Sekali lagi Dr Syihabuddin (Din Kapak Abdullah mencabar saya menjawab persoalan yang beliau keliru. Sebelum ini Syihabuddin mintak nyawa dengan Prof Madya Mohd Makmor dan Prof Madya Ernieda. Sekarang mintak nyawa dengan Dr Normala pula untuk cuba menegakkan benang yang basah.
The above is Syihabuddin’s response to my blog plost: Menjawab kekeliruan Dr Syihabuddin berkenaan kajian in vitro Kumar (Netherlands)
Hydroxycholoroquine (HCQ) vs Ivermectin (IVM)
Merujuk kepada status Facebook Syihabuddin, sebelum ini saya sudah terangkan kepada beliau bahawa the mechanism of hydroxycholoroquine dan ivermectin tidak sama, namun beliau masih tidak faham. Rujuk balik blog post Menjawab Dr Syihabuddin berkenaan dos ivermectin, di mana saya telah mengulas:
Mohon Syihabuddin jangan lagi cuba mengelirukan orangramai dengan memberi gambaran seolah the properties and mechanism of HCQ and IVM adalah sama.
Berkenaan IVM pula, telah kerap kali diterangkan kepada Syihabuddin bahawa it works with the immune system. Ya, memang Syihabuddin pun boleh claim HCQ juga “works with the immune system” (kononnya) namun in the case of ivermectin specifically:
Bukan setakat itu sahaja malah ada lagi teori mechanism of ivermectin on how it works at many levels — rujuk The mechanisms of action of Ivermectin against SARS-CoV-2: An evidence-based clinical review article.
Berkenaan kajian Vallejos cherry-picked by Syihabuddin, refer to the following response:
RCT with 501 relatively low-risk outpatients in Argentina showing hospitalization OR 0.65 [0.32-1.31]. With only 7% hospitalization, this trial is underpowered. The trial primarily includes low-risk patients that recover quickly without treatment, leaving minimal room for improvement with treatment. 74 patients had symptoms for >= 7 days and more than 25% of patients were hospitalized within 1 day (Figure S2). Among the 7 patients requiring ventilation, authors note that the earlier requirement in the ivermectin group may be due to those patients having higher severity at baseline. However, authors know the answer to this – it is unclear why it is not reported. There were more adverse events in the placebo group than the ivermectin group, suggesting a possible issue with dispensing or non-trial medication usage.
The companion prophylaxis trial [Vallejos], which reported more positive results, has not yet been formally published, suggesting a negative publication bias.
Authors pre-specify multivariate analysis but do not present it, however multivariate analysis could significantly change the results. Consider for example if just a few extra patients in the ivermectin group were in severe condition based on baseline SpO2. The lower mean SpO2 in the ivermectin group, and the shorter time to ventilation, are consistent with this being the case. Additionally, there are 14% more male patients in the ivermectin group.
An extremely large percentage of patients (55%) were excluded based on ivermectin use in the last 7 days. However, ivermectin may retain efficacy much longer (for example antiparasitic activity may persist for months [Canga]). A significant number of patients may also misrepresent their prior and future usage — the population is clearly aware of ivermectin, and patients with progressing disease may be motivated to take it, knowing that they may be in the control group. Another report states that 12,000 patients were excluded for recent use of ivermectin [scidev.net]).
RCTs have a fundamental bias against finding an effect for interventions that are widely available — patients that believe they need treatment are more likely to decline participation and take the intervention [Yeh], i.e., RCTs are more likely to enroll low-risk participants that do not need treatment to recover (this does not apply to the typical pharmaceutical trial of a new drug that is otherwise unavailable). This trial was run in a community where ivermectin was very widely known and used.
Source: Ivermectin study #105 of 121 – c19ivermectin.com
In other words, the Vallejos study is biased and unreliable. Syihabuddin should look at the totality of evidence as I had mentioned in my previous post. Like I said a couple of times before, Syihabuddin likes to cherry-pick stones while ignoring the mountain — evidently he still doesn’t get it.
Vero cells vs Calu-3 vs Lung alveolar cells
Secara ringkasnya, keberkesanan IVM berbeza bagi Vero, Calu-3 dan Lung Alveolar cells. Ini yang Syihabuddin dan Dr Normala mesti faham. It is a scientific and medical fact. Now let’s have a look at Dr Normala’s response:
In cell viral culture model, what matters most is whether the virus can easily infected the cells ie having the necessary receptor to allow viral entry and efficient propagation.
Vero is historically susceptible to viral infection, However, in the case of SARS-CoV2, Vero E6 produced better infection rate than normal Vero.
A group in Tokyo even developed a Vero cell clone expressing TMPRSS2 to enhance infectivity in this cell.
Ini masalahnya. Dr Normala hanya lihat kriteria infectivity — whether the virus can easily infect the cells, that the cells are susceptible to viral infection, that the cells have high infection rate. Ini mencerminkan kejahilan Dr Normala berkenaan mechanism of ivermectin — she can’t see the big picture. Of course lah the cell for the experiment must easily be infected with the virus tetapi Dr Normala langsung tidak sentuh berkenaan faktor-faktor lain yang penting sebelum membuat kesimpulan:
Saya telah kongsi maklumat lebih terperinci berkenaan Calu-3, alveolar, 15-lipoxygenase di blog post Menjawab kekeliruan Dr Syihabuddin berkenaan kajian in vitro Kumar (Netherlands). Sebagai ringkasan, saya petik fakta-fakta berikut:
– Alveolar macrophages are the most abundant innate immune cells in the distal lung parenchyma, located on the luminal surface of the alveolar space”. [Joshi et al]
– AMs [alveolar macrophages] are the main immune cells in the lung in steady-state and their function is mainly to dampen inflammatory responses. [Bissonnette et al]
– Human alveolar macrophages (HAM) are cells that may play a major role in host defense, and conversely display significant phlogistic potential… Human alveolar macrophages have 15-Lipoxygenase… [Levy et al]
– The main function of the lung is to perform gas exchange while maintaining lung homeostasis despite environmental pathogenic and non-pathogenic elements contained in inhaled air. Resident cells must keep lung homeostasis and eliminate pathogens by inducing protective immune response and silently remove innocuous particles… A large number of studies have revealed the importance of 12/15-LOX [Lipoxygenase] role in oxidative and inflammatory responses. [Singh & Rao]
Clearly Dr Normala has not considered the above factors that distinguish lung alveolar cells from Calu-3, otherwise she would have at least made mention of any of them. She only considered the infectivity of Calu-3 without understanding the mechanism of ivermectin working together with the immune system. Ivermectin inhbits the virus from docking with the cell and from replicating (which HCQ does not) plus other mechanisms of action while the immune system does the rest to eliminate the virus.
So, does it matter whether it is alveolar, bronchiole or kidney cells? It does matter
if the cells doesn’t have the specific receptor and target of the drugs. For example, if you developed a drug to inhibit Ace2, of course you wouldn’t want to grow your SARS-CoV2 in Vero cells.
Remdesivir, molnupiravir etc are antiviral with nucleoside analog as their major mechanism of action. Does it matter if you are using A549? NCI-H441? Calu3? HPMEC? 16HBE14o? BEAS-28?
And for ivermectin study, why do you think such discrepancies were reported? What is the mechanism of action of this drug to kill the virus? Or even to reduce the viral number?
Betul lah saya kata kan — Dr Normala is ignorant of the mechanism of ivermectin and how it reduces the viral load. Otherwise why is she asking? At least Dr Normala is spot on that it matters that the cells have the receptor, ACE2, but that is only relevant in the context of the virus infecting the cell and ivermectin’s role as inhibitor.
Dr Normala did not specify which studies revealed discrepancies but presumably she may be referring to conclusions by Virginia Schmith et al and Yeo et al based on pharmacokinetic model simulations. These had already been responded to. Refer to the following posts:
- Menjawab Dr Syihabuddin berkenaan dos ivermectin
- Ivermectin: Menjawab kekeliruan Dr Syihabuddin (KKM) kali ke-2
- Dr Syihabuddin’s failed attempt at proving his lie was not a lie
Nampaknya Syihabuddin pun tidak minta Dr Normala baca kertas-kertas kajian berikut sebelum memberi pandangan:
- The mechanisms of action of Ivermectin against SARS-CoV-2: An evidence-based clinical review article
- The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro
- Antivirals that target the host IMPα/β1-virus interface
Syihabuddin and his colleagues/associates have to get their head round the fact that in vitro studies cannot be used to decisively determine the therapeutic dosage of ivermectin in humans for treatment of covid-19. It is common sense that the conditions in which the virus replicates and infects the cells in vivo and in vitro differs significantly.
Also accept the fact that real world evidence shows that ivermectin is effective with dosage or toxicity not being an issue. (Refer to the section, “Studies on ivermectin” – Menjawab lagi soalan2 Dr Syihabuddin (Din Kapak Abdullah) yang tidak berkesudahan).
Just get on with saving lives with ivermectin based protocols instead of falsely claiming it is ineffective through misguided mathematical calculations and cherry-picking inconclusive laboratory experiments.
– AA –