Pressurized metered-dose inhalers using next-generation propellant HFO-1234ze(E) deposit negligible amounts of trifluoracetic acid in the environment

Pressurized metered-dose inhalers (pMDIs) deliver life-saving medications to patients with respiratory conditions and are the most used inhaler delivery device globally. pMDIs utilize a hydrofluoroalkane (HFA), also known as an F-gas, as a propellant to facilitate the delivery of medication into the lungs. Although HFAs have minimal impact on ozone depletion, their global warming potential (GWP) is more than 1,000 times higher than CO2, bringing them in scope of the F-Gas Regulation in the European Union (EU). The pharmaceutical industry is developing solutions, including a near-zero GWP “next-generation propellant,” HFO-1234ze(E). At the same time, the EU is also evaluating a restriction on per-and polyfluoroalkyl substances (PFAS) under the Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) regulation. Trifluoroacetic acid (TFA) is a persistent PFAS and a potential degradation product of HFO-1234ze(E). We quantified yield of TFA from HFO-1234ze(E) using a computational model under Europe-relevant atmospheric conditions. The modeling suggests that most HFO-1234ze(E) degrades into formyl fluoride within 20 days (≥85%) even at the highest examined altitude. These results suggest that TFA yield from HFO-1234ze(E) varies between 0%–4% under different atmospheric conditions. In 2022, France represented the highest numbers of pMDI units sold within the EU, assuming these pMDIs had HFO-1234ze(E) as propellant, we estimate an annual rainwater TFA deposition of ∼0.025 μg/L. These results demonstrate negligible formation of TFA as a degradation product of HFO-1234ze(E), further supporting its suitability as a non-persistent, non-bioaccumulative, and non-toxic future propellant for pMDI devices to safeguard access for patients to these essential medicines

A Mathematical model for Astrocytes mediated LTP at Single Hippocampal Synapses

Many contemporary studies have shown that astrocytes play a significant role in modulating both short and long form of synaptic plasticity. There are very few experimental models which elucidate the role of astrocyte over Long-term Potentiation (LTP). Recently, Perea & Araque (2007) demonstrated a role of astrocytes in induction of LTP at single hippocampal synapses. They suggested a purely pre-synaptic basis for induction of this N-methyl-D- Aspartate (NMDA) Receptor-independent LTP. Also, the mechanisms underlying this pre-synaptic induction were not investigated. Here, in this article, we propose a mathematical model for astrocyte modulated LTP which successfully emulates the experimental findings of Perea & Araque (2007). Our study suggests the role of retrograde messengers, possibly Nitric Oxide (NO), for this pre-synaptically modulated LTP.Comment: 51 pages, 15 figures, Journal of Computational Neuroscience (to appear

A Biophysical Model of the Mitochondrial ATP-Mg/Pi Carrier

Mitochondrial adenine nucleotide (AdN) content is regulated through the Ca2+-activated, electroneutral ATP-Mg/Pi carrier (APC). The APC is a protein in the mitochondrial carrier super family that localizes to the inner mitochondrial membrane (IMM). It is known to modulate a number of processes that depend on mitochondrial AdN content, such as gluconeogenesis, protein synthesis, and citrulline synthesis. Despite this critical role, a kinetic model of the underlying mechanism has not been developed and validated. Here, a biophysical model of the APC is developed that is thermodynamically balanced and accurately reproduces a number of reported data sets from isolated rat liver and rat kidney mitochondria. The model is based on an ordered bi-bi mechanism for hetero-exchange of ATP and Pi and also includes homo-exchanges of ATP and Pi to explain both the initial rate and time course data on ATP and Pi transport via the APC. The model invokes seven kinetic parameters regarding the APC mechanism and three parameters related to matrix pH regulation by external Pi. These parameters are estimated based on nineteen independent data curves; the estimated parameters are validated using six additional data curves. The model takes into account the effects of pH, Mg2+ and Ca2+ on ATP and Pi transport via the APC and supports the conclusion that the pH gradient across the IMM serves as the primary driving force for AdN uptake or efflux. Moreover, computer simulations demonstrate that extra-matrix Ca2+ modulates the turnover rate of the APC and not the binding affinity of ATP, as previously suggested.Comment: This paper has been withdrawn by the author due to some incorrect presentation in the results and discussion par