Robert F. Kennedy's book on "The Real Anthony Fauci." Hydroxychloroquine, Part Three

  In this series of critiques of Robert F. Kennedy, Jr.'s book "The Real Anthony Fauci: Bill Gates, Big Pharma, and the Global War on Democracy and Public Health," I left off discussing Kennedy's table of studies that show hydroxychloroquine is effective. 

Continuing with the table on page 22. I had intended just to sample a couple of the cited studies. But then the first study was retracted. The second study didn't even look at hydroxychloroquine. The third study was never published. 

So I continued to review the studies, one by one. In doing so, I intend to demonstrate that Kennedy is, in practically every detail, a liar who puts up phony evidence. When I'm done with the list of studies, I'll try to give an overall picture. How many were never published, how many that don't agree with what Kennedy presents, and how many the authors concluded that hydroxychloroquine doesn't work.

Here, below, is Kennedy's chart from page 22 of Chapter One of his book.

RFK Jr.'s list of "All thirty-two" studies with early intervention with hydroxychloroquine.

(Continuing from my last entry.)

Nineteenth study. Guisado-Vasco. Kennedy correctly references 2 deaths in 65 patients (3.1%) who had taken hydroxychloroquine before admission and 139 out of 542 who did not (25.8%). However, remarkably, an additional 493 patients out of 607 total took hydroxychloroquine after admission to the hospital and 125 of them died (25.4%). If you add early hydroxychloroquine to later hydroxychloroquine, 127 of 558 died (22.8%). Of the 607 patients in the study, additional drugs taken include lopinavir/ritonavir (487), cyclosporine A (an immunosuppressant, 253), glucocorticoids (antiinflammatory and immunosuppressant, 159), and tocilizumab (an immunosuppressant and antiinflammatory, 132), the magnitude of the numbers saying that two or more drugs were taken. Tocilizumab and cyclosporine A were also deemed to have promoted survival to a statistically significant degree. 

Twentieth study. Szente Fonseca. The Szente Fonseca study has a total of 717 patients with 334 receiving hydroxychloroquine (175 hydroxychloroquine alone and 159 hydroxychloroquine plus prednisone, a glucocorticoid), with 139 receiving prednisone alone, and 244 given neither prednisone nor hydroxychloroquine. Approximately half of all patients received azithromycin (53.3%) and/or ivermectin (47.4%) and/or oseltamavir (12.7%). To further confuse things, 65.7% of those in the category "hydroxychloroquine alone" received ivermectin and 42.9% were given azithromycin. A total of 122 patients were said to receive no medication, which would have made a good control, but they didn't report those results. All these categories and overlapping treatments (and lack of specificity as to how they overlap) really complicate making conclusions about what worked. 

The results were given in terms of number treated who were hospitalized out of total number hospitalized. Hydroxychloroquine alone, 25 out of 114. Prednisone alone, 14 out of 114. Hydroxychloroquine plus prednisone, 16 out 114. Numbers were not presented for the other treatments, however, not having hydroxychloroquine or prednisone would have 59 cases out of 114. This study is a bit maddening on not identifying basic information that could help determine effectiveness, especially the question, what was the rate of hospitalization for the 122 patients with no treatment? 

What does Kennedy conclude? 25/175 in the treatment were hospitalized versus 89 out of 542 in the control group. How did they get those figures? They seem to have considered hydroxychloroquine plus prednisone and every other treatment as part of the controls. 

This study is a mess.

Twenty-first study. Cadegiani.  Cadegiani, et al., looked at hydroxychloroquine, nitazoxanide (an antiprotozoal drug), and ivermectin, together with azithromycin. This is getting exhausting. If you want to prove something with certainty, stick to one thing, or two at the most. "Of the 585 subjects, all patients used azithromycin. A total of 357 patients used NIT [nitazoxanide], 159 used HCQ [hydroxychloroquine] and 110 patients used IVE [ivermectin], alone with azithromycin or in combination with other drugs." Several other drugs were mentioned as optional. Mercifully, Cadegiani describes the drugs taken in addition to hydroxychloroquine. All 159 patients on hydroxychloroquine took azithromycin, 21 also took ivermectin, 113 also took nitazoxanide, 86 also took spironolactone (an antidiuretic), and 7 also took dutasteride, an antiandrogen. I say mercifully because it is good for the sake of clarity, but it is impossible to pin down the role of hydroxychloroquine alone.

Kennedy presents the conclusion that 0/159 died in the hydroxychloroquine group and 2/137 in the control group. Cadegiani says that there was zero deaths in the treated population, all 585. He does not break out the numbers for the hydroxychloroquine treated patients, although zero is zero, which means that every treatment group and combination had zero deaths. Since the study had everyone treated, the control group of 137 were outside cases matched and added in.

Twenty-second study. Simova. Thirty-eight health care workers were found to be COVID positive. Half were asymptomatic. Thirty-three agreed to take azithromycin, hydroxychloroquine, and zinc. Five declined. Of the 33 who took the medication, none required hospitalization. Of the five who declined, two ended up being hospitalized. As an observational study, other than the small number of controls, this is not bad. It is a bias to allow the control group to define itself. Five of those taking hydroxychloroquine experienced prolonged heartbeat intervals (QTc intervals) which is a toxicity of the drug. They were discontinued from the treatment.

Twenty-third study. Omrani. There were three arms in this study, each with 152 participants. Azithromycin plus hydroxychloroquine, hydroxychloroquine alone, and no treatment. That would make for a good study design. Omrani presents the figure copied below as part of the results.

Placebo outperformed the drug treatments, although not to a statistically significant degree.
p = 0.072

Omrani set viral recovery on day 6, virus below detection, and day 14 as the primary and secondary endpoints of their study. Kennedy reported hospitalization. Omrani looked at that outcome. "The HC+AZ [hydroxychloroquine plus azithromycin] and placebo groups each had four participants hospitalized (for each group, 2.6% of 152). The HC group had three participants hospitalized (2.0% of 152). There was no association between group and proportion of hospitalized cases (p = 1.000 by Fisher's exact test)." (emphasis mine) Researchers seldom get a p = 1.0, absolutely no support for their hypothesis (or technically, for rejecting the null hypothesis). Omrani, in his discussion, is very critical of the use of hydroxychloroquine and provides a survey of studies that it reject its usefulness.

Twenty-fourth study. Agusti. This study looked at 142 patients. Eighty-seven agreed to treatment with hydroxychloroquine. The controls consisted of those who declined treatment (43) and those who had contraindications to hydroxychloroquine (12). Kennedy says that 2 of 87 of those treated and 4 of 55 of those not treated made the endpoint of the study which he described as "progression." I'm not sure how he came up with his numbers. The study measured whether someone continued to be positive for the virus at days 7, 10, 15, 22, and 28 after diagnosis. Agusti found, "In conclusion, our study failed to show a substantial benefit of HCQ [hydroxychloroquine] in viral dynamics and in resolution of clinical symptoms. Treatment with HCQ was associated with a numerically higher percentage of negative PCR-tests at some points during follow-up in comparison with the non-treatment group, and a shorter duration of some symptoms was also seen with HCQ, but differences were only marginally significant and not clinically relevant." 

Twenty-fifth study. Su. Although Su, et. al., does perform statistical analyses on their data, they do not provide the numbers of patients who were given particular treatments or how many improved compared those to controls. They don't even define controls. The conclusion from their statistical analyses are that "The early use of hydroxychloroquine decreased the improvement time and the duration of COVID-19 detection in throat and stool swabs." 

Twenty-sixth study. Amaravadi This is another case of a paper that failed to be published. The preprint version is available. Early in the text there is this strange statement: "Out of 5511 SARS-CoV-2 positive patients, 1072 met initial eligibility criteria for telephone-based recruitment, but only 34 subjects were able to be randomized." and "Six randomized patients failed to complete the study leaving 28 patients for analysis of the primary outcome." and ". . . this study was terminated early due to lack of feasibility." That is just painful to read. 

Twenty-seventh study. Roy. One problem with tracking down what Kennedy claims in his table is that he provides little information. For example, Roy. Which study is that? We have clues. It looked at recovery time (or did it? sometimes he gets that wrong), there were 14 in the treatment end and 15 in the control end. There is no published paper with Roy as the first author that includes the terms hydroxychloroquine and COVID. Okay, some of the studies Kennedy references were never peer reviewed and formally published. I finally found it.

Roy's paper is another one that does not exist outside of preprint. A total of 56 patients were divided into four groups. "1) having HCQ [hydroxychloroquine] 200 mg twice daily [14 patients] . . . 2) IVR [ivermectin] + DOX [doxycycline] . . . 3) AZR [azithromycin] and, the last group as per NIH guidelines who refused any treatment other than supportive treatment with antipyretics and oral rehydration solution. [15 patients]"  

Roy's conclusion? "Mild COVID-19 infection in patients having low-risk to progress can be managed symptomatically without any specific drug intervention." 

Twenty-eighth study. Mokhtari. My first impression: nearly 30,000 in a study. There are some quibbles with those numbers: 1898 were COVID test negative and another 4087 were not tested. Did they have COVID? 

A major problem with the study is that "HCQ [hydroxychloroquine] was added to the supportive care for patients with mild COVID-19 illness who did not require referral to the hospital." This presents a huge bias: those who did not receive hydroxychloroquine were healthier. Kennedy reports 27 deaths out of 7295 in the hydroxychloroquine group and 287 deaths out of 21464 in the control group, consistent with Mokhtari's presentation.

Twenty-ninth study. Million. Looked at 10,429 ambulatory patients. Of these, 8315 were prescribed hydroxychloroquine and azithromycin. Zinc was later included as the study went along. 

"The primary objective was to evaluate the age-specific 6-week IFR [infection fatality rate] of unselected adult outpatients infected with SARS-CoV-2 who were managed early in a dedicated COVID-19 day hospital offering standardized treatment based on HCQ+AZ. The secondary objective was to test whether the use of HCQ+AZ was associated with improved IFR and lower ICU [intensive care unit admission] and HC [hospitalization in a conventional ward] rates in this cohort."

So, Kennedy reported absolute death rates, 5 out of 8315 for those treated with hydroxychloroquine and azithromycin (plus or minus zinc), and 11 out of 2114 for those that weren't. If the ages of the two groups were equal, that would be in line with the study's goal. The study reported that no deaths took place in any patients who were under 60. It worked out to be that 18.0% of the treatment group were over 60 and 24.6% of the control group. Furthermore, this age difference became even more pronounced with older age with 5.9% of those in the treatment group being over 70 and 11.2% in the control group.

Adjusting for age, there was still a higher rate of mortality in the control group, but not nearly so dramatic as presented in Kennedy's numbers. As for the other two endpoints, hydroxychloroquine plus azithromycin did not reduce ICU or conventional ward hospital admissions to a statistically significant degree. 

 

Thirtieth study. Sobngwi. A total of 95 patients receiving hydroxychloroquine were evaluated in comparison to 92 who received doxycycline, an antibiotic. All patients received vitamin C and zinc. "The primary endpoint was the rate of clinical recovery determined by the percentage of participants who became or remained asymptomatic. Key secondary endpoints included the percentage of participants requiring hospitalization due to worsening symptoms, as well as the proportion of participants displaying a negative SARS-CoV-2 PCR test."

Kennedy reported one of their findings, recovery at day 10: 4 had not recovered in the doxycycline group and 2 had not recovered in the hydroxychloroquine group, a result deemed insignificant (p = 0.44). From the paper: "In conclusion, we did not observe any significant difference in terms of safety and efficacy between doxycycline and hydroxychloroquine-azithromycin for the management of mild COVID-19."

Thirty-first study. Rodrigues. This study is interesting in that it is the only one among the 32 that Kennedy admits shows negative results, that is, not favoring the use of hydroxychloroquine. This is kind of harsh. Just like Kennedy's decisions to say that hydroxychloroquine worked where there was insufficient evidence, there is insufficient evidence here to say that it didn't work.

The patients were randomly assigned either hydroxychloroquine plus azithromycin or placebo. 

"The primary outcome was the time to viral clearance within a 9-day evaluation period following enrolment after the onset of symptoms and the study enrolment dates. . . . Secondary outcomes of interest included: viral load reduction, improvement of symptoms, hospitalisation rates, and adverse effects to the trial medications."

Kennedy only reported hospitalization rates, saying 1 out of 42 in the hydroxychloroquine plus azithromycin group and 0 out of 42 in the placebo group. From the researchers' discussion: "In this randomised, double-blinded, placebo-controlled clinical trial evaluating outpatients with early and mild COVID-19 treated with HCQ/AZT or placebo, there was no benefit in the treatment arm on primary and secondary outcomes."

Thirty-second study. Sawanpanyalert. For the final study, there is a major problem. These researchers used chloroquine or hydroxychloroquine interchangeably and without distinction. These are not the same drugs. Hydroxyamphetamine is not the same amphetamine. Diacetylmorphine is illegal in the U.S. while morphine is not.

Their mix of drugs was complicated. "Among 533 symptomatic patients, 45 (8.4%) received CQ/HCQ alone [chloroquine or hydroxychloroquine], 10 (1.9%) received bPI alone [lopinavir/ritonavir], 197 (37.0%) received CQ/HCQ with bPI and 140 (26.3%) received FPV [favipiravir] with CQ/HCQ and/or bPI.  Of 132 patients who received azithromycin, 121 (91.7%) also received CQ/HCQ."

The lack of identifying when hydroxychloroquine was used prevents evaluating it for this commentary.

So, there are thirty two studies. The problems with these. 

Retracted: one.

Never published: four

Didn't include hydroxychloroquine at all: two.

Didn't identify what the results were for hydroxychloroquine: two. This number is being generous. Several more studies did not make clear what drugs were included in the hydroxychloroquine group versus control.

The authors state clearly that hydroxychloroquine was not shown to be effective: ten.

Studies with confidence intervals that negate a clear result: nineteen. 

Studies that mix hydroxychloroquine with a second drug or third drug (or more) as part of the protocol: fourteen. 

Many of the studies had hydroxychloroquine plus a second, third, or fourth treatment. These are problematic. Did hydroxychloroquine add anything to the therapy? Is it possible that the azithromycin, for example, did all the work? There was only one study that looked at hydroxychloroquine alone, hydroxychloroquine and azithromycin, azithromycin alone, and placebo. Several of the studies did not specify how many patients were receiving hydroxychloroquine alone versus hydroxychloroquine plus other treatments.

Earlier Kennedy had made the point that the lethality of COVID had been exaggerated. On page 5 of the first chapter, he said that even for the people hospitalized: "The real number [hospitalizations due to COVID] was less than one percent."

So what numbers does he show in his studies where hydroxychloroquine is cited as an early intervention (and not an intervention among those already hospitalized or critical)? There were twelve studies cited in the above table that had death as an outcome and which provided the numbers studied. (Excluding Bernabeu-Wittel (no totals to calculate percentage) and the study with the obtuse outcome of hospitalization/death). The control groups had the following as percent lethality: 

40.0%, 2.9%, 3.4%, 9.1%, 26.4%, 4.5%, 53.3%, 1.5%, 25.6%, 1.5%, 1.3%, 0.5%. 

Four studies had a death rate of over 25% among controls including one with over 50%. What the hell was going on in those studies?

Continued with a look at the book itself. 

Martin Hill Ortiz is a professor of pharmacology and author of several novels. 

My new novel, The Missing Floor, is now available from Oliver-Heber books. 

The Missing Floor, now available

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Robert F. Kennedy's book on "The Real Anthony Fauci." Hydroxychloroquine, Part Two

 

 There has been a long interval between my last post and this one. I apologize. I have been very busy.

In this series of critiques of Robert F. Kennedy, Jr.'s book "The Real Anthony Fauci: Bill Gates, Big Pharma, and the Global War on Democracy and Public Health," I left off discussing hydroxychloroquine.

Hydroxychloroquine in Perspective

RFK, Jr. puts forward a dizzying number of treatments for COVID. I counted 28 in his book, but it was a bit difficult to sort out the exact number. He sometimes presents the same treatment by different names as though each were different treatments. Although Kennedy included anti-stomach-acid agents, tea, IV hydrogen peroxide, intramuscular ozone, various vitamins, an antigout agent, an antidepressant, etc., he focused on two particular drugs: ivermectin and hydroxychloroquine. Having discussed ivermectin, a relatively safe compound that is not effective against COVID, I went on to discuss the safety issues and in vitro efficacy of hydroxychloroquine, concluding that hydroxychloroquine is a relatively unsafe drug that does have an in vitro effect against COVID viral replication in concentrations similar to those when it is given for other diseases. 

As I've noted before, Kennedy's book does not have page numbers, so the following citations come from my own hand-numbering. 

In Chapter One, on page 6, Kennedy said something honest, seemingly by accident. He says, "During the centuries that science has fruitlessly sought remedies against coronavirus (aka the common cold), only zinc has repeatedly proved its efficacy in peer reviewed studies." 

Getting beyond the strange notion that Kennedy thinks the coronavirus equals the common cold, he does point out that finding effective antivirals is really, really difficult. 

Contrast the above to the statement to this one, page 21. "Some 200 peer-reviewed studies by government and independent researchers deem HCQ [hydroxychloroquine] safe and effective against Coronavirus [sic], especially when taken prophylactically or when taken in the initial stages of illness along with zinc and Zithromax." Wait a moment, there are lots of peer-reviewed studies that point to a drug works against coronavirus?

He made the above claim at the time of his book being published in October 2001. On page 22, he presents a chart that he says demonstrates that out of 32 studies of hydroxychloroquine, 31 showed benefit. 

As with many presentations in Kennedy's book, there is the problem of having so many things wrong that it is hard to pick and choose what to focus on. Either I'm going to sound like I'm picking on everything, or else that I am implicitly saying, "other than this," it is fine. I've written a lot in my critiques of Kennedy's book so far. I probably could write ten times as much. However, since this table is so full of garbage, I will address it detail.

Chart presented on page 22 of RFK's book

So, he says 31 out of 32 studies showed benefits. That is not what his chart shows. Outcomes are presented with uncertainties (confidence intervals or [CI] as presented in the table). The range of uncertainty is presented as a horizontal line. When a particular line cross the odds ratio mark of one, that means that particular study could not say that the drug worked better than placebo or compared treatment. That degree of uncertainty takes place in 18 of the studies. An extreme is the study by Guérin which has a confidence interval of 0.02 to 9.06 which at the high extreme says treatment could be nine times worse than non-treatment. Only eight of the studies are noted to be randomized controls. Of these, only one has a confidence interval range below one, making the case that hydroxychloroquine doesn't work.

There are a lot more problems with the interpretation of the data. 

1. These are not all the studies of early treatment with hydroxychloroquine. They are not all peer-reviewed.
2. He mixed outcomes. Some refer to hydroxychloroquine in preventing death, some hospitalization, some progression, some viral positive, etc. These are unique and interesting questions that deserve their own analyses. Drugs can work in prophylaxis but not in treatment. You cannot just mash the results together. Often these studies looked at more than one thing. Kennedy only reports one in the table. 
3. In two of the studies there are a total of five controls. You can't get serious results from such a thing. Five more studies have less than 20. 
4. Six of the studies list the hydroxychloroquine dose as n/a, "not available." What kind of study leaves out dosing information from their publications?
5. A huge problem is that many of these studies are combination therapies. Analyzing combination therapies is a very thorny issue. Among other problems: did the hydroxychloroquine plus azithromycin show effectiveness because of the hydroxychloroquine, the azithromycin, or did you need both? Is it possible that the second drug made the combination worse than one drug alone? He says that zinc works against coronavirus. Is the zinc component doing all the work?

Since Kennedy regularly presents conclusions that are contrary to what is presented in the studies he cites, I decided to look at these studies in detail. I hadn't intended to look at them all, but then, once I started and founded study after study to be problematic, I kept on going. Some of the critiques are moderate. Some are jaw-dropping. For example, one study didn't look at hydroxychloroquine. Others weren't ever published in journals. 

Here's Looking at the Studies, Part One.

First one. Gautret. Retracted. 

Second one. Huang. Randomized clinical trial! However, this study doesn't examine hydroxychloroquine. It does have 22 patients divided into chloroquine and a second drug group, lopinavir/ritonavir. It provides several outcomes, including becoming virus results turning negative which interestingly, at 12 days had chloroquine tied with the second drug group with an ~80% success rate. Strangely, the lopinavir/ritonavir group had only a 50% discharge rate in spite of 80% being viral negative.

From Huang, et al. Only the hospital discharge data was dramatically different.

Third one. Esper. Never published, so how it is referred to as "peer-reviewed" is questionable. Maybe the peers did review it and rejected it. The study does not look terrible, but it did make the major mistake of defining those in the control group as those who refused the hydroxychloroquine plus azithromycin treatment. Allowing a control group to self-select is open to bias.

Fourth one. Ashraf. The RFK table says that 10 out 77 treated with hydroxychloroquine died while 2 out of 5 not treated with hydroxychloroquine died. I don't know how they got those figures out of the study. The study had a total of 100 patients with 94 receiving hydroxychloroquine. Further complicating interpretation is that 100% received oseltamivir (an anti-flu antiviral), and 60% received lopinavir/ritonavir (typically used for HIV). There were numerous other drugs. The authors note that azithromycin did not improve outcome. Worrisomely, three patients died during the 14 day follow-up to the study. "Of the 70 discharged patients, 40% had symptom aggravation, 8.6% were readmitted to the hospital, and three patients (4.3%) died." No information on their therapy.

Fifth one. Huang. I could find only one COVID hydroxychloroquine study published in the years 2020-21 with Huang as the first author. It showed a 44% increase in the death rate for those taking hydroxychloroquine-azithromycin to treat COVID (15.0% in the treatment group, 10.4% in the control group.)  Update: While I had searched for Huang studying hydroxychloroquine, Kennedy had referenced a study a Huang study of COVID and chloroquine. Chloroquine is not the same drug. 

Sixth one. Guérin. This study looked at control versus azithromycin versus azithromycin plus hydroxychloroquine. The control group had one death, an eighty-two year old man. Only 58% of the study participants were confirmed to have COVID. Hydroxychloroquine plus azithromycin did not perform better than azithromycin alone (p = 0.26).

Seventh one. Chen. As Kennedy's table says, Chen's study examined 30 patients. RFK identifies viral time as the outcome. The results were not favorable for hydroxychloroquine. "On day 7, COVID-19 nucleic acid of throat swabs was negative in 13 (86.7%) cases in the HCQ group and 14 (93.3%) cases in the control group (P>0.05)." The hydroxychloroquine group had more adverse effects, but the overall study size was small. (Being a common name, there is a study by another Chen of hydroxychloroquine and COVID in 2020, but that involved 61 patients, so it is not the one Kennedy is citing.)

Eighth one. Derwand. A total of 141 patients with confirmed COVID were treated with zinc, low-dose hydroxychloroquine, and azithromycin. Their outcomes were compared to 377 matched controls from the community. One death occurred in the treatment group and thirteen in the control group. All of this sounds impressive and I would have given this study the first thumbs up among the ones I've reviewed so far, except that the senior author is Zelenko, who well before this study made outrageous claims for his triple therapy. The fact that this is a retrospective study and has much fewer numbers than his previous reports (500 patients treated with 100% success rate) which involved treating people without ethical review board permission suggests that he is selecting his data.

Ninth one. Mitjà. His study looked at hydroxychloroquine in patients with mild COVID. As he concluded: "In patients with mild COVID-19, no benefit was observed with HCQ beyond the usual care."

Tenth one. Skipper. He had similar conclusions as did Mitjà: "Conclusion: Hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19." I don't know how Kennedy got the numbers he reported. They're different from those in the paper.

Eleventh one. Hong. You may have already noticed that in the columns treatment and control, sometimes Kennedy includes both total numbers and how many of those fit the outcomes (for example, for Skipper, 5/231 (treatment) and 8/234 (control)). In six instances, Kennedy just gives single numbers not providing what they mean. For Hong he lists viral positive as the outcome and 42 (treatment) and 48 (control). So what did the study do? They recruited 100 patients: 92 were treated with lopinavir/ritonavir, 90 were treated with hydroxychloroquine, and 22 were treated with dexamethasone. This means the large majority received both lopinavir/ritonavir AND hydroxychloroquine. How do you get 48 controls from that? And what does it mean to be a control? Viral shedding after 30 days was the endpoint of this study. The study did come to the conclusion that hydroxychloroquine was the only variable associated with protection, however Kennedy's presentation of the numbers is questionable.

Twelfth one. Bernabeu-Wittel.  This study looked at a wide range of interventions. "Ten key processes and interventions were established (provision of informatics infrastructure, medical equipment, and human resources, universal testing, separation of "clean" and "contaminated" areas, epidemiological surveys, and unified protocols stratifying for active or palliative care approach, among others)." As you may note in the above hydroxychloroquine treatment was not a main focus. In Kennedy's table it lists deaths as the end point with 189 deaths in the treatment section and 83 in the control. I cannot figure out how they got those figures or related them to those who took hydroxychloroquine in the study. The authors don't even reference hydroxychloroquine in the discussion or conclusions of their study.

Thirteenth one. Yu. According to Kennedy 1/73 died in the hydroxychloroquine treatment group versus 238/2604 in the control group. According to the Yu paper, "We found that fatalities are 18.8% (9/48) in HCQ group, which is significantly lower than 47.4% (238/502) in the NHCQ group (P<0.001)." The discrepancy between the 2604 and 502 can be relegated to the fact that they reported hydroxychloroquine treatment in only those in critical condition and all deaths came among those in critical condition. The reason for the difference between 1/73 and 9/48 is unclear.

Fourteenth one. Ly.  Ly, et al., looked at deaths in a nursing home among those testing positive for COVID with 116 receiving hydroxychloroquine/azithromycin and 110 in the control group. The patients were fairly old: with 43% of those in the treatment group being over 85 along with 56% of those in the control group. There was a dramatic difference in survival rate between women (14.0% death rate) and men (30.7% death rate). Those assigned to the drug treatment group were 60% women, this leaves unresolved whether age and gender were responsible for the better outcome for those treated. From the paper: "Through multivariate analysis, the death rate was positively associated with being male (30.7% vs. 14.0%, OR = 3.95 [1.65–9.44]; P = 0.002), aged > 85 years (26.1% vs. 15.6%, OR = 2.43 [1.04–5.69]; P = 0.041)."

Fifteenth one. Ip.  Ip, et. al., looked at patient charts to find 97 who had been treated with hydroxychloroquine and matched those with 970 who had not and then looked at outcomes. While the matching appeared studious, the hydroxychloroquine-treated patients had more significantly more comorbidities (suggesting any positive results would speak favorably for hydroxychloroquine). While a significant effect on death was not found (p = 0.578), when age was taken into account, they concluded that hydroxychloroquine lowered hospitalization rates (p = 0.045). 

Sixteenth one. Heras.  Heras looked at outcomes in 100 patients in nursing homes (average age, 85). 

Treatment was varied. "As for the treatment, five categories were defined: patients who received hydroxychloroquine and azithromycin, hydroxychloroquine only, hydroxychloroquine plus another antibiotic, beta-lactam, or quinolone antibiotics, and no treatment." Although most of the numbers are unclear in the presentation, 70% of the patients received hydroxychloroquine plus azithromycin and 17% received no treatment (which the paper confusingly says includes beta-lactam or quinolone antibiotics), leaving 13% (13 patients) divided into the other categories. 

Of the whole group, 24 patients died. The paper leaves unclear exactly how many did not receive hydroxychloroquine. It does provide enough information to determine that 8 of 70 who received hydroxychloroquine plus azithromycin died. It also says that 3 of 9 of those receiving hydroxychloroquine died (presumably meaning hydroxychloroquine alone). Their table goes on to say that there were 21 untreated with 13 deaths. (The results are presented like one of those puzzles that say the man with the red hat stood behind the lady with the blue pants.) None of the results in their paper align with Kennedy's numbers in his table. 

Seventeenth study. Kirenga. He looked at 56 patients with COVID, 29 of whom received hydroxychloroquine. Nearly all who received hydroxychloroquine also received an antibiotic. Interestingly, they averaged 34.2 years old, much younger than other studies. I admire the completeness of his study, he looked into or described many cofactors. The study was conducted at two hospitals. One hospital did not prescribe hydroxychloroquine, the other prescribed it to 94% of its patients. The median hospital stay was significantly shorter for the hospital that did not prescribe hydroxychloroquine (p = 0.012). His conclusion? "Outcomes did not differ by HCQ treatment status in line with other concluded studies on the benefit of using HCQ in the treatment of COVID-19." 

It is strange that Kennedy cites Kirenga in favor of hydroxychloroquine. Kirenga conducted a second study "a randomized open label Phase II clinical trial" looking at hydroxychloroquine. His conclusions: "Our results show that HCQ 400 mg twice a day for the first day followed by 200 mg twice daily for the next 4 days was safe but not associated with reduction in viral clearance or symptom resolution among adults with COVID-19 in Uganda."

Eighteenth study. Sulaiman has not published a peer-review article on the efficacy of hydroxychloroquine. He does have this non-peer reviewed article which is referenced by Kennedy. The study compared those who received only supportive care to those who received supportive care plus hydroxychloroquine, zinc, cetirizine (an antihistamine), and acetaminophen. "The primary outcome of interest was hospital admission within 28-days of presentation. The secondary outcome of the study was a composite of ICU admission and/or mortality during the 28-day follow up period." The numbers that Kennedy references in terms of mortality are consistent with those in the document.

Sulaiman does have a peer-reviewed article on the safety of hydroxychloroquine in 2733 patients (data from the above study). Those treated were prescribed hydroxychloroquine plus zinc, acetaminophen and an antihistamine. 6.7% of treated patients experienced drug-related toxicities and 4.1% withdrew from the study due to those toxicities. 

Continued with Entry 14. 

Martin Hill Ortiz is a professor of pharmacology and author of several novels. 

His new novel, The Missing Floor, from Oliver-Heber books. 

The Missing Floor

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Continuing with reviewing Robert F. Kennedy's book on Dr. Anthony Fauci. Entry Ten

   This is my tenth entry in my critique of Robert F. Kennedy, Jr.'s book, The Real Anthony Fauci: Bill Gates, Big Pharma, and the Global War on Democracy and Public Health. My first entry is here and you can follow the links from there. Why so many entries, why so many words? It is easy to hurl out lies. Truth-telling takes more time. The next installment is here.

I had hoped to get as far as the entries on ivermectin and hydroxychloroquine in my last installment. Instead, I'll start broaching those topics here. 

Ivermectin

Ivermectin is a great drug for treating certain worm infections. Two of the discoverers were rewarded with Nobel Prizes. At the concentrations used to treat worm infections, it has low toxicity. (Nothing is completely non-toxic.) Let's look at it for treating COVID-19.

Nobel Prize winners for the discovery of ivermectin

Principle #3. Finding compounds that work against viruses is hard. Attacking viruses through pharmacology is difficult.

The whole concept of antiviral therapy is to be toxic to the virus while being much less toxic to the host (e.g., human). This concept is called selective toxicity. Ozone kills viruses. It also kills human cells. Before there were good treatments for AIDS, there were a lot of treatments that had no selective toxicity, for example, taking the blood out of the body and heating it up to the point it killed the virus. That same method also killed the white blood cells which the virus was targeting anyhow. The method was useless.

Viruses are closer to being vectors than living creatures. They are guerilla warriors. They attach to specific human cells, enter them, possess a few mechanisms (through proteins called enzymes) to make more copies of their genetic information while plundering the cell's resources (like guerilla raiders), package those copies, and break out of the cell to go on to invade more cells. That provides precious few targets to attack. Most antiviral compounds target the few enzymes the virus uses to make more viruses, or they bind to the virus in the blood (antibodies/vaccines which produce antibodies), or they block entrance into the cell. There are damned few truly good antiviral drugs, those which are effective and which do not have significant toxicities. Ivermectin has been argued to have direct antiviral actions.

To be fair, I should note, that you can contribute to the health of a COVID patient without directly attacking the virus. Vitamin D, by supporting the immune system, does this. Dexamethasone, by lowering inflammation---which can become acute and even fatal during COVID's disease course---is helpful, even though dexamethasone lowers the immune system. 

Principle #3a. When it comes to judging a novel therapy, something that has been shown to work in the laboratory seldom works in real life.

Broadly speaking, to prove the effectiveness and safety of a drug, there are three stages: in vitro, preclinical trials (animal), and clinical trials (human). Let's start by looking at ivermectin in the laboratory. In the case of examining drugs that have already been approved, safety studies have mostly been done. In rare situations, using a known drug for a new indication may run into new toxicities. It should also be stressed that, just because safety studies have been done, that doesn't make an approved compound safe. Every drug has potential toxicities. Some of them have a lot of toxicities.

In vitro, colloquially means showing a drug has an effect in a test tube. More commonly, these experiments take place in well plates. A well plate is an array of tiny depressions. Each well provides an environment to examine a set of conditions. In this setting, testing an antiviral drug requires three ingredients: human cells (which the virus infects), the virus (often at different amounts representing different degrees of exposure), and different concentrations of the treatment being examined. If the treatment works in vitro, the drug rescues the cells from viral damage or death, or else limits or prevents viral growth. At the same time, some wells have the drug (at various concentrations) without the virus to examine whether the drug is toxic to the cells. (You can always kill the virus by killing the cells.) 

For drugs that work, its effects follow a dose-response relationship: more dose, more response, and  hopefully with little to no toxicity at the effective levels. With too little drug there is no effect. With increasing amounts of drug that works you achieve a maximal effect (for example, completely stopping the virus). The response follows a curved line between no effect and maximal effect and from that you can determine the concentration which is 50% effective in inhibiting the virus. 

Each "well" is like a tiny test tube.

From viral inhibition studies, ivermectin can be determined to have an anti-COVID effect in vitro. This can be seen in the graph below. 

Ivermectin, in vitro inhibition of COVID-19 (from Caly, et. al, Antiviral Res 2020 Jun:178:104787)

From the above graph, several things stand out. One is that the concentration of the drug that inhibits 50% of viral growth (IC50) is 2.8 µM. Secondly, strangely, even 2.0 µM seems to have little effect before a very steep drop. 

So, what does 2.8 µM mean? One small problem is that these concentrations tend to get reported in two ways in literature, either as µM (or nM) or else by µg/mL (or ng/mL). The number 2.8 µM is equivalent to 2450 ng/mL. 

This study found peak concentrations of ivermectin in plasma to treat worm in infections in humans to be 60 ng/mL. Other studies are summarized here, which compares the worm-treating dose to the COVID-treating dose: "even with the highest reported dose of approximately 1700 µg/kg (i.e., 8.5 times the FDA-approved dose of 200 µg/kg), the maximum plasma concentration was only 0.28µM" (one tenth the dose needed for 50% inhibition). 

Or, it could be worse than that. There are aspects of pharmacological effect that are not covered in vitro. Ivermectin has a plasma protein binding of 93.2% (seen in plasma, not in well plates). Therefore, only 6.8% of it is available in its active concentration inside the circulatory system. Even more critical is the intracellular concentration, since the antiviral effect takes place in the cell. 

The antiviral effect in humans takes place at a concentration that is forty to several hundred times above its human worm medicine dose. This is consistent with a general truth: in vitro effects rarely carry over to therapeutic effects in humans. 

Principle #4. Bad science does get published. Sometimes in respectable journals.

Principle #4a. Over time, good science tends to win out. Why the delay? Because good science is slow.

Bad science gets published, quite often in marginal journals. Some science journals exist solely to make money and have no regard for science integrity. "Scandals" pop up from time to time when scientists, seeking to expose such journals, send in joke articles that would be clearly rejected if anyone competent at the journals bothered only to read it. 

An extreme example of this was a scientist who sent off and had published an article that claimed, among other things, that the state New Mexico was part of the Galapagos Islands. Co-authors of the paper were claimed to be the Breaking Bad characters, Walter White and Jessie Pinkman. 

Being published is not the hallmark of being proven good. This makes it difficult for the non-scientist consumer (and for scientists as well) to evaluate the worth of a published scientific claim. 

While sometimes the claims that a bad treatment works only appears in sketchy journals. Sometimes good journals get things wrong. I have already discussed ivermectin in vitro. Here, I will go into clinical trials in humans.

One review in favor of the efficacy of ivermectin for the treatment of COVID-19 was published in the American Journal of Therapeutics, the first author being Pierre Kory, a strong advocate for ivermectin treatment. This paper was in a form of review called a meta-analysis. This sort of analysis combines the data from previous papers to see how they support or conflict with one another and what conclusion can be derived from those studies.

The review in American Journal of Therapeutics and its conclusions were brought into question nearly immediately. The review included unpublished studies (or "preprints," that are made available to read, but not yet approved for publication), eight in all. It included studies where the subjects did not provide prior consent. 

Using preprint articles is risky. Sometimes such papers never get published because they have fundamental flaws. The largest study, in terms of numbers of participants (Elgazzar, et al.), used in Kory's paper was unpublished and later retracted. Among its many problems, "The authors claimed they conducted the study between the 8th of June and 20th of September 2020, however most of the patients who died were admitted into hospital and died before the 8th of June according to the raw data." And "The main error is that at least 79 of the patient records are obvious clones of other records." Another study by Niaee, et al., was called into question for unrealistic data. A third study by Khan was called into question. 

The flaws in these studies are often uncovered by "science police." These are a network of scientists who review studies to ensure that they were properly done. Sometimes they find outright fraud. Eleven ivermectin studies are among the 461 (at the time of writing this) COVID papers that have been retracted. One study was withdrawn after its author admitted that, instead of COVID results, he had accidentally analyzed data from a file used to teach students statistical analyses. A science watch group, Retraction Watch has listed two of Kory's meta-analyses under their category of "Expressions of Concern" due to relying on specious studies, including the American Journal of Therapeutics meta-analysis.

Dr. Kory went on to write a book "The War on Ivermectin: The Medicine That Saved Millions and Could Have Ended the COVID Pandemic."

His book cover has that same design aesthetic as does Kennedy's. 

Cochrane reviews are sort of the "gold standard." They maintain high standards as to what studies are included in their reviews/analyses. While the Kory meta-analysis came out in May, 2021 and included 24 studies, Cochrane first came out in July, 2021 and found 14 studies that met their criteria. Drawing results from these were difficult because they (quite rightly) examined different questions. Was ivermectin good for prophylaxis? Was it useful for inpatient care? Was it useful for outpatient care? The paper came to the conclusion: "Based on the current very low‐ to low‐certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID‐19. The completed studies are small and few are considered high quality."

Cochrane made a follow-up review in June, 2022. Unfortunately, more time resulted in fewer studies being included. "We excluded seven of the 14 trials included in the previous review version; six were not prospectively registered and one was non‐randomized. This updated review includes 11 trials with 3409 participants investigating ivermectin plus standard of care compared to standard of care plus/minus placebo."

This time their conclusions were more brutal. "For outpatients, there is currently low‐ to high‐certainty evidence that ivermectin has no beneficial effect for people with COVID‐19. Based on the very low‐certainty evidence for inpatients, we are still uncertain whether ivermectin prevents death or clinical worsening or increases serious adverse events, while there is low‐certainty evidence that it has no beneficial effect regarding clinical improvement, viral clearance and adverse events. No evidence is available on ivermectin to prevent SARS‐CoV‐2 infection."

Note: Cochrane Reviews is notoriously rigorous in their analyses. It is hard to impress them. 

Kennedy's book has tables for three outcomes: prophylaxis, early treatment, and mortality. They list a total of 38 studies. All but one shows marked improvement using ivermectin. He almost entirely excluded studies that showed no effect or ambiguous results.

Kennedy's book goes on to interview Andrew Hill who had his own study about ivermectin retracted. 

A 2024 meta-analysis in International Journal of Antimicrobial Agents that looked at ivermectin in 7035 non-hospitalized patients came to the conclusion "In non-hospitalized COVID-19 patients, ivermectin did not have effect on clinical, non-clinical or safety outcomes versus controls. Ivermectin should not be recommended as treatment in non-hospitalized COVID-19 patients."

So, how to sort things out? The principle applies: good science is slow. That's because good science is rigorous. Bad science is slapdash. Maintain a high degree of skepticism until confirmatory work is done. But how will we know if the confirmatory work is true? This is difficult. Learning to sort the good from the bad can be done, but it often requires a lot of expertise that takes years to hone. As I have mentioned, there are watchdog groups in science who look for bad science. They are usually driven by a desire for integrity in science. Unfortunately, even experts make mistakes. Drugs get approved that shouldn't have been. 

To some extent this is related to a general problem we are faced with the dilemma of modern day life. Things out there are so complex that we have to rely on experts. How to sort out which experts to trust is a topic that is too long to cover here. People who claim to be experts are often self-described experts. (I used to go around proclaiming the cynical quote: "The bad news: the experts are always wrong. The really bad news: we're the experts.")

Continued with a summary of the most jaw-dropping quotes.  

Martin Hill Ortiz is the author of several novels including most recently the thriller, Floor 24. 

Floor 24
Oliver-Heber Books

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Robert F. Kennedy, Jr.'s Book on Fauci. A look at alternative drugs.

  This is my ninth entry in my critique of Robert F. Kennedy, Jr.'s book, The Real Anthony Fauci: Bill Gates, Big Pharma, and the Global War on Democracy and Public Health. My first entry is here and you can follow the links from there. Why so many entries, why so many words? It is easy to hurl out lies. Truth-telling takes more time.

A Multitude of Drugs

Two basic problems with this book, as I've already mentioned, are the lack of page numbers and the lack of attaching specific citations at the end of the chapters to specific statements in the book. It seems as though the book was self-published and unedited. 

One reason I skip over commenting on some individual claims by Kennedy, is that he makes many remarkable assertions and provides no sources: nothing that matches up to the citation list at the end of the chapters. These include quoting people, statistics, and studies he refers to.

A good example of this begins on page 10 of Chapter One. (I self-numbered the pages out of frustration.) A statement is made regarding the percentage of deaths that occurred in nursing homes. Referring to the citations at the end of the chapter, this corresponds to two references, numbers 45 and 46. Good. Skip over two pages and the next reference that can be attached to the claims about drugs/treatments is on page 13. It refers to the use of hyperbaric chambers in the treatment of COVID. Very specific and matches up to reference numbers, 48 and 49. This leaves at least two pages without any reference beyond number 47 which references the FLCC Alliance, mentioned on page 11. 

No references are provided for a multitude of assertions in those two pages, including the effectiveness of many, many compounds that are said to treat COVID. Several of the compounds he has already brought up: hydroxychloroquine, ivermectin, zinc, and vitamin D. Others he lists in a dizzying rap. "Monoclonal antibodies work great" [no they didn't], azithromycin, doxycycline, Celebrex (brand name for celecoxib), bromhexine, NAC (n-acetylcysteine---he also lists "glutathione precursor" which is NAC), IV vitamin C (for God's sake, why stick a needle in someone's arm to give them vitamin C?), quercetin, colchicine (which he strangely capitalizes, he capitalizes several generic drug names), aspirin, fluvoxamine (a pretty serious drug with lots of interactions), and famotidine (he also lists Pepcid separately, a brand of famotidine). These are just the compounds listed before he gets around to providing his next reference, which refers to mouthwashes. 

He promotes a whole variety of mouthwashes/nasal irrigants, including povidone iodine, hydrogen peroxide, hypochlorite, Listerine, and cetylpyridinium chloride. He provides a single footnote reference for this which links to an article that asks the question: Did viral rinsing help ASEAN control pandemic or swift action? (an article in the newspaper: India Today) The nasal rinsing study it cites took place in 2019, before COVID.

Some drugs he goes on to name make a limited amount of sense. Dexamethasone had been approved for treating COVID and it is virtually interchangeable in action with the ones he mentions, prednisone, budesonide, and hydrocortisone. (They are also rather toxic and should be reserved for severe cases. One of their toxicities is to lower the immune system. Dexamethasone is chosen because it is longer acting.)

IV Peroxide and Ozone and Other Interventions

This next part comes at the top of a page. As I read it, I thought, I must have skipped ahead as I turned pages. This sounded like satire or else that it must have been introduced with the phrase, "They accuse of us doing ridiculous things like . . ."

Dr. David Brownstein of Detroit. "'We've been treating viral diseases here for twenty-five years, COVID can't be any different.' In all that time, our office had never lost a single patient to flu or flu-like illness. We treated people in their cars with oral vitamins A, C, and D, and iodine. We administered IV solution outside all winter with IV hydrogen peroxide and vitamin C. We'd have them put their butts out the car window and shot them up with intramuscular ozone." (All winter is a strange statement. He published his article in July 2020 and COVID wasn't around for the winter before that.)

IV hydrogen peroxide and intramuscular ozone echo the claim that then President Donald Trump recommended injecting bleach to treat COVID. To be fair, Trump phrased it as a question.

Dr. Brownstein, along with his medical degree, is a graduate of the Desert Institute of Classical Homeopathy. He went on to describe his persecution for his work. "I've been in litigation with the Medical Board for about a year." This is followed by: "In July 2020, Brownstein and his seven colleagues published a peer-reviewed article describing his stellar success with early treatment. FTC sent him a letter warning him to take it down." Brownstein's article is not referenced in Kennedy's citations, but it is not too difficult to find. It was published in Science, Public Health Policy, and The Law, a journal that is directed to health policy rather than clinical studies. 

Brownstein described how he obtained his study participants. "For the calendar year of 2020, charts were retrospectively reviewed for the presence of COVID-19 diagnosis occurring from February 2020 through May 2020." February? The first case of COVID-19 in Michigan came on March 10, 2020. Furthermore, he said he retrospectively reviewed charts for his study but also said he had informed consent which, ethically, should have taken place before treatment.

Brownstein alluded to his jabbing the rear ends of his patients through their car windows in his manuscript. "Since we were only treating COVID-19 patients outside the office in the parking lot, intramuscular injections of ozone were deemed the easiest and safest modality."

Dr. Brownstein has published several books. Among the uses of ozone therapy he includes cancer, fatigue, infections, autoimmune diseases, and arthritis.

Kennedy goes on to cite a few more drugs and categories of drugs, mostly without references to support them. This seems to be a general strategy of Kennedy's. He seems to think that dozens of unsupported arguments are more impressive that a small number of supported arguments. 

On page 14, Kennedy says, "By that time [fall 2020], more than 200 studies supported treatment with hydroxychloroquine and 60 studies supported ivermectin." He provides no citation to support these numbers. Reviews and meta-analyses of the time don't cite so many studies. This is a good segue to examining ivermectin and hydroxychloroquine.

Let's Look at Ivermectin.

Ivermectin is a great drug for treating certain worm infections. Its discovery was rewarded with a Nobel Prize. At the concentrations used to treat worm infections, it has low toxicity. (Nothing is completely non-toxic.) Let's look at it for treating COVID-19.

Principle #3. Finding compounds that work against viruses is hard. Attacking viruses through pharmacology is difficult.

The whole concept of antiviral therapy is to be toxic to the virus while being much less toxic to the host (e.g., human). This concept is called selective toxicity. Ozone kills viruses. It also kills human cells. Before there were good treatments for AIDS, there were a lot of treatments that had no selective toxicity. One infamous example, taking the blood out of the body and heating it up to the point it killed the virus. That same method also killed the white blood cells which the virus was targeting anyhow. The method was useless.

Viruses are closer to being vectors than living creatures. They are guerilla warriors. They attach to specific human cells, enter them, possess a few mechanisms (through proteins called enzymes) to make more copies of their genetic information and viral shells while plundering the cell's resources (like guerilla raiders), package those copies, and break out of the cell to go on to invade more cells. That provides precious few targets to attack. Most antiviral compounds target the few enzymes the virus uses to make more viruses, or they bind to the virus in the blood (antibodies or vaccines which produce antibodies), or they block entrance into the cell. There are damned few truly good antiviral drugs, that is, those which are effective and which do not have significant toxicities. Ivermectin has been argued to have direct antiviral actions.

To be fair, I should note, that you can contribute to the health of a COVID patient without directly attacking the virus. Vitamin D, by supporting the immune system, does this. Dexamethasone, by lowering inflammation---which can become acute and even fatal during COVID's disease course---is helpful, even though dexamethasone lowers the immune system. 

Principle #3a. When it comes to judging a novel therapy, something that has been shown to work in the laboratory seldom works in real life.

Broadly speaking, to prove the effectiveness and safety of a drug, there are three stages: in vitro, preclinical trials (animal), and clinical trials (human). Let's start by looking at ivermectin in the laboratory. In the case of examining drugs that have already been approved, safety studies have mostly been done. In rare situations, using a known drug for a new indication may run into new toxicities. It should also be stressed that, just because safety studies have been done, that doesn't make an approved compound completely safe. Every drug has potential toxicities, some of them have a lot of toxicities.

In vitro, colloquially means showing a drug has an effect in a test tube. More commonly, these experiments take place in well plates. A well plate is an array of tiny depressions. Each well provides an environment to examine a set of conditions. In this setting, testing an antiviral drug requires three ingredients: human cells (which the virus infects), the virus (often at different amounts representing different degrees of exposure), and different concentrations of the treatment being examined. If the treatment works in vitro, the drug rescues the cells from viral damage or death, or else limits or prevents viral growth. At the same time, some wells have the drug (at various concentrations) without the virus to examine to what degree the drug is toxic to the cells. (You can always kill the virus by killing the cells.) 

For drugs that work, its effects follow a dose-response relationship: more dose, more response, and  hopefully with little to no toxicity at the effective levels. With too little drug there is no effect. With increasing amounts of drug that works you achieve a maximal effect (for example, completely stopping the virus). The response follows a curved line between no effect and maximal effect and from that you can determine the concentration which is effective in inhibiting 50% of the virus. 

Each "well" is like a tiny test tube.

Ivermectin has an anti-COVID effect in vitro. This can be seen in the graph below. 

Ivermectin, in vitro inhibition of COVID-19 (from above cited article).

From the above graph, several things stand out. One is that the concentration of the drug that inhibits 50% of viral growth (IC50) is 2.8 µM. Secondly, strangely, even 2.0 µM seems to have little effect before a very steep drop. 

So, what does 2.8 µM mean? One small problem in interpretation is that these concentrations tend to get reported in two ways in literature, either as µM (or nM) or else by µg/mL (or ng/mL). For ivermectin, the number 2.8 µM is equivalent to 2450 ng/mL. 

This study found peak concentrations of ivermectin in plasma to treat worm in infections in humans to be 60 ng/mL. Other studies are summarized here, which compares the worm-treating dose to the COVID-treating dose: "even with the highest reported dose of approximately 1700 µg/kg (i.e., 8.5 times the FDA-approved dose of 200 µg/kg), the maximum plasma concentration was only 0.28µM" (one tenth the dose needed for 50% inhibition). 

Or, it could be worse than that. There are aspects of pharmacological effect that are not examined in vitro. Ivermectin has a plasma protein binding of 93.2% (seen in plasma, not in well plates). Therefore, only 6.8% of it is available in its active concentration inside the circulatory system. Even more critical is the intracellular concentration, since the antiviral effect takes place in the cell. 

The antiviral effect in humans takes place at a concentration that is forty to several hundred times above its human worm medicine dose. This is consistent with a general truth: in vitro effects rarely carry over to therapeutic effects in humans. Contrary to Kennedy's galloping list of compounds, a good drug is hard to find.

Continued with clinical studies of ivermectin.

Martin Hill Ortiz is the author of several novels including most recently the thriller, Floor 24. 

Floor 24
Oliver-Heber Books

"From the mob underworld to the tops of new skyscrapers, Floor 24 is a heart-thumping New York 1920's historical mystery!" - Holly Newman, bestselling author of A Chance Inquiry mystery series

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