Structural snapshots of TRPV1 reveal mechanism of polymodal functionality.

Many transient receptor potential (TRP) channels respond to diverse stimuli and conditionally conduct small and large cations. Such functional plasticity is presumably enabled by a uniquely dynamic ion selectivity filter that is regulated by physiological agents. What is currently missing is a "photo series" of intermediate structural states that directly address this hypothesis and reveal specific mechanisms behind such dynamic channel regulation. Here, we exploit cryoelectron microscopy (cryo-EM) to visualize conformational transitions of the capsaicin receptor, TRPV1, as a model to understand how dynamic transitions of the selectivity filter in response to algogenic agents, including protons, vanilloid agonists, and peptide toxins, permit permeation by small and large organic cations. These structures also reveal mechanisms governing ligand binding substates, as well as allosteric coupling between key sites that are proximal to the selectivity filter and cytoplasmic gate. These insights suggest a general framework for understanding how TRP channels function as polymodal signal integrators.

Topical application of ozonated sunflower oil accelerates the healing of lesions of cutaneous leishmaniasis in mice under meglumine antimoniate treatment.

Besides being scarce, the drugs available for treating cutaneous leishmaniasis have many adverse effects. Ozone is an option to enhance the standard treatment due to the wound-healing activity reported in the literature. In this study, we evaluated the efficiency of ozonated sunflower oil as an adjuvant in treating cutaneous lesions caused by Leishmania amazonensis. BALB/c mice were infected with L. amazonensis, and after the lesions appeared, they were treated in four different schedules using the drug treatment with meglumine antimoniate (Glucantime®), with or without ozonated oil. After thirty days of treatment, the lesions' thickness and their parasitic burden, blood leukocytes, production of NO and cytokines from peritoneal macrophages and lymph node cells were analyzed. The group treated with ozonated oil plus meglumine antimoniate showed the best performance, improving the lesion significantly. The parasitic burden showed that ozonated oil enhanced the leishmanicidal activity of the treatment, eliminating the parasites in the lesion. Besides, a decrease in the TNF levels from peritoneal macrophages and blood leukocytes demonstrated an immunomodulatory action of ozone in the ozonated oil-treated animals compared to the untreated group. Thus, ozonated sunflower oil therapy has been shown as an adjuvant in treating Leishmania lesions since this treatment enhanced the leishmanicidal and wound healing effects of meglumine antimoniate.

Quantitative information from gadobenate dimeglumine-enhanced MRI can predict proliferative subtype of solitary hepatocellular carcinoma: a multicenter retrospective study.

OBJECTIVES: To investigate the value of quantitative parameters derived from gadobenate dimeglumine-enhanced magnetic resonance imaging (MRI) for predicting molecular subtype of hepatocellular carcinoma (HCC) and overall survival. METHODS: This multicenter retrospective study included 218 solitary HCC patients who underwent gadobenate dimeglumine-enhanced MRI. All HCC lesions were resected and pathologically confirmed. The lesion-to-liver contrast enhancement ratio (LLCER) and lesion-to-liver contrast (LLC) were measured in the hepatobiliary phase. Potential risk factors for proliferative HCC were assessed by logistic regression. The ability of LLCER and LLC to predict proliferative HCC was assessed by the receiver operating characteristic (ROC) curve. Prognostic factors were evaluated using the Cox proportional hazards regression model for survival outcomes. RESULTS: LLCER was an independent predictor of proliferative HCC (odds ratio, 0.015; 95% confidence interval [CI], 0.008-0.022; p < 0.001). The area under the ROC curve was 0.812 (95% CI, 0.748-0.877), higher than that of LLC, alpha-fetoprotein > 100 ng/ml, satellite nodules, and rim arterial phase hyperenhancement (all p ≤ 0.001). HCC patients with LLCER < -4.59% had a significantly higher incidence of proliferative HCC than those with the LLCER ≥ -4.59%. During the follow-up period, LLCER was an independent predictor of overall survival (hazard ratio, 0.070; 95% CI, 0.015-0.324; p = 0.001) in HCC patients. CONCLUSIONS: Gadobenate dimeglumine-enhanced quantitative parameter in the hepatobiliary phase can predict the proliferative subtype of solitary HCC with a moderately high accuracy. CLINICAL RELEVANCE STATEMENT: Quantitative information from gadobenate dimeglumine-enhanced MRI can provide crucial information on hepatocellular carcinoma subtypes. It might be valuable to design novel therapeutic strategies, such as targeted therapies or immunotherapy. KEY POINTS: • The lesion-to-liver contrast enhancement ratio (LLCER) is an independent predictor of proliferative hepatocellular carcinoma (HCC). • The ability of LLCER to predict proliferative HCC outperformed lesion-to-liver contrast, alpha-fetoprotein > 100 ng/ml, satellite nodules, and rim arterial phase hyperenhancement. • HCC patients with LLCER < -4.59% had a significantly higher incidence of proliferative HCC than those with the LLCER ≥ -4.59%.

Liver Imaging Reporting and Data System version 2018 category 5 for diagnosing hepatocellular carcinoma: an updated meta-analysis.

OBJECTIVE: We performed an updated meta-analysis to determine the diagnostic performance of Liver Imaging Reporting and Data System (LI-RADS, LR) 5 category for hepatocellular carcinoma (HCC) using LI-RADS version 2018 (v2018), and to evaluate differences by imaging modalities and type of MRI contrast material. METHODS: The MEDLINE and Embase databases were searched for studies reporting the performance of LR-5 using v2018 for diagnosing HCC. A bivariate random-effects model was used to calculate the pooled per-observation sensitivity and specificity. Subgroup analysis was performed based on imaging modalities and type of MRI contrast material. RESULTS: Forty-eight studies qualified for the meta-analysis, comprising 9031 patients, 10,547 observations, and 7216 HCCs. The pooled per-observation sensitivity and specificity of LR-5 for diagnosing HCC were 66% (95% CI, 61-70%) and 91% (95% CI, 89-93%), respectively. In the subgroup analysis, MRI with extracellular agent (ECA-MRI) showed significantly higher pooled sensitivity (77% [95% CI, 70-82%]) than CT (66% [95% CI, 58-73%]; p = 0.023) or MRI with gadoxetate (Gx-MRI) (65% [95% CI, 60-70%]; p = 0.001), but there was no significant difference between ECA-MRI and MRI with gadobenate (gadobenate-MRI) (73% [95% CI, 61-82%]; p = 0.495). Pooled specificities were 88% (95% CI, 80-93%) for CT, 92% (95% CI, 86-95%) for ECA-MRI, 93% (95% CI, 91-95%) for Gx-MRI, and 91% (95% CI, 84-95%) for gadobenate-MRI without significant differences (p = 0.084-0.803). CONCLUSIONS: LI-RADS v2018 LR-5 provides high specificity for HCC diagnosis regardless of modality or contrast material, while ECA-MRI showed higher sensitivity than CT or Gx-MRI. CLINICAL RELEVANCE STATEMENT: Refinement of the criteria for improving sensitivity while maintaining high specificity of LR-5 for HCC diagnosis may be an essential future direction. KEY POINTS: • The pooled per-observation sensitivity and specificity of LR-5 for diagnosing HCC using LI-RADSv2018 were 66% and 91%, respectively. • ECA-MRI showed higher sensitivity than CT (77% vs 66%, p = 0.023) or Gx-MRI (77% vs 65%, p = 0.001). • LI-RADS v2018 LR-5 provides high specificity (88-93%) for HCC diagnosis regardless of modality or contrast material type.

Comparison of Intralesional Sodium Stibogluconate versus Intralesional Meglumine Antimoniate for the Treatment of Leishmania major Cutaneous Leishmaniasis.

Israel is endemic for Old-World cutaneous leishmaniasis. The most common species is Leishmania major. However, the available treatment options are limited. This study's objective was to compare the authors' experience with different antimony intralesional treatments of Leishmania major cutaneous leishmaniasis. A retrospective evaluation was undertaken for cases of Leishmania major cutaneous leishmaniasis treated by pentavalent antimony in a university-affiliated medical centre in Israel. The previous treatment of intralesional sodium stibogluconate (Pentostam®) was compared with the current treatment of meglumine antimoniate (Glucantime®). One hundred cases of cutaneous leishmaniasis were treated during the study period, of whom 33 were treated with intralesional sodium stibogluconate and 67 were treated with intralesional meglumine antimoniate. The patients were 78 males and 22 females, mean age 24 (range 10-67) and there was a total of 354 skin lesions. Within 3 months from treatment, 91% (30/33) of the intralesional sodium stibogluconate group and 88% (59/67) of the intralesional meglumine antimoniate group had complete healing of the cutaneous lesions after an average of 3 treatment cycles (non-statistically significant). In conclusion, the 2 different medications have the same efficacy and safety for treating cutaneous leishmaniasis. Pentavalent antimoniate intralesional infiltration treatment is safe, effective, and well tolerated with minimal side effects for Old-World cutaneous leishmaniasis.

[Use of meglumine sodium succinate and NPWT therapy in the treatment of early and late complications of cholelistics]. / Ispol'zovanie meglyumina natriya suktsinata i NRWT-terapii v lechenii rannikh i pozdnikh oslozhnenii zhelchnokamennoi bolezni.

Gallstone disease remains an important medical and socially significant problem due to the increase in the proportion of patients of young and working age. At the same time, along with the increase in incidence, the number of complicated forms, such as choledocholithiasis in combination with stenosing duodenal papillitis (SDP) and obstructive jaundice, is increasing, which increases the importance of surgical approaches in the complex treatment of the disease and expands the range of conservative methods of therapy. In the given clinical observation of a young patient with severe cholelithiasis, accompanied by early and late complications, including the formation of postoperative scars and ventral hernias. At the last of the described stages of treatment during allohernioplasty, a complication developed in the form of a seroma followed by phlegmon of the anterior abdominal wall in the area of the implant, which served as the basis for including both local (NPWT therapy) and general (a course of infusions of a succinate-containing drug) methods in the treatment regimen, which contributed to more pronounced positive dynamics of the patient's condition.

A Randomized, Controlled, Noninferiority, Multicenter Trial of Systemic vs Intralesional Treatment With Meglumine Antimoniate for Cutaneous Leishmaniasis in Brazil.

BACKGROUND: Meglumine antimoniate (MA) remains the main treatment for cutaneous leishmaniasis (CL). Uncontrolled studies suggest that intralesional MA (IL-MA) may be noninferior and safer than systemic MA (S-MA). METHODS: Multicenter, randomized, controlled, open-label, phase 3 clinical trial to evaluate the efficacy and toxicity of IL-MA in 3 infiltrations at 14-day intervals compared with S-MA (10-20 mg Sb5+/kg/day, 20 days) for CL, with noninferiority margin of 20%. Primary and secondary outcomes were definitive cure at day 180 and epithelialization rate at day 90 of treatment, respectively. A 2-year follow-up was performed to assess relapses and emergence of mucosal lesions. Adverse events (AEs) were monitored according to the Division of AIDS AE grading system. RESULTS: We evaluated 135 patients. The cure rates (95% confidence interval) for IL-MA and S-MA treatment were, respectively, 82.8% (70.5-91.4) and 67.8% (53.3-78.3) per protocol (PP) and 70.6% (58.3-81.0) and 59.7% (47.0-71.5) per intention to treat (ITT). The epithelialization rates of the IL-MA and S-MA treatment were, respectively, 79.3% (66.6-88 + 8) and 71.2% (57.9-82.2) PP and 69.1% (55.2-78.5) and 64.2% (50.0-74.2) ITT. AEs in the IL-MA and S-MA groups were, respectively, clinical, 45.6% and 80.6%; laboratory, 26.5% and 73.1%; and electrocardiogram, 8.8% and 25.4%. Ten participants in the S-MA group and 1 in the IL-MA group were discontinued due to severe or persistent AEs. CONCLUSIONS: IL-MA provides a similar cure rate and results in less toxicity compared with S-MA and may be used as first-line therapy for CL patients. CLINICAL TRIALS REGISTRATION: REBEC: RBR-6mk5n4.

Gadolinium Deposition in the Rat Brain Measured with Quantitative MRI versus Elemental Mass Spectrometry.

Background T1-weighted MRI and quantitative longitudinal relaxation rate (R1) mapping have been used to evaluate gadolinium retention in the brain after gadolinium-based contrast agent (GBCA) administration. Whether MRI measures accurately reflect gadolinium regional distribution and concentration in the brain remains unclear. Purpose To compare gadolinium retention in rat forebrain measured with in vivo quantitative MRI R1 and ex vivo laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) mapping after gadobenate, gadopentetate, gadodiamide, or gadobutrol administration. Materials and Methods Adult female Sprague-Dawley rats were randomly assigned to one of five groups (eight per group) and administered gadobenate, gadopentetate, gadodiamide, gadobutrol (2.4 mmol/kg per week for 5 weeks), or saline (4.8 mL/kg per week for 5 weeks). MRI R1 mapping was performed at baseline and 1 week after the final injection to determine R1 and ΔR1. Postmortem brains from the same rats were analyzed with LA-ICP-MS elemental mapping to determine regional gadolinium concentrations. Student t tests were performed to compare results between GBCA and saline groups. Results Rats that were administered gadobenate showed gadolinium-related MRI ΔR1 in 39.5% of brain volume (ΔR1 = 0.087 second-1 ± 0.051); gadopentetate, 20.6% (ΔR1 = 0.069 second-1 ± 0.018); gadodiamide, 5.4% (ΔR1 = 0.055 second-1 ± 0.019); and gadobutrol, 2.2% (ΔR1 = 0.052 second-1 ± 0.041). Agent-specific gadolinium-related ΔR1 was detected in multiple forebrain regions (neocortex, hippocampus, dentate gyrus, thalamus, and caudate-putamen) in rats treated with gadobenate or gadopentetate, whereas rats treated with gadodiamide showed gadolinium-related ΔR1 in caudate-putamen. By contrast, LA-ICP-MS elemental mapping showed a similar regional distribution pattern of heterogeneous retained gadolinium in the forebrain of rats treated with gadobenate, gadopentetate, or gadodiamide, with the average gadolinium concentration of 0.45 µg · g-1 ± 0.07, 0.50 µg · g-1 ± 0.10, and 0.60 µg · g-1 ± 0.11, respectively. Low levels (0.01 µg · g-1 ± 0.00) of retained gadolinium were detected in the forebrain of gadobutrol-treated rats. Conclusion Differences in in vivo MRI longitudinal relaxation rate versus ex vivo elemental mass spectrometry measures of retained gadolinium in rat forebrains suggest that some forms of retained gadolinium may escape detection with MRI. © RSNA, 2022 Online supplemental material is available for this article.

The value of contrast-enhanced portal vein imaging at the hepatobiliary phase obtained with gadobenate dimeglumine for predicting decompensation and transplant-free survival in chronic liver disease.

OBJECTIVES: To investigate the value of contrast-enhanced portal vein imaging at the hepatobiliary phase obtained with gadobenate dimeglumine for predicting clinical outcomes in patients with chronic liver disease (CLD). METHODS: Three hundred and fourteen CLD patients who underwent gadobenate dimeglumine-enhanced hepatic magnetic resonance imaging were stratified into three groups: nonadvanced CLD (n = 116), compensated advanced CLD (n = 120), and decompensated advanced CLD (n = 78) groups. The liver-to-portal vein contrast ratio (LPC) and liver-spleen contrast ratio (LSC) at the hepatobiliary phase were measured. The value of LPC for predicting hepatic decompensation and transplant-free survival was assessed using Cox regression analysis and Kaplan-Meier analysis. RESULTS: The diagnostic performance of LPC was significantly better than LSC in evaluating the severity of CLD. During a median follow-up period of 53.0 months, the LPC was a significant predictor for hepatic decompensation (p < 0.001) in patients with compensated advanced CLD. The predictive performance of LPC was higher than that of the model for end-stage liver disease score (p = 0.006). With the optimal cut-off value, patients with LPC ≤ 0.98 had a higher cumulative incidence of hepatic decompensation than patients with LPC > 0.98 (p < 0.001). The LPC was also a significant predictive factor for transplant-free survival in patients with compensated advanced CLD (p = 0.007) and those with decompensated advanced CLD (p = 0.002). CONCLUSIONS: Contrast-enhanced portal vein imaging at the hepatobiliary phase obtained with gadobenate dimeglumine is a valuable imaging biomarker for predicting hepatic decompensation and transplant-free survival in CLD patients. KEY POINTS: • The liver-to-portal vein contrast ratio (LPC) significantly outperformed liver-spleen contrast ratio in evaluating the severity of chronic liver disease. • The LPC was a significant predictor for hepatic decompensation in patients with compensated advanced chronic liver disease. • The LPC was a significant predictor for transplant-free survival in patients with compensated and those with decompensated advanced chronic liver disease.

Pre-clinical Formulation Development of an in situ Meglumine Salt of AZD5991: A Novel Macrocyclic Mcl-1 Inhibitor.

PURPOSE: AZD5991 is a potent and selective macrocyclic inhibitor of Mcl-1 in clinical development. Developing an intravenous solution formulation for AZD5991 proved to be challenging primarily due to the poor intrinsic solubility of AZD5991. In this article are described studies performed to select a suitable crystalline form and to assess physicochemical properties of AZD5991 to aid in the design of a solution formulation for preclinical studies. METHODS: It is preferable that the preclinical formulation has a line of sight for clinical formulation. For AZD5991, a concentration of at least 20 mg/ml was required for toxicology studies. Toward this goal, extensive pre-formulation characterization of AZD5991 including solid form analysis, pH-solubility profiling and solubility determination in cosolvents and other solubilizing media were carried out. RESULTS & DISCUSSION: Crystalline Form A, which is more stable in aqueous solution and possesses acceptable thermal stability, was selected for preclinical and clinical development of AZD5991. Extensive solubility evaluation revealed an interesting pH-solubility profile that significantly enhances solubilization at pH > 8.5 to allow solution concentrations of at least 30 mg/ml by in situ meglumine salt formation. CONCLUSION: Developing pre-clinical formulations to support in vivo studies requires a good understanding of the physicochemical properties of the drug candidates. Candidates with challenging pharmaceutic properties like the novel macrocycle molecule AZD5991, demand extensive characterization in its polymorph landscape, solubility profile and suitability evaluation of the excipients. Meglumine, a pH-adjusting and solubilizing agent, was found to be the best choice for formulating AZD5991 into an intravenous product to support preclinical studies.

Transcrocetin Meglumine Salt Inhibits Spinal Glial Cell-Mediated Proinflammatory Cytokines and Attenuates Complete Freund's Adjuvant-Induced Inflammatory Pain.

INTRODUCTION: Inflammatory pain is a significant global clinical challenge that involves both unpleasant sensory and emotional experiences. The treatment of pain is imminent, and we are committed to seeking new analgesics for pain relief. Transcrocetin meglumine salt (TCMS), a saffron metabolite derived from the crocin apocarotenoids, has exhibited the ability to cross the blood-brain barrier and exert neuroprotective effects. In this study, we aimed to investigate whether TCMS could ameliorate complete Freund's adjuvant (CFA)-induced inflammatory pain in mice and elucidate its underlying mechanisms. METHODS: Here, we established an inflammatory pain model in mice by injecting CFA into the left hind paw. Three days later, we administered intraperitoneal injections of TCMS (10 mg/kg) or saline to the animals. We examined mechanical allodynia, thermal hypersensitivity, and anxiety behavior. Furthermore, the activation of glial cells and proinflammatory cytokines in the spinal cord were detected. RESULTS: Our results showed that TCMS significantly reversed the mechanical allodynia and thermal hypersensitivity in the CFA-injected mice. Furthermore, TCMS administration effectively inhibited the activation of microglia and astrocytes in the spinal cord induced by CFA. Additionally, TCMS suppressed the production and release of spinal proinflammatory cytokines, including TNF-α, IL-1ß, and IL-6, in CFA-injected mice. CONCLUSION: Taken together, our findings demonstrate that TCMS holds promise as an innovative analgesic due to its ability to ameliorate inflammatory reactions.

[Network Meta-analysis of Chinese medicine injections for activating blood and resolving stasis in adjuvant treatment of acute ischemic stroke].

Network Meta-analysis was employed to compare the efficacy of Chinese medicine injections for activating blood and resolving stasis combined with conventional western medicine in the treatment of acute ischemic stroke and the effects on platelet aggregation rate, fibrinogen(FIB), and hypersensitive C-reactive protein(hs-CRP), with a view to providing evidence-based medicine reference for clinical medication. CNKI, Wanfang, VIP, SinoMed, PubMed, Web of Science, Cochrane Library, and EMbase were searched for randomized controlled trial(RCT) on the treatment of acute ischemic stroke with Salvia Miltiorrhiza Ligustrazine Injection, Danhong Injection, Shuxuetong Injection, Xueshuantong Injection, Shuxuening Injection, Safflower Yellow Pigment Injection, and Ginkgo Diterpene Lactone Meglumine Injection combined with conventional western medicine. The retrieval time was from database inception to March 18, 2023. The articles were extracted by two researchers and their quality was evaluated. R 4.2.2 was used for network Meta-analysis. A total of 87 RCTs involving 8 580 patients were included. Network Meta-analysis showed that, in terms of reducing National Institutes of Health stroke scale(NIHSS) scores, the surface under the cumulative ranking curve(SUCRA) showed the order of Xueshuantong Injection + conventional western medicine(88.7%) > Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine(73.7%) > Shuxuetong Injection + conventional western medicine(69.7%) > Shuxuening Injection + conventional western medicine(51.8%) > Danhong Injection + conventional western medicine(43.7%) > Safflower Yellow Pigment Injection + conventional western medicine(36.8%) > Ginkgo Diterpene Lactone Meglumine Injection + conventional western medicine(35.3%) > conventional western medicine(1.7%). In terms of improving clinical total effective rate, SUCRA showed the order of Danhong Injection + conventional western medicine(63.0%) > Shuxuening Injection + conventional western medicine(59.0%) > Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine(58.9%) > Safflower Yellow Pigment Injection + conventional western medicine(57.1%) > Xueshuantong Injection + conventional western medicine(56.8%) > Shuxuetong Injection + conventional western medicine(54.6%) > Ginkgo Diterpene Lactone Meglumine Injection + conventional western medicine(50.5%) > conventional western medicine(0.03%). In terms of improving Barthel index, SUCRA showed the order of Danhong Injection + conventional western medicine(84.7%) > Shuxuetong Injection + conventional western medicine(72.4%) > Safflower Yellow Pigment Injection + conventional western medicine(61.6%) > Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine(44.6%) > Ginkgo Diterpene Lactone Meglumine Injection + conventional western medicine(43.2%) > Shuxuening Injection + conventional western medicine(42.2%) > conventional western medicine(1.4%). In terms of reducing platelet aggregation rate, SUCRA showed the order of Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine(82.4%) > Shuxuetong Injection + conventional western medicine(81.6%) > Ginkgo Diterpene Lactone Meglumine Injection + conventional western medicine(40.7%) > Danhong Injection + conventional western medicine(37.3%) > conventional western medicine(8.0%). In terms of reducing FIB, SUCRA showed the order of Danhong Injection + conventional western medicine(81.0%) > Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine(71.9%) > Ginkgo Diterpene Lactone Meglumine Injection + conventional western medicine(70.0%) > Shuxuetong Injection + conventional western medicine(46.7%) > Xueshuantong Injection + conventional western medicine(22.6%) > conventional western medicine(8.7%). In terms of reducing hs-CRP, SUCRA showed the order of Shuxuening Injection + conventional western medicine(89.9%) > Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine(78.8%) > Ginkgo Diterpene Lactone Meglumine Injection + conventional western medicine(52.4%) > Danhong Injection + conventional western medicine(47.6%) > Xueshuantong Injection + conventional western medicine(43.5%) > Shuxuetong Injection + conventional Western medicine(35.6%) > conventional western medicine(2.3%). The results indicated that Xueshuantong Injection + conventional western medicine, Danhong Injection + conventional western medicine, and Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine ranked the top three. Xueshuantong Injection + conventional western medicine had the best effect on reducing NIHSS scores. Danhong Injection + conventional western medicine showed the best performance of improving clinical total effective rate, improving Barthel index, and reducing FIB in the blood. Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine had the best effect on reducing platelet aggregation rate in the blood. Shuxuening Injection + conventional western medicine had the best effect on reducing hs-CRP. However, more high-quality RCTs are needed for verification in the future to provide more reliable evidence-based medical reference.

[Potential for infusion correction of COVID-19-associated endotheliopathy].

AIM: To evaluate the relationship between the systemic inflammatory response and the severity of COVID-19-associated endotheliopathy and the effect of succinate-containing crystalloid solution (sodium meglumine succinate) on it in patients with severe COVID-19. MATERIALS AND METHODS: Clinical and laboratory parameters of 53 intensive care unit's patients with COVID-19 complicated by community-acquired bilateral multisegmental pneumonia were analyzed. Intensive therapy complex of 27 patients (study group) included daily infusion of 1.5% solution of sodium meglumine succinate (Reamberin) in the daily dose of 10 ml/kg for at least 11 days (or during the whole stay in the unit). A similar volume of Ringer's solution was present in the control group of 26 patients. The levels of endotheliocytosis, homocysteine, and systemic inflammatory response were determined at all stages of the study. RESULTS: The evaluation of endotheliopathy degree in the meglumine succinate group showed a significant reduction of initially elevated levels of endotheliemia and homocysteinemia at all study stages. The pattern of changes in the study group was highly correlated (r=0.90-0.96) with the dynamics of systemic inflammatory response parameters-fibrinogenemia, C-reactive protein and interleukin-6 levels. As normalization of the immune imbalance, we regarded the termination of lymphopenia in the Reamberin group. CONCLUSION: Early inclusion of Reamberin infusion into intensive therapy of severe COVID-19, in comparison with Ringer's solution, leads to significant and stable correction of the severity of systemic inflammatory response, which in turn is naturally reflected in the severity of endothelial dysfunction, multiple organ failure, and also leads to a decrease in 28-day mortality.

[Infusion therapy with reamberin in military conditions]. / Ispol'zovanie rastvora reamberina v voennykh usloviyakh.

The article is devoted to infusion therapy with Reamberin 1.5% (Meglumine sodium succinate) in patients with various traumatic injuries. The authors substantiate the relevance and significance of this issue. Specifics and purposes of therapy are considered. The authors reviewed national studies devoted to clinical aspects and determined the main directions of therapy in emergency patients with mechanical injuries, burns, traumatic brain injury and cognitive impairment caused by combat trauma. Moreover, experimental studies of protective properties of Reamberin under combined action of cold, vibration and immobilization, as well as acute massive blood loss are analyzed.

MRA of the Supraaortic Vasculature: Comparison of Gadobutrol and Gadoterate Meglumine at 1.5 T.

BACKGROUND: Gadobutrol (GB) and gadoterate meglumine (GM) are contrast agents used for contrast-enhanced magnetic resonance angiography (CEMRA). Supraaortic vasculature (SAV) CEMRAs are used to evaluate stroke risk and neurologic symptoms. There is a need to compare the SAV CEMRA image quality obtained with GB and GM. PURPOSE: To intra-individually compare MRA images obtained with equimolar GB and GM at 1.5 T in the SAV. STUDY TYPE: Prospective, crossover. POPULATION: Twenty-eight subjects (54 ± 13 years; 17 female). FIELD STRENGTH/SEQUENCE: 1.5 T; three-dimensional (3D) gradient recalled echo. ASSESSMENT: Quantitative image quality was measured by normalized signal intensity (SIn ) [SIn  = SI blood/SD blood] and contrast ratio (CR) [CR = SI blood/SI muscle], determined by an observer (JWC) with 1 year of vascular imaging experience. Three radiologists (AS, PA, and MU) with (5, 5, and 6 years of) vascular imaging experience evaluated image quality by Likert-scale ratings (of image impression, wall conspicuity, and artifact absence). STATISTICAL TESTS: SIn and CR were compared with paired t-tests or Wilcoxon signed-rank tests and Bland-Altman plots. Qualitative ratings were compared with Wilcoxon signed-rank test. RESULTS: No significant difference in SIn was found between GB and GM. CRs with GB were significantly higher than GM at the right common carotid (6.9 ± 2.5 vs. 4.8 ± 1), left internal carotid (7.3 ± 2 vs. 4.4 ± 1.2), right internal carotid (7.7 ± 2.2 vs. 5 ± 1.1), and left vertebral (6.6 ± 2.2 vs. 4.5 ± 1.1) arteries. Bland-Altman plots showed relatively greater differences between GB and GM at higher CRs and SIn s. GM showed significantly higher artifact than GB (3.56 ± 0.52 vs. 3.36 ± 0.46) and significantly lower overall image quality (10.73 ± 1.45 vs. 11.26 ± 1.58) at the left vertebral artery. DATA CONCLUSION: At 1.5 T and equimolar demonstration, GB (0.1 mL/kg, i.e., 0.1 mmol/kg) showed higher CRs in the SAV compared to GM (0.2 mL/kg, i.e., 0.1 mmol/kg) at most vessels. Subjective image quality was not significantly different between the two agents for most vessels. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Respiratory anomalies associated with gadoxetate disodium and gadoterate meglumine: compressed sensing MRI revealing physiologic phenomena during the entire injection cycle.

OBJECTIVES: The goal of this study was to investigate the precise timeline of respiratory events occurring after the administration of two gadolinium-based contrast agents, gadoxetate disodium and gadoterate meglumine. MATERIALS AND METHODS: This retrospective study examined 497 patients subject to hepatobiliary imaging using the GRASP MRI technique (TR/TE = 4/2 ms; ST = 2.5 mm; 384 × 384 mm). Imaging was performed after administration of gadoxetate (N = 338) and gadoterate (N = 159). All GRASP datasets were reconstructed using a temporal resolution of 1 s. Four regions-of-interest (ROIs) were placed in the liver dome, the right and left cardiac ventricle, and abdominal aorta detecting liver displacement and increasing vascular signal intensities over time. Changes in hepatic intensity reflected respiratory dynamics in temporal correlation to the vascular contrast bolus. RESULTS: In total, 216 (67%) and 41 (28%) patients presented with transient respiratory motion after administration of gadoxetate and gadoterate, respectively. The mean duration from start to acme of the respiratory episode was similar (p = 0.4) between gadoxetate (6.0 s) and gadoterate (5.6 s). Its mean onset in reference to contrast arrival in the right ventricle differed significantly (p < 0.001) between gadoxetate (15.3s) and gadoterate (1.8 s), analogously to peak inspiration timepoint in reference to the aortic enhancement arrival (gadoxetate: 0.9s after, gadoterate: 11.2 s before aortic enhancement, p < 0.001). CONCLUSIONS: The timepoint of occurrence of transient respiratory anomalies associated with gadoxetate disodium and gadoterate meglumine differs significantly between both contrast agents while the duration of the event remains similar. KEY POINTS: • Transient respiratory anomalies following the administration of gadoterate meglumine occurred during a time period usually not acquired in MR imaging. • Transient respiratory anomalies following the administration of gadoxetate disodium occurred around the initiation of arterial phase imaging. • The estimated duration of respiratory events was similar between both contrast agents.

Gd-BOPTA-enhanced hepatobiliary phase MR imaging can predict the prognosis of patients with acute-on-chronic liver failure.

OBJECTIVES: To determine the value of gadobenate dimeglumine (Gd-BOPTA)-enhanced magnetic resonance imaging (MRI) from the hepatobiliary phase for predicting poor outcome in acute-on-chronic liver failure (ACLF) patients. METHODS: In this single-center retrospective study, 74 patients diagnosed as ACLF who underwent Gd-BOPTA-enhanced hepatobiliary magnetic resonance imaging were collected. The quantitative liver-spleen contrast ratio (Q-LSC) and the relative enhancement ratio of the biliary system (REB) at the hepatobiliary phase were measured. Cox proportional hazards regression models were used to evaluate prognostic factors. The capacity of the Q-LSC and REB to predict the 90-day outcome was evaluated via receiver operating characteristic (ROC) curve. RESULTS: During the follow-up period, twenty-eight of 74 ACLF patients (38%) had a poor outcome. The Q-LSC and REB were significant predictive factors (hazard ratio [HR] = 0.03 [0.002-0.54], p < 0.05; HR = 0.07 [0.01-0.88], p < 0.05) for prognosis in patients with ACLF. Moreover, the areas under the ROC curves of Q-LSC and REB for predicting poor outcome in patients with ACLF were 0.81 and 0.80, respectively. The most appropriate cutoff values for the Q-LSC and REB were 1.09 and 0.57, respectively. The ACLF patients with the Q-LSC ≤ 1.09 or REB ≤ 0.57 had a low cumulative survival. CONCLUSIONS: Gd-BOPTA-enhanced hepatobiliary phase MR imaging can predict poor outcome in patients with acute-on-chronic liver failure. KEY POINTS: • The quantitative liver-spleen contrast ratio at the hepatobiliary phase was a significant predictive prognostic factor in patients with acute-on-chronic liver failure. • The relative enhancement ratio of the biliary system at the hepatobiliary phase was a significant prognostic factor in patients with acute-on-chronic liver failure. • Gadobenate dimeglumine contrast-enhanced MR imaging from the hepatobiliary phase can predict poor outcome in patients with acute-on-chronic liver failure.

Influence of aging and gadolinium exposure on T1, T2, and T2*-relaxation in healthy women with an increased risk of breast cancer with and without prior exposure to gadoterate meglumine at 3.0-T brain MR imaging.

OBJECTIVES: We examined the effects of aging and of gadolinium-based contrast agent (GBCA) exposure on MRI measurements in brain nuclei of healthy women. METHODS: This prospective, IRB-approved single-center case-control study enrolled 100 healthy participants of our high-risk screening center for hereditary breast cancer, who had received at least six doses of macrocyclic GBCA (exposed group) or were newly entering the program (GBCA-naïve group). The cutoff "at least six doses" was chosen to be able to include a sufficient number of highly exposed participants. All participants underwent unenhanced 3.0-T brain MRI including quantitative T1, T2, and R2* mapping and T1- and T2-weighted imaging. The relaxation times/signal intensities were derived from region of interest measurements in the brain nuclei performed by a radiologist and a neuroradiologist, both board certified. Statistical analysis was based on descriptive evaluations and uni-/multivariable analyses. RESULTS: The participants (exposed group: 49, control group: 51) were aged 42 ± 9 years. In a multivariable model, age had a clear impact on R2* (p < 0.001-0.012), T2 (p = 0.003-0.048), and T1 relaxation times/signal intensities (p < 0.004-0.046) for the majority of deep brain nuclei, mostly affecting the substantia nigra, globus pallidus (GP), nucleus ruber, thalamus, and dentate nucleus (DN). The effect of prior GBCA administration on T1 relaxation times was statistically significant for the DN, GP, and pons (p = 0.019-0.037). CONCLUSIONS: In a homogeneous group of young to middle-aged healthy females aging had an effect on T2 and R2* relaxation times and former GBCA applications influenced the measured T1 relaxation times. KEY POINTS: The quantitative T1, T2, and R2* relaxation times measured in women at high risk of developing breast cancer showed characteristic bandwidth for all brain nuclei examined at 3.0-T MRI. The effect of participant age had a comparatively strong impact on R2*, T2, and T1 relaxation times for the majority of brain nuclei examined. The effect of prior GBCA administrations on T1 relaxation times rates was comparatively less pronounced, yielding statistically significant results for the dentate nucleus, globus pallidus, and pons. Healthy women with and without previous GBCA-enhanced breast MRI exhibited age-related T2* and T2 relaxation alterations at 3.0 T-brain MRI. T1 relaxation alterations due to prior GBCA administration were comparatively less pronounced.

Improved Pharmaceutical Properties of Honokiol via Salification with Meglumine: an Exception to Oft-quoted ∆pKa Rule.

Honokiol (HK), a BCS class II drug with a wide range of pharmacological activities, has poor solubility and low oral bioavailability, severely limiting its clinical application. In the current study, incorporating a water-soluble meglumine (MEG) into the crystal lattice of HK molecule was performed to improve its physicochemical properties. The binary mixture of HK and MEG was obtained by anti-solvent method and characterized by TGA, DSC, FTIR, and PXRD. The SCXRD analysis showed that two HK- molecules and two MEG+ molecules were coupled in each unit cell via the ionic interaction along with intermolecular hydrogen bonds, suggesting the formation of a salt, which was further confirmed by the XPS measurements. However, the ∆pKa value between HK and MEG was found to be less than 1, which did not follow the oft-quoted ∆pKa rule for salt formation. After salification with MEG, the solubility and dissolution rate of HK exhibited 3.50 and 25.33 times improvement than crystalline HK, respectively. Simultaneously, the powder flowability, tabletability and stability of HK-MEG salt was also significantly enhanced, and the salt was not more hygroscopic, and that salt formation did not compromise processability in that regard. Further, in vivo pharmacokinetic study showed that Cmax and AUC0-t of HK-MEG salt were enhanced by 2.92-fold and 2.01-fold compared to those of HK, respectively, indicating a considerable improvement in HK oral bioavailability.

Comparison of Gadobenate-Enhanced MRI and Gadoxetate-Enhanced MRI for Hepatocellular Carcinoma Detection Using LI-RADS Version 2018: A Prospective Intraindividual Randomized Study.

BACKGROUND. Gadobenate and gadoxetate show different degrees of intracellular accumulation within hepatocytes, potentially impacting these agents' relative performance for hepatocellular carcinoma (HCC) diagnosis. OBJECTIVE. The purpose of this article was to perform an intraindividual comparison of gadobenate-enhanced MRI and gadoxetate-enhanced MRI for detection of HCC and to assess the impact of inclusion of hepatobiliary phase images on HCC detection for both agents. METHODS. This prospective study enrolled 126 patients (112 men, 14 women; mean age, 52.3 years) at high risk for HCC who consented to undergo two 3-T liver MRI examinations (one using gadobenate [0.05 mmol/kg], one using gadoxetate [0.025 mmol/kg]) separated by 7-14 days. The order of the two contrast agents was randomized. All examinations included postcontrast dynamic and hepatobiliary phase images (120 minutes for gadobenate, 20 minutes for gadoxetate). Three radiologists independently reviewed the gadobenate and gadoxetate examinations in separate sessions and recorded the location of detected observations. Observations were classified using LI-RADS version 2018 and using a LI-RADS modification whereby hepatobiliary phase hypointensity may upgrade observations from category LR-4 to LR-5. Observations classified as LR-5 were considered positive interpretations for HCC. Diagnostic performance for histologically confirmed HCC (n = 96) was assessed. RESULTS. Across readers, sensitivity for HCC for gadobenate versus gadoxetate was 74.0-80.2% versus 54.2-67.7% using dynamic images alone and 82.1-87.4% versus 66.3-81.1% using dynamic and hepatobiliary phase images. For HCCs measuring 1.0-2.0 cm, sensitivity for gadobenate versus gadoxetate was 61.9% (all readers) versus 38.1-57.1% using dynamic images alone and 76.2-85.7% versus 52.4-61.9% using dynamic and hepatobiliary phase images. PPV for HCC ranged from 88.6% to 97.4% across readers, agents, and image sets. CONCLUSION. Sensitivity for HCC was higher for gadobenate than for gadoxetate, whether using dynamic images alone or dynamic and hepatobiliary phase images; the improved sensitivity using gadobenate was more pronounced for small HCCs. Whereas hepatobiliary phase images improved sensitivity for both agents, sensitivity of gadobenate using dynamic images alone compared favorably with that of gadoxetate using dynamic and hepatobiliary phase images. CLINICAL IMPACT. The findings support gadobenate as a preferred agent over gadoxetate when performing liver MRI in patients at high risk for HCC.