[Affiliation] Worldwide Regulatory Liaison, Biologics/Vaccines, Merck & Co., Inc., West Point, PA 19486-0004, USA. kenneth_brown@merck.com
The study:
#Abstract
The usually conservative approach of Merck & Co. to drug development became even more so in the Mectizan (ivermectin, MSD) programme because of adverse experiences following 'extra-label' use in Collie dogs and the discovery of a low threshold for acute neurotoxicity in CF-1 mice. Although a very cautious approach and rapid development programme ensued, Merck remained conservative and excluded children under the age of 5 years, pregnant women, and mother who were nursing children under the age of 3 months from treatment.
Collies and other herding dogs have a mutation that makes ivermectin dangerous. I don't know the details, esp. how dangerous.
A subsequent, more relaxed set of standards was based on vast human clinical experience, inadvertent use in hundreds of pregnant women without ill-effect, and new laboratory information indicating that the presence of a protective blood-brain barrier protein component (P-glycoprotein) helped to stop Mectizan from crossing the placenta and from crossing the blood-brain barrier in most animal species, including humans.
It was long thought that babies don't have blood-brain barriers. That theory has been set aside.
In 2019, 406 million (IIRC) people took ivermectin. Definitely 400-something million.
So you should expect about 2.3% of females worldwide to be pregnant at any moment (but rather less than that will know they're pregnant yet -- probably only about 2% of women will be both pregnant and aware that they're pregnant, though wider use of home pregnancy tests in many regions is changing this)
If we accept the statistic that 0.3% of women are pregnant and don't know it, then there would be about 600 women among the 406 million dosed in 2019, with ivermectin who took the drug not knowing they were pregnant. Over 20 years of Mass Drug Administration, at that rate of people getting ivermectin (I don't know if the annual number treated has been going up or down), maybe 10,000? If there were birth defects, someone probably would have noticed.
Speculating -- the number of pregnant women taking the drug could be much higher than 600 (and 10,000) if women want the drug and just deny their pregnancy and take the drug, out of fear of river blindness.
The 5 separate studies looking at the issue referenced in the malaria article are probably better evidence that ivermectin is benign, esp. doesn't cause birth defects.
Merck's finding is good enough for me.
This has allowed more groups to be included in Mectizan treatments: pregnant women living in areas where the risk of loss of sight because of onchocerciasis is very high; and women who are nursing children as young as 1 week of age. Mass distribution of the drug continues to be largely under community control and the likelihood of serious adverse experiences related to finding a human population with unusually low levels of P-glycoprotein (or no P-glycoprotein) seems remote.
A recent TIL for me is that P-glycoprotein is the "pump" that keeps crap out of our brains, makes the blood-brain barrier work.
The qualification for pregnant women "living in areas where the risk of loss of sight because of onchocerciasis is very high" suggests a trade-off between the two risks, river blindness vs birth defects. I don't see how the absolute safety of ivermectin for pregnant women would be any different for women not at risk for river blindness. The qualification confuses me. Is it really sound to say that ivermectin is safe for pregnant women, given the qualification?
I want to flat-out say ivermectin is safe for pregnant women -- but I'm biased, an ivermectin fanboy.
The dog toxicity appears to come from the same mutation that has been found in the rare cases of human toxicity. It allows the drug to cross the blood/brain barrier more easily.
Certain breeds, such as collies, sheepdogs, border collies, Australian shepherds, and other herding breeds are more susceptible to ivermectin toxicity due to the MDR1-allele mutation, known as the ATP-binding cassette polymorphism. This dog, being a mixed breed, could have had such a mutation. That said, in normal healthy dogs, we typically don’t see signs of ivermectin toxicosis until 2.5 mg/kg (where we can see mydriasis). At higher doses (e.g., 5 mg/kg), we can see signs of ataxia, tremoring and seizuring. Note that in normal healthy dogs, the LD50 is reported to be as high as 80 mg/kg (in healthy Beagles). In MDR-allele mutation dogs, the LD50 is reported to be as low as 0.12 mg/kg!
Usually what get dogs in trouble is wolfing down livestock health products. The dosages found in cattle and horse products lead to overdoses.
When prescribing medications it's normal to weigh the risks and benefits. If the risk is river blindness, it's a very serious risk so it makes sense to use the most powerful drug you've got. If the risk is scabies and the woman is pregnant, since it is a minor ailment, it's probably worth looking at other treatments.
Note that in normal healthy dogs, the LD50 is reported to be as high as 80 mg/kg (in healthy Beagles).
Wow that is a massive dose. 400 times the FDA's 200 mcg/kg, right? How do they figure that out?
Usually what get dogs in trouble is wolfing down livestock health products. The dosages found in cattle and horse products lead to overdoses.
I read about someone's dog getting ill from eating horse excrement.
Also, IIRC, a dog took 40 times the recommended amount (for dogs) and got sick -- and like every other ivermectin story I've ever heard, recovered. Seriously: every story.
I'm not sure there's a such thing as a fatal overdose, with ivermectin. If there is, I don't think it's known.
that has been found in the rare cases of human toxicity
ARE there such cases? There was the recently-reported 13-year-old with a mutation who went into coma after taking ivermectin (and recovered within 48 hours). Are there others? If so, I really want to know about them.
When prescribing medications it's normal to weigh the risks and benefits. If the risk is river blindness, it's a very serious risk so it makes sense to use the most powerful drug you've got. If the risk is scabies and the woman is pregnant, since it is a minor ailment, it's probably worth looking at other treatments.
If there are other treatments that are certified safe for pregnant women. It seems like no one would ever study how safe a drug is for pregnant women, because the downside could be so terrible. "To test this scabies treatment that we sell for $25, let's study whether it causes birth defects, so we can expand our market 2%." What's the ROI if a kid comes out bad (which happens even when NO drugs are involved) and there's a massive lawsuit looking for $$$$$$$$ for a lifetime of palliative care?
Thanks for the links! Gotta crash now, I'll check them tomorrow.
Permethrin topical has been assigned to pregnancy category B by the FDA. Animal studies have revealed no evidence of impaired fertility or harm to the fetus. There are no controlled data in human pregnancy. Permethrin topical is only recommended for use during pregnancy when benefit outweighs risk.
So no one did a clinical trial of pregnant women and permethrin.
Ivermectin has been assigned to pregnancy category C by the FDA. Animal studies have revealed evidence of teratogenicity, but at doses that were also maternotoxic to the pregnant female. The manufacturer considers ivermectin contraindicated during pregnancy.
Is the FDA's information old, or did Merck not tell them it's OK, or am I being rose-colored glasses about this study?
[-] TrumpLyftAlles | 1 points | Aug 26 2020 00:54:12
TL;DR: Merck, the company that invented ivermectin and donated a billion doses in 2019 for Mass Drug Adminstrations, is safe for pregnant women.
This is part of the backing research for the post about malaria that says ivermectin is safe for pregnant women and the babies of nursing mothers. The author works (or worked) for Merck:
[Affiliation] Worldwide Regulatory Liaison, Biologics/Vaccines, Merck & Co., Inc., West Point, PA 19486-0004, USA. kenneth_brown@merck.com
The study:
#Abstract The usually conservative approach of Merck & Co. to drug development became even more so in the Mectizan (ivermectin, MSD) programme because of adverse experiences following 'extra-label' use in Collie dogs and the discovery of a low threshold for acute neurotoxicity in CF-1 mice. Although a very cautious approach and rapid development programme ensued, Merck remained conservative and excluded children under the age of 5 years, pregnant women, and mother who were nursing children under the age of 3 months from treatment.
Collies and other herding dogs have a mutation that makes ivermectin dangerous. I don't know the details, esp. how dangerous.
A subsequent, more relaxed set of standards was based on vast human clinical experience, inadvertent use in hundreds of pregnant women without ill-effect, and new laboratory information indicating that the presence of a protective blood-brain barrier protein component (P-glycoprotein) helped to stop Mectizan from crossing the placenta and from crossing the blood-brain barrier in most animal species, including humans.
It was long thought that babies don't have blood-brain barriers. That theory has been set aside.
In 2019, 406 million (IIRC) people took ivermectin. Definitely 400-something million.
From this less-than-authoritative but pretty convincing (to me at least) source (a redditor):
So you should expect about 2.3% of females worldwide to be pregnant at any moment (but rather less than that will know they're pregnant yet -- probably only about 2% of women will be both pregnant and aware that they're pregnant, though wider use of home pregnancy tests in many regions is changing this)
If we accept the statistic that 0.3% of women are pregnant and don't know it, then there would be about 600 women among the 406 million dosed in 2019, with ivermectin who took the drug not knowing they were pregnant. Over 20 years of Mass Drug Administration, at that rate of people getting ivermectin (I don't know if the annual number treated has been going up or down), maybe 10,000? If there were birth defects, someone probably would have noticed.
Speculating -- the number of pregnant women taking the drug could be much higher than 600 (and 10,000) if women want the drug and just deny their pregnancy and take the drug, out of fear of river blindness.
The 5 separate studies looking at the issue referenced in the malaria article are probably better evidence that ivermectin is benign, esp. doesn't cause birth defects.
Merck's finding is good enough for me.
This has allowed more groups to be included in Mectizan treatments: pregnant women living in areas where the risk of loss of sight because of onchocerciasis is very high; and women who are nursing children as young as 1 week of age. Mass distribution of the drug continues to be largely under community control and the likelihood of serious adverse experiences related to finding a human population with unusually low levels of P-glycoprotein (or no P-glycoprotein) seems remote.
A recent TIL for me is that P-glycoprotein is the "pump" that keeps crap out of our brains, makes the blood-brain barrier work.
The qualification for pregnant women "living in areas where the risk of loss of sight because of onchocerciasis is very high" suggests a trade-off between the two risks, river blindness vs birth defects. I don't see how the absolute safety of ivermectin for pregnant women would be any different for women not at risk for river blindness. The qualification confuses me. Is it really sound to say that ivermectin is safe for pregnant women, given the qualification?
I want to flat-out say ivermectin is safe for pregnant women -- but I'm biased, an ivermectin fanboy.
What do you think?
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[-] wallahmaybee | 2 points | Aug 26 2020 03:32:39
The dog toxicity appears to come from the same mutation that has been found in the rare cases of human toxicity. It allows the drug to cross the blood/brain barrier more easily.
https://vetgirlontherun.com/ivermectin-toxicosis-in-a-dog-vetgirl-veterinary-ce-videos/
Certain breeds, such as collies, sheepdogs, border collies, Australian shepherds, and other herding breeds are more susceptible to ivermectin toxicity due to the MDR1-allele mutation, known as the ATP-binding cassette polymorphism. This dog, being a mixed breed, could have had such a mutation. That said, in normal healthy dogs, we typically don’t see signs of ivermectin toxicosis until 2.5 mg/kg (where we can see mydriasis). At higher doses (e.g., 5 mg/kg), we can see signs of ataxia, tremoring and seizuring. Note that in normal healthy dogs, the LD50 is reported to be as high as 80 mg/kg (in healthy Beagles). In MDR-allele mutation dogs, the LD50 is reported to be as low as 0.12 mg/kg!
Usually what get dogs in trouble is wolfing down livestock health products. The dosages found in cattle and horse products lead to overdoses.
When prescribing medications it's normal to weigh the risks and benefits. If the risk is river blindness, it's a very serious risk so it makes sense to use the most powerful drug you've got. If the risk is scabies and the woman is pregnant, since it is a minor ailment, it's probably worth looking at other treatments.
permalink
[-] TrumpLyftAlles | 2 points | Aug 26 2020 03:46:04
Note that in normal healthy dogs, the LD50 is reported to be as high as 80 mg/kg (in healthy Beagles).
Wow that is a massive dose. 400 times the FDA's 200 mcg/kg, right? How do they figure that out?
Usually what get dogs in trouble is wolfing down livestock health products. The dosages found in cattle and horse products lead to overdoses.
I read about someone's dog getting ill from eating horse excrement.
Also, IIRC, a dog took 40 times the recommended amount (for dogs) and got sick -- and like every other ivermectin story I've ever heard, recovered. Seriously: every story.
I'm not sure there's a such thing as a fatal overdose, with ivermectin. If there is, I don't think it's known.
permalink
[-] TrumpLyftAlles | 1 points | Aug 26 2020 03:42:38
that has been found in the rare cases of human toxicity
ARE there such cases? There was the recently-reported 13-year-old with a mutation who went into coma after taking ivermectin (and recovered within 48 hours). Are there others? If so, I really want to know about them.
When prescribing medications it's normal to weigh the risks and benefits. If the risk is river blindness, it's a very serious risk so it makes sense to use the most powerful drug you've got. If the risk is scabies and the woman is pregnant, since it is a minor ailment, it's probably worth looking at other treatments.
If there are other treatments that are certified safe for pregnant women. It seems like no one would ever study how safe a drug is for pregnant women, because the downside could be so terrible. "To test this scabies treatment that we sell for $25, let's study whether it causes birth defects, so we can expand our market 2%." What's the ROI if a kid comes out bad (which happens even when NO drugs are involved) and there's a massive lawsuit looking for $$$$$$$$ for a lifetime of palliative care?
permalink
[-] wallahmaybee | 1 points | Aug 26 2020 03:59:55
Test on pregnant mice in labs. Test on beagles in labs.
Yes, the 13 year old boy is one of these cases. The mutation is not a new discovery.
https://pubmed.ncbi.nlm.nih.gov/10331089/ https://pubmed.ncbi.nlm.nih.gov/17185560/ https://pubmed.ncbi.nlm.nih.gov/11503014/ https://pubmed.ncbi.nlm.nih.gov/12208746/
Looks like we've been aware of variation in sensitivity to drugs for a long time.
Topical permethrin is also a treatment for scabies.
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[-] TrumpLyftAlles | 1 points | Aug 26 2020 04:08:02
Thanks for the links! Gotta crash now, I'll check them tomorrow.
Permethrin topical has been assigned to pregnancy category B by the FDA. Animal studies have revealed no evidence of impaired fertility or harm to the fetus. There are no controlled data in human pregnancy. Permethrin topical is only recommended for use during pregnancy when benefit outweighs risk.
So no one did a clinical trial of pregnant women and permethrin.
Ivermectin has been assigned to pregnancy category C by the FDA. Animal studies have revealed evidence of teratogenicity, but at doses that were also maternotoxic to the pregnant female. The manufacturer considers ivermectin contraindicated during pregnancy.
Is the FDA's information old, or did Merck not tell them it's OK, or am I being rose-colored glasses about this study?
permalink