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
Showing posts with label Pharmacology. Show all posts
Showing posts with label Pharmacology. Show all posts
Wednesday, April 29, 2020
Tuesday, April 28, 2020
Clinical correlate: Sildenafil contraindicated for pilots
Hello
PDE-6 is present in the eyes.
Thursday, April 16, 2020
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
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
Wednesday, April 15, 2020
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
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
Friday, April 3, 2020
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.
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
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
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)
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
Tuesday, March 31, 2020
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 |
Wednesday, March 25, 2020
COVID-19: Remdesivir (GS-5734)
Here is a short post about Remdesivir (GS-5734).
Compound:
A '-cyano-substituted adenosine nucleotide analog prodrug.
Compound:
A '-cyano-substituted adenosine nucleotide analog prodrug.
Saturday, March 21, 2020
Recent updates about treatment of COVID19
All things you need to know about COVID19
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
Thank you..
- Drashtant
Sunday, March 15, 2020
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
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
Friday, January 24, 2020
Mnemonic for Drug induced Cardiomyopathy
Hello everyone ....
Aunty = Anthracycline = Doxorubicin, Daunorubicin , Mitoxantrone
Cycling = Cyclophosphamide
paVEd = VEGF Inhibitors = Bevacizumab
Trails = Trastuzumab
Aunty is cycling 🚴♀️ on paved trails to protect her heart 💓
Aunty = Anthracycline = Doxorubicin, Daunorubicin , Mitoxantrone
Cycling = Cyclophosphamide
paVEd = VEGF Inhibitors = Bevacizumab
Trails = Trastuzumab
Friday, January 3, 2020
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
Monday, December 23, 2019
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
Sunday, December 22, 2019
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.
(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.
Wednesday, December 18, 2019
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.
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
http://woanchyi818.blogspot.com/2015/03/calcium-channel-blockers-ccbs.html
good luck :)
Murad
Monday, November 25, 2019
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
Sunday, November 17, 2019
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.
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.
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.
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.
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