Role of curcumin on chloroquine phosphate-induced reproductive toxicity

The present study was conducted to screen the efficacy of curcumin against chloroquine phosphate (CQ)-induced reproductive toxicity in adult male Swiss albino mice. Animals were given oral doses of 100, 200, 300?mg/kg body weight (b.w.), and high dose of CQ (300?mg/kg b.w.) + curcumin (80?mg/kg b.w.) for 45 days. Animals of the withdrawal group were given high dose of CQ (300?mg/kg b.w.) for 45 days and, at day 46, were kept for another 45 days. Effects were observed on some key enzymes, such as alkaline phosphatase, which was found to be decreased, whereas acid phosphatase was increased and succinate dehydrogenase and adenosine triphosphatase were decreased. Oxidative parameters, such as superoxide dismutase declined, whereas thiobarbituric acid-reactive substances were found to be elevated. Protein level was also decreased. Gravimetric indices were also recorded. Results obtained indicated adverse effects of CQ in a dose-dependent manner. The presence of curcumin with CQ alleviated its toxic effects. Hence, it can be concluded that curcumin has beneficial influences and appears able to ameliorate CQ toxicity.     

Ameliorative effect of curcumin on hepatotoxicity induced by chloroquine phosphate

India is one of the most endemic areas, where malaria predominates and its control has become a formidable task. Chloroquine phosphate (CQ) on account of its rapid action on blood schizontocide of all the malarial parasite strains has become the most widely prescribed drug for prophylaxis and treatment of malaria. Toxicity of CQ is most commonly encountered at therapeutic and higher doses of treatment. Thus, the present study was undertaken to evaluate the protective effect of Curcumin, a herbal antioxidant obtained from Curcuma longa, on hepatic biochemical and histopathological status of CQ induced male mice. Swiss albino male mice were administered oral doses of CQ (100mg/kg body wt., 200mg/kg body wt. and 300mg/kg body wt.) and CQ+curcumin (300mg/kg body wt.+80mg/kg body wt.) for 45 days. A withdrawal of high dose treatment for 45 days was also studied. Administration of CQ brought about a significant decrease in Protein content with a decline in SDH, ATPase and ALKase activities, whereas ACPase activity was found to be significantly increased following CQ treatment. Antioxidant enzyme SOD registered a significant reduction as opposed to TBARS which was found to be elevated in a significant manner in the CQ treated groups as compared to control. Gravimetric indices (body weight and organ weight) declined significantly following CQ treatment. Administration of curcumin exhibited significant reversal of CQ induced toxicity in hepatic tissue. Protein content, SDH, ATPase, ALKase, ACPase, SOD, TBARS, body weight and organ weight were found to be comparable to that of control group after curcumin administration. Thus, obtained results led us to conclude the curative potential of curcumin against CQ induced hepatotoxicity.     

Evaluation of ameliorative effect of curcumin on imidacloprid‐induced male reproductive toxicity in wistar rats

This study was undertaken to investigate the toxic effects of imidacloprid (IM) on male reproductive system and ameliorative effect of curcumin (CMN) in male Wistar rats. For this purpose, IM (45 and 90 mg/kg, body weight) and CMN (100 mg/kg, body weight) were administered orally to the rats either alone or in combinations for a period of 28 days. At the end of experiment, male reproductive toxicity parameters (total sperm count and sperm abnormalities), testosterone level, steroidal enzymatic activity [3β‐hydroxysteroid dehydrogenase (3β‐HSD) and 17β‐HSD], and oxidative stress indicators were estimated in testis and plasma. IM treatments resulted in significant decrease (p < 0.05) in total epididymal sperm count, sperm motility, live sperm count, and increase (p < 0.05) in sperm abnormalities. Activities of gamma‐glutamyl transpeptidase, lactate dehydrogenase‐x, and sorbitol dehydrogenase were significantly increased (p < 0.05), while, 3β‐HSD and 17β‐HSD enzymatic activity along with testosterone concentration in testis and plasma were decreased significantly (p < 0.05) in IM‐treated rats. IM exposure resulted in significant increase (p < 0.05) in LPO and decrease (p < 0.05) in GSH level along with decreased activities of CAT, SOD, GPx, and GST. IM‐treated rats showed histopathological alterations in testis and epididymis. However, the reproductive toxicity parameters, oxidative stress indicators, and histopathological changes were minimized and functional restorations were noticed by co‐administration of CMN in IM‐treated rats. The results of this study suggest that IM‐induced male reproductive toxic effects could be ameliorated by CMN supplementation. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1250–1263, 2016.     

Effect of hyperthermia on acute chloroquine toxicity in rabbits

The problem of sudden and unexpected death after the parenteral administration of a therapeutic dose of choloroquine in fibrile patients was investigated using rabbits. Hyperthermia was produced in both conscious and anaesthetized rabbits using a Megatherm Junior diathermy machine. Lead II of the electrocardiogram, respiration and blood pressure were monitored during slow i.v. injection of chloroquine. In hyperthermic rabbits, striking cardiac arrhythmias, circulatory collapse and death occured at a dose level $\text{1}\text{3}$ as great as in normal rabbits. Animals that had been heated and allowed to cool before the injection, tolerated $\text{2}\text{3}$ of the lethal dose for normal rabbits, and twice as much as the hyperthermic rabbits.     

A two generation reproductive toxicity study with curcumin, turmeric yellow, in Wistar rats.

The reproductive toxicity of curcumin, turmeric yellow, in Wistar rats was studied in order to generate additional relevant toxicity information for the use of curcumin in humans by oral administration. The two generation reproduction study was designed and conducted in accordance with OECD Guideline No. 416 [OECD, 1983. Guidelines for Testing of Chemicals, Guideline No. 416. Two Generation Reproduction Toxicity Study, adopted on 26th May 1983] and in compliance with Good Laboratory Practices (OECD, 1997 Principles of Good Laboratory Practice for the Testing of Chemicals. OECD, C(97)186/Final). The curcumin, mixed in the experimental diet at the concentrations of 1500, 3000 and 10,000 ppm was fed to three groups of rats, i.e., low, mid and high dose groups, and studied for two successive generations. A concurrent control group received experimental diet without the curcumin mixture. There were no treatment related adverse toxicological effects in the parental animals. No gross or microscopic changes were observed in any of the organs. None of the reproductive parameters were affected and there were no effects on the offspring other than a small reduction in pre-weaning body weight gain of the F2 pups at the highest dose level. It was concluded that the no observed adverse effect level (NOAEL) for reproductive toxicity of curcumin, fed in the diet for two successive generations to rats in this study was 10,000 ppm, which is equivalent to 847 and 959 mg/kg bodyweight (bw) per day for male rats and 1043 and 1076 for females for F0 and F1 generations, respectively. This study was the final toxicology study on curcumin reviewed by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) at the 61st Meeting, 2003. The JECFA group considered that the small body weight reduction in the F2 pups of the highest dose group prevented this from being regarded as a no adverse effect level, and so allocated an ADI for curcumin of 0-3 mg/kg bw based on the intake of 250-320 mg/kg bw in the mid-dose group as the NOEL.     

匹多莫德的生殖毒性实验研究

目的研究匹多莫德(pidotimod,PDM)对实验大鼠在致畸敏感期的生殖毒性。方法健康Wis-tar雌性受孕大鼠,于受孕后5~15d灌胃给予200、4008、00mg/kg的匹多莫德,至受孕后20d处死动物,检测各项指标,对匹多莫德的致畸敏感期生殖毒性进行评价。结果口服匹多莫德200、4008、00mg/kg后,匹多莫德对受孕大鼠的黄体数、着床率、胎儿数、胎儿体重及性别、胎儿内脏及骨骼检查等各项检测指标均无明显变化,同对照组比较差异无统计学意义。结论匹多莫德在本实验所用剂量时无致畸作用,这种用于大鼠的剂量,相当于该药的人用最大剂量的8倍、16倍、32倍,所以人用此药是安全的。     

Effect of curcumin on chromium-induced oxidative damage in male reproductive system

Hexavalent chromium, an environmental contaminant, undergoes redox cycling with generation of free radicals inside the biological system. Curcumin, the yellow bioactive component of turmeric has established its antioxidant activities. The present study evaluates possible ameliorating effects of curcumin on potassium dichromate (K(2)Cr(2)O(7)) (hexavalent chromium) induced reproductive toxicity in adult male Sprague-Dawley rats. Three experimental groups, each consisting of eight rats, were treated with 0.4mg K(2)Cr(2)O(7)/kg bw/day, 0.4mg K(2)Cr(2)O(7)/kg bw/day+20mg curcumin/kg bw on every alternate day and 20mg curcumin/kg bw on every alternate day, respectively, for 26 days. Altered testicular histology, reduced sperm count, low testosterone level, decreased accessory sex organs weight, enhanced lipid peroxidation along with reduced SOD and catalase activities were observed following K(2)Cr(2)O(7) exposure while curcumin supplementation along with K(2)Cr(2)O(7) exposure had shown to prevent the altered parameters. The results thus suggest that curcumin may have a protective role against chromium(VI) induced oxidative damage in male reproductive system.     

Cardiovascular toxicity and distribution kinetics of intravenous chloroquine.

Chloroquine diphosphate (3 mg base kg-1) was given by constant rate intravenous injection over 10 min to 12 healthy adult male volunteers. Plasma concentrations of chloroquine and the principal metabolite desethylchloroquine, electrocardiograph intervals, and arterial blood pressure were measured at frequent intervals to determine the relationship between cardiovascular effects and plasma concentrations. Peak plasma concentrations ranged between 784 and 6649 (mean 2913) ng ml-1. The decline in plasma concentrations was multiexponential with an initial rapid distribution phase; mean (+/- s.d.) first order rate constant 0.65 +/- 0.14 min-1, and an estimated apparent volume of the central compartment of 0.18 +/- 0.15 l kg-1. There was no serious toxicity, but subjective side effects were reported in all patients and there was a significant fall in systolic blood pressure (110 +/- 9.5 to 101 +/- 12.5 mm Hg; P = 0.03) and rise in heart rate which paralleled the change in plasma chloroquine concentrations. Coincident with changes in blood pressure, there was a significant prolongation of the electrocardiograph QRS interval; 81 +/- 15 to 92 +/- 13 ms (P less than 0.01) but no change in the QTc interval. These findings suggest that the cardiovascular toxicity of parenteral chloroquine is related to transiently high plasma concentrations occurring early in the distribution phase. This results from incomplete distribution from a central compartment that is approximately one thousand times smaller than the eventual total apparent volume of distribution at steady state. Rate of administration is therefore a major determinant of toxicity.     

Retinal toxicity of chloroquine hydrochloride administered by intraperitoneal injection

Chloroquine is quinolone derivative known to exert dose-related retinal toxicity, albeit in a variable manner. It is thought that variability in the presentation of chloroquine retinopathy may be the result of perturbations in drug bioavailability subsequent to oral ingestion. In order to better understand the ramifications of bioavailability on the development of retinal injury subsequent to chloroquine use, this study investigated the relationship between retinal injury and chloroquine administration via intraperitoneal rather than oral administration. Four-week-old C57/6J mice underwent daily intraperitoneal injection of 10 mg kg(-1) chloroquine hydrochloride for a total of 62 days. Following treatment, tissue was fixed in preparation for analysis by light and transmission electron microscopy. Treated animals demonstrated marked abnormality of the outer retinal layers described as complete loss of the outer plexiform layer as well as photoreceptors and photoreceptor nuclei. The retinal pigmented epithelium demonstrated focal atrophy, loss of nuclei and pigment irregularity. Findings in the inner retina were notable for the loss of Müller cells and the presence of membranous cytoplasmic bodies. Retinae of control animals were entirely normal. In contrast to previous studies in the murine model examining chloroquine retinopathy subsequent to oral administration, this study suggests that intraperitoneal chloroquine administration facilitates retinal toxicity, presumably due to heightened drug absorption and bioavailability. It is posited that an increased rate of drug accumulation within the retina leads to an enhanced lysosomotrophic drug effect due to inability of the lysosome to compensate for chloroquine-induced elevation in pH through re-acidification of the intra-lysosomal content.     

Ameliorative effect of curcumin on aflatoxin-induced toxicity in serum of mice

The present investigation was an attempt to evaluate the ameliorative effect of curcumin on aflatoxin-induced toxicity on serum and blood of mice. Aflatoxin was obtained by growing Aspergillus parasiticus in SMKY liquid medium. Pure curcumin (97% purity) was purchased from Hi-Media Laboratories Pvt. Ltd., Mumbai, India. Young adult male albino mice were orally administered with low dose and high dose (750 and 1500 microg/kg body weight) with and without curcumin (2 mg/0.2 mL olive oil/animal/day) for 45 days. On 46th day the animals were sacrificed by cervical dislocation. For serum parameters blood was collected in non-EDTA containing vails from heart of the dissected mice. Serum parameters are creatinine, protein, AST and ALT. The results revealed dose dependent increase in creatinine, AST and ALT and decrease in protein in serum parameters of mice. Treatment with curcumin along with aflatoxin ameliorates aflatoxin-induced changes in serum parameters.     

Role of iodine in diiodomethyl-p-tolylsulfone induced reproductive toxicity in rats: proposed mode of action

The biocide diiodomethyl-p-tolylsulfone (DIMPTS) caused dystocia, decreased neonatal survival and hypothyroidism in rat reproduction studies resembling the effects caused by iodine. One molecule of DIMPTS contains two iodine moieties that are hydrolyzed upon ingestion and systemically absorbed, suggesting iodine toxicity as a probable mode of action for the effects observed in rats. This study compared the effects induced by DIMPTS and an equimolar concentration of its de-iodinated analogue, methyl-p-tolylsulfone (MPTS). Groups of 20 female Sprague Dawley rats were fed diets supplying 80 mg DIMPTS/kg/day, 32 mg MPTS/kg/day or control feed from prior to breeding through lactation and gonadal function, mating performance, conception, gestation, parturition, lactation, survival, growth and development of pups evaluated through postnatal day 7. Serum thyroid hormones and iodine levels in milk and sera were also determined. Females given DIMPTS had increased incidence of vulvar discharge and dystocia, decreased litter size, decreased body weights and feed consumption, increased thyroid weights, thyroid follicular cell hypertrophy with decreased colloid, decreased triidothyronine, and increased thyroid stimulating hormone levels. DIMPTS pups had decreased neonatal survival and body weights. These effects were associated with elevated levels of iodine in milk and sera. In contrast, MPTS did not produce similar effects in adult females or their offspring. These data support the hypothesis that the dystocia, altered neonatal survival and hypothyroidism following repeated dietary administration of DIMPTS were due to excessive iodine released from DIMPTS during absorption and metabolism.     

Role of lysosomes in hepatic accumulation of chloroquine

At therapeutic free concentrations (120-360 nM in rheumatoid arthritis), the accumulation ratio for chloroquine (7-chloro-4-[[4-(diethylamino)-1-methylbutyl]amino]-quinoline; CQ) in viable isolated rat hepatocytes is 795 +/- 33, which is of the same order of magnitude as in vivo hepatic uptake in the rat. The accumulation ratio is much lower in nonviable hepatocytes (12.4 +/- 0.5), showing that accumulation in membranes of hepatocytes accounts for a negligible proportion (less than 3%) of total accumulation at therapeutic free concentrations. This also indicates that the predominant mechanism of accumulation is dependent on structural integrity of cells and/or organelles. The accumulation ratio for CQ in viable hepatocytes is markedly reduced by NH4Cl and the metabolic inhibitors KCN and NaF. Since intralysosomal pH is known to be elevated in the presence of some weak bases (including NH4Cl and CQ) and metabolic inhibitors, this suggests that hepatic accumulation of CQ is a consequence of ion trapping in the acidic interior of lysosomes. Accumulation is linear at therapeutic free CQ concentrations; however, at CQ concentrations well above the therapeutic range, the accumulation ratio is markedly reduced. This is consistent with the known capacity of CQ to raise intralysosomal pH at these concentrations.     

Dietary curcumin prevents ocular toxicity of naphthalene in rats

Administration of naphthalene is known to cause cataract formation in rats and rabbits and naphthalene-initiated cataract is frequently used as a model for studies on senile cataract in humans. Oxidative stress has been implicated in the mechanism of naphthalene-induced cataract. Curcumin, a constituent of turmeric, a spice used in Indian curry dishes, is an effective antioxidant and is known to induce the enzymes of glutathione-linked detoxification pathways in rats. During the present studies, we have examined whether low levels of dietary curcumin could prevent naphthalene-induced opacification of rat lens. The presence of apoptotic cells in lens epithelial cells was also examined by catalytically incorporating labeled nucleotide to DNA with either Klenow fragment of DNA polymerase or by terminal deoxynucleotidyl transferase (TdT), which forms polymeric tail using the principle of TUNEL assay. The results of these studies demonstrated that the rats treated with naphthalene and kept on a diet supplemented with only 0.005% (w/w) curcumin had significantly less opacification of lenses as compared to that observed in rats treated only with naphthalene. Our studies also demonstrate, for the first time, that naphthalene-initiated cataract in lens is accompanied and perhaps preceded by apoptosis of lens epithelial cells and that curcumin attenuates this apoptotic effect of naphthalene.     

生殖毒性试验的质量保证

生殖毒性试验是毒理学试验中最为复杂、繁琐,技术要求最高的试验,在药品非临床研究质量管理规范（GLP）和质量保证（QA）检查方面有其特殊性.现从实验室资质的确认、试验关键阶段的检查、研究资料和报告的审查、特殊评价项目的质量保证和现场检查等5个方面介绍生殖毒性试验质量保证的程序、要求和注意事项.     

含吲哚美辛固定式宫内节育器的生殖毒性研究

目的：应用健康未交配过昆明种小鼠对固定式宫内节育器进行生殖毒性研究.方法：观察不同剂量含吲哚美辛固定式宫内节育器对动物性功能、发情周期、交配行为、受孕、分娩、授乳和断乳的影响,以及对子代生长发育、幼鼠发病率、死亡率的影响和是否具有致畸性的作用.结果：在人体使用量的等效剂量下,该节育器未见引起明显的生殖毒性作用,而中、高剂量组对受试动物具有一定的生殖毒性作用.结论：含吲哚美辛固定式宫内节育器,在相对于人体剂量使用条件下对生殖过程无明显毒性作用.     

Assessment of reproductive toxicity under REACH

The European REACH regulation requires the evaluation of reproductive toxicity in screening tests according to OECD TG 421 and 422 for substances above the tonnage level of 10 tons/year. The overall aim of this paper is to increase flexibility in combination with a reduced number of experimental animals. Therefore, in contrast to the existing approach the registrant should have the possibility to file a dossier for a substance at the level of 10 tons/year and above also on the basis of data from a developmental toxicity study (OECD TG 414) plus a full-scale subacute toxicity study (OECD TG 407 according to the 1995 protocol). The proposed new test strategy takes into account overall considerations of duty of care and animal welfare. It enables an assessment of developmental toxicity on a definitive instead of a screening level. Registrants should be allowed to select between these two options, either the existing approach (OECD TG 421/407 and alternatively TG 422) or the approach proposed in this paper (OECD TG 407 plus TG 414).     

依替米星一般生殖毒性研究

依替米星 10 0、2 0 0和 40 0 mg/(kg· d) ,sc给于 SD雄、雌性大鼠分别连续 9周和 2周后合笼 ,雄鼠给药至 11周 ,雌鼠给药至妊娠第 15天。实验结果表明 ,40 0 mg/(kg·d)对雄鼠、雌鼠及胎仔均有毒性 ,表现为雄鼠从给药第 4周起体重增长受到抑制 (给药 4、5、周 P<0 .0 5 ,P<0 .0 1) ,雌鼠交配前和交配后体重增长也受到抑制 (交配前给药第 11、14天 ,P<0 .0 5 ,P<0 .0 1,交配后怀孕第 7、11～ 15天 ,P<0 .0 5 ) ,且孕鼠的黄体数减少 (P<0 .0 1) ,胎仔骨骼检查见胸骨节第一中心及耻骨未骨化 ,剑突和指 ,趾骨化点减少。 2 0 mg/(kg·d)对雄、雌大鼠的体重、交配率、妊娠率 ,孕鼠的黄体数 ,着床数 ,活胎、死胎数及胎仔体重、外形、内脏组织 ,骨骼均无影响。因此依替米星是不具有一般生殖毒性的药物。     

复脑苏I段生殖毒性研究

目的：观察复脑苏对SD大鼠的I段生殖毒性。方法：采用SD大鼠，雌雄各80只，分为3个剂量组（7．5、15．0和30mg／kg）和一个对照组（0．85％生理盐水），每组20只大鼠。雄鼠于交配前28d给药；雌鼠于交配前14d给药，给药至妊娠后第6天。实验组和对照组给药容量为1mL／100g体重，均采用尾静脉给药。雄鼠于交配后剖杀；1／2孕鼠于妊娠第14天剖杀，另1／2自然分娩。观察雄鼠、雌鼠和F1代仔鼠的相关指标。结果：复脑苏在各受试剂量下，对雄性大鼠的精子发生无明显影响，表现为活精子数、精予畸形率、脏器系数与对照组比较无统计学差异（P〉0．05）；病理学检查显示，未引起睾丸、附睾明显的病理学改变。复脑苏在各受试剂量下，对雌性大鼠的生殖功能也未见明显影响，表现为交配率、受孕率、流产率、活胎率、吸收胎率与对照组比较差异无统计学意义（P〉0．05）；也不影响仔鼠的出生存活率和哺育存活率。结论：在受试剂量下复脑苏对雄性和雌性大鼠无生殖毒性。