Clinical vignette: Meningitis due to Listeria monocytogenes

Hello

Listeria monocytogenes is the 3rd most common organism that causes bacterial meningitis.
Cephalosporins do not cover this gram - positive bacteria under its spectrum. More aptly saying, the cephs do not kill this bacteria. So, especially in high-risk patients such as neonates, elderly, and the immunocompromised, cephalosporins are given in combination with ampicillin, and never alone.

Ceftriaxone is avoided for use in neonates due to its decreased biliary metabolism and sludging.
The choice of ceph in neonates and other high-risk groups in the case of meningitis is cefotaxime.

That's all
- Jaskunwar Singh

Clinical correlate: Sildenafil contraindicated for pilots

Hello

Not just type-5, but Sildenafil is also a phosphodiesterase type-6 inhibitor.

PDE-6 is present in the eyes.

Thioamides in pregnancy

Hello

Propylthiouracil is a pro. It always comes first (used in first trimester of pregnancy).
Methimazole causes Malformations in the embryo (teratogenic).

There are two M's in MethiMazole. This drug is used in second (and third trimester of pregnancy).
Propylthiouracil piles up, causing liver toxicity, thus limiting its use.

Hope it helps
- Jaskunwar Singh

Clinical pearl : TNF-alpha therapy

Hello

In case of granulomatous diseases, macrophages activated by Th1 cells lead to increased levels of TNF-alpha. Now, TNF-alpha induces and maintains granuloma formation. Basic, right?

So we give anti-TNF drugs (adalimumab, infliximab, etc.). However, they cause the granuloma to break down, thus leading to disseminated disease.

Bottom line - Always remember to check for the presence of latent TB before starting anti-TNF therapy.

That's all
- Jaskunwar Singh

COVID-19: Coronavirus and hemoglobin

Hello Awesomites!

Please refer to the diagrams for better understanding.

Why do we have abnormal hemoglobin-related biochemical indices in COVID-19 patients?
Reports demonstrate that the hemoglobin and neutrophil counts decrease in most patients with SARS-CoV-2 infection, and values of serum ferritin, erythrocyte sedimentation rate, C-reactive protein, albumin, and lactate dehydrogenase increase significantly.

What makes hemoglobin an attractive molecule for the coronavirus?
Porphyrins!

Porphyrins in the human body are mostly iron porphyrins i.e heme. And a lot of heme is not free, but bound to hemoglobin. Viruses require porphyrins to survive. Therefore, the novel coronavirus targets hemoglobin, attacks heme, and hunts porphyrins.

Structure of SARS-CoV-2

Image by Upasana Yadav

The possible mechanism is that orf1ab bound to the alpha chain and attacks the beta chain, causing conformational changes in the alpha and beta chains; ORF3 attacks the beta chain and exposes heme. ORF10 then quickly attaches to the beta chain and directly impacts the iron atoms on the heme of the beta chain. The heme is dissociated into porphyrin, and orf1ab finally captures porphyrin. Orf1ab plays a vital role throughout the attack. Attack of oxidized hemoglobin by viral proteins leads to less and less hemoglobin that can carry oxygen. The invasion of viral proteins on deoxidized hemoglobin will cause less and less hemoglobin that can carry carbon dioxide.

This study found that ORF8 and surface glycoprotein had a function to combine with porphyrin to form a complex, while orf1ab, ORF10, ORF3a coordinately attack the heme on the 1-beta chain of hemoglobin to dissociate the iron to form the porphyrin. This mechanism of the virus inhibited the normal metabolic pathway of heme, and made people show symptoms of the disease.

What causes the high infectivity of the novel coronavirus?
Medical workers have detected the novel coronavirus from urine, saliva, feces, and blood. The virus can also live in body fluids. In such media, porphyrin is a prevalent substance. At the beginning of life, virus molecules with porphyrins directly move into the original membrane structure by porphyrin permeability. This study showed that the E2 glycoprotein and Envelope protein of the novel coronavirus could bind well to porphyrins. Therefore, the coronavirus may also directly penetrate the human cell membrane through porphyrin. (Means If the virus can bind with porphyrins, it can enter these secretory cells without ACE2 receptors by using the membrane permeability)

What is the importance of knowing the above information?
The drugs based on this mechanism: Chloroquine and Favipiravir.

The primary function of the Envelope protein is to help the virus enter host cells. The primary role of Favipiravir is to prevent the virus from entering host cells and catching free porphyrins. Favipiravir's ability to improve respiratory distress is lower. Favipiravir can only prevent the binding of Envelope protein and porphyrin.

Chloroquine could prevent orf1ab, ORF3a, and ORF10 from attacking the heme to form the porphyrin and inhibit the binding of ORF8 and surface glycoproteins to porphyrins to a certain extent, effectively relieve the symptoms of respiratory distress.

The infectivity of the nCoV pneumonia was not completely prevented by the drugs, because the binding of E2 glycoprotein and porphyrin was not inhibited.

Note for Diabetic patients
Diabetic patients and older people have higher glycated hemoglobin. Glycated hemoglobin was reduced by the attack, which made patients' blood sugar unstable. Since the porphyrin complexes of the virus produced in the human body inhibited the heme anabolic pathway.
Written by Upasana Yadav
(Courtesy:-Thank you Ikan for all the help) 

References:
1. Wenzhong, liu; hualan, Li (2020): COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism. ChemRxiv. Preprint. https://doi.org/10.26434/chemrxiv.11938173.v5
Link to the article: https://chemrxiv.org/articles/COVID-19_Disease_ORF8_and_Surface_Glycoprotein_Inhibit_Heme_Metabolism_by_Binding_to_Porphyrin/11938173

COVID-19: Summary of drugs that are under investigation for use as potential treatment options

SARS -CoV-2 that causes the famous disease, COVID-19, has no FDA approved treatment yet. Researchers around the world are using drugs that have previously demonstrated efficacy against similar virus types clinically or based on their in-vitro activity. Many clinical trials are also underway to demonstrate the most efficacious drug which can be used against this disease. Let's go through them today.

COVID-19: Summary of drugs that are under investigation for use as potential treatment options

COVID-19: Remdesivir (GS-5734)

Here is a short post about Remdesivir (GS-5734).

Compound:
A '-cyano-substituted adenosine nucleotide analog prodrug.

Mnemonic for TNF-alpha inhibitors

https://youtu.be/S9Z2ObWhPlA

Video by Drashtant

Recent updates about treatment of COVID19

All things you need to know about COVID19 

https://www.youtube.com/watch?v=A6WpCkjqJSM

Recent Updates: 

At present Best Option = HydroxyCQ +/- Azithromycin 

HydroxyCQ for 10 day ( 200 mg TDS ) 

As ACE 2 enzyme is receptor for SARS-Cov-2 & these RAS inhibitors ⬆️ ACE2 enzyme. So hypothetically, there's an ⬆️ Risk of Covid19. But the guidelines recommend that ACEI / ARBs should not be discontinued. 

Drugs under Clinical Trials:

Remdesivir (USA) 

Ritonavir-Lopinavir 

Tocilizumab (IL6) 

Sarilumab (IL6) 

Favipiravir+ Tocilizumab 

Meplazumab (CD147) 

Fingolimod 

Darunavir + Cobicistat 

Which Rx is used in your country now?  Please comment below ⬇️

Thank you.. 

- Drashtant 

Isatuximab (Novel monoclonal antibody)

Isatuximab (a novel monoclonal antibody that binds
selectively to CD38), which is widely expressed on the plasma
cells, and kills myeloma cells via multimodal mechanisms
including antibody-dependent cellular cytotoxicity,
antibody-dependent cellular phagocytosis, complement-
dependent cellular cytotoxicity, and immune cell
depletion or inhibition of immunosuppressive cells, as has been described with daratumumab.

 Additionally, isatuximab, similar to other CD38 antibodies, modulates
the NADase enzymatic activity of CD38.
However, isatuximab differentiates itself from daratumumab in its
ability to induce direct apoptosis without cross-linking, and in its binding epitope.

Isatuximab is approved in combination with pomalidomide and dexamethasone for adult patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

A pretty amazing mechanism, right?


Kirtan

Mnemonic for Drug induced Cardiomyopathy

Hello everyone ....

Aunty is cycling 🚴‍♀️ on paved trails to protect her heart 💓 

Aunty = Anthracycline = Doxorubicin, Daunorubicin , Mitoxantrone 

Cycling = Cyclophosphamide 

paVEd = VEGF Inhibitors = Bevacizumab 

Trails = Trastuzumab

Olanzapine dose in CINV

Hi!

Olanzapine, an anti-psychotic, has been used in the patients of cancer for its beneficial effects on chemotherapy-induced nausea and vomiting (CINV) at a dose of 10 mg due to its anti-emetic action (neurotransmitter blockade at serotonin and dopamine receptors).

But due to its major adverse impact of daytime sedation, recent studies and randomized controlled trials have concluded its revised dose to be 5 mg for CINV.

To be noted here that the anti-emetic use of olanzapine is still off label, an unlicensed drug used for this purpose.

That's all

- Jaskunwar Singh

Important Mnemonics for Oral hypoglycaemic drugs in Diabetes

Hello everyone .. 

I make mnemonics for some important side effects of oral hypoglycemic drugs. 

You must know that because you may prescribe it for 1 out of 11 adults in whole population the of world….!!

Side effects of Oral hypoglycaemic drugs along with it's class & mechanism of action 

#Mnemonic 1

Big Men ForminG Poor Diabetic neuropathy ( D/Dx B12 Deficiency ➡️ confirmed by doing  B12 LAB test.)

Biguanide = Metformin 

Inhibit mGPD 

It causes Vitamin B12 Deficiency & Lactic Acidosis (LA) 

#Mnemonic 2 

1st Key to SUccess is Lord "Ram"

1st Gen SUlfonylureas

Closes K+ Channel 

Ram = Disulfiram like reaction….

#Mnemonic 3 

Paragliding makes your heart failed or maybe a fracture or bladder injury 

Para = PPAR Y

Gliding = Glitazone activates it...

#Mnemonic 4

"Rosy red Blood don't reach to heart (MI) but goes into Pee = Red Pi ( Pee = Urine in Bladder Cancer )

MI (rosiglitazone) 

Bladder cancer (pioglitazone)

#Mnemonic 5

“Change your Daily Personal Passivity (DPP) otherwise your heart fails” 

DPP  = DPP-4 inhibitors 

#Mnemonic 6

“Candid Status is Very Good in Love Test”

SGLT-2 inhibitors can cause Vulvovaginal Candidiasis 

Drugs category & their Suffix 

Pramlintide = Amylin Analogue 

1st gen Sulfonylureas = “Amide”

2nd gen Sulfonylureas = “Ride” & “Zide”

Meglitinides = “Nide”

DPP-4 Inhibitors = “Gliptin”

Glitazones / thiazolidinediones = “Zone”

SGLT -2 Inhibitors = “Flozin”

#Mnemonic 7

Alpha glucosidase inhibitors = "Please Side your Car & Pay Toll"

Acarbose & Miglitol 

#Clinical Pearls 

Weight neutral = DPP 4 & Alpha Glucosidase inhibitors 

SGLT2 inhibitors & GLP-1 = Used in CVD

( Cardiovascular diseases) patients

In case of Renal failure you can only give 2 type of drugs orally = DPP 4 inhibitors & Glitazones 

Injectables can be given in renal failure.

3 times / day dosing = Pramlintide , Alpha Glucosidase inhibitors & Glinide 

Regular Insulin ( Short acting ) is preferred for 

DKA ( IV)

Hyperklaemia (Add Glucose)

Stress Hyperglycemia

Thank you :)

- Dr. Drashtant Prajapati

Therapeutics in Sickle Cell Anemia

Apart from Hydroxyurea, Analgesics and vasodilators like phosphodiesterase inhibitors, certain tantalizing novel drugs have been approved for Sickle cell anemia.... Let's take a closer look at them.

(1) Voxelotor (HbS polymerization inhibitor) binds covalently to N-terminal valine of alpha chain of HbS (around 30% of HbS in individual cell) stabilizing it's oxygenated form and causing left ward shift of dissociation curve without impairing oxygen delivery to tissues.

Consistently reduces hemolysis and viscosity with in 2 weeks of administration... FIRST EVER therapy targeting core defect.

Dihydropyridine vs non-Dihydropyridine CCBs mnemonic

Dihydropyridine vs non-Dihydropyridine CCBs were always a struggle to me because they are both CCBs but at the same time they have some differences.

I hope that the following mnemonic will help in reminding you which one is Dihydro and which one is not :D :

The mnemonic (remember DIE HARD movie and Bruce Willis)

I am a DIe Hard FAN

DIHydropyridine CCBs:
FAN
F- felodipine
A- amlodipine
N- nicardipine

So non-Dihydropyridine CCBs are Verapamil and Dilitazem.

The original FAN mnemonic was posted here:
http://woanchyi818.blogspot.com/2015/03/calcium-channel-blockers-ccbs.html

good luck :)

Murad

Aurora kinases

Hello friends, Let's talk about Aurora kinases today.... Aurora sounds so beautiful, right ?

Aurora kinases represent serine threonine kinases with instrumental role in cell division.

Specifically, Aurora kinase A is required for duplication and separation of centromere, and Aurora B is required for attachment of microtubules to centromere.

They are often over expressed in tumors resulting in defective cytokinesis during cell division, eventually causing aneuploidy and driving the carcinogenesis.

Now, it really gets interesting; usually when functioning of microtubules are perturbed say by paclitaxel, then spindle check point inhibitor is activated leading to cell demise by upregulation of P53, PUMA and other mediators.

But in case of Aurora kinase inhibition, cells keep on dividing especially in case of P53 mutated cells. Since centromeres will not segregate, it ultimately leads to tetraploid genome and four centromeres in a cell, causing catastrophic mitosis in subsequent cell cycle effectively tearing apart the genome.

They are significant because often when other tyrosine kinase inhibitors targeting EGFR, VEGFR, FGFR are used, tumors over express Aurora kinases, there by over riding the inhibition mediated by tyrosine kinase inhibitors.... So targeting them is key to maintain remission in patients already on kinase inhibitors.

Few examples of drugs in trials: Monastrol, Hesperidin.

It's called Aurora because of the similarity between the appearance of microtubule spindles during cell division and Aurora Borealis.

Pretty Majestic, right?

Submitted by Kirtan Patolia 

Pharmacologic treatment of pulmonary hypertension (notes and mnemonics)

Hi!

Vasodilator response: A favorable vasodilator response is defined as a fall in mPAP of 10 mm Hg or greater to less than 40 mm Hg with an unchanged or improved cardiac output, in response to an agent such as inhaled NO or IV epoprostenol.

Istradefylline

Istradefylline (Selective Adenosine 2A receptor antagonist), inhibits the adenosine's inhibitory effect on GABAergic transmission in direct nigro-striatal pathway while simultaneously inhibiting adenosine's stimulatory effect on GABAergic transmission in indirect nigro-striato-pallidal pathway, ultimately leading to stimulation of thalamo-stimulatory direct pathway and inhibition of thalamo-inhibitory indirect pathway.

Selinexor

Selinexor (Selective inhibitor of nuclear export) inhibits XPO1 (exporter protein 1).

XPO1 is often overexpressed in tumors leading to transport of tumor suppressor proteins like p16, p14, p27 from nucleus to cytoplasm and there by evading the apoptosis.

Luspatercept

Here is a submission by Kirtan on Luspatercept!

Luspatercept (recombinant fusion protein containing Activin receptor type IIB moeity) blocks excessive SMAD2/3 activity (Mothers against decapentaplegic homolog) lying downstream of TGF-beta signalling by binding endogenous TGF-beta family members, including Bone morphogenetic proteins (BMP), Activin, Inhibin, Lefty A/B, Artemin, Persephin, GDF, GDNF and MIS.