Percutaneous Penetration Kinetics of Nitroglycerin and Its Dinitrate Metabolites Across Hairless Mouse Skin in Vitro

The percutaneous penetration kinetics of the antianginal, nitroglycerin (GTN), and its primary metabolites, 1,2- and 1,3-glyceryl dinitrate (1,2- and 1,3-GDN), were evaluated in vitro, using full-thickness hairless mouse skin. GTN and the 1,2- and 1,3-GDNs were applied (a) in aqueous solution as pH 7.4 phosphate-buffered saline (PBS) and (b) incorporated into lipophilic ointment formulations. The cutaneous transformation of GTN to its dinitrate metabolites was detected, but no interconversion between 1,2-GDN and 1,3-GDN was observed. Following application of the nitrates in PBS solution, all three compounds exhibited steady-state transport kinetics. The steady-state flux of GTN (8.9 ± 1.5 nmol cm^–2 hr^–1) was significantly greater (P < 0.05) than those of 1,2-GDN (0.81 ± 0.54 nmol cm^–2 hr^–1) and 1,3-GDN (0.72 ± 0.20 nmol cm^–2 hr^–1). The corresponding permeability coefficient () for GTN (20 ± 3 × 10^–3 cm hr^–1) was significantly larger than the corresponding values for 1,2-GDN (1.4 ± 0.9 × 10^–3 cm hr^–1) and 1,3-GDN (1.2 ± 0.4 × 10^–3 cm hr^–1), which were statistically indistinguishable (P > 0.05). Further analysis of the transport data showed that the differences between GTN and the GDNs could be explained by the relative stratum corneum/water partition coefficient (K _s) values of the compounds. The apparent partition parameters, defined as = K _s · h [where h is the diffusion path length through stratum corneum (SC)] were 19.8 ± 2.5 × 10^–2 cm for GTN and 1.91 ± 1.07 × 10^–2 and 1.81 ± 0.91 × 10^–2 cm for 1,2- and 1,3-GDN, respectively. However, when the nitrates were administered in an ointment base, the apparent partition parameter (') and permeability coefficient (') of GTN markedly decreased, to 2.51 ± 0.75 × 10^–2 cm and 1.6 ± 0.3 × 10^–3 cm hr^–1, respectively. In contrast, the ' and ' results for 1,2- and 1,3-GDN were not significantly different (P > 0.05) from the corresponding and values, which were measured following dosing as aqueous solutions. As a result, the steady-state fluxes of all three nitrates from the ointment formulation were comparable (GTN, 154 ± 28 nmol cm^–2 hr^–1; 1,2-GDN, 162 ± 22 nmol cm^–2 hr^–1; 1,3-GDN, 162 ± 34 nmol cm^–2 hr^–1). It follows that the dinitrates can be as efficiently delivered across the skin as GTN when a suitable formulation is employed. This finding may support transdermal therapy using 1,2- or 1,3-GDN if, indeed, they are found to be pharmacologically effective.     

Correction of Hypercortisolemia with an Improved Cognitive Function and Muscle Mass after Transsphenoidal Surgery in an Older Patient with Cushing's Disease

Cushing''s disease causes numerous metabolic disorders, cognitive decline, and sarcopenia, leading to deterioration of the general health in older individuals. Cushing''s disease can be treated with transsphenoidal surgery, but thus far, surgery has often been avoided in older patients. We herein report an older woman with Cushing''s disease whose cognitive impairment and sarcopenia improved after transsphenoidal surgery. Although cognitive impairment and sarcopenia in most older patients show resistance to treatment, our case indicates that normalization of the cortisol level by transsphenoidal surgery can be effective in improving the cognitive impairment and muscle mass loss caused by Cushing''s disease.     

Intravenous immunoglobulin for acute exacerbation of fibrotic idiopathic interstitial pneumonias

Background and aim:Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a fatal condition with no established treatment. Intravenous immunoglobulin (IVIG) is a unique therapy with both anti-inflammatory and anti-infective effects. Therefore, we hypothesized that IVIG may have a positive effect on AE of interstitial pneumonia. This study aimed to determine the effect of IVIG in patients with AE of fibrotic idiopathic interstitial pneumonias (IIPs), including IPF.Methods:We retrospectively analyzed consecutive patients who were diagnosed with AE of fibrotic IIPs and treated with pulse corticosteroid therapy (methylprednisolone 500–1000 mg/day for 3 days) between April 2018 and May 2021 at Kagawa Rosai Hospital and KKR Takamatsu Hospital.Results:This study included 52 patients with AE of fibrotic IIPs (IPF,41; fibrotic IIPs other than IPF,11). Thirteen patients received IVIG (5 g/day for 3–5 days) concurrently with pulse corticosteroid therapy. The remaining 39 patients were assigned to the control group. The survival rate on day 90 was significantly higher in the IVIG group than that in the control group (76.9% vs. 38.5%, p = 0.02). IVIG administration (odds ratio [OR], 0.11; 95% confidence interval [CI], 0.02–0.69; p = 0.02) and C- reactive protein (OR, 1.19; 95% CI, 1.06–1.33, p < 0.01) were independently associated with 90-day mortality.Conclusions:The results indicate that administration of IVIG may improve the survival of patients with AE of fibrotic IIPs. We are now conducting a prospective study to confirm the effect of IVIG on AE of IPF since May 2022 (jRCT1061220010).     

Incidence of second primary cancers among survivors of childhood cancer: A population‐based study,Osaka, Japan, 1975–2015

Second primary cancer (SPC) is one of the most life‐threatening late effects of childhood cancers. We investigated the incidence and survival outcomes of SPC in childhood cancer patients in Japan. Data were obtained from the population‐based Osaka Cancer Registry. Individuals diagnosed with cancer at age 0–14 years during 1975–2014 and survived 2 months or longer were followed through December 2015. The risk of developing SPC was assessed with standardized incidence ratio (SIR), excess absolute risk (EAR, per 100,000 person‐years), and cumulative incidence. Multivariable Poisson regression analysis was carried out to assess relative risks of SPC by treatment method. Survival analysis was undertaken using the Kaplan–Meier method. Of 7229 childhood cancer survivors, 101 (1.4%) developed SPC after a median of 11.6 years. Overall SIR was 5.0, which corresponded with 84.3 EAR. The cumulative incidence was 0.9%, 2.1%, and 3.4% at 10, 20, and 30 years, respectively. Among all SPCs, the type that contributed most to the overall burden was cancers in the central nervous system (EAR = 28.0) followed by digestive system (EAR = 15.1), thyroid (EAR = 8.3), and bones and joints (EAR = 7.8); median latency ranged from 2.0 years (lymphomas) to 26.6 years (skin cancers). Patients treated with radiotherapy alone were at a 2.58‐fold increased risk of developing SPC compared to those who received neither chemotherapy nor radiotherapy. Among patients who developed SPCs, 5‐year and 10‐year survival probabilities after SPC diagnosis were 61.7% and 52.0%, respectively. Risk‐based long‐term follow‐up planning is essential to inform survivorship care and help reduce the burden of SPCs in childhood cancer survivors.     

Radiation-induced angiosarcoma of the parotid gland after postoperative radiotherapy for hypopharyngeal carcinoma

Secondary carcinogenesis within the irradiation range is one of the most severe problems in cancer survivors. A 60-year-old woman developed hypopharyngeal carcinoma, and she received radical surgery and postoperative radiotherapy. Eight years later, brown pigmentation and induration were observed in the left subaural region. Fine-needle aspiration biopsy revealed malignancy and the parotid tumor was diagnosed as recurrence of hypopharyngeal carcinoma. Neoadjuvant chemotherapy followed by radical parotidectomy was performed. The pathological diagnosis was angiosarcoma, which was most likely induced by past irradiation. About two months after surgery, lung metastases were detected. Docetaxel did not affect to lung metastases, but paclitaxel therapy was partially effective. The lung tumors increased in size, and brain metastases developed, resulting in death. Both neoadjuvant chemotherapy and radical surgery played important roles in the local disease control. Administration of newer agents as adjuvant chemotherapeutic agent should also be considered for improving the prognosis.     

Associations of Education With Overall Diet Quality Are Explained by Different Food Groups in Middle-aged and Old Japanese Women

BackgroundThe disparity of overall diet quality by personal educational attainment has been a public issue. However, it remains unknown which food groups contribute to the disparity. This cross-sectional study assesses which food groups explain associations between education and overall diet quality in Japanese women.MethodsA total of 3,788 middle-aged (mean age, 47.7 years) and 2,188 older women (mean age, 74.4 years), who lived in 47 prefectures in Japan, provided data on their education (low, middle, and high) and dietary intakes from a diet history questionnaire. A diet quality score (possible score 0–70) was calculated based on seven food components. Mean diet quality scores, with adjustment for lifestyle and neighborhood variables, were estimated by education using a general linear model, and Dunnett’s multiple comparison was conducted. Additionally, mean scores of each food component were estimated by education and compared using the same manner.ResultsAfter adjustment for lifestyle and neighborhood variables, mean diet quality score of high or middle education was higher than low education for both generations. Middle-aged women with high and middle education had higher scores of ‘milk’, ‘snacks, confection, and beverages’, ‘fruits’, and ‘vegetable dishes’ than those with low education. Older women with high and middle education had higher scores of ‘sodium from seasonings’ and ‘fruits’ than those with low education.ConclusionsThis study suggests that positive associations between education and diet quality are explained by different food groups in middle-aged and older Japanese women, which are independent of lifestyle and neighborhood variables.Key words: education, diet quality, Japanese     

Early stage clear cell adenocarcinoma of the colon examined in detail with image-enhanced endoscopy: a case report

Primary clear cell adenocarcinoma (CCA) of the colorectum is a rare tumor. We report on a 48-year-old man with early stage CCA in the descending colon who underwent detailed examination with image-enhanced endoscopy, such as magnifying endoscopy with narrow-band imaging and crystal violet staining. The tumor was treated successfully with endoscopic mucosal resection at our hospital.