Gene signatures to therapeutics:Assessing the potential of ivermectin against t(4;14)multiple myeloma

BACKGROUND Multiple myeloma(MM)is a terminal differentiated B-cell tumor disease characterized by clonal proliferation of malignant plasma cells and excessive levels of monoclonal immunoglobulins in the bone marrow.The translocation,(t)(4;14),results in high-risk MM with limited treatment alternatives.Thus,there is an urgent need for identification and validation of potential treatments for this MM subtype.Microarray data and sequencing information from public databases could offer opportunities for the discovery of new diagnostic or therapeutic targets.AIM To elucidate the molecular basis and search for potential effective drugs of t(4;14)MM subtype by employing a comprehensive approach.METHODS The transcriptional signature of t(4;14)MM was sourced from the Gene Expression Omnibus.Two datasets,GSE16558 and GSE116294,which included 17 and 15 t(4;14)MM bone marrow samples,and five and four normal bone marrow samples,respectively.After the differentially expressed genes were identified,the Cytohubba tool was used to screen for hub genes.Then,the hub genes were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis.Using the STRING database and Cytoscape,protein–protein interaction networks and core targets were identified.Potential small-molecule drugs were identified and validated using the Connectivity Map database and molecular docking analysis,respectively.RESULTS In this study,a total of 258 differentially expressed genes with enriched functions in cancer pathways,namely cytokine receptor interactions,nuclear factor(NF)-κB signaling pathway,lipid metabolism,atherosclerosis,and Hippo signaling pathway,were identified.Ten hub genes(cd45,vcam1,ccl3,cd56,app,cd48,btk,ccr2,cybb,and cxcl12)were identified.Nine drugs,including ivermectin,deforolimus,and isoliquiritigenin,were predicted by the Connectivity Map database to have potential therapeutic effects on t(4;14)MM.In molecular docking,ivermectin showed strong binding affinity to all 10 identified targets,especially cd45 and cybb.Ivermectin inhibited t(4;14)MM cell growth via the NF-κB pathway and induced MM cell apoptosis in vitro.Furthermore,ivermectin increased reactive oxygen species accumulation and altered the mitochondrial membrane potential in t(4;14)MM cells.CONCLUSION Collectively,the findings offer valuable molecular insights for biomarker validation and potential drug development in t(4;14)MM diagnosis and treatment,with ivermectin emerging as a potential therapeutic alternative.

Efficacy and safety of ivermectin in patients with mild and moderate COVID-19:A randomized controlled trial

Objective:To evaluate the effectiveness and safety of ivermectin in patients with mild and moderate COVID-19.Methods:This study was a single-center,randomized,open-label,controlled trial with a 2-arm parallel-group design on 68 patients with COVID-19.According to the 1:1 ratio between the study groups(ivermectin group and standard treatment group),patients were randomly admitted to each intervention arm.Results:The mean age of the participants in the ivermectin group was(48.37±13.32)years.Eighteen of them were males(54.5%)and the participants in the control group had a mean age of(46.28±14.47)years,with nineteen of them being males(59.4%).As a primary outcome,after 5 days of randomization,there was no significant difference between the ivermectin group and the control group in the length of stay in the hospital(P=0.168).ICU admission(P=0.764),length of stay in ICU(P=0.622),in-hospital mortality(P=0.427),adverse drug reactions,and changes in the mean difference of laboratory data had not any significant difference between the two groups(except for urea change).In addition,the radiologic findings of the two groups of patients were not significantly different.Linear regression analysis showed that for every 10 years increase of age,0.6 day of hospitalization duration was increased.There was no statistically significant association between other variables and clinical outcomes.Conclusions:Among adult hospitalized patients with moderate to severe COVID-19,there was no significant relationship between the administration of ivermectin single dose in a five-day course and clinical improvement,and mortality of the participants.

Ivermectin的制剂研究

Ｉｖｅｒｍｅｃｔｉｎ的制剂研究扈洪波朱蓓蕾李俊锁中国农业大学动物医学院北京１０００９４Ａｖｅｒｍｅｃｔｉｎｓ（ＡＶＭ）是目前世界上最为优良的一类广谱高效抗寄生虫药。对该类药物的结构改造和制剂研究是近些年来兽药研究领域的热点课题。通过结构改造，现已成功...

Ivermectin缓控释制剂的研究进展

近年来 ,ivermectin(伊维菌素 ,IVM)缓、控释制剂广泛应用于动物寄生虫及多种疫病的防治 ,本文就其作用、制剂、优点。

Pharmacokinetics of Ivermectin in Salvelinus leucomaenis Following Two Ways of Administration

[Objective] This study was aimed to study the pharmacokinetics of iver- mectin in Salvelinus leucomaenis following a single oral administration or intraperi- toneal injection. [Method] After a single oral administration or intraperitoneal injection of ivermectin with a dosage of 0.3 mg/kg body weight, samples were taken at dif- ferent time points and determined by high-performance liquid chromatography-ultravi- olet detection （HPLC-UV）. The pharmacokinetic parameters were calculated by 3p97 software. [Result] The concentration-time relations of ivermectin in plasma, muscle, liver and kidney were well described by one-department open model with first-order absorption. After oral administration, the pharmacokinetic parameters in plasma were as follows： Tmax=4.503 h, Cmax=0.252mg/L, t1/2ka=0.476 h, t1/2ka=331.160 h, AUC=121.524 （mg/L） .h. After intraperitoneal injection, the pharmacokinetic parameters in plasma were as follows： Tmax=2.751 h, Cmax=0.230 mg/L, t1/2ka=0.306 h, t1/2ka=153.868 h, AUC= 51.689 （mg/L） .h. [Conclusion] There were differences in the pharmacokinetics of ivermectin in Salvelinus leucomaenis between two different administration routes, and intraperitoneal injection led to more rapid absorption than oral administration.

Ivermectin 驱猪消化道线虫试验报告

Ivermectin 是美国默克公司生产的驱除线虫及体外寄生虫的广谱驱虫药,该药属大环内脂类化合物,是由放线菌 Streptomy-ces avermitilis 经发酵而得。为评价 Iverm-ectin 驱除肠道线虫的效果及对猪的安全性。采用300ug/kg 剂量一次皮下注射进行了二批试验。Ivermectin 试验猪共55头,对照猪40头,均为自然感染猪。效果检查包括:试验前后各种线虫虫卵的数量变化,每组于用药后14天各解剖5头猪,以观察药物的驱虫效果。结果表明 Ivermectin 能有效地驱除猪蛔虫,有齿食道口线虫、类圆线虫、但对鞭虫仅有60%的驱净率。

伊维菌素(Ivermectin)晶体结构的研究

用单晶Ｘ射线衍射法测定了伊维菌素Ｉｖｅｒｍｅｃｔｉｎ（Ｈ２Ｂ１ａ）的结构。Ｉｖｅｒｍｅｃｔｉｎ由大于８０％的Ｈ２Ｂ１ａ和小于２０％的Ｈ２Ｂ１ｂ组成。Ｈ２Ｂ１ａ属单斜晶系，Ｃ２空间群，晶胞参数为ａ＝４０７６３（６）Ａ，ｂ＝９２９５（３）Ａ，ｃ＝１４９６６（３）Ａ，β＝１０６９３（１）°，Ｖ＝５４２５（２）Ａ３，Ｚ＝４，Ｄｃ＝１１５６ｇ·ｃｍ－３，μ（ＭｏＫ∞）＝００８４ｍｍ－１，Ｒ＝００６５８。Ｈ２Ｂ１ａ呈沿Ｃ轴排列的链状结构，同时通过２次轴对称，实际结构为由两条链状分子呈平行分布，相互间距离一定，但方向相反的双链，类似于生物大分子的链状结构。

Syntheses and Bioactivity of 4″-Sulfonate-5-triphenylsilyl Avermectin B_(1a) and Ivermectin B_(1a) Derivatives

Fourteen new derivatives of avermectin B_(1a) and ivermectin B_(1a) were synthesized from C_5-O-triphenylsilyl avermectin B_(1a) and ivermectin B_(1a)(yield from 40% to 83%). Their chemical structures were characterized by means of IR, ()~1H NMR, ()^(13)C NMR and FAB-MS spectrometries. Some of them show excellent insecticidal activity.

Clinical pharmacokinetics profile of ivermectin 1% cream after dermal applications on the face

AIM: To investigate the pharmacokinetics profile of Ivermectin 1% cream after topical treatment in patients with papulopustular rosacea(PPR).METHODS: Ivermectin 1% cream is a new, effective, and safe treatment for PPR. The human pharmacokinetic(PK) profile of ivermectin and its circulating metabolites were assessed following topical application of ivermectin 1% cream to the face. Clinical PK assessments were conducted after 4 wk of treatment using healthy volunteers and PPR subjects. Additionally, PK sampling was conducted up to 1 year of treatment in clinical phase 3 studies. Plasma concentrations of ivermectin and ivermectin metabolites were determined using high-performance liquid chromatography with fluorescence detection after a specific derivation to increase sensitivity.RESULTS: Systemic exposure to ivermectin was quantifiable at low levels in healthy and moderate to severe PPR subjects following the first topical application of ivermectin 1% cream(mean Cmax of 0.5 ± 0.2 ng/mL and 0.7 ± 0.5 ng/mL in healthy volunteers and PPR subjects, respectively). Ivermectin plasma levels reached a plateau after 2 wk of repeated topical application, indicating that steady-state concentrations had been reached. No further ivermectin plasma accumulation was observed during the long-term clinical studies that investigated ivermectin treatment up to 1 year. Investigation of ivermectin metabolites indicated that 2 circulating metabolites represented more than 10% of parent drug systemic exposure at steady state. Repeated topical application of ivermectin 1% cream resulted in lower systemic exposure levels when compared with orally administered ivermectin, suggesting limited transdermal absorption of ivermectin. Topically applied ivermectin is cleared from the plasma slowly(with a prolonged plasma half-life when compared to the oral route).CONCLUSION: Applications of ivermectin 1% cream result in low systemic exposure levels. Steady–state conditions are achieved by 2 wk without further accumulation under chronic treatment.

Efficacy and safety of ivermectin for COVID-19:A systematic review and meta-analysis

Objective:To critically evaluate the trials that have assessed the efficacy and safety of ivermectin COVID-19 and to validate the rationality of using this drug in the management of COVID-19 either as a prophylactic or therapeutic agent.Methods:The authors conducted a systematic search through various databases,i.e.,Cochrane library,Pub Med,clincialtrials.gov,and preprint servers,for publications from 2020 to May 2021.The keywords used for the search were:"COVID-19 and ivermectin"(with filter set for"trials").All the trials assessing efficacy in prophylaxis and treatment of COVID-19 were included for analysis.The primary outcome was the proportion of patients showing disease progression.Secondary outcomes were mean duration of hospitalization and resolution of symptoms,the proportion of patients testing positive on day 5-7,the mortality rate in severe cases,incidence of serious adverse events,and contacts of COVID-19 positive patients who turned RT-PCR positive after prophylaxis treatment.Results:A total of 17 clinical trials were included for the evaluation.Ivermectin proved to be a beneficial add-on therapy,as it reduced the risk of disease progression(OR 0.47,95%CI 0.30-0.74,P=0.001),led to early resolution of symptoms(MD-1.16,95%CI-1.52--0.81,P<0.001),and had less duration of hospitalization(MD-2.21,95%CI-3.23--1.19,P<0.001).In addition,ivermectin was better in providing effective prophylaxis(OR 0.13,95%CI 0.05-0.30,P<0.001).The incidence of serious adverse events was low.Conclusions:As an adjunct to standard care,ivermectin has shown its efficacy and safety in treating and prophylaxis in COVID-19 disease.These results should be interpreted cautiously as these trials had significant shortcomings.

Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: A randomized multi-center clinical trial

Objective: To evaluate different doses of ivermectin in adult patients with mild COVID-19 and to evaluate the effect of ivermectin on mortality and clinical consequences.Methods: A randomized, double-blind, placebo-controlled, multicenter clinical trial was performed at five hospitals. A total of 180 mild hospitalized patients with COVID-19 confirmed by PCR or chest image tests were enrolled and allocated to six arms including hydroxychloroquine 200 mg twice per day, placebo plus hydroxychloroquine 200 mg twice per day, single dose ivermectin(200 μg/kg), three low interval doses of ivermectin(200, 200, 200 μg/kg), single dose ivermectin(400 μg/kg), and three high interval doses of ivermectin(400, 200, 200 μg/kg). The primary endpoint of this trial was all-cause of mortality or clinical recovery. The radiographic findings, hospitalization and low O_2 saturation duration, and hematological variables of blood samples were analyzed. Results: A total of 16.7%(5/30) and 20.0%(6/30) patients died in arms treated with hydroxychloroquine 200 mg twice per day and placebo plus hydroxychloroquine 200 mg twice per day, respectively, and a reduction in mortality rate in patients receiving ivermectin treatment to 0%, 10%, 0% and 3.3% for arms 1-4 were observed. Risk of mortality was also decreased about 15% in the ivermectin treated arms. Conclusions: Ivermectin as an adjunct reduces the rate of mortality, time of low O_2 saturation, and duration of hospitalization in adult COVID-19 patients. The improvement of other clinical parametersshows that ivermectin, with a wide margin of safety, had a high therapeutic effect on COVID-19.

Reversal Effects of Ivermectin and Moxidectin on Multidrug Resistance in C6/adr Cells in vitro

Multidrug resistance(MDR)is a serious obstacle encountered in cancer treatment.This study was performed to explore the reversal MDR activity of ivermectin(IVM)from avermectin family and moxidectin(MOX)belonging to milbemycin family.The two compounds(5μmol•L-1)showed strong potency to increase adriamycin cytotoxicity toward adriamycin-resistant rat glioma cells C6/adr with fold reversal(FR)of 31.02 and 13.40,respectively.In addition,the mechanisms of them on p-glycoprotein(P-gp)-mediated MDR demonstrated that the two compounds significantly increased the intracellular accumulations of adriamycin and Rh123 via inhibiting P-gp efflux.Based on the analysis of P-gp,MDR1 and MRP1 gene expressions by using immunofluorescence flow cytometry and RT-PCR,the results revealed that the two compounds could down regulate the expression of P-gp,and that MDR1 and MRP1 gene expressions were down regulated.These findings suggested that ivermectin and moxidectin probably represented potent agents for reversing MDR in cancer therapy,and especially ivermectin was a better modulator.

Comparison of Two Pour-On Formulations of Ivermectin against Gastrointestinal Worms, Fleas and Lice in Naturally Infected Stray Dogs

The aim of the present study was to evaluate the efficacy of two commercial pour-on ivermectin formulations against intestinal parasites (IP), fleas and lice in naturally infested stray dogs. Eighteen crossbreed dogs with eggs of IP as well as adult fleas and lice were included in the trial. On day 0, the dogs were randomly divided into 3 groups of 6 animals each: a group receiving a single pour-on treatment with 0.5% ivermectin (500 mcg/kg), a group treated similarly with 0.2% iver-mectin (200 mg/kg), and a control group. Fecal and skin analyses were carried out on days 0, 7, 14, 21 and 28 to determine the reduction of eggs and the number of fleas and lice. Weight gain was also measured on day 28. On day 30, the dogs were humanely sacrificed in order to count adult IP. Efficacy was measured as the percentage of the reduction of eggs per gram fecal mass (EPGF), of adult IP, fleas and lice relative to the control group. For the eggs of IP, ivermectin at 0.5% showed an efficacy of 100% against ascarids and 79% against Ancylostoma caninum. ivermectin at 0.2% removed 90.2% of the ascarids and 50.4% of A. caninum. For adult IP, the efficacy of 0.5% iver-mectin against Toxocara canis and A. caninum was 100%, and for 0.2% ivermectin it was 62.4% and 76.4% for T. canis and A. caninum, respectively. Both compounds were 100% effective against lice and 96% and 71.1% efficacious against fleas, respectively. However, neither treatment was effective against Dypilidium caninum. Weight gain in treated dogs was statistically different from that of the controls (p < 0.05). We concluded that 0.5% pour-on ivermectin showed better efficacy than 0.2% pour-on ivermectin in the reduction of eggs and adult intestinal parasites and fleas;it was similarly efficacious against lice.

Evaluation of Onchocerciasis: A Decade of Post Treatment with Ivermectin in Zainabi and Ririwai Doguwa Local Government Area of Kano State

Rapid Assessment Method (RAM) were carried out to assess the current situation of Onchocerciasis after repetition of annual community directed distribution of Ivermectin in Zainabi and Ririwai of Doguwa Local Government area of Kano State. Certain manifestations, like nodules, leopard skin and blindness, were used to measure the endemicity level in the community. The subjects of 30 - 50 years who are engaged in rural occupation, resident in that community, were examined for the presence of nodules, skin lesion and blindness. The common manifestation in both communities is nodules with 3 (3.40%) and 2 (3.44%). Leopard skin and blindness were found in Zainabi with 2 (2.27%) and 2 (2.27%). The manifestation of Onchocerciasis was found in older age groups of 49 - 70 and 50 - 69 respectively, which give an indication that the disease was eliminated in the community due to mass distribution of Ivermectin in the previously known endemic community. We recommend mass distribution of Mectizan in other identified endemic foci.

国产伊维菌素(Ivermectin)驱除犬钩虫、巴西日圆线虫、鼠蛲虫的效果

目的观察国产伊维菌素对犬钩虫、巴西日圆线虫、鼠蛲虫的驱虫效果。方法采用犬钩虫—狗、巴西日圆线虫—大鼠及鼠蛲虫—大鼠动物模型进行研究。结果单次口服０．０２５ｍｇ／ｋｇ伊维菌素对犬钩虫的虫卵减少率、驱虫率和治愈率高达１００％，服药后４８ｈ内排出９７％虫体；单次灌胃０．６２ｍｇ／ｋｇ对巴西日圆线虫的驱虫率达９９．１％，完全治愈剂量为１．１１ｍｇ／ｋｇ；单次灌胃２．０ｍｇ／ｋｇ对鼠蛲虫的驱虫率和治愈率均达１００％。结论国产伊维菌素具有剂量小、疗效高、作用快、副反应轻等特点。

Ivermectin Efficacy against Triatoma infestans in vivo Using Hen Model

Chagas disease is endemic in south America. One of the major preventive actions is removing the vector TI （Triatoma infestans） from household. Although households are frequently sprayed to eliminate TI, pets and domestic animals are natural storage for vector survival. This work proposes TI elimination from farm animals using IVM （ivermectin）, as a new strategy to Chagas disease control. Rhode island hens were divided into TG （treatment groups） and CG （control groups）. TG received IVM while CG received DMSO. TI used in the assay was fifth instar nymphs. Hens served as food source for TI. Blood was extracted for IVM chromatographic pharmacokinetic analysis. The pharmacokinetic models that best fitted the IVM plasma profiles were determined by means of the minimum Akaike information criterion estimation （MAICE） test. In TG nymphs mortality was 23.25% to 47.5% at 24-120 h, respectively. IVM plasma profile showed a first-order one-compartment model with a rapid absorption reaching a Cmax （maximum concentration） of 64.7 ± 15.4 ng/mL at 48 h （Troop） post-application. Our data shows that TI mortality is directly related to the plasma concentration of IVM and is up to 47.5% at 120 h. Therefore, ivermectin may have a potential effect on controlling TI vector in peri-domestic level.

一种广谱新药伊维菌素(Ivermectin)治疗人体寄生虫病研究概况

伊维菌素(Ivermectin)系一种新大环内酯类抗生素埃维菌素(Avermectins)的衍生物,是由埃维链霉菌(Streptomyces avermitilis)产生的物质之一,具有广谱的抗寄生虫作用。1978年发现它对马盘尾丝虫和牛盘尾丝虫有杀灭效果,1981年开始对它进行临床试验,1983～1985年临床试验证实了疗效和安全性。

The combined effect of bromadiolone and ivermectin (iBr) in controlling both rodents and their fleas

Rodent pests not only cause severe agricultural loss but also spread zoonotic pathogens to human beings.Antico-agulant rodenticides are widely used to decrease the population densities of rodents but often lead to the spillover of ectoparasites becausefleas and ticks may gather on surviving rodents.Therefore,it is necessary to killfleas and ticks before culling rodents to minimize the risk of pathogen transmission.In this study,we used a mixture of ivermectin(an antiparasitic drug)and bromadiolone(an anticoagulant rodenticide)to control both rodent andflea/tick abundances.We found that in a laboratory test,0.01%ivermectin bait was not lethal for greater long-tailed hamsters after 7 days of treatment,while 0.1%ivermectin bait was lethal for approximately 33%of treated rodents.In afield test,bait containing 0.001%,0.005%,0.01%,and 0.05%ivermectin decreased the number offleas per vole of Brandt’s voles to 0.42,0.22,0.12,and 0.2,respectively,compared with 0.77 in the control group,indicating that 0.01%ivermectin bait performed best in removingfleas.In another laboratory test,bait containing a 0.01%ivermectin and 0.005%bromadiolone mixture caused the death of all voles within 6–14 days after the intake of the bait.In thefield test,the bait containing 0.01%ivermectin and 0.005%bromadiolone reduced the average number offleas per vole to 0.35,which was significantly lower than the 0.77 of the control group.Our results indicate that a 0.01%ivermectin and 0.005%bromadiolone mixture could be used to control both rodents andfleas to minimize the spillover risk of disease transmission when using traditional rodenticides.

Effectiveness of ivermectin mass drug administration in the control of soil-transmitted helminth infections in endemic populations: a systematic review and meta-analysis

Background Current soil-transmitted helminth(STH)control guidelines endorse the use of albendazole or meben-dazole for school-based targeted preventive chemotherapy(PC),yet their reduced efficacy against Strongyloides sterc-oralis and Trichuris trichiura presents significant limitations.Emerging evidence indicates that community-wide PC[or mass drug administration(MDA)]using ivermectin,commonly used in other neglected tropical disease(NTD)control programs,may play an important role in controlling these parasites.We conducted a systematic review and meta-analysis to evaluate the effectiveness of ivermectin PC in reducing STH prevalence in endemic populations.Methods We searched Pubmed,EMBASE,and Web of Science on February 14,2023,for studies that investigated the effectiveness of ivermectin PC,either alone or in combination with other anthelmintic drugs,on STH infec-tions,and provided a measure of STH prevalence before and after PC.We calculated pooled prevalence reductions for each STH using random-effects meta-analyses.Our protocol is available on PROSPERO(registration number CRD42023401219).Results A total of 21 were eligible for the systematic review,of which 15 were eligible for meta-analysis.All studies delivered ivermectin through MDA.The pooled prevalence reduction of S.stercoralis following MDA with ivermec-tin alone was 84.49%(95%CI:54.96-94.66)across five studies and 81.37%(95% CI:61.62-90.96)across seven studies with or without albendazole.The prevalence reduction of T.trichiura was 49.93%(95%CI:18.23-69.34)across five studies with ivermectin alone,and 89.40%(95%CI:73.66-95.73)across three studies with the addition of albendazole.There was high heterogeneity for all syntheses(I^(2)>65%).Conclusions This study underscores the key role of ivermectin-based MDA in addressing limitations in current global STH guidelines in terms of limited efficacy against S.stercoralis and T.trichiura.Based on these findings,revising inter-national STH guidelines to include ivermectin is a promising option to progress the control and eventual elimination ofSTHsandotherNTDs.