Subacute myelo-optico-neuropathy (SMON) and clioquinol: -A response to doubts about clioquinol causation theory-.
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Clioquinol↗
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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↗
[Subacute myelo-optic-neuropathy (S.M.O.N.) following treatment with clioquinol (author's transl)].
2 patients, who were treated with clioquinol after radical resection of carcinoma of the rectum and colostomy, developed symmetrical sensorimotor polyneuropathy, mild posterior tract ataxia, bilateral pyramidal tract lesions and optic neuropathy, a clinical picture compatible with subacute myelo-optic-neuropathy (S.M.O.N.). One patient had neurological symptoms after having received 750 g of clioquinol, 3 years after treatment started, and impairment of vision was noted after having received 1200 g. The other patient had neurological symptoms 6 weeks after clioquinol was first given, having received 65 g, the average daily dose being 1.5 g, and vision was impaired after 765 g had been administered. On examination 12 and 14 months after clioquinol had been discontinued, the first patient's vision was slightly improved, but he was otherwise unchanged, while the vision of the other patient was unchanged, but she had otherwise deteriorated slightly neurologically. Electrophysiological examinations confirmed the clinical observations. A multifactor etiology of the syndrome: neurotoxicity of clioquinol, paraneoplastic neuropathy and malabsorption, is discussed.
Abdomen, Acute↗
Primary irritant dermatitis from topical clioquinol.
During the 2-year period 1976--1977, seven patients were studied with primary irritant dermatitis from topical preparations containing clioquinol. During the same period contact hypersensitivity to the compound was recorded in 35 eczema patients. Six of the seven patients with clioquinol irritancy had used creams containing 3% large crystal clioquinol and fluorinated steroids. One patient had used 6% small crystal clioquinol cream. Challenge tests with 3% small crystal and large crystal clioquinol creams showed that crystal size did not affect the appearance of irritant dermatitis.
Administration, Topical↗
Transient global amnesia after clioquinol: five personal observations from outside Japan.
Five personal observations of an acute amnestic episode in younger individuals after intake of clioquinol are described together with three observations from the medical literature. In five of these cases the episode began after an unusually large dose, in three after a therapeutic one with a latency of about 24 hours. The clinical aspect closely resembled classical transient global amnesia but the episode after clioquinol lasted longer (24 hours to three days) and a more or less extensive retrograde amnesia persisted permanently. In one patient after three tablets of Mexase a clioquinol concentration of 12 microgram/ml in plasma was found 24 hours after the specified dose, which is an unexpectedly high concentration compared to those reported as late as 24 hours after a single equal dose of Mexase or any other clioquinol-containing preparation. Another patient had a brief relapse two years after the first episode, after a single therapeutic dose of another clioquinol preparation.
Adult↗
Clioquinol and 2,5-hexanedione induce different types of distal axonopathy in the dog.
The central distal axonopathy induced in dogs by the administration of high doses of clioquinol is contrasted with the central-peripheral distal axonopathy precipitated by intoxication with 2,5-hexanedione. Mature, pure-bred Beagle dogs received a daily oral dose of 400 mg/kg of clioquinol for up to 7 months, or 1 ml per animal (approximately corresponding to 110 mg/kg) of 2,5-hexanedione for up to 5 months. Intoxicated and control animal were killed and perfused at monthly intervals, so that the spatial-temporal development of the lesion could be followed and correlated with clinical symptoms. During the treatment, dogs intoxicated with 2,5-hexanedione developed symptoms of peripheral neuropathy consisting of flaccid weakness, muscle atrophy, hind-limb foot-drop and areflexia. By contrast, the dogs surviving clioquinol intoxication exhibited a stiff-legged gait, hyperreflexia but no muscle atrophy. Light and electron microscope examination of central and peripheral nervous tissue from dogs intoxicated with 2,5-hexanedione revealed giant axonal swelling and distal axonal degeneration. By contrast, dogs receiving clioquinol showed a distal axonal degeneration confined to the optic tract and the long spinal cord tracts, without any visible involvement of peripheral nerves.
Animals↗
Comparison of the acute toxicity of clioquinol, histamine, and chloroform in different strains of mice.
The oral LD50'S of clioquinol, histamine and chloroform and the intravenous LD50 of histamine were determined separately in male and female mice of the Tif : MAGf (SPF), Tif : MF2f (SPF), C3H/Tif Bomf, DBA2/J Bomf, C57Bl/6J/Bomf and A/J Bomf strains. Mice of the Tif : MAGf (SPF) outbred strain and the Tif : MF2f(SPF) hybrids tended to be more resistant than the inbred strains, with exception of C57Bl/6J/Bomf, which proved least susceptible to the lethal effects of the tested preparations. The toxicity of chloroform was more pronounced in the males than in the females, and C3H/Tif Bomf proved more susceptible than all other strains. The toxicity of clioquinol and histamine was not related to sex.
Animals↗
The determination of clioquinol in biological materials by extractive alkylation and gas-liquid chromatography.
Clioquinol, or 5-chloro-7-iodo-8-hydroxyquinoline (Vioform), and the internal standard, 5,7-dichloro-8-hydroxyquinoline are extracted from biological material in the form of their tetrahexylammonium salts into dichloromethane, where, in the presence of a methylating agent, both clioquinol and the standard are spontaneously transformed into their O-methyl derivatives. These derivatives can be purified by base-specific extraction and subsequently determined by gas chromatography; concentrations down to 10 ng per sample may be assayed. The method is compared with a previously reported procedure based on the O-acetyl derivatives.
Adipose Tissue↗
The oral toxicity of clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) in beagle dogs.
When clioquinol was administered to Beagle dogs, disturbances in gait which were associated with abnormal reflexes and reactions, were seen in animals receiving 250 and 400 mg/kg body weight per day. Histopathological examination of the central nervous system (CNS) showed pathological change in the posterior columns of the spinal cord.
Animals↗
Clioquinol toxicity in the dog.
A number of instances have been reported in the scientific literature in which acute intoxication with halogenated oxyquinolines has led in some species to convlusions, often followed by death. The toxicity of repeated doses of clioquinol has been investigated extensively in the dog. The clinical syndrome induced in this species is characterized by anorexia, weight loss, extremem muscle weakness and emaciation. In some animals surviving this impairment of condition for several weeks, neuropathy of the central nervous system, but not of the peripheral nerves ensued. It is suggested that these toxicological manifestations are less dependent on the dose-level than on the degree of absorption. Some suggestions regarding the aetiology of the lesions are made.
Animals↗
Subacute myelo-optic neuropathy and clioquinol. An epidemiological case-history for diagnosis.
Between about 1955 and 1970, some 100,000 Japanese were diagnosed as having subacute myelooptic neuropathy (SMON), a new disease characterized by abdominal and neurological manifestations, the former nearly always preceding the latter. Circumstantial evidence obtained in 1969-70 suggested that SMON might have been caused by clioquinol (CQL), a gastrointestinal disinfectant, and led to the suspension of further sales of CQL in Japan. However, several inconsistencies for the CQL theory of SMON have now emerged; first, CQL had been widely used in Japan for nearly 20 years before SMON occurred. Secondly, the SMON epidemic began to subside several months before CQL sales were suspended. Thirdly, a large proportion of SMON patients--probably about one-third and possibly more--had not taken CQL within six months of the onset of the disease (the modal interval between first taking CQL and the onset of SMON being about three weeks, and more than 100 days in only 4% of SMON patients); of the remaining two-thirds or so, many had taken CQL as part of the treatment of the first (that is, abdominal) symptoms of SMON itself. Fourthly, there was no dose-response relationship. Finally, SMON rarely, if ever, occurred outside Japan. CQL could, however, have been involved in the causation of SMON as an optional enhancer of some other necessary cause; the history of post-war environmental pollution in Japan is compatible with this hypothesis. Over-readiness to accept postulated toxic effects of medicines and chemicals as proven is likely to do at least as much harm as good to individual and community health.
Abdomen↗
Demonstration of antibody activity to clioquinol in sera of experimental rabbits and patients with subacute myelo-optico-neuropathy.
Antibody to clioquinol(5-chloro-7-iodo-8-hydroxyquinoline:CIHQ) was detected by passive hemagglutinating reaction in rabbits receiving a prolonged administration of Emaform which was once a commercial preparation of CIHQ. The antibody was shown to be in the immunoglobulin fractions by separation with a specific immunoadsorbent, and it had relatively broad antigenic specificity. The antibody was also demonstrated in sera from patients who suffered from Subacute Myelo-Optico-Neuropathy (SMON) and from normal healthy individuals. However, its titer and frequency of positive reactors in the former were higher than those in the latter, and the two groups could be differentiated each other in frequency distribution patterns of the antibody proprietors. From these results, we discussed on desirable application of sero-epidemiological study to assessment of effects of chemical pollutants on living systems.
Adult↗
[Comparative studies on Bi-Nerisona cream (diflucortolone valerinate + chlorquinaldol) and on a combination preparation (betamethasone valerinate + gentamicin + tolnaftate + clioquinol) in a double-blind trial].
Bi-Nerisone cream and a control preparation, also in the form of a cream, have been clinically tested on 343 patients by means of a double blind study. Equilvalent results were obtained without registering any significant statistical differences, a finding, however, proving to be of great importance as Bi-Nerisone only contains two active substances (Diflucortolone valerat + Chlorquinaldol), whereas the control preparation contains a total of four (Betamethasone valerate + Gentamycin + Tolnaftate + Clioquinol).
Betamethasone Valerate↗
Electrophoretic studies of clioquinol binding to human serum proteins.
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Blood Proteins↗
Hyperbaric oxygen therapy for peripheral nerve damage induced in rabbits with clioquinol.
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Animals↗
Extractive alkylation of biological samples of clioquinol or chloroquinaldol and determination by electron capture gas chromatography.
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Chloroquinolinols↗