Are the postmortem concentration changes of the synthetic cannabinoid cumyl-5F-P7AICA and its N-pentanoic acid metabolite dependent on the environmental conditions? - A systematic study following pulmonary administration to pigs.

The number of fatal cases involving synthetic cannabinoids (SCs) is increasing. However, interpretation of postmortem (PM) toxicological findings is challenging, due to unknown PM intervals and possible redistribution processes or instabilities. Only sparse data on SCs are available. Therefore, a controlled pig study was performed to determine the PM stability of cumyl-5F-P7AICA under different environmental conditions. Ten pigs inhalatively received 200 µg/kg body weight cumyl-5F-P7AICA each. Six hours later, they were euthanized and biopsies of the main tissues and body fluids were taken. Animals were stored in air or water (n=5 each) and samples were repeatedly taken for three days. Quantification of cumyl-5F-P7AICA and its N-pentanoic acid metabolite (NPA) was performed using standard addition or a fully validated method (blood) followed by LC-MS/MS. Time-dependent concentration changes of cumyl-5F-P7AICA were observed in liver, bile fluid and muscle specimens at both conditions. Concentrations of NPA only changed considerably in duodenum content of animals stored in air. Environment-dependent concentrations changes were only observed for cumyl-5F-P7AICA in kidney and the NPA metabolite in duodenum content. Overall, cumyl-5F-P7AICA and its metabolite seem to be quite stable in PM specimens. Hence, also central blood might be analyzed, if no peripheral blood is available.

Near Add Power of Glaucoma Patients with Early Presbyopia.

Purpose: Glaucoma medication may accelerate the progression of presbyopia. The aim of this study was to compare presbyopia between controls and patients with glaucoma in their 40s. Methods: This was a cross-sectional study of bilateral phakic participants aged between 40 and 49, which included controls (n = 114, mean age 46.1 ± 2.7 y) and patients with primary open-angle glaucoma (n = 105, 46.4 ± 2.7 y) who had been using FP receptor agonists, beta blockers, and carbonic anhydrase inhibitors for at least six months. We compared the near add power between the two groups. Results: The mean near add power and the prevalence of symptomatic presbyopia (near add power ≥ 1.50 D) were 1.16 ± 0.74 D and 42.1% for controls and 1.77 ± 0.71 D (p < 0.01) and 79.0% (p < 0.01) for glaucoma patients, respectively. The odds ratio (OR) and confidence interval for symptomatic presbyopia were associated with age (1.36, 1.21-1.52), ganglion cell complex thickness (0.96, 0.94-0.99), presence of glaucoma (6.19, 3.13-12.23), and number of glaucoma medications (4.26, 2.42-7.43). Among medications, only FP receptor agonists (5.79, 2.68-12.32) produced significant results. Survival analysis showed that glaucoma patients reached the threshold of a near add power of +1.50 D significantly sooner than controls (p < 0.05; log-rank test). Conclusions: Glaucoma patients, especially those using FP receptor agonists, had higher near add power than controls.

Oxygenation Index, Oxygen Saturation Index vs PaO2/FiO2 *PEEP: A Secondary Analysis of OXIVA-CARDS Study.

Background: The classification of Berlin definition is based on the PaO2/FiO2 ratio, which has been found to have a poor association with mortality. Airway pressures reflect lung compliance and the settings of mechanical ventilators. In this study, we aimed to investigate the change in the severity of COVID-19-associated acute respiratory distress syndrome (ARDS) classification using [PaO2/FiO2 × PEEP] (P/FP) ratio compared to the traditional P/F ratio, and whether the P/FP ratio improves the predictive validity of in-hospital mortality. Methods: Our study sample included patients from the OXIVA-CARDS study. In this secondary analysis, we examined the oxygenation index and oxygen saturation index in relation to the P/FP ratio, as well as the risk of P/FP in mortality. We used Pearson's correlation to assess the relationships between various parameters. Receiver operating characteristic analysis with Youden's index was used to compare the prognostic value of the oxygenation index (OI), oxygen saturation index (OSI), P/F ratio, P/FP ratio, and SaO2/FiO2 ratio for predicting overall mortality. Multiple logistic regression was also performed to determine the impact of mean airway pressure (Pmean), S/F ratio, OI, and P/FP ratio on mortality. Results: A total of 201 patients (with 1543 measurements) were included in the analysis. Overall, 522 (34%) were reclassified into either more or less severe categories. Patients who were classified as having severe ARDS based on the P/FP ratio had significantly lower P/FP ratio, oxygenation index, and A-a O2 gradient as compared to those classified as having severe ARDS based on the P/F ratio (p < 0.05) at all levels of ARDS severity. On multivariate regression analysis, only the OI significantly impacted mortality (p < 0.05). Conclusion: We observed that the oxygen index and oxygen saturation index were more sensitive than the PaO2/FiO2 ratio and P/FP ratio. Additionally, only the oxygenation index had a significant impact on mortality. By including airway pressures in the calculation of the OI, its predictive ability is enhanced compared to using the S/F ratio, P/F ratio, or P/FP ratio. Highlights: The sensitivity of mortality by including Pmean is higher as compared to when only PEEP is taken into consideration. P/FP is a weak predictor of mortality as compared to OI and OSI. How to cite this article: Vadi SMR, Sanwalka N, Suthar D. Oxygenation Index, Oxygen Saturation Index vs PaO2/FiO2 *PEEP: A Secondary Analysis of OXIVA-CARDS Study. Indian J Crit Care Med 2024;28(10):917-922.

High-Performance CsPbI3 Quantum Dot Photodetector with a Vertical Structure Based on the Frenkel-Poole Emission Effect.

The selection of photoactive materials and the design of device structures are critical to the photoelectronic performance of photodetectors. This study reports on a vertically structured photodetector device with rapid, stable, and efficient photoelectric performance across the UV-visible broadband range based on the Si++/SiO2/Au/single-layer graphene/CsPbI3 quantum dots (QDs) configuration. In this specific device structure, a relatively high conductivity Si++/SiO2 wafer was used as the substrate, a CsPbI3 QD film with high light absorption was used as the photoactive layer, and a monolayer graphene with high conductivity was inserted between the substrate and the CsPbI3 QD film to form a heterojunction with the QD film. Based on the Frenkel-Poole emission effect arising from the high trap state density within the SiO2 layer, the device exhibited excellent photoelectric performances. Especially at a wavelength of 365 nm, a photocurrent responsivity of 2319 A/W, a specific detectivity of 1.15 × 1014 Jones, an external quantum efficiency of 7883%, and an on/off time of 39/36 ms at a Si++ terminal voltage of -80 V and an optical power density of 84.03 nW/cm2 can be achieved.

Rest Tremor in Parkinson's Disease Is Associated with Ipsilateral Striatal Dopamine Transporter Binding.

BACKGROUND: The cardinal motor symptoms of Parkinson's disease (PD) include rigidity, bradykinesia, and rest tremor. Rigidity and bradykinesia correlate with contralateral nigrostriatal degeneration and striatal dopamine deficit, but association between striatal dopamine function and rest tremor has remained unclear. OBJECTIVE: The aim of this study was to investigate the possible link between dopamine function and rest tremor using Parkinson's Progression Markers Initiative dataset, the largest prospective neuroimaging cohort of patients with PD. METHODS: Clinical, [123I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane ([123I]FP-CIT) single photon emission computed tomography (SPECT), and structural magnetic resonance imaging data from 354 early PD patients and 166 healthy controls were included in this study. We employed a novel approach allowing nonlinear registration of individual scans accurately to a standard space and voxelwise analyses of the association between motor symptoms and striatal dopamine transporter (DAT) binding. RESULTS: Severity of both rigidity and bradykinesia was negatively associated with contralateral striatal DAT binding (PFWE < 0.05 [FWE, family-wise error corrected]). However, rest tremor amplitude was positively associated with increased ipsilateral DAT binding (PFWE < 0.05). The association between rest tremor and binding remained the same controlling for Hoehn & Yahr stage, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score, bradykinesia-rigidity score, or motor phenotype. The association between rest tremor and binding was independent of bradykinesia-rigidity and replicated using 2-year follow-up data (PFWE < 0.05). CONCLUSION: In agreement with the existing literature, we did not find a consistent association between rest tremor and contralateral dopamine defect. However, our results demonstrate a link between rest tremor and increased or less decreased ipsilateral DAT binding. Our findings provide novel information about the association between dopaminergic function and parkinsonian rest tremor. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

TwinF interface inhibitor FP802 prevents retinal ganglion cell loss in a mouse model of amyotrophic lateral sclerosis.

Motor neuron loss is well recognized in amyotrophic lateral sclerosis (ALS), but research on retinal ganglion cells (RGCs) is limited. Ocular symptoms are generally not considered classic ALS symptoms, although RGCs and spinal motor neurons share certain cell pathologies, including hallmark signs of glutamate neurotoxicity, which may be triggered by activation of extrasynaptic NMDA receptors (NMDARs). To explore potential novel strategies to prevent ALS-associated death of RGCs, we utilized inhibition of the TwinF interface, a new pharmacological principle that detoxifies extrasynaptic NMDARs by disrupting the NMDAR/TRPM4 death signaling complex. Using the ALS mouse model SOD1G93A, we found that the small molecule TwinF interface inhibitor FP802 prevents the loss of RGCs, improves pattern electroretinogram (pERG) performance, increases the retinal expression of Bdnf, and restores the retinal expression of the immediate early genes, Inhibin beta A and Npas4. Thus, FP802 not only prevents, as recently described, death of spinal motor neurons in SOD1G93A mice, but it also mitigates ALS-associated retinal damage. TwinF interface inhibitors have great potential for alleviating neuro-ophthalmologic symptoms in ALS patients and offer a promising new avenue for therapeutic intervention.

Prominent loss of striatal dopamine transporter binding in frontotemporal lobar degeneration with the MAPT N279K mutation present as early as at prodromal stage without parkinsonism.

Our research found out, from 123I-FP-CIT SPECT scans of three familial frontotemporal dementia (fFTD) individuals with MAPT N279K mutation and similar autopsy findings of frontotemporal degeneration with severe neuronal loss in the substantia nigra, that prominent decrease of dopamine transporter binding (z-score < -5.0) was present at prodromal fFTD without parkinsonism.

Comparison of the ability of different quantitative indices in 123I-FP-CIT single-photon emission computed tomography to differentiate dopaminergic neurodegenerative disease.

PURPOSE: By imaging dopamine transporter (DAT) uptake in the striatum, 123I-FP-CIT SPECT can differentiate dopaminergic neurodegenerative disease (dNDD) and non-dNDD, which differ in pathophysiology and clinical management. Our aim was to compare and validate the diagnostic abilities of various 123I-FP-CIT SPECT quantitative indices for dNDD. MATERIALS AND METHODS: Distribution volume ratio (DVR) and binding ratio (BR), measures of DAT uptake capacity, were measured by analyzing clinical 123I-FP-CIT SPECT images of 29 patients with dNDD, including dementia with Lewy bodies and Parkinson's disease, and 18 patients with non-dNDD, using Montreal Neurological Institute space-based anatomical standardization and an atlas template, which utilizes statistical parametric mapping. Additionally, we computed the specific binding ratio (SBR) based on Bolt's method and the maximum and mean standardized uptake values (SUVmax and SUVmean, respectively). RESULTS: The caudate-to-occipital lobe, putamen-to-occipital lobe, and striatum-to-occipital lobe ratios (COR, POR, and SOR, respectively) on DVR and POR and SOR on BR were significantly lower in dNDD than in non-dNDD, with areas under the ROC curve (AUCs) of 0.941-0.960, showing high diagnostic accuracy for dNDD. However, the AUC of COR on BR was 0.839, indicating lower diagnostic performance. SBR had an AUC of 0.921, while SUVmax and SUVmean had AUCs of 0.906 and 0.900, respectively. Although striatal asymmetry on both DVR and BR exhibited AUCs of 0.728 and 0.734 and asymmetry on SBR showed an AUC of 0.757, the ratio-based DAT quantitative indices were superior. There were strong positive correlations of DVR with BR, DVR with SBR or SUVmax, BR with SBR or SUVmax, and SBR with SUVmax. CONCLUSION: COR, POR, and SOR on DVR and POR and SOR on BR were the most useful DAT quantitative indices. These indices can be compared with SBR and SUV, suggesting that comprehensive evaluation improves the diagnostic accuracy of dNDD.

Neuromelanin-targeted 18 F-P3BZA PET/MR imaging of the substantia nigra in rhesus macaques.

BACKGROUND: Neuromelanin is mostly located in dopaminergic neurons in the substantia nigra (SN) pars compacta, and can be detected by magnetic resonance imaging (MRI). It is a promising imaging-base biomarker for neurological diseases. We previously developed a melanin-specific probe N-(2-(diethylamino)-ethyl)-18F-5-fluoropicolinamide (18F-P3BZA), which was initially developed for the imaging of melanoma. 18F-P3BZA exhibited high levels of binding to the melanin in vitro and in vivo with high retention and favorable pharmacokinetics. In this study we further investigated whether 18F-P3BZA could be used to quantitatively detect neuromelanin in the SN in healthy rhesus macaques. RESULTS: 18F-P3BZA exhibited desired hydrophobicity with estimated log Know 5.08 and log D7.4 1.68. 18F-P3BZA readily crossed the blood-brain barrier with brain transport coefficients (Kin) of 40 ± 8 µL g-1s-1. 18F-P3BZA accumulated specifically in neuromelanotic PC12 cells, melanin-rich melanoma cells, and melanoma xenografts. Binding of 18F-P3BZA to B16F10 cells was much higher than to SKOV3 cells at 60 min (6.17 ± 0.53%IA and 0.24 ± 0.05%IA, respectively). In the biodistribution study, 18F-P3BZA had higher accumulation in B16F10 tumors (6.31 ± 0.99%IA/g) than in SKOV3 tumors (0.25 ± 0.09%IA/g). Meanwhile, 18F-P3BZA uptake in B16F10 tumors could be blocked by excess cold 19F-P3BZA (0.81 ± 0.02%IA/g, 88% inhibition, p < 0.05). PET/MRI 18F-P3BZA provided clear visualization of neuromelanin-rich SN at 30-60 min after injection in healthy macaques. The SN to cerebella ratios were 2.7 and 2.4 times higher at 30 and 60 min after injection. In in vitro autoradiography studies 18F-P3BZA exhibited high levels of binding to the SN, and almost no binding to surrounding midbrain tissues. CONCLUSION: 18F-P3BZA PET/MRI clearly images neuromelanin in the SN, and may assist in the early diagnosis of neurological diseases associated with abnormal neuromelanin expression.

Relationships between neuroimaging biomarkers and glymphatic-system activity in dementia with Lewy bodies.

Alpha-synuclein deposits in the brain have been suspected to cause Parkinson's disease and dementia with Lewy bodies (DLB). It was recently revealed that the glymphatic system is largely responsible for the removal of alpha-synuclein. We investigated changes in the glymphatic system's activity by determining the DTI­ALPS (diffusion tensor image analysis along the perivascular space) index in DLB patients. Twenty-six patients with DLB and 43 healthy subjects underwent diffusion tensor imaging (DTI) scanning at our hospital during the period April 2013 to March 2023. We retrospectively computed each subject's DTI­ALPS index to evaluate his/her glymphatic-system activity and then analyzed the relationships between the subjects' DTI­ALPS index data and their DLB neuroimaging biomarker values. A significant reduction of the DTI­ALPS index was observed in the patients with DLB compared to the healthy subjects. Significant positive correlations were also detected in the DLB group between the DTI­ALPS index and the regional gray matter volume in the left insula and between the index and the specific binding ratio of 123I-N-ω-fluoropropyl-2ß-carboxymethoxy-3ß-(4-iodophenyl)nortropane ([123I]-FP-CIT). These results indicate that (i) the DTI­ALPS index is a good biomarker of the progression of DLB, and (ii) this index might be effective to distinguish DLB from other neurocognitive disorders.

Development and method validation of a sampling technique for a reproducible detection of synthetic cannabinoids in exhaled breath using an in vitro pig lung model.

Alternative matrices, especially exhaled breath (EB), have gained increasing attention for a few years. To interpret toxicological findings, knowledge on the toxicokinetic (TK) properties of a substance in EB is indispensable. Whilst such data are already accessible for various drugs (e.g. Δ9-tetrahydrocannabinol), they are still not available for new psychoactive substances, particularly synthetic cannabinoids (SCs). As SCs raise a high public health concern, the aim of this study was to assess these data in future TK studies in pigs. For this purpose, an in vitro sampling technique of EB was initially developed, being prospectively applied to anesthetized and ventilated pigs for the detection of SCs in a controlled and reproducible manner as exemplified by cumyl-5F-P7AICA. Furthermore, a method for the qualitative and quantitative detection of cumyl-5F-P7AICA in EB using glass fiber filters (GFF) was established und fully validated. Therefore, cumyl-5F-P7AICA (0.5 mg/mL in ethanol abs.) was initially nebulized using a ventilation machine and a breathing tube, as they are also used in surgeries. The aerosol was delivered into a simulated pig lung. To collect EB, a pump was connected to that part of the breathing tube, that contains EB (expiratory limb), and sampling was performed repeatedly (n=6) for 15 min (2 L EB/min) each using GFF. For extraction of the substance, the GFF were macerated with acetone and the remaining experimental components were rinsed with ethanol. After sample preparation, the extracts were analyzed by LC-MS/MS. In the complete experimental setup, about 40% of the initially nebulized cumyl-5F-P7AICA dose was found with 3.6 ± 1.3% being detected in the GFF. Regarding the comparably high loss of substance, the open ventilation system and a conceivable adsorption of the SC in the ventilator have to be considered. However, the herein introduced approach is promising to determine the TK properties of cumyl-5F-P7AICA in EB.

Pharmacokinetic Bioequivalence between Generic and Originator Orally Inhaled Drug Products: Validity of Administration of Doses above the Approved Single Maximum Dose.

Pharmacokinetic bioequivalence of orally inhaled drug products is a critical component of the US FDA's "weight of evidence" approach, and it can serve as the sole indicator of safety and effectiveness of follow-on inhalation products approved in Europe and some other geographic areas. The approved labels of the orally inhaled drug products recommend the maximum number of actuations that can be administered in a single dose on one occasion. This single maximum dose may consist of one or more inhalations depending upon the product. Bioequivalence studies for the inhalation drug product registrations in the US and EU have employed single and multiple actuation doses, in some cases over and above the approved single maximum labeled doses, thus, inconsistent with the approved labeling of the reference products. Pharmacokinetics of inhaled drug products after single and multiple doses may be different, with implications for bioequivalence determined at single and multiple doses. Scientific literature indicates that the relative bioavailability of the Test and Reference products may differ between administrations of doses in one and multiple inhalations. Multiple doses not only alter the pharmacokinetics but also may reduce the sensitivity of the bioassay to actual differences between the Test and Reference product performances. Ability of the pharmacokinetic bioassay to accurately determine the extent of difference between two products may also be substantially reduced at high doses. Therefore, in our opinion, pharmacokinetic bioequivalence to support regulatory approvals of inhalation products at doses above the recommended single maximum dose should be avoided. Furthermore, the bioequivalence of products (if any) established at doses exceeding the approved single maximum doses should be revisited to determine if the products maintain bioequivalence when evaluated at the clinically relevant single maximum doses.

THz Metamaterial Sensitivity Enhancement by Reduction of Substrate's Fabry-Pérot Oscillations Using Back Plates as an Optical De-Coupler.

This work presents a new method for the enhancement of sensitivity in Terahertz (THz) spectroscopy on metamaterial (MM) in terms of its resonance frequency shift (ΔF), by attaching the dielectric back plate to the MM's silicon (Si) wafer. The dielectric back plates are designed to minimize the Fresnel reflections at the backside of the substrate, identical to a broadband antireflective (AR) plate tailored for THz. Utilizing broadband AR technology, we demonstrate the concept of decoupling MM resonance from the substrate's Fabry-Pérot (FP) oscillations. This is done by effectively coupling the THz light out of the high-permittivity substrate, resulting in the improved quality factor of the MM resonance and overall plasmonic enhancement on the metasurface. The back plate acts as a surface plasmonic enhancer to the THz MM by increasing the field intensity on the front metasurface, leading to enhancement of dielectric response (MM's ΔF). This makes the MM resonance ultrasensitive to the minor changes of particle size/concentration under test spread on the metasurface, contributing to enhanced resonance ΔF. The plate also makes the Si substrate optically lossless, enabling the full effect of MM resonance shift and increasing the resonance ΔF by 8-fold compared with MM's fabricated on conventional Si substrates. This research is backed-up with system-level CST simulations and experimental THz impedance spectroscopy of the MM. This method and chip structure is CMOS compatible having potential applications for any resonant MM fabricated on a substrate aimed to maximize dielectric sensitivity for biosensing and nanoparticle THz spectroscopy.

Synergistic effect of magnesium stearate and fine lactose in improving aerosolization performance of fluticasone propionate in dry powder formulation.

Magnesium stearate (MgSt) and lactose fines are often used as ternary components in carrier-based dry powder inhalers (DPIs) to improve fine particle fraction (FPF), but whether they act synergistically to improve aerosolization performance of DPI formulations is currently less studied. In addition, the applicability of utilizing powder rheological parameters to predict the FPF needs to be further verified. Thus, in this study, using fluticasone propionate (FP) as a model drug, effect of lactose fines addition in 0.5% MgSt containing DPI formulations on their powder and aerodynamic properties was explored. Influence of MgSt and fines mixing order on the DPIs performance was also investigated. The results showed that addition of lactose fines (1-10%) in 0.5% MgSt containing formulations could further improve flowability and enhance adhesion of the mixtures, and they could act synergistically to improve FPF. Moreover, the presence of 0.5% MgSt can greatly reduce the amount of lactose fines required to achieve the comparable FPF. The mixing order can affect distribution of MgSt on the carrier surface, with higher FPF noted when MgSt was mixed with carrier first, followed by lactose fines. A good linear relationship between powder rheological parameters such as basic flowability energy (BFE), Permeability and FPF was disclosed. In conclusion, in FP based DPIs, MgSt and lactose fines act synergistically to enhance FPF by tuning powder characteristics. Good flowability (27.39%) and strong adhesion (72.61%) contributed to the enhanced drug deposition in the lung.

Combination Therapy of Lenvatinib and Hepatic Arterial Infusion Chemotherapy Using Cisplatin With Lipiodol and 5-Fluorouracil: A Potential Breakthrough Therapy for Unresectable Advanced Hepatocellular Carcinoma.

INTRODUCTION: In 2021, the LEOPARD trial reported that the combination of lenvatinib+one-shot cisplatin infusion might contribute to improving the results of conventional advanced hepatocellular carcinoma (HCC) treatment. Thus, combination therapy with lenvatinib and catheterization has emerged as a focal point in treating advanced HCC. Conversely, the New FP regimen consists of low-dose cisplatin (CDDP) combined with 5-fluorouracil (5-FU) and lipiodol via hepatic arterial infusion chemotherapy (HAIC), with a high response rate of approximately 70%. Therefore, lenvatinib+New FP (LEN-New FP) may be a more promising treatment for HCC. Here, we report six patients who were administered LEN+New FP and achieved high therapeutic efficacy. Among them, one case had an interesting clinical course, which has been described in detail. MATERIALS AND METHODS: This study included six patients who were administered 12 mg or 8 mg of lenvatinib once daily based on a body weight of ≥60 kg or <60 kg, respectively, along with 50 mg of cisplatin in 5-10 mL lipiodol, and a continuous infusion of 5-FU (1500 mg/5 days) infused every 2-4 weeks. Tumor evaluations were performed 4-8 weeks after the initiation of New FP administration and every 8-12 weeks thereafter. RESULTS: The median patient age was 65 years. All patients had a history of prior treatment with atezolizumab and bevacizumab and one of the factors associated with poor overall survival for New FP monotherapy, such as a maximum tumor diameter ≥7 cm and bilobular multifocal distribution. Four (67%) patients had severe vascular invasion. The best objective response and disease control rates were 83% and 100%, respectively. The best response of the target lesion was complete remission in four out of six patients. CONCLUSION: The LEN-New FP combination for advanced HCC showed a high response rate and was more effective in high-risk patients with factors associated with poor overall survival than that reported with conventional New FP monotherapy. Additionally, LEN-New FP exhibited extremely high objective response and disease control rates and was well tolerated, including in cases where it was considered second- or third-line systemic chemotherapy for advanced HCC. Thus, LEN-New FP can serve as a breakthrough therapy for advanced HCC based on appropriate case selection.

Validation of a method for the determination of Aderamastat (FP-025) in K2EDTA human plasma by LC-MS/MS.

Aderamastat (FP-025) is a small molecule, selective matrix metalloproteinase (MMP)-12 inhibitor, under development for respiratory conditions which may include chronic inflammatory airway diseases and pulmonary fibrosis. To support evaluation of the pharmacokinetic parameters of Aderamastat in humans, we developed and validated a high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) analytical method for the quantification of Aderamastat in human plasma. This assay was validated in compliance with the Food and Drug Administration (FDA) Good Laboratory Practice Regulations (GLP) and European Medicines Agency (EMA) guidelines. K2EDTA human plasma samples were spiked with internal standard, processed by liquid-liquid extraction, and analyzed using reversed-phase HPLC with Turbo Ion Spray® MS/MS detection. Separation was done using a chromatographic gradient on 5 µm C6-Phenyl 110 Å, 50*2 mm analytical column at a temperature of 35 °C. The LC-MS/MS bioanalytical method, developed by QPS Taiwan to determine the concentration of Aderamastat in K2EDTA human plasma, was successfully validated with respect to linearity, sensitivity, accuracy, precision, dilution, selectivity, hemolyzed plasma, lipemic plasma, batch size, recovery, matrix effect, and carry-over. These data indicate that the method for determination of Aderamastat concentrations in human K2EDTA plasma can be used in pharmacokinetics studies and subsequent clinical trials with Aderamastat. Authors declare that, this novel data is not published and not under consideration for publication by another journal than this journal. All data will be made available on request.

Benefits and Challenges of Drug-Coated Balloons in Peripheral Artery Disease: From Molecular Mechanisms to Clinical Practice.

Multiple clinical trials have reported favorable outcomes after drug-coated balloon therapy for peripheral artery disease in above-the-knee and below-the-knee lesions and in both de novo and in-stent restenosis. However, there are still insufficient data to identify and tackle the risk factors associated with a higher risk of restenosis, which is the primary concern for patients who are treated with an endovascular approach. A modern armamentarium, which includes improved lesion preparation techniques such as plaque modification balloons, mechanical atherectomy, intravascular lithotripsy, and imaging, is crucial for obtaining better long-term clinical outcomes. Moreover, a better understanding of the molecular properties of drug-coated balloons has led to improved devices that could tackle the shortcomings of previous generations. This comprehensive review focuses on drug-coated balloon technology as a tool to treat peripheral artery disease and the effects of the molecular mechanisms involved in preventing vascular restenosis.

Clinical assessment and striatal dopaminergic activity in healthy controls and patients with Parkinson's disease: a Bayesian approach.

OBJECTIVES: We aimed to evaluate correlations between striatal dopamine transporter (DAT) uptake and clinical assessments in both patients with Parkinson's disease (PD) and healthy controls. METHODS: This study enrolled 193 healthy controls, and 581 patients with PD. They underwent various clinical assessments and 123I-FP-CIT SPECT scans. After reconstruction, attenuation correction, and normalization of SPECT images, counts were measured from the bilateral caudate and putamen, and the occipital cortex for reference. Count densities for each region were extracted and used to calculate striatal binding ratios (SBRs) for each striatal region. SBR is calculated as (target region/reference region)-1. After logarithmic transformation of striatal SBRs, we analyzed the effects of clinical assessments on striatal SBRs using Bayesian hierarchical modeling. RESULTS: MDS-UPDRS total score, part I, part II, part III, Epworth Sleepiness Scale, REM sleep behavior disorder screening questionnaire, SCOPA-AUT total score were negatively associated with striatal SBR in patients with PD. Also, HVLT recognition discrimination was positively associated with striatal SBR in both healthy controls and patients with PD. In healthy control, MDS-UPDRS part II, MOCA, SCOPA-AUT total score were positively associated with striatal SBR. CONCLUSION: We demonstrated that motor symptom, sleep disturbance, autonomic symptom, and cognition of patients with PD were associated with striatal dopaminergic activity. In healthy controls, motor symptoms, autonomic symptom, and cognition were associated with striatal dopaminergic activity, some of which showing the opposite direction with patients with PD. This result might provide new insight to underlying mechanism of dopamine system with motor and non-motor assessments.

Micronano Lasers Based on Aggregation-Induced Emission Molecules: Diverse Resonant Cavities Investigation.

Aggregation-induced emission (AIE) molecules have great potential to enhance the performance of micronano lasers due to their excellent aggregated luminescence properties, so it is valuable to expand their applications in micronano lasers. In this work, a typical AIE active fluorescent dye motif 9,10-bis(2,2-diphenylvinyl) anthracene (BDPVA) was selected as the gain medium. First, drop-casting was used to fabricate BDPVA single-crystal nanowires, which can be used as Fabry-Perot (FP)-type resonators with a lasing threshold of 49.4 µJ/cm2. Furthermore, we innovatively doped BDPVA molecules as gain mediums into external polymer Whispering-Gallery-Mode (WGM)-type resonators via the emulsion self-assembly method. Fabricated BDPVA-doped polystyrene (PS) microspheres exhibit a much lower lasing threshold of 9.04 µJ/cm2. These results prove that the BDPVA molecules, in addition to realizing the reported AIE single-crystal lasers, can also be used as a guest-doped gain medium in the resonant cavity for obtaining better fluorescence gain. In addition, multimode tunability of two types of lasers has been successfully achieved by tuning the structure of the resonant cavity. This work further expands the application potential of AIE materials and will provide a useful reference for the rational design and fabrication of photonic micronano laser components using AIE materials.

Serum phosphorus levels associated with nigrostriatal dopaminergic deficits in drug-naïve Parkinson's disease.

INTRODUCTION: A major component of Lewy bodies is phosphorylated α-synuclein. This post-translational modification of α-synuclein, phosphorylation, may consume a great amount of serum phosphorus. We aimed to investigate serum phosphorus levels and their associations with clinical phenotype and the degeneration of cardiac sympathetic and nigrostriatal dopaminergic neurons in patients with Parkinson's disease (PD). MATERIALS AND METHODS: We examined serum phosphorus levels in 127 participants (drug-naïve PD, 97; age- and sex-matched controls, 30). Associations of serum phosphorus levels with clinical features, heart-to-mediastinum (H/M) ratio on cardiac 123I-metaiodobenzylguanidine scintigraphy and striatal specific binding ratio of 123I-2-carbomethoxy-3-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) were examined. RESULTS: Serum phosphorus levels were 3.4 ± 0.5 mg/dL in patients with PD and were not different from those in controls after controlling for age and sex (p = 0.850). Serum phosphorus levels were significantly lower in patients with PD and decreased H/M ratio than in those with PD and normal H/M ratio (3.3 ± 0.4 mg/dL vs. 3.6 ± 0.5 mg/dL, p = 0.003). Lower serum phosphorus levels were significantly associated with more severe degeneration of nigrostriatal dopaminergic neurons in patients with PD and decreased H/M ratio. However, this association was not observed in patients with PD and normal H/M ratio. CONCLUSIONS: Serum phosphorus levels and their association with nigrostriatal dopaminergic degeneration are different between patients with decreased H/M ratio and those with normal H/M ratio. Serum phosphorus levels may reflect the degree of nigrostriatal dopaminergic degeneration in patients with decreased H/M ratio, namely, Body-First PD.