Comparison of ephedrine and pseudoephedrine contents in 34 Kampo extracts containing Ephedrae Herba used clinically in Japan.

Ephedrae Herba is among the important crude drugs prescribed in Kampo medicine for the treatment of cold, flue, rhinitis, nasal congestion, cough, and asthma. The active ingredients of Ephedrae Herba, ephedrine (E) and pseudoephedrine (PE), are potent sympathomimetic compounds that stimulate α-, ß1-, and ß2-adrenoceptors resulting in dilatation and alleviation of nasal mucosal hyperemia. Hypertension, palpitations, insomnia, and dysuria are the main adverse effects of E and PE, which can be avoided by determining the actual contents of these alkaloids in Kampo extracts containing Ephedrae Herba. However, the extraction efficiencies of E and PE from Ephedrae Herba contained in Kampo formulas in combination with other crude drugs remain unknown. Therefore, we comprehensively determined the E and PE contents of 34 Kampo extracts containing Ephedrae Herba used clinically in Japan. The E and PE contents per daily dosage in Kampo extracts were generally proportional to the compounding amount of Ephedrae Herba. In contrast, the extraction efficiencies of E or PE were not constant and not influenced by the pH of the extracts. We assume that the extraction efficiencies of E and PE may be independently affected by other constituent crude drugs. Thus, it is necessary to investigate the cause and mechanism in the future. In conclusion, these results show that the E and PE content of each Kampo formulation can be estimated from the compounding amount of Ephedrae Herba. Therefore, the amount of Ephedrae Herba should be carefully considered to ensure the safe use of Kampo formulations containing Ephedrae Herba.

Clinical Risk Factors of Licorice-Induced Pseudoaldosteronism Based on Glycyrrhizin-Metabolite Concentrations: A Narrative Review.

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 11ß-hydroxysteroid dehydrogenase (11ßHSD2), which decomposes cortisol into inactive cortisone in the distal nephron, thereby inducing mineralocorticoid receptor activity. Among the several reported glycyrrhizin-metabolites, 18ß-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 11ßHSD2 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 11ßHSD2 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.

Effect of Schisandrae Fructus on glycyrrhizin content in Kampo extracts containing Glycyrrhizae Radix used clinically in Japan.

Glycyrrhizae Radix is an important crude drug in Japan and is the most frequently prescribed drug in Kampo medicines for the treatment of a wide range of diseases. Glycyrrhizin (GL), the major active ingredient of Glycyrrhizae Radix, has various pharmacological actions but causes adverse effects such as pseudoaldosteronism. In a previous study, the GL content of shoseiryuto was found to be unexpectedly low, and Schisandrae Fructus in shoseiryuto reduced the pH value of the decoction and drastically decreased the extraction efficiency of GL from Glycyrrhizae Radix. In the present study, we investigated the extraction efficiency of GL from Glycyrrhizae Radix in decoctions comprising Glycyrrhizae Radix and five different fruit-derived crude drugs. Among the five fruit-derived crude drugs tested, Schisandrae Fructus markedly decreased both the pH value of the decoction and the extraction efficiency of GL. A comparison of the pH value of the decoction and the GL content of 12 Kampo prescriptions (containing at least Glycyrrhizae Radix and Schisandrae Fructus) showed that the GL content per daily dose was proportional to the compounding amount of Glycyrrhizae Radix, and that the extraction efficiency of GL from Glycyrrhizae Radix was strongly correlated with the pH value of the decoction. In addition, the pH value of the decoction was similar to the pH value documented in interview forms provided by pharmaceutical companies. These results suggested that the GL content in Glycyrrhizae Radix-containing Kampo products can be estimated from both the compounding amounts of Glycyrrhizae Radix and the pH value documented in their interview forms. Knowledge of GL content will help avoid adverse reactions due to Glycyrrhizae Radix.

Correction to: Comparison of glycyrrhizin content in 25 major kinds of Kampo extracts containing Glycyrrhizae Radix used clinically in Japan.

The article Comparison of glycyrrhizin content in 25 major kinds of Kampo extracts containing Glycyrrhizae Radix used clinically in Japan, written by Mitsuhiko Nose, Momoka Tada, Rika Kojima, Kumiko Nagata, Shinsuke Hisaka, Sayaka Masada, Masato Homma and Takashi Hakamatsuka, was originally published Online First without open access. After publication in volume 71, issue 4, page 711-722 the author decided to opt for Open Choice and to make the article an open access publication. Therefore, the copyright of the article has been changed to

Comparison of glycyrrhizin content in 25 major kinds of Kampo extracts containing Glycyrrhizae Radix used clinically in Japan.

Glycyrrhizae Radix is the most frequently used crude drug in Japan and is prescribed in Kampo medicine for the treatment of a wide range of diseases. The major active ingredient of Glycyrrhizae Radix, glycyrrhizin (GL), has been shown to possess various pharmacological actions, but is also known to cause adverse effects such as pseudoaldosteronism. To avoid the adverse effects of GL, precautions have been indicated on the package inserts of Glycyrrhizae Radix-containing formulas depending on the amount of Glycyrrhizae Radix they contain. However, it remains unknown whether the extraction efficiency of GL from Glycyrrhizae Radix is constant throughout the different combinations of crude drugs in Glycyrrhizae Radix-containing formulas. To confirm the basis of the safety regulation, in this study we comprehensively determined the GL content of 25 major kinds of Kampo extracts compounding Glycyrrhizae Radix. We found that the GL content per daily dosage in all Kampo extracts are generally proportional to the compounding amount of Glycyrrhizae Radix, except in the case of shoseiryuto (Sho-seiryu-To). We also found that Schisandrae Fructus in Sho-seiryu-To decoction caused a lowered pH condition and drastically decreased the extraction efficacy of GL from Glycyrrhizae Radix. Moreover, we were able to confirm that the extraction efficiency of GL from Glycyrrhizae Radix is dependent on the pH value of the extraction solvent. The extraction efficiency of GL in the 25 kinds of Kampo extracts was not constant but it correlates significantly with the pH value of the decoction. Furthermore, the GL contents are well correlated with pseudoaldosteronism incidence data obtained from the Japanese Adverse Drug Event Report (JADER) database on the 25 kinds of Kampo extracts. This suggests that the GL content is a better index to consider to avoid the adverse effects of Glycyrrhizae Radix-containing Kampo formulas.

Liquorice-induced hypokalaemia in patients treated with Yokukansan preparations: identification of the risk factors in a retrospective cohort study.

OBJECTIVE: To 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). DESIGN: Retrospective cohort study. SETTING: Patients receiving YK preparations for dementia and other psychiatric disorders in the University of Tsukuba Hospital in Japan. PARTICIPANTS: 389 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 MEASURE: The occurrence rate of hypokalaemia and assessment of the risk factors for YK preparation-induced hypokalaemia. RESULTS: Of 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). CONCLUSIONS: Serum 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.

[Education Program of Kampo-medicine for Undergraduates in Preparation for Clinical Setting].

Kampo-medicine has become popular in Japanese medical practice combined with western medicine. For example, Daikenchu-To for intestinal obstruction after surgical operation, Shakuyakukanzo-To and Goshajinki-Gan for anti-cancer agents-induced neuropathy, and Yokkan-San for behavioral psychological symptoms of dementia are alternatively used in addition to conventional treatments in Japan. However, combined use of Kampo-medicine and western medicine may cause unexpected adverse events including undesirable drug-drug interactions because Kampo-medicine was not originally developed to be used with western medicine. Although adverse effects of Kampo-medicine are rare compared with those of western medicine, severe events such as liver dysfunction and interstitial pneumonia have been reported in increasing trends. Medical staff including pharmacists, therefore, should be aware of the onset of adverse events before the patients' symptoms become severe. Several adverse effects are caused by chemical constituents such as glycyrrhizin in licorice for pseudoaldosteronism and geniposide in Gardeniae fructus for mesenteric phlebosclerosis. To understand the adverse effects of Kampo-medicine, pharmacists should learn trends in current medication as well as pharmacology and toxicology of the chemical constituents in pharmacognosy. These issues should also be addressed in educational materials for students of clinical pharmacy and pharmacy practice.

Expression of phosphatidylserine-specific phospholipase A(1) mRNA in human THP-1-derived macrophages.

The expression of phosphatidylserine-specific phospholipase A(1) (PS-PLA(1)) is most upregulated in the genes of peripheral blood cells from chronic rejection model rats bearing long-term surviving cardiac allografts. The expression profile of PS-PLA(1) in peripheral blood cells responsible for the immune response may indicate a possible biological marker for rejection episodes. In this study, PS-PLA(1) mRNA expression was examined in human THP-1-derived macrophages. The effects of several immunosuppressive agents on this expression were also examined in in vitro experiments. A real-time RT-PCR analysis revealed that PS-PLA(1) mRNA expression was found in human THP-1-derived macrophages. This expression was enhanced in the cells stimulated with lipopolysaccharide (LPS), a toll-like receptor (TLR) 4 ligand. Other TLR ligands (TLR2, 3, 5, 7, and 9) did not show a significant induction of PS-PLA(1) mRNA. The time course of the mRNA expression profiles was different between PS-PLA(1) and tumor necrosis factor-α (TNF-α), which showed a maximal expression at 12 and 1 h after LPS stimulation, respectively. Among the observed immunosuppressive agents, corticosteroids, prednisolone, 6α-methylprednisolone, dexamethasone, and beclomethasone inhibited PS-PLA(1) expression with half-maximal inhibitory concentrations less than 3.0 nM, while methotrexate, cyclosporine A, tacrolimus, 6-mercaptopurine, and mycophenoic acid showed either a weak or moderate inhibition. These results suggest that the expression of PS-PLA(1) mRNA in THP-1-derived macrophages is activated via TLR4 and it is inhibited by corticosteroids, which are used at high dosages to suppress chronic allograft rejection.

[Case of intractable ventricula fibrillation by a multicomponent dietary supplement containing ephedra and caffeine overdose].

Multicomponent dietary supplement containing ephedra and caffeine (DSEC) was widely used for weight loss and energy enhancement. The Food and Drug Administration (FDA) banned the sale of DSEC in 2004 because of side effects such as cardiotoxity. We report a rare case of intractable ventricular fibrillation, requiring frequent defibrillation, by DSEC overdose. The direct cardiotoxity of ephedra, synergistic effect of caffeine and ephedra, and hypokalemia may cause refractory ventricular arrhythmia.

[Effects of long term administration of Shakuyaku-kanzo-To and Shosaiko-To on serum potassium levels].

Typical adverse effects of Shakuyaku-kanzo-To (SKT), an herbal medicine containing licorice, is a licorice-induced pseudoaldosteronism with hypokalemia and hypertension. The risk factors for this side effect are still unclear. To identify the risk factors, we surveyed 37 cases of licorice-induced pseudoaldosteronism in the literature and serum potassium levels in our patients receiving SKT and Shosaiko-To (SST), which contain 6 g and 1.5 g of licorice in the daily dose, respectively. In the case report survey, pseudoaldosteronism developed a median 35 (range 2-231) days after the administration of SKT, which is shorter than after SST (450, range 150-2190 days) and other licorice products including glycyrrhizin (210, range 14-730 days). A significant correlation was observed between the glycyrrhizin contents in the licorice preparations and the dosing periods for developing pseudoaldosteronism (r=-0.700, p<0.01). A negative correlation was also observed between serum potassium level and dosing period for SKT, but not for SST. The difference in age (65.3+/-11.6 vs. 57.2+/-17.3 y) and dosing period (57.3+/-66.3 vs. 19.0+/-24.3 days) between the patients with and without hypokalemia after the administration of SKT was statistically significant (p<0.05). The occurrence rate of hypokalemia including pseudoaldosteronism was around 80% with SKT administration for more than 30 days for patients exceeding 60 years old. It was suggested that patient age (>60 y) and dosing period of SKT (>30 days) might be risk factors for developing pseudoaldosteronism or hypokalemia as well as coadministration of drugs inducing hypokalemia.

[Combination use of kampo-medicines and drugs affecting intestinal bacterial flora].

The intestinal bacteria, Eubacterium sp. and Bifidobacterium sp., participate in the metabolism of active kampo-ingredients, glycyrrhizin (GL), sennoside (SEN) and baicalin (BL). Since antibiotics and bacterial preparations, Bifidobacterium longum (LAC-B), Clostridium butyricum (MIYA-BM), and Streptococcus faecalis (BIOFERMIN), affect the bacterial population in intestinal bacterial flora, metabolism of the active kampo-ingredients in the bacterial flora may be altered by their combined administration. We investigated 1199 prescriptions including kampo-medicines for 308 patients. Combination use of kampo-medicines with antibiotics and bacterial preparations occurred with 7% and 10% of the kampo-prescription, respectively. Most antibiotics have activity against intestinal bacteria, except that cephems and macrolides are not active against to E. coli. This means that antibiotics may lower the metabolism of GL, SEN and BL when administered in combination. On the other hand, it is also highly possible that bacterial preparations increase the number of Eubacterium sp. and Bifidobacterium sp., resulting in enhanced metabolism of GL and SEN when they are used concomitantly with kampo-medicines. The present results suggested that the drug interactions of kampo-medicines with antibiotics and bacterial preparations should be confirmed in clinical studies.