Levamisole: Action, Pharmacology, Dosage and Administration

[Pharmacology]

(1) Pharmacodynamics: Levamisole is a broad-spectrum, highly effective, and low-toxic anthelmintic drug. It is highly effective against adult and larval stages of various gastrointestinal and pulmonary nematodes in many animals. Although levamisole has stronger anthelmintic activity and lower toxicity than thiabendazole, due to the numerous toxic reactions observed with injectable administration (hydrochloride), the preparations approved for marketing in the United States have recently been changed to 13.65% levamisole phosphate injection (with weaker local irritation). Levamisole hydrochloride is mostly formulated into oral preparations such as boluses, drenches, and paste.

The traditional view on the anthelmintic mechanism of levamisole is that it inhibits fumarate reductase in various worms (e.g., Ascaris suum, Ascaridia galli, Toxocara cati, Dictyocaulus viviparus, Haemonchus contortus, etc.). The drug is absorbed through the worm’s cuticle, rapidly reaching the site of action of the corresponding enzyme. The drug molecule undergoes hydrolysis to form a water-insoluble compound that interacts with one or more -SH groups in the enzyme’s active site, causing fumarate reductase to lose its activity and form stable S-S bonds, thereby affecting energy production. In addition, the effect of levamisole on nematode enzymes occurs under anaerobic conditions, while mammalian metabolism differs from that of worms. Therefore, the drug does not affect the animal’s enzyme system. Recent studies have also confirmed that levamisole is a ganglion stimulant, meaning the drug can cause neuromuscular depolarization in resting worms, leading to sustained muscle contraction and paralysis. Furthermore, the drug’s cholinomimetic effect also facilitates the rapid expulsion of paralyzed worms.

Levamisole also has an immunopotentiating effect in animals. It can restore immune function in immunodeficient or immunosuppressed animals, but its effect on the immune function of normal organisms is not significant. For example, it can restore the impaired immune function of elderly animals and animals suffering from chronic diseases to normal; it can increase the number of macrophages and enhance their phagocytic function; although it has no antimicrobial activity, it can improve the resistance of affected animals to bacterial and viral infections. However, low doses (1/3 to 1/4 of the anthelmintic dose) should be used, as excessive doses can lead to immunosuppressive effects.

The mechanism by which levamisole tablets enhance immunity is as follows: it restores impaired cellular immune function to normal, enhances or restores delayed-type hypersensitivity skin reactions in immunocompromised individuals, and promotes PHA-induced L cell proliferation responses. It enhances the chemotaxis and phagocytic function of macrophages. The presumed mechanism involves increasing the cGMP level in L cells and reducing the cAMP level.

The pharmacodynamics of levamisole in animals also indicate that it has both muscarinic and nicotinic effects. Therefore, the resulting symptoms of poisoning (such as salivation, defecation, and dyspnea due to smooth muscle contraction) are similar to those of organophosphate poisoning.

In fact, the toxicity of this product is related to the inhibition of cholinesterase, thereby triggering the muscarinic effects of acetylcholine, such as pupillary constriction, bronchoconstriction, increased gastrointestinal motility, bradycardia, and other cholinergic nervous system excitation. However, it is worth noting that the nicotinic symptoms caused by levamisole poisoning are generally masked by the more pronounced muscarinic effects.

(2) Pharmacokinetics: After oral administration of radiolabeled levamisole to rats at a dose of 15 mg/kg, its absorption and excretion are very rapid. Approximately 40% is excreted in urine within 12 hours. Over the subsequent 8 days, the excretion rate is only 8%. Fecal excretion accounts for 41% of the administered dose within the 8-day period, with most of it eliminated within 12-24 hours. Only a very small amount is excreted through exhaled air, with the amount excreted within 48 hours accounting for only 0.2% of the administered dose. After intramuscular injection in animals, peak plasma concentration (10 μg/mL) is reached within half an hour, which is twice as high as the peak concentration after oral administration. Recent animal studies have shown that the apparent volume of distribution of intravenously injected levamisole is 2.5 L/kg in pigs and 3.1 L/kg in goats. The elimination half-life is 5-6 hours in pigs, 3-4 hours in goats, 4-6 hours in cattle, and 3-4 hours in dogs. Tissue residue of this product is low. 12-24 hours after administration, tissue residue accounts for only 0.9% of the administered dose and is mainly found in excretory and metabolic organs such as the liver and kidneys. Studies in rats and other animals have confirmed that after 7 days of administration, no drug residue is detected in muscles, liver, kidneys, fat, blood, and urine. Furthermore, it has been confirmed that the toxicity of levamisole metabolites is much lower than that of the parent drug. Therefore, tissue residue analysis only needs to focus on the parent drug, levamisole.

[Indications]

Levamisole is currently being used in clinical trials as an adjuvant therapy after surgery for lung cancer and breast cancer, or after chemotherapy for acute leukemia and malignant lymphoma. In addition, levamisole can also be used for autoimmune diseases such as rheumatoid arthritis and lupus erythematosus, as well as upper respiratory tract infections, childhood respiratory infections, hepatitis, bacillary dysentery, furuncles, and abscesses. Preliminary trials have shown significant short-term efficacy against refractory bronchial asthma. According to reports, levamisole has a certain therapeutic effect on persistent hepatitis and individuals who are persistently positive for hepatitis B surface antigen. Furthermore, researchers have successfully used levamisole to treat viral infections such as herpes zoster and common warts. In malignant tumors, studies have found that using levamisole in combination with chemotherapy, radiotherapy, and surgery to treat nasopharyngeal carcinoma, bronchial carcinoma, lung cancer, gastric cancer, colon cancer, leukemia, malignant melanoma, and lymphoreticular cell sarcoma has yielded satisfactory results. Other studies indicate that levamisole can help maintain long-term stability in tumor remission, thus its use in treating residual tumors may prevent recurrence or metastasis. In tuberculosis, clinical studies have found that adding levamisole to the conventional anti-tuberculosis treatment regimen in tuberculosis patients can improve the cure rate and significantly reduce the recurrence rate. In leprosy, researchers have found that individuals with lepromatous leprosy have significant defects in cellular immunity, and the use of levamisole can improve their cure rate and significantly reduce their recurrence rate. Other diseases in which researchers have successfully used levamisole include recurrent aphthous stomatitis, refractory bacterial infections, refractory viral infections, angioimmunoblastic lymphadenopathy, Crohn’s disease, chronic ulcerative colitis, and other diseases related to immune imbalance.

1. Recurrent and chronic infections, including viral, bacterial, or fungal infections of the skin, mucous membranes, respiratory tract, eyes, and systemic infections. 1.1. Recurrent aphthous stomatitis and recurrent herpes labialis: Levamisole treatment leads to ulcer healing and a longer period without recurrence. 1.2. Recurrent upper respiratory tract infections in children: Levamisole treatment significantly reduces the frequency, duration, and severity of upper respiratory tract infections. 1.3. Patients with acne conglobata, recurrent furunculosis, and other pyogenic skin infections experience symptom relief after levamisole treatment. In children with congenital immunodeficiency accompanied by recurrent skin or bronchial infections, the frequency or severity of infections is reduced after medication.
2. Viral hepatitis: Cellular immunity may be impaired in viral hepatitis. In immunosuppressed individuals with acute hepatitis B, it can develop into chronic hepatitis B with a positive hepatitis B surface antigen (HBsAg). Because levamisole can restore the function of deficient macrophages and stem cells, it has a good effect on persistent hepatitis and acute HBsAg-positive hepatitis B patients. Reports indicate that there is a significant difference in HBsAg seroconversion between hepatitis B HBsAg-positive patients treated with levamisole and those not treated, suggesting that levamisole has a certain effect in promoting HBsAg seroconversion. Clinical symptoms in the treatment group also showed significant improvement.
3. Tumors: In some patients with inoperable breast cancer, oral levamisole after radiotherapy prolongs survival. In some patients with recurrent lung cancer, levamisole administration before and after surgery can delay recurrence, indicating that levamisole can enhance cellular immune function and help prevent tumor growth, dissemination, and metastasis. Another report showed that after surgery for bronchial carcinoma, the recurrence rate and cancer-related deaths were significantly lower in the group treated with levamisole one year later compared to the control group. The effect was more pronounced in squamous cell lung carcinoma, with a more significant reduction in distant metastasis than in local recurrence. In addition, the combined use of levamisole during tumor chemotherapy can help restore bone marrow suppression caused by chemotherapy drugs.
4. Rheumatoid arthritis: Levamisole treatment for rheumatoid arthritis shows improvement in both subjective and objective indicators, with definite efficacy. Patients experience reduced pain, shorter duration of morning stiffness, reduced joint swelling, increased grip strength, improved function, and a reduction in the dosage of anti-inflammatory drugs. Levamisole itself has no anti-inflammatory effect; its mechanism of action in treating rheumatoid arthritis is through stimulating immune function.
5. Biliary ascariasis: In recent years, real-time ultrasound imaging has shown that super-high doses of levamisole are effective in cases where part of the Ascaris worm has entered the common bile duct. However, in patients where the entire worm has entered the bile duct, the onset of action is slow. This is mainly because the concentration of levamisole in the bile duct is lower than in the duodenal lumen, which is insufficient to kill the Ascaris in the bile duct. However, using super-high doses of levamisole to increase the drug concentration in the bile duct can rapidly kill the Ascaris. After the worm dies, its peristalsis disappears, reducing irritation to the bile duct and alleviating biliary spasm, leading to pain relief or disappearance in patients. The dead worm is slowly expelled from the bile duct through intestinal peristalsis and bile flow.
6. Systemic lupus erythematosus: Systemic lupus erythematosus is a disseminated, multisystemic connective tissue vasculitis with characteristic immunological defects. The primary defect is due to stem cell dysfunction. Levamisole can improve stem cell dysfunction in patients with systemic lupus erythematosus, restore stem cell function, and re-establish normal control over the B cell system, leading to the elimination of the hyperactive state of the B cell system.
7. Treatment of bronchial asthma: Levamisole can stimulate stem cells to enhance immune capacity. On the one hand, it can eliminate antigen invasion and prevent the occurrence of allergic reactions; on the other hand, it can prevent further reduction of bronchial β-receptor function, stabilizing bronchial excitability and thus controlling and preventing the onset of bronchial asthma.

Because levamisole itself has no anti-inflammatory or antiviral effects, it works by regulating the immune response. Therefore, the onset of drug efficacy is relatively slow, and the duration of medication should be longer.

(1) Cattle and Sheep: Levamisole is highly effective against adult gastrointestinal nematodes in ruminants, including abomasal parasites (Haemonchus, Ostertagia), small intestinal parasites (Cooperia, Trichostrongylus, Nematodirus), large intestinal parasites (Oesophagostomum), and lungworms (Dictyocaulus). A single oral or injectable dose has a worm expulsion rate exceeding 96% against these adult parasites. Except for Trichostrongylus axei, its efficacy exceeds that of thiabendazole, but its effect on Trichuris is unstable. However, it can almost completely eliminate immature Cooperia and lungworms. It also has an expulsion effect of over 87% on immature Ostertagia and Haemonchus. For Thelazia (eyeworms) in cattle, in addition to oral or subcutaneous injection, a 1% solution of 2 mL can be directly injected into the conjunctival sac for treatment. Data confirms that levamisole is still highly effective against Haemonchus contortus and Ostertagia circumcincta resistant to benzimidazoles. In the United States, for cattle and sheep, in addition to specific formulations for oral (bolus, solution, tablet) and injectable administration, there is also a special pour-on formulation. The latter has a weaker effect (requiring an increased dose of 10 mg/kg) and is even less effective in severely cold weather.

(2) Pigs: Different administration methods (drinking water, mixed feed, drenching, or subcutaneous injection) have roughly the same anthelmintic effect. The therapeutic dose (8 mg/kg) has an expulsion rate close to 99% against Ascaris suum, Strongyloides ransomi, and Metastrongylus apri. It is quite effective against Oesophagostomum (72%-99%) and Stephanurus dentatus (kidney worms). In addition, some data also confirms that levamisole is highly effective against Hyostrongylus rubidus. For Trichuris suis infection, injection (95%) is more effective than administration in feed (40%). Some larval stages of swine nematodes can also be expelled by levamisole, such as the 3rd and 4th stage immature Metastrongylus apri, as well as immature Ostertagia and Ascaris suum, with expulsion rates above 90%. However, its efficacy against the 3rd stage immature stages of the latter two worms is below 65%.

(3) Poultry: Administering 36 or 48 mg/kg body weight daily to chicks in drinking water results in an expulsion rate of over 95% against adult Ascaridia galli, Heterakis gallinarum, and Capillaria obsignata. The expulsion rate for immature worms and larvae is also good. The above method has good palatability and does not cause toxic symptoms. Administration in drinking water is also very effective against Thelazia (Oxyspirura mansoni) in chickens. Direct instillation of a 10% levamisole solution into the chicken eye is non-irritating and can kill all worms within 1 hour. It is quite effective against Syngamus trachea in turkeys. After drinking the medicated water, all worms are expelled from the turkey’s mouth in about 16 hours, but it must be administered at a daily dose of 3.6 mg/kg for 3 consecutive days. Levamisole (70 mg/kg) administered orally is also effective against Amidostomum anseris in geese. In pigeons infected with Ascaridia columbae, oral administration at a dose of 40 mg/kg twice (24-hour interval) results in a fecal egg negative rate of about 92%.

(4) Dogs and Cats: Administering levamisole orally to dogs at a daily dose of 10 mg/kg for two consecutive days, or a single subcutaneous injection of 10 mg/kg to cats, has an expulsion rate exceeding 95% against canine ascarids (Toxocara canis, Toxascaris leonina) and hookworms (Ancylostoma spp., Uncinaria spp.). However, it is ineffective against whipworms (Trichuris vulpis). Severely infected dogs with ascarids and hookworms usually require repeated medication. In dogs infected with Dirofilaria immitis, subcutaneous injection at a daily dose of 7.5 mg/kg for 30 consecutive days is required to eliminate symptoms. Levamisole can also be used as a microfilaricide for canine heartworm at a dose of 5.5 mg/kg twice daily (12-hour interval) for 6 consecutive days (if the dog’s microfilariae remain positive, continue for 15 days). Due to frequent vomiting in dogs during medication, the widespread use of levamisole has been limited. In the United States, many feline lungworms (Aelurostrongylus abstrusus) have developed resistance to various drugs, but experiments have shown that oral administration at different doses six times at two-day intervals (7.5 mg/kg on days 1, 3, and 5; 15 mg/kg on days 7 and 9; and 30 mg/kg on day 11) can eliminate symptoms and result in negative fecal larvae.

(5) Horses: Levamisole has similar efficacy against equine parasites as in other animals, and is particularly effective against adult Parascaris equorum and Oxyuris equi. Administration at a dose of 7.5-15 mg/kg (drench or mixed feed) or subcutaneous injection at 5-10 mg/kg can eliminate Parascaris equorum. For equine lungworms (Dictyocaulus arnfieldi), intramuscular injection at a dose of 5 mg/kg twice with a 3-4 week interval achieves a 94% expulsion rate. Even at doses above 40 mg/kg, levamisole has poor efficacy (17%-85%) against various large and small strongyles. Since doses above 20 mg/kg can cause adverse reactions and death in horses, coupled with its limited effect on large strongyles, the widespread use of levamisole in horses has been limited.

(6) Wild Animals: Since necropsy cannot be used for identification testing in wild animals, efficacy is usually determined based on fecal egg counts, which may not reflect the true worm burden of the host. Oral or subcutaneous injection of 2.5 mg/kg of levamisole for the main parasites of zebu cattle (Haemonchus, Bunostomum, Cooperia, etc.) has an expulsion rate of 90%-100%. In elephants suffering from gastrointestinal parasitism, administration at a dose of 2.5 mg/kg also significantly improves clinical symptoms. In chimpanzees severely infected with Onchocerca volvulus, daily injection of 10 mg/kg for 15 consecutive days can significantly improve clinical symptoms. In aquatic snakes and grass snakes suffering from Rhabdias lung infection, a single intraperitoneal injection of 5 mg/kg, in addition to improving clinical symptoms, also eliminates parasitic larvae in the feces.

(7) Regulation of Host Immune Function: Levamisole can also enhance the body’s immune function, especially in elderly or chronically ill animals. It regulates immune function by enhancing the activity of T lymphocytes and phagocytes. Therefore, it is particularly effective in immunosuppressed animals. Calves artificially inoculated with parainfluenza-3 virus, infectious bovine rhinotracheitis, and bovine viral diarrhea recover much faster when treated with levamisole compared to symptomatic treatment alone. The currently recommended dosage regimen for cattle, dogs, and cats for immunomodulation is 3 consecutive days of administration, followed by 3 days off, and then another 3 days of administration as one cycle. For chronic diseases, this cycle can be repeated continuously, with a daily dose of 1/4 to 1/3 of the anthelmintic dose.

[Drug Interactions]

(1) Because levamisole has cholinomimetic effects on the animal body, this product should not be used within 14 days of using organophosphorus compounds or diethylcarbamazine.
(2) This product should not be used in combination with tetrachloroethylene to avoid increasing toxicity.

[Precautions]

(1) Levamisole has a narrow safety margin in animals, especially with injectable administration, where poisoning and even death occasionally occur. Therefore, except for lungworms where injection is suitable in monogastric animals, oral administration is generally preferred.

(2) Horses are relatively sensitive to levamisole, and camels are even more sensitive. Accurate calculation of the dosage is essential to prevent accidents. Dogs and cats are also sensitive, and oral administration often causes vomiting, affecting efficacy. Injectable administration (especially high doses) often leads to severe reactions (salivation, muscle tremors) and even death. Some overseas veterinary hospitals even recommend premedication with atropine before using high doses to prevent fatal poisoning.

(3) The symptoms of levamisole poisoning (such as salivation, defecation, dyspnea, and bradycardia) are similar to those of organophosphate poisoning. Atropine can be used as an antidote in such cases. If severe respiratory depression occurs, artificial respiration with oxygen may be attempted.

(4) Levamisole hydrochloride injection is highly irritating to local tissues, causing severe reactions, while levamisole phosphate is slightly less irritating. Therefore, specialized phosphate formulations are commonly used overseas for subcutaneous and intramuscular injection. However, mild local reactions of short duration may still occur.

(5) For safety reasons, injectable administration should not be used in animals in the late stages of pregnancy or under stress conditions such as castration, dehorning, or vaccination.

(6) Withdrawal periods: Oral levamisole tablets: cattle 2 days, sheep 3 days, not to be used during lactation, pigs 3 days. Levamisole injection: cattle 14 days, sheep 28 days, not to be used during lactation, pigs 28 days.

[Dosage and Administration]

Each tablet contains 25mg. For anthelmintic purposes, the usual dose is 1.5-2.5mg/kg body weight, which means 125mg (five tablets) taken orally at once in the evening. To enhance immunity, the usual adult dosage is 1-2 tablets three times a day for 3 days a week, followed by a 4-day break. (The provided text includes various specific dosages recommended by different doctors, such as one tablet three times a day for three days followed by a four-day break for one year, or 50mg three times a day for two days followed by a five-day break. These should be followed as per a physician’s instructions). Levamisole can improve the patient’s resistance to bacterial and viral infections.

General method of use: Intermittent administration is generally adopted, i.e., 150 mg daily for 3 consecutive days each week; the pediatric dose is calculated at 2.5 mg/kg per day, usually divided into three doses daily or taken as a single dose after meals. Because levamisole treatment for the above-mentioned diseases is not directly targeted at the cause, the onset of efficacy is generally slow. For example, the treatment of rheumatoid arthritis often requires continuous use for 4-6 months to see significant effects; breast cancer requires continuous use for 9-12 months to achieve the maximum therapeutic effect; viral infections such as recurrent aphthous stomatitis and common warts also usually require continuous administration for about 3 months to be effective. Therefore, both doctors and patients should not be impatient and should not blindly increase the dosage or discontinue treatment. It is worth noting that the main toxic side effects of levamisole include granulocytopenia and thrombocytopenia, which can be fatal in severe cases.

To avoid accidents, the following points should be noted before treatment: 1. The drug should be used after a definite diagnosis (such as the above diagnoses) and after ruling out contraindications; 2. Unless absolutely necessary (such as systemic lupus erythematosus and after ruling out contraindications), it should be avoided to use it concurrently with glucocorticoids; 3. During treatment, a routine blood test should be performed once a week to observe whether there is a decrease in white blood cells and platelets; once a decrease in white blood cells or platelets occurs, the drug should be discontinued immediately and symptomatic and supportive treatment should be given.

Oral administration of levamisole hydrochloride: per kg body weight, cattle, sheep, pigs 7.5mg, dogs, cats 10mg, poultry 25mg. Subcutaneous or intramuscular injection of levamisole hydrochloride injection: per kg body weight, cattle, sheep, pigs 7.5mg, dogs, cats 10mg, poultry 25mg. The injection dosage of levamisole phosphate injection is the same as that of levamisole hydrochloride injection.

[Pharmaceutical Preparations and Specifications]

Levamisole Hydrochloride Tablets: (1) 25mg (2) 50mg
Levamisole Hydrochloride Injection: (1) 2mL: 0.1g (2) 5mL: 0.25g (3) 10mL: 0.5g
Levamisole Phosphate Injection: (1) 5mL: 0.25g (2) 10mL: 0.5g (3) 20mL: 1g