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ANALYSIS OF ALBENDAZOLE PROFILE AS THE MOST POPULAR ANTHELMINTIC AGENT
Semchenko K.
PhD of Pharmacy, Associate Professor of Department of Pharmaceutical Technology of Drugs, NUPh
Vyshnevska L.
Doctor of Pharmacy, Professor, Head of Department of Pharmaceutical Technology of Drugs, NUPh
Polovko N.
Doctor of Pharmacy, Professor of Department of Pharmaceutical Technology of Drugs, NUPh
Romas K.
PhD of Pharmacy, Senior lecturer of Department of Pharmaceutical Technology of Drugs, NUPh
Abstract
The problem of helminthiases is particularly relevant in the recent years as this group of diseases is met in all countries of the world. With the purpose of the further creation of new complex anthelminthic drug for the treatment of helminthiases of digestive system, the profile of albendazole was studied. On the basis of the findings it was set that it is rational to develop complex anthelminthic drugs, which must include albendazole, as well as an additional anthelmintic agent to provide a broad spectrum of action.
Keywords: albendazole, helminthiasis, PASS analysis, drug profile
Helminthiases is the worldwide healthcare problem
Introduction. The development of dosage forms involves careful selection of active and auxiliary substances. Particular attention should be paid to the study of the profile of active substances.
Parasitic disease is one of the most pressing problems of the present. The existing on the pharmaceutical market range of medicines for the treatment of helminthiasis currently includes 19 drugs based on praziquantel, mebendazole, albendazole, piperazine, piranthel, levamisole. It has been established that among the an-thelmintic agents presented, foreign medicines dominate (63.2%), while Ukrainian producers offer fewer drugs (36.8%) [10].
In view of the above, it is promising to develop new domestic medicines with anthelmintic activity, which will ensure the needs of the population of the country in quality and affordable domestic drugs.
The national program for the import substitution of drugs provides the development of new drugs of domestic production, which can successfully compete with similar drugs of foreign production not only in terms of price, but also in efficacy and safety.
In view of the above, it is promising to develop new domestic medicines with anthelmintic activity,
which will ensure the needs of the population of the country in quality and affordable domestic drugs.
Therefore, in order to create a new anthelmintic drug, we aimed to study the profile of albendazole as an active ingredient, since this active pharmacological ingredient is included in the overwhelming majority of protocols for the treatment of helminthiasis of the digestive system [1, 4, 8].
Materials and methods. As the material of the research the proper open access literature sources about albendazole were used.
The methods of bibliosemantic analysis of the literature data and PASS-analysis of albendazole structural formula was used.
Data processing was performed using the methods of economic and statistical analysis and the results processing - with the help of computer programs. Prediction of activity of the main biologically active substances was performed with PASS-analysis (http://www.way2drug.com).
Results.
Physical and chemical properties
Albendazole is a carbamate of benzimidazole based on a bicyclic ring structure in which the benzene ring is fused to the 4- and 5- position of the imidazole ring. Gross formula: C12H15N3O2S; molar mass 265.34 g/mol (Fig. 1).
Fig. 1. Structural formula of albendazole
Albendazole is a white or yellowish powder, anhydrous, slightly soluble in formic acid, weakly soluble in ether and methylene chloride, and practically insoluble in ethyl alcohol and water. Pharmacological activity
The spectrum of pharmacological activity of albendazole is quite broad (Table 1).
Table 1
Probability of activity Type of pharmacological activity
0,955 Flavin-monooxygenase substrate
0,947 Substrate FMO3
0,847 Anthelmintic (nematodes)
0,834 Anthelmintic (general)
0,826 Antiparasitic
0,734 Nicotinic a4-p4 receptor agonist
It is now known that albendazole shows anthel-mintic activity in relation to many causative agents of helminthiasis of digestive system, including various types of intestinal worms and protozoa. Albendazole is used in the treatment of the following diseases:
• nematodosis (ascariasis, enterobiasis, anky-lostomiasis, necatoriasis, trichinosis, tenaeus, opisthor-chiasis, clonorhosis);
Unlike theoretical calculations, the practical experience of treatment with drugs based on albendazole allowed to establish such side effects of the substance with its long-term administration [2, 3]:
• common: stomach pain, fever, nausea;
• rare: black, residual emptying, gums bleeding, blood in urine or stool, pain in the sternum, chills, cough, pain or difficult urination, red spots on the skin, sore throat, ulcers or white spots on the lips or mouth, swollen glands, unusual bleeding or bruising, unusual fatigue or weakness, dizziness, loss of hair;
• isolated cases: peeling or weakening of the skin, blurred vision, dark urine, diarrhea, general feeling of fatigue or weakness, headache, joint pain or muscle, red irritated eyes, seizures, lasting stomach ache, vomiting, yellow eyes or skin.
Features of usage in special groups of patients
Also, albendazole has certain features of use in such groups of patients as pregnant women, nursing mothers and children.
Albendazole belongs to category C. The risk of administration in pregnant women has not been investigated. Nevertheless, in animal experiments, the terato-genic effect (embryotoxicity and defects in the development of the skeleton) was detected.
In a number of guidelines of European countries for the treatment of helminthiasis of the digestive system, women of reproductive age are recommended to undergo a pregnancy test before starting administration of drugs with albendazole, and, in the case of positive results, to select anthelmintic medicines based on other
active substances. The use of albendazole during pregnancy is possible in the hospital in case of urgent need.
Also, albendazole is prescribed with caution to nursing mothers, since albendazole has been ingested in milk of animals, although no such a finding has been made in humans. Usually, it is recommended to stop breastfeeding while undergoing therapy with albend-azole.
The most albendazole-based medicines have age limits of 3 years [11, 13]. Echinococcosis rarely occurs in infants and young children. When neurocyster-oscopy, the efficacy of albendazole in children is equal to that in adults.
Drugs based on albendazole are contraindicated in patients with hypersensitivity to compounds of the ben-zimidazole class.
Medicines based on albendazole are prescribed with caution when the suppression of bone marrow hematopoiesis, liver failure, cirrhosis of the liver, cys-ticercosis with the involvement of the mesh of the eye.
In neurocysticercrosis with eye defects prior to treatment it is necessary to carry out a study of the retina due to the risk of deterioration of its pathology. It is recommended to conduct the appropriate therapy with glucocorticosteroids to prevent hypertension in the first week of anticystolic and anti-inflammatory drugs intake.
Discussion. Thus, it can be concluded that despite the existing side effects and possible toxicity albend-azole remains the drug of choice in treatment of hel-minthiases of digestive system.
However, in order to develop the new drug with wide range of anthelminthic activity that could satisfy the needs in high-level quality complex drugs it is recommended to combine albendazole with the other an-thelminthic drug. As the Ukrainian helminthologists often enhance therapeutic scheme with simultaneous usage of albendazole and praziquantel or pyrantel it is advisable to study the features and perspectives of their
combination in one dosage form, namely: spectrum of pharmacological activity, potentiation, side effects and degree of toxicity. the specified direction is the theme of our further research.
primary metabolite, albendazole sulfoxide.
In contrast to the initial drug, albendazole sulfox-ide is well absorbed and when administered at a standard dose (400 mg) gives peak plasma concentrations in the range of 0.22-0.25 mg/l within 2-3 hours after intake [3]. Albendazole sulfoxide binds to plasma proteins by 70 %, which ensures its distribution throughout the body: it has been detected in urine, bile, liver, bone marrow, cystic fluid, and cerebrospinal fluid.
It is known that long-term administration of albendazole results in inhibition of N-demethylation of amidopyrin, which leads to a gradual decrease in the concentration of albendazole sulfoxide caused by an increase in sulfation. It has been established that while treatment with albendazole (200 mg three times a day) during 4 weeks, the concentration of albendazole sul-foxide in the plasma of patients was approximately 20 % lower than in the first half of the treatment period [3].
Albendazole sulfoxide is metabolised in the liver to the secondary metabolite of albendazole sulfone and other oxidative metabolites that have no pharmacological activity. The expected half-life of albendazole sulfoxide is 8.5 - 12 hours. It is excreted in the form of various metabolites mainly by the kidneys, as well as from bile.
Drugs based on albendazole are recommended to be taken during meals, since taking them simultaneously with fatty food increases the level of absorption of albendazole 2-6 times. Grapefruit juice leads to a 3fold increase in Cmax of albendazole sulfoxide.
The concentration of albendazole sulfoxide in the blood varies significantly with concomitant use with such drugs as dexamethasone, praziquantel and cimet-idine.
The stationary concentration of albendazole sul-foxide in plasma was approximately 56 % higher when 8 mg dexamethasone was administered with each dose of albendazole (15 mg/kg/day) in patients with neuro-cysteroscope.
Overdose with albendazole may be manifested by nausea, vomiting, sleep, vision, speech and digestion disturbances, visual hallucinations, dizziness, fatigue, jaundice, brownish-red or orange skin, urine, sweat, saliva, tear fluid, and faeces in proportion to the dose taken.
In case of overdose, symptomatic therapy and general supportive measures are recommended. Peculiarities of administration with the other drugs
Praziquantel (40 mg/kg) in healthy subjects (n=10) increased the mean maximum plasma concentration and area under the curve of albendazole sulfox-ide by approximately 50 % compared to a separate group of subjects (n=6) receiving pure albendazole. The mean Tmax and the mean half-life of albendazole sulfoxide in plasma did not change. The pharmacoki-netics of praziquantel was unchanged at the concomitant administration of albendazole (400 mg) [3, 5, 6, 9].
The concentration of albendazole sulfoxide in bile and cystic fluid was increased (approximately 2-fold)
in patients with echinococcal cysts receiving cimetidine (10 mg/kg/day) (n=7) as compared to pure albendazole (20 mg/kg/day) (n=12). Concentration of albendazole sulfoxide in plasma did not change after 4 hours after intake [3, 5].
After a single dose of albendazole (400 mg), the pharmacokinetics of theophylline (aminophylline 5.8 mg/kg, infusion over 20 minutes) did not change. Albendazole induces cytochrome P450 1A in human he-patoma cells; therefore, it is recommended to control the concentration of theophylline in the plasma during and after treatment.
Also, albendazole is an inducer of the microsomal enzymes of cytochrome P450 and accelerates the metabolism of many drugs.
Drugs such as ritonavir, phenytoin, carbamaze-pine and phenobarbital can lower the concentration of albendazole sulfoxide in plasma [12]. Since clinical significance for such cases has not been established, monitoring of the efficacy of treatment with simultaneous administration of these drugs with albendazole should be monitored.
Side effects
When appointing albendazole, special attention should be paid to probable adverse reactions. Singledose therapy with albendazole (400 mg) rarely leads to side effects. Longer courses of therapy, for example, in the treatment of cystic and alveolar echinococcal infections, can lead to abnormal liver function causing toxic effects on the bone marrow.
Possible side effects of albendazole and the probability of their manifestation according to PASS analysis are presented in Table 2.
• stronhyloidosis;
• neurocystysercosis, caused by a larval form of pork chop;
• echinococcosis of the liver, lungs, peritoneum, caused by the larval form of the canine belt worm;
• giardiasis;
• toxocarosis;
• skin migratory larvae [3, 7, 12, 14].
Mechanism of action and resistance
Mechanism of action of albendazole is to break the metabolism of helminths. Medicines of benzimidazole groups provoke metabolic disturbances, selectively bind to P-tubulin and inhibit polymerization which causes a violation of the cytoplasmic formation of microtubules. The deterioration of glucose uptake has also been noted, which leads to depletion of glycogen and decrease in ATP reserves. Experimental evidence suggests that albendazole not only kills the adult stages of intestinal worms, but also kills or sterilizes eggs and larvae.
However, the mechanism of resistance of helminths to benzimidazoles in general and albendazole in particular should be considered: specific changes in the amino acids of P-tubulin protein lead to a decrease in affinity for it, which significantly reduces the pharmacological effect [3].
Dosing and metabolism
Dose of the drug is determined by the physician depending on the type of the agent and the intensity of the invasion. Typically, the dose of albendazole is 400
mg.
Albendazole is poorly absorbed in the gastrointestinal tract (less than 5 %). Concentrations of albend-azole in the unchanged state are negligible or uncertain in plasma. Bioavailability after oral administration is about 30%.
Albendazole is rapidly metabolized in the liver during the "first passage" to the primary metabolite, al-bendazole sulfoxide.
In contrast to the initial drug, albendazole sulfox-ide is well absorbed and when administered at a standard dose (400 mg) gives peak plasma concentrations in the range of 0.22-0.25 mg/l within 2-3 hours after intake [3]. Albendazole sulfoxide binds to plasma proteins by 70 %, which ensures its distribution throughout the body: it has been detected in urine, bile, liver, bone marrow, cystic fluid, and cerebrospinal fluid.
It is known that long-term administration of al-bendazole results in inhibition of N-demethylation of amidopyrin, which leads to a gradual decrease in the concentration of albendazole sulfoxide caused by an increase in sulfation. It has been established that while treatment with albendazole (200 mg three times a day) during 4 weeks, the concentration of albendazole sul-foxide in the plasma of patients was approximately 20 % lower than in the first half of the treatment period [3].
Albendazole sulfoxide is metabolised in the liver to the secondary metabolite of albendazole sulfone and other oxidative metabolites that have no pharmacological activity. The expected half-life of albendazole sul-foxide is 8.5 - 12 hours. It is excreted in the form of various metabolites mainly by the kidneys, as well as from bile.
Drugs based on albendazole are recommended to be taken during meals, since taking them simultaneously with fatty food increases the level of absorption of albendazole 2-6 times. Grapefruit juice leads to a 3fold increase in Cmax of albendazole sulfoxide.
The concentration of albendazole sulfoxide in the blood varies significantly with concomitant use with such drugs as dexamethasone, praziquantel and cimet-idine.
The stationary concentration of albendazole sul-foxide in plasma was approximately 56 % higher when 8 mg dexamethasone was administered with each dose of albendazole (15 mg/kg/day) in patients with neuro-cysteroscope.
Overdose with albendazole may be manifested by nausea, vomiting, sleep, vision, speech and digestion disturbances, visual hallucinations, dizziness, fatigue,
jaundice, brownish-red or orange skin, urine, sweat, saliva, tear fluid, and faeces in proportion to the dose taken.
In case of overdose, symptomatic therapy and general supportive measures are recommended. Peculiarities of administration with the other drugs
Praziquantel (40 mg/kg) in healthy subjects (n=10) increased the mean maximum plasma concentration and area under the curve of albendazole sulfox-ide by approximately 50 % compared to a separate group of subjects (n=6) receiving pure albendazole. The mean Tmax and the mean half-life of albendazole sulfoxide in plasma did not change. The pharmacoki-netics of praziquantel was unchanged at the concomitant administration of albendazole (400 mg) [3, 5, 6, 9].
The concentration of albendazole sulfoxide in bile and cystic fluid was increased (approximately 2-fold) in patients with echinococcal cysts receiving cimetidine (10 mg/kg/day) (n=7) as compared to pure albendazole (20 mg/kg/day) (n=12). Concentration of albendazole sulfoxide in plasma did not change after 4 hours after intake [3, 5].
After a single dose of albendazole (400 mg), the pharmacokinetics of theophylline (aminophylline 5.8 mg/kg, infusion over 20 minutes) did not change. Al-bendazole induces cytochrome P450 1A in human he-patoma cells; therefore, it is recommended to control the concentration of theophylline in the plasma during and after treatment.
Also, albendazole is an inducer of the microsomal enzymes of cytochrome P450 and accelerates the metabolism of many drugs.
Drugs such as ritonavir, phenytoin, carbamaze-pine and phenobarbital can lower the concentration of albendazole sulfoxide in plasma [12]. Since clinical significance for such cases has not been established, monitoring of the efficacy of treatment with simultaneous administration of these drugs with albendazole should be monitored.
Side effects
When appointing albendazole, special attention should be paid to probable adverse reactions. Singledose therapy with albendazole (400 mg) rarely leads to side effects. Longer courses of therapy, for example, in the treatment of cystic and alveolar echinococcal infections, can lead to abnormal liver function causing toxic effects on the bone marrow.
Possible side effects of albendazole and the probability of their manifestation according to PASS analysis are presented in Table 2.
Table 2
Side effects of albendazole by PASS analysis
Probability of occurrence Type of side effect
0,872 Edema
0,859 Diarrhea
0,847 Anemia
0,799 Hepatitis
0,777 Weakness
0,763 Hyperthermic reaction
0,761 Agranulocytosis
0,763 Conjunctivitis
0,706 Anorexients
0,710 Leukopenia
0,656 Thrombocytopenia
0,632 Apathy
0,614 Weight loss
0,592 Nephritis
0,581 Tachycardia
0,577 Dizziness
0,569 Total toxic effect
0,527 Sleep disturbance
0,518 Sensory disturbances
0,477 Teratogenic effect
0,509 Dermatitis
0,466 Embryotoxic effect
0,481 Violation of vision
0,483 Nausea
0,432 Pain
0,447 Reproductive dysfunction
0,424 Hematotoxic effect
0,390 Myocarditis
0,412 Vomit
0,386 Hypertonic effect
0,396 Headache
0,347 Facsimile
0,363 Psychomotor disturbances
0,357 Hepatotoxic
0,303 Spermicide
0,328 Horeoathetosis
0,319 Ataxia
0,304 Dyskinesia
0,284 Postural (orthostatic) hypotension
0,280 Neutrophic effect
0,263 Violations of behavior
0,251 Reduced visual acuity
0,247 Hematuria
0,210 Chorea
0,256 Cholestasis
0,181 Stimulator of salivary secrets
0,215 Parkinsonism
0,231 Acidosis
Unlike theoretical calculations, the practical experience of treatment with drugs based on albendazole allowed to establish such side effects of the substance with its long-term administration [2, 3]:
• common: stomach pain, fever, nausea;
• rare: black, residual emptying, gums bleeding, blood in urine or stool, pain in the sternum, chills, cough, pain or difficult urination, red spots on the skin, sore throat, ulcers or white spots on the lips or mouth,
swollen glands, unusual bleeding or bruising, unusual fatigue or weakness, dizziness, loss of hair;
• isolated cases: peeling or weakening of the skin, blurred vision, dark urine, diarrhea, general feeling of fatigue or weakness, headache, joint pain or muscle, red irritated eyes, seizures, lasting stomach ache, vomiting, yellow eyes or skin.
Features of usage in special groups of patients Also, albendazole has certain features of use in
such groups of patients as pregnant women, nursing mothers and children.
Albendazole belongs to category C. The risk of administration in pregnant women has not been investigated. Nevertheless, in animal experiments, the terato-genic effect (embryotoxicity and defects in the development of the skeleton) was detected.
In a number of guidelines of European countries for the treatment of helminthiasis of the digestive system, women of reproductive age are recommended to undergo a pregnancy test before starting administration of drugs with albendazole, and, in the case of positive results, to select anthelmintic medicines based on other active substances. The use of albendazole during pregnancy is possible in the hospital in case of urgent need.
Also, albendazole is prescribed with caution to nursing mothers, since albendazole has been ingested in milk of animals, although no such a finding has been made in humans. Usually, it is recommended to stop breastfeeding while undergoing therapy with albend-azole.
The most albendazole-based medicines have age limits of 3 years [11, 13]. Echinococcosis rarely occurs in infants and young children. When neurocyster-oscopy, the efficacy of albendazole in children is equal to that in adults.
Drugs based on albendazole are contraindicated in patients with hypersensitivity to compounds of the ben-zimidazole class.
Medicines based on albendazole are prescribed with caution when the suppression of bone marrow hematopoiesis, liver failure, cirrhosis of the liver, cys-ticercosis with the involvement of the mesh of the eye.
In neurocysticercrosis with eye defects prior to treatment it is necessary to carry out a study of the retina due to the risk of deterioration of its pathology. It is recommended to conduct the appropriate therapy with glucocorticosteroids to prevent hypertension in the first week of anticystolic and anti-inflammatory drugs intake.
Discussion. Thus, it can be concluded that despite the existing side effects and possible toxicity albend-azole remains the drug of choice in treatment of hel-minthiases of digestive system.
However, in order to develop the new drug with wide range of anthelminthic activity that could satisfy the needs in high-level quality complex drugs it is recommended to combine albendazole with the other an-thelminthic drug. As the Ukrainian helminthologists often enhance therapeutic scheme with simultaneous usage of albendazole and praziquantel or pyrantel it is advisable to study the features and perspectives of their combination in one dosage form, namely: spectrum of pharmacological activity, potentiation, side effects and
degree of toxicity. the specified direction is the theme of our further research.
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