg/kg sid for 30 days plus ivermectin (min., 6 mcg/kg) on Days 0 and 30; Group 2 received doxycycline orally at 10 mg/kg sid until individual dogs became microfilaria negative (72–98 doses) and ivermectin every other week for six to seven doses. These dogs served as microfilaremic blood donors for the current mosquito studies.Aedes aegypti were allowed to feed on group-pooled blood samples from treated Groups 1-M and 2-M and untreated control Group 3-M on Days 22 (Study M-A) and 42 (Study M-C) and from Groups 1-M and 2-M on Day 29 (Study M-B) after treatment was started. From the Day 22 mosquito feeding, two dogs in Groups 1-M and 2-M and one dog in Group 3-M were given 50 L3 by SC inoculation. From the Day 29 feeding, two dogs in Groups 1-M and 2-M were given 50 L3. From the Day 42 feeding, two dogs in Group 1-M received 30 L3, while two dogs in Group 2-M and one dog in Group 3-M received 40 L3. All 14 dogs were necropsied for recovery and enumeration of adult heartworms 163–183 days PI.ResultsNone of the 12 dogs that received L3 from mosquitoes fed on blood from treated dogs 22, 29 or 42 days after treatment started had any adult heartworms at necropsy, while the two control dogs had a total of 26 and 43 heartworms, respectively.ConclusionsTreatment of microfilaremic dogs with doxycycline plus an ML, which later renders the L3 incapable of normal development in the animal host, widens the scope of the multimodal approach to heartworm prevention in reducing the spread of heartworm disease.Graphical

Long-term evaluation of viability of microfilariae and intravenously transplanted adult Dirofilaria immitis in microfilaremic dogs treated with low-dose, short- and long-treatment regimens of doxycycline and ivermectin

BackgroundMicrofilarial (mf) counts were monitored over 21.3 months for any rebound that might occur in counts, and adulticidal efficacy was assessed following administration of low dosage with short- and long-treatment regimens of doxycycline and ivermectin to heartworm-microfilaremic dogs.MethodsTwelve heartworm-naïve beagles infected with 10 pairs of adult Dirofilaria immitis by intravenous transplantation were randomly allocated to three groups of four dogs. All treatments started on day 0. On day 0, Group 1 (short-treatment regimen) received doxycycline orally at 10 mg/kg once daily for 30 days plus ivermectin orally (minimum, 6 mcg/kg) on days 0 and 30. Group 2 (long-treatment regimen) received doxycycline orally at 10 mg/kg once daily until individual dogs became mf-negative (72–98 days) and ivermectin every other week until individual dogs became mf-negative (6–7 doses). Group 3 was the untreated control. Mf counts and antigen (Ag) tests were conducted. Dogs were necropsied for recovery and enumeration of heartworms on day 647.ResultsDay −1 mean mf counts were 15,613, 23,950, and 15,513 mf/ml for groups 1, 2, and 3, respectively. Mean counts for Groups 1 and 2 declined until days 239 and 97, respectively, when all were negative. Group 3 had high mf counts throughout the study. There was not a rebound in mf counts in any of the treated dogs after they became amicrofilaremic. All dogs in group 1 and group 3 were Ag-positive throughout the study and had at least one live female worm at necropsy. All dogs in treated Group 2 were positive for Ag through day 154, but were antigen-negative on days 644 and 647, as all had only male worms. Mean live adult worm recoveries for Groups 1, 2, and 3 were 6.8 (range, 5–8), 3.3 (range, 1–6), and 16.0 (range, 14–17), respectively, with a percent reduction in adult worm counts of 57.5% for Group 1 and 79.3% for Group 2.ConclusionsThese data lend support to the use of the American Heartworm Society Canine Guidelines for adulticide therapy recommending the initiation of doxycycline plus a macrocyclic lactone (ML) at the time of the heartworm-positive diagnosis.Graphical

Computational simulations of tumor growth and treatment response: Benefits of high-frequency, low-dose drug regimens and concurrent vascular normalization.

Implementation of effective cancer treatment strategies requires consideration of how the spatiotemporal heterogeneities within the tumor microenvironment (TME) influence tumor progression and treatment response. Here, we developed a multi-scale three-dimensional mathematical model of the TME to simulate tumor growth and angiogenesis and then employed the model to evaluate an array of single and combination therapy approaches. Treatments included maximum tolerated dose or metronomic (i.e., frequent low doses) scheduling of anti-cancer drugs combined with anti-angiogenic therapy. The results show that metronomic therapy normalizes the tumor vasculature to improve drug delivery, modulates cancer metabolism, decreases interstitial fluid pressure and decreases cancer cell invasion. Further, we find that combining an anti-cancer drug with anti-angiogenic treatment enhances tumor killing and reduces drug accumulation in normal tissues. We also show that combined anti-angiogenic and anti-cancer drugs can decrease cancer invasiveness and normalize the cancer metabolic microenvironment leading to reduced hypoxia and hypoglycemia. Our model simulations suggest that vessel normalization combined with metronomic cytotoxic therapy has beneficial effects by enhancing tumor killing and limiting normal tissue toxicity.

Population Pharmacokinetics of Total Rabbit Anti-thymocyte Globulin in Non-obese Adult Patients Undergoing Hematopoietic Cell Transplantation for Hematologic Malignancy.

Rabbit anti-thymocyte globulin (rATG), a therapeutic polyclonal antibody against human T cells, is commonly used in conditioning therapy prior to allogeneic hematopoietic cell transplantation (HCT). Previous studies successfully developed an individualized rATG dosing regimen based on "active" rATG population PK (popPK) analysis, while "total" rATG can be a more logistically favorable alternative for early HCT outcomes. We conducted a novel popPK analysis of total rATG. Total rATG concentration was measured in adult human-leukocyte antigen (HLA) mismatched HCT patients who received a low-dose rATG regimen (total 2.5-3mg/kg) within 3days prior to HCT. PopPK modeling and simulation was performed using nonlinear mixed effect modeling approach. A total of 504 rATG concentrations were available from 105 non-obese patients with hematologic malignancy (median age 47years) treated in Japan. The majority had acute leukemia or malignant lymphoma (94%). Total rATG PK was described by a two-compartment linear model. Influential covariate relations include ideal body weight [positively on both clearance (CL) and central volume of distribution], baseline serum albumin (negatively on CL), CD4+ T cell dose (positively on CL), and baseline serum IgG (positively on CL). Simulated covariate effects predicted that early total rATG exposures were affected by ideal body weight. This novel popPK model described the PK of total rATG in the adult HCT patients who received a low-dose rATG conditioning regimen. This model can be used for model-informed precision dosing in the settings with minimal baseline rATG targets (T cells), and early clinical outcomes are of interest.

All-oral low-dose chemotherapy TEPIP is effective and well-tolerated in patients with peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is a rare and heterogenous hematologic malignancy with poor prognosis especially in elderly and frail patients who are not eligible for intensive treatment. The resulting palliative setting necessitates tolerable but effective schedules for outpatient treatment. TEPIP is a locally developed, all-oral low-dose regimen comprising trofosfamide, etoposide, procarbazine, idarubicin, and prednisolone. In this observational retrospective, single-center study, the safety and efficacy of TEPIP was evaluated in 12 patients (pts.) with PTCL treated at the University Medical Center Regensburg between 2010 and 2022. The endpoints were overall response rate (ORR) and overall survival (OS), and adverse events were individually reported according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria. The enrolled cohort was characterized by advanced age (median 70 years), extensive disease (100% Ann Arbor ≥stage 3), and poor prognosis (75% high/high-intermediate international prognostic index). The most common subtype was angioimmunoblastic T-cell lymphoma (8/12), and 11/12 patients had relapsed or refractory disease at TEPIP onset with a median of 1.5 prior treatment regimens. After a median of 2.5 TEPIP cycles (total of 83 cycles), the ORR was 42% (complete remission 25%), and the OS reached a median of 185 days. Any grade of adverse event (AE) occurred in 8/12 patients, with four patients showing AE ≥CTCAE grade 3 (33%), and the AEs were mainly non-hematological. TEPIP demonstrated competitive efficacy with a tolerable safety profile in a highly palliative cohort of patients with difficult-to-treat PTCL. The all-oral application, which makes outpatient treatment possible, is particularly noteworthy.

Carbetocin Versus Oxytocin at Elective Caesarean Delivery: A Double-blind, Randomized, Controlled, Noninferiority Trial of Low-dose and High-dose Regimens

(Anaesthesia. 2022;77:892–900) Oxytocin and carbetocin are both uterotonics, and are recommended for prophylactically combatting postpartum uterine atony. They are currently used at high doses but some advocate for lower doses that would carry less risk for adverse effects. This double-blind, randomized, controlled non-inferiority study compared carbetocin and oxytocin at low and high doses during elective cesarean delivery (CD).

Low-Dose Bevacizumab for the Treatment of Focal Radiation Necrosis of the Brain (fRNB): A Single-Center Case Series.

Focal radiation necrosis of the brain (fRNB) is a late adverse event that can occur following the treatment of benign or malignant brain lesions with stereotactic radiation therapy (SRT) or stereotactic radiosurgery (SRS). Recent studies have shown that the incidence of fRNB is higher in cancer patients who received immune checkpoint inhibitors. The use of bevacizumab (BEV), a monoclonal antibody that targets the vascular endothelial growth factor (VEGF), is an effective treatment for fRNB when given at a dose of 5-7.5 mg/kg every two weeks. In this single-center retrospective case series, we investigated the effectiveness of a low-dose regimen of BEV (400 mg loading dose followed by 100 mg every 4 weeks) in patients diagnosed with fRNB. A total of 13 patients were included in the study; twelve of them experienced improvement in their existing clinical symptoms, and all patients had a decrease in the volume of edema on MRI scans. No clinically significant treatment-related adverse effects were observed. Our preliminary findings suggest that this fixed low-dose regimen of BEV can be a well-tolerated and cost-effective alternative treatment option for patients diagnosed with fRNB, and it is deserving of further investigation.

A systematic review of isotretinoin dosing in acne vulgaris

AbstractHow does low‐dose oral isotretinoin compare with recommended and high‐dose oral isotretinoin in terms of efficacy, adverse effect profile, duration of remission, economic profile and rate and severity of relapse? A systematic literature search of EMBASE, MEDLINE, PubMed and The Cochrane Library from 1983 to July 2022 was conducted to identify randomised control trials (RCTs), cohort studies and cross‐sectional studies investigating the treatment of acne vulgaris with oral isotretinoin. This systematic review of the literature sought to explore and compare the use of different isotretinoin dosing regimens. Primary outcomes were efficacy, relapse, and safety profiles of oral isotretinoin of varying doses. Secondary outcomes included adverse events and economic considerations. The quality of studies, including risk of bias was assessed using GRADE (Grading of Recommendations, Assessment, Development and Evaluations). A total of 32 studies were included. Severe acne responds better to conventional or high fixed daily doses of isotretinoin. In cases of mild to moderate acne, where oral isotretinoin was prescribed, clearance rates were comparable with low, conventional or high dosage regimens. Despite this, relapse was more frequent in those treated with a lower dose. The severity of mucocutaneous adverse effects worsens as the dose of isotretinoin is increased. Comparison between studies was challenging due to differing methods of assessment, outcome measures and duration of follow‐up. This review highlights the need for an adequately powered RCT comparing low, conventional and high doses of oral isotretinoin to establish optimal dosing for treatment and prevention of relapse in acne vulgaris.

Efficacy of low-dose rituximab in minimal change disease and prevention of relapse

BackgroundMinimal change disease (MCD) is a major cause of nephrotic syndrome (NS) in children and a minority of adults. The higher tendency to relapse put patients at risk for prolonged exposure to steroids and other immunosuppressive agents. B cell depletion with rituximab (RTX) may be beneficial to the treatment and prevention of frequently relapsing MCD. Therefore, this study aimed to verify the therapeutic/preventive effects of low-dose RTX on the relapse in adult with MCD.MethodsA total of 33 adult patients were selected for the study, including 22 patients with relapsing MCD in relapse treatment group who were treated with low-dose RTX (200 mg per week × 4 following by 200 mg every 6 months) and 11 patients in relapse prevention group with complete remission (CR) after steroid therapy were treated with RTX (200 mg ×1 every 6 months) for preventing the relapse of MCD.ResultsOf the 22 patients with MCD in relapse treatment group, there were 21 cases (95.45%) of remission [2 (9.09%) partial remission (PR), 19 (86.36%) CR], 1 (4.56%) no remission (NR) and 20 (90.90%) relapse-free. The Median duration of sustained remission was 16.3 months (3, 23.5 months, inter quartile range (IQR)). 11 patients in the relapse prevention group during a follow-up of 12 months (9–31 months) had no relapse. The average dose of prednisone in two groups after RTX treatment was significantly lower than before treatment.ConclusionThe results of this study suggested low-dose RTX can significantly reduce relapse rate and steroid dose in adults with MCD with fewer side effects. Low-dose RTX regimens may be beneficial for the treatment of relapsing MCD in adults and may be the preferred regimen for patients at high risk for the development of adverse events from corticosteroids.

The impact of intraoperative frozen section in patients with clinically node-negative breast cancer (cN0/ycN0) who received neoadjuvant systemic therapy

BackgroundWhen surgical axillary staging reveals residual metastatic deposits in breast cancer (BC) patients who had received neoadjuvant chemotherapy (NACT), axillary lymphonodectomy is indicated. In this study, we investigate whether it is reasonable to perform intraoperative frozen section (FS) of the removed sentinel lymph nodes (SLNs) in cases where NACT had been administered in patients who had a clinically negative nodal status at the time of diagnosis. Patients and methodsWe analyzed data from 101 BCE patients with 103 carcinomas who were diagnosed between 2014 and 2021 and met the above-mentioned criteria. ResultsIn three cases (2.8% of the study group), histologically active tumor tissue was detected in the removed axillary LNs. Discontinuation of therapy/the use of a low-dose NACT regimen was a significant factor for positive LNs (p = 0.02) at the subsequent surgical procedure; tumor progression during therapy approached borderline significance (p = 0.058).Among patients who had completed NACT with the planned standard dose regimen, and in which the primary tumors showed a response to therapy (n = 94), only one case had histologically detected residual metastases in the SLNs. ConclusionsCertified breast centers aim to improve the outcome of the patients. However, these specialized centers should also focus on economic aspects. This means that diagnostic and therapeutic procedures should be continuously critically reviewed in order to avoid unnecessary expenses. In BC patients with clinically node negative disease who completed NACT as planned and in which the tumor showed a good response to therapy, time consuming and costly FS of the SLNs removed should be omitted.

Physiologically-based pharmacokinetic modelling to predict intragastric rifabutin concentrations in the treatment of Helicobacter pylori infection.

Sustained intragastric antibiotic exposure is important for Helicobacter pylori eradication, yet little is known about gastric pharmacology of commonly used H. pylori regimens. For rifabutin, differing intragastric concentrations based on dosing regimen may account for differences in reported eradication rates. To compare intragastric rifabutin concentrations between low-dose rifabutin (50 mg three time daily; as in RHB-105) and generically dosed rifabutin 150 mg once daily, 150 mg twice daily, and 300 mg once daily using a validated Physiologically-based pharmacokinetic (PBPK) model. We obtained plasma pharmacokinetic data from the RHB-105 clinical development programs and used it to develop and validate a whole-body PBPK model using PK-SIM software. We modified the existing rifabutin model to include the impact of omeprazole on gastric pH and emptying time. Modelled intragastric rifabutin exposure was expressed as the time that each regimen maintained its concentration ≥MIC90 . Rifabutin 50 mg three times daily achieved significantly longer times with intragastric concentration above MIC90 (22.3 ± 1.1 h) than 150 mg once daily (8.3 ± 1.7 h), 150 mg twice daily (16.3 ± 2.3 h), or 300 mg once daily (8.5 ± 1.9 h) while providing the lowest mean maximal plasma concentration and mean area under the plasma concentration-time curve of all regimens studied. PBPK modelling showed rifabutin 50 mg three times daily had higher intragastric exposure times than 150 mg once daily or twice daily, or 300 mg once daily. This low-dose rifabutin regimen provides the highest potential for H. pylori eradication while minimising systemic rifabutin exposure.

Abstract 1661: Heart-sparing ALK5 inhibitor for treatment of gastrointestinal and liver cancers

Abstract Transforming growth factor beta (TGFβ) signaling has been implicated in many cancers and fibrotic diseases. Recent pharmacological intervention has shown promising activities in preclinical models and early clinical trials. There are over 15 investigational agents targeting this pathway currently in the clinic, but none have been approved. In particular, small molecule TGFβ inhibitors targeting ALK5 (TGFβ type 1 receptor) have been limited by mechanism-based heart valve toxicity to low dose and intermittent dosing regimens. NEX002 is an oral liver-targeted ALK5 inhibitor with low heart exposure for the treatment of liver cancer and other gastrointestinal cancers with liver metastases. The compound was designed following drug design principles from known liver-specific drugs, such as the statins. In animals, NEX002 exerts preferential distribution (pharmacokinetic) and target inhibition (pharmacodynamic) in liver over the heart. NEX002 has demonstrated activity in several intrahepatic and subcutaneous tumor models, and significantly enhanced the durability of anti-tumor efficacy in combination with lenvatinib, a VEGFR inhibitor approved for the treatment of hepatocellular carcinoma. No heart valve toxicity was observed when benchmarked against galunisertib (systemic ALK5 inhibitor) in toxicity studies with repeated daily dosing. These data suggest that our liver-targeted/heart-sparing approach may allow more robust target engagement compared to systemic ALK5 inhibitors through higher dose or more frequent dosing. Citation Format: Andrew T. Miller, Qihui Jin, David Plouffe, Manny Corpuz, Evelyn Rodrigo, Tom Y.- Wu. Heart-sparing ALK5 inhibitor for treatment of gastrointestinal and liver cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1661.

Minor Oral Surgery with Out Stopping the Daily Low Dose of Aspirin Therapy

OBJECTIVES Patients with the low-dose long-term aspirin regime have a severe risk of excessive bleeding during surgery, placing them at risk of "adverse thrombotic events". This study aims to evaluate the bleeding in patients undergoing minor oral surgery procedures without stopping daily low-dose aspirin therapy. METHODOLOGY A descriptive cross-sectional hospital-based investigation involved the patient with minor oral surgery at "Altamash Institute of Dental Medicine, Karachi, Pakistan" from mid-April 2021 to mid-June 2021, who were between the age group 30 to 75 with a low-dose aspirin regime. The data was collected via a questionnaire to record the variables, i.e. duration of aspirin, postoperative medications, platelets count, clotting time, normal bleeding time, and intraoperative bleeding time. RESULTS 51 patients, of which 32 were males while 19, were females. The normal bleeding time was comparatively analyzed with the intraoperative bleeding time using SPSS statistical software version 22. The results revealed that the mean bleeding time for the patients with a low-dose aspirin regime during minor oral surgery was 5.49 ± 1.07, while for the patients with a stopped aspirin dose was 4.57 ± 1.07. The comparative analysis using a t-test doesn't reveal significant statistical differences of p<0.05 between both groups. CONCLUSION We concluded that minor oral surgical procedures could safely be done without altering or stopping the low-dose, long-term aspirin regime.

Low-Dose TMP-SMX for Pneumocystis jirovecii Pneumonia Prophylaxis in Pediatric Solid Organ Transplant Recipients.

Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that adversely affects solid organ transplant (SOT) recipients. Published guidelines endorse 5 to 10 mg/kg/day (trimethoprim component) trimethoprim-sulfamethoxazole (TMP-SMX) as the recommended regimen for PJP prevention, often resulting in drug-related adverse effects. We investigated the use of a low-dose TMP-SMX regimen given at 2.5 mg/kg/dose once daily every Monday, Wednesday, and Friday at a large pediatric transplantation center. A retrospective chart review was conducted, including patients ages 0 to 21 years who underwent SOT from January 1, 2012, to May 1, 2020, and who were subsequently started on PJP prophylaxis with low-dose TMP-SMX for a minimum of 6 months. The primary end point was the incidence of breakthrough PJP infection on the low-dose TMP-SMX regimen. Secondary end points include the prevalence of adverse effects characteristic of TMP-SMX. A total of 234 patients were included in this study, and 6 of 234 patients (2.6%) were empirically transitioned to treatment dosing of TMP-SMX given a clinical concern for PJP, although none received a diagnosis of PJP. There were 7 patients (2.6%) who experienced hyperkalemia, 36 (13.3%) had neutropenia, and 22 (8.1%) had thrombocytopenia (all grade 4). Clinically significant serum creatinine elevations were seen in 43 of 271 patients (15.9%). Elevations of liver enzymes were seen in 16 of 271 patients (5.9%). Rash was documented in 4 of 271 patients (1.5%). In our patient cohort, low-dose TMP-SMX preserves the efficacy of PJP prophylaxis while providing an acceptable adverse effect profile.

Targeted Metabolomics of Organophosphate Pesticides and Chemical Warfare Nerve Agent Simulants Using High- and Low-Dose Exposure in Human Liver Microsomes.

Our current understanding of organophosphorus agent (pesticides and chemical warfare nerve agents) metabolism in humans is limited to the general transformation by cytochrome P450 enzymes and, to some extent, by esterases and paraoxonases. The role of compound concentrations on the rate of clearance is not well established and is further explored in the current study. We discuss the metabolism of 56 diverse organophosphorus compounds (both pesticides and chemical warfare nerve agent simulants), many of which were explored at two variable dose regimens (high and low), determining their clearance rates (Clint) in human liver microsomes. For compounds that were soluble at high concentrations, 1D-NMR, 31P, and MRM LC-MS/MS were used to calculate the Clint and the identity of certain metabolites. The determined Clint rates ranged from 0.001 to 2245.52 µL/min/mg of protein in the lower dose regimen and from 0.002 to 98.57 µL/min/mg of protein in the high dose regimen. Though direct equivalency between the two regimens was absent, we observed (1) both mono- and bi-phasic metabolism of the OPs and simulants in the microsomes. Compounds such as aspon and formothion exhibited biphasic decay at both high and low doses, suggesting either the involvement of multiple enzymes with different KM or substrate/metabolite effects on the metabolism. (2) A second observation was that while some compounds, such as dibrom and merphos, demonstrated a biphasic decay curve at the lower concentrations, they exhibited only monophasic metabolism at the higher concentration, likely indicative of saturation of some metabolic enzymes. (3) Isomeric differences in metabolism (between Z- and E- isomers) were also observed. (4) Lastly, structural comparisons using examples of the oxon group over the original phosphorothioate OP are also discussed, along with the identification of some metabolites. This study provides initial data for the development of in silico metabolism models for OPs with broad applications.

Survey of Buprenorphine Low-dose Regimens Used by Healthcare Institutions.

Buprenorphine microdosing ("low-dosing") allows for initiation of buprenorphine without requiring patients to endure withdrawal. Case studies suggest its favorable utility as an alternative to conventional buprenorphine induction. However, published regimens vary in duration, dosage forms used, and timing of full opioid agonist discontinuation. This cross-sectional survey study sought to determine how buprenorphine low-dosing is approached by medical institutions across the United States. The primary end point was characterization of inpatient buprenorphine low-dosing regimens. Situations and types of patients in which low-dosing is used and obstacles to institutional protocol development were also collected. An online survey was disseminated through professional pharmacy organizations and personal contacts. Responses were collected over 4 weeks. Twenty-three unique protocols were collected from 25 institutions. Most protocols used buccal (8 protocols) or transdermal (8 protocols) buprenorphine as first doses before transitioning to sublingual buprenorphine. The most common starting doses were buprenorphine 20 μg/h transdermal, 150 μg buccal, and 0.5 mg sublingual. Patients unable to tolerate conventional buprenorphine induction or those who potentially used fentanyl nonmedically were most likely to be prescribed low-dosing. The most common obstacle to developing an internal low-dosing protocol was lack of existing consensus guidelines. Similar to published regimens, internal protocols are variable. Buccal first doses may be used more commonly in practice based on survey results, while transdermal first doses are more commonly reported in publications. More research is needed to determine whether differences in starting formulations impact safety and efficacy of buprenorphine low-dosing in the inpatient setting.