Improvement in drug solubility is a major challenge for developing pharmaceutical products. It was demonstrated earlier that aqueous solubilities of weakly basic drugs could be increased greatly by interaction with weak acids that would not form salts with the drugs, and the highly concentrated solutions thus produced converted to amorphous solids upon drying. The technique was called acid-base supersolubilization (ABS). The current investigation explored whether the ABS principle could also be applied to weakly acidic drugs. By taking flurbiprofen (pKa 4.09; free acid solubility 0.011 mg/mL) as the model weakly acidic drug and tromethamine, lysine, meglumine, and NaOH as bases, it was studied which of the bases would result in ABS. While in the presence of NaOH and tromethamine, flurbiprofen converted to salts having aqueous solubility of 11-19 mg/mL, the solubility increased to > 399 mg/mL with lysine and > 358 mg/mL with meglumine, producing supersolubilization. However, crystallization of lysine salt was observed with time, followed by some decrease in solubility after reaching maximum solubility with lysine. In contrast, the supersolubilization was maintained with meglumine, and no crystallization of meglumine salt was observed. Upon drying, flurbiprofen-meglumine solutions produced amorphous materials that dissolved rapidly and produced high drug concentrations in aqueous media. Thus, the ABS principle also applies to acidic drugs depending on the weak base used.

OBJECTIVE: To evaluate the performance of hepatobiliary MRI parameters as predictors of clinical response to chemotherapy in patients with initially unresectable colorectal cancer liver metastases (CRLM).
METHODS: Eighty-five patients with initially unresectable CRLM were retrospectively enrolled from two hospitals and scanned using gadobenate dimeglumine-enhanced MRI before treatment. Therapy response was evaluated based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Conventional parameters (i.e., signal intensity [SI]) and radiomics features of portal venous phase (PVP) and hepatobiliary phase (HBP) images were analyzed between the responders and non-responders. Next, the combined model was constructed, and the area under the receiver operating characteristic (ROC) curve (AUC) was calculated. The relationship between the combined model and progression-free survival (PFS) was analyzed using Cox regression.
RESULTS: Of the 85 patients from two hospitals, 42 were in the response group, and 43 were in the non-response group. Upon conducting five-fold cross-validation, the normalized relative enhancement (NRE) of CRLM during the PVP yielded an AUC of 0.625. Additionally, a radiomics feature derived from the tumor area in the HBP achieved an AUC of 0.698, while a separate feature extracted from the peritumoral region in the HBP recorded an AUC of 0.709. The model that integrated these three features outperformed the individual features, achieving an AUC of 0.818. Furthermore, the combined model exhibited a significant correlation with PFS (P < 0.001).
CONCLUSIONS: The combined model, based on baseline hepatobiliary MRI, aids in predicting chemotherapeutic response and PFS in patients with initially unresectable CRLM.

Hyperpolarized 13C-labeled fumarate probes tissue necrosis via the production of 13C-malate. Despite its promises in detecting tumor necrosis and kidney injuries, its clinical translation has been limited, primarily due to the low solubility in conventional glassing solvents. In this study, we introduce a new formulation of fumarate for dissolution dynamic nuclear polarization (DNP) by using meglumine as a counterion, a nonmetabolizable derivative of sorbitol. We have found that meglumine fumarate vitrifies by itself with enhanced water solubility (4.8 M), which is expected to overcome the solubility-restricted maximum concentration of hyperpolarized fumarate after dissolution. The achievable liquid-state polarization level of meglumine-fumarate is more than doubled (29.4 ± 1.3%) as compared to conventional dimethyl sulfoxide (DMSO)-mixed fumarate (13.5 ± 2.4%). In vivo comparison of DMSO- and meglumine-prepared 50-mM hyperpolarized [1,4-13C2]fumarate shows that the signal sensitivity in rat kidneys increases by 10-fold. As a result, [1,4-13C2]aspartate and [13C]bicarbonate in addition to [1,4-13C2]malate can be detected in healthy rat kidneys in vivo using hyperpolarized meglumine [1,4-13C2]fumarate. In particular, the appearance of [13C]bicarbonate indicates that hyperpolarized meglumine [1,4-13C2]fumarate can be used to investigate phosphoenolpyruvate carboxykinase, a key regulatory enzyme in gluconeogenesis.

OBJECTIVE: Conventionally, MRI aids in differentiating acute unilateral peripheral vestibulopathy/vestibular neuritis (AUPV/VN) from mimickers. Meanwhile, the diagnostic utility of MRIs dedicated to the inner ear remains to be elucidated for diagnosing AUPV/VN.
METHODS: We prospectively recruited 53 patients with AUPV/VN (mean age ± SD = 60 ± 15 years, 29 men). Initial MRIs were performed with a standard protocol, and an additional axial 3D-fluid-attenuated inversion recovery (3D-FLAIR) sequence was obtained 4 h after intravenous injection of gadoterate meglumine. Abnormal enhancement was defined as a signal intensity that exceeded the mean + 2SD value on the healthy side. The findings of neurotologic evaluation and MRIs were compared.
RESULTS: Overall, the inter-rater agreement for gadolinium enhancement was 0.886 (Cohen\'s kappa coefficient). Enhancement was observed in 26 patients (49%), most frequently in the vestibule (n = 20), followed by the anterior (n = 12), horizontal (HC, n = 8), posterior canal (n = 5), and superior (n = 3) and inferior (n = 1) vestibular nerves. In multivariable logistic regression analysis, the enhancement was associated with decreased HC gain in video head-impulse tests (p = 0.036), increased interaural difference in ocular vestibular-evoked myogenic potentials (p = 0.001), and a longer onset-to-MRI time span (p = 0.024). The sensitivity and specificity were 92.3% and 81.5%, respectively, with an area under the curve of 0.90 for predicting gadolinium enhancement.
CONCLUSIONS: Robust gadolinium enhancement was observed on 4-hour-delayed 3D-FLAIR images in nearly half of the patients with AUPV/VN, with a good correlation with the results of neurotologic evaluation. The positivity may be determined by the extent of vestibular deficit, timing of imaging acquisition, and possibly by the underlying etiology causing AUPV/VN. MRIs may aid in delineating the involved structures in AUPV/VN.

We present the first case of mucocutaneous leishmaniasis in Algeria, diagnosed in an immunocompetent 42-year-old man exhibiting an infiltrated and ulcerated plaque leading to macrocheilitis of the entire lower lip. He was a police officer who lived in a village in Ain El Hammam (Kabylie region, known as an active focus of zoonotic visceral leishmaniasis) without any history of travel for the previous 3 years. He suffered from cutaneous lesions for 22 months due to the misdiagnosis of a skin lesion resembling other diseases such as Crohn disease or sarcoidosis. A compilation of clinical, histopathological, parasitological, and molecular examinations revealed Leishmania infantum as the etiologic agent. The patient was treated with meglumine antimoniate, which resulted in the complete disappearance of the lesion 4 months after treatment.

OBJECTIVE: To compare the ability of gadolinium ethoxybenzyl dimeglumine (Gd-EOB-DTPA) and gadobenate dimeglumine (Gd-BOPTA) to display the 3 major features recommended by the Liver Imaging Reporting and Data System (LI-RADS 2018v) for diagnosing hepatocellular carcinoma (HCC).
METHODS: In this retrospective study, we included 98 HCC lesions that were scanned with either Gd-EOB-DTPA-MR or Gd-BOPTA-M.For each lesion, we collected multiple variables, including size and enhancement pattern in the arterial phase (AP), portal venous phase (PVP), transitional phase (TP), delayed phase (DP), and hepatobiliary phase (HBP). The lesion-to-liver contrast (LLC) was measured and calculated for each phase and then compared between the 2 contrast agents. A P value < .05 was considered statistically significant. The display efficiency of the LLC between Gd-BOPTA and Gd-EOB-DTPA for HCC features was evaluated by receiver operating characteristic (ROC) curve analysis.
RESULTS: Between Gd-BOPTA and Gd-EOB-DTPA, significant differences were observed regarding the display efficiency for capsule enhancement and the LLC in the AP/PVP/DP (P < .05), but there was no significant difference regarding the LLC in the TP/HBP. Both Gd-BOPTA and Gd-EOB-DTPA had good display efficiency in each phase (AUCmin > 0.750). When conducting a total evaluation of the combined data across the 5 phases, the display efficiency was excellent (AUC > 0.950).
CONCLUSIONS: Gd-BOPTA and Gd-EOB-DTPA are liver-specific contrast agents widely used in clinical practice. They have their own characteristics in displaying the 3 main signs of HCC. For accurate noninvasive diagnosis, the choice of agent should be made according to the specific situation.

OBJECTIVE: To compare the ability to depict MRI features of hepatobiliary agents in microvascular infiltration (MVI) of hepatocellular carcinoma (HCC) during different stages of dynamic enhancement MRI.
METHODS: A retrospective study included 111 HCC lesions scanned with either Gd-EOB-DTPA or Gd-BOPTA. All cases underwent multiphase dynamic contrast-enhanced scanning before surgery, including arterial phase (AP), portal venous phase (PVP), transitional phase (TP), delayed phase (DP), and hepatobiliary phase (HBP). Two abdominal radiologists independently evaluated MRI features of MVI in HCC, such as peritumoral hyperenhancement, incomplete capsule, non-smooth tumor margins, and peritumoral hypointensity. Finally, the results were reviewed by the third senior abdominal radiologist. Chi-square (χ2) Inspection for comparison between groups. P < 0.05 is considered statistically significant. Receiver operating characteristic (ROC) curve was used to evaluate correlation with pathology, and the area under the curve (AUC) and 95% confidence interval (95% CI) were calculated.
RESULTS: Among the four MVI evaluation signs, Gd-BOPTA showed significant differences in displaying two signs in the HBP (P < 0.05:0.000, 0.000), while Gd-EOB-DTPA exhibited significant differences in displaying all four signs (P < 0.05:0.005, 0.006, 0.000, 0.002). The results of the evaluations of the two contrast agents in the DP phase with incomplete capsulation showed the highest correlation with pathology (AUC: 0.843, 0.761). By combining the four MRI features, Gd-BOPTA and Gd-EOB-DTPA have correlated significantly with pathology, and Gd-BOPTA is better (AUC: 0.9312vs0.8712).
CONCLUSIONS: The four features of hepatobiliary agent dynamic enhancement MRI demonstrate a good correlation with histopathological findings in the evaluation of MVI in HCC, and have certain clinical significance.

BACKGROUND: This study examined the experiences of owners of dogs with leishmaniosis who treated their dogs with daily subcutaneous meglumine antimoniate injections. The owners\' perceived ease of administering the injections, the occurrence of problems and the effects on the owners and on the dog‒owner bond were evaluated.
METHODS: Dogs prescribed meglumine antimoniate as a treatment for leishmaniosis were identified using the database of the veterinary pharmacy of the Faculty of Veterinary Medicine, Utrecht University. An online questionnaire was sent to the owners of these dogs to evaluate the perceived ease of administering the injections, the occurrence of problems and the effects on the owner and the dog-owner bond.
RESULTS: Responses were received from 64 dog owners. Most respondents (78%) reported that administering the injections was not difficult. Pain or the development of nodules at the injection site was reported in 50% and 40% of the dogs, respectively. Polyuria was reported in 44% of the dogs. Some owners reported that administering the injections had a negative impact on their psychological wellbeing (20%), and some would have liked more veterinary support (11%).
CONCLUSIONS: Some questions were answered by a limited number of people, and their responses may not be representative.
CONCLUSIONS: Dog owners remain highly motivated to persevere with meglumine antimoniate treatment and are willing to administer the injections themselves. The availability of active support when needed during the therapy cycle may further improve their acceptance of and confidence in giving the injections.

The multifactorial basis of therapeutic response can obscure the relation between antimicrobial drug susceptibility and clinical outcome. To discern the relationship between parasite susceptibility to meglumine antimoniate (SbV) and therapeutic outcome of cutaneous leishmaniasis, risk factors for treatment failure were considered in evaluating this relationship in ninety-one cutaneous leishmaniasis patients and corresponding clinical strains of Leishmania (Viannia) panamensis. Parasite susceptibility to 32 μg SbV/mL (plasma Cmax) was evaluated in primary human macrophages, PBMCs, and U937 macrophages. Early parasitological response to treatment was determined in lesions of a subgroup of patients, and pathogenicity of Sb-resistant and sensitive clinical strains was compared in BALB/c mice. Parasite survival in cell models and patient lesions was determined by qRT-PCR of Leishmania 7SLRNA transcript. Parasite loads in BALB/c mice were quantified by limiting dilution analysis. The disparate Sb-susceptibility of parasite subpopulations distinguished by isoenzyme profiles (zymodemes) was manifest in all cell models. Notably, Sb-resistance defined by parasite survival, was most effectively discerned in U937 macrophages compared with primary human host cells, significantly higher among strains from patients who failed treatment than cured and, significantly associated with treatment failure. Each unit increase in transformed survival rate corresponded to a 10.6-fold rise in the odds of treatment failure. Furthermore, treatment failure was significantly associated with naturally Sb-resistant zymodeme 2.3 strains, which also produced larger lesions and parasite burdens in BALB/c mice than Sb-sensitive zymodeme 2.2 strains. The confounding effect of host risk factors for treatment failure in discerning this association was evidenced in comparing strains from patients with and without the defined risk factors for treatment failure. These results establish the association of natural resistance to meglumine antimoniate with treatment failure, the importance of host risk factors in evaluating drug susceptibility and treatment outcome, and the clinical and epidemiological relevance of natural Sb-resistance in L. (V.) panamensis subpopulations.

OBJECTIVE: Unexpected accumulations of gadolinium in various organs were reported after the administration of gadolinium-based contrast agents, making desirable to reduce the dose while maintaining equivalent diagnostic performance. The aim of this study was to evaluate the contrast enhancement performance of high relaxivity gadopiclenol compared with gadoterate meglumine in abdominal contrast-enhanced magnetic resonance angiography (CE-MRA).
METHODS: In a first study in healthy rabbits, axial 3D gradient echo sequences were applied at 4.7 T to study arterial enhancement as a function of gadopiclenol dose (0.025, 0.05, 0.075, and 0.1 mmol Gd/kg) or gadoterate meglumine at 0.1 mmol Gd/kg (n = 5-6/group). The increase in signal-to-noise ratio (ΔSNR) in the aorta at the first pass was measured and compared. In a second, crossover study in 6 healthy pigs, abdominal CE-MRA sequences were acquired at 3 T with gadopiclenol at 0.05 mmol Gd/kg or gadoterate meglumine at 0.1 mmol Gd/kg at a 1-week interval. Quantitatively on the maximum intensity projection (MIP) images, the mean MIP SNR within the aorta of both groups was compared. Qualitatively, a blinded comparison of the angiograms was performed by an experienced radiologist to determine the preferred contrast agent.
RESULTS: In the rabbit, ∆SNR is linearly correlated with the gadopiclenol dose ( P = 0.0010). Compared with gadoterate meglumine 0.1 mmol Gd/kg, an increase in the ∆SNR is observed after 0.05, 0.075, and 0.1 mmol Gd/kg of gadopiclenol (+63% P = 0.0731, +78% P = 0.0081, and +72% P = 0.0773, respectively), whereas at 0.025 mmol Gd/kg, ∆SNR is in the same range as with gadoterate meglumine 0.1 mmol Gd/kg (+15% P > 0.9999). In pigs, contrast enhancement after gadopiclenol at 0.05 mmol/kg is +22% superior to MIP SNR after gadoterate meglumine at 0.1 mmol Gd/kg ( P = 0.3095). Qualitatively, a preference was shown for gadopiclenol images (3/6) over the gadoterate meglumine examinations (1/6), with no preference being shown for the remainder (2/6).
CONCLUSIONS: First-pass CE-MRA is feasible with gadopiclenol at 0.05 mmol Gd/kg with at least the same arterial signal enhancement and image quality as gadoterate meglumine at 0.1 mmol Gd/kg.