Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

TOLRESTAT

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Tolrestat, an aldose reductase inhibitor, was investigated for the control and prevention of complications of chronic diabetes; however it was withdrawn from the market due to reports of poor efficacy and adverse effects to the liver.

Specific Substances

    1) Alredase(R)
    2) AY-27,773
    3) Molecular Formula: C16-H14-F3-N-O3-S
    4) N-(6-methoxy-5-trifluoromethyl-1-naphthyl
    5) (thiocarbonyl))-N-methylglycine
    6) CAS 82964-04-3

Available Forms Sources

    A) USES
    1) Tolrestat, an aldose reductase inhibitor, was investigated for the control and prevention of complication of chronic diabetes.

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Adverse effects seen during clinical trials include elevated liver enzymes, dizziness, and some skin rashes (did not differ greatly from placebo). This agent was withdrawn from the market due to poor efficacy and reports of adverse effects to the liver.
    B) WITH POISONING/EXPOSURE
    1) Overdoses by aldose reductase inhibitors have not been reported. Most of these agents are still undergoing clinical trials. Since the exact role of aldose reductase is uncertain, the effect of an overdose of the inhibitors is also uncertain. Patients should be carefully observed and any overdose complications reported.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Hyperpnea is a theoretical possibility.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Elevation of liver enzymes has been reported during clinical trials.
    0.2.11) ACID-BASE
    A) WITH POISONING/EXPOSURE
    1) Hyperchloremic acidosis is a theoretical possibility.
    0.2.12) FLUID-ELECTROLYTE
    A) WITH POISONING/EXPOSURE
    1) Hyperchloremia is theoretically possible.

Laboratory Monitoring

    A) This compound may be analyzed by ultraviolet spectrophotometric and high-performance liquid chromatographic methods. RBC sorbitol as well as liver enzymes may be useful parameters to measure during overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Consider gastric decontamination after ingestions of 1200 milligrams or more in an adult.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.

Range Of Toxicity

    A) The usual dose is 200 mg/day. Up to 1200 mg in a single dose has been taken by adults without adverse effects.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Adverse effects seen during clinical trials include elevated liver enzymes, dizziness, and some skin rashes (did not differ greatly from placebo). This agent was withdrawn from the market due to poor efficacy and reports of adverse effects to the liver.
    B) WITH POISONING/EXPOSURE
    1) Overdoses by aldose reductase inhibitors have not been reported. Most of these agents are still undergoing clinical trials. Since the exact role of aldose reductase is uncertain, the effect of an overdose of the inhibitors is also uncertain. Patients should be carefully observed and any overdose complications reported.

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hyperpnea is a theoretical possibility.
    3.6.2) CLINICAL EFFECTS
    A) HYPERVENTILATION
    1) WITH POISONING/EXPOSURE
    a) Hyperpnea is a theoretical possibility, since the chloride shift is inhibited in vitro (Gunn & Gunn, 1989). This has not been demonstrated in humans.

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Elevation of liver enzymes has been reported during clinical trials.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Elevation of liver enzymes has been reported during clinical trials (Tech Info, 1986).

Acid-Base

    3.11.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hyperchloremic acidosis is a theoretical possibility.
    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Inhibition of the chloride shift in erythrocytes has been demonstrated in vitro. While the clinical significance of this is uncertain, it is theoretically possible that hyperchloremic acidosis could result (Gunn & Gunn, 1989).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) This compound may be analyzed by ultraviolet spectrophotometric and high-performance liquid chromatographic methods. RBC sorbitol as well as liver enzymes may be useful parameters to measure during overdose.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) RBC SORBITOL - Sorbitol accumulates in human red blood cells. This is blocked by aldose reductase inhibitors.
    a) It has been suggested that RBC sorbitol levels may be an indicator of tissue sorbitol (Sestanj et al, 1984).
    b) Sorbitol levels in non-diabetics are 10+/-1 nanomol/gram hemoglobin (Raskin et al, 1985).
    2) LIVER ENZYMES - Since a few patients showed moderate increases in liver enzymes in clinical trials, overdose cases should have liver enzymes evaluated.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Both an ultraviolet spectrophotometric method and a high-performance liquid chromatographic method have been developed to analyze tolrestat.
    a) The limits of detection are 15 mcg/mL and 0.2 mcg/mL respectively in serum (Hicks & Kraml, 1984).
    b) With some modifications, the limits of detection of a 2 mL serum sample may be lowered to 25 ng/mL (Hicks & Kraml, 1984).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) This compound may be analyzed by ultraviolet spectrophotometric and high-performance liquid chromatographic methods. RBC sorbitol as well as liver enzymes may be useful parameters to measure during overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) No specific dose has been determined as toxic, but 1200 mg has been tolerated with no adverse effects. Until more data is available, consider gastric decontamination if adult ingestions are greater than 1200 mg.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    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).
    6.5.2) 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) Treatment is SYMPTOMATIC and SUPPORTIVE.

Range Of Toxicity

Summary

    A) The usual dose is 200 mg/day. Up to 1200 mg in a single dose has been taken by adults without adverse effects.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) The usual dose is 100 milligrams twice daily (Raskin et al, 1985).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Up to 1200 milligrams in a single dose has been given to non-diabetic test subjects without adverse effects (Hicks & Kraml, 1984).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) NORMAL LEVELS - After a 25 milligram dose the maximum-minimum levels were 1,500 nanograms/milliliter and 50 nanograms/milliliter, respectively (Hicks & Kraml, 1984).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Tolrestat inhibits (dose related) sorbitol formation in intact human red blood cells incubated in the presence of glucose (Simard-Duquesne et al, 1985).
    B) Tolrestat has effectively suppressed polyol accumulation. Polyols, notably sorbitol and fructose, have been implicated in the degenerative changes seen in the lens and nerve tissues of diabetics (Hicks & Kraml, 1984; Kemper & Dvornik, 1986).

Toxicologic Mechanism

    A) Toxicity has yet to be established for this compound. Aldose reductase has been found in several tissues and is responsible for the production of sorbitol (and eventually fructose) in the tissues.
    B) The physiologic role of aldose reductase in most tissues remains unknown, and no physiologic significant amounts of accumulated sorbitol has been detected. Thus, the effect of an aldose reductase inhibitor is unknown (Kador et al, 1985).
    C) The aldose reductase-initiated accumulation of sorbitol only appears to be significant during hyperglycemia, and in many tissues aldose reductase must compete directly with hexokinase for glucose utilization. Aldose reductase only becomes important after hexokinase is saturated, as in diabetes.

Physicochemical

Molecular Weight

    A) 357.35 (Budavari, 1996)

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) Budavari S: The Merck Index, 12th ed, Merck & Co, Inc, Whitehouse Station, NJ, 1996.
    3) Cayen MN, Hicks DR, & Ferdinandi ES: Metabolic disposition and pharmacokinetics of the aldose reductase inhibitor tolrestat in rats, dogs, and monkeys. Drug Metab Dispos 1985; 13:412-419.
    4) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    5) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    6) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    7) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    8) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    9) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    10) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    11) Gunn RB & Gunn HB: Inhibition of erythrocyte anion exchange by tolrestat, an inhibitor of aldose reductase. Metabolism 1989; 38:801-804.
    12) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    13) Hicks DR & Kraml M: Determination of tolrestat, a novel aldose reductase inhibitor, in serum and tissues. Ther Drug Monit 1984; 6:328-333.
    14) Kador PF, Kinoshita JH, & Sharpless NE: Aldose reductase inhibitors: a potential new class of agents for the pharmacological control of certain diabetic complications. J Med Chem 1985; 28:841-849.
    15) Kemper C & Dvornik D: Prevention of neural myoinositol depletion in diabetic rats by aldose reductase inhibition with tolrestat (42372). Proc Soc Exp Biol Med 1986; 182:505-510.
    16) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    17) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    18) Raskin P, Rosenstock J, & Challis P: Effect of tolrestat on red blood cells sorbitol levels in patients with diabetes. Clin Pharmacol Ther 1985; 38:625-630.
    19) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    20) Sestanj K, Bellini F, & Fung S: N-((5-(trifluoronethyl)-6- methoxy-1-naphthalenyl)thioxomethyl)-N- methylglycine (tolrestat), a potent, orally active aldose reductase inhibitor. J Med Chem 1984; 27:255-256.
    21) Simard-Duquesne N, Greselin E, & Dubuc J: The effects of a new aldose reductase inhibitor (tolrestat) in galactosemic and diabetic rats. Metabolism 1985; 34:885-892.
    22) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    23) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.