BIOCHEMISTRY, BIOMEDICINE & PHARMACEUTICS

                                              Highlights of Vosoritide Program - Vosoritide is the FDA approved drug for the treatment of Achondroplasia  - Developed by Biomarin, and received orphan designation from FDA and EMA - New Drug Application Under Review by FDA with Set PDUFA August 2020 - EMA validated the marketing authorization application - Publication of positive outcome data from Phase 3 study in Lancet Achondroplasia is   the most common form of disproportionate short stature in humans, it is characterized by slowing of endochondral ossification, which results in disproportionate short stature and disordered architecture in the long bones, spine, face, and base of the skull.  This condition is caused by a mutation in the fibroblast growth factor receptor 3 gene (FGFR3), a negative regulator of bone growth. Beyond disproportionate short stature...

  Metabolic Pathway for Phenylalanine and Tyrosine  ( For MCQ Practice click here ) Conversion of Phenylalanine to Tyrosine  - Phenylalanine hydroxylase (PAH) converts phenylalanine to tyrosine  - PAH is encoded by the PAH gene located in Chromosome 12 and consist of 13 exons  - Tetrameters with each monomer consisting of the catalytic site, regulator site, and subunit binding domain  - Phenylalanine hydroxylase is tetrahydrobiopterin (BH4) requiring enzyme  - Dihydrobioteridine reductase catalyzes the conversion of dihydrobiopteridine to tetrahydrobiopterin  - Deficiency of enzyme caused phenylketonuria  Figure- Overview of Phenylalanine and Tyrosine Metabolism   Transamination of Tyrosine  - Tyrosine aminotransferase catalyzes the conversion to tyrosine to p-hydroxyphenylpyruvate  - Tyrosine aminotransferase is a Pyridoxal-5-phosphate requiring enzyme  - In the process, alpha-ketoglutarate is converted into glutama...

Hemoglobin Gene Structure and Arrangement The human hemoglobins are encoded in two tightly linked structures: Alpha Gene Family:  - Alpha gene cluster is encoded by genes located in chromosome 16 - The alpha gene cluster contains  zeta gene that is expressed in the embryonic stage,  the alpha-like genes that are not expressed (pseudogenes) Alpha genes that encode the alpha subunit of hemoglobin Beta Gene Family - The gene for the beta-globin chain is located on chromosome 11 - The beta gene cluster consists of  the beta gene encodes for beta-subunit of adult hemoglobin two gamma genes (G γ  and A γ ) that encode the γ chain of fetal hemoglobin the delta gene that codes for the subunit present in HbA2   Expression of Hemoglobin During Various Developmental Stages Embryonic Hemoglobin:  Red blood cells first appear about six weeks after conception, these RBCs contain the embryonic hemoglobin synthesized by the yolk sac. These include Hb Portland ( ζ 2 γ ...

 Bead Extraction and Heat Dissociation (BEHD) For Mitigation of Drug Interference BEHD is the method developed for mitigating drug interference. BEHD method utilizes heat denaturation for the dissociation of the ADA-drug complex present in the samples. The samples are subsequently incubated with the sample and ADA is allowed to bind with Biotin-Drug and captured using streptavidin coated magnetic beads.  Next, the samples are eluted using weak acids such as acetic acid or glycine, neutralized, and assayed in the ADA or NAb assay. The heat denaturation steps become critical when the drugs that are used to capture ADAs are susceptible to harsher acid-base conditions. This BEHD is used for the detection of ADA for cytokine therapy.  Protocol For BEHD : i) Heat Denaturation for Dissociation for ADA-Drug Complex 50ul to 100 ul of the serum samples containing ADAs are treated with mild heat at 62 degrees Celsius for 1 hour in thermocycler and allow the dissociation of ...

CRESEMBA (isavuconazonium sulfate) is an azole antifungal indicated for use in the treatment of Aspergillosis & Mucor mycosis Indication of CRESEMBA Invasive aspergillosis Invasive mucormycosis Contraindications of CRESEMBA Hypersensitivity to CRESEMBA  Coadministration with strong CYP3A4 inhibitors, such as ketoconazole or high-dose ritonavir Coadministration with strong CYP3A4 inducers, such as rifampin, carbamazepine, St. John’s wort, or long acting barbiturates  Use in patients with familial short QT syndrome  Warning & Precautions for Use of CRESEMBA Hepatic Adverse Drug Reactions: Serious hepatic reactions have been reported. Evaluate liver-related laboratory tests at the start and during the course of CRESEMBA therapyInfusion-related reactions were reported during intravenous administration of CRESEMBA. Discontinue the infusion if these reactions occur Hypersensitivity Reactions: Serious hypersensitivity and severe skin reactions, such as anaphylaxi...

Anifrolumab is the FDA approved antibody therapy for Systemic Lupus Erythematosus Anifrolumab-fnia is a type I interferon (IFN) receptor antagonist, immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that is produced in mouse myeloma cells (NS0) by recombinant DNA technology. The molecular weight is approximately 148 kDa.  Indication of SAPHNELO/Anifrolumab: SAPHNELO is a type I interferon (IFN) receptor antagonist indicated for the treatment of adult patients with moderate to severe systemic lupus erythematosus (SLE), who are receiving standard therapy. Limitations of Use:  The efficacy of SAPHNELO has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. The use of SAPHNELO is not recommended in these situations. Contraindications SAPHNELO is contraindicated in patients with a history of anaphylaxis with anifrolumab-fnia Warning and Precautions Serious Infections: Serious and sometimes fatal infections have occu...

Evinacumab is FDA Approved Antibody Therapy for Homozygous Familial Hypercholesterolemia EVKEEZA/Evinacumab-dgnb is a recombinant human monoclonal antibody that binds to and inhibits ANGPTL3. ANGPTL3 is a member of the angiopoietin-like protein family that is expressed primarily in the liver and plays a role in the regulation of lipid metabolism by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL). Evinacumab-dgnb inhibition of ANGPTL3 leads to a reduction in LDL-C, HDL-C, and triglycerides (TG). Evinacumab-dgnb reduces LDL-C independent of the presence of LDL receptor (LDLR) by promoting very-low-density lipoprotein (VLDL) processing and clearance upstream of LDL formation. Evinacumab-dgnb blockade of ANGPTL3 lowers TG and HDL-C by rescuing LPL and EL activities, respectively Indication of EVKEEZA: EVKEEZA is an ANGPTL3 (angiopoietin-like 3) inhibitor indicated as an adjunct to other low-density lipoprotein-cholesterol (LDL-C) lowering therapies for the treatment of ...