Determination of in-vitro Equivalence of Paracetamol Tablets

Bioequivalence studies are the usually accepted method to determine the therapeutic equivalence of two drugproducts. Because in-vivo bioequivalence studies are time consuming and expensive to conduct, majorregulatory authorities have introduced biowaivers for some selected medicines belonging to BCS class 1 andIII drugs. Comparative dissolution tests are used in biowaiver procedure to waiver the bioequivalencerequirement. We performed this study to see whether two brands of paracetamol tablets are bioequivalentusing the in-vitro methodology. In the first stage of this research study, British Pharmacopeia 2012 qualitytests were performed on the two selected paracetamol tablet products to determine whether they arepharmaceutically equivalent. In the second stage in-vitro equivalence of the two products was determinedusing the biowaiver testing procedure given by the World Health Organization. Dissolution profiles weregenerated at pH values, 1.2, 4.5 and 6.8. Results were compared through two model independent methods,difference factor (f1) and similarity factor (f2). The two paracetamol tablet products tested, complied with allthe quality requirements of the British Pharmacopeia 2012. For the two products, the difference factor (f1)was below the 15 and similarity factor (f2) was above the 50 in all dissolution test conditions. These resultsconfirm that the two products are pharmaceutically equivalent. The test product is also bioequivalent to thereference product in-vitro, and therefore they can be interchangeable during clinical use. This study showsthat in-vivo bioequivalence testing can be waived using the in-vitro method, for some pharmaceuticalproducts such as paracetamol tablets.KEYWORDS: Paracetamol tablets, Biowaivers, Dissolution profile

Structure-Based Exploration and Exploitation of the S4 Subsite of Norovirus 3CL Protease in the Design of Potent and Permeable Inhibitors

Human noroviruses are the primary cause of epidemic and sporadic acute gastroenteritis. The worldwide high morbidity and mortality associated with norovirus infections, particularly among the elderly, immunocompromised patients and children, constitute a serious public health concern. There are currently no approved human vaccines or norovirus-specific small-molecule therapeutics or prophylactics. Norovirus 3CL protease has recently emerged as a potential therapeutic target for the development of anti-norovirus agents. We hypothesized that the S4 subsite of the enzyme may provide an effective means of designing potent and cell permeable inhibitors of the enzyme. We report herein the structure-guided exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design and synthesis of effective inhibitors of the protease

Antiviral Drug Discovery: Norovirus Proteases and Development of Inhibitors

Proteases are a major enzyme group playing important roles in a wide variety of biological processes in life forms ranging from viruses to mammalians. The aberrant activity of proteases can lead to various diseases; consequently, host proteases have been the focus of intense investigation as potential therapeutic targets. A wide range of viruses encode proteases which play an essential role in viral replication and, therefore, constitute attractive targets for the development of antiviral therapeutics. There are numerous examples of successful drug development targeting cellular and viral proteases, including antivirals against human immunodeficiency virus and hepatitis C virus. Most FDA-approved antiviral agents are peptidomimetics and macrocyclic compounds that interact with the active site of a targeted protease. Norovirus proteases are cysteine proteases that contain a chymotrypsin-like fold in their 3D structures. This review focuses on our group’s efforts related to the development of norovirus protease inhibitors as potential anti-norovirus therapeutics. These protease inhibitors are rationally designed transition-state inhibitors encompassing dipeptidyl, tripeptidyl and macrocyclic compounds. Highly effective inhibitors validated in X-ray co-crystallization, enzyme and cell-based assays, as well as an animal model, were generated by launching an optimization campaign utilizing the initial hit compounds. A prodrug approach was also explored to improve the pharmacokinetics (PK) of the identified inhibitors

Determination of in-vitro equivalence of paracetamol tablets

Bioequivalence studies are the usually accepted method to determine the therapeutic equivalence of two drugproducts. Because in-vivo bioequivalence studies are time consuming and expensive to conduct, majorregulatory authorities have introduced biowaivers for some selected medicines belonging to BCS class 1 andIII drugs. Comparative dissolution tests are used in biowaiver procedure to waiver the bioequivalencerequirement. We performed this study to see whether two brands of paracetamol tablets are bioequivalentusing the in-vitro methodology. In the first stage of this research study, British Pharmacopeia 2012 qualitytests were performed on the two selected paracetamol tablet products to determine whether they arepharmaceutically equivalent. In the second stage in-vitro equivalence of the two products was determinedusing the biowaiver testing procedure given by the World Health Organization. Dissolution profiles weregenerated at pH values, 1.2, 4.5 and 6.8. Results were compared through two model independent methods,difference factor (f1) and similarity factor (f2). The two paracetamol tablet products tested, complied with allthe quality requirements of the British Pharmacopeia 2012. For the two products, the difference factor (f1)was below the 15 and similarity factor (f2) was above the 50 in all dissolution test conditions. These resultsconfirm that the two products are pharmaceutically equivalent. The test product is also bioequivalent to thereference product in-vitro, and therefore they can be interchangeable during clinical use. This study showsthat in-vivo bioequivalence testing can be waived using the in-vitro method, for some pharmaceuticalproducts such as paracetamol tablets.KEYWORDS: Paracetamol tablets, Biowaivers, Dissolution profile

Structure-Guided Design of Conformationally-Constrained Cyclohexane Inhibitors of SARS-CoV-2 3CL Protease

A series of non-deuterated and deuterated dipeptidyl aldehyde and masked aldehyde inhibitors that incorporate in their structure a conformationally-constrained cyclohexane moiety was synthesized and found to potently inhibit SARS-CoV-2 3CL protease in biochemical and cell-based assays

Design, Synthesis, and Evaluation of Novel Prodrugs of Transition State Inhibitors of Norovirus 3CL Protease

Ester and carbamate prodrugs of aldehyde bisulfite adduct inhibitors were synthesized in order to improve their pharmacokinetic and pharmacodynamic properties. The inhibitory activity of the compounds against norovirus 3C-like protease in enzyme and cell-based assays was determined. The ester and carbamate prodrugs displayed equivalent potency to those of the precursor aldehyde bisulfite adducts and precursor aldehydes. Furthermore, the rate of ester cleavage was found to be dependent on alkyl chain length. The generated prodrugs exhibited low cytotoxicity and satisfactory liver microsomes stability and plasma protein binding. The methodology described herein has wide applicability and can be extended to the bisulfite adducts of common warheads employed in the design of transition state inhibitors of serine and cysteine proteases of medical relevance

Design, Synthesis, and Evaluation of Novel Prodrugs of Transition State Inhibitors of Norovirus 3CL Protease

Ester and carbamate prodrugs of aldehyde bisulfite adduct inhibitors were synthesized in order to improve their pharmacokinetic and pharmacodynamic properties. The inhibitory activity of the compounds against norovirus 3C-like protease in enzyme and cell-based assays was determined. The ester and carbamate prodrugs displayed equivalent potency to those of the precursor aldehyde bisulfite adducts and precursor aldehydes. Furthermore, the rate of ester cleavage was found to be dependent on alkyl chain length. The generated prodrugs exhibited low cytotoxicity and satisfactory liver microsomes stability and plasma protein binding. The methodology described herein has wide applicability and can be extended to the bisulfite adducts of common warheads employed in the design of transition state inhibitors of serine and cysteine proteases of medical relevance

Structure-Guided Design of Potent Inhibitors of SARS-CoV-2 3CL Protease: Structural, Biochemical, and Cell-Based Studies.

We describe herein the results of our studies related to the application of X-ray crystallography, the Thorpe-Ingold effect, deuteration, and stereochemistry in the design of highly potent and non-toxic inhibitors of SARS-CoV-2 3CLpro to combat SARS-CoV-2 and emerging variants.</p