Hydroxyurea-related ileocecal region ulcers as a rare complication:A case report

BACKGROUND Hydroxyurea,an antimetabolite,is frequently prescribed for various hemato-logical disorders,and its common side effects include gastrointestinal problems,cutaneous or mucosal lesions and pyrexia/fever.CASE SUMMARY This study reports the case of a 67-year-old woman who developed recurrent abdominal pain after 10 years of continuous hydroxyurea therapy for primary thrombocythemia.Colonoscopy revealed an ileocecal ulcer.After discontinuing hydroxyurea therapy for 6 months,follow-up colonoscopy showed a significant reduction in the ulceration.CONCLUSION We consider cecal ulcers as a rare complication of hydroxyurea therapy which typically resolves upon stopping the drug.

Influence of Hemoglobin S Haplotypes on the Responses to Hydroxyurea Treatment in Children with Sickle Cell Disease in Abidjan, Côte d’Ivoire

Background: In Côte d’Ivoire so far, the circulating haplotypes have been inferred on the phenotypic profiling of SCD patients. The impact of the circulating haplotypes on the use of Hydroxyurea has not been assessed yet. Therefore the objective of this study is to identify in Abidjan the HbS haplotypes that modulate HU treatment responses. Methods: In a cross-sectional descriptive and analytical study, children aged 5 to 15 years with SCD, and carrying the hemoglobin phenotypes SSFA2 and SFA2, were recruited into a HU treatment cohort. Various parameters on the haplotypes and the outcomes of the treatment were analyzed. Results: Thirty nine children with SCD were included. The phenotypic profile of the cohort was 86.6% of SSFA2 and 15.4% of SFA2. Three haplotypes were found, the Benin haplotype, the Senegal haplotype, and an atypical one. The participants belonged to three genotypes, Benin/atypical (64.1%), Benin/Senegal (33.3%) and Senegal/Senegal (2.6%). Overall, HU treatment was successful in all haplotypes with 12 out of 39 patients failing treatment after 12 months in the Benin haplotype group. The association between HU treatment success and the Benin haplotype was found in terms of the decrease in the number of white blood cells and the students missing class. Conclusion: The study revealed that inferring haplotype based on the phenotypic profile could be inaccurate. The proportion of atypical haplotype that were not previously described in Côte d’Ivoire was high. All the haplotypes seemed to be associated with HU treatment success but some patients with Benin haplotype did not respond well.

Review on Hydroxyurea Usage in Young Children with Sickle Cell Disease: Examining Hemoglobin Induction, Potential Benefits, Responses, Safety, and Effectiveness

Sickle cell disease (SCD) is a prevalent condition, particularly in the countries of sub-Saharan Africa, where the presence of specific genes associated with Malaria contributes to its high prevalence. Patients with sickle cell disease frequently experience painful episodes necessitating hospitalization, and their hemoglobin levels are typically lower than those of the general population. There are different treatment options available to manage complications, such as transfusing blood, hydroxyurea, and strong anti-pains. However, with all these treatments, patients still commonly experience pain crises and suffer from organ damage. Hydroxyurea, the sole approved medication for sickle cell anemia in developed and developing countries, is widely used in children despite being primarily indicated for adults. Multiple studies have demonstrated the efficacy of hydroxyurea in inducing HbF production in young children with SCD. Elevated HbF levels have been associated with improved clinical outcomes, including a reduction in vaso-occlusive crises, acute chest syndrome, and the need for blood transfusions. Furthermore, increased HbF levels have been shown to ameliorate disease-related organ damage, such as pulmonary hypertension and sickle cell retinopathy. The response to hydroxyurea treatment in young children with SCD is variable. Some patients achieve substantial increases in HbF levels and experience significant clinical benefits, while others may have a more modest response. Factors influencing the response include baseline HbF levels, genetic modifiers, treatment adherence, and dose optimization. Safety is a crucial consideration when using hydroxyurea in young children. Studies have shown that hydroxyurea is generally well-tolerated, with the most common adverse effects being myelosuppression, gastrointestinal symptoms, and dermatological manifestations. However,long-term effects and potential risks, such as renal dysfunction and reproductive impacts, require further investigation. The effectiveness of hydroxyurea in young children with SCD has been demonstrated in various clinical trials and observational studies. These studies have shown a significant reduction in disease-related complications and improved quality of life. However, optimal dosing, treatment duration, and long-term outcomes are still areas of ongoing research. This review focuses on recent studies investigating the benefits, effectiveness, responses, and safety of hydroxyurea in pediatric individuals diagnosed with sickle cell disease.

Cistanche deserticola decoction alleviates the testicular toxicity induced by hydroxyurea in male mice

This study aimed to evaluate testicular toxicity induced by hydroxyurea （HU） and the possible counteracting effect of an aqueous extract of Cistanche deserticola （CD）. HU is an antineoplastic drug that has potential reproductive toxicity, and Herba Cistanche has been used as a tonic for the reproductive system for thousands of years. Sixty mice were randomly divided into five groups. Except mice in normal group, the rest received HU （400 mg kg^-1 body weight） intragastrically. Meanwhile, mice in normal and HU control groups received purified water, and the rest received intragastrically three doses of CD decoctions （1.5, 3.0 and 6.0 g crude drug kg^-1 body weight, respectively） daily for 4 weeks. Severe testes lesions were observed, testes weight （P〈0.01） and serum luteinising hormone levels （P〈0.0 1） were also decreased significantly, in the HU groups. Three doses of CD decoctions alleviated the spermatogenetic cell degeneration induced by HU and modulated the serum sex hormones levels to some extent.

The apoptosis of HEL cells induced by hydroxyurea

Hydroxyurea has been used to synchronize cultured cells to S-phase and used to treat patients with sicklecell anemia. Recently, we found that hydroxyurea can induce the apoptosis of HEL (human erythroleukemia) cells.The induced HEL cells showed ultrastructurally chromatin condensation with regular crescents at the nuclear edges and apoptotic bodies. However, the cells of K562, another human erythroleukemia cell line, did not show such morphological changes. Under fluoroscope, the HEL cells after induction often displayed a clear reduction in nuclear diameter and nuclear chromatin cleavage and condensation and the presence of nuclear ring and apoptotic bodies. Analysis with flow cytometry showed that the percentage of apoptotic cells is about 30-40% after HEL cells were induced by hydroxyurea for 3 days. DNA ladder can be observed by electrophoretic analysis.

Function of GATA transcription factors in hydroxyurea-induced HEL cells

HEL cells, a human erythroleukemia cell line, mainly express the fetal (r)globin gene and trace amount of the embryonic (E)globin gene, but not adult (B) globin gene. Here we show that hydroxyurea (HU) can induce HEL cells to express adult (B) globin gene and lead these cells to terminal differentiation. Results showed in Gel mobility shift assays that GATA factors could specifically bind to the regulatory elements of human B- globin gene, including the proximal regulatory element (the B- promoter) and the distal regulatory elements (the DNase I hypersensitive sites in the LCR, HS2-HS4 core sequences). However, the DNA binding patterns of GATA factors were quite different between HU-induced and uninduced HEL cells. Western-blot analysis of nuclear extracts from both the uninduced and HU- induced HEL cells revealed that the level of GATA-2 transcription factor decreased, whereas the level of GATA-1 transcription factor increased following the time of hydroxyurea induction. Furthermore, using RT-PCR analysis the expression of human B-globin gene in HU-induced HEL cells could be blocked again when HEL cells were incubated in the presence of antisense oligonucleotides for hGATA-1, suggesting that the upregulation of hGATA-1 transcription factor might be critical for the expression of human β- globin gene in HU-induced HEL cells.

INDUCTION OF C-MYC GENE AMPLIFICATION BY HYDROXYUREA AND ITS INHIBITION BY HOMOHARRINGTONINE

Induction of c-myc gene amplification in L1210 cells by hydroxyurea and its inhibition by homohar-ringtonine were investigated using the DNA-DNA molecular hybridization technique. When the cells were treated with hydroxyurea 1.0 mM for 16 hours, and incubated a further 16 hours in a drug-free medium, the c-myc gene amplified 23.5-fold. If homohar-ringtonine 50 μM was used at the same time as hydroxyurea, gene amplification did not occur. Cycloheximide, an inhibitor of protein biosynthesis, produced a similar effect. Our results indicated that a (or some) protein factor(s) might be involved in gene amplification. Detailed analysis showed that the synthesis of this protein factor(s) started 4 hours before the initiation of the S phase but did not continue in the S phase. It was also found that this protein factor(s) was very labile and began to degrade 2 hours after its appearance.

Hydroxyurea-induced cutaneous squamous cell carcinoma: A case report

BACKGROUND Hydroxyurea(HU)is a non-alkylating antineoplastic agent that is active in the Sphase of the cell cycle and inhibits the enzyme ribonucleoside reductase.HU is currently used to treat leukemia,sickle cell anemia,psoriasis,and chronic myeloproliferative disorders.Although HU is easy to use and effective and has high tolerance,there have been numerous reports of cutaneous complications during long-term therapy with HU.CASE SUMMARY We report a 67-year-old woman on long-term HU therapy for primary myelofibrosis who developed concurrent skin lesions during treatment.The first skin lesion appeared on the dorsum of her right hand in 2015.Despite continuous use of HU,her cutaneous changes were neglected.Approximately 3 years ago,she had multiple nodular and keratotic lesions on both hands with sharp margins,branny desquamation,and dotted hyperpigmentation.Furthermore,she developed acutely numerous ulcerative lesions on her hands and legs.Topical wound therapy with dressing changes and parenteral antibiotics was applied for management of the lesions.Most of the wounds healed after HU withdrawal.Lesions on both hands were replaced by scabs.Nevertheless,the wound on her left ankle reached 9 cm×7 cm in size in January 2018.Pathology confirmed welldifferentiated squamous cell carcinoma at the ulcer area.In addition,her left foot was severely affected and radical surgery with a below-the-knee amputation was suggested followed by preventive right groin nodal dissection.CONCLUSION In patients receiving continuous HU therapy,close dermatologic follow-up is critical for the early diagnosis and selection of appropriate treatment for cutaneous lesions.

Gap Junctional Intercellular Communication Increases Cytotoxicity and Reduces Resistance to Hydroxyurea

Background: Gap junctions enable small molecules to diffuse between adjacent cells and have been associated with greater cytotoxicity of radiation and anti-cancer drugs. We investigated?whether this gap junctional intercellular communication (GJIC) affected the cytotoxicity of the classic?ribonucleotide reductase (RR) inhibitor and anti-cancer agent, hydroxyurea (HU). Materials and Methods: We used GJIC-proficient and deficient, connexin 43-expressing WB rat liver epithelial cell lines. We compared HU toxicity by crystal violet assay, effects of the drug on deoxynucleotide pools by HPLC, and ability of GJIC to increase toxicity of HU-resistant cells through a bystander effect in co-culture experiments. Results: GJIC-proficient cells were three- to five-fold more sensitive (IC50?0.1 mM) to HU than GJIC-deficient derivatives (IC50?0.3 - 0.5 mM). This sensitivity depended upon GJIC because treatment of GJIC-proficient cells with the GJIC blocker oleamide decreased HU toxicity by approximately 60% - 80% and restoration of GJIC in GJIC-deficient cells by stable transduction of connexin 32-encoding?Gjb1?increased HU toxicity (IC500.1 mM). The effects were not due to connexin expression?per se?or its localization since all cell lines expressed comparable quantities of connexin 43 that was localized to the plasma membrane. Also HU sensitivity was not related to differential effects on nucleotide metabolism in the cells. Thymidine triphosphate levels increased and deoxyadenosine triphosphate levels decreased similarly (15% - 20%) in GJIC-proficient and deficient cells over 24 h of HU treatment. More importantly, when HU-resistant cells were co-cultured with sensitive cells, the resistant cells were killed only when GJIC?was present. Conclusion: The data suggest that GJIC enhances cytotoxicity and decreases resistance?to HU. These results may be important clinically if GJIC can be enhanced in drug-resistant cells.

羟基脲(Hydroxyurea)对细胞周期与珠蛋白基因表达的影响(简报)

已有许多证据表明羟基脲能增加镰状细胞贫血及β-地贫病人的胎儿型血红蛋白(HbF)的合成。最近,有人报道羟基脲也能使一些患有β-地贫病人的β-珠蛋白基因表达增加。K562细胞是人红白血病细胞株,它只能表达胚胎型(ε-)与胎儿型(γ-)珠蛋白基因,而不能表达成年型(β-)珠蛋白基因。因此。

Treatment of β-Thalassemia With Hydroxyurea (HU)——Effects of HU on Globin Gene Expression

A newly developed method of RT-PCR/competitive PCR for measuring the relative and ab-solute content of globin mRNAs as well as micro-globin chain biosynthetic assay have been used to study thealterations of globin gene expressions in the patients with β-thalassemia pre-and post-hydroxyurea(HU)treatment.It was found for the first time that HU had the effect of enhancing β-globin gene expression insome patients.Two cases with β-thalassemia who were subjected to HU treatment for over two years showeda marked increase in β-globin mRNA level and β-globin chain synthesis,resulting in more effective erythro-poiesis and the alleviation of clinical symptoms.

IRF4 and IRF8 expression are associated with clinical phenotype and clinico-hematological response to hydroxyurea in essential thrombocythemia

The morbidity and mortality of myeloproliferative neoplasms(MPNs)are primarily caused by arterial and venous complications,progression to myelofibrosis,and transformation to acute leukemia.However,identifying molecular-based biomarkers for risk stratification of patients with MPNs remains a challenge.We have previously shown that interferon regulatory factor-8(IRF8)and IRF4 serve as tumor suppressors in myeloid cells.In this study,we evaluated the expression of IRF4 and IRF8 and the JAK2V617F mutant allele burden in patients with MPNs.Patients with decreased IRF4 expression were correlated with a more developed MPN phenotype in myelofibrosis(MF)and secondary AML(sAML)transformed from MPNs versus essential thrombocythemia(ET).Negative correlations between the JAK2V617F allele burden and the expression of IRF8(P<0.05)and IRF4(P<0.001)and between white blood cell(WBC)count and IRF4 expression(P<0.05)were found in ET patients.IRF8 expression was negatively correlated with the JAK2V617F allele burden(P<0.05)in polycythemia vera patients.Complete response(CR),partial response(PR),and no response(NR)were observed in 67.5%,10%,and 22.5%of ET patients treated with hydroxyurea(HU),respectively,in 12 months.At 3 months,patients in the CR group showed high IRF4 and IRF8 expression compared with patients in the PR and NR groups.In the 12-month therapy period,low IRF4 and IRF8 expression were independently associated with the unfavorable response to HU and high WBC count.Our data indicate that the expression of IRF4 and IRF8 was associated with the MPN phenotype,which may serve as biomarkers for the response to HU in ET.

羟基脲联合沙利度胺治疗JAK2V617F阳性骨髓增殖性肿瘤的临床疗效及安全性评价

目的研究羟基脲联合沙利度胺治疗JAK2V617F阳性骨髓增殖性肿瘤(MPN)的临床疗效及安全性评价。方法采用前瞻性分析方法,选取2020年1月—2023年1月在我院门诊或住院接受荧光定量PCR检测确定为JAK2V617F阳性MPN的患者80例为研究对象,根据治疗方案分为观察组(40例)与对照组(40例)。对照组采用沙利度胺治疗,观察组患者采用羟基脲联合沙利度胺治疗。统计并比较两组患者治疗前及治疗后6、12个月的临床疗效,JAK2V617F突变负荷,血小板(PLT)、白细胞(WBC)、血红蛋白(HGB)、红细胞比容(HCT)水平,骨髓纤维化程度,骨髓形态学及用药安全性。结果治疗后,观察组总有效率显著高于对照组(P<0.05);治疗后6、12个月,两组患者JAK2V617F突变负荷,PLT、HGB水平,MPN-10评分,MF分级均显著低于治疗前,且观察组均显著低于对照组(P<0.05);而WBC、HCT水平无明显变化(P>0.05);观察组患者骨髓细胞异常增生发生率明显低于对照组(P<0.05);两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论羟基脲联合沙利度胺治疗JAK2V617F阳性MPN患者具有显著效果,可有效改善临床症状,降低JAK2V617F阳性突变负荷,逆转骨髓纤维化水平。

羟基脲引起骨髓抑制致丹毒并伴疑似药物热1例

1临床资料患者男性,68岁,2023年9月4日主诉“间断头晕半年”入院。既往有“右侧下肢静脉曲张;高血压病”病史,否认血液病病史。入院查体:体温36.5℃;脉搏68次/min;血压142/71 mmHg(1 mmHg=0.133 kPa);经皮血氧饱和度91%~95%(低流量吸氧1 L/min);口唇及双手末端颜色发绀,双肺呼吸音粗,未闻及干湿性啰音。右侧上肢脉搏较左侧差。右侧下肢静脉曲张,小腿远端有皮肤色素沉着。

抗癌青黄汤、羟基脲片结合治疗慢性髓系白血病的疗效分析

目的观察对慢性髓系白血病患者使用抗癌青黄汤、羟基脲片治疗的效果。方法选取2021年3月—2023年5月本院收治的48例慢性髓系白血病患者为研究对象,并随机分为对照组和实验组,每组24例。其中,对照组采用羟基脲片治疗,实验组则采用羟基脲片+抗癌青黄汤治疗,对比两组治疗效果、安全性、血清学指标、症候变化分数。结果治疗前,两组骨髓中不成熟粒细胞水平、白细胞计数、症候变化对比,差异无统计学意义(P>0.05);治疗后,症候变化、骨髓中不成熟粒细胞水平、白细胞计数比较,实验组优于对照组,安全性、疗效比较,实验组优于对照组,差异有统计学意义(P<0.05)。结论慢性髓系白血病患者在接受羟基脲片联合抗癌青黄汤的综合治疗后,其病症控制效果及安全性得到了显著提升。该治疗方案有助于患者及早缓解各类不适症状,有效降低病情炎症因子水平,进而显著提高生存质量。

负压引流治疗白血病伴发的鼻中隔脓肿1例

慢性粒细胞性白血病伴发的鼻中隔脓肿临床并不多见,由于原发病本身难以根治,抗白血病药物又不能任意停用,其治疗过程中影响预后的不利因素自然要增加不少。对于这种特殊的鼻中隔脓肿患者,如何减轻有创操作的副反应,降低治疗风险从理论到实践均值得进一步探索。我科近期诊治1例患者,采用的是以脓肿穿刺置针行持续负压引流为主的治疗方法,取得了满意的治疗效果,现报告如下。

淫羊藿总黄酮对免疫功能低下小鼠的免疫增强作用

淫羊藿总黄酮对大剂量氢化考的松和羟基脲所致免疫功能低下模型小鼠免疫功能有增强作用．淫羊藿总黄酮能显著增强这两种模型的特异性免疫和非特异性免疫功能。

淫羊藿总黄酮促进免疫功能低下小鼠IL-2和NK活性的实验研究

目的 探讨淫羊藿总黄酮对免疫功能低下小鼠的免疫促进作用。方法 分别采用淫羊藿总黄酮 32 5 ,6 5 0和 130 0 mg/ (kg· d)与羟基脲 32 0 mg/ (kg· d) ,ig小鼠 ,同时以正常和模型小鼠作对照 ,实验第 11天用 3H - Td R掺入法和同位素释放法检测各组小鼠 IL- 2和 NK细胞活性 ,并计算脾脏指数。结果 淫羊藿总黄酮有拮抗羟基脲抑制模型小鼠 IL - 2和 NK细胞活性的作用 ,尤以 6 5 0 m g/ (kg· d)剂量组效果最为显著。模型组小鼠体重和脾脏指数与正常组和治疗组相比显著减少。

淫羊藿对小鼠MPS吞噬功能和红细胞免疫粘附功能的影响及相关性研究

目的 :探讨柔毛淫羊藿对MPS吞噬功能和红细胞免疫粘附功能的影响及在清除体内CIC过程中这 2种功能的相关性。方法 :采用炭粒廓清试验法、红细胞酵母菌混合花环法、PEG沉淀法进行免疫指标检测。结果 :发现柔毛淫羊藿可显著提高羟基脲所致免疫功能低下小鼠炭粒廓清指数 (P <0 0 5 ) ,升高RBC C3bR花环率 (P <0 0 1) ,降低RBC IC花环率 (P <0 0 1) ,降低血清CIC含量 (P <0 0 1) ,相关分析表明 ,各组小鼠炭粒廓清指数与RBC C3bR花环率呈正相关 (r =0 71～ 0 78) ,与RBC IC花环率呈负相关 (r =- 0 72～ - 0 80 )。结论 :柔毛淫羊藿可显著促进免疫功能低下小鼠MPS的吞噬能力和红细胞免疫粘附功能 ,降低体内CIC ,而正常的MPS吞噬功能是红细胞发挥有效免疫粘附IC作用的重要前提。

大蒜根尖细胞有丝分裂同步化诱导与中期染色体分离

本研究以大蒜（Ａｌｌｉｕｍ ｓａｔｉｖｕｍ）根尖为材料，用ＨＵ－ ＡＰＭ 双阻断法对细胞有丝分裂中期同步化和前、后、末期部分同步化作了探讨，表明在１．２５ｍ ｍｏｌ／ＬＨＵ，４μｍｏｌ／ＡＰＭ 处理可使细胞有丝分裂中期指数（Ｍｅｔ．Ｉ）达３５％ ，１８ｈｒ 的ＨＵ 单独处理可检测到２７％ 的前期分裂细胞。ＨＵ 对后、末期的部分同步化也有明显作用，约有１７％ 的后、末期细胞被检测到。用Ｓｃｈｕｂｅｒｔ 介绍的方法，分离出中期染色体，每微升悬浮液中含１７０ 条染色体。