TrumpLyftAlles | 20 points
Effects of Ivermectin therapy on the sperm functions of Nigerian onchocerciasis patients (Nigeria 2011) Ivermectin decreases sperm counts and increases sperm abnormalities[-] stereomatch | 4 points
EDIT:
In the analysis below, I make the argument that onchocerciasis affects sperm function, as it does everything else, and has a reputation for affecting male *fertility in the affected indigenous populations.
And that this is evidenced also be the low proportion of normal sperm function that they could find (~~37pct~~ 9.6pct) at the beginning of the study.
I make the case that the decline in sperm function in this 9.6pct subset is an outcome of the worms continuing to ravage the body - since importantly ivermectin does not kill the adult worms and only affects the larvae. Thus it is entirely believable that the damage observed is an outcome of that process, rather than the postulated 11 months long lasting effects of a single dose of Ivermectin (!) If such a dramatic effect of the drug alone existed, it would have been observed many times over, over the course of it's 40 year history where it has been prescribed prolifically.
My conclusion is that it is a very badly designed study with no design intent to prove anything - since it confounds by design by confusing continuing worm damage that adult worms will continue to do (since they are not targeted by ivermectin) with a postulated long term impact of a single day dose of Ivermectin (a dose that otherwise has not been observed to cause such damage, given how prolifically it has been prescribed over 40 years).
In this study we screened a total of 385 patients who were diagnosed of onchocerciasis. Out of which, 37 (9.6%) were eligible for further tests, as their sperm counts were normal while the remaining patients had very low sperm counts and were therefore not used for further tests or were too weak after the preliminary screening tests and were not considered eligible for further test/studies. We therefore investigated the effects of ivermectin therapy on the sperm functions of these eligible 37 diagnosed patients of onchocerciasis who were of ages between 28 and 57 years.
So ~~37pct~~ 9.6pct only had normal sperm - perhaps their cherry-picking the currently ok subjects (ie ~~37pct~~ 9.6pct for further testing of sperm outcomes after ivermectin therapy) happened to pick the early cases who had not yet been damaged by chronic onchocerciasis.
Their sperm function "after ivermectin therapy" may just have been a function of onchocerciasis taking it's toll over time on these early cases. Because Ivermectin therapy does not immediately kill the adult worms (see below).
The standard treatment for onchocerciasis or river blindness is 0.2mg/kg by body weight given once a year for ~~2 years~~ 10-15 years or so - ie 0, 12 months, 24 months etc. (see references below that mention 10-15 and 15-17 years).
https://pubmed.ncbi.nlm.nih.gov/1674401/ The reproductive lifespan of Onchocerca volvulus in West African savanna 1991
It is concluded that the reproductive lifespan of the savanna strain of O. volvulus lies between 9 and 11 years, and that 95% of the parasites reach the end of reproduction before the age of 13 to 14 years.
https://www.sciencedirect.com/science/article/pii/S0001706X10002111 Review Elimination of human onchocerciasis: History of progress and current feasibility using ivermectin (Mectizan®) monotherapy 2010
Using a strategy of 6-monthly treatments with high coverage rates, the Onchocerciasis Elimination Program for the Americas has interrupted transmission in seven of the thirteen foci in the Americas and is on track to eliminate onchocerciasis in the region by 2015. Treatments given annually or semi-annually for 15–17 years in three hyperendemic onchocerciasis foci in Mali and Senegal also have resulted in a few infections in the human population with transmission levels below thresholds postulated for elimination.
Such a low one-time dose of ivermectin having such a dramatic effect 11 months later (when Ivermectin has a half-life of 18 hours) seems surprising - esp compared to the wider ravages that onchocerciasis must be doing to these possibly early patients of onchocerciasis (9.6pct still had normal sperm at beginning of study) - where it had yet to take it's toll or was about to take it's toll.
This confusion could have just as easily been cleared up by having a control group of similar patients but not given ivermectin. I would not be surprised if they too experienced sperm function reduction.
Or even easier conduct a study on normal individuals and see if a single dose of Ivermectin has any effect on sperm function visible 11 months later.
There are probably lots of individuals who take it as prophylaxis in Africa - yet study was not done on those - yet that would be the group to test.
So it looks like a badly designed study.
Also if ivermectin has such a dramatic effect - it would have been noticed by the doctors in Africa and certainly by the public who usually are sensitive to such effects - being prescribed over 40 years and being considered for mass use to eradicate recalcitrant malaria by the WHO.
And it's use beyond Africa as a deworming agent.
If nothing else the impact on fertility or damage to offspring would have been noticed in the animal industry - where it is used extensively - animals are bathed in it to tackle infestation by parasites.
The presumption that is indirectly assumed in this paper is that ivermectin should have stopped onchocerciasis and prevented sperm function damage - which it didn't do.
However, the function of ivermectin for onchocerciasis is that it seems to kill the microfilariae (larvae) and does not harm the adult worms. So it gradually allows attrition of the worm infestation throughout the body without rapid kills (which has danger of leaving dead worm in place in the eye etc.).
And here is the smoking gun that devastates this paper:
https://www.cdc.gov/parasites/onchocerciasis/treatment.html Parasites - Onchocerciasis (also known as River Blindness)
People who are found to be infected with O. volvulus should be treated in order to prevent long-term skin damage and blindness. The recommended treatment is ivermectin, which will need to be given every 6 months for the life span of the adult worms (i.e., 10–15 years) or for as long as the infected person has evidence of skin or eye infection. Ivermectin kills the larvae and prevents them from causing damage but it does not kill the adults.
So ivermectin DOES NOT kill the worms outright - it leaves the adult worms in place allowing them to die off according to their own lifecycle, but prevents larvae from replenishing the worm population.
Also note the lifespan of the adult worm is 10-15 years !!
This very clearly means that ivermectin WILL NOT lead to immediate killing of the adult worms - which mean that the sperm damage shown in this study may very well be due to the continuing damage from the adult worm left in place by ivermectin.
This seems like a far more likely continuing factor than the alternative of single dose ivermectin having impact that is visible 11 months later.
A sign that sperm function impairment may be a side-effect of onchocerciasis is signaled by the statistic mentioned above in the Abstract - that they only could find 9.6pct normal sperm function subject at the start of the trial - which seems very low!
Doing a google search on - onchocerciasis male fertility - turns up mention of it's perceived effect on male fertility as seen by indigenous populations affected by the disease:
https://journals.sagepub.com/doi/pdf/10.1177/004947558701700408 Onchocerciasis and pregnancy 1987
INTRODUCTION Onchocerciasis is best known for its ocular manifestations and hence the popular name river blind-ness. Yet the microfilariae which penetrate the eye can invade other parts of the body including liver, kidney, lungs, spleen and cerebrospinal fluid. Documentation of specific systemic effects include weight loss associated with intensity of infection and musculoskeletal pain associated with presence of microfilariae in skin-snipst. Pain and weight loss may not be as dramatic as blindness, but their contribution to the overall debilitating effects of morbidity should not be ignored. They give a hint that onchocerciasis may be capable of more wide- spread harm than previously thought. Both clinical and cultural clues to another potential effect of onchocerciasis - involvement with the female reproductive system - have been mentioned by some authors. Clinical evidence includes micro-filariae found in gynaecologic smears and in vaginal irrigation specimens. Intrauterine transmission of onchocerciasis has been postulated when positive skin-snips were taken from newborn babies and infants. On the cultural side, traditional societies living in endemic areas think that onchocerciasis may be responsible for human reproductive problems. In East Africa, the Ulanga people believe onchocerciasis can cause habitual abortion. The Yoruba of Ibarapa District, Oyo State, Nigeria, have no doubt that the disease can cause impotence in males and infertility and spontaneous abortions in females. The second point is that long experience in endemic areas provides indigenous populations with empirical evidence about common diseases. Much of the list of perceived onchocerciasis effects in Table 1 shows that Idere women's knowledge matches that of modern science. This implies that other perceived effects should not be dismissed out of hand but be the focus of further enquiry. The small amount of clinical evidence assembled to date does indicate that microfilariae can be found in the female reproductive system. It may be that predominantly male medical scientists have overlooked an issue that women in an endemic onchocerciasis zone see as important.
[-] Excellent-Garden1718 | 3 points
Thank you for this. Very helpful.
[-] TrumpLyftAlles | 2 points
Amazing job, Stereo. The argument I like best is they would have noticed in the cattle and pig businesses. I would think they would notice in the human population if fertility fell. Absolutely they would notice in the agricultural big animal business.
[-] stereomatch | 1 points
If Ivermectin is so toxic, why hasn't that been highlighted in WHO related publications?
Could it be the compulsion to push programs through for example for mass administration of ivermectin for recalcitrant malaria forces them to ignore some of the dangers or minimize them?
https://www.who.int/malaria/mpac/mpac-sept2016-invermectin-session9.pdf
Malaria Policy Advisory Committee Meeting 14–16 September 2016, Geneva, Switzerland
Ivermectin for malaria transmission control Technical consultation meeting report WHO Headquarters, Geneva 30 March–1 April 2016
3.6 Pharmacokinetic considerations regarding the safety of the use of ivermectin for malaria
When used at the dose currently approved for onchocerciasis or lymphatic filariasis (150–400 mcg/kg one to four times a year) or Strongyloides stercoralis (200 mcg/kg in a single dose), ivermectin is remarkably safe for humans weighing more than 15 kg (36).
More frequent administration has been recommended for use against scabies in Australia (39). If the dose or frequency required to reduce malaria transmission is higher, it will be important to establish the safety of the new treatment schemes. Based on pharmacokinetic modelling, a regime consisting of a daily dose of 600 mcg/kg for 3 days has the potential to sustain ivermectin concentrations lethal to Anopheles mosquitoes for at least 1 week (41).
The extensive data available in the context of the Mectizan® donation programme suggest that the current dose approved for onchocerciasis or lymphatic filariasis is extremely safe. By inference, prudent exploration of the safety of higher doses is warranted. In fact, single doses as high as 2000 mcg/kg (10-fold the dose currently used for onchocerciasis) and cumulative doses of up to 3200 mcg/kg in 1 week have been well tolerated by healthy volunteers (42).
Drug–drug interactions with concomitant therapy, such as artemisinin combination therapies (ACTs), have not been well explored. In a small study in Burkina Faso, coadministration with artemeter-lumefantrine was well tolerated [7]; preliminary data from Kenya have suggested that coadministration with DHA-piperaquine could also be safe (Ter Kuile, personal communication).
There are extremely limited safety data on children under 15 kg, who are not currently covered under the US FDA or Australian TGA approval for ivermectin (39, 43). Use during pregnancy has not been studied extensively, presenting a potential risk if the mass administration includes women of childbearing age. In effect, if the population coverage needs to be increased to include these special populations, additional data will be needed.
Ivermectin MDA for malaria would yield an indirect personal benefit if it could be demonstrated that it reduces local malaria transmission. Transmission (defined as infection incidence) should be the primary endpoint of any pivotal study. The precise measure of transmission would need to be tailored according to the endemicity of the study site.
If ivermectin is administered to individuals with a high burden of the filarial nematode Loa loa (particularly above 30 000 mf/ml), there is risk of a severe adverse event (SEA) in the form of encephalopathy syndrome that might cause death (44). The mechanism of this complication is unclear (45, 46), which means that ivermectin MDA for blocking malaria transmission would be precluded from large areas of Central Africa. Therefore, more research on this mechanism is urgently needed. Current management strategies include enhanced community and health worker awareness, as well as case management guidelines (44). The Rapid Assessment Procedure for Loiasis (RAPLOA) (47) can help predict the Loa loa community prevalence based on common manifestations of the disease.
Key conclusions
At the doses recommended for MDA and the treatment of onchocerciasis, LF or strongyloides, ivermectin has a remarkable safety profile. Limited data suggest that higher doses are also safe;
Preliminary evidence suggests that ivermectin can be given safely in conjunction with antimalarials;
Operational research on the impact of ivermectin MDA will address the need to include children under 15 kg and pregnant women currently excluded from ivermectin MDA for NTDs;
The Loa loa-associated encephalopathy induced by ivermectin is a serious problem that precludes large populations from receiving ivermectin and requires additional research to identify appropriate risk-mitigation strategies.
3.8 3.8 Safety of ivermectin in MDA campaigns
Given its mechanism of action, the central nervous system (CNS) is the primary target of ivermectin toxicity in all species examined.
Preclinical safety studies to support deployment against nematodes have included 14 weeks of daily repeated administration in rats and dogs (57), establishing a “no observed adverse event level” (NOAEL) of 400 and 500 mcg/kg/day, respectively. This duration is considerably longer than that of the scheme expected to reduce malaria vector survival. Additionally, a 2-week study in immature Rhesus monkeys with daily doses of up to 1200 mcg/kg found no treatment-related adverse events (57). In another study using ascending doses in Rhesus monkeys, emesis was first observed at the 2000 mcg/kg dose (57) – a level that is significantly higher than the exposure required to kill feeding mosquitoes.
Phase I trials in healthy volunteers in the US have suggested that a single dose of up to 2000 mcg/kg is well tolerated (42). Multiple-dose studies in human volunteers have shown that cumulative doses of up to 3200 mcg/kg in a week (42) or quarterly doses of up to 800 mcg/kg (58) are well tolerated. The adult dose approved by the US FDA for onchocerciasis and LF is 150–200 mcg/kg; multiple-dose regimens at this dose have been approved in Australia for scabies (39).
Until March 2015, the cumulative number of ivermectin tablets used worldwide was 2.7 billion, accounting for more than 928 million patient-years of treatment (Hetty Waskin MD, Merck, personal communication). Most of these tablets have been used in the context of MDA programmes for onchocerciasis or LF.
With the standard dose of 150–200 mcg/kg, the most common, direct adverse events seen in disease programmes or field studies have been hypersensitivity and inflammatory/allergic reactions (arthralgia 9.3%, lymphadenopathy 1.2–12.6%, rash/pruritus 22.7% and fever 22.6%) (36).
Patients with existing hyperreactive onchodermatitis may be more likely to experience severe adverse reactions. There are no published reports of life threatening immune reactions such as Stevens Johnson Syndrome, despite the fact that this possibility is noted on the label (36). Ivermectin MDAs at higher concentrations have been performed for NTDs. Ivermectin (400 mcg/kg) MDAs have been administered safely to thousands of people in India (59), Cameroon (60), Papua New Guinea (61) and French Polynesia (62) with minimal adverse events reported.
Ramaiah et al. (59) have conducted the largest human study to date of ivermectin MDA at 400 mcg/kg; in the study, five entire villages, roughly 10 000 people, were treated by MDA nine times over an 11-year period.
French regulatory authorities have recommended ivermectin (400 mcg/kg) MDA in selected areas (62). The primary safety concern is Loa loa-associated encephalopathy, which places a geographical restriction on the deployment of ivermectin. However, the mechanism is not well understood. The clinical safety of ivermectin during pregnancy has not been appropriately studied. Preclinical studies in pregnant mice, rats and rabbits have shown teratogenicity at doses toxic to the mother (400 mcg/kg, 5000 mcg/kg and 3000 mcg/kg during pregnancy days 6–18, respectively) (36, 57). Ivermectin has been shown to produce delayed development and increase pup mortality in rats at maternal doses of 1600 mcg/kg (57).
To track exposure in pregnancy, 1276 reports of inadvertent exposure in pregnant women have been filed, of which 442 were in the first trimester (63-66).
Toxicology studies in neonatal Rhesus monkeys have shown no adverse reactions after 2 weeks of daily 100 mcg/kg doses (57). Safety in paediatric patients weighing less than 15 kg has not been evaluated, and this population is currently not included on the US FDA-approved label (36).
Key conclusions
The central nervous system is the primary target of ivermectin toxicity in mammals;
In animal studies, ivermectin has been found to be teratogenic at or near maternotoxic doses;
Safety in paediatric patients weighing less than 15 kg has not been established;
Additional data may be needed to support the use of higher dose/repeated dosing regimens.
[-] converter-bot | 1 points
15.0 kg is 33.04 lbs
The big question is if those effects reverse in the long term or not. How long were they followed up? 11 months of treatment is also a lot.
[-] lemonflava | 1 points
Right, wonder if the effect is transitory or permanent? This is such an extreme assertion to make that Ivermectin damages testicular function, billions of people have taken this drug and continue to have children..
[-] Excellent-Garden1718 | 2 points
I see that they were treated for 11 months. I'm not seeing where it says how often the dose was given. Once, twice, monthly, weekly, daily? Am I missing it?
Good info. Might not be suitable for everyone in the case of ongoing prophylaxis.
[-] AgInAustin | 5 points | Jan 06 2021 15:58:14
I was a bit concerned about this. The length of use was long and the study doesn't say anything about the sperm functions after Ivermectin dose was stopped. Perhaps this study https://www.sciencedirect.com/science/article/pii/S0753332220300317?via%3Dihub will ease our concerns. It seems to show that Selenium and Vitamin E mitigate the testicular effects. If I have to take Ivermectin if I catch Covid, I will also make sure that I am taking a supplement that contains both Selenium and Vitamin E.
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[-] ibexrecurve | 3 points | Jan 06 2021 18:53:05
Also Alpha Lipoic Acid.
https://onlinelibrary.wiley.com/doi/abs/10.1111/and.12891
Meanwhile, the administration of ALA with IVM prevented testicular damage and improved all previous parameters. We concluded that ivermectin has undesirable effects on male fertility and altered expression of IGFBP‐3 and HSPA1 genes in the testes, while the administration of alpha lipoic acid can ameliorate the adverse effects of ivermectin.
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[-] TrumpLyftAlles | 1 points | Jan 07 2021 21:48:57
TIL! Luckily I've been taking ALA all along!
(Unluckily the issue is sadly moot.)
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