Mazindol

DEA NFLIS-Drug Category -> Stimulants

DEA Schedule IV Controlled Substance -> Stimulants

Pharmaceuticals -> Synthetic Cannabinoids or Psychoactive Compounds

3.7

1.81

White crystalline solid from ethanol ... crystals from acetone-hexane

WHITE TO OFF-WHITE POWDER; DOES NOT EXHIBIT POLYMORPHISM

Soluble in ethanol

INSOL IN WATER

1.39e-01 g/L

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

198-199

198-199 °C

Danger

H300 (97.5%): Fatal if swallowed [Danger Acute toxicity, oral]

P261, P262, P264, P270, P271, P280, P301+P316, P302+P352, P304+P340, P316, P321, P330, P361+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 40 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

DEA schedule IV controlled substance

3H-Imidazo2,1-aisoindol-5-ol, 5-(4-chlorophenyl)-2,5-dihydro-: Does not have an individual approval but may be used under an appropriate group standard

Schedules of controlled substances are established by section 202 of the Controlled Substances Act (21 U.S.C. 812). Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances having a stimulant effect on the central nervous system, including its salts, isomers and salts of isomers: Mazindol, Schedule IV, DEA Code #: 1605.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies discontinued drug products, incl mazindol, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Food and Drug Administration (FDA) is withdrawing approval of 80 new drug applications (NDAs) and 75 abbreviated new drug applications (ANDAs). /Mazindol listed in table/ The holders of the applications notified the agency in writing that the drug products were no longer marketed and requested that the approval of the applications be withdrawn. EFFECTIVE DATE: September 17, 2003.

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

Concurrent use /of other CNS stimulation-producing medications or thyroid hormones with appetite suppressants/ may increase the CNS stimulant effects of either these medications or the appetite suppressant. /Appetite suppressants, sympathomimetic/

The sympathomimetic effects of appetite suppressants /when used with monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline/ may be potentiated, possibly resulting in a hypertensive crisis; concurrent use is contraindicated; appetite suppressant should not be administered during or within 14 days following the administration of and MAO inhibitor. /Appetite suppressants, sympathomimetic/

Vasopressant effect may be potentiated; if necessary to administer a pressor amine agent to a patient who has recently received an appetite suppressant, initiating pressor therapy in reduced dosage and monitoring blood pressure at frequent intervals are recommended. /Appetite suppressants, sympathomimetic/

Anorectic effects of the appetite suppressant may be antagonized /when use with phenothiazines/. /Appetite suppressants, sympathomimetic/

For more Interactions (Complete) data for MAZINDOL (10 total), please visit the HSDB record page.

Using large amounts of these drugs can result in a condition known as amphetamine psychosis -- which can result in auditory, visual and tactile hallucinations, intense paranoia, irrational thoughts and beliefs, delusions, and mental confusion.

Although the mechanism of action of the sympathomimetics in the treatment of obesity is not fully known, these medications have pharmacological effects similar to those of amphetamines. Unlike other sympathomimetic appetite suppressants such as phentermine, mazindol is thought to inhibit the reuptake of norepinephrine rather than to cause its release.

/HUMAN EXPOSURE STUDIES/ Approximately half of the overdosage cases involved accidental ingestion in children 1-4 years of age. The reported doses ingested ranged from 4-40 mg. All recovered.

/SIGNS AND SYMPTOMS/ In cases in which overdosages have been reported, the symptoms listed below were cited: irritability, agitation, hyperactivity, tachycardia, arrhythmia (premature ventricular contractions occurred in the patient also taking phenmetrazine), tachypnea.

/SIGNS AND SYMPTOMS/ Chronic toxicity resulting from anorexigenic agents may produce severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. Psychosis, often clinically indistinguishable from schizophrenia, may also occur. Withdrawal symptoms including extreme fatigue, mental depression, and changes in the EEG during sleep have been reported when amphetamines and related drugs were abruptly discontinued following excessive use of these agents.

/CASE REPORTS/ A 25 year-old female died after ingesting a massive dose of 200 mg mazindol and an undetermined amount of ethanol.

For more Human Toxicity Excerpts (Complete) data for MAZINDOL (7 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

Mazindol

DILI Positive

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Treatment of dogs with high doses of mazindol for long periods resulted in some corneal opacities which were reversible when the drug was withdrawn.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Teratogenicity studies in rats and rabbits showed an increase in neonatal mortality and in rats a possible increase in rib anomalies.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ ... After prolonged administration of mazindol in dogs, withdrawal symptoms were observed when the drug was abruptly discontinued. In addition, monkeys have self-administered the drug.

While data specific to mazindol were not located(SRC, 2005), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through subsoils into aquifers(1).

Maintain open airway and assist ventilation if necessary. Treat agitation, seizures, coma, and hypothermia if they occur. Continually monitor temperature, other vital signs, and the ECG for a minimum of 6 hours. Hypertension is best treated with parenteral vasodilator such as phentolamine or nitroprusside. Treat tachyarrhythmias with propranolol or esmolol. Treat arterial vasospasm /with/ nitroglycerin sublingually ... /or/ iv. Intracoronary artery nitroglycerin may be required if there is no response to intravenous infusion. Also consider using a calcium antagonist. /Amphetamines/

Do not induce vomiting because of the risk of abrupt onset of seizures. Administer activated charcoal. Gastric emptying is not necessary if activated charcoal can be given promptly. Dialysis and hemoperfusion are not effective. Repeat dose charcoal has not been studied... /Amphetamines/

LD50 Mouse oral 106 mg/kg

LD50 Rat oral 180 - 320 mg/kg

LD50 Rabbit oral 98 mg/kg

LD50 Dog oral 9 mg/kg

Schedules of controlled substances are established by section 202 of the Controlled Substances Act (21 U.S.C. 812). Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances having a stimulant effect on the central nervous system, including its salts, isomers and salts of isomers: Mazindol, Schedule IV, DEA Code #: 1605.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies discontinued drug products, incl mazindol, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Food and Drug Administration (FDA) is withdrawing approval of 80 new drug applications (NDAs) and 75 abbreviated new drug applications (ANDAs). /Mazindol listed in table/ The holders of the applications notified the agency in writing that the drug products were no longer marketed and requested that the approval of the applications be withdrawn. EFFECTIVE DATE: September 17, 2003.

A - Alimentary tract and metabolism

QA - Alimentary tract and metabolism

Mazindol is a sympathomimetic amine that stimulates the central nervous system (nerves and brain), leading to increased your heart rate and blood pressure, and decreased appetite. Since the appetite-suppressing effect of the drug tends to decrease after few weeks of treatment, sympathomimetic appetite suppressants are typically used short-term weight-loss program.

Unlike other sympathomimetic appetite suppressants such as phentermine, mazindol is thought to inhibit the reuptake of norepinephrine rather than to cause its release.

Mechanism of anorexiant & other central actions is unknown, but lowering of brain 5-hydroxytryptamine & elevation of dopamine levels both may be involved. Also mazindol interferes with neuronal reuptake of both brain & peripheral norepinephrine.

The mechanism of action of mazindol has not been clearly defined. Although mazindol is used in the treatment of obesity as an anorexigenic, it has not been firmly established that the pharmacologic action is primarily one of appetite suppression; other CNS actions and/or metabolic effects may be involved. Results in animal studies show that mazindol exerts its effects primarily on the septal area of the brain, specifically the limbic system. The drug appears to alter norepinephrine metabolism by inhibiting the normal neuronal uptake mechanism.

Saturable low-affinity binding sites for (3)H mazindol have been demonstrated in crude synaptosomal membranes from rat brain using both a centrifugation and a filtion assay. Studies on the regional distribution of these binding sites revealed that the hypothalamus and brainstem had the highest density of sites. Kinetic analysis of the binding of (3)H mazindol to hypothalamic membranes demonstrated a single class of noninteracting binding sites with an apparent affinity constant (KD) of 10.2 +/- 0.7 microM and maximal number of binding sites (Bmax) of 786 + or - 94 pmol/mg of protein. Specific (3)H mazindol binding was rapidly reversible, temperature sensitive, labile to pretreatment with proteolytic enzymes, and inhibited by physiological concn of sodium. In most peripheral tissues, such as the liver and kidney, very low levels of binding were observed; however, the adrenal gland had a relatively high density of sites. The potency of a series of anorectic drugs in inhibiting specific (3)H mazindol binding to hypothalamic membranes was highly correlated with their anorectic potencies in rats, but not with their motor stimulatory effects. These results suggest the presence of a specific drug recognition site in the hypothalamus that may mediate the anorectic activity of mazindol and related phenylethylamines.

The action of an anorexiant, mazindol was investigated, and found that it reduced food intake by directly suppressing neurons in the lateral hypothalamus, inhibited gastric acid secretion, increased motor activity, decreased glucose absorption, and inhibited insulin secretion. It thus appears that the main effect of mazindol is to decrease food intake through suppressing feeding centers in the hypothalamus.

10-13 hours

Half-life is 10-13 hours. Duration of action is 8 to 15 hours.

12 to 24 hr

Hepatic.

Major metabolite in urine in rat, dog, and human: 5-(para-chlorophenyl)-2,5-dihydro-5-hydroxy-(3)h-imidazo(2,1-alpha)isoindol-3-o.

Hepatic. Half Life: 10-13 hours

A loosely defined group of drugs that tend to increase behavioral alertness, agitation, or excitation. They work by a variety of mechanisms, but usually not by direct excitation of neurons. The many drugs that have such actions as side effects to their main therapeutic use are not included here.

Drugs that block the transport of adrenergic transmitters into axon terminals or into storage vesicles within terminals. The tricyclic antidepressants (ANTIDEPRESSIVE AGENTS, TRICYCLIC) and amphetamines are among the therapeutically important drugs that may act via inhibition of adrenergic transport. Many of these drugs also block transport of serotonin.

Drugs that block the transport of DOPAMINE into axon terminals or into storage vesicles within terminals. Most of the ADRENERGIC UPTAKE INHIBITORS also inhibit dopamine uptake.

Single oral dose of 2-mg produced peak blood level of 2.5 ng/mL, for 6 hr. Multiple doses 2-mg 3/day for 4 days caused max concentration of 10.8 ng/mL 2 hr following last dose on day 4.

Excreted primarily in the urine as unchanged drug and conjugated metabolites.

Following oral administration, mazindol is readily absorbed from the GI tract. The drug has an onset of action of 30-60 minutes and a duration of action of 8-15 hours. Therapeutically effective blood concentrations reportedly are 3-12 ng/mL, and blood concentrations achieved with recommended dosage are 2-4 ng/mL. Mazindol is excreted primarily in urine as unchanged drug and conjugated metabolites.

THERAP CAT: anorexic; CNS stimulant /Former/

Appetite suppressant /Former/

MEDICATION

Mazindol is used in short-term (a few weeks) treatment of exogenous obesity in conjunction with a regimen of weight reduction based on caloric restriction, exercise, and behavior modification in patients with a body mass index of 30 kg of body weight per height in meters squared (kg/m²) or in patients with a body mass index of 27 kg/m² in the presence of risk factors such as hypertension, diabetes, or hyperlipidemia.

Preparation: W.J. Houlihan, DE 1814540; W.J. Houlihan, M.K. Eberle, DE 1930488; eidem US 3597445 (1969, 1970, 1970 all to Sandoz)

Preperation: T.S. Sulkowski, US 3763178 (1973 to American Home Prod.)

Mazindol is prepared by treating the dilithio reagent, obtained from 2-phenylimidazoline, with methyl 4-chlorobenzoate.

DOSAGE FORMS: TABLETS: 2 MG.

Mazanor(R), Sanorex (R): tablets, 1 and 2 mg

Controlled substance 21CFR1308.14

The Food and Drug Administration (FDA) is withdrawing approval of 80 new drug applications (NDAs) and 75 abbreviated new drug applications (ANDAs). /Mazindol listed in table/ The holders of the applications notified the agency in writing that the drug products were no longer marketed and requested that the approval of the applications be withdrawn. EFFECTIVE DATE: September 17, 2003.