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At least 19 recordsLinked to original sources
PubMed1986

Absorption, distribution and metabolism of clioquinol in clioquinol-sensitive and -resistant neonatal rats.

Three types of rats with respect to sensitivity to clioquinol have been identified, the highly sensitive (S-rat), the intermediately sensitive, and the resistant (R-rat). In a toxicity test that lasted for 20 d after birth, the difference in sensitivity to clioquinol between S- and R-rats was confirmed by repeated subcutaneous administration of a clioquinol suspension prepared with polysorbate 80 (clioquinol dose of 150 or 300 mg/kg/d). Plasma and tissue concentrations of clioquinol and the rate of metabolism of the drug in neonatal S- and R-rats were measured. Plasma concentration of clioquinol in 1-d-old S-rats after a single subcutaneous administration was higher than that in the same age R-rats and the area under the mean plasma concentration-time curve for the S-rats was approximately twice that for the R-rats. In addition, clioquinol concentrations in liver, kidney and brain of S-rats at 9 h after the administration were more than twice those of the R-rats. From the experiments on the formation of clioquinol glucuronide and sulfate with 9000 g supernatant fraction of liver, it was suggested that the difference in the plasma concentration after the administration may be responsible for the difference in the metabolizing rate of clioquinol.

Animals↗
PubMed1998

Clioquinol-zinc chelate: a candidate causative agent of subacute myelo-optic neuropathy.

BACKGROUND: 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol) was used clinically three decades ago as an oral antiparasitic agent and to increase intestinal absorption of zinc in patients with acrodermatitis enteropathica, a genetic disorder of zinc absorption. Use of clioquinol was epidemiologically linked to subacute myelo-optic neuropathy (SMON), characterized by peripheral neuropathy and blindness, which affected 10,000 patients in Japan. Discontinuation of oral clioquinol use led to elimination of SMON, however, the mechanism of how clioquinol induces neurotoxicity is unclear. MATERIALS AND METHODS: We tested the effect of clioquinol-metal chelates on neural crest-derived melanoma cells. The effect of clioquinol chelates on cells was further studied by electron microscopy and by a mitochondrial potential-sensitive fluorescent dye. RESULTS: Of the ions tested, only clioquinol-zinc chelate demonstrated cytotoxicity. The cytotoxicity of clioquinol-zinc chelate was extremely rapid, suggesting that its primary effect was on the mitochondria. Electron microscopic analysis demonstrated that clioquinol-zinc chelate caused mitochondrial damage. This finding was further confirmed by the observation that clioquinol-zinc chelate caused a decrease in mitochondrial membrane potential. CONCLUSIONS: We demonstrate that clioquinol, in the presence of zinc, is converted to a potent mitochondrial toxin. The phenomenon of clioquinol mediated toxicity appears to be specific to zinc and is not seen with other metals tested. Since clioquinol has been shown to cause increased systemic absorption of zinc in humans, it is likely that clioquinol-zinc chelate was present in appreciable levels in patients with SMON and may be the ultimate causative toxin of SMON.

Chelating Agents↗
PubMed1988

Effects of 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol) and nerve growth factor on DNA, RNA and protein syntheses in neonatal rat superior cervical ganglia.

To investigate molecular mechanisms involved in the neurotoxicity of clioquinol (5-chloro-7-iodo-8-hydroxyquinoline), the inhibitory effects of this drug on DNA, RNA and protein syntheses were examined, in relation to the action of nerve growth factor (2.5S NGF). We used an organ culture of neonatal rat superior cervical ganglion (SCG). Ten microM clioquinol inhibited completely DNA and protein syntheses and abolished the stimulatory effect of NGF on RNA synthesis. With regard to the chemical structure of clioquinol, hydroxylation at the 8th carbon of quinoline is essential for the inhibition of DNA, RNA and protein syntheses, and the hydrophobicity of the 8-HQ derivatives is a required property for potent inhibition. Compared with effects of EDTA, alizarine, sodium alizarine sulfate, o-phenanthroline and alpha,alpha'-dipyridyl, the loss of the NGF-induced stimulation of RNA synthesis by clioquinol does not seem to be primarily caused by its metal-chelating property. Clioquinol did not significantly alter the uptake rate of thymidine, uridine and leucine, thereby suggesting that the primary action of clioquinol on inhibition of DNA, RNA and protein syntheses does not relate to uptake of the precursor into SCG. Clioquinol did not significantly alter the degradation of 3H-uridine-labeled RNA. NGF suppressed the degradation of RNA and this suppression was overcome by clioquinol. The release of free uridine from SCG into the culture medium was enhanced by clioquinol and was partially suppressed by NGF. The inhibitory effects of clioquinol were completely prevented by bovine serum albumin (BSA), but not by NGF even at a 5-fold concentration of clioquinol.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Intestinal absorption and metabolism of clioquinol in the rat.

Plasma concentrations of clioquinol and its metabolites after single or repeated oral administration of clioquinol, absorption region of clioquinol in gastrointestinal tract, and intestinal metabolism were studied in rats. Plasma concentrations of clioquinol after oral administration of four different doses (20, 100, 200 and 400 mg/kg) were lower than those of the two metabolites, clioquinol glucuronide and sulfate. Mean maximal plasma concentration of unchanged drug was in the range of 1-8 nmol/ml. Clioquinol was absorbed poorly from the stomach and fairly from the small intestine. Bile was an important route for excretion of clioquinol in rats. The mesenteric venous plasma from the closed intestinal loops of both jejunal and ileal regions was analyzed for clioquinol and the metabolites and it was found that clioquinol glucuronide was formed predominantly in both regions. From the results of the present studies, intestinal metabolism of clioquinol can be pointed out as a major factor for difficulty to cause clioquinol intoxication.

Animals↗
PubMed1998

Transmethylation reactions and autoradiographic distribution of vitamin B12: effects of clioquinol treatment in mice.

The catastrophic epidemic of subacute myelo-optic neuropathy (SMON) affected Japan around 1970 with thousands of victims. The cause was attributed to high doses of locally acting oxyquinolines. It has been speculated that oxyquinoline derivatives of the clioquinol type can disturb the retention of vitamin B12 through chelation of Co2+. In the present paper, possible effects of clioquinol on the uptake and tissue distribution of [57Co]-cyanocobalamin have been studied in mice. In vivo experiments showed markedly decreased accumulation of radiolabelled vitamin B12 in the kidney and skin in animals that were pre-treated with clioquinol. The chloroform:water partition coefficients for [57Co]-cyanocobalamin in the presence or absence of clioquinol were also determined. No statistically significant alterations in the partition coefficient for [57Co]-cyanocobalamin in the presence of clioquinol was evident, indicating that clioquinol does not bind cobalt. In addition, transmethylation reactions in the CNS in mice treated with clioquinol were studied. Specific activities of methionine adenosyltransferase, and S-adenosylhomocysteine levels were not affected. In contrast, clioquinol treatment caused a significant increase in the levels of S-adenosylmethionine in the brain. The data of the present study show that clioquinol treatment can affect the accumulation of vitamin B12 in the kidney and the skin but not in the brain. These results do not support the hypothesis that clioquinol causes its damage to the nervous system by a direct chemical interaction with vitamin B12.

Animals↗
PubMed1984

Effect of 5-chloro-7-iodo-8-hydroxy-quinoline (clioquinol) on the uptake and distribution of nickel, zinc and mercury in mice.

5-Chloro-7-iodo-8-hydroxy-quinoline (clioquinol) was found to induce a very marked increase in the concentration of 63Ni2+ in various tissues of mice when given orally together with the metal, compared with oral administrations of 63Ni2+ only. Markedly increased tissue concentrations, although less expressed than for the 63Ni2+, were also observed for 65Zn2+. Clioquinol increased the tissue levels of 203Hg2+ to a lesser extent. When clioquinol was given intraperitoneally and 63Ni2+ was given intravenously there were also very markedly increased tissue levels of the metal, compared with intravenous injections of 63Ni2+ only. It was also shown that the urinary excretion of 63Ni2+ was greatly increased in mice given the metal orally together with clioquinol, compared with mice given the 63Ni2+ only. Clioquinol and other 8-hydroxy-quinolines form lipophilic chelates with metallic cations and the observed effects on the tissue-disposition of the metals are probably due to a facilitated penetration through the cellular membranes. Determinations of the chloroform:water partition coefficients showed the highest lipophilicity for the nickel-clioquinol-complex followed in decreasing order by the complexes with zinc and mercury. These data suggest that the ability of the clioquinol to affect the uptake of the metals in the cells may be related to the relative lipophilicity of the metal-clioquinol-complexes. Clioquinol and other halogenated 8-hydroxy-quinolines are linked with the SMON-syndrom, which has been observed preferentially in Japan. It is suggested that the pathogenesis of SMON may involve an accumulation of toxic concentrations of metals in the tissues due to facilitated uptake by complex-formation with halogenated 8-hydroxy-quinolines.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Anticancer activity of the antibiotic clioquinol.

Clioquinol, a metal chelator, has been used for many years as an antimicrobial agent and more recently as a potential treatment for Alzheimer's disease. Because it binds copper and zinc, metals essential for the activity of the enzyme superoxide dismutase-1 (SOD1), a potential target for anticancer drug development, we investigated its effects on human cancer cells. Treatment with clioquinol reduced the viability of eight different human cancer cell lines in a concentration-dependent manner, with IC(50) values in the low micromolar range. Biochemical analysis revealed that clioquinol induced cancer cell death through apoptotic pathways that require caspase activity. Although clioquinol induced modest inhibition of SOD1 activity in treated cells, comparable inhibition by a known SOD1 inhibitor, diethyldithiocarbamate, did not result in cytotoxicity. The addition of copper, iron, or zinc did not rescue cells from cliquinol-induced cytotoxicity but enhanced its killing, arguing against metal chelation as its major mechanism of action. To test if clioquinol might act as an ionophore, a fluorescent probe was used to monitor intracellular zinc concentrations. The addition of clioquinol resulted in elevated levels of intracellular zinc, indicating that clioquinol acts as a zinc ionophore. In an in vivo xenografts mouse model, clioquinol inhibited tumor growth of xenografts over a 6-week period, without inducing visible toxicity. Our results show that clioquinol has anticancer effects both in vitro and in vivo. Transition metal ionophores may be a subclass of metal chelators with anticancer activity deserving of further development.

Animals↗
PubMed2006

Clioquinol for the treatment of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) may result in senile plaques being formed outside the brain as accumulation of beta-amyloid (Ass). OBJECTIVES: To evaluate the efficacy of clioquinol for the treatment of cognitive impairment due to Alzheimer's disease. SEARCH STRATEGY: The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched on 20 May 2005 using the terms clioquinol and PBT1. The Register contains records from major health care databases and many ongoing trial databases and is updated regularly. The Internet was searched using the term: clioquinol PBT1 Alzheimer*. SELECTION CRITERIA: Randomised double-blind trials in which treatment with clioquinol was administered to participants with Alzheimer's disease in parallel group comparison with placebo are included. DATA COLLECTION AND ANALYSIS: Two reviewers (RM, LJ) independently assessed the quality of trials according to the Cochrane Collaboration Handbook. The primary outcome measures of interest were cognitive function (as measured by psychometric tests) and global impression. The secondary outcome measures of interest were in the following areas: quality of life, functional performance, effect on carer, safety and adverse effects, and death. MAIN RESULTS: There was one included trial of clioquinol compared with placebo in 36 patients. AUTHORS' CONCLUSIONS: It is not clear from the trial that clioquinol shows any positive clinical result on patients with AD. The two statistically significant positive results were seen for the more severely affected subgroup of patients. This effect was not maintained at the 36 week end-point. The sample size was small. Details of randomisation procedure or blinding were not reported. Further studies are needed to evaluate the potential for clioquinol as a treatment of AD. Trials of longer duration are also required, particularly because information about the side-effects of long-term use of clioquinol is limited.

Aged↗
PubMed2000

Changes in uptake of vitamin B(12) and trace metals in brains of mice treated with clioquinol.

Clioquinol is a hydroxyquinoline antibiotic that has been associated with severe side-effects in the CNS. The syndrome caused by clioquinol treatment, subacute myelo-optic neuropathy (SMON), is considered as one of the worst drug disasters of this century. The precise biochemical mechanism behind SMON is not fully understood. Clioquinol can form strong lipophilic chelates with divalent cations and therefore it has been speculated that the drug may disturb the retention of vitamin B(12) through chelation of Co(2+). In the present study, the tissue distribution and uptake capacity of [57Co]cyanocobalamin were estimated in mice treated with clioquinol or saline. The concentrations of some trace metals were also determined in brain tissue. Accumulation of vitamin B(12) in the brain and its concentration in blood were decreased by clioquinol treatment. The mean concentrations of several trace metals were also lowered in the brain while the concentration of cobalt in the brain was not affected, suggesting that clioquinol does not bind to the cobalt in vitamin B(12). Moreover, a significant decrease in the levels of S-adenosylmethionine (SAM) was observed in the brain after clioquinol treatment. This may be a consequence of decreased vitamin B(12) levels. From these results, it can be concluded that chronic treatment with clioquinol may alter the tissue homeostasis of vitamin B(12) in the brain.

Amebicides↗
PubMed1988

Changes in lipid peroxide concentrations in plasma and tissues by repeated administration of clioquinol to neonatal rats.

The changes in lipid peroxide concentrations in plasma and tissues after subcutaneous administration of clioquinol to clioquinol-sensitive (S-rats) and -resistant neonatal rats (R-rats) were investigated. When a fixed dose of 150 mg/kg/d of clioquinol was given to R-rats for 14 d after birth, no significant difference in lipid peroxide concentrations in plasma, liver, kidney, brain and spinal cord at 5, 10 and 15 d was observed between clioquinol-treated and untreated rats. However, with increasing doses of clioquinol to R-rats every 5 d (150----300----600 mg/kg/d), the lipid peroxide concentrations at 15 d were higher in plasma, brain and spinal cord of clioquinol-treated rats than in those of untreated rats. These results suggested that repeated administrations of large doses of clioquinol to rats increased the lipid peroxides in nerve tissues. With S-rats at 5 d after birth, the lipid peroxide concentrations in liver were approximately twice those in R-rats regardless of the clioquinol administration.

Animals↗
PubMed1989

Sex difference of the metabolic disposition of clioquinol in rats.

The order of plasma levels of clioquinol and its conjugates in male rats after intraduodenal administration of 32.7 mumol/kg dose of clioquinol was clioquinol sulfate (C-Sul) greater than glucuronide (C-Glu) much greater than clioquinol, whereas that in female rats was C-Glu greater than C-Sul much greater than clioquinol. Total (urine + bile) recovery was almost the same among male and female rats. The percentage of excretion amounts of C-Sul (urine + bile) to the total excretion amounts for 24 h in male rats after intravenous administration of clioquinol was about twice that in female rats, while the percentage of excretion amounts of C-Glu to the total excretion amounts in male rats was smaller than that in female rats. In intravenous administration of 16.4 mumol/kg dose of C-Glu, C-Sul and clioquinol other than C-Glu were found in bile and urine of male and female rats. The percentage of excretion amounts of C-Sul and C-Glu (urine + bile) to the total excretion amounts was similar among male and female rats, respectively. In intravenous administration of 16.4 mumol/kg dose of C-Sul, C-Glu and clioquinol other than C-Sul were found in bile and urine of male and female rats, and the percentage of excretion amounts of C-Sul (urine + bile) to the total excretion amounts in male rats was 1.3 fold that in female rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Determination of 5-chloro-7-iodo-8-quinolinol (clioquinol) in plasma and tissues of hamsters by high-performance liquid chromatography and electrochemical detection.

This paper describes a method of determining clioquinol levels in hamster plasma and tissue by means of HPLC and electrochemical detection. Clioquinol was separated on a Nucleosil C18 300 mm x 3.9 mm i.d. 7 microm column at 1 ml/min using a phosphate/citrate buffer 0.1M (400 ml) with 600 ml of a methanol:acetonitrile (1:1, v/v) mobile phase. The retention times of clioquinol and the IS were, respectively, 11.6 and 8.1 min; the quantitation limit (CV>8%) was 5 ng/ml in plasma and 10 ng/ml in tissues. The intra- and inter-assay accuracies of the method were more than 95%, with coefficients of variation between 3.0 and 7.7%, and plasma and tissue recovery rates of 72-77%. There was a linear response to clioquinol 5-2000 ng/ml in plasma, and 10-1000 ng/g in tissues. The method is highly sensitive and selective, makes it possible to study the pharmacokinetics of plasma clioquinol after oral administration and the distribution of clioquinol in tissues, and could be used to monitor plasma clioquinol levels in humans.

Administration, Oral↗
PubMed2006

Clioquinol and docosahexaenoic acid act synergistically to kill tumor cells.

Clioquinol, an 8-hydroxyquinoline derivative (5-chloro-7-iodo-8-hydroxyquinoline) with antimicrobial properties, has recently been found to have cytotoxic activity towards human cancer cell lines at concentrations achieved by oral administration. This study was initiated to determine whether clioquinol could potentiate the antitumor effects of two drugs, doxorubicin and docosahexaenoic acid (DHA), believed to act in part via the generation of reactant oxidant species. At low micromolar concentrations, clioquinol had little effect upon cell viability and did not potentiate doxorubicin's cytotoxicity. Clioquinol significantly enhanced DHA's cytotoxic effects, an interaction that was shown to be synergistic by isobolographic analysis. Clioquinol exhibited a synergistic interaction with DHA in reducing nuclear factor-kappaB activity and inducing apoptosis, and the combination reduced the level of several molecules that promote cell survival, including Akt, p65, and Bcl-2. Interestingly, clioquinol neither induced lipid peroxidation itself nor increased peroxidation brought about by the addition of DHA. However, when cells were pretreated with antioxidant vitamin E, the synergism of clioquinol and DHA was blocked, indicating the essential role of lipid peroxidation for their action. These findings reveal a novel antitumor drug combination that synergistically targets major cell survival signaling pathways.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1979

Percutaneous absorption of clioquinol (Vioform).

The percutaneous absorption of clioquinol from three different preparations for skin treatment (Vioform cream, Locacorten-Vioform cream and Vioform-Hydrocortisone cream) was evaluated. After topical dosages corresponding to 30 mg clioquinol, concentrations in the blood were below the detection limit of the analytical procedure, i.e., smaller than 0.02 micrograms/ml; therefore the percutaneous absorption was evaluated by measuring cumulative urinary excretion of clioquinol and was compared to that found after an equivalent oral dose. The study was carried out in 4 healthy volunteers. The topical preparations were applied under occlusive dressings. Following epicutaneous application of the three topicals in quantities containing 30 mg clioquinol each, the urinary excretion of the drug was between 1.2 and 3.6% of the applied dose. When the same dose of clioquinol was administered orally to two volunteers, 52.4 and 92.9% of the dose was excreted in the urine. Taking the urinary elimination as the minimal amount of drug absorbed, the extent of percutaneous absorption from the three dermatological preparations amounted to 1.2-3.6% of the applied dose. There was no difference in the pattern of urinary excretion products among the three topicals and the oral formulation. The bulk of clioquinol was excreted as glucuronide (mean: 96 +/- 3%) and only a small fraction was excreted as sulfate (mean: 3.8 +/- 3%). A small amount of free clioquinol (1.1%) was measured in 1 subject only after the oral dose.

Administration, Oral↗