A series of valproic acid salicylanilide esters were designed and synthesized based on the principle of prodrug. The structures of the target compounds were confirmed by MS, 1H NMR and 13C NMR. Anti-tumor activities of these compounds against K562, A549, A431 cells in vitro were investigated by MTT assay and SRB assay. The results indicated that the compounds 6h-6j were found to have stronger cell growth inhibitory action than gefitinib, and comparable to niclosamide, which are worth to be intensively studied further.
Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Drug Design ; Esters ; Humans ; Inhibitory Concentration 50 ; K562 Cells ; Molecular Structure ; Prodrugs ; chemical synthesis ; chemistry ; pharmacology ; Salicylanilides ; chemical synthesis ; chemistry ; pharmacology ; Structure-Activity Relationship ; Valproic Acid ; chemical synthesis ; chemistry ; pharmacology

OBJECTIVETo study the effect of Oncomelania hupensis hupensis of niclosamide, and exploring the main influencing factors.

METHODSThe samples of Oncomelania hupensis hupensis were collected from 37 sampling sites in 33 counties of 10 provinces by means of stratified random sampling methods in accordance with the categories of Oncomelania hupensis hupensis habitats. Samples were randomly located into study group and control group. Oncomelania hupensis hupensis of the study group was marinated in different concentration liquor of niclosamide which was confected with water for 24 hours or 48 hours, then LC50 of niclosamide by which Oncomelania hupensis hupensis was killed and amount calculated. The influencing factors of the mortality of Oncomelania hupensis hupensis in the study group was statistically analyzed by 2 test and by multiple logistic regression using SPSS 13.0 statistical software.

RESULTSThe mortality of Oncomelania hupensis hupensis of the two test groups which were marinated in 0.5 mg/L liquor for 48 hours and 1.0 mg/L liquor for 24 hours was 100%. The effect of Oncomelania hupensis hupensis killed by niclosamide was markedly reduced along with the reduction of drug concentration. The average LC50 rates of niclosamide liquor by which Oncomelania hupensis hupensis killed for the 24 hours and 48 hours in the study group, were 0.0939 mg/L and 0.0625 mg/L, respectively. There was significant difference between the two test groups (chi(2) = 5.001, P <0.01) . In determinate range of concentration, the mortality of Oncomelania hupensis hupensis showed significant difference among the geographic types of habitat ( chi(2) = 4.264, P < 0.05). By means of multiple logistic regression using SPSS 13.0 statistical software, the estimate value of coefficient of regression on the influence factors, drug concentration, test time and the geographic types of habitat were 2. 047 ( OR = 5. 573), 0.263 ( OR = 2.924) and 0. 187- 0.210 ( OR = 1.969- 2. 560), respectively.

CONCLUSIONNiclosamide could kill Oncomelania hupensis hupensis effectively. The main influencing factors on the efficacy of niclosamide by which Oncomelania hupensis hupensis was killed, appeared to be drug concentration, time of testing and the geographic types of habitat.

Animals ; China ; Ecosystem ; Molluscacides ; toxicity ; Niclosamide ; toxicity ; Snails ; drug effects

Anthelmintic effect of niclosamide [N-(2-chloro-4-nitrophenyl)-5-chloro-salicylamide)] on Metagonimus infection was carried out to the cases in area of Seomjin-river. The drug, one tablet contains 0.5 g of niclosamide was supplied from Bu-gwang pharmaceutical company in Seoul. Sixty five cases were divided into three groups by the regimen: Group l given 2 g(4 tablets) for one day, Group II for two successive days and Group III for three successive days. Stool examination was done before and 2-3 weeks after the drug administration by formalin-ether concentration and Stoll's dilution egg counting techniques. The results were as follows: Egg negative conversion (cured) and egg reduction (more than 80 percent decrease) rates were 28.6 percent, 10.7 percent in group I, and 31.8 percent, 27.3 percent in group II. But of those in group III treated for three successive days, 73.3 percent was cured and 26.7 percent showed egg reduction, and the general egg reduction rate was 95.1 percent. The results in the present trial suggested that the niclosamide has anthelmintic efficacy when it is used in 2 g for more than three successive days.
parasitology-helminth-trematoda-Metagonimus yokogawai ; niclosamide-chemotherapy-metagonimiasis

The infection of Metagonimus yokogawai has been known to be present nationwidely and endemic in some parts in Korea. In order to select a highly effective compound against Metagonimus infections, the therapeutic effects were observed in 156 cases who were treated with several anthelmintic i.e. bithionol, niclosamide, niclofolan and praziquantel. All of the above drugs showed highly effective to the treatment of metagonimiasis by a single or two medication days. The egg reduction rates were in the range of 80.2 to 100 per cent. However, relatively low cure rates(8.3 to 37.5 percent) were observed in the groups treated by two doses of 30 mg/kg of bithionol, a single day treatment with 100 mg/kg of niclosamide and two doses of 1.0 mg/kg of niclofolan. On the other hand, the high cure rates were observed at the following dose rates of each drugs, i.e. the cure rate of 66.7 percent was obtained at two doses of 100 mg/kg of niclosamide, 88.9 percent of cure rate was observed at two doses of 2.0 mg/kg of niclofolan and a single dose of 10 and 20 mg/kg of praziquantel were shown as 85.0 percent and 88.0 percent of cure rates respectively. But the complete radical cure was obtained in the group treated by two doses of 20 mg/kg of praziquantel in 10 metagonimiasis cases. From the above results praziquantel was shown as the most highly effective against metagonimiasis and it was well tolerated without any side effect. Therefore, praziquantel is a very promising drug for mass treatment against metagonimiasis.
parasitology-helminth-trematoda ; Metagonimus yokogawai-metagonimiasis ; bithionol ; niclosamide ; niclofolan ; praziquantel ; chemotherapy

Five cases of Diphyllobothrium latum infection were proved by collection of worms after treatment with bithionol, niclosamide or praziquantel, during 1975-1983. The patients were 4 males and one female aged 10-64 years residing in Seoul or Wando-gun, Chollanam-do, Korea. All of them remembered the history of eating several kinds of raw marine fish and 2 persons said they ate the raw flesh of perch, Lateolabrax japonicus. Three among them experienced abdominal pain, 2 natural discharge of a chain of segments, but none revealed any sign of anemia. The average egg size in stool varied 59-67 x 41-48 micrometer according to cases. The eggs were characterized by ovoid to elliptical shape, terminal operculum, and distinct abopercular protuberance. One naturally discharged segment (30 cm) and 4 complete strobilae (320~680 cm) with scolices obtained after treatments were examined. The morphological characters of proglottids such as rosette-form uterus with 3-6 loops, vaginal pore included in the cirrus sac, separated seminal vesicle from cirrus sac etc. were all compatible with D. latum. These are the 7th~11th cases of D. latum infection proved by worms in Korea.
parasitology-helminth-cestoda ; Diphyllobothrium latum ; case report ; diphyllobothriasis ; chemotherapy-praziquantel ; niclosamide ; bithionol ; praziquantel

OBJECTIVETo prove that synthetic Are combination with snail-killing drug Nic can increase the effects of snail-killing remarkably.

METHODSIn indoor immersing experimentation, the experiments were divided into 4 groups, 30 snails in each group, to observe the rate of opening operculum, the rate of climbing adhesion and the rate of death at 3, 6 and 24 hours respectively. In field experimentation, we intermixed 0.1 mg/L Are with 0.2 mg/L Nic as sample as contrasted with 2 mg/L Nic and non-drug group. Immersing method (we chose three slots each size were 10 m x 2 m x 1 m.) and insufflation method (we chose three patch of bottomlands each area were 10 m x 5 m.) were used to kill snails separately and the death rate of fish, at the same time was observed.

RESULTSIn the room, as we added 0.1 mg/L Are to the solution of 0.1 mg/L and 0.2 mg/L Nic separately, the opening operculum rate for 6 hours was increased from 20% and 12% to 100% and 95%, the climbing adhesion rate for 6 hours decreased from 17% and 53% to 3% and 5%, the death rate for 24 hours increased from 25% and 40% to 90% and 100%. In the field, the snails death rate in sample group and in contrastive group applied with immersing method and insufflation method for 72 hours were 95.9%, 93.3% and 100%, 95.8%; only one small fish (2 cm long) died in sample group, and all fishes died in Nic group, and all fish were alive in non-drug group.

CONCLUSIONIt proved that synthetic Are combination with snail-killing drug Nic might decrease Nic dosage and toxicity and increase the effects of snail-killing.

Animals ; Arecoline ; pharmacology ; Drug Synergism ; Molluscacides ; pharmacology ; Niclosamide ; pharmacology ; Snails ; drug effects

OBJECTIVETo evaluate the effect of snail control through soil pasting mixed with niclosamide.

METHODSFour sites were selected in different epidemic areas in Sichuan province. Soil pasting mixed with niclosamide was carried on, and the dosage was 0 g/m2, 4 g/m2, 6 g/m2, 8 g/m2 and 10 g/m2 respectively. The mortality rate of snail and the density of snail were observed after 7, 15, 30, 90 and 180 days.

RESULTSThe mortality rate of snail was more than 43.3% in blank group after 30 days. The mortality rate of snail was from 75.3% to 100.0% at 4 g/m2 group after 30 days. The mortality rate of snail in 4 g/m2 group was significantly higher than that in the blank group (chi2 = 31.27, P < 0.05). There was no significant difference in the mortality rate of snail among all study groups (chi2 = 1.07, P > 0.05). The decrease rate of snail density was more than 90%. The mortality rate of snail was about 30% higher in Chantu group than Qutu group. The unit cost of Pasting-Mixing Drug with Soil was from 5 to 7 times of spray method, but the total cost was similar for the. two methods at the endpoint of the snail control.

CONCLUSIONThe effect of soil pasting mixed with niclosamide is good, and the dosage of 4-6 g/m2 is suggested in snail control.

Animals ; Molluscacides ; Niclosamide ; Pest Control ; Schistosomiasis ; epidemiology ; prevention & control ; Snails ; Soil

OBJECTIVE: To establish a snail control approach for spraying chemicals with drones against Oncomelania hupensis in complex snail habitats in hilly regions, and to evaluate its molluscicidal effect. METHODS: The protocol for evaluating the activity of spraying chemical molluscicides with drones against O. hupensis snails was formulated based on expert consultation and literature review. In August 2022, a pretest was conducted in a hillside field environment (12 000 m²) north of Dafengji Village, Dacang Township, Weishan County, Yunnan Province, which was assigned into four groups, of no less than 3 000 m² in each group. In Group A, environmental cleaning was not conducted and 5% niclosamide ethanolamine salt granules were sprayed with drones at a dose of 40 g/m², and in Group B, environmental cleaning was performed, followed by 5% niclosamide ethanolamine salt granules sprayed with drones at a dose of 40 g/m², while in Group C, environmental cleaning was not conducted and 5% niclosamide ethanolamine salt granules were sprayed with knapsack sprayers at a dose of 40 g/m², and in Group D, environmental cleaning was performed, followed by 5% niclosamide ethanolamine salt granules sprayed with knapsack sprayers at a dose of 40 g/m². Then, each group was equally divided into six sections according to land area, with Section 1 for baseline surveys and sections 2 to 6 for snail surveys after chemical treatment. Snail surveys were conducted prior to chemical treatment and 1, 3, 5, 7 days post-treatment, and the mortality and corrected mortality of snails, density of living snails and costs of molluscicidal treatment were calculated in each group. RESULTS: The mortality and corrected mortality of snails were 69.49%, 69.09%, 53.57% and 83.48%, and 68.58%, 68.17%, 52.19% and 82.99% in groups A, B, C and D 14 days post-treatment, and the density of living snails reduced by 58.40%, 63.94%, 68.91% and 83.25% 14 days post-treatment relative to pre-treatment in four groups, respectively. The median concentrations of chemical molluscicides were 37.08, 35.42, 42.50 g/m² and 56.25 g/m² in groups A, B, C and D, and the gross costs of chemical treatment were 0.93, 1.50, 0.46 Yuan per m² and 1.03 Yuan per m² in groups A, B, C and D, respectively. CONCLUSIONS The molluscicidal effect of spraying 5% niclosamide ethanolamine salt granules with drones against O. hupensis snails is superior to manual chemical treatment without environmental cleaning, and chemical treatment with drones and manual chemical treatment show comparable molluscicidal effects following environmental cleaning in hilly regions. The cost of chemical treatment with drones is slightly higher than manual chemical treatment regardless of environmental cleaning. Spraying 5% niclosamide ethanolamine salt granules with drones is recommended in complex settings with difficulty in environmental cleaning to improve the molluscicidal activity and efficiency against O. hupensis snails.
Niclosamide/pharmacology* ; Ethanolamine/pharmacology* ; Unmanned Aerial Devices ; China ; Molluscacides/pharmacology* ; Ethanolamines

This study was developed and validated for the determination of oxyclozanide residue concentrations in beef and commercial milk, using high-performance liquid chromatography system. Oxyclozanide was successfully separated on a reverse phase column (Xbridge-C18, 4.6x250 mm, 5 microm) with a mobile phase composed of acetonitrile and 0.1% phosphoric acid (60:40, v/v%). This analytical procedure involved a deproteinization process using acetonitrile for beef and 2% formic acid in acetonitrile for commercial milk, dehydration by adding sodium sulfate to the liquid analytical sample, and a defatting process using n-hexane; after these steps, the extract was exposed to a stream of nitrogen dryness. The final extracted sample was dissolved in the mobile phase and filtered using a 0.45 microm syringe filter. This method had good selectivity and recovery (70.70+/-7.90-110.79+/-14.95%) from the matrices. The LOQs ranged from 9.7 to 9.8 microg/kg for beef and commercial milk. The recoveries met the standards set by the CODEX guideline.
Acetonitriles ; Chromatography, High Pressure Liquid ; Chromatography, Liquid ; Dehydration ; Formates ; Milk ; Nitrogen ; Oxyclozanide ; Phosphoric Acids ; Rivers ; Sodium ; Sulfates ; Syringes

Niclosamide, an oral antihelminthic drug, has been used to treat tapeworm infection for about 50 years. Niclosamide is also used as a molluscicide for water treatment in schistosomiasis control programs. Recently, several groups have independently discovered that niclosamide is also active against cancer cells, but its precise mechanism of antitumor action is not fully understood. Evidence supports that niclosamide targets multiple signaling pathways (NF-κB, Wnt/β-catenin, Notch, ROS, mTORC1, and Stat3), most of which are closely involved with cancer stem cells. The exciting advances in elucidating the antitumor activity and the molecular targets of this drug will be discussed. A method for synthesizing a phosphate pro-drug of niclosamide is provided. Given its potential antitumor activity, clinical trials for niclosamide and its derivatives are warranted for cancer treatment.
Animals ; Antineoplastic Agents ; pharmacokinetics ; pharmacology ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Humans ; Mechanistic Target of Rapamycin Complex 1 ; Multiprotein Complexes ; metabolism ; NF-kappa B ; metabolism ; Neoplasm Metastasis ; Neoplasms ; metabolism ; pathology ; Neoplastic Stem Cells ; drug effects ; Niclosamide ; pharmacokinetics ; pharmacology ; Reactive Oxygen Species ; metabolism ; Receptors, Notch ; metabolism ; STAT3 Transcription Factor ; metabolism ; Signal Transduction ; drug effects ; TOR Serine-Threonine Kinases ; metabolism ; Wnt Signaling Pathway ; drug effects