RESUMO
Recently, it was found that paracetamol can extend the therapeutic window of l-DOPA treatment for Parkinson's disease [Golding (2019) BJPharm, 4(2), Article 619]. It has been posited that the effect could be due to paracetamol and its metabolite, NAPQI, inhibiting pain signals in the spinal column. In this work, we examine the possibility that the therapeutic effect of the paracetamol for the Parkinson's disease patient may be due to an inhibition of the enzymes that metabolize dopamine and/or l-DOPA, thus effectively extending the lifetime of the l-DOPA treatment. In this work, we use the M062X/6-311+G* level of theory to calculate the electronic binding energies (including explicit desolvation) of several ligands (paracetamol, NAPQI, dopamine, and l-DOPA) with a series of enzymes important to the production and metabolism of dopamine and compare them to calculated binding energy values for the natural substrates for those enzymes in order to predict possible inhibition. Benchmark interaction energies for a subset of the systems studied are calculated using the more accurate second-order Møller-Plesset perturbation (MP2) method in order to calibrate the accuracy of the M062X method. If we assume that the interaction energies calculated here can serve as a proxy for in vivo inhibition, then we can predict that paracetamol and NAPQI should not inhibit the natural production of dopamine and may in fact inhibit the metabolism of l-DOPA and dopamine, thus extending the length of l-DOPA treatments.
RESUMO
BACKGROUND: The United Kingdom (UK) was one of the first countries to pioneer heart transplantation from donation after circulatory death (DCD) donors. To facilitate equity of access to DCD hearts by all UK heart transplant centers and expand the retrieval zone nationwide, a Joint Innovation Fund (JIF) pilot was provided by NHS Blood and Transplant (NHSBT) and NHS England (NHSE). The activity and outcomes of this national DCD heart pilot program are reported. METHODS: This is a national multi-center, retrospective cohort study examining early outcomes of DCD heart transplants performed across 7 heart transplant centers, adult and pediatric, throughout the UK. Hearts were retrieved using the direct procurement and perfusion (DPP) technique by 3 specialist retrieval teams trained in ex-situ normothermic machine perfusion. Outcomes were compared against DCD heart transplants before the national pilot era and against contemporaneous donation after brain death (DBD) heart transplants, and analyzed using Kaplan-Meier analysis, chi-square test, and Wilcoxon's rank-sum. RESULTS: From September 7, 2020 to February 28, 2022, 215 potential DCD hearts were offered of which 98 (46%) were accepted and attended. There were 77 potential donors (36%) which proceeded to death within 2 hours, with 57 (27%) donor hearts successfully retrieved and perfused ex situ and 50 (23%) DCD hearts going on to be transplanted. During this same period, 179 DBD hearts were transplanted. Overall, there was no difference in the 30-day survival rate between DCD and DBD (94% vs 93%) or 90 day survival (90% vs 90%) respectively. There was a higher rate of ECMO use post-DCD heart transplants compared to DBD (40% vs 16%, p = 0.0006), and DCD hearts in the pre pilot era, (17%, p = 0.002). There was no difference in length of ICU stay (9 DCD vs 8 days DBD, p = 0.13) nor hospital stay (28 DCD vs 27 DBD days, p = 0.46). CONCLUSION: During this pilot study, 3 specialist retrieval teams were able to retrieve DCD hearts nationally for all 7 UK heart transplant centers. DCD donors increased overall heart transplantation in the UK by 28% with equivalent early posttransplant survival compared with DBD donors.
