Ivermectin: Menjawab kekeliruan Dr Syihabuddin (KKM) kali ke-2

Posting #1 (AA). Asalnya saya menulis di Facebook: IS IT TRUE HIGH DOSAGE OF IVERMECTIN IS REQUIRED FOR EFFECTIVENESS?

Posting #2 (DS). Dr Syihabuddin kemudian menjawab: Menjawab Azmi Arshad II Isu Dos Ivermectin

Posting #3 (AA). Saya kemudian menjawab balik: MENJAWAB DAKWAAN DR SYIHABUDDIN BERKENAAN DOS IVERMECTIN di Facebook. Juga boleh baca di blog ini.

Posting #4 (DS). Dr Syihabuddin kemudian menjawab balik: Menjawab Azmi Arshad Siri 2

Respons Dr Syihabuddin tidak mengandungi sebarang ulasan saintifik kenapa penjelasan yang saya telah beri dalam Posting #3 (AA) adalah tidak tepat atau tidak saintifik. Orangramai boleh menilai sendiri jawapan beliau tersebut di atas — did Dr Syihabuddin educate you or is he trying to confuse you?

In summary, his response is merely (i) bare denial or wilful ignorance of the scientific rationale that had been provided, (ii) a regurtitation of his original claim based on his continued misunderstanding of the results of Caly et al’s in vitro study, (iii) empty rhetoric, and (iv) ad hominem remarks in his conclusion. Some days ago he then made further remarks:

Introduction

Let’s go through the whole of his post but it is very important to first understand the following key facts, which were neglected or deliberately ignored by Dr Syihabuddin:

(i) The properties of vero/hSLAM cells (monkey kidney cells) and human lung cells are vastly different vis-a-vis when someone is infected with covid, concentration of ivermectin and the immune system response (but Dr Syihabuddin doesn’t seem to know the difference);

(ii) In Caly et al’s in vitro study, they used 5 µM of ivermectin onto vero/hSLAM cells. Had it been lung cells, the quantity required would be much less than 5 µM (but Dr Syihabuddin doesn’t seem to know the difference);

(iii) Caly et al deduced that, for vero/hSLAM cells, the IC₅₀ would be 2 µM. (The IC₅₀ is the concentration of drug, e.g. ivermectin, required for 50% inhibition). The 2 µM is relevant for only vero/hSLAM cells, not human lung cells. For lung cells (which were not available at the time of the experiment), the IC₅₀ would be much lower, which is an indisputable scientific and medical fact (but Dr Syihabuddin doesn’t seem to know the difference);

(iv) Refer to Posting #3 (AA) to understand how ivermectin works and why it is effective even with less than 1:1 drug to virus ratio — look at the schematics especially. (But Dr Syihabuddin doesn’t seem to know this).

Now let’s address all parts of Dr Syihabuddin’s responses. I have divided his Facebook post into 6 sections (I – VI). There will inevitably be repetitions of facts and explanations in response to each section so please bear with me.

Section I

Dr Syihabuddin kata:

2. Terima kasih kerana membalas jawapan saya, boleh rujuk jawapan tuan Azmi¹. Saya dapati Tuan Azmi tidak mengulas pengiraan saya dan tidak mengulas pengiraan VD Schmitz terhadap kajian Caly. Daripada ulasan panjang beliau, apa yang saya nampak premis utama beliau menolak penjelasan saya adalah beliau mendakwa kajian Caly menggunakan tisu monyet, bukan tisu manusia, kajian VD Schmitz pula adalah pengiraan menggunakan pharmacokinetic formula. Tidak ada jawapan balas direct yang mengatakan pengiraan saya dan VD Schmitz salah, saya tak jumpa.

Saya tulis panjang lebar, dengan bagi gambarajah2 lagi, itu pun Dr Syihabuddin tak faham. He still could not get the picture. Orang awam faham dan saya rasa doktor2 lain pun faham tapi doktor KKM tak faham. Kalau tak mampu faham, jangan jadi doktor. Kalau faham tapi buat2 tak faham, jangan jadi doktor tetapi boleh jadi motivational speaker ajar orang bagaimana nak mengelak, berbelit dan kelentong.

(i) “tisu monyet, bukan tisu manusia”: Sekali lagi Dr Syihabuddin cuba mengelirukan orangramai. It’s not about MONKEY tissue vs HUMAN tissue. Bukan sekadar tisu monyet vs tisu manusia tapi monkey KIDNEY cell vs human LUNG cell. Sebagaimana diulas, the human lung cell will easily have much higher concentration of ivermectin compared to a monkey kidney cell. Bermakna manusia tidak perlu telan dos 10x atau 32x ganda dos biasa ivermectin untuk mencapai tahap konsentrasi berkesan di paru-paru. Dr David Jans, Dr Kylie Wagstaff dan Dr Pierre Kory telah mengulas kenapa monkey kidney cell digunakan dalam kajian in vitro Caly et al ketika itu – jangan buat2 tak nampak.

(ii) “VD Schmith menggunakan pharmacokinetik formula”: Ini isu kecil, bukan premis utama. It is merely an accuracy issue, not a fundamental issue. This is further elaborated towards the end of this article.

(iii) “Pengiraan 32x oleh Dr Syihabuddin:” Dr Syihabuddin kata: “Tidak ada jawapan balas direct yang mengatakan pengiraan saya dan VD Schmitz salah, saya tak jumpa.” Pertama, saya tidak pernah kata pengiraan VD Schmith salah. Dr Syihabuddin keliru atau membohong. Tujuan kajian VD Schmith bukan untuk dapatan 32x ganda dos biasa tetapi untuk predict samada ivermectin berkesan dengan menggunakan dos biasa (bukan 32x ganda dos seperti didakwa oleh Dr Syihabuddin). Dr Syihabuddin hanya syok sendiri dengan pengiraan 32x beliau yang budak sekolah pun boleh buat. This is further elaborated towards the end of this article.

Keduanya, bermaksud Dr Syihabuddin tidak faham ulasan2 berikut dalam Posting #3 (AA):

Dr Syihabuddin menganggap ulasan-ulasan tersebut adalah “tidak fakta sains” dan hanya “denial“. Beliau kata lah. Padahal ulasan-ulasan tersebut adalah daripada pakar-pakar perubatan/sains, bukan daripada mufti, ahli politik, mekanik atau hairdresser.

Section II

Dr Syihabuddin kata:

3. Untuk pengetahuan Tuan Azmi, dalam penentuan dos sesuatu ubat yang baru, memang perkara biasa saintis makmal akan menyiasat dos toxicity, dos berkesan dalam haiwan dahulu. Kemudiannya mereka akan melakukan penukaran dos haiwan kepada dos manusia dengan menggunakan beberapa formula juga. Tetapi ini untuk ubat atau compound yang baru.

4. Untuk ubat yang lama seperti Ivermectin, dos selamat dan toxicity manusia sudah diketahui. Anjing 10mg/kg, mice and rats 25-50mg/kg and 40-50mg/kg respectively (rujuk Merck Stromectol). Dos toxic kepada manusia pula boleh dirujuk kepada haiwan². Data yang ada daripada FDA, highest human plasma dose adalah 0.28 uM atau 1700uG/kg, ini adalah 8.5 kali ganda lebih tinggi daripada dos biasa.

Semua tu saya rasa semua orang faham. Namun apa yang Dr Syihabuddin susah sangat nak faham adalah bahawa kajian in vitro Caly et al bukan untuk menentukan dos yang berkesan tapi untuk menunjukkan ivermectin menghalang virus dari menjangkiti sel dan menghalang virus dari replicate dalam badan.

Oleh kerana sudah diketahui dos selamat bagi manusia, maka kajian2 in vivo telah dibuat dengan dos biasa, sekitar 200-400 µg/kg/dos, bukannya dengan 6,000 µg/kg/dos. Itu realitinya. Maka persoalan selanjutnya adalah samada dos 200-400 µg/kg/dos adalah berkesan. Jangan merepek lagi pasal 32x ganda dos biasa sebab tiada siapa suruh buat kajian dengan dos 32x ganda. Hanya orang bodoh telan 30 biji pil sekaligus.

Virginia et al menggunakan population pharmacokinetics model (“PK model”) untuk PREDICT samada dos biasa berkesan. Walaupun model tersebut belum pernah dibuktikan memberi pengiraan yang tepat to what extent ivermectin mencapai konsentrasi di paru-paru manusia, this is not a big issue to me. Namun, kita juga tidak tahu sepenuhnya parameters dan variables incorporated into the PK model by Virginia (Note: Virginia, Schmith, Virginia et al, Virgina Schmith will be used interchangeably).

However, we know Virginia Schmith assumed that ivermectin was taken in a fasted state (perut kosong), which would result in 2.5 times lower concentration (and Virginia is aware of this difference). Manakala ivermectin lebih berkesan bila diambil selepas makan, seeloknya selepas makan fatty meal (kalau bukan healthy high-fat meal, McDonald’s Big Mac pun okay).

Yang pasti, Virginia tidak membuat kesimpulan berasaskan kajian dengan virus covid, tisu mamalia dan ivermectin. Saya ingat Dr Syihabuddin dah faham dengan ulasan kenapa dapatan berdasarkan kajian in vitro boleh berbeza dengan hasil kajian in vivo (vis-a-vis mechanics of IVM and immune system response) tapi nampaknya Dr Syihabuddin masih keliru.

Manakala samada berkesan untuk mencegah atau merawat penyakit covid, sudah ada banyak kajian2 in vivo manusia dan observational studies. Cuma kajian2 tersebut tidak diterima oleh Dr Syihabuddin sebab beliau termasuk dalam golongan ‘Ivermectin Deniers’ sebagaimana dinyatakan dalam Posting #3 (AA). Tanpa memberi apa-apa ulasan saintifik, Dr Syihabuddin menolak ulasan-ulasan oleh Dr David Jans, Dr Kylie Wagstaff dan Dr Pierre Kory, Asiya Kamber Zaidi & Puya Dehgani-Mobaraki dan kumpulan doktor Department of Pharmacology, All India Institute of Medical Sciences.

Section III

Dr Syihabuddin kata:

5. Kenapa ivermectin bermasalah untuk Covid dalam kajian makmal:-

A. Dos yang digunakan Caly adalah terlalu tinggi, 32 kali ganda lebih tinggi daripada dos paling tinggi pernah diambil bagi individu seberat 80kg. Sepatutnya apabila kita dah tahu dos maksimum manusia 0.28 uM, maka yang afdhal adalah kita menggunakan dos yang lebih rendah seperti 0.1 uM, itu yang sepatutnya dibuat oleh Caly. Kerana kesilapan beliau, saintis daripada berbelas negara menggunakan kajian beliau sebagai rujukan ke atas kajian manusia.

B. Jawapan Caly dan ketuanya untuk menempis kononnya kajiannya tidak boleh digunakan untuk menentukan dos dalam manusia adalah denial pada saya. Awak dah buat kajian yang guna dos terlalu tinggi, awak kena bertanggungjawab. Menuduh orang lain falasi, tak menutup kesalahan awak. Tiada siapa nafikan, kajian beliau membuktikan ivermectin boleh membunuh Covid dengan berkesan but at what dose? Ini bukan sekadar persoalan saya, ini juga persoalan Prof Dr Mohd Makmor, dekan Fakulti Farmasi UKM.

From the above (A & B), there are six points I want to address:

(i) Mendakwa Caly menggunakan dos terlalu tinggi mencerminkan kejahilan Dr Syihabuddin, mungkin sebab beliau tidak membaca dengan teliti dan memahami rujukan-rujukan yang telah diberi kepada beliau. Dr Syihabuddin is referring to the 5 µM used by Caly. Persoalan “dos terlalu tinggi” tidak timbul sebab sukatan tersebut digunakan atas sel vero/hSLAM dan tidak relevan untuk paru-paru manusia. Kenapa guna 5 µM atas sel vero/hSLAM dan tidak guna sukatan lebih rendah untuk sel paru-paru? Seperti telah diperjelaskan dahulu:

Dr Syihabuddin perlu faham bahawa eksperimen in vitro Caly et al tersebut di buat pada bulan Jan/Feb tahun lepas. As explained by Dr Wagstaff, at that time the covid virus had only been isolated once,which was only a few days before they did the study so they had no choice but to use Vero/hSLAM cells (green monkey kidney cells) instead of lung cells. [Posting #3]

“Some people claim that [Caly] shows that therapeutic concentrations are not easily reached in humans. This is incorrect. The authors explain why their in vitro study cannot be used to determine the effective dose in vivo, and state that the concentration required is very unlikely to be an issue [Wagstaff]. The study used monkey kidney cells (the only choice at the time of the experiments), which lack adaptive immune responses and do not produce interferon. Authors also note that ivermectin accumulates in lung and other tissues, that subsequent experiments with lung cells show many times greater concentrations, and that the average lung concentration shown in modeling studies exceeds the effective level shown in their research. Authors note that ivermectin works with the immune system and a 1:1 ratio of drug to virus is unlikely to be required.” – ivmmeta.com

(ii) Juga, memang kajian in vitro telah kemudian dibuat dengan dos yang lebih rendah seperti diulas oleh Dr Pierre Kory, whom I quoted in Posting #3 (AA), where he said in the video: “When they repeated the experiment in lung alveolar cells, they have achieved inhibitory concentrations in alveolar lung cell models easily”. And as I said in my previous post, that study has not yet been published pending peer review, presumably to give no room for ivermectin deniers to dispute the findings and conclusion. In any case, the publication would be academic because, as also mentioned a number of times, many in vivo studies already prove that ivermectin is effective with normal oral dosage.

(iii) Hebat Dr Syihabuddin mendakwa Caly et al buat kesilapan. Ni namanya bodoh sombong. Dr Syihabuddin masih cuba mengelirukan orangramai sehingga sanggup membohong kononnya Caly buat kesilapan. Jelas sejelas-jelasnya Caly telah menyatakan dos 5 µM tersebut diguna pada sel Vero/hSLAM, iaitu monkey kidney cells, dan bukannya sel paru-paru. Caly tidak pernah mencadangkan apa-apa dos untuk manusia. Dr Syihabuddin membohong. Saintis-saintis lain pun faham:

“The in vitro potency of ivermectin against Covid-19 virus is a testimony that this drug can be utilized to manage those patients who have been infected with SARS-CoV-2. Since the conditions in which the virus replicates and infects the cells in vivo and in vitro DIFFERS, a DECISIVE COMMENT about how ivermectin may prove to be beneficial to the patients CANNOT BE CONSTRUCTED YET.” — Dhyuti Gupta, Ajaya Kumar Sahoo, Alok Singh, Department of Pharmacology, All India Institute of Medical Sciences,Raipur, Chhattisgarh, India.

“the study by Caly et al merely indicated that ivermectin was foudng to have anti-SARS-CoV-2 ACTIVITY in vitro — no more, no less.” — Asiya Kamber Zaidi & Puya Dehgani-Mobaraki

Saintis-saintis lain faham bahawa Caly tidak mencadangkan apa-apa dos untuk manusia. Dr Syihabuddin yang masih tak faham dan masih cuba menyebarkan fake news.

(iv) Let me give another example of Dr Syihabuddin’s lack of logical reasoning. Dr Syihabuddin sendiri mengatakan, “Kerana kesilapan beliau, saintis daripada berbelas negara menggunakan kajian beliau sebagai rujukan ke atas kajian manusia.” Ya, ini benar. Namun, adakah saintis-saintis tersebut membuat kajian dengan 32x dos biasa? Tidak. Mereka tidak menggunakan 32x ganda dos biasa dalam kajian mereka sebab mereka lagi cerdik dari Dr Syihabuddin. Mereka tahu 5 µM yang digunakan dan IC50 = 2 µM adalah relevan hanya untuk sel vero/hSLAM dan bukannya sel paru-paru manusia. Sekiranya mereka salah faham kajian Caly macam Dr Syihabuddin, mereka akan bagi sekurang-kurangnya 30 biji pil kepada persakit-pesakit covid-19 untuk telan sekaligus untuk dikaji kesannya.

(v) Dr Syihabuddin membuat pengiraan dan kesimpulan seolah tahap konsentrasi ivermectin dalam monkey kidney cell (Vero/hSLAM) dan sel paru2 manusia adalah sama maka beliau menetapkan 32x ganda dos untuk manusia. Ini bukan kesilapan Caly. Ini adalah kesilapan Dr Syihabuddin. Dr Syihabuddin yang menetapkan dos 32x ganda dos biasa, bukan Caly. Dr Syihabuddin jahil tidak tahu bezakan tahap konsentrasi dalam sel vero/hSLAM dan sel paru-paru manusia.

(vi) Dr Syihabuddin kata:

“Jawapan Caly dan ketuanya untuk menempis kononnya kajiannya tidak boleh digunakan untuk menentukan dos dalam manusia adalah denial pada saya. Awak dah buat kajian yang guna dos terlalu tinggi, awak kena bertanggungjawab.”

Ini hanya air liur daripada Dr Syihabuddin. This is pure rhetoric. Orang yang ada akal boleh lihat bahawa jawapan Caly, Dr David Jans, Dr Kylie Wagstaff dan Dr Pierre Kory adalah jawapan berasaskan sains manakala jawapan Dr Syihabuddin adalah BARE DENIAL berasaskan ego dan emosi. Dr Syihabuddin langsung tidak mengulas kenapa dia yakin konsentrasi 5µM yang digunakan untuk monkey kidney cell dan nilai IC₅₀=2µM yang berkaitan adalah sama bagi sel paru2 manusia. In fact, Caly even stated in the paper:

“The critical next step in further evaluation for possible benefit in COVID-19 patients will be to examine a multiple addition dosing regimen that mimics the current approved usage of ivermectin in humans.”

Maaf saya kata, Dr Syihabuddin tidak profesional, tidak amanah, tidak cukup berilmu dan tidak berintegriti. This is, again, poor scholarship.

Tiga contoh berasingan untuk orang faham kekeliruan Dr Syihabuddin

Contoh 1: BMW S1000RR vs Proton X70

Saya isi minyak 3 liter V-Power dalam BMW S1000RR dan saya mencapai kelajuan sehingga 260 km/h di NKVE. Dr Syihabuddin isi 30 litre V-Power dalam Proton X70 tapi hanya mencapai kelajuan 180 km/h. Dr Syihabuddin membuat kesimpulan V-Power tidak bagus walaupun isi 10 kali ganda V-Power. Dr Syihabuddin tidak faham BMW S1000RR (“sel paru-paru”) dan Proton X70 (“monkey kidney cell”) berbeza walaupun menggunakan minyak yang sama. Horsepower lain, torque lain, gear ratio lain, power to weight ratio lain etc. Antara faktor-faktor lain, paru-paru ada interferon, monkey kidney takde.

Contoh 2: Honda CD70 vs Lamborghini Aventador

Lamborghini Aventador punya fuel consumption adalah 25.7 km/litre atau 3.88 litres/100km. Honda CD70 pula, fuel consumption adalah 80km/litre atau 1.25 litres/100km. Saya naik Honda dan Dr Syihabuddin suka bergaya so dia naik Lamborghini. Saya isi minyak 4 liter dalam motosikal. Dr Syihabuddin isi 10 liter dalam kereta. Saya bertolak dari Shah Alam dan selamat sampai ke Legoland. On the way saya nampak Dr Syihabuddin berdiri di lorong kecemasan Lebuhraya Utara-Selatan. Minyak habis. Kesian. Kesimpulannya Honda CD70 (“paru-paru”) perlu hanya 4 liter (“dos biasa”) berbanding Lamborghini (“monkey kidney cell”) yang perlu menggunakan lebih banyak minyak (10 liter pun tak cukup) untuk sampai ke Legoland.

Contoh 3: Tuala murah vs Tuala mahal

Pernah kan bandingkan tuala mandi cotton (kapas) dan tuala mandi polyester? Lepas mandi bila lap dengan tuala polyester, badan masih tak kering kering. Tak puas rasa. Dengan tuala mandi kapas lepas sekali dua kali lap badan rasa kering dan selesa. Kenapa berbeza? Air sama – H₂O jugak. The polyester towel does not absorb as much water as the cotton towel. What if you use leather (kain kulit) to dry yourself compared to a high quality bath towel? You’ll see an even bigger difference. Maka sekiranya air dicurah pada kain kulit, hanya berapa % akan diserap manakala hampir semua air akan diserap oleh tuala yang mahal dalam masa yang singkat. Tuala mandi kapas (“paru-paru”) meresap lebih banyak air (“ivermectin”) dengan mudah dan cepat berbanding tuala polyester atau kain kulit (“monkey kidney cell”).

Or you can watch this towel advertisement video to understand what I mean.

Contoh-contoh tersebut di atas adalah untuk memberi fahaman (i) terdapat banyak perbezaan antara sel vero/hSLAM (e.g. tiada interferon) dan sel paru-paru manusia (ii) tidak perlu guna dos tahap tinggi untuk ivermectin berkesan sebagaimana juga telah diulas secara saintifik kenapa tidak perlu 1:1 drug to virus ratio dan (iii) ivermectin mencapai konsentrasi lebih tinggi dan mudah dalam sel paru-paru berbanding monkey kidney cells.

Section IV

Dr Syihabuddin kata:

C. Kita lihat ubat antiviral lain dalam Covid, AT 527, tidak pula menggunakan dos yang sebegitu tinggi. Ini juga repurposed drug, daripada ubat hepatitis C kepada Covid. Tidak melibatkan penggunaan dos yang terlampau tinggi dalam kajian makmal. Exo CD 24, juga tidak menggunakan dos yang terlampau tinggi seperti Caly lakukan, dan ini juga repurposed drug.

Dr Syihabuddin sendiri yang membuat kesilapan mendakwa ivermectin perlu digunakan dengan dos 32x ganda dos biasa, kemudian kata tidak sama dengan ubat antiviral lain yang tidak pula menggunakan dos yang sebegitu tinggi. This is a fallacious comparison.

Kita boleh lihat ivermectin tidak menggunakan dos yang sebegitu tinggi dalam kajian-kajian manusia dan juga telah diulaskan dalam Posting #3 (AA) dan di atas kenapa tidak perlu dos melampau.

• Ivermectin for COVID-19: real-time meta analysis of 65 studies
• Database of all ivermectin COVID-19 studies. 120 studies, 77 peer reviewed, 65 with results comparing treatment and control groups
• COVID-19 early treatment: real-time analysis of 982 studies

Tiada siapa perlu telan 30 biji ivermectin sekaligus untuk ivermectin berkesan. Dr Syihabuddin asyik ketinggalan bas.

Section V

Dry Syihabuddin kata:

D. Masalah penyerapan ivermectin ke paru-paru, Caly sendiri mencadangkan 2 uM sebagai kepekatan berkesan di paru-paru, tetapi mengikut pengiraan VD Schmitz, dan pengiraan ini adalah makruf dalam drug comparison, – population pharmacokinetic model for ivermectin oleh Duthaler dan ditambah lagi dengan formula ball park accumalation ratio untuk mengira ratio plasma kepada darah, didapati

(i) Walaupun dengan dos 10 kali ganda daripada dos dibenarkan, kepekatan berkesan di paru-paru tetap tidak dapat dicapai, paling tinggi pun 0.0873 uM.

(ii) Walaupun dengan dos 10 kali ganda dan berulang, kepekatan berkesan di paru-paru tetap tidak dapat dicapai, paling tinggi pun 0.820 uM.

(iii) Menggunakan ball park accumalation ratio untuk pengiraan lung:plasma ratio, jika dos mingguan dalam dos dibenarkan, hanya 1 per 20 daripada IC50 @ kepekatan berkesan @ 2 uM. Jika 3 kali seminggu, hanya 1 per 10 IC50. Jika dos harian, hanya 1 per 4 IC50, dengan menggunakan ball park accumalation ratio formula.

E. Maka masalah utama ivermectin mengikut kajian makmal dan predictive study ini adalah kadar penyerapannya yang rendah di paru-paru dan bukan sekadar dos yang terlampau tinggi digunakan, ada 2 premis di situ. Hal ini tidak berlaku dalam AT 527 Roche, satu antiviral drug yang sedang dalam kajian fasa 3 untuk Covid, Moonsong fasa 2, MorningSky fasa 3.

(a) Dr Syihabuddin membohong

Mendakwa “Caly sendiri mencadangkan 2 uM sebagai kepekatan berkesan di paru-paru” adalah satu PEMBOHONGAN oleh Dr Syihabuddin. Caly tidak pernah mencadangkan kepekatan dos 2µM untuk ivermectin berkesan di paru-paru. Apa yang dinyatakan dalam kertas kajian Caly?

“To test the antiviral activity of ivermectin towards SARS-CoV-2, we infected Vero/hSLAM cells with SARS-CoV-2 isolate Australia/VIC01/2020 at an MOI of 0.1 for 2 h, followed by the addition of 5 μM ivermectin.”

“To further determine the effectiveness of ivemectin, cells infected with SARS-CoV-2 were treated with serial dilutions of ivermectin 2 h post infection and supernatant and cell pellets collected for real-time RT-PCR at 48 h (Fig. 1 C/D). As above, a >5000 reduction in viral RNA was observed in both supernatant and cell pellets from samples treated with 5 μM ivermectin at 48 h, equating to a 99.98%reduction in viral RNA in these samples. Again, no toxicity was observed with ivermectin at any of theconcentrations tested. The IC₅₀ of ivermectin treatment was determined to be ~2 μM under these conditions.” [Caly et al]

Saya ulangi: Jelas sejelas-jelasnya Caly et al menyatakan dos tersebut diguna pada sel Vero/hSLAM (monkey kidney cells), bahawa IC₅₀=2µM tersebut merujuk kepada sel Vero/hSLAM dan bukannya sel paru-paru. Lagipun ini telah diperjelaskan kepada Dr Syihabuddin dalam posting yang lepas tetapi Dr Syihabuddin dengan tidak malunya masih cuba mengelirukan orangramai dengan membohong.

(b) PK model yang digunakan oleh Duthaler tidak mensimulasi konsentrasi di paru-paru

Ya, tidak dinafikan Dr Virginia Schmith pakar dalam penggunaan PK model tapi Virginia menggunakan population PK model yang tidak berupaya meramalkan (predict) konsentrasi ivermectin dalam paru-paru. Malah PK model tersebut adalah khusus untuk buat simulasi untuk predict konsentrasi ivermectin dalam plasma & dried blood spots dan bukannya paru-paru manusia. Namun Dr Syihabuddin pakar kelentong. Nonetheless, the PK model is not a major issue.

(c) Konsentrasi akan lebih tinggi sekiranya ivermectin diambil selepas makan

Also bear in mind Virgina Schmith buat assumption ivermectin is given in a fasted state. This means the lung concentration will be lower by more than 2.5x compared to taking ivermectin after a meal. Virginia sendiri mengakui PK model yang digunakan oleh Durathel berasaskan ivermectin diambil dengan ‘high-fat breakfast’ tetapi beliau pula membuat pengiraan berdasarkan ivermectin diambil semasa perut kosong (maka bioavailability ivermectin menjadi ~2.5x ganda lebih rendah).

(d) Tidak hairan kepekatan/konsentrasi dicapai oleh Virginia adalah jauh lebih rendah dari 2 µM

Merujuk kepada perenggan (i), (ii) dan (iii), Dr Syihabuddin copy-paste angka-angka tersebut dari kertas kajian Virginia Schmith, which is fine. Namun, persoalan tersebut telah dijawab bahawa realitinya IC₅₀ = 2 µM adalah bagi sel vero/hSLAM dan adalah TIDAK RELEVAN bagi sel paru-paru manusia.

Isu sebenarnya adalah samada dos biasa ivermectin akan sampai tahap konsentrasi di paru-paru yang diperlukan untuk berkesan dan persoalan tersebut juga telah pun dijawab. In this respect, saya dah kerap kali kata IC50 tidak perlu setinggi 2 µM tapi asyik masuk telinga kiri dan keluar telinga kanan Dr Syhihabuddin. 0.0873 µM may well be the relevant IC50 for human lungs or 0.82 µM for that matter. Furthermore, the simulated number would have been 2.5x time higher if ivermectin was taken after a meal since Virginia assumed ivermectin was taken on an empty stomach.

Unlike hydrocholoroquine (HCQ), which may need ≥ 1:1 drug ratio, ivermectin requires less concentration in the lungs. Why? Rujuk balik respons Caly dan my analogy about drowning a person in a bath tub vs the water torture method [Posting #3 (AA)]. Rujuk juga contoh analogy BMW S1000RR vs Proton CX70 dan Honda CD70 vs Lamborghini (Section III di atas). It had already beeen explained that the IC₅₀ was expected to be much lower than 2 µM for human lungs so Dr Syihabuddin has no leg to stand on in this respect.

In addition, while ivermectin prevents the virus from docking with the cells and from replicating, sistem imun akan bertindak untuk membunuh virus. Perlu faham bukan ivermectin sahaja yang buat kerja. Sebab itu protocol rawatan termasuk sekali vitamin C, vitamin D, zinc etc. Dr Syihabuddin perlu faham bahawa the treatment of coivd-19 is not a one-drug solution and that ivermectin works together with the immune system.

(e) Kesimpulan Virginia berasaskan perbandingan dengan IC₅₀=2µM sebagai benchmark

It is important to note that the basis of Virginia concluding that ivermectin would not be effective at the normal dose was NOT because of the absolute value of the IC₅₀ derived from the simulation but due to the fact that the simulated IC₅₀ was well below 2 µM. Virginia was under the impression that IC₅₀ was 2 µM for lung cells whereas it was the value for vero/hSLAM. It is very clear what Virginia said:

“Plasma ivermectin concentrations of total (bound and unbound) and unbound concentrations do not reach the IC50 reported by Caly et al even for dose level 10× higher than the approved dose, or after repeat dosing.”

What was the IC₅₀ reported by Caly et al? Yup, 2 µM…. relevant only to vero/hSLAM or monkey kidney cells, not human lung cells. Meaning, if Caly et al had reported that the IC₅₀ for lung cells was, hypothetically speaking, 0.08 µM then obviously Virginia would have concluded that ivermectin was effective at the normal dose (because 0.0873 µM > 0.08 µM). It’s that simple to understand.

Section VI

Dr Syihabuddin kata:

Kesimpulan saya, mungkin Tuan Azmi boleh cuba jawab direct to the point, refute the calculation, refute my calculation, refute VD Schmitz calculation, refute ball park calculation, refute population pharmacokinetic model Duthaler. Setakat refute macam tu, quote author kata apa walhal author pun denial tak menjawab persoalan, tuduh saya macam-macam, setakat gitu orang awam dan tukang sorak kat tepi tu bolehlah awak makan, tetapi tidak fakta sains. Kita bukan ahli politik dalam perbincangan sains, ulasan mestilah saintifik, bukan populist, Tuan Azmi bukan Mat Sabu kan?!Apa pun saya ucap terima kasih, good discussion. Harap saya boleh komen kat wall tuan, terima kasih.

Dr Syihabuddin kata saya refute dakwaan beliau adalah dengan “tidak fakta sains“. Ini bukan kali pertama beliau menjawab begitu. When I first rebutted him, he also came back with “tidak ada scientific rationale yang boleh menjawab isu masalah dos tersebut”. Sekarang dia cabar saya:

“refute my calculation, refute VD Schmitz calculation, refute ball park calculation, refute population pharmacokinetic model Duthaler”

Dr Syihabuddin bin Mohd (KKM)

Dr Syihabuddin nampaknya emosi dan pakai tembak suruh saya refute ini refute itu. Dr Syihabuddin knows very well that his claim (that 32x normal dose is required for ivermectin to be effective) has been rebutted with scientific facts tapi bagi beliau hanya sekadar menjawab balik “refute macam tu… setakat gitu orang awam dan tukang sorak kat tepi tu bolehlah awak makan, tetapi tidak fakta sains“. This is just empty rhetoric from Dr Syihabuddin. Orangramai boleh menilai there is no substance in Dr Syihabuddin’s response. Adakah itu sahaja yang Dr Syihabuddin mampu menjawab? Tapke, saya layan.

(i) “refute my calculation”

Dr Syihahuddin’s argument relying on his own calculation is called a circular argument.

“Circular arguments occur when a person’s argument repeats what they already assumed before without arriving at a new conclusion. Circular arguments often use a claim as both a premise and a conclusion. This fallacy only appears to be an argument when in fact it’s just restating one’s assumptions.”

Dr Syihabuddin’s calculation may be arithmetically correct but based on a false assumption. For avoidance of doubt, the following is proof that Dr Syihabuddin’s calculation was based on the dosage for vero/hSLAM cells and not human lung cells.

Sepertimana saya menjawab sebelum ini, 5 µM tersebut TIDAK RELEVAN untuk paru-paru manusia. Seperti dinyatakan dalam kertas kajian, Caly et al menggunakan 5 µM untuk vero/hSLAM cells iaitu monkey kidney cells dalam kajian in vitro mereka tetapi Dr Syihabuddin menggunakan 5 µM dalam pengiraan beliau untuk manusia seolah tahap konsentrasi ivermectin dalam paru-paru manusia adalah sama dengan kidney monyet. This, again, demonstrates the lack of diligence by Dr Syihabuddin.

“The study used monkey kidney cells (the only choice at the time of the experiments), which lack adaptive immune responses and do not produce interferon.” – Dr Kylie Wagstaff

Realitinya, dos biasa memadai bagi manusia atas sebab-sebab yang telah diulas, termasuk tahap konsentrasi paru-paru adalah sekurang-kurangnya 6-8 lebih tinggi dari vero/hSLAM dan bahawa mengambil ivermectin selepas makan menyebabkan 2.5x ganda konsentrasi berbanding bila makan semasa perut kosong.

Rujuk juga contoh2 BMWS1000RR vs Proton X70, Honda CD70 vs Lamborghini, tuala murah vs tuala mahal.

Pendek kata, pengiraan Dr Syihabuddin adalah karut. Dr Syihabuddin keeps barking up the wrong tree despite repeatedly being told it’s the wrong tree. Otherwise he’s chasing his own tail. I’m just amused how proud he feels at showing off his calculation of 32x which belongs in the bin.

(ii) “refute VD Schmitz calculation”

Dr Syihabuddin tidak spesifik calculation yang mana satu. Sekiranya berkenaan 32x atau 35x ganda dos biasa perlu untuk ivermectin, persoalan ini telah dijawab — hanya perlu calculator untuk semak. Budak sekolah rendah pun boleh calculate. Artihmetically correct but not relevant to human lung cells. Dr Syihabuddin hanya syok sendiri dengan pengiraan 32x tersebut.

Namun, sekiranya berkenaan dengan dos biasa, IC₅₀ adalah lebih rendah dari 2 µM, buat apa nak refute? In fact, I agree subject to the points I mentioned, namely concentration achieved in the lungs would be higher (>2.5x) if ivermectin was taken after a meal and with regard to the accuracy of Virginia’s model (which is not such a big issue to me) versus Jermain’s mPBPK model per (iv) below.

That notwithstanding, for the sake of humouring Dr Syihabuddin, let’s see what VD Schmith said in the report:

We can see from the above extract that Virginia Schmith is much more sensible and honest than Dr Syihabuddin. Why do I say that? First let’s recall what I had repeatedly said in Posting #3 (AA), which Dr Syihabuddin has been unable to grasp (maybe because he talks more than he listens).

“… they [Caly et al] had no choice but to use Vero/hSLAM cells (green monkey kidney cells)instead of lung cells. Therefore the IC50 based on Caly et al’s invitro study is not the relevant IC50 for human lung cells”

“Whether the number Dr Syihabuddin comes up with is 32, 10 or 1, it still cannot be considered reliable nor relevant. Why? Because the IC50 was in relation to monkey kidney cells (Vero/hSLAM), not human lung cellsor even a monkey’s lung cells.

“Dr Wagstaff mengulas kenapa pengiraan berdasarkan simulasi in vitro mereka (samada Yeo et al, Virginia et al atau Dr Syihabuddin) tidak boleh digunakan untuk menentukan dos yang berkesan atau kenapa tidak relevan untuk manusia.

“Therefore, Dr Syihabuddin’s calculation is not only irrelevant but obsolete because subsequent to the in vitro study, in vivo studies have also already been done.” [based on normal dosage]

“… note that ivermectin accumulates in lung and other tissues, that subsequent experiments with lung cells show many times greater concentrations, and that the average lung concentration shown in modeling studies exceeds the effective level shown in their research”

Apa Virginia Schmith pula kata?

Nevertheless, if ivermectin did contribute to these clinical findings, it would suggest that the in vitro findings [maksudnya sebanyak 5 µM digunakan pada sel vero/hSLAM] by Caly et al do not correlate with the very small amounts of the drug in lung tissue in humans, concentrations in lung homogenate do not correlate with concentrations at the site of action or those expected based on ivermectin’s large volume of distribution, concentrations of the drug do not need to reach the IC50 for clinical benefit (i.e., the IC50 is NOT RELEVANT), distribution into or retention in the lung tissue of humans is greater than in cattle, or that accumulation in lung tissue is much greater (> 20-fold). — Virginia D Schmith et al

Read the above at least 2 or 3 times to understand what Virginia is saying. Now, let me elaborate.

Virginia ackowledged that there was a study by Patel et al that showed ivermectin was effective. If that was the case, Virginia would readily admit that the IC₅₀ is not relevant (i.e. IC₅₀ = 2 µM is not relevant for human lungs). And indeed it makes perfect sense that the IC₅₀ is not relevant because the IC₅₀ stated by Caly et al (2 µM) was relevant only to vero/hSLAM cells (monkey kidney cells) and NOT RELEVANT for human lungs.

Is it possible that Virginia made a mistake in assuming that the IC₅₀ = 2 µM was for human lungs? Yes, absolutely. How can I be so sure? Well, remember what I said in my previous Posting #3 (AA):

Adakah Virgina sebut dalam kertas kajian bahawa sebanyak 5 μM concentration IVM digunakan dan nilai IC50 2μM adalah merujuk kepada kajian atas Vero/hSLAM dan bukannya sel paru2? No. Adakah Virginia merujuk kepada ulasan Caly et al yang menjawab dakwaan Yeo et al dan Noel? No.

Also from the same previous posting:

Kenapa artikel Yeo et al penting sebagai rujukan? Sebab di situ lah terkandung response daripada Caly et al berkenaan isu dos. Dalam artikel yang ditulis oleh Dr Syihabuddin pula, beliau hanya merujuk kepada kajian Virginia. (Rujuk Gambarajah 6). Therefore, he was telling only one side of the story. Tiada rujukan kepada artikel Yeo et al dan response dari Caly et al. Kertas kajian Virginia bukan sahaja langsung tidak sebut pasal response Caly et al tapi juga tidak menyatakan (atau sengaja menyembunyi fakta) IC50=2μM dari kajian Caly et al adalah merujuk kepada sel Vero/hSLAM dan bukannya sel paru2. Dr Syihabuddin pun sama. Kenapa Dr Syihabuddin masih tidak menjawab ulasan yang diberi oleh Dr Kylie Wagstaff pada May 2020 dan pada May 2021 dan juga ulasan Dr Pierre Kory pada Jun 2021? Kenapa asyik mengulangi dapatan Virginia yang telah dibalas dan mengulangi pengiraan sendiri sahaja?

That is called intellectual dishonesty.

Kertas kajian Virginia (October 2020) tiada langsung sebut vero/hSLAM, tiada rujukan kepada artikel Yeo et al, dan tiada rujukan kepada respons Caly et al (David Jans dan Kylie Wagstaff) kepada Yeo et al dan Noel.

Meaning, firstly, Virginia made a mistake assuming that the dosage of 5 µM and IC₅₀ of 2 µM was for human lungs (and Dr Syihabuddin continues to make that mistake even after clarification), when, in fact, the word “lung” does not appear even once in Caly et al’s scientific paper. Therefore, in all probablility, Virginia wrongly assumed the 5 µM and 2 µM were in relation to lungs and not realise that those values were for vero/hSLAM cells, without having the benefit of subsequent clarifications on the matter.

Secondly, Caly et al’s response to Yeo et al & Noel explained why only low/normal dosage of ivermectin was required, which would have supported Virginia’s own alternative hypothesis that “the IC50 is not relevant” and “accumulation in lung tissue is much greater” — and these points were further driven home by Dr Kylie Wagstaff in May 2021 and Dr Pierre Kory in June 2021.

Now let’s recall the purpose of Virginia’s simulation.

Was it to show 32x normal dosage was required to be effective? No. Itu terlalu mudah. At most, you just need a calculator for that, not a population phamarcokinetics model. Budak sekolah rendah pun boleh membuat pengiraan yang Dr Syihabuddin buat dengan bangganya.

And indeed, as hypothesised by Virginia, the IC₅₀ is not relevant (if Patel et al’s study is considered reliable), which is what Dr Syihabuddin keeps failing to understand. Virginia can be forgiven for the oversight because she missed Yeo et al’s article and because Dr Kylie Wagstaff’s and Dr Pierre Kory’s explanations were made only after Virginia’s article was published but Dr Syihabuddin has no excuse whatsoever because I cited those explanations to him.

(iii) “refute ball park calculation”

There is nothing really to refute. However, note that the calculation was based on ivermectin being administered in a fasted state (semasa perut kosong). If taken with a high-fat meal, the concentration would be 2.5 times higher as even acknowledged by Virgina Schmith. Takpe, saya layan retorik kosong Dr Syihabuddin.

Now, read carefully where Virginia et al says “… do not reach the IC₅₀ reported by Caly et al even for dose level 10x higher than the approved dose“. What was the IC₅₀ reported by Caly et al? 2 µM. And for what kind of cells would the IC₅₀ value be 2 µM? Yup… vero/hSLAM cells or monkey kidney cells, not human lung cells. Which means the IC₅₀ for human lung cells would indeed be much lower. Also, the concentration achieved would be higher if ivermectin was taken in a fed state (i.e. with a meal) instead of a fasted state as simulated by Virginia. Which means Virginia’s figures are broadly CONSISTENT with Dr Kylie Wagstaff’s assertion that the IC₅₀ for human lung cells will indeed be much lower than 2 µM based on normal dose.

So, apa benda Dr Syihabuddin cabar saya refute the ball-park accumulation figures? Memang saya setuju dari segi dasarnya. Yang saya refute adalah ramalan Dr Syihabuddin manusia perlu 32x dos untuk ivermectin berkesan, which is based on his ignorance and lack of understanding why Caly et al had to use 5 µM and of the relevant IC₅₀. Virginia tidak pun menggunakan population PK model untuk membuat pengiraan tersebut dan Virginia tidak cuba membuktikan melalui simulasi manusia akan perlu 32x ganda dos. Again, Dr Syihabuddin is barking up the wrong tree.

Apa pun, selain formula tersebut tidak semestinya tepat (cattle lung vs human lung), kalau betul pun kita berbalik kepada dapatan fakta saintifik asas bahawa ivermectin berkesan dengan dos rendah/biasa dan dengan konsentrasi rendah di paru-paru (for which the reasons have been explained). So, tiada makna untuk refute ball park calculation tersebut i.e kalau betul betul lah, kalau salah salah lah, asalkan IC₅₀ much lower than 2 µM. What matters is that the relatively low concentration (i.e. IC₅₀ lower than 2 µM) derived by Virginia is broadly consistent with in vivo and clinical/observational studies, such as Patel’s observational study cited by Virginia.

(iv) “refute population pharmacokinetic model Duthaler”

Pelik betul Dr Syihabuddin mencabar saya refute PK model tersebut. This model was developed in 2018 to depict population pharmacokinetics of plasma and dried blood spots concentrations over time for oral ivermectin. I have no reason to believe the model is not accurate/reliable for the purpose it was developed. However, Dr Syihabuddin does not seem to know that this model did not simulate lung exposure in humans following oral administration of ivermectin. That is why Virgina made her own modifications/adjustments to the formula/parameters on top of the model to try to predict concentration in human lung based on cattle lung data.

In fact, only AFTER Virgina’s paper was published did Jermain et al indeed develop a Minimal Physiologically-Based Pharmacokinetic Model (mPBPK) to Simulate Lung Exposure in Humans Following Oral Administration of Ivermectin. Bermaksud apa? It means the PK model used by Virgina, (i.e. the same model used by Duthaler), did not have features to simulate lung exposure. Sebab itu saya kata simulasi pharmacokinetics bukan macam Airbus Flight Simulator — it does not cater for all events and variables — tapi Dr Syihabudin buat2 bodoh tak faham (atau mungkin dia benar2 tak faham) dan taksub dengan model simulasi Virginia. It’s sort of like Virginia used a Boeing 737 flight simulator and made adjustments for it to simulate a Boeing 777 (and it’s not for me to judge whether Virginia’s model is accurate — it would have to be proven through in vivo studies). A physiologically-based PK model (PBPK model) would be more complex and may be more accurate but, still, I don’t have a problem with the Duthaler model.

This notwithstanding, it’s not a problem at all if Dr Syihabuddin considers Virginia’s model to be perfect because it doesn’t contradict the fact that the IC₅₀ for human lungs is expected to be well below 2 µM in any case. Cuma Dr Syihabuddin yang keliru dan tak faham kenapa IC₅₀ untuk paru2 manusia adalah lebih rendah berbanding monkey kidney cell.

Anyway, compare the difference in schematics between the new mPBPK model vs Duthaler’s model:

Bukan nak kata model baru mPBPK is perfect but Duthaler’s model was obviously less adequate for the purpose of predicting concentration of ivermectin in human lungs. Even then, Jermain said about their mPBPK model, “The main limitations of our approach are the inability to validate our simulated human lung exposure with any published values as well as not being able to simulate drug accumulation in tissue after multiple dosing.” That notwithstanding, I have to repeat that ivermectin does not need to be highly concentrated in the lungs for the reasons previously explained, so it does not matter that even the new mPBPK model predicts that IC₅₀ does not reach 2 µM — because memang it isn’t supposed to — since that value applied only to vero/hSLAM cells and not lung cells i.e. the IC₅₀ value is expected to be much lower for lung cells.

Ringkasan bahagian “refute“

(i) Dakwaan Dr Syihabuddin manusia perlu ambil 32x ganda dos biasa untuk ivermectin berkesan adalah karut dan wajar ditongsampahkan.

(ii) Dapatan Virginia dengan penggunaan population pharmacokinetiks model bahawa IC₅₀ tidak mencapai 2 µM adalah konsisten dengan ulasan saintifik bahawa ivermectin hanya perlu dos rendah/biasa (i.e. < 2 µM) dan juga konsisten dengan hujah IC₅₀ = 2 µM (bagi sel vero/hSLAM) adalah tidak relevan bagi paru-paru manusia;

(iii) Dapatan Virginia berkenaan ball-park accumulation adalah secara dasarnya konsisten dengan ulasan saintifik seperti yang disebut di perengggan (ii); dan

(iv) Tiada masalah dengan population pharmacokinetiks model yang digunakan oleh Virginia dan Duthaler walaupun kurang canggih dan belum dibuktikan tepat untuk mensimulasi konsentrasi ivermectin dalam paru-paru manusia. The mPBPK model by Jermain et al looks more sophisticated. The use of a PK model is not a big issue but no PK model is comprehensive and accurate enough to simulate the mechanics and pharamacokinetics of ivermectin working with the immune system. As I’ve said before, a PK model is not like an Airbus flight simulator.

Kesimpulan

Dr Syihabuddin bergantung hanya kepada dua premis utama untuk membuat kesimpulan 32x ganda dos biasa diperlukan untuk ivermectin berkesan.

– Premis pertama adalah pengiraan beliau dengan menggunakan formula dan calculator (i.e. Dr Syihabuddin’s circular argument). Saya telah mengulas kenapa kesimpulan beliau perlu 32x ganda dos biasa untuk ivermectin berkesan bagi manusia adalah salah dan karut.

– Premis kedua adalah simulated prediction oleh Virginia bahawa IC50 tidak mencapai 2 µM kononnya bermaksud ivermectin tidak berkesan dengan dos biasa. Saya telah mengulas kenapa 2 µM tersebut tidak relevan sebagai threshold untuk paru-paru dan kenapa IC50 sebenar untuk paru-paru memang jauh lebih rendah.

Semua persoalan utama berkenaan dos telah dijawab dengan fakta sains, logik dan common sense.

Penutup

Saya telah menyahut cabaran Dr Syihabuddin untuk refute ini itu, walaupun beliau sendiri tak tahu apa tujuan sebenar mencabar saya refute. Now it’s my turn and he must reciprocate. I reproduced Dr Syihabuddin’s post 100% and addressed section by section. I would like for Dr Syihabuddin to do the same – so the people know he has covered all the points when responding to all the expalanations given and also specifically to refute the following:

1. Refute that concentration of ivermectin in human lung cells will be higher than for vero/hSLAM cells (monkey kidney cells).
2. Refute that the IC50 value for human lung alveolar cells (for ivermectin to be effective) will be lower than for vero/hSLAM cells.
3. Refute that the required drug:virus ratio in the lungs will be lower than 1:1 for ivermectin.
4. Refute that the purpose/conclusion of Virginia’s simulation was NOT to show that 32x approved/normal dose of ivermectin was required for it to be effective against covid-19 but merely that the concentration achieved was below 2 µM.
5. Refute that Caly et al would have required less than 5 µM had ivermectin been administered to human lung alveolar cells instead of vero/hSLAM cells.
6. Refute that Virgina’s conclusion that the concentration achieved being less than 2 µM is not inconsistent with the assertion that low/normal dosage is enough for ivermectin to be effective.
7. Refute that by taking ivermectin in a fed state, as opposed to a fasted state (as simulated by Virginia), the concentration of ivermectin in the lungs would be at least 2.5 times higher.
8. Refute that Durathel’s model did not simulate lung exposure after ivermectin is orally administered
9. Refute that Jermain et al’s mPBPK model is more comprehensive than Durathel’s model for the purpose of predicting lung exposure after ivermectin is orally administered (since Dr Syihabuddin taksub dengan Durathel’s model).
10. Refute that the mechanism of hydrocholoroquine and ivermectin are very different. (This is relevant to exposing Dr Harith Kamal’s ignorance).
11. Refute that lungs have interferons and monkey kidney cells do not (i.e. an example that ivermectin works with the immune system)
12. Refute the following assertion by David Jans and Kylie Wagstaff: “ivermectin’s key direct target in mammalian cells is a not a viral component, but a host protein important in intracellular transport; the fact that it is a host-directed agent (HDA) is almost certainly the basis of its broad-spectrum activity against a number of different RNA viruses in vitro. The way a HDA can reduce viral load is by inhibiting a key cellular process that the virus hijacks to enhance infection by suppressing the host antiviral response. Reducing viral load by even a modest amount by using a HDA at low dose early in infection can be the key to enabling the body’s immune system to begin to mount the full antiviral response before the infection takes control.”

Dr Syihabuddin’s refutation must be supported with proper references, scientific rationale or at least logical reasoning. I suggest he form a team with other doctors (including Dr Harith Kamal, Dr Luqman Alhakim and Prof Dr Mohd Makmor) to respond to all of the above, which will give readers some assurance Dr Syihabuddin bukan hanya syok sendiri. I also recommend that Dr Syihabuddin rope in Dr Azman Abdullah, Dr Iskandar Mirza, Dr Ahmad Samhan and Dr Rafidah Abdullah, another bunch of arrogant doctors who think they are God’s gift to mankind.

Also, Dr Syihabuddin should issue an apology for falsely claiming “Caly sendiri mencadangkan 2 uM sebagai kepekatan berkesan di paru-paru”. Ini adalah dakwaan palsu dan tidak bertanggungjawab.

People should be able to see Dr Syihabuddin’s ignorance, lack of substance, poor level of comprehension and dishonesty. If not for this kind of arrogant KKM medical personnel spreading misinformation and denying people effective early treatment, we could have avoided the excessive number of cases, hospitalisations and deaths. Blood is on their hands.

– AA –