Trial of Intravenous Immune Globulin in Dermatomyositis.

BACKGROUND: Intravenous immune globulin (IVIG) for the treatment of dermatomyositis has not been extensively evaluated. METHODS: We conducted a randomized, placebo-controlled trial involving patients with active dermatomyositis. The patients were assigned in a 1:1 ratio to receive IVIG at a dose of 2.0 g per kilogram of body weight or placebo every 4 weeks for 16 weeks. The patients who received placebo and those without confirmed clinical deterioration while receiving IVIG could enter an open-label extension phase for another 24 weeks. The primary end point was a response, defined as a Total Improvement Score (TIS) of at least 20 (indicating at least minimal improvement) at week 16 and no confirmed deterioration up to week 16. The TIS is a weighted composite score reflecting the change in a core set of six measures of myositis activity over time; scores range from 0 to 100, with higher scores indicating greater improvement. Key secondary end points included at least moderate improvement (TIS ≥40) and major improvement (TIS ≥60), and change in score on the Cutaneous Dermatomyositis Disease Area and Severity Index. RESULTS: A total of 95 patients underwent randomization: 47 patients were assigned to the IVIG group, and 48 to the placebo group. At 16 weeks, 79% of the patients in the IVIG group (37 of 47) and 44% of those in the placebo group (21 of 48) had a TIS of at least 20 (difference, 35 percentage points; 95% confidence interval, 17 to 53; P<0.001). The results with respect to the secondary end points, including at least moderate improvement and major improvement, were generally in the same direction as the results of the primary end-point analysis, except for the change in creatine kinase level (an individual core measure of the TIS), which did not differ meaningfully between the two groups. Over 40 weeks, 282 treatment-related adverse events occurred in the IVIG group, including headache (in 42% of patients), pyrexia (in 19%), and nausea (in 16%). A total of 9 serious adverse events that were considered to be related to IVIG occurred, including 6 thromboembolic events. CONCLUSIONS: In this 16-week trial involving adults with dermatomyositis, the percentage of patients with a response of at least minimal improvement based on a composite score of disease activity was significantly greater among those who received IVIG than among those who received placebo. IVIG was associated with adverse events, including thromboembolism. (Funded by Octapharma Pharmazeutika; ProDERM ClinicalTrials.gov number, NCT02728752.).

A pilot study of anti-nephrin antibodies in podocytopaties among adults.

AIM: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are podocytopathies characterized by damage to the glomerular filtration barrier, leading to proteinuria and nephrotic syndrome. The production of anti-podocyte antibodies has been proposed as potential circulating factors contributing to the development of these conditions. The aim of the study is to evaluate the levels of anti-nephrin antibodies in patients with podocytopathies and healthy subjects. METHODS: In this study, a total of 77 patients with active glomerulopathy and 11 healthy subjects were included. Forty one patients were diagnosed with FSGS, 11 with MCD, and 25 with MN. To measure the levels of anti-nephrin antibodies, enzyme-linked immunosorbent assay was used. RESULTS: The levels of antibodies to nephrin were significantly higher in patients with MCD 61.2 [28.9-66.3] ng/mL and FSGS 32.5 [17.2-58.4] ng/mL compared to MN 20.3 [14.4-38.4] and healthy individuals 15.3 [12-18.9] ng/mL, p < .05. In patients with primary FSGS, the levels of antibodies to nephrin were significantly higher 45.2 [20-64.3] ng/mL compared to patients with secondary FSGS 26.7 [11.2-44.1] ng/mL, p < .05. There were no significant differences in the remission rate between the anti-nephrin antibodies positive and negative groups (log-rank test: p = .158). CONCLUSION: The level of anti-nephrin antibodies was found to be significantly higher in patients with MCD and pFSGS compared to those with sFSGS, MN, and healthy subjects. Anti-nephrin antibodies in MCD and primary FSGS may be associated with the severity of podocytopathies, however they did not have an impact on the response to therapy.

C(21)-Di- and monofluorinated scaffold for thevinol/orvinol-based opioid receptor ligands.

Defluorination of the readily available 21,21,21-trifluorothevinone (7) with Mg + Me3SiCl allows the preparation of 21,21-difluorothevinone (10) and 21-fluorothevinone (11), which can be used as the starting compounds for syntheses of 21,21-difluoro- and 21-fluoro-substituted relatives of thevinols and orvinols. Taken together, thevinols and orvinols are well known to constitute a family of the highly potent 4,5α-epoxy-18,19-endo-(etheno/ethano)morphinan-type opioid receptor ligands. Alternatively, 10 and 18,19-dihydro-21,21-difluorothevinone (13) have been synthesized by the addition of Me3SiCHF2 to the carbonyl function of thevinal (12) and dihydrothevinal (18) followed by oxidation of the intermediate C(21)-difluorinated secondary alcohols. 21,21-Difluorothevinols were obtained both by the addition of RMgX or RLi to the 21,21-difluoroketones and by the addition of Me3SiCHF2 to the carbonyl function of the non-fluorinated 18,19-endo-(etheno/ethano)morphinan ketones. In general, these addition reactions have been shown to result in mixtures of the C(21)-epimeric alcohols. However, in some cases, the reactions proceeded with high stereoselectivity allowing the isolation of one of the epimeric alcohols by conventional crystallization. Preparations of the 21,21-difluorothevinols bearing an allyl, cyclopropylmethyl, or cyclobutylmethyl group at the N(17) nitrogen are also reported.

Control of the diastereoselectivity at C(20) in the formation of C(21)-fluorinated thevinols.

A method is reported to control the stereoselectivity at C(20) in the syntheses of 20-R-21,21,21-trifluorothevinols (12), the opioid ligands incorporating fluorine atoms within the pharmacophore associated with the surroundings of the C(20) carbon atom. The C(20)-alcohols 12 can be prepared either by reaction of 21,21,21-trifluorothevinone (9) with RM (R = alkyl; M = Li, MgX) or by reaction of thevinone (2) and related non-fluorinated ketones with CF3SiMe3. In general, alcohols 12 were formed as mixtures of the C(20)-epimers, with the major epimers of the alcohols obtained from the aforementioned reactions exploiting RLi vs. CF3SiMe3 with opposite absolute configurations at C(20). Some individual C(20)-epimers of the fluorinated alcohols 12 were isolated from the reaction mixtures in pure form by trivial crystallization. The reactions of the ketones with RMgX (R ≠ Me) and RLi (R = tertiary or secondary alkyl) resulted in the reduction of the carbonyl function to produce the secondary alcohols 11a,b rather than the tertiary alcohols 12. The additives of the salts were found to affect the composition of the products in the reactions of 9 with alkyl organomagnesium and organolithium reagents.

A cross-sectional study of antibodies to ubiquitin proteasome system in different glomerulopathies.

BACKGROUND: Recently, evidence has emerged that the ubiquitin system, which is involved in extracellular protein degradation, is most susceptible to damage in podocytes in cases of podocytopathies. We studied anti-ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) antibodies in glomerulopathies with proteinuria. MATERIALS AND METHODS: 71 patients with glomerulopathy and 11 healthy subjects were included in our study. 44 patients had nephrotic syndrome, and 27 did not. Serum levels of anti-UCHL1 antibodies were measured by ELISA. RESULTS: The levels of anti-UCHL1 antibodies were significantly higher in focal segmental glomerulosclerosis (FSGS) patients than in minimal change disease (MCD), IgA nephropathy, membranous nephropathy, or membranoproliferative glomerulonephritis patients and control group. The levels of UCHL1 antibodies in serum did not correlate with 24-hour proteinuria, blood pressure, glomerulosclerosis percentage, or area of tubulointerstitial fibrosis, but did correlate with serum creatinine and estimated glomerular filtration rate (eGFR). During the development of the ROC curve (AUC = 0.766 (95% CI 0.634 - 0.897)) for FSGS vs. other forms of glomerulopathies, a readjustment of the sensitivity of 75% and specificity of 61% were established. A former increase in anti-UCHL1 antibody levels above 1.93 ng/mL may be a marker of FSGS OR 3.617 (95% CI 1.051 - 12.447), p = 0.041. CONCLUSION: An increase in the level of anti-UCHL1 antibodies in the serum was noted in FSGS, which suggests that these antibodies could be a potential biomarker for FSGS patients.

Targeted MRM Quantification of Urinary Proteins in Chronic Kidney Disease Caused by Glomerulopathies.

Glomerulopathies with nephrotic syndrome that are resistant to therapy often progress to end-stage chronic kidney disease (CKD) and require timely and accurate diagnosis. Targeted quantitative urine proteome analysis by mass spectrometry (MS) with multiple-reaction monitoring (MRM) is a promising tool for early CKD diagnostics that could replace the invasive biopsy procedure. However, there are few studies regarding the development of highly multiplexed MRM assays for urine proteome analysis, and the two MRM assays for urine proteomics described so far demonstrate very low consistency. Thus, the further development of targeted urine proteome assays for CKD is actual task. Herein, a BAK270 MRM assay previously validated for blood plasma protein analysis was adapted for urine-targeted proteomics. Because proteinuria associated with renal impairment is usually associated with an increased diversity of plasma proteins being present in urine, the use of this panel was appropriate. Another advantage of the BAK270 MRM assay is that it includes 35 potential CKD markers described previously. Targeted LC-MRM MS analysis was performed for 69 urine samples from 46 CKD patients and 23 healthy controls, revealing 138 proteins that were found in ≥2/3 of the samples from at least one of the groups. The results obtained confirm 31 previously proposed CKD markers. Combination of MRM analysis with machine learning for data processing was performed. As a result, a highly accurate classifier was developed (AUC = 0.99) that enables distinguishing between mild and severe glomerulopathies based on the assessment of only three urine proteins (GPX3, PLMN, and A1AT or SHBG).

Integrated Multiresonator Quantum Memory.

We develop an integrated efficient multiresonator quantum memory scheme based on a system of three interacting resonators coupled through a common resonator to an external waveguide via switchable coupler. It is shown that high-precision parameter matching based on step-by-step optimization makes it possible to efficiently store the signal field and enables on-demand retrieval of the signal at specified time moments. Possible experimental implementations and practical applications of the proposed quantum memory scheme are discussed.

Induction and maintenance of remission with mycophenolate mofetil in ANCA-associated vasculitis: a systematic review and meta-analysis.

BACKGROUND: Uncertainties exist about the use of mycophenolate mofetil (MMF) in anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitis (AAV), particularly for remission maintenance. METHODS: Systematic review and meta-analysis of phase II and III trials assessing the use of MMF in AAV, granulomatosis with polyangiitis and microscopic polyangiitis (MPA). A comprehensive search of several databases (Medline, EMBASE, Cochrane, Web of Science, Scopus) from inception to 5 May 2020 has been conducted. Trial data were extracted to estimate odds ratios (ORs) and estimates (ES) for MMF efficacy (remission-induction and maintenance). Severe adverse effects (SAEs) were collected. RESULTS: From 565 articles captured, 10 met the predefined criteria, 5 phase II and 5 III trials; 4 assessed remission-induction, 3 remission maintenance and 3 both. The pooled OR for remission-induction at 6 months was 1.06 (95% confidence interval 0.74, 1.52), with no significant difference by subgroup meta-analysis of trials stratified by different study-level features (i.e. kidney disease, MPA, myeloperoxidase-ANCA positivity, newly diagnosed disease) (P > 0.05). The overall ES for remission maintenance at the end of follow-up ranged between 51% and 91% (I2 = 74.8%). Subgroup meta-analysis identified kidney involvement as a possible source of heterogeneity, yielding a significantly higher rate of sustained remission in trials enrolling only patients with kidney involvement (92%, 76-100%) versus those enrolling patients with and without kidney involvement (56%, 45-66%). Results were similar in multiple sensitivity analyses. During follow-up, the frequency of SAEs in MMF-based treatment arms was 31.8%. CONCLUSIONS: In AAV, MMF use was significantly associated with higher sustained remission rates in trials enrolling only patients with kidney involvement. These findings might influence clinical practice.

Non-specular reflection of a narrow spatially phase-modulated Gaussian beam.

The lateral and angular Goos-Hänchen shifts undergone upon reflection on a dielectric plate by a spatially phase-modulated Gaussian beam are derived. It is shown that the amplitude and direction of both lateral and angular shifts are very sensitive to the degree of spatial phase modulation of the incident beam, so that such modulation thus provides a means to control those shifts. It is also shown that the modulation incurs some beam reshaping upon reflection. Analytical calculations of the lateral shift are found to be in good agreement with numerical simulations of beam propagation before and after reflection. In these simulations, the required spatial transverse phase modulation is achieved by focusing a microwave Gaussian beam onto the dielectric plate with a non-spherical lens or a flat-surfaced thin lamella exhibiting a suitable gradient of its refractive index. The optimal parameters governing the spatial phase modulation are discussed to achieve: (i) enhancement of the lateral shift of a spatially phase-modulated beam in comparison to that of a non-modulated beam and (ii) simultaneous large values of reflectivity and of the lateral shift, while keeping the reshaping of the reflected beam to a minimum.

Potential Urine Proteomic Biomarkers for Focal Segmental Glomerulosclerosis and Minimal Change Disease.

Primary focal segmental glomerulosclerosis (FSGS), along with minimal change disease (MCD), are diseases with primary podocyte damage that are clinically manifested by the nephrotic syndrome. The pathogenesis of these podocytopathies is still unknown, and therefore, the search for biomarkers of these diseases is ongoing. Our aim was to determine of the proteomic profile of urine from patients with FSGS and MCD. Patients with a confirmed diagnosis of FSGS (n = 30) and MCD (n = 9) were recruited for the study. For a comprehensive assessment of the severity of FSGS a special index was introduced, which was calculated as follows: the first score was assigned depending on the level of eGFR, the second score-depending on the proteinuria level, the third score-resistance to steroid therapy. Patients with the sum of these scores of less than 3 were included in group 1, with 3 or more-in group 2. The urinary proteome was analyzed using liquid chromatography/mass spectrometry. The proteome profiles of patients with severe progressive FSGS from group 2, mild FSGS from group 1 and MCD were compared. Results of the label free analysis were validated using targeted LC-MS based on multiple reaction monitoring (MRM) with stable isotope labelled peptide standards (SIS) available for 47 of the 76 proteins identified as differentiating between at least one pair of groups. Quantitative MRM SIS validation measurements for these 47 proteins revealed 22 proteins with significant differences between at least one of the two group pairs and 14 proteins were validated for both comparisons. In addition, all of the 22 proteins validated by MRM SIS analysis showed the same direction of change as at the discovery stage with label-free LC-MS analysis, i.e., up or down regulation in MCD and FSGS1 against FSGS2. Patients from the FSGS group 2 showed a significantly different profile from both FSGS group 1 and MCD. Among the 47 significantly differentiating proteins, the most significant were apolipoprotein A-IV, hemopexin, vitronectin, gelsolin, components of the complement system (C4b, factors B and I), retinol- and vitamin D-binding proteins. Patients with mild form of FSGS and MCD showed lower levels of Cystatin C, gelsolin and complement factor I.

Identification and Quantification by NMR Spectroscopy of the 22R and 22S Epimers in Budesonide Pharmaceutical Forms.

The authors developed four variants of the qNMR technique (1H or 13C nucleus, DMSO-d6 or CDCl3 solvent) for identification and quantification by NMR of 22R and 22S epimers in budesonide active pharmaceutical ingredient and budesonide drugs (sprays, capsules, tablets). The choice of the qNMR technique version depends on the drug excipients. The correlation of 1H and 13C spectra signals to molecules of different budesonide epimers was carried out on the basis of a comprehensive analysis of experimental spectral NMR data (1H-1H gCOSY, 1H-13C gHSQC, 1H-13C gHMBC, 1H-1H ROESY). This technique makes it possible to identify budesonide epimers and determine their weight ratio directly, without constructing a calibration curve and using any standards. The results of measuring the 22S epimer content by qNMR are comparable with the results of measurements using the reference HPLC method.

Association of venous thromboembolic events with skin, pulmonary and kidney involvement in ANCA-associated vasculitis: a multinational study.

OBJECTIVE: To investigate the occurrence of venous thromboembolic events (VTE) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, Turkey, Russia, UK and North America. METHODS: Patients with a definite diagnosis of AAV who were followed for at least 3 months and had sufficient documentation were included. Data on VTE, including either deep vein thrombosis or pulmonary embolism, were collected retrospectively from tertiary vasculitis centres. Univariate and multivariate regression models were used to estimate odds ratios (ORs) and 95% CIs. RESULTS: Over a median follow-up of 63 (interquartile range: 29, 101) months, VTE occurred in 278 (9.7%) of 2869 AAV patients with a similar frequency across different countries (from 6.3% to 13.7%), and AAV subtype [granulomatosis with polyangiitis: 9.8% (95% CI: 8.3, 11.6%); microscopic polyangiitis: 9.6% (95% CI: 7.9, 11.4%); and eosinophilic granulomatosis with polyangiitis: 9.8% (95% CI: 7.0, 13.3%)]. Most VTE (65.6%) were reported in the first-year post-diagnosis. Multiple factor logistic regression analysis adjusted for sex and age showed that skin (OR 1.71, 95% CI: 1.01, 2.92), pulmonary (OR 1.78, 95% CI: 1.04, 3.14) and kidney [eGFR 15-60 ml/min/1.73 m2, OR 2.86 (95% CI: 1.27, 6.47); eGFR <15 ml/min/1.73 m2, OR 6.71 (95% CI: 2.94, 15.33)] involvement were independent variables associated with a higher occurrence of VTE. CONCLUSION: Two-thirds of VTE occurred during the initial phase of active disease. We confirmed previous findings from smaller studies that a decrease in kidney function, skin involvement and pulmonary disease are independently associated with VTE.

A Prospective Pilot Study of Graft-versus-Host Disease Prophylaxis with Post-Transplantation Cyclophosphamide and Ruxolitinib in Patients with Myelofibrosis.

INTRODUCTION: This prospective study evaluated a calcineurin inhibitor-free graft-versus-host disease (GVHD) prophylaxis regimen of ruxolitinib in combination with post-transplant cyclophosphamide (PTCy). Patents and Methods: Twenty patients with primary or secondary myelofibrosis were prospectively enrolled. Reduced intensity conditioning was performed, followed by allogeneic stem cell transplantation from related (n = 7) or unrelated (n = 13) donors. GVHD prophylaxis included only PTCy and ruxolitinib (45 mg) from day-7 to day-2, and 15 mg from day+5 to day+100. This trial was registered at www.clinicaltrials.gov as #NCT02806375. RESULTS: Primary engraftment was documented in 17 patients. One patient experienced primary graft failure and 2 died before engraftment. Eleven patients demonstrated severe poor graft function (SPGF), which required ruxolitinib dose reduction. The regimen was well tolerated, with grade 3-4 non-haematological toxicity in 30%, viral reactivation in 45%, and severe sepsis in 15% of patients. The incidence of acute GVHD grade II-IV was 25%, grade III-IV GVHD was 15%, and moderate chronic GVHD was 20%, with no severe cases. Only 2 patients required systemic steroids. Haematological relapse was documented in 1 patient. Two-year non-relapse mortality was 15%, 2-year overall survival was 85%, and 2-year event-free survival was 72%. CONCLUSION: GVHD prophylaxis with PTCy and ruxolitinib is associated with low toxicity, good acute and chronic GVHD control, and low relapse incidence. However, the relatively high rate of SPGF should be taken into account. SPGF could possibly be mitigated by ruxolitinib dose reduction.

Acute kidney damage in COVID-19 patients.

The presentation of kidney damage in Coronavirus disease 2019 (COVID-19) varies significantly. According to recent studies, the development of acute kidney injury (AKI) in severe cases of COVID-19 infection significantly worsens the prognosis of these patients. The pathological changes in kidneys might be caused directly by the cytopathic effect mediated by local replication of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or indirectly because of systemic immune response or hypercoagulation, so-called immunothrombosis. Other causes, such as hypovolemia and hypoxia, may also contribute to AKI. Acute kidney disease often develops in elderly patients with underlying comorbidities or in critically ill patients with severe respiratory failure. It is known that AKI is a risk factor for mortality in COVID-19 patients.

International Consensus on ANCA Testing in Eosinophilic Granulomatosis with Polyangiitis.

An international consensus on anti-neutrophil cytoplasm antibodies (ANCA) testing in eosinophilic granulomatosis with polyangiitis (EGPA) is presented. ANCA, specific for myeloperoxidase (MPO), can be detected in 30-35% of EGPA patients. MPO-ANCA should be tested with antigen-specific immunoassays in any patient with eosinophilic asthma and clinical features suggesting EGPA, including constitutional symptoms, purpura, polyneuropathy, unexplained heart, gastrointestinal or kidney disease, and/or pulmonary infiltrates or hemorrhage. A positive MPO-ANCA result contributes to the diagnostic work­up for EGPA. Patients with MPO-ANCA associated EGPA have more frequently vasculitis features, such as glomerulonephritis, neuropathy, and skin manifestations than patients with ANCA negative EGPA. However, the presence of MPO-ANCA is neither sensitive nor specific enough to identify whether a patient should be subclassified as having "vasculitic" or "eosinophilic" EGPA. At present, ANCA status cannot guide treatment decisions, that is, whether cyclophosphamide, rituximab or mepolizumab should be added to conventional glucocorticoid treatment. In EGPA, monitoring of ANCA is only useful when MPO-ANCA was tested positive at disease onset.

Urinary Markers of Podocyte Dysfunction in Chronic Glomerulonephritis.

Chronic glomerulonephritis (CGN) is a disease with a steady progressive course that involves the development of nephrosclerosis, which is especially evident in clinical courses with incidences of high proteinuria (PU). Currently, proteinuria is considered the main laboratory feature (sign) of CGN activity and progression because proteinuria is closely related to the process of tubulointerstitial fibrosis, which is correlated with the grade of renal insufficiency. The injury to podocytes, which are key components of the filtration barrier, plays a central role in proteinuria development. The detachment of podocytes from the glomerular basement membrane leading to podocytopenia is suggested to induce glomerulosclerosis and hyalinosis with obliteration of capillary loops and the progression of chronic kidney disease. Urinary markers of podocyte dysfunction could serve as useful tools while monitoring the activity and prognosis of CGN. In this chapter, the most important mechanisms of podocyte loss and urinary markers of this process are discussed.

Urinary Protein and Peptide Markers in Chronic Kidney Disease.

Chronic kidney disease (CKD) is a non-specific type of kidney disease that causes a gradual decline in kidney function (from months to years). CKD is a significant risk factor for death, cardiovascular disease, and end-stage renal disease. CKDs of different origins may have the same clinical and laboratory manifestations but different progression rates, which requires early diagnosis to determine. This review focuses on protein/peptide biomarkers of the leading causes of CKD: diabetic nephropathy, IgA nephropathy, lupus nephritis, focal segmental glomerulosclerosis, and membranous nephropathy. Mass spectrometry (MS) approaches provided the most information about urinary peptide and protein contents in different nephropathies. New analytical approaches allow urinary proteomic-peptide profiles to be used as early non-invasive diagnostic tools for specific morphological forms of kidney disease and may become a safe alternative to renal biopsy. MS studies of the key pathogenetic mechanisms of renal disease progression may also contribute to developing new approaches for targeted therapy.

Development and Validation of 2-Azaspiro [4,5] Decan-3-One (Impurity A) in Gabapentin Determination Method Using qNMR Spectroscopy.

The authors developed a 1H qNMR test procedure for identification and quantification of impurity A present in gabapentin active pharmaceutical ingredient (API) and gabapentin products. The validation studies helped to determine the limit of quantitation and assess linearity, accuracy, repeatability, intermediate precision, specificity, and robustness of the procedure. Spike-and-recovery assays were used to calculate standard deviations, coefficients of variation, confidence intervals, bias, Fisher's F test, and Student's t-test for assay results. The obtained statistical values satisfy the acceptance criteria for the validation parameters. The authors compared the results of impurity A quantification in gabapentin APIs and capsules by using the 1H qNMR and HPLC test methods.

Light and corona: guided-wave readout for coronavirus spike protein-host-receptor binding.

We show that waveguide sensors can enable a quantitative characterization of coronavirus spike glycoprotein-host-receptor binding-the process whereby coronaviruses enter human cells, causing disease. We demonstrate that such sensors can help quantify and eventually understand kinetic and thermodynamic properties of viruses that control their affinity to targeted cells, which is known to significantly vary in the course of virus evolution, e.g., from SARS-CoV to SARS-CoV-2, making the development of virus-specific drugs and vaccine difficult. With the binding rate constants and thermodynamic parameters as suggested by the latest SARS-CoV-2 research, optical sensors of SARS-CoV-2 spike protein-receptor binding may be within sight.

Fluorinated and [18F]fluorinated morphinan based opioid ligands.

It is well documented in the literature that opioid receptors modulate a large number of physiological functions (pain perception, breathing, mood, gastrointestinal motility, etc.). Natural opiates and 4,5α-epoxymorphinan derivatives obtained by their chemical modifications, which are frequently referred to as semi-synthetic opioids, are among the most important types of opioid ligands. On the other hand, fluorinated compounds have a remarkable record in medicinal chemistry providing developmental candidates for therapeutic applications. The reasons are very similar steric impacts of hydrogen and fluorine along with the influence of substituting fluorine for hydrogen in the molecules of exogenous compounds on their lipophilicity, metabolism, conformation and other properties. This review focuses on the functionalization of 4,5α-epoxymorphinans and their derivatives via substitutions with fluorine or fluorine-containing groups in the search for improved pharmacological profile opioid ligands and 18F-containing opioid receptor radioligands for PET. These functionalizations are typically associated with substituents either at the C(3)-O, C(6)-O, and N(17) positions of the 4,5α-epoxymorphinan core or at C(7) in the thebaine based Diels-Alder type adducts. The syntheses resulted in the preparation of both single fluorinated derivatives or short sets of fluorinated derivatives and the families of fluorine-containing opioids allowing, in principle, the structure-activity relationship studies.