Degradation of Pharmaceuticals Through Sequential Photon Absorption and Photoionization – the Case of Amiloride Derivatives

Photodegradation of pharmaceutical and agrochemical compounds is an important concern for health and the environment. Amiloride derivatives undergo clean photosubstitution in protic solvents. We have studied this apparent photo-SNAr reaction with a range of experimental and computational techniques. Available evidence points to a mechanism starting with photoexcitation followed by absorption of a second photon to eject an electron to give a radical cation intermediate. Subsequent substitution reaction with the protic solvent is assisted by a general base, possibly strengthened by the proximal solvated electron. Final recombination with the solvated electron generates the observed product. Quantum chemical computations reveal that excited state antiaromaticity is relieved when an electron is ejected from the photoexcited molecule by the second photon, leading to a weakly aromatic radical cation. The mechanism indicated here could have wide applicability to photoinduced degradation of similar heteroaromatic compounds in the environment as well as in protic solvents. There are also strong similarities to a class of increasingly popular synthetic photoredox methods

Degradation of Pharmaceuticals through Sequential Photon Absorption and Photoionization in Amiloride Derivatives

Haloaromatic drug molecules of the amiloride family are plagued by photodegradation with associated toxicity. Herein, we report on the photodegradation of analogs of amiloride, which are known to undergo photosubstitution in water. Model compounds built on the same scaffold undergo clean photosubstitution also in alcoholic solvent, where a certain amount of photodehalogenation is normally expected. Available evidence points to a mechanism starting with photoexcitation followed by photoionization to give a radical cation intermediate. Subsequent substitution reaction with the protic solvent is assisted by a general base, possibly strengthened by the proximal solvated electron. Recombination with the solvated electron generates the observed product. Quantum chemical computations reveal that excited state antiaromaticity is relieved when an electron is ejected from the photoexcited molecule by the second photon. The mechanism indicated here could have wide applicability to photoinduced degradation of similar heteroaromatic compounds in the environment, as well as to a class of increasingly popular synthetic photoredox methods

Assessing real-world gait with digital technology? Validation, insights and recommendations from the Mobilise-D consortium.

Although digital mobility outcomes (DMOs) can be readily calculated from real-world data collected with wearable devices and ad-hoc algorithms, technical validation is still required. The aim of this paper is to comparatively assess and validate DMOs estimated using real-world gait data from six different cohorts, focusing on gait sequence detection, foot initial contact detection (ICD), cadence (CAD) and stride length (SL) estimates.Twenty healthy older adults, 20 people with Parkinson's disease, 20 with multiple sclerosis, 19 with proximal femoral fracture, 17 with chronic obstructive pulmonary disease and 12 with congestive heart failure were monitored for 2.5 h in the real-world, using a single wearable device worn on the lower back. A reference system combining inertial modules with distance sensors and pressure insoles was used for comparison of DMOs from the single wearable device. We assessed and validated three algorithms for gait sequence detection, four for ICD, three for CAD and four for SL by concurrently comparing their performances (e.g., accuracy, specificity, sensitivity, absolute and relative errors). Additionally, the effects of walking bout (WB) speed and duration on algorithm performance were investigated.We identified two cohort-specific top performing algorithms for gait sequence detection and CAD, and a single best for ICD and SL. Best gait sequence detection algorithms showed good performances (sensitivity > 0.73, positive predictive values > 0.75, specificity > 0.95, accuracy > 0.94). ICD and CAD algorithms presented excellent results, with sensitivity > 0.79, positive predictive values > 0.89 and relative errors < 11% for ICD and < 8.5% for CAD. The best identified SL algorithm showed lower performances than other DMOs (absolute error < 0.21 m). Lower performances across all DMOs were found for the cohort with most severe gait impairments (proximal femoral fracture). Algorithms' performances were lower for short walking bouts; slower gait speeds (< 0.5 m/s) resulted in reduced performance of the CAD and SL algorithms.Overall, the identified algorithms enabled a robust estimation of key DMOs. Our findings showed that the choice of algorithm for estimation of gait sequence detection and CAD should be cohort-specific (e.g., slow walkers and with gait impairments). Short walking bout length and slow walking speed worsened algorithms' performances. Trial registration ISRCTN - 12246987