IDA Ireland

Objective This study was performed to appraise the effect of modulation of formulation pH and abdominal pH on the pharmacokinetics (PK) of the selected compounds from different drugs of the Biopharmaceutics Classification System (BCS) when administered via cassette dosing in rats. Methods Pharmacokinetics of four different BCS class drugs viz. propranolol HCl, diclofenac sodium, atenolol, and acetazolamide (BCS-I, II, III, and IV, respectively) in different formulation pH conditions and different abdominal pH conditions were evaluated. The animal groups were dosed orally. Results Propranolol HCl exhibited a significant increase in area under the curve (AUC0–last) when the alimentary canal pH was modulated to acidic (195%), and a significant increase in maximum concentration at a given time point (C max) (102%) for formulation with basic pH in healthy animals. Diclofenac exhibited a significant increase in AUC0–last when the alimentary canal pH was modulated to acidic (95%), and a significant decrease in C max (55%) for formulation with basic pH in healthy animals. Atenolol displayed a substantial increase in AUC0–last in basic pH conditions in the alimentary canal (38%), and a significant decrease in AUC0–last (49%) for basic pH formulation in healthy animals. Acetazolamide demonstrated a considerable increase in AUC0–last when alimentary canal pH was modulated to basic (55%), and a substantial enhancement in AUC0–last (39%) for acidic pH formulation in healthy animals. Conclusion The results suggest that both alimentary canal conditions with acidic and basic pH and formulation with acidic and basic pH have a considerable influence on the PKs of different compounds not only based on their acid dissociation constant (pKa) but also independently on the pH in the area of absorption in the alimentary canal and salt form of the compound.

Drug-resistant hepatitis B virus (HBV) strains necessitate the development of novel antiviral agents. In our previous report, we identified a 7-deazaadenine-based neplanocin analogue II (NepA) as a potent anti-HBV compound (EC50 = 0.77 µM, CC50 > 100 µM) with unique therapeutic potential. This pseudonucleoside analogue (NA) II reduced HBsAg production and promoted pregenomic RNA (pgRNA) degradation in the HepG2.2.15.7 cell line. Notably, its mechanism of action is distinct from those of nucleoside polymerase inhibitors and operates independently of S-adenosylhomocysteine hydrolase (SAHase) inhibition. To further explore the structure-activity relationship (SAR), we synthesized a series of NepA analogues with selected modifications at the 5'- and 2'-positions of the carbasugar. This series includes 5'- and 2'-hydroxy masking (O-Me, 4a-4g and 13), 5'-OH truncation (7a and 7b), and steric interference at the 5'-OH position (10a and 10b). All analogues were synthesized through a concise synthetic route from a common intermediate (2a-2g). Among these, two derivatives exhibited notable antiviral activity: one is 5'-hydroxy masked (4a, EC50 = 3.0 µM, CC50 > 100 µM) and the other is 5'-hydroxy truncated (7a, EC50 = 3.6 µM, CC50 > 100 µM). These findings suggest that HBV polymerase inhibition may not be the sole antiviral mechanism of pseudo-NA (II), highlighting the need for further mechanistic investigations. This study provides valuable insights for the development of next-generation HBV therapeutics.

During the earlier period of the 20 <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">th</sup> century, following a brief flirtation with laissez-faire economic policies in the 1920's, there was a decisive shift towards economic nationalism and protectionism based on "infant-industry" arguments. This was in line with much conventional economic theory at the time. At the time those working in agriculture accounted for over 50% of the labour-force and agricultural based exports accounted for almost 90% of all exports. Over 90% of these exports went to the U.K. and Ireland was heavily dependent on imports from the U.K. for industrial products. From the 1930's determined efforts were made to build up an indigenous industrial capability by the introduction of duties, ranging from 15% to 75%, on a wide variety of imported goods and the parallel promotion of industrial enterprises in Ireland. At the same time legislation was introduced to provide that Irish nationals must hold a majority of the nominal share capital and voting rights in new manufacturing enterprises. Political and economic decisions taken in the middle part of the century, like the negotiation of the Anglo/Irish free trade agreement; the relaxing of company ownership rules; the establishment of the Industrial Development Authority to promote foreign direct investment, had a significant impact on the development of the economy over the following 50 years and changed Ireland from an agricultural economy to one where most of the top 10 companies worldwide in the pharmaceutical, electronic, medical devices, finance and software sectors now have significant and strategic operations in Ireland. Economic and industrial policy was used as a tool to create jobs and employment. The requirement that projects must be internationally trading helped to diversify the economy away from its dependence on UK markets and was also used as a way of encouraging the entrepreneurial spirit and the development of the indigenous industry sector. How has Ireland changed from an agricultural to an industrial economy and what have been the challenges for education and vocational training to meet the changing needs of industry in the first instance and the services sector in latter years. As the economy now moves from a cost competitive mode to a high cost mode how does Ireland prepare to adjust and what are the challenges. What is the next stage of FDI - Ireland must move from being the producer to being the creator of solutions to other people's challenges providing solutions that are superior to those provided by competing economies.