Licorice, the dried root or stolon of Glycyrrhiza glabra or G. ularensis, is commonly used worldwide as a food sweetener or crude drug. Its major ingredient is glycyrrhizin. Hypokalemia or pseudoaldosteronism (PsA) is one of the most frequent side effects of licorice intake. Glycyrrhizin metabolites inhibit type 2 11β-hydroxysteroid dehydrogenase (11βHSD2), which decomposes cortisol into inactive cortisone in the distal nephron, thereby inducing mineralocorticoid receptor activity. Among the several reported glycyrrhizin-metabolites, 18β-glycyrrhetyl-3-O-sulfate is the major compound found in humans after licorice consumption, followed by glycyrrhetinic acid. These metabolites are highly bound to albumin in blood circulation and are predominantly excreted into bile via multidrug resistance-associated protein 2 (Mrp2). High dosage and long-term use of licorice are constitutional risk factors for PsA. Orally administered glycyrrhizin is effectively hydrolyzed to glycyrrhetinic acid by the intestinal bacteria in constipated patients, which enhances the bioavailability of glycyrrhizin metabolites. Under hypoalbuminemic conditions, the unbound metabolite fractions can reach 11βHSD2 at the distal nephron. Hyper direct-bilirubin could be a surrogate marker of Mrp2 dysfunction, which results in metabolite accumulation. Older age is associated with reduced 11βHSD2 function, and several concomitant medications, such as diuretics, have been reported to affect the phenotype. This review summarizes several factors related to licorice-induced PsA, including daily dosage, long-term use, constipation, hypoalbuminemia, hyper direct-bilirubin, older age, and concomitant medications.

ObjectiveTo evaluate serum potassium levels and rates of hypokalaemia in patients treated with liquorice-containing Japanese traditional Kampo-medicines Yokukansan (YK) and Yokukansan-ka-chinpihange (YKCH).DesignRetrospective cohort study.SettingPatients receiving YK preparations for dementia and other psychiatric disorders in the University of Tsukuba Hospital in Japan.Participants389 patients (male/female: 174/215, 68.6±16.1 years) were treated with YK preparations for 231 days (range 6–2788 days). Patients whose potassium levels were <3.6 mEq/L before administration of YK preparations, and drug non-compliant patients, were excluded.Main outcome measureThe occurrence rate of hypokalaemia and assessment of the risk factors for YK preparation-induced hypokalaemia.ResultsOf the 389 patients treated with YK preparations, 94 (24.2%) developed hypokalaemia (potassium levels <3.6 mEq/L) 34 days (range 1–1600 days) after administration of the preparations. 36 (38.3%) patients had co-administration with lower potassium-inducing drugs (LPIDs; diuretics, glucocorticoids, mineralocorticoids and glycyrrhizin), which was more frequent in the patients without hypokalaemia (17.3%) (p<0.05). A Cox proportional hazard model identified four risk factors for hypokalaemia: YK administration (not YKCH) (HR 3.093, 95% CI 1.408 to 6.798), co-administration of LPIDs (HR 2.743, 95% CI 1.754 to 4.289), hypoalbuminaemia at baseline (HR 2.145, 95% 1.360 to 3.384), and full dosage administration (7.5 g/day) (HR 1.600, 95% CI 1.005 to 2.549).ConclusionsSerum potassium monitoring should be done at least monthly in patients with the following risk factors: LPID co-administration, YK administration, hypoalbuminaemia, and full dosage administration.

Abstract. Several reports have shown that some dopamine receptor ligands modulate the ischemia-reperfusion injury in animal models; however, its underling mechanisms are still unclear. In this study, we sought to establish an in vitro experimental model of hypoxia/reoxygenation (H/R) using HT22 cells that originated from mouse hippocampal neurons and to examine protective the effect of dopamine-receptor ligands against H/R-induced cell injury. The treatment with hypoxia for 18 h followed by reoxygenation for 6 h induced the elevation of intracellular reactive oxygen species (ROS) and reduction of mitochondrial membrane potential; however, lactate dehydrogenase (LDH) release was not changed at this time point. LDH release was increased after reoxygenation for 18 h and longer, and this increase in LDH release was suppressed by dopamine receptor agonists such as apomorphine and apocodeine. The suppressive effects of these agonists were reversibly inhibited by L750667, a D 4 -receptor antagonist but not by D 2 -or D 3 -receptor antagonists. In addition, PD168077, a selective dopamine D 4 -receptor agonist, also protected against H/Rinduced cell death. These results suggest that H/R causes oxidative stress-induced cell death and that the activation of dopamine D 4 receptors protects against H/R-induced cell death in HT22 cells.

Background: Immune checkpoint inhibitor (ICI)-related myositis with myocarditis is a rare but potentially fatal immune-related adverse event. However, its clinical features, response to immunosuppressive treatment, and prognosis remain poorly understood. Here, we describe the clinical course of patients with ICI-related myositis overlapping with myocarditis treated at our institution and a systematic review focusing on the response to immunosuppressive therapy.Methods: We identified patients who developed ICI-induced myositis with myocarditis and were treated at our hospital using a retrospective chart review of electronic medical records. For the systematic review, studies reporting ICI-induced myositis with myocarditis were identified using the Cochrane Library and PubMed databases.Results: Of the 625 patients treated with ICIs, four developed myositis with concurrent myocarditis. All the patients received immunosuppressive therapy. We assessed the activity of myocarditis and myositis based on temporal changes in troponin and creatine kinase (CK) levels. In all patients, peak troponin values appeared later than the peak CK values (median, 17 days). The median time from the start of ICI therapy to the peak of troponin and CK levels was 42.5 and 28 days, respectively. In all patients, CK levels decreased rapidly and steadily after the initiation of immunosuppressants. However, troponin levels were unstable and increased. In all patients, CK levels normalized within one month (range, 12–27 days), but troponin levels took several months to normalize (range, 84–161 days). Fourteen cases of ICI-related myositis with myocarditis were included in the systematic review. Of the 14 cases, 12 (86%) had their CK level decreased after the initial steroid treatment, but the troponin level increased and was higher than that before the start of treatment. In addition, the peak troponin values appeared later than the peak CK values (a median of 6.5 days). Eight (89%) of 9 long-term follow-up patients had troponin levels above the normal range even after CK normalization.Conclusion: In most cases of ICI-related myositis with myocarditis, troponin levels increased after the initial steroid treatment despite decreased CK levels, and exceeded pre-steroid levels. In addition, troponin remained elevated for several months after CK normalized.

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