Replies to post #366936 on Tornado Alley (PROG)

[PegnVA]

Excellent advice!...
May I continue to urge YOU, not to take the vaccine, so that another American can get their vaccine just a tiny bit faster. Instead YOU should buy some Ivermectin horse paste from Tractor Supply. At the first sign of the sniffles gulp it down. Suppose to come in an Apple flavor! If YOU need help in converting precent paste into ug/kg, just contact Dr Stella Immanuel. She's still in good with your cult hero Trumpy - right? Since YOU are still in a serious need for deworming, take a dose just for the hell of it.

[Zorax]

I concur with the suggestions to not partake in the vaccines, buy some horse wormer and take immediately, but also to find the busiest public rest room and lick some toilet bowls to get covid-19 right away and build his immunity.

[fuagf]

DragonBear, Your half-life comment was something i'd neither heard of nor considered in Ivermectin discussion. It led to some good reading.

Proc Jpn Acad Ser B Phys Biol Sci. 2011 Feb 10; 87(2): 13–28.
doi: 10.2183/pjab.87.13

PMCID: PMC3043740
PMID: 21321478

Ivermectin, ‘Wonder drug’ from Japan: the human use perspective

Andy CRUMP*1 and Satoshi OMURA*1†

[...]

Ivermectin proved to be even more of a ‘Wonder drug’ in human health, improving the nutrition, general health and wellbeing of billions of people worldwide ever since it was first used to treat Onchocerciasis in humans in 1988. It proved ideal in many ways, being highly effective and broad-spectrum, safe, well tolerated and could be easily administered (a single, annual oral dose). It is used to treat a variety of internal nematode infections, including Onchocerciasis, Strongyloidiasis, Ascariasis, cutaneous larva migrans, filariases, Gnathostomiasis and Trichuriasis, as well as for oral treatment of ectoparasitic infections, such as Pediculosis (lice infestation) and scabies (mite infestation).14) Ivermectin is the essential mainstay of two global disease elimination campaigns that should soon rid the world of two of its most disfiguring and devastating diseases, Onchocerciasis and Lymphatic filariasis,

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3043740/

At that point i wandered to

Lymphatic filariasis and onchocerciasis

Prof Mark J Taylor, PhD
Prof Achim Hoerauf, MD
Prof Moses Bockarie, PhD

Published:August 24, 2010DOI:https://doi.org/10.1016/S0140-6736(10)60586-7

Summary

Lymphatic filariasis and onchocerciasis are parasitic helminth diseases that constitute a serious public health issue in tropical regions. The filarial nematodes that cause these diseases are transmitted by blood-feeding insects and produce chronic and long-term infection through suppression of host immunity. Disease pathogenesis is linked to host inflammation invoked by the death of the parasite, causing hydrocoele, lymphoedema, and elephantiasis in lymphatic filariasis, and skin disease and blindness in onchocerciasis. Most filarial species that infect people co-exist in mutualistic symbiosis with Wolbachia bacteria, which are essential for growth, development, and survival of their nematode hosts. These endosymbionts contribute to inflammatory disease pathogenesis and are a target for doxycycline therapy, which delivers macrofilaricidal activity, improves pathological outcomes, and is effective as monotherapy. Drugs to treat filariasis include diethylcarbamazine, ivermectin, and albendazole, which are used mostly in combination to reduce microfilariae in blood (lymphatic filariasis) and skin (onchocerciasis). Global programmes for control and elimination have been developed to provide sustained delivery of drugs to affected communities to interrupt transmission of disease and ultimately eliminate this burden on public health.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60586-7/fulltext?version=printerFriendly

Then returned to the first one to get more on the half-life in the body angle. Again to

Ivermectin, ‘Wonder drug’ from Japan: the human use perspective

Andy CRUMP*1 and Satoshi OMURA*1†

Editor: Satoshi OMURA

[...]

Onchocerciasis

The origins of ivermectin as a human drug are inextricably linked with Onchocerciasis (or River Blindness), a chronic human filarial disease caused by infection with Onchocerca volvulus worms. The parasites are transmitted via the bite of infected blackflies of the genus Simulium, which breed in highly-oxygenated, fast-flowing rivers and watercourses. In the human body, immature larval forms of the parasite create nodules in subcutaneous tissue, where they mature into adult worms. After mating, female worms can release up to 1000 microfilariae a day for some 10–14 years. These move through the body, and when they die they cause a variety of conditions, including skin rashes, lesions, intense itching, oedema and skin depigmentation (Fig. ?(Fig.2 ).2 ). Microfilariae also invade the eye, causing visual impairment and loss of vision, onchocerciasis being the second leading cause of blindness caused by an infectious disease.17) The disease causes visual damage for some 1–2 million people, around half of who will become blind.18)


Figure 2.
Mali: an old man, blinded by onchocerciasis, with leopard skin on his legs and nodules on his abdomen. Credit line: WHO/TDR/Crump.

In the early-1970s, the disease was endemic in 34 countries: 27 in Africa; 6 in the Americas; and 1 in the Arabian Peninsula. The World Health Organization (WHO) later estimated that 17.7 million people were infected worldwide, of whom some 270,000 were blind, and another 500,000 severely visually disabled. The burden of onchocerciasis was particularly extreme in the hyper-endemic belt across sub-Saharan Africa. Communities in these areas exhibited high rates of visual disability caused by Onchocerciasis, up to 40% in some areas, which caused immeasurable negative impact on individual and community health, reducing economic capacity and productivity, and leading to the abandonment of fertile agricultural lands.19)

By 1973, Onchocerciasis had been recognised by the then head of the World Bank, Robert McNamara, as a major disease of massive health and socioeconomic importance and one in dire need of combating in West Africa, and he became the key agent for change. In 1974, following international recognition of the dramatic consequences of disabling and disfiguring Onchocerciasis in Africa, four United Nations agencies, including the World Bank, launched the Onchocerciasis Control Programme in West Africa (OCP). The programme covered 1.2 million km2, protecting 30 million people in 11 countries from River Blindness.

Drug donation

For over a decade, OCP operations were exclusively based on the spraying of insecticides by helicopters and aircraft over the breeding sites of vector blackflies in order to kill their larvae. Following the registration of ivermectin (produced under the brand name Mectizan®) for human use in 1987, in a hitherto unprecedented move and with unheralded commitment, Mectizan® was donated by the manufacturing company, Merck & Co. Inc., to treat onchocerciasis in all endemic countries for as long as it was needed. The resultant drug donation programme was the first, largest, longest running and most successful of all—and proved a model for all others that have followed. Ivermectin began to be distributed in 1988, with operations being organized through the independent Mectizan Donation Program (MDP) established and funded by Merck. Thereafter, OCP control operations changed from exclusive vector control to larviciding combined with ivermectin treatment or, in some areas, to ivermectin treatment alone. Ivermectin swiftly became the drug of choice for the treatment of Onchocerciasis due to its unique and potent microfilaricidal effects, the absence of severe side effects and its excellent safety. It is now the sole tool being used in disease elimination campaigns in the 16 other African countries where the disease exists, orchestrated by the African Programme for Onchocerciasis Control (APOC), which commenced operations in 1996. A single annual dose of 150 µg/kg of ivermectin, given orally, can reduce the level of skin microfilariae to zero and, by interfering with worm embryogenesis, can delay the build-up of new microfilariae for a period of up to two years. OCP was closed in December 2002 after virtually stopping disease transmission in all target nations except Sierra Leone where operations were hampered by civil war.

[...]

Development of ivermectin for human use

In the mid-1970s, the global community mobilized itself to address the major problems of neglected tropical diseases. Following the setting up of the OCP in 1974, the UN-based Special Programme for Research & Training in Tropical Diseases (TDR) was established in 1975.20) Onchocerciasis, one of two filarial infections among TDR’s eight target diseases, was at that time a major public health problem affecting 20–40 million people in endemic areas. At exactly this time, a specialized novel anthelmintic mouse screening model in Merck’s research laboratories was identifying the avermectins in the microbial sample sent by the Kitasato Institute, of which ivermectin would become the most successful derivative.

At the time, there were no safe and acceptable drugs available to treat Onchocerciasis, which had plagued Africa for centuries, effectively leading to the creation of the OCP and its vector control focus. TDR quickly found that, despite many pharmaceutical companies, such as Bayer, Hoffman-LaRoche, CIBA-Geigy and Rhône-Poulenc, carrying out routing screening for filaricidal compounds, no companies were interested in developing suitable anti-Onchocerca drugs, as there was no apparent commercial market. Worse still, Onchocerca species would not develop to maturity in any rodents, making it impossible to screen compounds in an animal model against the target organism.21) It had been shown that O. volvulus could infect chimpanzees (Pan troglodites) but it was deemed unethical to use these animals for the necessary large-scale research, even though some testing of compounds was undertaken.22,23) Consequently, the OCP opted to devote operations to aerial larviciding via helicopters and small fixed-wing planes. It was a very ‘vertical’ programme, mainly coordinated through the World Bank and other UN agencies, with multimillion dollar contracts given to a US-based helicopter company and to an American chemical company for the insecticides.

[...]

In reality, ivermectin’s role in human medicine effectively began in April 1978 inside the Merck company, several years before the drug emerged on the Animal Health market. The highly potent bioactivity of a fermentation broth of an organism isolated by the Kitasato Institute in Tokyo, which had been sent to Merck’s research laboratories in 1974, was first identified in 1975. The active compounds were identified by the international multidisciplinary collaborative team as the avermectins, with the subsequently-refined ivermectin derivative being designated the optimal compound for development. Merck scientists, under the direction of Dr William Campbell, found that the drug was active against a wide range of parasites of livestock and companion animals.10) The informed foresight of a Merck researcher, Ms. L.S. Blair, resulted in the discovery that the drug was effective against skin-dwelling microfilariae of Onchocerca cervicalis in horses. These did not actually cause clinical disease and so the finding was of little commercial significance. However, O. cervicalis belongs to the same genus as O. volvulus, and upon reading the experimental reports, Dr Campbell surmised that there might be some merit in testing for impact against the latter. In July 1978, he sent ivermectin (as a coded sample), together with the results of the horse trial, to the TDR-supported tertiary cattle screen in Australia. The results, obtained in November 1978, showed that ivermectin was “highly effective in preventing patent infections with both O. gibsoni and O. gutturosa”. This reinforced Campbell’s growing belief that ivermectin would be effective against human onchocerciasis. Consequently, in December, he proposed to the Merck Laboratories’ Research Management Council that “an avermectin could become the first means of preventing the blindness associated with onchocerciasis” and that “discussions be held with representatives of WHO to determine the most appropriate approach to the problem—from the medical, political and commercial points of view”.27,28) Senior management approved the lead taken by Campbell and research funding to investigate the potential use of ivermectin in humans was approved by Dr Roy Vagelos, then President of the research laboratories.

TDR reactions to the initial data about ivermectin were rather muted, especially as it was searching for a macrofilaricide and ivermectin appeared to have little impact on adult worms. In late-1979, a TDR official visited Merck and, although the meeting resulted in TDR’s technical contribution to Merck’s ivermectin research, there was no ensuing discussion about collaboration to develop ivermectin for use in human Onchocerciasis.

Fortunately for all, in January 1980, Merck decided to proceed independently to Phase I (safety) trials. Clinical trials of ivermectin began in 1981, with a Phase I trial in 32 patients in Senegal followed by another trial in Paris among 20 West African immigrants. These trials were independently organized and funded by Merck, with a staff member, Dr Mohamed Aziz, previously of WHO, being the caring and committed driving force behind them. Dr Aziz started the study in Senegal with safety uppermost in his mind. It began with a very low dose of 5 µg/kg and found that a single dose of ivermectin, 30 µg/kg, substantially decreased the number of skin microfilariae. It also established that the effect lasted for at least 6 months, with no serious adverse events being observed. The subsequent Paris study confirmed these results and showed that doses up to 200 µg/kg were well tolerated.29,30)

When Merck officials visited TDR and OCP in 1982 to present the results from the Phase I trials, each side recognised the immense potential and collaboration in earnest began.

Evidence suggests that collaboration between these major partners commenced in a complex environment of mutual wariness, suspicion and shared hope that ivermectin would indeed prove to be an effective treatment for Onchocerciasis. The situation was compounded by the fact that Merck saw ivermectin as a potentially commercial product to be used for individual patient treatment, and moved forward constantly seeking an income return on its investment. In contrast, TDR, together with OCP, saw the drug as a new community-level tool that could possibly interrupt parasite transmission and thereby help reduce the prevalence of the disease in endemic communities. TDR and OCP consequently regarded community-based trials under field conditions as an essential step towards mass-treatment programmes, as opposed to the individual treatment in hospitals favoured by the commercial partner. The continual negotiation with respect to the cost of the drug eventually resulted in a commitment from Merck in July 1985 to supply it in sufficient quantities and at the lowest possible price consistent with the interests of the company, later confirming that it would be made available to “… governments and patients at no cost to them for the treatment of Onchocerciasis”.31)

With respect to official registration of ivermectin for human use, Merck, focussing on the single-patient approach, pressed ahead on its own and submitted an application to the French health authorities in 1987 based solely on the studies of the first 1,206 onchocerciasis patients, expecting to receive approval later that year, which it subsequently did.24,32) In its submission, Merck indicated a price of $3 per tablet, meaning that a treatment dose would cost $6, well beyond an affordable amount for those most in need.

[...]

Advantages of ivermectin for treating Onchocerciasis

Ivermectin proved to be virtually purpose-built to combat Onchocerciasis, which has two main manifestations, dermal damage resulting from microfilariae in the skin and ocular damage arising from microfilariae in the eye. Until the advent of ivermectin, despite its drawbacks, DEC was the drug of choice traditionally used to treat patients with onchocercal infection. DEC acts quickly to eliminate microfilariae from the anterior chamber of the eye and keeps the eye clear for a year or more. However, the rapidity of clearance often causes ocular damage as a result of an exaggerated inflammatory reaction. Conversely, ivermectin proved to slightly increase microfilariae in the eye upon treatment, followed by a gradual reduction, reaching to near zero, similar to DEC, within six months (Fig. ?(Fig.4 ).4 ). Most significantly, little or no resultant ocular damage occurs. Unlike DEC, it is believed that the large molecular size of ivemectin, a macrocylic lactone, prevents it from crossing the blood/aqueous humour barrier, stopping it entering the anterior chamber and exerting an effect directly on microfilariae.34) This makes ivermectin an ideal treatment for patients with ocular involvement.

IMAGE

Similarly, evaluation of the impact of DEC and ivermectin on dermal microfilariae, confirmed that both caused almost complete clearance within two days after treatment, reducing the load to virtually zero within eight days. However, although both drugs produce long-term suppression of the reappearance of microfilariae, ivermectin is superior, virtually eliminating all microfilariae and maintaining that status for some 90 days, whereas the effect of DEC wanes after little more than a week (Fig. ?(Fig.5 ).5 ). Thus, ivermectin is also an ideal treatment for dermal involvement.35) In addition to being perfectly tailor-made for Onchocerciasis, ivermectin has progressed to become a ‘wonder drug’ for other diseases too.

IMAGE

Effectiveness against other filarial diseases

[...]

Mode of action

Initially, researchers working on the development of ivermectin believed that it blocked neurotransmitters, acting on GABA-gated Cl- channels, exhibiting potent disruption at GABA receptors in invertebrates and mammals. GABA is recognised as the primary inhibitory neurotransmitter in the somatic neuromuscular system of nematodes. Subsequently, they discovered that it was in fact glutamate-gated Cl- channels (GUCl-) that were the target of ivermectin and related drugs. This discovery opened up a completely new spectrum of possibilities, as these channels, although playing fundamental roles in nematodes and insects, are not accessible in vertebrates.41–43) Ivermectin, while paralyzing body-wall and pharyngeal muscle in nematodes has no such impact in mammals, as it cannot cross the blood-brain barrier into the mammalian Central Nervous System, where GABA receptors are located. For a long time, it was believed that ivermectin was contra-indicated in children under the age of five or who weighed less than 5 kg, as there was a fear of neurotoxicity, the drug possibly being able to cross the as yet not fully developed blood/brain barrier. However, evidence has emerged that is probably not the case.44)

In the human body, ivermectin exerts a peculiar and singular effect that remains poorly understood. The immune response to filarial infection is complex, involving Th2-type systems which counter infective L3 larvae and microfilariae, whereas a combination of Th1 and Th2 pathways are involved in resisting adult worms. It is believed that female adult worms are able to manipulate the immunoregulatory environment, possibly via interleukin 10 (IL-10) levels, to ensure the survival of their microfilarial offspring.45) Ivermectin treatment of Onchocercal filarial infection causes the disappearance of microfilariae from the peripheral skin lymphatics. It does so relatively quickly and with long-lasting effect, while also inhibiting adult female worms from releasing additional microfilariae.46) Dermal microfilarial loads are generally reduced by 78% within two days, and by some 98% two weeks after treatment. They remain at extremely low levels for about 12 months, with 70% of female worms slowly resuming production of microfilaria 3–4 months after treatment, but at an irreversibly curtailed 35% of original production.47) Regular treatment consequently decreases incidence of infection, interrupts transmission and reduces morbidity and disability. However, the actual mechanism by which ivermectin exerts its effect on Onchocercal microfilariae remains unclear.48) In binding to GUCl-, ivermectin disrupts neurotransmission that is regulated via these channels in nematodes. But in culture, the drug has little direct effect on microfilariae when administered at pharmacologically relevant concentrations. It is now believed that the drug actually disrupts the fundamental host-parasite equilibrium. The half-life of ivermectin in humans is 12–36 hours, while metabolites may persist for up to three days.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3043740/

Aha finally got it! Damn interesting reading. Again my observation is that you seem
obviously to have some pretty deep knowledge into this area that i never contemplated.

Thanks, heaps for your half-life tip. All interesting stuff. And in the reading of it, again the fact that big-Pharma, though as
most all and most everyone has it's dark side, is sure as hell not all bad. Not as all bad as some would have us to believe.

Now have to water the garden. Damn, at after ten am a couple of hours late.