scholarly journals Chitosan as possible inhibitory agents and delivery systems in leukemia

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Parinaz Zivarpour ◽  
Jamal Hallajzadeh ◽  
Zatollah Asemi ◽  
Fatemeh Sadoughi ◽  
Mehran Sharifi

AbstractLeukemia is a lethal cancer in which white blood cells undergo proliferation and immature white blood cells are seen in the bloodstream. Without diagnosis and management in early stages, this type of cancer can be fatal. Changes in protooncogenic genes and microRNA genes are the most important factors involved in development of leukemia. At present, leukemia risk factors are not accurately identified, but some studies have pointed out factors that predispose to leukemia. Studies show that in the absence of genetic risk factors, leukemia can be prevented by reducing the exposure to risk factors of leukemia, including smoking, exposure to benzene compounds and high-dose radioactive or ionizing radiation. One of the most important treatments for leukemia is chemotherapy which has devastating side effects. Chemotherapy and medications used during treatment do not have a specific effect and destroy healthy cells besides leukemia cells. Despite the suppressing effect of chemotherapy against leukemia, patients undergoing chemotherapy have poor quality of life. So today, researchers are focusing on finding more safe and effective natural compounds and treatments for cancer, especially leukemia. Chitosan is a valuable natural compound that is biocompatible and non-toxic to healthy cells. Anticancer, antibacterial, antifungal and antioxidant effects are examples of chitosan biopolymer properties. The US Food and Drug Administration has approved the use of this compound in medical treatments and the pharmaceutical industry. In this article, we take a look at the latest advances in the use of chitosan in the treatment and improvement of leukemia.

2014 ◽  
Vol 33 (2) ◽  
pp. 75-85 ◽  
Author(s):  
Pramod Terse ◽  
Kory Engelke ◽  
Kenneth Chan ◽  
Yonghua Ling ◽  
Douglas Sharpnack ◽  
...  

Decitabine (5-aza-2′-deoxycytidine; DAC) in combination with tetrahydrouridine (THU) is a potential oral therapy for sickle cell disease and β-thalassemia. A study was conducted in mice to assess safety of this combination therapy using oral gavage of DAC and THU administered 1 hour prior to DAC on 2 consecutive days/week for up to 9 weeks followed by a 28-day recovery to support its clinical trials up to 9-week duration. Tetrahydrouridine, a competitive inhibitor of cytidine deaminase, was used in the combination to improve oral bioavailability of DAC. Doses were 167 mg/kg THU followed by 0, 0.2, 0.4, or 1.0 mg/kg DAC; THU vehicle followed by 1.0 mg/kg DAC; or vehicle alone. End points evaluated were clinical observations, body weights, food consumption, clinical pathology, gross/histopathology, bone marrow micronuclei, and toxicokinetics. There were no treatment-related effects noticed on body weight, food consumption, serum chemistry, or urinalysis parameters. Dose- and gender-dependent changes in plasma DAC levels were observed with a Cmax within 1 hour. At the 1 mg/kg dose tested, THU increased DAC plasma concentration (∼10-fold) as compared to DAC alone. Severe toxicity occurred in females receiving high-dose 1 mg/kg DAC + THU, requiring treatment discontinuation at week 5. Severity and incidence of microscopic findings increased in a dose-dependent fashion; findings included bone marrow hypocellularity (with corresponding hematologic changes and decreases in white blood cells, red blood cells, hemoglobin, hematocrit, reticulocytes, neutrophils, and lymphocytes), thymic/lymphoid depletion, intestinal epithelial apoptosis, and testicular degeneration. Bone marrow micronucleus analysis confirmed bone marrow cytotoxicity, suppression of erythropoiesis, and genotoxicity. Following the recovery period, a complete or trend toward resolution of these effects was observed. In conclusion, the combination therapy resulted in an increased sensitivity to DAC toxicity correlating with DAC plasma levels, and females are more sensitive compared to their male counterparts.


Author(s):  
Yitang Sun ◽  
Jingqi Zhou ◽  
Kaixiong Ye

Abstract Identifying causal risk factors for severe coronavirus disease 2019 (COVID-19) is critical for its prevention and treatment. Many associated pre-existing conditions and biomarkers have been reported, but these observational associations suffer from confounding and reverse causation. Here, we perform a large-scale two-sample Mendelian randomization (MR) analysis to evaluate the causal roles of many traits in severe COVID-19. Our results highlight multiple body mass index (BMI)-related traits as risk-increasing: BMI (OR:1.89, 95% CI:1.51–2.37), hip circumference (OR:1.46, 1.15–1.85), and waist circumference (OR:1.82, 1.36–2.43). Our multivariable MR analysis further shows that the BMI-related effect is driven by fat mass (OR:1.63, 1.03–2.58), but not fat-free mass (OR:1.00, 0.61–1.66). Several white blood cell counts are negatively associated with severe COVID-19, including those of neutrophils (OR:0.76, 0.61–0.94), granulocytes (OR:0.75, 0.601–0.93), and myeloid white blood cells (OR:0.77, 0.62–0.96). Furthermore, some circulating proteins are associated with an increased risk of (e.g., zinc-alpha-2-glycoprotein) or protection from severe COVID-19 (e.g., interleukin-3/6 receptor subunit alpha). Our study shows that fat mass and white blood cells underlie the etiology of severe COVID-19. It also identifies risk and protective factors that could serve as drug targets and guide the effective protection of high-risk individuals.


PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248671
Author(s):  
Yuan Zhu ◽  
Jing Zhang ◽  
Yiming Li ◽  
Fang Liu ◽  
Qing Zhou ◽  
...  

Background Thrombocytopenia has been proved to be associated with hospital mortality in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. However, the detailed association of thrombocytopenia with subsequent progression of organ functions and long-term prognosis in critically ill COVID-19 patients remains to be explored. Methods Medical records of 167 confirmed cases of critically ill COVID-19 from February 16 to March 21, 2020 were collected in this two-center retrospective study. 180-day’s outcome and clinical organ development in patients with thrombocytopenia and non-thrombocytopenia were analyzed. Findings Among all 167 patients, the median age was 66 years and 67.07% were male. Significant differences were noticed in laboratory findings including white blood cells, blood urea, total bilirubin, lactate dehydrogenase and SOFA score between groups of thrombocytopenia and non-thrombocytopenia. Older age, lower platelet count and longer activated partial thromboplastin time at admission were determined to be risk factors of 28-day mortality, and all three, together with higher white blood cells were risk factors of 180-day mortality. Subsequent changes of six-point ordinal scale score, oxygenation index, and SOFA score in patients with thrombocytopenia showed marked worsening trends compared with patients without thrombocytopenia. Patients with thrombocytopenia had significantly higher mortality not only in 28 days, but also in 90 days and 180 days. The time-course curves in non-survival group showed a downtrend of platelet count and oxygenation index, while the curve of six-point ordinal scale kept an uptrend. Kaplan-Meier analysis indicated that patients with thrombocytopenia had much lower probability of survival (p<0.01). Interpretation The thrombocytopenia was associated with the deterioration of respiratory function. Baseline platelet count was associated with subsequent and long-term mortality in critically ill COVID-19 patients.


2020 ◽  
Vol 5 (7) ◽  

Though multiple myeloma cancer (MMC) remains incurable, research into improving the therapeutic strategy has increased dramatically in recent years. But it is unclear if sustained improvements have been achieved. We studied the survival times of 48 patients diagnosed and treated with alkylating agents. The semi-parametric Cox proportional hazard model was employed to examine the survival probability taking into account the sixteen risk factors presumed to be contributing to the survival times. A careful and rigorous assessment of the risk factors based on the AIC of the stepwise selection technique revealed seven risk factors, and one interaction term are statistically significantly contributing to the survival times. They are blood urea nitrogen (BUN)/serum creatinine, white blood cells (WBC), Bence Jone protein in the urine (BJPU), fractures, proteinuria, gender, platelets, and the interaction of infections and serum calcium. The final Cox-PH model was well-validated and satisfied the key assumptions. The identified risk factors are rank according to the prognostic effect on the survival time based on the hazard ratio. Blood urea nitrogen (BUN)/serum creatinine was the greatest prognostic factor (most contributing factor, and highly negatively related to the MMC deaths or survival times), followed by white blood cells (WBC), and normal platelet was found to be the minimum prognostic factor (least contributing factor to MMC death or survival times). This study offers prognostic and therapeutic significance for further enhancement in the treatment strategy of the multiple myeloma cancer disease.


2014 ◽  
Vol 926-930 ◽  
pp. 1049-1053
Author(s):  
Ming San Miao ◽  
Lin Guo ◽  
Shuo Tian

Abstract Objective: To investigate the effect of Motherwort total alkaloids on prostatitis model of mice.Methods:Different groups of mice for Motherwort total alkaloids are given high,medium,low suspension.Observe the number of white blood cells , lecithin corpuscle density groups in prostatic fluid and the morphological changes of prostate,testis, epididymis.Results:Compared with the model group, the Motherwort total alkaloidss high, medium dose group can significantly reduce the number of white blood cells of prostate in mice model of prostatitis and increase lecithin corpuscle number (P<0.01); the Motherwort total alkaloidss high dose group significantly reduce the pathological changes of prostatitis (P<0.01); the Motherwort total alkaloidss medium dose group significantly reduce the pathological changes of prostatitis (P<0.05). the Motherwort total alkaloidss high dose group significantly reduce the pathological changes of testis (P<0.05)and it can significantly reduce the pathological changes of the epididymis (P<0.01).Conclusion:Motherwort total alkaloids has a therapeutic effect on prostatitis model of mice .


2019 ◽  
Vol 143 (2) ◽  
pp. 131-139 ◽  
Author(s):  
Elena Parovichnikova ◽  
Vera Troitskaya ◽  
Andrey Sokolov ◽  
Olga Gavrilina ◽  
Zalina Akhmerzaeva ◽  
...  

T-cell acute lymphoblastic leukemia (T-ALL) is a rare disease usually treated with intensive, high-dose consolidation chemotherapy followed by an allotransplant in a substantial number of patients. The data of the RALL-2009 study on 125 adult T-ALL patients suggest that similar total chemotherapy doses given less intensively over a longer interval without interruptions and with an auto- rather than an allotransplant produce outcomes like current more intensive protocols and an allotransplant: 9-year cumulative incidence of relapse (CIR), leukemia-free survival (LFS), and survival were 24% (95% CI 16–33%), 70% (95% CI 59–79%) and 62% (95% CI 51–72%). In a landmark analysis, subjects achieving a complete remission and receiving an autotransplant had a lower 9-year CIR (9% [95% CI 2–22%] vs. 29% [95% CI 16–43%]; p = 0.0076) and better LFS (91% [95% CI 79–98%] vs. 58% [95% CI 41–74%]; p = 0.0009) and survival (92% [95% CI 77–99%] vs. 60% [95% CI 44–77%]; p = 0.001) compared with subjects not receiving an autotransplant. In a multivariate analysis, white blood cells ≥100 × 109/L at study entry were significantly associated with worse LFS (HR = 2.842 [95% CI 1.131–7.143]; p = 0.0263) and survival (HR = 6.085 [95% CI 1.918–19.3]; p = 0.0022) because of more early deaths (HR = 2.42 [95% CI 1.04–5.67]; p = 0.041). Receiving an autotransplant correlated with a lower CIR (HR = 0.23 [95% CI 0.07–0.73]; p = 0.0136) and better LFS (HR = 0.27 [95% CI 0.08–0.85]; p = 0.0256) and survival (HR = 0.158 [95% CI 0.045–0.550]; p = 0.0037).


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3378-3378 ◽  
Author(s):  
Jeffrey R Shearstone ◽  
Apurva Chonkar ◽  
Kailash Bhol ◽  
Simon S Jones ◽  
Matt Jarpe

Abstract Elevated levels of HbG mRNA, leading to the formation of fetal hemoglobin, is known to ameliorate disease severity in sickle cell and β-thalassemia patients. We have previously shown that the small molecule ACY-957 is a selective inhibitor of HDAC1/2 which induces HbE and HbG in cultured human primary CD34+ cells (Shearstone et al, ASH Annual Meetings 2012-14). In this work, we describe the pharmacokinetics and HbE/HbG induction following once daily oral dosing of ACY-957 in rat and monkey. To determine the duration of ACY-957 exposure required to induce HbE and HbG in vivo, we first tested ACY-957 in drug washout experiments performed in cultured primary erythroid progenitors. The aminobenzamide class of HDAC inhibitors, such as ACY-957, are known to have slow on rates for HDAC1/2 (Kral et al, Biochemistry 2014; Lauffer et al, J Biol Chem 2013). We found that a 6 h pulse of ACY-957 (1 μM) resulted in undetectable increases in histone H3 lysine 9 acetylation (H3K9ac) and that 4 or 8 h pulses of ACY-957 (1 μM) resulted in undetectable HbE and HbG induction. However, continued exposure resulted in a 2.5-fold and 7-fold increase in H3K9ac after 24 and 48 h of incubation, respectively, leading to a time-dependent increase in HbE and HbG. Based on this data, we hypothesized that in vivo studies would require ACY-957 levels of 1 μM for 24 h in order to observe elevated HbE and HbG. Non-fasted Sprague Dawley rats or cynomolgus monkeys received a single oral dose of 20 mg/kg or 12.5 mg/kg ACY-957, respectively, and pharmacokinetic analysis yielded comparable results with T1/2 = 11.8 and 10.9 h, Cmax = 7.8 and 2.4 μM, and Tmax = 5.3 and 4.0 h, in rat and monkey, respectively. At 24 h post dose, ACY-957 plasma levels in rat and monkey were 1.6 and 0.6 μM, respectively. These findings suggested that the targeted drug exposure could be met with a single daily oral dose of ACY-957. Since ACY-957 induced HbE in cultured human primary erythroid progenitors, we attempted to measure HbE induction in rat as a surrogate marker for HbG in primate. Rats were dosed with 0, 10 or 30 mg/kg (n=4 per group) by oral gavage, once daily for 6 days, followed by a 13 day washout period. Peripheral blood was sampled every 3 days for isolation of total RNA. Complete blood counts were performed on day 0, 6 and 18. The low and high dose groups showed ACY-957 plasma levels of 1.3 or 5.2 μM, respectively, at 24 h post final dose. No abnormal clinical signs were found during the in-life phase, although a minor, reversible delay in rat weight gain was observed in the high dose group. White blood cells were suppressed by 33% and 68% at day 6 in low and high dose groups, respectively, but recovered to baseline levels by day 18. ACY-957 administration led to a dose-dependent increase in HbE relative to HbB that was detectable at day 3, peaked at day 6, and returned to baseline levels by day 9. Maximum induction of HbE was 2-fold and 5.6-fold for the low and high dosing groups, respectively, relative to animals receiving vehicle only. Next, monkeys were dosed at 0, 25 or 75 mg/kg (n=3 per group) by oral gavage, once daily for 5 days, followed by a 14 day washout period. Peripheral blood was sampled every 2 to 3 days for isolation of total RNA and analysis of complete blood counts. The low and high dose groups showed ACY-957 plasma levels of 1.9 or 8.0 μM, respectively, at 24 h post final dose. No abnormal clinical signs were found during the in-life phase. White blood cells were suppressed by 25% and 61% at day 5, but recovered to baseline levels by day 9. ACY-957 administration led to a dose-dependent increase in HbE and HbG relative to HbB that was detectable at day 5, peaked at day 7, and returned to baseline levels by day 12. Maximum induction of HbG was 2.2-fold and 7.2-fold for the low and high dosing groups, respectively, relative to animals receiving vehicle only. These results demonstrate that ACY-957 induces HbE in rat and HbG in monkey to a similar extent. ACY-957 appeared well tolerated in both animals, although a reversible suppression of white blood cells was observed. Together, these findings suggest that optimization of dose and schedule could be performed in rats by monitoring HbE as a surrogate for HbG in primates. The optimized regime could then be validated in cynomolgus monkey. Accordingly, we have initiated experiments that explore the effects of several different ACY-957 dose schedules on HbE induction and white blood cell suppression in rats during a 4 week dosing and 2 week recovery period, which will also be presented. Disclosures Shearstone: Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Chonkar:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Bhol:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Jones:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership. Jarpe:Acetylon Pharmaceuticals, Inc.: Employment, Equity Ownership.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 215-215
Author(s):  
Corentin Orvain ◽  
Sylvain Chantepie ◽  
Xavier Thomas ◽  
Martine Escoffre-Barbe ◽  
Francoise Huguet ◽  
...  

Abstract Background: The prognosis of central nervous system (CNS) involvement in adult patients with acute lymphoblastic leukemia (ALL) has been historically associated with a dismal outcome. Whereas the prognosis of adult patients with ALL has greatly improved since the advent of pediatrics-inspired regimens, the prognostic impact of CNS involvement has not been formerly reevaluated. We report herein the impact of CNS involvement in patients included in the pediatric-inspired prospective GRAALL-2005 study. Methods: All patients received a 5-drug induction therapy with native E. Coli-ASP intravenous injections. Patients in complete remission (CR) received two consolidation courses with alternating cycles including high dose cytarabine (2g/m2/12h on days 1 and 2), high dose methotrexate (3 g/m2 on day 1), and cyclophosphamide. All patients in persistent CR and with no indication for allogeneic stem cell transplantation (SCT) received late intensification, followed by one last consolidation course. Patients with initial CNS involvement, clinically and/or cytologically (cerebrospinal fluid), were recommended to receive an increased number of triple intrathecal therapy, CNS irradiation, and were eligible for allogeneic SCT in first CR. They received less Asp injections during induction therapy to avoid CNS adverse events. CNS irradiation included two lateral fields encompassing the skull, facial, the base of the skull, and the first two cervical vertebrae at a dose of 24 grays for those not receiving allogeneic SCT and 15 grays for those receiving allogeneic SCT. Results: Between 2006 and 2014, 784 adult patients with newly diagnosed Philadelphia-negative ALL were included with 55 (7%) having initial CNS involvement. These patients were more likely to be of T-phenotype (51 versus 32%, p=.004) and had more white blood cells at diagnosis (median 23 G/l versus 11 G/l, p=.02). Most patients (36 pts, 66%) were classified as CNS-3 (&gt; 5 white blood cells/µl and a positive cytospin and/or clinical signs) whereas 5 patients (9%) were CNS-2 (&lt; 5 white blood cells/µl and a positive cytospin), and 14 (25%) have data pending. Among patients with details regarding CNS involvement, 25/41 (61%) had clinical signs including trigeminal anesthesia (9 pts, 36%), facial paralysis (4 pts, 16%), extremities paresthesia (4 pts, 16%), visual signs (2 pts, 8%), meningeal syndrome (2 pts, 8%), and motor deficit (2 pts, 8%), and 4/18 (22%) had radiological signs. Induction death, CR1 rate, and negative minimal residual disease after induction were similar whether patients had CNS involvement or not (6 vs 6%, 89 vs 89%, 73 vs 62%, 26 vs 22%, respectively). Patients with CNS involvement had a worse outcome than those without with a median event-free survival (EFS) of 391 days (versus not reached for patients without CNS involvement, HR: 1.7, 95% CI: 1.2 - 2.5, p=.002) and a median overall survival (OS) of 608 days (versus not reached for patients without CNS involvement, HR: 1.8, 95% CI: 1.3 - 2.6, p=.001) (figure). Similar results were observed when patients who received allogeneic SCT in CR1 were censored at the time of graft. As recommended, patients with CNS involvement were more likely to receive allogeneic SCT than those without (53 versus 34%, p=.01), with a median time of 169 days. A 150-day landmark analysis, excluding 12 patients with an EFS event before 150 days, was performed to study the impact of allogeneic SCT on the outcome of patients with CNS involvement. Allogeneic SCT had no impact on either EFS (HR: .5, 95% CI: .2 - 1.2, p=.15) or OS (HR: .8, 95% CI: .3 - 1.8, p=.53). Conclusion: Despite improved outcome in young adult ALL patients with pediatrics-inspired protocols, CNS involvement remains a poor-risk feature. The historical use of allogeneic SCT does not improve outcome. Specific regimens should be developed for adult ALL patients with CNS involvement. Figure 1 Figure 1. Disclosures Huguet: Amgen: Other: Advisor; BMS: Other: Advisor; Celgene: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Novartis: Other: Advisor; Pfizer: Other: Advisor. Barbieux: ASTRA-ZENECCA: Consultancy. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Boissel: Bristol-Myers Squibb: Honoraria, Research Funding; Servier: Consultancy, Honoraria; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; CELGENE: Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria. Mathilde: ABBVIE: Consultancy; SERVIER: Consultancy.


2020 ◽  
Vol 4 (2) ◽  
Author(s):  
Huaide Lin

Objective:  To analyze the factors affecting the efficacy of ?-interferon in the treatment of chronic hepatitis B (CHB). Methods: A total of 100 patients with CHB treated in our hospital from June 2018 to June 2019 were selected. All patients were treated with ?-interferon to evaluate the efficacy, and the factors affecting the effect of ?-interferon on CHB were analyzed. Results: After treatment, 54 patients fully responded and 46 patients did not; the levels of white blood cells, HBV DNA, and HBsAg in the complete response group were lower than those in the incompletely response group, and the differences were statistically significant (P <0.05); Multivariate logistic regression analysis found that serum HBV DNA and HBsAg were independent factors affecting the efficacy of ?-interferon in the treatment of CHB (OR> 1, P<0.05). Conclusion: Serum HBV DNA and HBsAg are risk factors that affect the efficacy of ?-interferon in the treatment of CHB. Monitoring the changes of serum HBV DNA and HBsAg levels has important clinical significance for predicting the efficacy.


2003 ◽  
Vol 197 (6) ◽  
pp. 711-723 ◽  
Author(s):  
Lynda Bennett ◽  
A. Karolina Palucka ◽  
Edsel Arce ◽  
Victoria Cantrell ◽  
Josef Borvak ◽  
...  

Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease characterized by flares of high morbidity. Using oligonucleotide microarrays, we now show that active SLE can be distinguished by a remarkably homogeneous gene expression pattern with overexpression of granulopoiesis-related and interferon (IFN)-induced genes. Using the most stringent statistical analysis (Bonferroni correction), 15 genes were found highly up-regulated in SLE patients, 14 of which are targets of IFN and one, defensin DEFA-3, a major product of immature granulocytes. A more liberal correction (Benjamini and Hochberg correction) yielded 18 additional genes, 12 of which are IFN-regulated and 4 granulocyte-specific. Indeed immature neutrophils were identified in a large fraction of SLE patients white blood cells. High dose glucocorticoids, a standard treatment of disease flares, shuts down the interferon signature, further supporting the role of this cytokine in SLE. The expression of 10 genes correlated with disease activity according to the SLEDAI. The most striking correlation (P &lt; 0.001, r = 0.55) was found with the formyl peptide receptor-like 1 protein that mediates chemotactic activities of defensins. Therefore, while the IFN signature confirms the central role of this cytokine in SLE, microarray analysis of blood cells reveals that immature granulocytes may be involved in SLE pathogenesis.


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