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

Pharmacophore model for pentamidine analogs active against Plasmodium falciparum

Pentamidine and its analogs constitute a class of compounds that are known to be active against Plasmodium falciparum, which causes the most dangerous malarial infection. Malaria is a widespread disease known to affect hundreds of millions of people and presents a perceivable threat of spreading. Hence, there is a need for well-defined scaffolds that lead to new, effective treatment. Here we present a pentamidine-based pharmacophore constructed using GALAHAD that would aid targeted synthesis of leads with enhanced properties, as well as the development of lead scaffolds. The study was supported by high-quality biological in vitro data of 22 compounds against the P. falciparum strains NF54 and K1. The model established reveals the importance of hydrophobic phenyl rings with polar oxygen and amidine substituents and the hydrophobic linking chain for the activity against malari

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

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