Effects of imeglimin on mitochondrial function, AMPK activity, and gene expression in hepatocytes.

Imeglimin is a recently launched antidiabetic drug structurally related to metformin. To provide insight into the pharmacological properties of imeglimin, we investigated its effects on hepatocytes and compared them with those of metformin. The effects of imeglimin on mitochondrial function in HepG2 cells or mouse primary hepatocytes were examined with an extracellular flux analyzer and on gene expression in HepG2 cells by comprehensive RNA-sequencing analysis. The effects of the drug on AMPK activity in HepG2 cells, mouse primary hepatocytes, and mouse liver were also examined. Treatment of HepG2 cells or mouse primary hepatocytes with imeglimin reduced the oxygen consumption rate coupled to ATP production. Imeglimin activated AMPK in these cells whereas the potency was smaller than metformin. Bolus administration of imeglimin in mice also activated AMPK in the liver. Whereas the effects of imeglimin and metformin on gene expression in HepG2 cells were similar overall, the expression of genes encoding proteins of mitochondrial respiratory complex III and complex I was upregulated by imeglimin but not by metformin. Our results suggest that imeglimin and metformin exert similar pharmacological effects on mitochondrial respiration, AMPK activity, and gene expression in cultured hepatocytes, whereas the two drugs differ in their effects on the expression of certain genes related to mitochondrial function.

Survey of glucocorticoid dose escalation in patients with adrenal insufficiency during the peri-COVID-19 vaccination period.

There is uncertainty regarding the need for COVID-19 peri-vaccination glucocorticoid coverage in patients with adrenal insufficiency. In this survey conducted in a single tertiary medical institution, 167 consecutive outpatients taking physiological glucocorticoids because of adrenal insufficiency were included. The patients declared if they developed an adrenal crisis after vaccination, and the amount and duration of an increase in their glucocorticoid dosage, if any. None of the patients without preventive glucocorticoid increase suffered an adrenal crisis after COVID-19 vaccination. Only 8.3% (14 cases) and 27.5% (46 cases) of the patients needed to escalate the dose of glucocorticoids when systemic symptoms appeared after the first and second injections, respectively. Glucocorticoids were increased in patients <60 years of age more than in patients ≥60 years of age at the time of both the first (p = 0.026) and second injections (p = 0.005). Sex and the causes of adrenal insufficiency were not associated with the frequency of the patients who needed glucocorticoid dose escalation. In the cases with increased glucocorticoids, the median dosage for escalation was 10 mg (hydrocortisone equivalent). In conclusion, even without prophylactic glucocorticoid administration, adrenal crisis did not occur during the peri-COVID-19 vaccination period. The dose escalation of steroid was more frequent in younger patients following the second vaccination. Careful monitoring of adverse effects and the appropriate management of glucocorticoids when necessary are essential following COVID-19 vaccinations.

Acromegaly caused by a somatotroph adenoma in patient with neurofibromatosis type 1.

Although acromegaly has been reported in patients with Neurofibromatosis type 1 (NF1), these cases have not been associated with growth hormone (GH)-producing somatotroph adenoma, but with optic pathway glioma. A 68 year-old Japanese woman, who had been clinically diagnosed with NF1, was referred to our hospital due to a thyroid tumor and hypercalcemia. Acromegaly was suspected due to her facial features, and subsequent examinations revealed the presence of GH excess with a pituitary tumor, leading to the diagnosis of acromegaly. Histological and immunohistochemical analysis demonstrated an eosinophilic pituitary adenoma with diffuse positivity for GH, indicating typical somatotroph adenoma. In addition, her thyroid tumor was diagnosed histologically as follicular thyroid carcinoma (FTC) with primary hyperparathyroidism (PHPT). To investigate the pathogenesis of this untypical multiple endocrine tumor case of NF1, genetic analysis was performed using peripheral leukocytes and tissue of resected tumors. A heterozygous novel germline nonsense mutation (p.Arg1534*) in exon 35 of the NF1 gene was detected from peripheral leukocytes, which results in a truncated protein lacking the critical domain for GTPase activity, strongly suggesting its causal role in NF1. The loss of heterozygosity (LOH) in exon 35 of the NF1 gene was not detected in the somatotroph adenoma, parathyroid adenoma, and FTC. Although any mutations of the following genes; MEN1, CDKN1B, and PAX8-PPARγ were not detected, a heterozygous GNAS R201C mutation was detected in the somatotroph adenoma. To our knowledge, this is the first rare MEN1-like case of genetically diagnosed NF1 complicated with acromegaly caused by a somatotroph adenoma.

Adalimumab with Methotrexate in Treatment-Naïve Japanese Patients with Rheumatoid Arthritis at Risk of Progressive Structural Joint Damage: A Postmarketing Observational Study.

INTRODUCTION: The objective of this study was to evaluate the real-world safety and effectiveness of adalimumab with methotrexate (MTX) in disease-modifying antirheumatic drug (DMARD)- and biologic-naïve Japanese patients with rheumatoid arthritis (RA) at risk of progressive structural joint damage. METHODS: This multicenter, prospective, observational, postmarketing surveillance study was conducted between February 2013 and April 2015 at 84 centers in Japan. Patients with RA at risk of progressive structural joint damage were enrolled and initiated treatment with adalimumab and MTX. Adverse events were recorded up to week 28. Effectiveness/disease activity was assessed using the Disease Activity Score based on a 28-joint count with erythrocyte sedimentation rate and C-reactive protein (DAS28-4ESR and DAS28-4CRP), Clinical Disease Activity Index, and Simplified Disease Activity Index at 0, 4, 12, and 24 weeks. DAS28-4CRP response was evaluated in the low-dose (<8 mg/week) and high-dose (≥8 mg to ≤16 mg/week) MTX groups at week 24. RESULTS: One hundred fifty-seven of 163 patients comprised the safety cohort: mean (SD) age, 56.5 (13.9) years; females, 65.6%; rheumatoid factor positive, 73.2%; anti-cyclic citrullinated peptide antibody positive, 66.9%; bone erosions, 51.6%; mean disease duration, 9.5 months. The majority of patients (≥80%) had moderate or high disease activity at baseline, and ≥50% with available data achieved remission or low disease activity at week 24 (DAS28-4CRP <3.2). Five serious adverse drug reactions occurred in four patients, including pyelonephritis, Pneumocystis jiroveci pneumonia, interstitial lung disease, pleurisy, and pericarditis; the outcomes were either recovered or recovering. Significant improvements/reductions in disease activity over 24 weeks were noted in all effectiveness measures (P < 0.0001). Most of the population achieved DAS28-4CRP remission (<2.6) at week 24 regardless of the MTX dose. CONCLUSION: Adalimumab in combination with MTX could be a beneficial treatment option for DMARD- and biologic-naïve Japanese patients with RA at risk of progressive structural joint damage. FUNDING: AbbVie GK and Eisai. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01783730.