Ivermectin
Abstract
Ivermectin is a group of medicinal drugs under the larger group of avermectins. It was first discovered in the early 1970’s and accepted for use in the 1980’s in veterinary medicine applications and later for human conditions treatment. Biosynthesis of ivermectin is done from the primary compound avermectin and was discovered by a group of scientists who were led by Professor Satoshi Omura (Eng). The results of their research were later forwarded to the MSD research laboratories which isolated the compound avermectin from the sampled soil that was studied. Synthesis of avermectin results into eight main groups that have been discussed below, the most effective of the avermectins, however, is found to be the avermectins that are synthesized resulting in the formation of double bonds between the carbon atoms.
Ivermectin is applied for different purposes and forms the main veterinary medicine used in the treatment of the domestic animals. In humans too the drug has been developed and has been widely used in the treatment of parasitic conditions like river blindness that mainly was found in West African states ("Ivermectin Overdose" 159-159). As any other medicinal drug the use of ivermectin results in side effects that may range from weakness for the patients, wrong use may also result in toxicity of the patients.
The use of avermectins for both humans and veterinary animal’s treatment has led to the reduction in prevalence for parasite and warm caused conditions. The patent period for the first class of ivermectins that was developed by the MSD research laboratories, however, expired in 1995; this gave way for the synthesis of different forms of ivermectins (Eraslan et al. 2181-2185). The different forms of ivermectins that are now in the market, therefore, may have different chemical compositions and are subject to research.
Introduction
Ivermectin is an effective antiparasitic medication; it is mainly applied in the treatment of conditions like head lice, scabies river blindness among many other parasitic conditions. Its mode of application ranges from oral or via the skin. A lot of Caution should, however, be taken to avoid the mouth as possible ("Ivermectin Overdose" 159-159). Wrong prescription and use of this drug lead to various side effects that range from a patient having red eyes, dry skin and or burning sensation on the patient’s skin.
Research is still underway to determine whether it is safe for use during pregnancy, it is, however, safe for use in lactating mothers. Ivermectin falls in the avermectin family of medicines, its use results into increased permeability of the cell membrane thus leading to paralysis and eventual death of the parasite. Having been discovered in the year 1975, it was first introduced into medical use in the year 1981 and has since made it into the list of the essential medicines key for any basic health system according to the WHO. The cost of the medicine ranges from country to country for example in the US it costs $0.12 for a single course of treatment ("Ivermectin Overdose" 159-159). Ivermectin can also be used in the treatment of animals for example in the treatment of heartworm and other diseases as may be prescribed by a veterinary doctor.
Traditionally this drug has been applied as an antiparasitic agent used in the treatment of conditions resulting from worm infections. In humans, it is used in the treatment of onchocerciasis also known as river blindness. It should, however, be noted that it is also effective against other warm infection conditions other than the river blindness and also against Epidermal parasitic skin diseases (Tom).
Having been introduced in the 1970’s Ivermectin became a revolutionary drug in the 1980’s at a time when it was used parasitic conditions. It was initially used as a veterinary medicine in the control and treatment of nematode in cattle, horses, and pigs. Ivomec that is the injectable form of the drug soon became the most profitable veterinary drug in the whole world.
Soon the use of Ivermectin for human treatment was realized by Merck and used in the control of onchocerciasis which was the main causative agent of river blindness that had hit West Africa in the early 1980’s. Through far-reaching partnerships with the affected country governments and the WHO, it was possible to supply the drug to the affected countries ("Ivermectin Overdose" 159-159). The patent period that had been made by Merck elapsed in the year 1996, this period was however extended to various countries. The expiry of the ivermectin patent period also led to the production of ivermectin by various companies resulting into the availability of ivermectin from different companies.
It is, however, wise to note that the bioavailability of drugs is dependent on the formulation and manufacturing procedure. Thus, chemical analysis of different ivermectin manufactured by different companies and that of Merck may differ. Thus, clinical trials for various formulations of the drug should be studied to be able to realize the differences and the similarities ("Ivermectin Overdose" 159-159).
In an analysis report on the use of ivermectin for the treatment of the occurrence of parasitological conditions and their side effects on treatment in a Brazilian population that were heavily parasitized. The results showed that ivermectin is highly effective compared to the other alternatives of the drug, for example, the use of ivermectin lead to a 94% reduction in the prevalence of the parasitic caused conditions within a period of 9 months.
In public health, ivermectin finds a range of applications in the control of strongyloidiasis and scabies. It acts by interfering with the infection cycle through the therapeutic effect and also its effect on transmission. Follow-up studies that have been conducted on the effects of the use of ivermectin have shown no adverse or negative effects on the offspring or the pregnant woman.
Structure of Ivermectin
Ivermectin has a molecular formula of C95H146O28.
Applications of Ivermectin
Ivermectin falls in the avermectin class of medicinal drugs. It has a variety of applications in veterinary medicine and human medicine. In veterinary medicine, for example, it is used to treat infections caused by a nematode, insect and acarine parasites found in several animal hosts. In humans, it has become the main treatment prescription for onchocerciasis making it the prescription of choice for the condition (Eraslan et al. 2181-2185). Other conditions that are also under research for possible mitigation by the mentioned drug include; strongyloidiasis, ascariasis, trichuriasis and enterobiasis.
The drug has a wide range of application ranges also in veterinary medicine in the treatment of conditions resulting from infections by ectoparasites. It should, however, be noted that currently no sufficient data exist that can support the use of ivermectin in the treatment of ectoparasites in humans. Scabies and pediculosis are the most commonly known ectoparasites found in Egypt (Eraslan et al. 2181-2185). The parasite is found burrowed superficially in the skin and does not extend beyond the stratum cornium. Signs and symptoms of this condition range from papules, vesicles, serpentine burrows and nocturnal itching which are normally used as positive pointers towards this infection.
Different treatment agents have different effectiveness rates, for example, the use of crotamiton results in reduced effectiveness by almost 70% when compared to the use of 1% lindane lotion. The wide use of Benzyl benzoate at concentrations of between 20-35% consecutively results in severe irritation that may include itching and inflammation of the eyes and other sensitive areas like the pubic parts. There are several agents also being applied for treatment of different conditions at different concentrations (Dalzell). A section of the agents has not been researched deeply to determine the specific effects on the body.
Biosynthesis of Ivermectin
Ivermectin falls in the class of avermectin and thus are biosynthesized in the same way as other avermectins. The gene cluster is initially sequenced from the S. avermitilis; this is then closely followed by the coding of the biosynthesis gene cluster responsible for the four main steps of ivermectin production.
Polyketide synthases produce the avermectin aglycon; the aglycon is then modified into sugars, the modified sugars are then modified and then the glycosylation occurs on the modified avermectin aglycon. Production of eight avermectins having minute structural differences is done by the gene cluster. Polyketide synthase is used in the synthesis of the avermectin’s initial aglycon mainly of four proteins which are; AVES 1, AVES 2, AVES 3 and AVES 4.
The enzyme activity that takes place during this activity is similar to the type I polyketide synthases. The starting units for the synthesis can either be 2-methylbutyrl CoA or in other cases an isobutyrl CoA (Walker et al. 1199-1207). An extension of the starting uniot by approximately seven acetate units occur resulting in the formation of the avermectin classes of drugs. The formation of the intramolecular cyclic ester results from the release of thioesterase domin of the AVES 4 which is the initial aglycon (Dalzell).
There is a further modification of the avermectin initial aglycon through the action of enzymes through a process known as biosynthetioc gene clustering ("Ivermectin" 29-29). The cytochrome P450 monooxygenase found in the AveE results in accelerated furan ring formation between C6 and C8. The NAD(P)H-dependent ketoreducatse found in the AveF results in the reduction of the C5 keto group to an hydroxyl group. The dehydratase activity occurring in module two is influenced by the action of AveC this affects C22-C23, it is however not clear by what mechanism it does this. SAM-dependent C% is found in AveD and results in O-methyltransferase activity (Eng). The action of either AveC or AveD on the aglycon determines the resultant avermectin aglycon that is whether the resultant avermectin series is to produce series A or series B and also series 1 and two respectively (Oakley). So far eight avermectins molecules are having closely related structures have been isolated and identified. The avermectin molecules are as a result of fermentation from the bacterium Streptomyces avermitilis below is a table of the eight molecules.
Research has proved the biocidal activity that the avermectins poses against a variety of parasites. The most common parasites that have been countered by the use avermectins include; roundworms, lungworms, mite, lice among many other parasites. In tropical regions cattle have suffered from the infestation of pests like ticks that has also been eradicated and or controlled by the use of the avermectins (Eng). From the table.1 above, it should be noted that avermectins having –CH=CH- are the most active regarding functionality on the target parasites.
Conclusion
The invention of ivermectin started by the isolation of avermectins in 1974 with a group of researchers who were headed by Professor Satoshi Omura, through their research and activities they were able to isolate an organism that had promising antimicrobial properties in a sample of soil. The soil sample was then passed over to the Merck, Sharpe and Dohme (MSD) laboratories in the US for further research (Bhowmick). The MSD research laboratories were able to isolate the natural family of products that later became known as the avermectins. It is worth noting that over time, scientists have looked at soil samples as a major source of potential medicines, for example, the tetracyclines and the streptomycin. The use of avermectin results into pest control and therefore is encouraged. It is, however, important for ivermectins to be developed to result in more specific forms of avermectins that can be applied in specified potencies depending on their substituents. For example, ivermectin is 22,23-dihydroavermectin (Oakley).
Ivermectin can be made from avermectinns by the addition of two hydrogen atoms thus resulting in the reduction of the double bond (C=C) in the avermectin.
The use of ivermectin in the treatment of nemathelminthes and or nematodes has made it one of the most important veterinary drugs in the protection of cattle, sheep, pigs, horses and dogs against parasites including heartworm infections. In humans, the drug is used in the treatment of river blindness and other parasitic caused conditions.
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