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HYDROXYQUINOLINES

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) The halogenated hydroxyquinolines have antibacterial, antifungal, and antiprotozoal activity.

Specific Substances

    A) BROBENZOXALDINE (SYNONYM)
    1) 5,7-dibromo-2-methyl-8-quinolylbenzoate
    2) Broxaldine
    3) CAS 3684-46-6
    BROXYQUINOLINE (SYNONYM)
    1) 5,7-dibromo-8-quinolinol
    2) CAS 521-74-4
    CHLOROQUINALDOL (SYNONYM)
    1) 5,7-Dichloro-2-methyl-8-quinolinol
    2) Chlorquinaldol
    3) Hydroxydichloroquinaldine
    4) CAS 72-80-0
    CLIOQUINOL (SYNONYM)
    1) 5-chloro-8-hydroxy-7-iodoquinol
    2) 5 chloro-7-iodo-8-hydroxy-quinoline
    3) 5-chloro-7-iodoquinolin-8-ol
    4) 7-iodo-5-chloro-8-hydroxyquinoline
    5) 7-iodo-5-chloroxine
    6) Chloroiodoquine
    7) Iodochlorhydroxyquin
    8) Iodochlorhydroxyquinol
    9) Iodochlorhydroxyquinoline
    10) CAS 130-26-7
    IODOQUINOL (SYNONYM)
    1) 5,7-Di-iodoquinolin-8-ol
    2) Diiodohydroxyquin
    3) Diiodoxychinolinum
    4) Diiodoxyquinoleine
    5) Diodoquin
    6) Diiodohydroxyquinoline
    7) CAS 83-73-8

Available Forms Sources

    A) FORMS
    1) IODOQUINOL (DIIODOHYDROXYQUINOLINE) has been available as 210 mg and 650 mg tablets (Prod Info Yodoxin(R) oral tablets, 2010)
    2) Because of the neurotoxicity seen between 1955 and 1970, clioquinol and similar halogenated hydroxyquinolines have been taken off the market in many countries (Swain et al, 1986).
    3) Various hydroxyquinolines
    a) Chiniofon (Yatren(R)) is a combination of 7-iodo-8-hydroxyquinoline-5-sulfonic acid, its sodium salt and some sodium bicarbonate.
    b) Intestopan Forte(R) contains two hydroxyquinolines, broxyquinoline and brobenzoxaldine (Swain et al, 1986).
    B) USES
    1) The halogenated hydroxyquinolines are used to treat intestinal amoebiasis (Swain et al, 1986), and for treatment of acrodermatitis enteropathica (a rare skin disease) (Ellenhorn & Barceloux, 1988).
    2) IODOQUINOL (DIIODOHYDROXYQUINOLINE) was approved for the treatment of intestinal amebiasis (Prod Info Yodoxin(R) oral tablets, 2010). It has also be used for Dientamoeba fragilis infections, in balantidiasis (as an alternative to tetracycline), and in Blastocystis hominis infections. It was formerly used to treat acrodermatitis enteropathica (S Sweetman , 2002).
    3) CLIOQUINOL is a halogenated hydroxyquinoline with antibacterial and antifungal activity. It was formerly given orally to treat intestinal amoebiasis. In addition, it was used for the prophylaxis and treatment of traveller's diarrhea. Because of the neurotoxicity seen between 1955 and 1970, clioquinol and similar halogenated hydroxyquinolines have been taken off the market in many countries (S Sweetman , 2002; Swain et al, 1986). In several countries, clioquinol is now mainly used as creams and ointments (3%) to treat skin infections. In addition, it is applied together with a corticosteroid in inflammatory skin conditions complicated by bacterial or fungal infections (S Sweetman , 2002).
    4) TILBROQUINOL is an antiprotozoal agent with properties similar to those of diiodohydroxyquinoline. To treat intestinal infections including amoebiasis, tilbroquinol and tiliquinol are used together (S Sweetman , 2002).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: The halogenated hydroxyquinolines have antibacterial, antifungal, antiprotozoal activity. Iodoquinol was approved for the treatment of intestinal amebiasis. Clioquinol was formerly given to treat intestinal amebiasis and traveller's diarrhea. Because of the neurotoxicity seen between 1955 and 1970, clioquinol and similar halogenated hydroxyquinolines have been taken off the market in many countries. In several countries, clioquinol is now mainly used as creams and ointments (3%) to treat skin infections.
    B) PHARMACOLOGY: These agents have antibacterial, antifungal, and some antitrichomonal activity. The exact mechanism of action of iodoquinol is unknown. Iodoquinol produces its amebicidal effect at the site of infection against Entamoeba histolytica and can be used against trophozoite and cyst forms. It is poorly absorbed from the gastrointestinal tract and can reach high concentrations in the intestinal lumen.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) These compounds may cause gastrointestinal upset, diarrhea, allergic reactions, and thyroid enlargement, but they are primarily known for their neurotoxicity, with both spinal cord and optic nerve damage. Iodoquinol therapy can cause skin eruptions (eg, acneiform papular and pustular, bullae, vegetating or tuberous iododerma), urticaria, pruritus, nausea, vomiting, abdominal pain, diarrhea, fever, chills, headache, vertigo, and enlarged thyroid. Seizures and encephalopathy were observed in a 9-year-old boy who received iodoquinol therapy. Prolonged high-dose treatment with 8-hydroxyquinoline can cause optic neuritis, optic atrophy, and peripheral neuropathy. Hepatotoxicity has been reported with tiliquinol and tilbroquinol use. Chronic administration of high doses of clioquinol has resulted in a condition called subacute myelo-optico-neuropathy (SMON). Symptoms include abdominal pain, diarrhea, paresthesias leading to paraplegia, and loss of vision. The drug affects the long fibres of the spinal cord, and the optic nerve. A woman developed muscle wasting, optic neuritis, sphincter disturbances, and flaccid paraplegia after taking clioquinol for a month.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Clinical events following exposure are anticipated to be an extension of adverse events. Overdose may produce CNS toxicity.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the effects of clioquinol/hydrocortisone or iodoquinol/hydrocortisone on pregnancy. They are rated as FDA pregnancy category C.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, mental status, and liver enzymes following an overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Patients who are taking this medication chronically, or who have overdosed should have folic acid and vitamin B12 levels monitored.
    E) Monitor visual fields and optic nerve function following an overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for persistent seizures and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions or persistent seizures.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) It is unknown if hemodialysis would be effective in overdose.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs and mental status. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a local poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETICS
    1) Absorption: Only partly and irregularly absorbed from the gastrointestinal tract. Excretion: No free forms found in urine for 10 hours after a single oral 300 mg dose.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause neurotoxicity.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) These agents are generally poorly absorbed, and symptoms from a single exposure are unlikely.
    2) Remove contaminated clothing and jewelry and irrigate exposed areas with copious amounts of water. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICOLOGY: IODOQUINOL: Overdose data with iodoquinol are limited. Seizures and encephalopathy were observed in a 9-year-old boy who received 420 mg of iodoquinol 3 times daily for 12 days. CLIOQUINOL: Extended treatment with oral doses greater than 2 grams daily has caused toxicity with subacute myelo-optico-neuropathy being most significant. Due to this toxicity, oral preparations of clioquinol are unavailable in most countries, including the United States. A woman who was taking about clioquinol 1 to 1.5 grams daily (total dose: 28 grams) for a month, developed muscle wasting, optic neuritis, sphincter disturbances, and flaccid paraplegia. The following provides the estimated clioquinol neurotoxic dose-response: Little or No Risk: 750 mg/day for 4 weeks or less. 1% Incidence of Neurotoxicity: 750 to 1,500 mg/day for less than 2 weeks. 35% Incidence of Neurotoxicity: 750 to 1,500 mg/day for over 2 weeks. When doses higher than these are administered, toxicity may start within 24 hours of initiation of these doses.
    B) THERAPEUTIC DOSES: IODOQUINOL (DIIODOHYDROXYQUINOLINE): ADULTS: To treat intestinal amebiasis, 3 tablets (210 mg each) 3 times daily orally for 20 days OR 1 tablet (650 mg each) 3 times daily orally for 20 days. PEDIATRIC: To treat intestinal amebiasis, 10 to 13.3 mg/kg 3 times daily for 20 days. MAX daily dose is 1.95 g. CLIOQUINOL: To treat intestinal amebiasis, 250 mg 3 times daily orally for 10 days were recommended. This regimen was repeated after an 8-day rest period. Due to the risk of neurotoxicity, oral preparations of clioquinol are unavailable in most countries including the United States.

Clinical Effects

Summary Of Exposure

    A) USES: The halogenated hydroxyquinolines have antibacterial, antifungal, antiprotozoal activity. Iodoquinol was approved for the treatment of intestinal amebiasis. Clioquinol was formerly given to treat intestinal amebiasis and traveller's diarrhea. Because of the neurotoxicity seen between 1955 and 1970, clioquinol and similar halogenated hydroxyquinolines have been taken off the market in many countries. In several countries, clioquinol is now mainly used as creams and ointments (3%) to treat skin infections.
    B) PHARMACOLOGY: These agents have antibacterial, antifungal, and some antitrichomonal activity. The exact mechanism of action of iodoquinol is unknown. Iodoquinol produces its amebicidal effect at the site of infection against Entamoeba histolytica and can be used against trophozoite and cyst forms. It is poorly absorbed from the gastrointestinal tract and can reach high concentrations in the intestinal lumen.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) These compounds may cause gastrointestinal upset, diarrhea, allergic reactions, and thyroid enlargement, but they are primarily known for their neurotoxicity, with both spinal cord and optic nerve damage. Iodoquinol therapy can cause skin eruptions (eg, acneiform papular and pustular, bullae, vegetating or tuberous iododerma), urticaria, pruritus, nausea, vomiting, abdominal pain, diarrhea, fever, chills, headache, vertigo, and enlarged thyroid. Seizures and encephalopathy were observed in a 9-year-old boy who received iodoquinol therapy. Prolonged high-dose treatment with 8-hydroxyquinoline can cause optic neuritis, optic atrophy, and peripheral neuropathy. Hepatotoxicity has been reported with tiliquinol and tilbroquinol use. Chronic administration of high doses of clioquinol has resulted in a condition called subacute myelo-optico-neuropathy (SMON). Symptoms include abdominal pain, diarrhea, paresthesias leading to paraplegia, and loss of vision. The drug affects the long fibres of the spinal cord, and the optic nerve. A woman developed muscle wasting, optic neuritis, sphincter disturbances, and flaccid paraplegia after taking clioquinol for a month.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Clinical events following exposure are anticipated to be an extension of adverse events. Overdose may produce CNS toxicity.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) IODOQUINOL: Iodoquinol therapy can cause fever and chills (Prod Info Yodoxin(R) oral tablets, 2010).

Heent

    3.4.2) HEAD
    A) WITH THERAPEUTIC USE
    1) GREEN TONGUE: An iron chelate of clioquinol may result in a green color or green 'fur' on the tongue in some patients (Takasu et al, 1970; Imanari & Tamura, 1970)
    3.4.3) EYES
    A) OPTIC NEUROPATHY has been reported following toxic exposures.
    1) INCIDENCE: Has been reported in a number of cases involving clioquinol. In one study, the incidence of optic atrophy was about 5% and the incidence of impaired vision was between 24% and 38% (Rose & Gawel, 1984; Grant & Schuman, 1993).
    2) PRESENTATION: There is still controversy as to whether this condition was due solely to the clioquinol, but decreased visual acuity with vacuolation and loss of axons in the optic tract has been seen in dogs (Tateishi et al, 1973; Schaumburg et al, 1978). Clinically, ophthalmoscopic abnormalities appear to be confined to pallor of the disc in eyes with optic atrophy (Grant & Schuman, 1993).
    3) VISUAL IMPAIRMENT: Bilateral visual impairment was one of the major signs reported with clioquinol toxicity (Rose & Gawel, 1984).
    4) CASE REPORT: OPTIC ATROPHY was reported in a 72-year-old who took 200 mg of clioquinol per day for 27 years (Ricoy et al, 1982). Optic nerve atrophy has also been reported in children given clioquinol for treatment of acrodermatitis enteropathica (Hanakago & Uono, 1981).
    5) PATHOLOGY: Autopsies done to identify the cause of the lost vision showed degeneration of optic nerve axons. This condition was most severe next to the geniculate nucleus but also extended to the retina with degeneration and disappearance of retinal ganglion cells (Okuda et al, 1971; Shiraki, 1975).
    6) CASE REPORT: Prolonged high-dose treatment with 8-hydroxyquinoline can cause optic neuritis and optic atrophy (Prod Info Yodoxin(R) oral tablets, 2010).
    7) CLIOQUINOL: CASE REPORT: A 55-year-old woman who was taking about clioquinol 1 to 1.5 grams daily (total dose: 28 grams) for a month, developed muscle wasting, optic neuritis, sphincter disturbances, and flaccid paraplegia (Castaigne et al, 1973).
    8) CASE REPORT: Optic neuropathy was reported in a 12-year-old boy given 1.5 grams per day (total dose of 40 grams over 27 days) of broxyquinoline (Strandvik & Zetterstrom, 1968).
    9) CLIOQUINOL: CASE REPORT: Optical neuritis, characterized by bilateral centrocaecal scotomata, was the sole manifestation of clioquinol neurotoxicity in a 12-year-old child (Reich & Billson, 1973).
    10) CLIOQUINOL: CASE REPORT: A patient developed subacute myelo-optico-neuropathy after taking tilbroquinol and tiliquinol for 4 years (S Sweetman , 2002).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) AMNESIA
    1) CLIOQUINOL: TRANSIENT GLOBAL AMNESIA: Confusional states resembling transient global amnesia have been reported with excessive doses of clioquinol. There is often a latency period before onset, ranging from 18 to 48 hours. The condition may last one to three days. A permanent retrograde amnesia for just a few days or up to two months has also been seen (Kaeser, 1984).
    a) These cases are more often associated with acute, high dose episodes, rather than the chronic overdosage picture seen with SMON (Ferrier et al, 1987). There have been some early indications that this amnesia may be related to similar episodes years later (Ferrier et al, 1987).
    B) NEUROPATHY
    1) SUMMARY: Subacute myelo-optico-neuropathy (SMON) was reported in up to 10,000 patients by the Japanese (Tsubaki et al, 1965). This condition consisted of a subacute onset of myelopathy, optic neuropathy, and peripheral neuropathy. The peripheral neuropathy component is not seen as frequently (S Sweetman , 2002; Ellenhorn & Barceloux, 1988; Wadia, 1984).
    2) INCIDENCE: The incidence of SMON in most of the early Japanese studies ranged from 3.4% to 43.6% (Rose & Gawel, 1984). Up to 10 to 15% remained permanently disabled (Thomas, 1984). There are many questions concerning the Japanese epidemic of SMON and its association with clioquinol, and not all believe that the cases seen are due solely to this drug (Swain et al, 1986; Shigematsu, 1975).
    3) Although it is suggested that the Japanese epidemic might be due to genetic susceptibility, several similar cases of subacute myelo-optico-neuropathy associated with clioquinol or related hydroxyquinoline derivatives (eg; broxyquinoline, diiodohydroxyquinoline) have been reported in other countries (S Sweetman , 2002). A case of subacute myelo-optico-neuropathy was reported in a patient who had taken tilbroquinol together with tiliquinol for 4 years (S Sweetman , 2002).
    4) COMMON EFFECTS: One of the more common effects seen was persistent symmetrical dysesthesia, primarily affecting legs and trunk. Acute or subacute bilateral ascending paresthesia and dysesthesia of the lower limbs was considered one of the cardinal signs of SMON (Rose & Gawel, 1984).
    5) RARE EFFECTS: Effects such as spastic ataxic paraparesis, hypotonic weakness in the lower limbs, seizures, psychic disturbances, bilateral visual impairment, and blindness were uncommonly to rarely seen (Rose & Gawel, 1984).
    6) NERVE ENDINGS: A muscle biopsy on a man who had developed SMON after taking between 1,500 and 1,800 mg of clioquinol per day for years showed severe degenerative changes of the presynaptic nerve endings and unique paracrystalline inclusions in the sole plate region (Otte et al, 1977).
    7) Prolonged high-dose treatment with 8-hydroxyquinoline can cause peripheral neuropathy (Prod Info Yodoxin(R) oral tablets, 2010).
    C) VERTIGO
    1) WITH THERAPEUTIC USE
    a) IODOQUINOL: Iodoquinol therapy can cause vertigo (Prod Info Yodoxin(R) oral tablets, 2010).
    D) HEADACHE
    1) WITH THERAPEUTIC USE
    a) IODOQUINOL: Iodoquinol therapy can cause headache (Prod Info Yodoxin(R) oral tablets, 2010).
    E) FLACCID PARAPLEGIA
    1) WITH POISONING/EXPOSURE
    a) CLIOQUINOL: CASE REPORT: A 55-year-old woman who was taking about 1 to 1.5 grams per day (total dose 28 grams) for a month, developed muscle wasting, optic neuritis, sphincter disturbances, and flaccid paraplegia (Castaigne et al, 1973).
    F) SEIZURE
    1) WITH THERAPEUTIC USE
    a) IODOQUINOL: CASE REPORT/CHILD: Seizures and encephalopathy were seen in a 9-year-old boy who received 420 mg iodoquinol three times daily for 12 days. Although an existing seizure disorder could not be ruled out, the boy had no history of it or any other etiology and an EEG demonstrated diffuse severe encephalopathy (Fisher et al, 1993).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) Seizures have been reported in overdosed animals, most likely due to hippocampal lesions (Krinke et al, 1978).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) IODOQUINOL: Iodoquinol therapy can cause abdominal pain (Prod Info Yodoxin(R) oral tablets, 2010).
    b) CLIOQUINOL: Abdominal pain was frequently seen in patients with the clinical diagnosis of subacute myelo-optico-neuropathy (SMON) (Rose & Gawel, 1984; Egashira & Matsuyama, 1982).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) IODOQUINOL: Iodoquinol therapy can cause diarrhea (Prod Info Yodoxin(R) oral tablets, 2010).
    b) CLIOQUINOL: Diarrhea was frequently seen in patients with the clinical diagnosis of subacute myelo-optico-neuropathy (SMON) (Rose & Gawel, 1984; Egashira & Matsuyama, 1982).
    C) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) IODOQUINOL: Iodoquinol therapy can cause nausea, vomiting, abdominal pain, and diarrhea (Prod Info Yodoxin(R) oral tablets, 2010).
    b) CLIOQUINOL: Other abdominal symptoms such as sphincter disturbances were frequently seen in patients with the clinical diagnosis of subacute myelo-optico-neuropathy (SMON) (Rose & Gawel, 1984; Egashira & Matsuyama, 1982).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) CASE REPORT: A 54-year-old woman developed hepatotoxicity after taking tiliquinol (200 mg/day) and tilbroquinol (800 mg/day) for 4 days (Caroli-Bosc et al, 1996).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOCELLULAR DAMAGE
    a) HEPATIC DAMAGE has been reported in animals after overdose with these agents (Gosselin et al, 1984)

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL URINE
    1) WITH THERAPEUTIC USE
    a) GREEN URINE may be seen due to a chelate of iron (Igata et al, 1970).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Thrombocytopenia with hemorrhages was observed in a 68-year-old man who ingested 1 gram of dibromohydroxyquinoline and 100 mg of dibromobenzoxyquinoline (Gosselin et al, 1984)

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN FINDING
    1) WITH THERAPEUTIC USE
    a) IODOQUINOL: Iodoquinol therapy can cause skin eruptions (eg, acneiform papular and pustular, bullae, vegetating or tuberous iododerma), urticaria, and pruritus (Prod Info Yodoxin(R) oral tablets, 2010).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) GOITER
    1) WITH THERAPEUTIC USE
    a) CLIOQUINOL: Thyroid enlargement was noted after therapeutic use of clioquinol (Ellenhorn & Barceloux, 1988).
    b) IODOQUINOL: Iodoquinol therapy can cause enlarged thyroid (Prod Info Yodoxin(R) oral tablets, 2010).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) The halogenated hydroxyquinolines have produced frequent allergic reactions in humans, and have included both sensitization (1.4 to 1.9%) and cross-sensitization to such agents as quinoline-based antimalarial drugs, and in a few cases, potassium iodide (S Sweetman , 2002; Kernekamp & van Ketel, 1980).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the effects of clioquinol/hydrocortisone or iodoquinol/hydrocortisone on pregnancy. They are rated as FDA pregnancy category C.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) CLIOQUINOL/HYDROCORTISONE
    a) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info DERMASORB(TM) AF COMPLETE KIT topical cream, 2013).
    2) IODOQUINOL/HYDROCORTISONE
    a) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info Vytone(TM) Cream with aloe topical cream, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) CLIOQUINOL/HYDROCORTISONE
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info DERMASORB(TM) AF COMPLETE KIT topical cream, 2013).
    2) IODOQUINOL/HYDROCORTISONE
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info VYTONE(TM) topical cream, 2013).
    B) PREGNANCY CATEGORY
    1) Clioquinol/hydrocortisone and iodoquinol/hydrocortisone are classified as FDA pregnancy category C (Prod Info Vytone(TM) Cream with aloe topical cream, 2013; Prod Info DERMASORB(TM) AF COMPLETE KIT topical cream, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) CLIOQUINOL/HYDROCORTISONE
    a) At the time of this review, no data were available to asses the potential effects of exposure to this agent during lactation in humans (Prod Info DERMASORB(TM) AF COMPLETE KIT topical cream, 2013).
    2) IODOQUINOL/HYDROCORTISONE
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info Vytone(TM) Cream with aloe topical cream, 2013).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) CLIOQUINOL/HYDROCORTISONE
    a) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent (Prod Info DERMASORB(TM) AF COMPLETE KIT topical cream, 2013).
    2) IODOQUINOL/HYDROCORTISONE
    a) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent (Prod Info Vytone(TM) Cream with aloe topical cream, 2013).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, mental status, and liver enzymes following an overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Patients who are taking this medication chronically, or who have overdosed should have folic acid and vitamin B12 levels monitored.
    E) Monitor visual fields and optic nerve function following an overdose.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Patients who are taking this medication chronically, or who have overdosed should have folic acid and vitamin B12 levels monitored (Ellenhorn & Barceloux, 1988).
    B) LABORATORY INTERFERENCE
    1) THYROID FUNCTION TEST: The iodine in clioquinol may interfere with the interpetation of the thyroid function test.
    a) Orally administered clioquinol in a dose of 500 mg/day for 2 weeks caused an increase in the protein bound iodine to 118 mcg/100 mL (Sonkenson et al, 1968). This is true even if applied to the skin.
    b) Hodgson-Jones (1970) reported an increase in serum bound iodine of between 10 and 13.5 mcg/l00 mL when clioquniol was given topically. These tests by may be disturbed for up to 3 months (JEF Reynolds , 1989).
    2) PFU Test: Clioquinol may react with the ferric chloride to produce a false positive reaction.
    4.1.3) URINE
    A) OTHER
    1) GREEN URINE: Patients taking clioquinol may experience green urine or feces due to an iron chelate (Igata et al, 1970).
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) VISUAL FIELDS: Patients who are taking this medication, or who have overdosed should have visual fields and optic nerve functions checked (Ellenhorn & Barceloux, 1988).
    b) NEUROLOGIC STATUS should be monitored (Ellenhorn & Barceloux, 1988).

Radiographic Studies

    A) RADIOGRAPHIC-OTHER
    1) Iodoquinol has been detected on radiographs after oral ingestion (Fisher et al, 1991).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a local poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs and mental status. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, mental status, and liver enzymes following an overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Patients who are taking this medication chronically, or who have overdosed should have folic acid and vitamin B12 levels monitored.
    E) Monitor visual fields and optic nerve function following an overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for persistent seizures and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs, mental status, and liver enzymes following an overdose.
    3) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    4) Patients who are taking this medication chronically, or who have overdosed should have folic acid and vitamin B12 levels monitored.
    5) Monitor visual fields and optic nerve function following an overdose.
    C) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Eye Exposure

    6.8.2) TREATMENT
    A) SUPPORT
    1) No specific treatment has been effective, other than discontinuation of the drug. In some cases there has been improvement of vision over the several months immediately following discontinuation of the clioquinol (Grant, 1986).
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) Remove contaminated clothing and jewelry and irrigate exposed areas with copious amounts of water. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) LACK OF INFORMATION
    1) It is unknown if hemodialysis would be effective in overdose.

Abstracts

Case Reports

    A) ADULT
    1) CLIOQUINOL: A 45-year-old man was treated for diarrhea with clioquinol. After a total dose of 5 grams (10 days into the treatment), he began hallucinating and was agitated. He subsequently complained of hypersensitivity of the face, and tingling of the extremities on the left side. His acute psychosis was dealt with by administration of 15 mg of diazepam and chlorpromazine. By the 4th day his symptoms had resolved, but he was amnesic for the acute episode (Kaeser, 1984).

Range Of Toxicity

Summary

    A) TOXICOLOGY: IODOQUINOL: Overdose data with iodoquinol are limited. Seizures and encephalopathy were observed in a 9-year-old boy who received 420 mg of iodoquinol 3 times daily for 12 days. CLIOQUINOL: Extended treatment with oral doses greater than 2 grams daily has caused toxicity with subacute myelo-optico-neuropathy being most significant. Due to this toxicity, oral preparations of clioquinol are unavailable in most countries, including the United States. A woman who was taking about clioquinol 1 to 1.5 grams daily (total dose: 28 grams) for a month, developed muscle wasting, optic neuritis, sphincter disturbances, and flaccid paraplegia. The following provides the estimated clioquinol neurotoxic dose-response: Little or No Risk: 750 mg/day for 4 weeks or less. 1% Incidence of Neurotoxicity: 750 to 1,500 mg/day for less than 2 weeks. 35% Incidence of Neurotoxicity: 750 to 1,500 mg/day for over 2 weeks. When doses higher than these are administered, toxicity may start within 24 hours of initiation of these doses.
    B) THERAPEUTIC DOSES: IODOQUINOL (DIIODOHYDROXYQUINOLINE): ADULTS: To treat intestinal amebiasis, 3 tablets (210 mg each) 3 times daily orally for 20 days OR 1 tablet (650 mg each) 3 times daily orally for 20 days. PEDIATRIC: To treat intestinal amebiasis, 10 to 13.3 mg/kg 3 times daily for 20 days. MAX daily dose is 1.95 g. CLIOQUINOL: To treat intestinal amebiasis, 250 mg 3 times daily orally for 10 days were recommended. This regimen was repeated after an 8-day rest period. Due to the risk of neurotoxicity, oral preparations of clioquinol are unavailable in most countries including the United States.

Therapeutic Dose

    7.2.1) ADULT
    A) CLIOQUINOL/HYDROCORTISONE
    1) Apply a thin layer of cream topically to the affected area 3 to 4 times daily (Prod Info DERMASORB(TM) AF COMPLETE KIT topical cream, 2013).
    B) IODOQUINOL (DIIODOHYDROXYQUINOLINE)
    1) To treat intestinal amebiasis, 3 tablets (210 mg each) 3 times daily orally for 20 days OR 1 tablet (650 mg each) 3 times daily orally for 20 days (Prod Info Yodoxin(R) oral tablets, 2010).
    C) IODOQUINOL/HYDROCORTISONE
    1) TOPICAL
    a) Apply to affected area 3 to 4 times daily (Prod Info Vytone(TM) Cream with aloe topical cream, 2013)
    7.2.2) PEDIATRIC
    A) CLIOQUINOL/HYDROCORTISONE
    1) LESS THAN 2 YEARS OF AGE: Not recommended for use in children up to 2 years of age (Prod Info DERMASORB(TM) AF COMPLETE KIT topical cream, 2013).
    2) 2 YEARS OF AGE AND OLDER: Apply thin layer of cream (clioquinol 3%/hydrocortisone 0.5%) topically to affected area 3 or 4 times daily; consider limiting therapy to no more than twice daily for 2 weeks or less (Prod Info DERMASORB(TM) AF COMPLETE KIT topical cream, 2013).
    B) IODOQUINOL (DIIODOHYDROXYQUINOLINE)
    1) To treat intestinal amebiasis, 10 to 13.3 mg/kg 3 times daily for 20 days. MAX daily dose is 1.95 g (Prod Info Yodoxin(R) oral tablets, 2010).
    C) IODOQUINOL/HYDROCORTISONE
    1) TOPICAL
    a) PATIENTS AGED 12 YEARS AND OLDER: Apply to affected area 3 to 4 times daily (Prod Info Vytone(TM) Cream with aloe topical cream, 2013)
    b) PATIENTS UNDER 12 YEARS OF AGE: Safety and efficacy have not been established (Prod Info Vytone(TM) Cream with aloe topical cream, 2013)

Maximum Tolerated Exposure

    A) IODOQUINOL
    1) CHILD: Seizures and encephalopathy were seen in a 9-year-old boy who received 420 mg iodoquinol 3 times daily for 12 days. Although an existing seizure disorder could not be ruled out, the boy had no history of it or any other etiology and an EEG demonstrated diffuse severe encephalopathy (Fisher et al, 1993).
    B) CLIOQUINOL
    1) The following provides the estimated clioquinol neurotoxic dose-response (Ellenhorn & Barceloux, 1988):
    a) Little or No Risk: 750 mg/day for 4 weeks or less
    b) 1% Incidence of Neurotoxicity: 750 to 1,500 mg/day for less than 2 weeks
    c) 35% Incidence of Neurotoxicity: 750 to 1,500 mg/day for over 2 weeks
    d) When doses higher than these are administered, toxicity may start within 24 hours of initiation of these doses.
    2) When 316 clioquinol treated patients (75 who developed subacute myelo-optic neuropathy [SMON]) were reviewed, it was concluded that up to 440 mg of clioquinol per day could be tolerated, even if taken chronically (Nakae & Igata, 1971).
    3) In the Japanese cases, the average total amount of clioquinol taken by the SMON cases was 40.1 grams (Ellenhorn & Barceloux, 1988).
    4) In non-Japanese studies, patients who experienced the full condition usually had taken large doses (up to 15 grams) for considerable periods of time. Patients who had taken more than 4 grams in a 14-hour period had a tendency to develop encephalopathy (Baumgartner et al, 1979).
    5) One patient developed symptoms after ingesting clioquinol 1,800 mg for 5 days (Nakae & Igata, 1971).
    6) A 55-year-old woman who was taking about clioquinol 1 to 1.5 grams daily (total dose: 28 grams) for a month, developed muscle wasting, optic neuritis, sphincter disturbances, and flaccid paraplegia (Castaigne et al, 1973).
    7) There have been cases of neurological toxicity where the total dosage was under 100 grams (Rose & Gawel, 1984). Alternatively, patients have taken up to 500 to 700 mg of clioquinol per day for more than a year without experiencing toxicity (Selby, 1972).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) Patients who were treated with a 3 percent clioquinol ointment to 40 percent of their bodies (estimated 15 to 20 grams of ointment) developed serum levels of 0.8 to 1.2 micrograms per milliliter over the next 4 hours (Ellenhorn & Barceloux, 1988).
    b) Blood levels of up to 12 micrograms/milliliter have been recorded without clinical symptoms (Anon, 1984).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) CLIOQUINOL
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 590 mg/kg (RTECS , 2002)
    2) LD50- (ORAL)MOUSE:
    a) 69 mg/kg (RTECS , 2002)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) >5 gm/kg (RTECS , 2002)
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 3400 mg/kg (RTECS , 2002)
    5) LD50- (ORAL)RAT:
    a) >5 gm/kg (RTECS , 2002)
    6) LD50- (SUBCUTANEOUS)RAT:
    a) 5 gm/kg (RTECS , 2002)

Pharmacology Toxicology

Toxicologic Mechanism

    A) Japanese studies have indicated degenerative changes in the visual pathways, the lateral corticospinal tracts of the lower spinal cord, and the rostral portions of the gracile fasciculi (Tateishi et al, 1973; Schaumburg et al, 1978).
    B) The SMON type injury appears to be an action on the spinal cord, causing a centrotractopathy. The main pathology found in SMON are retrobulbar optic nerve damage, and degenerative changes in the spinal cord long tracts (Hanakago & Uono, 1981)
    C) The amnesia-type effect appears to be an action on the hippocampus (Anon, 1984).
    D) Clioquinol may increase the penetration of metallic cations into cells by forming lipophilic metal-chelates (Tjalve, 1984).

Physicochemical

Physical Characteristics

    A) CLIOQUINOL: A brown to yellow, bulky powder, without appreciable odor (Windholz, 1983)

Molecular Weight

    A) CLIOQUINOL: 305.5

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) Epileptic fits were noted in mongrel dogs who were given single doses of Entero-Vioform (Hangartner, 1965; Schantz, 1965).
    B) Dogs who survived the acute encephalopathy developed acute amnestic disturbances. There were both species and strain variability in both the toxic dose and the symptoms seen (Tateishi et al, 1972).`
    C) Clioquinol caused decreased visual acuity with vacuolation and loss of axons in the optic tract, when dogs were overdosed (Tateishi et al, 1973).
    11.1.6) FELINE/CAT
    A) Epileptiform seizures were reported in a cat after licking clioquinol powder (Kaeser, 1984). Other neurological symptoms similar to the SMON seen in humans have been seen in poisoned cats (Tateishi et al, 1972).

References

General Bibliography

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    9) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
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