Onchocerciasis

**Ivermectin Treatment for Onchocerca //volvulus// infection (Onchocerciasis or River Blindness**) =__ Motivation and Background __= River blindness is an infectious disease that affects populations in the wet climates of northern South America and more prevalently Sub-Saharan Africa. Generally, populations with the greatest risk of contracting river blindness are those living near streams and rivers. These wet regions are suitable breeding grounds for black flies, the vectors of river blindness.

Black flies feed on animal blood, and its bite releases parasitic worms called Onchocerca //volvulus// (O. //volvulus//) into the skin of animals. Once inside the human host the O. //volvulus// will begin to form nodules that protects it from the human immune system. Therefore, the adult and larvae worms may travel throughout the human body without triggering immune responses from the host. On a daily basis, the female worms produce thousands of larvae, and the larvae do not become discernable in the skin until about 10 to 20 months after the initial infection. [2]



**Figure 1**. Life cycles of O. volvulus in its transmission between humans and black flies. [2] The variety of symptoms from an O. //volvulus// infection are caused by the body’s immune response to dead or dying larvae. Symptoms include inflammation in the skin causing itchy rashes, nodule formation under skin, changes in color of skin resulting in “leopard skin”, and thinning of the skin. Eventually, the O. //volvulus// infection will lead to blindness if left untreated. Vision loss begins with inflammations in the eye. Due to larvae dying in the eye, lesions are created which result in clouding of the cornea and result in blindness. In conjunction, inflammation in the optic nerve also occurs leading to permanent vision loss. [2,5]

 Mostly seen in the countries of Sub-Saharan Africa, river blindness causes a socioeconomic burden. Villagers who contract river blindness become disabled to farm, leading to issues such as food shortages, starvation, malnutrition, poverty, and low fertility rates. The disease also causes many farmers to move away from the fertile and swampy regions for growing crops. An African Programme for Onchocerciasis (APOC) has been created international partnerships to supply healthcare and drugs to fight the river blindness endemic in the countries of Sub-Saharan Africa. [4]

[1] Althoff, T.; Hibbs, R. E.; Banerjee, S.; Gouaux, E., X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors. Nature 2014, 512 (7514), 333-337. [2] DPDx. Parasites- Onchocerciasis (also known as River Blindness). http://www.cdc.gov/parasites/onchocerciasis/biology.html (accessed 02/07/2016). [3] Ejere, H.; Schwartz, E.; Wormald, R.; Evans, J., Ivermectin for onchocercal eye disease (river blindness). Cochrane Database of Systematic Reviews 2012, (12). [4] Jamison, D. F., RG. Makgoba, MW. et al., Disease and Mortality in Sub-Saharan Africa. 2nd edition.; World Bank: Washington (DC), 2006. [5] Ogbru, O.; Davis, C. P. Ivermectin. http://www.medicinenet.com/ivermectin-oral/page2.htm (accessed 02/07/2016). [6] Organic Chemists Fighting Blindness. http://www.rsc.org/Membership/Networking/InterestGroups/OrganicDivision/organic-chemistry-case-studies/organic-chemistry-improved-health.asp (accessed 02/07/2016). [7] Vagelos, R. History. http://web.stanford.edu/group/parasites/ParaSites2005/Ivermectin/History.htm (accessed 02/07/2016). [8] Wolstenholme, A., Glutamate-gated Chloride Channels. The Journal of Biological Chemistry 2012, 287 (48), 40232-40238.
 * References: **

http://www.cdc.gov/parasites/onchocerciasis/biology.html http://www.medicinenet.com/ivermectin-oral/page2.htm http://www.rsc.org/Membership/Networking/InterestGroups/OrganicDivision/organic-chemistry-case-studies/organic-chemistry-improved-health.asp http://web.stanford.edu/group/parasites/ParaSites2005/Ivermectin/History.htm = = =__Target Information __= Merck & Co., a major pharmaceutical company, is producing and supplying Ivermectin which targets the glutamate gated chloride ion channels (GluCls) within the worm larvae.
 * External links: **

** Location **
<span style="font-family: Arial,Helvetica,sans-serif;">Ivermectin targets the glutamate gated chloride ion channels (GluCls) within the worm. An abundance of them are found on the sensory neurons, interneurons, and motor neurons in nematodes (round worms).

** Function in a normal cell **
<span style="font-family: Arial,Helvetica,sans-serif;">This means GluCls are heavily involved with mediating behavioral functions and affect reproductive rate of nematodes such as the O. //volvulus//. On a cellular level, Ivermectin binds to the GluCls, keeping the ligand-gated chloride ion channels open. This causes an increase in the permeability of the cell membrane to chloride ions. An influx of chloride ions then lead to the hyperpolarization of the neurons. This inhibits the neuron’s ability to cross the threshold action potential necessary to send electrochemical messages. Therefore, Ivermectin successfully compromises the functioning of the worm’s nervous system, halting necessary behavioral functions for survival, and leading to death of the worm larvae. [1,8]

<span style="font-family: Arial,Helvetica,sans-serif;">In a recent study of a member of the nematode phylum, C. //elegans//, a schematic was produced visually showing how Ivermectin was oriented worked to open the GluCls. This study was used to understand how Ivermectin may work inside the body of the O. //volvulus// larvae.

**Figure 2.** Diagram shows, Ivermectin molecule binding between the M1 and M3 channel subunits. An interaction with the M2 subunit keeps the GluCl channels open. [8] Also, the Ivermectin binding site alters the conformation of the glutamate binding side through allosteric interactions between M2 and M3 subunits of the GluCl channels. [1,8] Therefore, glutamate is inhibited from binding to the GluCls. =__<span style="font-family: Arial,Helvetica,sans-serif; font-size: 90%;">Drug Information about Ivermectin __= <span style="font-family: Arial,Helvetica,sans-serif;">Ivermectin is derived from a family of drugs called avermectin, a naturally occurring compound formed from fermentation products by bacteria, Streptomyces //avermitilis,// in the soil. It was discovered in the labs of Merck & Co. in 1975 and was initially developed for veterinary drugs. Due to the elimination of a single double bond from the avermectin structure, Ivermectin was engineered to become less toxic to animals. [8]

**Figure 3**. Schematic figure showing the removal of a single bond from Avermectin using Wilkinson’s catalyst to form Ivermectin. [6]
 * Formula ** : <span style="color: #333333; font-family: Arial,Helvetica,sans-serif; font-size: 14px;">C <span style="color: #333333; font-family: Arial,Helvetica,sans-serif; font-size: 14px; vertical-align: sub;">95 <span style="color: #333333; font-family: Arial,Helvetica,sans-serif; font-size: 14px;">H <span style="color: #333333; font-family: Arial,Helvetica,sans-serif; font-size: 14px; vertical-align: sub;">146 <span style="color: #333333; font-family: Arial,Helvetica,sans-serif; font-size: 14px;">O 28


 * Molecular weight ** : <span style="color: #333333; font-family: Arial,Helvetica,sans-serif;">1736.16g


 * CAS Number ** : <span style="color: #333333; font-family: Arial,Helvetica,sans-serif; font-size: 14px;">70288-86-7


 * Delivery method ** : Annual oral dosage


 * Side effects ** : itching, rash, dizziness, insomnia, abdominal pain, constipation, vomiting, low blood pressure, facial swelling, and increased heart rate


 * Other names ** : Stromectol or Mectizan


 * Maker or company ** : Merck & Co.


 * Is it patented ** ? Yes

<span style="font-family: 'Arial',sans-serif; font-size: 13.33px;">Through clinical trials, it has been proven that a single annual dosage of 150-200 mcg/kg of Ivermectin is enough to decrease the density of O. //volvulus// larvae close to zero for up to 12 months. However, Ivermectin is unable to kill adult O. //volvulus//. So, it is only useful in reducing reproduction rate of adult female O. //volvulus// while killing the thousands of larvae that have been produced since the initial infection. [3,8] Clinical studies also lack results for Ivermectin usage in pregnant women, seniors above the age of 65, and pediatric patients weighing less than 15kgs. Therefore, it would not be safe to use on patients exhibiting those circumstances. [5] __**<span style="font-family: Arial,Helvetica,sans-serif; font-size: 13pt;">Origin **__ <span style="font-family: 'Arial',sans-serif; font-size: 13.33px;">Dr. William Campbell, the head of the discovery team at Merck & Co. recognized properties of Ivermectin that hinted at the drug’s potential for tackling river blindness. Merck & Co. then encouraged the investigation of Dr. Campbell’s hypothesis and eventually human clinical trials of Ivermectin began in 1981. From the clinical trials, Ivermectin was proved to be a safe and effective in killing larvae of O. //volvulus//. Since it could not kill the adult O. volvulus, the World Health Organization (WHO) lost interest in Ivermectin’s potential. However, continued success in clinical trials, WHO regained their interested and funded a research initiative for the development of Ivermectin. Finally, in 1987 the first approval of Stromectol occurred in France. [8] Today, it is manufactured by Merck and Co. and distributed internationally to treat river blindness. [8]
 * Clinical Trials Information **


 * Alternatives to this drug ** : None

<span style="font-family: 'Arial',sans-serif; font-size: 13.33px;">Ivermectin is still not a considered a complete cure because Ivermectin does not effectively kill mature worms. However, it has already been proven to be impactful, as 60 million people are being currently treated in the affected regions. [8] The Ivermectin treatment has also brought hope of building a healthier, more prosperous future for the people and the countries affected by river blindness. <span style="font-family: Arial,Helvetica,sans-serif;">Treatment of ringworms in animals and head lice in humans
 * M **** iscellaneous **
 * Other uses **