Real-time in situ X-ray micro-computed tomography study of the effect of impurities on the crystallization of amorphous nifedipine.

Controlling the physical stability of noncrystalline active pharmaceutical ingredients remains a major challenge in the development of amorphous formulations such as amorphous solid-dispersion (ASD) formulations. To establish new evaluation and formulation strategies, the spatial distribution of the crystal phase in bulk amorphous nifedipine (NFD) was investigated as a model. The crystallization of amorphous NFD and the effect of a deliberately added impurity were investigated using powder X-ray diffraction (PXRD), differential scanning calorimetry and real-time in situ X-ray micro-computed tomography (X-ray CT). The stability data of amorphous samples, i.e., NFD and a mixture of NFD with an oxidative degradation product of NFD, impurity A (Imp A), at a weight ratio of 90:10, presented as percent amorphous remaining, suggests that Imp A accelerates the bulk crystal growth of NFD. Real-time in situ X-ray CT results showed surface-enhanced crystal growth and cavity formation in solid NFD samples. Moreover, the crystals were heterogeneous in density. These results suggest that Imp A affects the physical stability of the amorphous NFD. X-ray CT equipped with a heating unit can aid in-situ evaluation and assessment of physicochemical properties and physical stability of amorphous samples and formulations.

Co-Treatment with Steroid and Dupilumab for Eosinophilic Chronic Rhinosinusitis after Eosinophilic Pneumonitis Caused by Dupilumab.

Eosinophilic chronic rhinosinusitis (ECRS) is a Type 2 inflammatory disease that manifests as chronic inflammation of the paranasal sinus. IL-4/IL-13 receptor monoclonal antibodies (dupilumab) to suppress Type 2 inflammation have become a good treatment option for patients who are refractory to surgery. Most patients respond normally, although significant side effects such as eosinophilic pneumonia may occur, requiring discontinuation of dupilumab. Here, we present a case in which dupilumab administration caused a side-effect of eosinophilic pneumonia. A 65-year-old woman presented with nasal obstruction and olfactory dysfunction due to a nasal polyp. Her symptoms temporarily improved with dupilumab; however, dupilumab was discontinued due to eosinophilic pneumonia. Discontinuation of dupilumab resulted in the rapid resolution of eosinophilic pneumonia and reappearance of nasal polyps. We, therefore, resumed dupilumab treatment in combination with low-dose steroids; eosinophilic pneumonia did not flare up, and the nasal polyps shrank steadily. There is no established treatment strategy in cases where a side effect of eosinophilic pneumonia arises while treating ECRS with dupilumab. Based on the described case, we recommend that a combination of a low-dose steroids and dupilumab be considered as a treatment option to counter the side-effect of eosinophilic pneumonia induced by dupilumab alone.

Organized Hematoma after Intra-Arterial Chemoradiotherapy for Maxillary Sinus Cancer: A Case Report.

An organized hematoma (OH) is a relatively rare benign lesion of the paranasal sinuses. Traditionally, it has been reported to occur following trauma, surgery, and sinus hemorrhagic lesions and in various bleeding predispositions. OHs are sometimes difficult to differentiate from malignancy because of the similar clinical symptoms and bone destruction. It is especially difficult when OHs occur in the same location as the primary tumor after treatment of a malignant tumor. In this paper, we report two cases of OH that occurred after intra-arterial chemoradiotherapy (IACRT) for maxillary sinus cancer. In one case, FDG accumulation was found in PET/CT and suspected to be a cancer recurrence. However, the postoperative pathology showed no malignant findings. This suggests that OH may show accumulation on 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET). In both cases, bleeding from the maxillary sinus continued after surgery. In one case, recurrence was observed, and in the other, nasal irrigation prevented the pooling of blood in the maxillary sinus, and no recurrence was observed. These cases suggest that OH after IACRT may easily recur because the bleeding continues even after surgery. In such cases, nasal irrigation or preoperative embolization may be helpful to avoid recurrence.

Development of infectious mononucleosis as an unusual manifestation of COVID-19.

It has generally been reported that patients with COVID-19 show a fever, cough, and/or respiratory failure as the most common clinical symptoms but some have unusual symptoms, such as anosmia, diarrhea, and throat pain. We herein report a 26-year-old woman with chief complaints of lymphadenopathy and a fever. First, she underwent a laboratory examination, which showed a high proportion of atypical lymphocytes (19%) and an increase in hepatic enzyme activities, and was then hospitalized with a diagnosis of infectious mononucleosis (IM). However, the blood examination did not show any increase in anti-Epstein-Barr virus VCM-IgM. Subsequently, she developed tonsillar hypertrophy with purulent plugs. An additional examination for infection of other pathogens revealed positivity only for SARS-CoV-2 in a loop-mediated isothermal amplification (LAMP) test. The patient was transferred to the COVID-19-specific isolation ward, and none of the ward staff, patients, or either of the two otolaryngologists who had directly examined this patient showed positive signs for SARS-CoV-2 in a LAMP test. Consequently, this case suggests that even if patients show clinical symptoms and signs of common diseases for otolaryngologists, such as IM, we should keep in mind the possibility of COVID-19 without arbitrarily assuming that IM is caused by Epstein-Barr virus.

Validation of epistaxis severity score for hereditary hemorrhagic telangiectasia in Japan.

OBJECTIVE: This study aimed to assess the health-related QoL (HR-QoL) of patients with hereditary hemorrhagic telangiectasia (HHT), with emphasis on the role/social aspects, and validate the Japanese version of the epistaxis severity score (ESS) in these patients. METHODS: The Japanese version of the ESS was created through forward and reverse translation, and consultation with the original author. A validation analysis was performed by comparing ESS severity with the invasiveness of previous treatments for epistaxis and assessing the correlation between the ESS and HR-QoL. Medical history forms, ESS questionnaires, and the Medical Outcomes Study Short Form 36 (SF-36) were distributed to participants with HHT in August 2020. The relation between the ESS and summary scores of SF-36 was assessed by performing analysis of variance and Spearman's correlation. RESULTS: In total, 73 participants were included in this study. The average ESS was 5.02; there were mild (32.9%), moderate (45.2%), and severe (21.9%) epistaxis groups. Patients with higher ESS received a significantly more invasive treatment (Fisher's exact test, p < 0.05). The ESS was also negatively correlated with the physical component score (PCS) (r = -0.489, p < 0.001). Comorbid liver and gastrointestinal arteriovenous malformations significantly reduced the PCS (p < 0.05). Multiple regression analysis revealed that the ESS was a significant variable (p < 0.01). The role/social component score was significantly lower in the severe ESS group than in the mild or moderate group. CONCLUSION: The Japanese version of the ESS was considered valid and may be useful as an outcome measure of future HHT-associated epistaxis trials in Japan.

Discrimination of ranitidine hydrochloride crystals using X-ray micro-computed tomography for the evaluation of three-dimensional spatial distribution in solid dosage forms.

A non-destructive discrimination method for crystals in solid dosage drug forms was first developed using a combination of Raman spectroscopy and X-ray micro-computed tomography (X-ray CT). Identification of the crystal form of an active pharmaceutical ingredient (API) at the appropriate pharmaceutical dosage is crucial, as the crystal form is a determinant of the quality and performance of the final formulation. To develop a non-destructive analytical methodology for the discrimination of solid API crystals in a solid dosage form, we utilized a combination of Raman spectroscopy and X-ray CT to differentiate between ranitidine crystal polymorphs (forms 1 and 2) in tablet formulations containing three excipients. The difference in electron density correlated with the true density between ranitidine polymorphs, thereby enabling the discrimination of crystal forms and visualization of their three-dimensional spatial localization inside the tablets through X-ray CT imaging. Furthermore, X-ray CT imaging revealed that the crystal particles were of varying densities, sizes, and shapes within the same batch. These findings suggest that X-ray CT is not only an imaging tool but also a unique method for quantitative physicochemical characterization to study crystal polymorphs and solid dosage forms.

Atropisomeric Chiral Diiododienes (Z,Z)-2,3-Di(1-iodoalkylidene)tetralins: Synthesis, Enantiomeric Resolution, and Application in Asymmetric Catalysis.

The C2-symmetric tetralin-fused 1,4-diiodo-1,3-butadiene derivatives, (Z,Z)-2,3-di(1-iodoalkylidene)tetralin 1a-c, are atropisomeric and can be resolved into the two persistent axially chiral enantiomers by HPLC on a chiral stationary phase. The enantiomerically pure compounds can serve as chiral organocatalysts for dearomatizing spirolactonization to show good performance in up to 73% ee.

Mitogen-activated protein kinase 4-like carrying an MEY motif instead of a TXY motif is involved in ozone tolerance and regulation of stomatal closure in tobacco.

The mitogen-activated protein kinases (MAPKs/MPKs) are important factors in the regulation of signal transduction in response to biotic and abiotic stresses. Previously, we characterized a MAPK from tobacco, Nicotiana tabacum MPK4 (NtMPK4). Here, we found a highly homologous gene, NtMPK4-like (NtMPK4L), in tobacco as well as other species in Solanaceae and Gramineae. Deduced amino acid sequences of their translation products carried MEY motifs instead of conserved TXY motifs of the MAPK family. We isolated the full length NtMPK4L gene and examined the physiological functions of NtMPK4L. We revealed that NtMPK4L was activated by wounding, like NtMPK4. However, a constitutively active salicylic acid-induced protein kinase kinase (SIPKK(EE)), which phosphorylates NtMPK4, did not phosphorylate NtMPK4L. Moreover, a tyrosine residue in the MEY motif was not involved in NtMPK4L activation. We also found that NtMPK4L-silenced plants showed rapid transpiration caused by remarkably open stomata. In addition, NtMPK4L-silenced plants completely lost the ability to close stomata upon ozone treatment and were highly sensitive to ozone, suggesting that this atypical MAPK plays a role in ozone tolerance through stomatal regulation.

Tobacco MAP kinase phosphatase (NtMKP1) negatively regulates wound response and induced resistance against necrotrophic pathogens and lepidopteran herbivores.

Mitogen-activated protein kinase (MAPK) cascades are universal signal transduction pathways in eukaryotic cells. In tobacco, two MAPK, wound-induced protein kinase (WIPK) and salicylic acid (SA)-induced protein kinase (SIPK), are activated by biotic and abiotic stresses. Both WIPK and SIPK positively regulate the biosynthesis of jasmonic acid (JA) or ethylene (ET) while negatively regulating SA accumulation. We showed previously that recombinant tobacco MAPK phosphatase (NtMKP1) protein dephosphorylates and inactivates SIPK in vitro, and overexpression of NtMKP1 repressed wound-induced activation of both SIPK and WIPK. To elucidate the role of NtMKP1 in response to biotic and abiotic stresses, we generated transgenic tobacco plants in which NtMKP1 expression was suppressed. Suppression of NtMKP1 expression resulted in enhanced activation of WIPK and SIPK and production of both JA and ET upon wounding. Wound-induced expression of JA- or ET-inducible genes, basic PR-1 and PI-II, was also significantly enhanced in these plants. Furthermore, NtMKP1-suppressed plants exhibited enhanced resistance against a necrotrophic pathogen, Botrytis cinerea, and lepidopteran herbivores, Mamestra brassicae and Spodoptera litura. These results suggest that NtMKP1 negatively regulates wound response and resistance against both necrotrophic pathogens and herbivorous insects through suppression of JA or ET pathways via inactivation of MAPK.