PM Dose Research Articles

Effects of Polymannuronic Acid on the Intestinal Microbiota in Mice after Long-Term Intragastric Administration.

Polymannuronic acid (PM) is an alginate oligosaccharide derived from brown algae with a characterized structure and excellent biological activities. Herein, mice were given different doses of PM through 30-day-long-term intragastric administration, and the contents of the jejunum, ileum, and colon were analyzed by 16S rRNA gene sequencing technology for microbial diversity, and relevant experiments were verified according to the analysis results so as to comprehensively evaluate the effects of PM on the intestinal flora. The PM (400 mg/kg and 100 mg/kg) could regulate the microflora balance at the phylum level and increase the microflora richness in the jejunum, ileum, and colon of the mice. The PM could induce more strains that are negatively correlated with Escherichia, thereby reducing the relative abundance of Escherichia. Analysis of bacterial function showed that high and low doses of PM could promote lipid metabolism in the bacterial communities. Moreover, the PM could reduce serum total cholesterol and cholesterol ester levels in a concentration-dependent manner. High-dose PM could lead to colonic intestinal inflammation by increasing the relative abundance of multiple bacterial groups in the jejunum, ileum, and colon. Moreover, high-dose PM could increase lipopolysaccharide-binding protein and interleukin-1β levels. Therefore, the dose of PM plays an important role in its efficacy, and its biological activity is dosedifferent.

Anti-Inflammatory and Antinociceptive Activity of Herbal Lipospheres of Pentaclethra macrophylla (Fabaceae) Stem Bark Extract

Purpose: Inflammation of various degrees is common among humans. There are associated side effects with orthodox delivery systems and anti-inflammatory agents; hence, the study investigated the characteristics of herbal lipospheres and the anti-inflammatory potency of the lipospheres formulated from Pentaclethra macrophylla with the view to having a drug with a better delivery system and lesser side effects. Methods: Herbal lipospheres were formulated using solidified reverse micellar solutions (SRMS) of P90H and goat fat and characterized for particle size and morphology, pH time dependent analysis, encapsulation efficiency (EE%), and Fourier Transform infrared spectroscopy. The in vitro antinociceptive and anti-inflammatory studies were carried out using membrane stabilization by hypotonicity-induced hemolysis and the determination of anti-platelet aggregatory activity models. The in vivo antinociceptive and anti-inflammatory studies on egg albumin- and formaldehyde-induced arthritis models were conducted. A total white blood cell count and differential blood count were carried out on the rats. Results: The results showed that there was no change in pH for the PM-unloaded lipospheres and 2.5 g of PM-loaded lipospheres from day 1 to day 7, but there was a mild variation in the rest of the formulations. The EE ranged from 35.2% to 94%, increasing according to the drug concentration. The photomicrographs of the lipospheres showed that the particles were spherical in shape. The particle sizes were within the acceptable range for lipospheres. FTIR showed no interaction. In the arthritis study, PM-loaded lipospheres inhibited edema consistently throughout the duration of observation. Inhibition of the membrane increased steadily with an increase in concentration of PM in the lipospheres and the standard drug. The platelet aggregatory inhibition decreased steadily with an increase in concentration of the PM in the lipospheres as well as the standard. The T50 dose of PM had the highest percentage of WBC, and it decreased as the treatment doses increased from T100 to T200. There were no significant differences among the Neutrophil counts of the different groups. Conclusions: The study, therefore, showed that the methanol extract of Pentaclethra macrophylla formed efficient herbal lipospheres with antinociceptive and anti-inflammatory activities.

Contributions of particulate and gas phases of simulated burn pit smoke exposures to impairment of respiratory function

Objective Inhalation of smoke from the burning of waste materials on military bases is associated with increased incidences of cardiopulmonary diseases. This study examined the respiratory and inflammatory effects of acute inhalation exposures in mice to smoke generated by military burn pit-related materials including plywood (PW), cardboard (CB), mixed plastics (PL), and a mixture of these three materials (MX) under smoldering (0.84 MCE) and flaming (0.97 MCE) burn conditions. Methods Mice were exposed nose-only for one hour on two consecutive days to whole or filtered smoke or clean air alone. Smoldering combustion emissions had greater concentrations of PM (∼40 mg/m3) and VOCs (∼5–12 ppmv) than flaming emissions (∼4 mg/m3 and ∼1–2 ppmv, respectively); filtered emissions had equivalent levels of VOCs with negligible PM. Breathing parameters were assessed during exposure by head-out plethysmography. Results All four smoldering burn pit emission types reduced breathing frequency (F) and minute volumes (MV) compared with baseline exposures to clean air, and HEPA filtration significantly reduced the effects of all smoldering materials except CB. Flaming emissions had significantly less suppression of F and MV compared with smoldering conditions. No acute effects on lung inflammatory cells, cytokines, lung injury markers, or hematology parameters were noted in smoke-exposed mice compared with air controls, likely due to reduced respiration and upper respiratory scrubbing to reduce the total deposited PM dose in this short-term exposure. Conclusion Our data suggest that material and combustion type influences respiratory responses to burn pit combustion emissions. Furthermore, PM filtration provides significant protective effects only for certain material types.

The Efficacy of Same Day Plerixafor Dosing on CD34+ Haematopoietic Stem Cell Collection: A Single Centre Australian Experience

Introduction: Haematopoietic stem cell (HSC) transplantation is an important therapeutic option for many haematological conditions, as well as, some solid organ cancers. Plerixafor (a selective inhibitor of CXCR4) can be used in patients for primary stem cell mobilisation; those who have previously failed stem cell mobilisation ("rescue" or "Planned"); or in patients with a poor peripheral CD34+ response to GCSF and/or chemotherapy mobilisation ("on demand", "just in time" or "pre-emptive"). In Australia, Plerixafor is funded for patients with CD34+ count <10 cells/µl on day of collection or if first apheresis has yielded CD34+ <1 x 106cells/kg. In these patients, Plerixafor is administered the evening prior to the planned morning collection but this presents logistical issues as it has to be given after hours. Therefore, it was proposed to administer Plerixafor followed by same day HSC collection to improve the logistics of these "just in time" collections. Methods: A retrospective case note audit identified 96 patients who received Plerixafor for HSC collection between 03/2017 and 06/2021. Patients were categorised into PM (late afternoon/evening dosing) and AM (morning dosing). Transplant HSC dose target was >2 x 106/kg. Results: Of the 96 patients, 17 received 2 doses of plerixafor with 4 of these patients receiving both an AM and PM dose. These 4 patients were excluded from the final analysis. Of the 92 patients remaining, 57% (n=52) of patients received PM and 43% (n=40) AM dosing. Median age was 64 years (range 23 to 78). 58% were male (n=53) and 42% female (n=39). Underlying malignancy included Myeloma (n=51), Lymphoma (n=37) and Solid malignancy (n=4). Median pre plerixafor blood CD34+ count was 8.7x10^6/kg (range 0.3-35.5) in the PM group and 9.2 (range 1.6-38.2) in AM group prior to collection. Median number of HSCs collected post-plerixafor administration was 4.97 x106/kg (range 0.91-34.97) for PM group vs 4.16 x106/kg (range 0.71-9.52) AM group. Total median HSC number collected for patients in the PM group was 6.6x106cells/kg (range 3.14-8.18) vs 5.16x106/kg (range = 2.46-6.45) in the AM group. The AM group had an increased median HSC collected post plerixafor of 83% vs PM median of 75%. A transplantable HSC dose was collected in 97% of those in the AM group and 96% in the PM group. Median number of apheresis procedures with PM dosing was 2 (range 1-5) vs 2.4 with AM dosing (range 1-4). Conclusion: While post plerixafor HSC collection doses were higher with PM dosing this is countered by the total median HSC collection being higher in the AM group. These findings show that same day plerixafor dosing is a feasible option with similar numbers of patients achieving their target HSC collection.

Analyze the Effect of Steaming on the Chemical Constituents, Defecation and Liver Injury of Polygonum Multiflorum Radix (Heshouwu) by Multiple Analysis Techniques Combined with Multivariate Statistics.

Steaming is a characteristic pharmaceutical skill in Traditional Chinese Medicine (TCM). Polygonum multiflorum radix (PM) and its steamed products have been used in Asia for centuries. Raw Polygonum multiflorum radix (RPM) is commonly used to promote defecation but can exert toxicity, especially in liver injury. However, RPM can be made converted into Polygoni multiflori radix praeparata (PMP) by steaming; this is considered a good method to reduce defecation and liver injury caused by PM in Asia. The chemical constituents of TCM are the key to its action. We systematically analyzed the effect of steaming on PM constituents, defecation, and liver injury. We identified 13 main constituents from PM and PMP; the results showed that after being steamed, two constituents (TSG, catechin) had decreased, six constituents (such as procyanidin B1 or B2) had disappeared, four constituents (such as emodin, physcion) had increased, emodin-8-O-β-D-glucoside remained unchanged in PMP. Pharmacological experiments showed that PM could promote defecation; however, there were no obvious effects in response to PMP. Only a high dose of PM for 14 days caused some degree of liver injury, although this injury disappeared after 14 days of drug withdrawal. Network pharmacology and molecular docking studies showed that TSG, emodin and physcion were the most effective in promoting defecation and causing liver injury. Collectively, our findings show that steaming can reduce the effect of PM on promoting defecation and reducing liver injury. TSG may be one of the important constituents in PM that can promote defecation and cause liver injury.

Assessing potential liver injury induced by Polygonum multiflorum using potential biomarkers via targeted sphingolipidomics

Context Polygonum multiflorum Thunb. (Polygonaceae) (PM) can cause potential liver injury which is typical in traditional Chinese medicines (TCMs)-induced hepatotoxicity. The mechanism involved are unclear and there are no sensitive evaluation indicators. Objective To assess PM-induced liver injury, identify sensitive assessment indicators, and screen for new biomarkers using sphingolipidomics. Materials and methods Male Sprague–Dawley (SD) rats were randomly divided into four groups (control, model with low-, middle- and high-dose groups, n = 6 each). Rats in the three model groups were given different doses of PM (i.g., low/middle/high dose, 2.7/8.1/16.2 g/kg) for four months. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the plasma and liver were quantitatively analyzed. Fixed liver tissue sections were stained with haematoxylin and eosin and examined under a light microscope. The targeted sphingolipidomic analysis of plasma was performed using high-performance liquid chromatography tandem mass spectrometry. Results The maximal tolerable dose (MTD) of PM administered intragastrically to mice was 51 g/kg. Sphingolipid profiling of normal and PM-induced liver injury SD rats revealed three potential biomarkers: ceramide (Cer) (d18:1/24:1), dihydroceramide (d18:1/18:0)-1-phosphate (dhCer (d18:1/18:0)-1P) and Cer (d18:1/26:1), at 867.3–1349, 383.4–1527, and 540.5–658.7 ng/mL, respectively. A criterion for the ratio of Cer (d18:1/24:1) and Cer (d18:1/26:1) was suggested and verified, with a normal range of 1.343–2.368 (with 95% confidence interval) in plasma. Conclusions Three potential biomarkers and one criterion for potential liver injury caused by PM that may be more sensitive than ALT and AST were found.

Permanganate/Bisulfite Pre-Oxidation of Natural Organic Matter Enhances Nitrogenous Disinfection By-Products Formation during Subsequent Chlorination

The permanganate/bisulfite (PM/BS) process is a novel oxidation process, which can degrade micropollutants within several seconds. As natural organic matter (NOM) ubiquitously exists in an aquatic environment, the PM/BS process will inevitably react with NOM, which may impact the disinfection-by-products (DBPs) formation during subsequent chlorination. This study investigated the effect of PM/BS pre-oxidation of NOM on DBP formation. It was found that TOC removal reached a plateau when the molar ratio of PM to BS was 1:5. Increasing ratios of PM to BS decreased the intensity and area of fluorescence spectroscopy. PM and BS doses, pre-oxidation time, pH of solutions and concentration of Br− impacted the formation potential of various DBPs. PM/BS pre-oxidation decreased the formation of TCM while increasing the yields of N-DBPs, thus increasing the risk of water quality. Calculated toxicity analysis showed that a general increase in CTI was observed with PM/BS pre-oxidation, indicating that PM/BS pre-oxidation had a negative effect on risk control of overall cytotoxicity. Although the PM/BS process could accelerate the degradation of micropollutants, the elevated DBPs formation, especially highly toxic N-DBPs, needs enough attention to control water-quality risk.

Risk assessment of particulate matter by considering time-activity-pattern and major microenvironments for preschool children living in Seoul, South Korea.

Preschool children aged 3-6 years are vulnerable to exposed to particulate matter ("PM10" and "PM2.5"). It is required in evaluating the risk based on dose of preschool children. Microenvironments which preschool children mainly visited were classified. Inhalation type was adapted in each microenvironment in consideration of intensity of activity. The exposure scenario was described as preschool children had been living in Seoul, South Korea, and dose was calculated by considering time-activity-pattern with major microenvironments and inhalation type of preschool children for 24 h. Monte-Carlo simulation technique is used to estimate dose of particulate matter in probabilistic distribution by age and sex. The contribution of exposure by microenvironments and inhalation type was calculated. Risk assessment was performed based on WHO interim target-3 24-h concentration in order to estimate. Sensitivity analysis was performed to determine the effective variable of dose. As a result of the study, the dose of PM was higher for boys than girls and tended to decrease with age. The overall contributions of PM doses by microenvironments were daycare center, home, other facilities, transit, and outdoors, respectively, although differed between daycare center and home priority by age and sex. Especially, the contribution of daycare center and home was very high, accounting over 85% of the total. The overall contributions of PM doses by inhalation type were "run," "stable," "sleep," and "walk inhalation," respectively. The results of hazard quotient showed that "PM10" exceeded the WHO interim target-3 24-h concentration standard by about 10% and "PM2.5" exceeded about half. Through sensitivity analysis, PM concentration was confirmed as a major influence variable for doses. This study was able to affirm the overall exposure status of "PM10" and "PM2.5" for preschool children, and this is expected to be used in regulation and public health.

Safety and efficacy of reduced-dose pentamidine as second-line treatment for HIV-related pneumocystis pneumonia

ObjectivesParenteral pentamidine isethionate (PM) 4 mg/kg/day is recommended as an alternative therapeutic regimen after failure of first-line treatment for pneumocystis pneumonia (PCP). However, the dose is often reduced to 3 mg/kg/day in clinical settings because of high rates of adverse events and drug toxicity. Although considered equally efficacious, this lower dose has not been well evaluated. MethodsThis was a single-center, retrospective cohort study that analyzed 75 patients with HIV-PCP who were treated with trimethoprim-sulfamethoxazole, but discontinued treatment because of treatment failure or adverse events; they were then administered 3 mg/kg/day of intravenous PM as a salvage therapy. The primary outcomes were the regimen completion rate with the reduced PM dose. Results and conclusionsIn total, 40 (53.3%) of the eligible patients completed PCP therapy with reduced-dose PM salvage treatment. The overall survival rate of PCP was 73 (97.3%). The median duration of second-line PM treatment was 8.0 days (interquartile range: 6.0–10.0). Although, the adverse events with reduced-dose PM were observed in 41 (54.7%), including 35 treatment-limiting adverse events, grade 3 or 4 adverse events occurred in only three patients (thrombocytopenia, one patient; neutropenia, two patients). Life-threating adverse events, such as hypoglycemia and arrhythmia, were not observed with reduced-dose PM. Salvage therapy with reduced-dose PM for patients with HIV-PCP is relatively safe and effective; moreover, life-threating adverse events did not occur. This therapy could be recommended for patients with HIV-PCP who fail to respond to first-line treatment with trimethoprim-sulfamethoxazole.

Night- Time Chronotherapy With Diuretics: Effect On Sleep Quality And Duration In Patients With Hypertension In Lusaka, Zambia

Poor sleep plays an important role in the prevalence of hypertension. It increases the prevalence rate to 60%. The night-time dosing of blood pressure-lowering drugs has yielded positive results. Scholars have rarely investigated the relationship between night-time dosing of diuretics and the quality of sleep. The study aimed at evaluating the quality and duration of sleep while on night-time dosing of diuretics and determine the commonly used blood pressure-lowering medication at University Teaching Hospital. The study was a Prospective Cohort Study with 12 weeks of follow-up. The sample consisted of 46 patients with hypertension and on a diuretic, 25 of whom were taking their medication in the evening at 10 PM (study group), and 18 were in the 10 AM dosing schedule as a control. Overall, 43 were included in the analysis. Baseline and follow-up at 2, 8 and 12 Sleep quality and duration, and blood pressure level were available for 43 (93.5%) individuals. The study recruited more women (76.1%) and the majority were on hydrochlorothiazide and amiloride combination (65.2%). The 10 PM dosing showed better quality of sleep and duration, and blood pressure-lowering as the follow-up continued with a p-value of less than 0.05 for Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS), and for the blood pressure-lowering at 12 weeks. The study showed beneficial effects of 10 PM dosing of diuretics in hypertensive patients and the diuretic effect does not affect the quality and duration of sleep. Further, 10 PM dosing lowers the blood pressure significantly compared with 10 AM.

S5. DOES THE TIME OF DRUG ADMINISTRATION ALTER THE ADVERSE EVENT RISK OF LURASIDONE?

BackgroundLurasidone is once a day oral medication, which could be administered any time of the day, but the relationship between the timing of administration and the risk of developing adverse events has not been systematically evaluated.The purpose of this study was to examine whether there is a difference in the risk of adverse events between lurasidone administration in the morning and at night in the treatment of adult schizophrenia.MethodsRandomized placebo-controlled trials (RCTs) of lurasidone in adults with acute exacerbation of schizophrenia were analyzed for the incidence of akathisia, somnolence, and nausea.We compared the risk of each adverse event and the risk differences (RDs) for each lurasidone dose versus placebo in patients taking lurasidone in the morning (AM dosing group) and those taking lurasidone at night (PM dosing group).ResultsNine RCTs were included in the analysis (six RCTs with AM dosing and three RCTs with PM dosing). In the AM dosing group, lurasidone doses of 20, 40, 80, and 120 mg/day were evaluated, and in the PM dosing group, lurasidone doses of 20, 40, 80, and 160 mg/day were evaluated.The risk of akathisia increased in a dose-dependent manner in AM dosing group, this tendency, however, was not observed in PM dosing group. In addition, RD tended to be larger in AM dosing group than in PM dosing group at the same dose [AM dosing group: 20 mg/day=-4.1%, no significantly different from placebo (ns); 40 mg/day=7.1%, p<0.001; 80 mg/day=9.1%, p<0.001; 120 mg/day=20.3%, p<0.001, PM dosing group: 20 mg/day=3.2%, ns; 40 mg/day=2.3%, ns; 80 mg/day=8,7%, p<0.001; 160 mg/day=6.5%, p<0.01].Similarly, the risk of somnolence increased in a dose-dependent manner in AM dosing group, however, this tendency was not clearly observed in PM dosing group. RD tended to be larger in AM dosing group than in PM dosing group at the same dose (AM dosing group: 20 mg/day=0.1%, ns; 40 mg/day=3.6%, p<0.05; 80 mg/day=4.9%, p<0.01; 120 mg/day=9.3%, p<0.001, PM dosing group: 20 mg/day=-0.4%, ns; 40 mg/day=2.8%, p<0.05: 80 mg/day=0.2%, ns; 160 mg/day=5.8%, p<0.05).There was no clear dose-dependent trend associated with nausea and RD was similar between AM and PM dosing group (AM dosing group: 20 mg/day=0.2% ns; 40 mg/day=3.8%, p<0.05; 80 mg/day=3.8%, ns; 120 mg/day=6.6%, ns, PM dosing group: 20 mg/day=-1.6%, ns; 40 mg/day=-1.7%, ns; 80 mg/day=5.5%, p<0.01; 160 mg/day=2.8%, ns).DiscussionThe risk of adverse events in the treatment of schizophrenia with lurasidone can vary depending on the timing of administration. In particular, for akathisia and somnolence, the incidence risks were reduced when lurasidone was administered in PM. Unlike with AM administration, the dose-dependence in the risks of these adverse events were not observed in lurasidone PM administration.The timing of lurasidone administration could be considered in effort to minimize potential adverse events.

Abstract B20: Repurposing of fenofibrate to prevent and treat PM-induced pulmonary fibroblast-mediated inflammation: Mechanism involved in SIRT1-SREBP1-PIR/NLRP3 inflammasome axis

Abstract Particulate matter (PM) has been shown to have strong link with a variety of human morbidity and mortality. World Health Organization (WHO) recognizes air pollution as an invisible killer responsible for around 7 million global deaths per year, including 43% from chronic obstructive pulmonary disease (COPD), 29% from lung cancer, 25% from heart diseases, 24% from stroke, and 24% from pneumonia. Cardiopulmonary disease is considered as the leading PM-induced complication. The main mechanism involved in PM-induced cardiopulmonary disease is through upregulation of redox-sensitive signaling pathways, mediated by nuclear factor kappa B (NF-κB). We analyzed transcriptomics data by microarray chips in human pulmonary fibroblasts (HPF) after being treated by different doses of PM, and our result identified sterol regulatory element-binding protein 1 (SREBP1) as the top 1 transcription factor activated after PM exposure in HPF. Our analysis showed that Pirin (PIR), an iron-dependent redox regulator of NF-κB, was the most significantly and plausible transcriptional targets of SREBP1. Additionally, SREBP1, directly deacetylated and inhibited by Sirtuin 1 (SIRT1), increased the expression of inflammasome markers, e.g., NACHT, LRR and PYD domains containing protein 3 (NLPR3), Apoptosis-Associated Speck-Like Protein Containing CARD (ASC), and interleukin-1β (IL-1β), were documented. Our results further showed PM-induced inflammation could be reversed by inhibitors of SIRT1, SREBF1, and PIR. We concluded that SIRT1-SREBP1-PIR/NLRP3 inflammasome axis may play a key role in PM-induced sequel and may present new targets. Fenofibrate, clinically prescribed for dyslipidemia, prevented atrial fibrillation rabbits from atrial metabolic remodeling through the SIRT1-SREBP1 pathway. Moreover, in vivo fenofibrate was reported to regulate hyperglycemia-induced metabolic memory and reduce the inflammatory response via SIRT1-dependent suppression of NF-κB. On the basis of previous work and this study, we may repurpose fenofibrate as an anti-PM drug to prevent and treat PM-induced cardiopulmonary disease, which can be used in combination with COPD, heart disease, or anticancer medicines in future research. Citation Format: Chia-Ping Tien, Yu-Chan Chang, Shih-Chieh Hung, Michael Hsiao. Repurposing of fenofibrate to prevent and treat PM-induced pulmonary fibroblast-mediated inflammation: Mechanism involved in SIRT1-SREBP1-PIR/NLRP3 inflammasome axis [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B20.

Efficacy and Safety of Basal Analog Regimens in Type 2 Diabetes Mellitus: Systematic Review and Meta-Analysis of Randomized Controlled Trials

IntroductionThis study compared basal analog (BA: glargine U100/mL and detemir) and premix (PM: human, lispro and aspart biphasic) insulin regimens in terms of their efficacy and safety in type 2 diabetes mellitus patients.MethodsSearches of MEDLINE, Embase, and CENTRAL identified primary randomized controlled trials (RCTs) ≥ 12 weeks in duration that compared BA or PM insulin regimens in adults with T2DM, with ≥ 30 patients per arm. A systematic literature review and a pairwise meta-analysis were performed using a random effects model adjusted for between-study variability. Analyses were conducted based on frequency of bolus insulin and PM injections, PM ratio and type, BA type, race, follow-up period, and baseline glycosylated hemoglobin (HbA1c).ResultsTwenty-two primary RCTs with 9691 patients were included. The BA and PM regimens yielded similar changes in HbA1c and postprandial glucose levels, with a statistically significant reduction in fasting glucose [mean difference (MD) − 0.61 mmol/L (95% confidence interval (CI) − 0.90, − 0.32), I2 = 89.6%]. The BA regimens showed significantly reduced rates of total hypoglycemia [odds ratio (OR) 0.77 (95% CI 0.64, 0.92), I2 = 65.3%] and changes in body weight [MD − 0.48 kg (95% CI − 0.86, − 0.11), I2 = 75.7%] compared to PM regimens. Stratification by PM type and dosing ratio demonstrated statistically significant reductions in HbA1c favoring BA compared to human [MD − 0.39% (95% CI − 0.60, − 0.18), I2 = 61.8%] or 50/50-ratio [MD − 0.22% (95% CI − 0.40, − 0.04), I2 = 0.0%] PM regimens. Other subgroup analyses found no difference in HbA1c change between the BA and PM regimens.ConclusionWhen compared to PM regimens, BA regimens yielded similar efficacies and better safety profiles in patients with type 2 diabetes mellitus.FundingSanofi (Shanghai, China).Electronic supplementary materialThe online version of this article (10.1007/s13300-019-0606-6) contains supplementary material, which is available to authorized users.

Susceptibility-Related Factor and Biomarkers of Dietary Supplement Polygonum multiflorum-Induced Liver Injury in Rats.

Polygonum multiflorum [PM, synonym Reynoutria multiflora (Thunb.) Moldenke.], a well-known and commonly used Traditional Chinese Medicine and herbal dietary supplement for nourishing the kidney and liver, etc., has aroused wide concern for its reported potential hepatotoxicity. Previous clinical cases and experimental studies have suggested that mild immune stress (MIS) may be one of the susceptibility-related factors of idiosyncratic drug-induced liver injury (IDILI) caused by PM. In this paper, we found that the same dose of PM caused abnormal liver biochemical indicators and liver tissue damage in MIS model rats, while it did not result in liver injury in normal rats, further confirming that MIS is a susceptibility factor for PM-IDILI. Plasma chemokine/cytokine profiling indicated that the MIS model group was significantly different from the other groups, showing a significant upregulation of plasma chemokines, while the MIS/PM group showed upregulated expression of chemokines or pro-inflammatory cytokines. Liver histopathological examination indicated a small amount of inflammatory cytokine infiltration in the MIS group, but no hepatocyte injury, consistent with the plasma profiles of increased chemokines and unchanged inflammatory cytokines. Notably, metabolomics characterization showed that MIS caused reprogramming of these metabolic pathways (such as phenylalanine and glutamate pathways), which was associated with acute phase reactions and inflammatory responses. These results suggested that MIS may promote an immune response to the initial cellular injury induced by PM in the liver, and MIS-induced upregulation of chemokines and metabolic reprogramming may an important mechanism that mediates the susceptibility to PM-IDILI. Furthermore, via receiver operating characteristic (ROC) curves analysis, we identified 12 plasma cytokines (e.g., IP-10, MCP-1 and MIP-1α) and nine metabolomics biomarkers (e.g., L-Phenylalanine, Creatinine, and L-glutamine) with differential capabilities (all ROC AUC > 0.9) of identifying susceptibility model animals from normal ones, which might be of referable value for the clinical recognition of PM-IDILI susceptible individuals.

Evaluation of Underlying Cause of Genitourinary (GU) Adverse Events (AEs) in Patients with Myelodysplastic Syndromes upon Oral Administration of Rigosertib: Safety and Pharmacokinetic Analysis of Rigosertib across Three Clinical Trials

Introduction: Oncogenic mutations of Ras genes have been implicated in number of human cancers whereby the cells grow uncontrollably, and evade death signals (Ledford, Nature, 520, 278, 2015). Rigosertib is a small molecule that inhibits cellular signaling in cancer cells by acting as a Ras mimetic (Athuluri-Divakar SK, Cell 2016). Rigosertib, as a single agent, was evaluated in a Phase III clinical trial in refractory MDS patients where the drug was administered as a 3 day continuous IV infusion every other week (NCT01241500). Rigosertib has also been evaluated in Phase I/II trials via oral route of administration in patients with solid malignancies (NCT01168011); and with myelodysplastic syndromes (NCT01926587). We performed pharmacokinetic and safety analysis of 253 patients across three different trials. The pharmacokinetics and safety profile of orally administered Rigosertib was evaluated in patients with MDS and solid malignancies. The results were compared to data obtained from high risk MDS patients receiving intravenous rigosertib therapy. In this investigation, we present evidence that differential GU toxicity of Rigosertib is probably related to the route of administration and dosing regimen; and independent of the underlying disease state.Methods: Data was analyzed from three clinical studies. Study NCT01241500 was conducted with MDS patients (n = 184) who were administered Rigosertib by continuous IV infusion (1800 mg/day for 72 hours) every 2 weeks. Blood samples were collected at 6, 24, 30, 48, 56 and 72 hours after infusion initiation. In Study NCT01168011, patients with advanced solid tumors (n=33) received oral Rigosertib (560 mg) Q12 hours of a 28-day cycle (3 weeks on, 1 week off). Study NCT01926587, conducted in MDS patients (n=36) with oral administration Rigosertib in combination with parenteral Azacitidine, evaluated the same AM dose but a lower 280 mg PM dose. In both studies, pharmacokinetic assessment was conducted after administration of the AM dose (560 mg) on day 1 of cycle 1. Blood samples were collected predose and 0.5, 1, 1.5, 2, 4, 6 and 8 hours after administration. For Study NCT01168011, urine was collected for 24 hours (0-4, 4-8 and 8-24 hrs) to determine the percent of dose excreted in urine. Rigosertib concentrations in plasma and urine were determined by a validated LC/MS-MS method. Rigosertib pharmacokinetic parameters were estimated using non-compartmental analysis. Treatment emergent adverse events were recorded throughout each study.Results: There was no difference in Rigosertib pharmacokinetic parameters between the two patient populations (Table 1) upon oral administration, and the plasma concentration-time profiles were super imposable (Figure 1). Approximately 2% of the orally administered dose was recovered in the urine. In both studies, the most common AEs observed were GU AEs (dysuria, hematuria). The incidence of grade ≥2 GU toxicity observed with oral dosing was 17 of 33 (52%) and 17 of 36 (47%) in Study NCT01168011 and NCT01926587, respectively. The incidence of GU AEs in both the studies was comparable even though the PM dose was lower (560 mg vs 280mg) in study NCT01926587. Peak plasma concentration and AUC0-∞ were similar in patients with or without urinary symptoms. Compared to oral dosing, the incidences of GU AEs were dramatically lower (10%) following IV infusion despite 8-fold higher and more prolonged systemic exposure (Table 2).Conclusions: This study demonstrates that the urinary adverse events and systemic exposure are similar in patients with either solid malignancies or MDS treated with orally administered rigosertib. The incidence of GU AEs is relatively high in spite of the very low amount (2%) of the administered dose eliminated through the renal route. In contrast, the GU AEs are significantly lower when Rigosertib is administered by IV infusion despite of 8 fold higher exposure. This is probably due to the short half-life of drug and dosing holiday of 12 days between two doses within the cycle. The higher incidence of GU AE upon oral administration is likely related to the dwell time of high concentration of drug in the bladder at night in patients treated daily for 3/4 weeks. This was successfully addressed in the clinical trial, NCT01926587 expansion with risk mitigation strategies, by deploying a novel dosing regimen derived through pharmacokinetic modeling and simulation (Taft, et al; ASH 2018 Abstract Submitted). [Display omitted] DisclosuresManiar:Onconova Therapeutics, Inc: Employment, Equity Ownership. Ren:Onconova Therapeutics, Inc: Employment, Equity Ownership. Zbyszewski:Onconova Therapeutics, Inc: Employment, Equity Ownership. Petrone:Onconova Terapeutics Inc.: Employment, Equity Ownership. Fruchtman:Onconova Therapeutic Inc: Employment, Equity Ownership. Taft:Onconova Therapeutics, Inc: Research Funding.

Amelioration of Rigosertib Treatment Related Genitourinary (GU) Adverse Events (AEs) in Patients with Myelodysplastic Syndromes: Implementation of Novel Dosing Regimen Derived through Pharmacokinetic Modeling in Phase 2 Study of Oral Rigosertib in Combination with Azacitidine

Introduction: Rigosertib is a small molecule inhibitor of cellular signaling pathways in cancer cells by acting as a Ras mimetic. The inhibitory effect is mediated by Rigosertib binding to the Ras-binding domain found in many Ras effector proteins (Athuluri-Divakar SK, Cell 2016). Oral administration of Rigosertib was initially evaluated in lower risk MDS patients. The drug, administered as 560 mg BID (q12hr; 2/3 wks), was associated with high rates of transfusion independence but with significant GU AEs (Raza, et al, Blood 2017 130:1689). Subsequently, a reduction in the PM dose to 280 mg led to a decrease in GU AEs, suggesting a causal relationship with nocturnal bladder drug concentration. When oral administration of Rigosertib was tested with standard dose of parenteral Azacitidine in a Phase I/II trial (NCT01926587) at a dose of 560/280 mg (Q12hrs, 3/4 weeks), the ORR was 77%; with 60% for the HMA relapsed/refractory group for the high risk MDS patients. The impressive response rate, in the combination treatment, was also associated with significant GU AEs. Hence, it is important to understand the underlying cause and devise ways to maximize response rates with minimization of GU AEs.Previously, it was established that GU AEs were unlikely to be related to the higher systemic exposure of the drug (Maniar, et al ASH 2018, Abstract submitted) but attributed to the nocturnal dwell time of high drug concentration in the bladder of patients treated with continuous oral administration (3/4 weeks). In this investigation, we developed a pharmacokinetic model to simulate the systemic and bladder exposure of Rigosertib after repeated oral dosing. The overall aim was to identify and implement an oral dosing regimen for Rigosertib that would maximize the systemic exposure with minimization of nocturnal bladder concentration, thereby potentially mitigating or eliminating the GU AE's.Methods: A 2-compartment model with 1st order absorption and elimination (Figure 1) was fitted to data collected from patients with solid malignancies at a 560 mg dose (n=25). Model parameter estimates were then used to generate a virtual population of 100 patients. Each virtual patient was randomly assigned parameter values based on the 95% confidence interval for each parameter estimate obtained through the modeling analysis. Model simulations were then performed to evaluate the steady state systemic and urinary exposure of Rigosertib in the virtual population after treatment with different dosing schedules (Figure 2). Besides plasma exposure (Cmax, AUC), the predicted rigosertib bladder concentration during the sleep-cycle was also assessed. From this analysis, optimal dosing regimens were selected for evaluation in a Phase 2 study in HR-MDS patients in combination with Azacitidine. The model was validated by comparing the predicted systemic exposure with observed data using these optimal dosing regimens, and by comparing Grade 3 GU AE's events from the pre- and post-optimization of dosing regimen (NCT01926587).Results: The model-predicted steady state plasma concentration-time profile of Rigosertib for different dosing regimens is shown in Figure 3. The duration of exposure of drug above minimum effective concentration (MEC, 0.175 ug/ml) was not changed by varying the dosing regimen. Importantly, model simulations demonstrated that BID dosing, with the dosing interval of 8 hours, would reduce the bladder concentration of Rigosertib by as much as 70% during sleep without compromising systemic drug exposure (Table 1). As illustrated in Table 2, model simulated Rigosertib exposure (Cmax, AUC) compared favorably with data from patients treated with the novel twice daily dosing regimens (560mg/560mg and 840 mg/280mg, dosing interval of 8 hours), thereby validating the model. Preliminary safety data from the on-going trial demonstrates that the Grade 3 GU AEs were significantly reduced (12%) with the optimized dosing regimen compared to the pre-optimized dosing regimen (29%) despite using a higher total dose of drug (1120 mg vs 840 mg).Conclusions: This study demonstrates the utility of pharmacokinetic modeling for designing a dosing regimen directed at reducing the incidence of toxicity. The identified dosing regimen, along with mitigation strategies, successfully reduced the risk of Grade 3 GU AEs of rigosertib without compromising the duration of systemic exposure of Rigosertib above MEC in HR MDS patients. [Display omitted] DisclosuresTaft:Onconova Therapeutics, Inc: Research Funding. Ren:Onconova Therapeutics, Inc: Employment, Equity Ownership. Zbyszewski:Onconova Therapeutics, Inc: Employment, Equity Ownership. Morgan:Onconova Therapeutics, Inc: Consultancy. Petrone:Onconova Terapeutics Inc.: Employment, Equity Ownership. Fruchtman:Onconova Therapeutic Inc: Employment, Equity Ownership. Maniar:Onconova Therapeutics, Inc: Employment, Equity Ownership.

Simultaneous stabilization/solidification of Mn2+ and NH4+-N from electrolytic manganese residue using MgO and different phosphate resource

This study examined simultaneous stabilization and solidification (S/S) of Mn2+ and NH4+-N from electrolytic manganese residue (EMR) using MgO and different phosphate resource. The characteristics of EMR NH4+-N and Mn2+ S/S behavior, S/S mechanisms, leaching test and economic analysis, were investigated. The results show that the S/S efficiency of Mn2+ and NH4+-N could reach 91.58% and 99.98%, respectively, and the pH value is 8.75 when the molar ratio of Mg:P is 3:1 and the dose of PM (MgO and Na3PO4·12H2O) is 8wt%. In this process, Mn2+ could mainly be stabilized in the forms of Mn(H2PO4)2·2H2O, Mn3(PO4)2·3H2O, Mn(OH)2, and MnOOH, and NH4+-N in the form of NH4MgPO4·6H2O. Economic evaluation indicates that using PM process has a lower cost than HPM and HOM process for the S/S of Mn2+ and NH4+-N from EMR at the same stabilization agent dose. Leaching test values of all the measured metals are within the permitted level for the GB8978-1996 test suggested when the dose of PM, HPM and HOM is 8wt%.

Investigation of Liver Injury of Polygonum multiflorum Thunb. in Rats by Metabolomics and Traditional Approaches.

Liver injury induced by Polygonum multiflorum Thunb. (PM) have been reported since 2006, which aroused widespread concern. However, the toxicity mechanism of PM liver injury remained unclear. In this study, the mechanism of liver injury induced by different doses of PM after long-term administration was investigated in rats by metabolomics and traditional approaches. Rats were randomly divided into control group and PM groups. PM groups were oral administered PM of low (10 g/kg), medium (20 g/kg), high (40 g/kg) dose, while control group was administered distilled water. After 28 days of continuous administration, the serum biochemical indexes in the control and three PM groups were measured and the liver histopathology were analyzed. Also, UPLC-Q-TOF-MS with untargeted metabolomics was performed to identify the possible metabolites and pathway of liver injury caused by PM. Compared with the control group, the serum levels of ALT, AST, ALP, TG, and TBA in middle and high dose PM groups were significantly increased. And the serum contents of T-Bil, D-Bil, TC, TP were significantly decreased. However, there was no significant difference between the low dose group of PM and the control group except serum AST, TG, T-Bil, and D-Bil. Nine biomarkers were identified based on biomarkers analysis. And the pathway analysis indicated that fat metabolism, amino acid metabolism and bile acid metabolism were involved in PM liver injury. Based on the biomarker pathway analysis, PM changed the lipid metabolism, amino acid metabolism and bile acid metabolism and excretion in a dose-dependent manner which was related to the mechanism of liver injury.

Therapeutic response and long-term outcome of differentiated thyroid cancer with pulmonary metastases treated by radioiodine therapy.

ObjectiveTo explore the therapeutic response (TR) and long-term outcomes of iodine-131 (I-131) treatment for patients with differentiated thyroid cancer and pulmonary metastases (DTC+PM), as well as the association between the assessment of TR and long-term outcomes.MethodsThis retrospective study comprised 151 DTC+PM patients. TR was evaluated by changes in serum levels of thyroglobulin, anatomic imaging and iodine uptake in pulmonary nodules; logistic regression was applied to identify predictors. Overall survival (OS) was calculated using the Kaplan–Meier method and predictive factors of outcome by multivariate analyses.ResultsAfter I-131 treatment, 17 patients achieved a complete response, 71 a partial response, and 63 no response. Age, pulmonary nodule size, iodine-concentration within PM, extra-PM, frequency and cumulative dose of I-131 treatment were significant for TR. OS was 72.2% at 5, 55.2% at 10 and 51.3% at 15 years. After adjustment for other factors, age, pulmonary nodule size, extra-PM, frequency and cumulative dose of I-131 treatment were significant. A significant difference of survival rate in patients with different TR group was observed.ConclusionsThere was a supportive response and prognosis for I-131 treatment upon DTC+PM patients. Older patients and those with non-I-131-avid PM were more likely to have no response to I-131 treatment, and greater benefits could be achieved by patients who complete treatment. Long-term outcome was better in patients with age <45 years, pulmonary nodule size <2 cm, without extra-PM, and the frequency of iodine treatment ≥5 times. The predictive power of the TR on long-term prognosis was favorable.

Is it important to disclose how treatments are selected in clinical research and clinical care?

ABSTRACTBackground: Current practice and policies maintain that it is very important to disclose to potential research subjects that their treatment will be selected by randomization. In contrast, it typically is not considered important to disclose to patients how doctors select their treatment. Unfortunately, when the available treatment options are similar to one another, this approach has the potential to inadvertently undermine both clinical research and clinical care. Hence, it is important to assess whether, in the context of similar treatment options, individuals support current practice of using very different disclosure practices in research and care. Methods: Respondents were randomly presented with either (1) a “drug” scenario involving two medications for hypertension (called CTD and TRT) whose risk–benefit profiles are very similar, or (2) a “dose timing” scenario involving morning versus nighttime dosing of the same antihypertensive. Respondents were asked whether, in the presented scenario, they agree, using a 7-point scale (1 = strongly disagree, 4 = neutral, 7 = strongly agree), that it is important to disclose to potential research subjects that whether they receive CTD or TRT/AM or PM dosing will be determined by randomization. Respondents were also asked whether they agree, using the same 7-point scale, that it is important to disclose to patients who face the same treatment options how their doctor will decide whether they receive CTD or TRT/AM or PM dosing. Results: The survey was sent to 3330 online GfK KnowledgePanel members and completed by 2130 (response rate, 64.0%). Respondents indicated that it is somewhat important to disclose to potential subjects that whether they receive CTD or TRT/AM or PM dosing will be determined by randomization (mean, 5.10 [95% CI, 5.02 to 5.17]). Respondents also indicated that it is slightly more important to disclose to patients who face the same treatment options how the doctor will decide whether they receive CTD or TRT/AM or PM dosing (mean, 5.29 [95% CI, 5.22 to 5.36]; p < .001). In addition, 66.4% indicated that, in the setting of similar options, it is equally important to disclose how treatment is selected in research and care, 20.5% indicated it is more important to disclose this information in clinical care, and 13.1% indicated it is more important to disclose it in research. Conclusion: When the available options are similar to each other, individuals do not support current practice and policies that maintain that disclosure of how treatments are selected is very important in clinical research but not important in clinical care. Future research will be needed to evaluate the feasibility of developing disclosure practices and policies for this context that are consistent with individuals' views.