Representative Side Effects Caused by Kampo prescriptions :Pseudoaldosteronism, Drug-induced Liver Injury and Drug-Induced Lung Injury / 日本東洋医学雑誌

The Japan society of oriental medicine created a committee of medical safety in 2017. The first activity was to summarize the representative side effects of Kampo medicine and to enlighten members of our society about them. In this report, we documented the knowledge to keep in mind at present on pseudoaldosteronism, drug-induced liver injury, and drug-induced lung injury. Since these three major side effects may cause clinically severe conditions, it is very important to detect them early and take appropriate measures. Therefore, proper examinations at the right time are necessary while taking Kampo medicine.

A Case of Pseudoaldosteronism Caused by Tokakujokito During Receiving Insulin / 日本東洋医学雑誌

A 51-­year-­old woman with a 10-­year history of diabetes visited our clinic for treatment of stiff shoulder and constipation. She was 156 cm tall and weighed 68 kg. The blood pressure was normal. Physical examination revealed no significant abnormalities. After she took the usual amount of tokakujokito for 3 days, hypertension and facial edema, legs edema, weight gain, and headache were observed. Pseudoaldosteronism inhibits 11 β-­hydroxysteroid dehydrogenase Type 2, which is an active glycyrrhizin (GL) and its metabolites glycyrrhizic acid, 3-­monoglucuronyl-­glycyrrhizic acid metabolize and inactivate cortisol to cortisone. As a result, excessive cortisol acts on the mineralocorticoid receptor and promotes sodium reabsorption and excretion of potassium (K+), resulting in water retention and hypokalemia in the body. Insulin also causes hypokalemia because it also takes K+ at the same time as it takes blood glucose in the cell. As a result of these two different processes, it was thought that pseudoaldosteronism developed in low dose licorice. Glycyrrhizin-­containing preparation should be careful used in patients receiving insulin.

<b>A Case of Pseudoaldosteronism that Occurred in 63-year-old Woman for the First Time After 3-year Administration of Tokishigyakukagoshuyushokyoto</b> / 日本東洋医学雑誌

A 47-year-old woman visited our clinic, and thereafter she had taken various Kampo medicines until she turned 58 years old. She took each medicine, containing 1-3.5 g/day of glycyrrhiza, for one or two months. Hypertension or edema was not observed in those days. From the age of 60, she took 7.5 g of tokishigyakukagoshuyushokyoto, containing 2 g of glycyrrhiza, day after day. Hypertension or edema was not observed for 35 months. However, when she was 63 years old, pseudoaldosteronism with headache, hypertension, edema,and hypopotassemia was observed for the first time. This case suggests that administration period or patient's age influences the development of pseudoaldosteronism.

<b>The Effectiveness of Shimotsuto Extract for Patients with Muscle C</b><b>ramp</b> / 日本東洋医学雑誌

The effectiveness of the Kampo medicine shakuyakukanzoto extract for patients with muscle cramp is well known, but recently side effects related to pseudoaldosteronism have also been reported. To avoid this issue, Kampo medicines without <i>Glycyrrhizae Radix </i>are needed for treatment of muscle cramp. We investigated the therapeutic effect of shimotsuto extract, which has traditionally been used to treat anemia, in 26 patients (mean age : 70.7 ± 12.1 years) with muscle cramp. Improvement of the symptom was noted in 18 patients (69%), with no change in 8 patients (31%). The abdominal muscle tension of the former patients was significantly lower than the latter. Here, the cases of four representative patients in whom muscle cramp was improved by shimotsuto are described. The response rate to shimotsuto was similar to that of shakuyakukanzoto. Our results suggest that shimotsuto extract is a suitable alternative to shakuyakukanzoto for treatment of muscle cramp in older non-robust type patients not in need of emergency care.

<b>Relationship Between Incidence of Pseudoaldosteronism and Daily Dose of Glycyrrhiza : Review of the L</b><b>iterature</b> / 日本東洋医学雑誌

Incidence of glycyrrhiza-induced pseudoaldosteronism is not well understood. We examined relationships between pseudoaldosteronism incidence and daily glycyrrhiza dose in previous clinical studies. The incidence in patients administered glycyrrhiza 1 g/day was 1.0% (mean). The incidence with 2 g/day, 4 g/day and 6 g/day were 1.7% (mean), 3.3% and 11.1% (mean), respectively. Thus a dose-dependent trend toward pseudoaldosteronism incidence was suggested by previous literature.

Clinical Characteristics of Side Effects Induced by Administration of Glycyrrhizae Radix and Scutellaria Radix under the Therapy Based on Kampo Diagnosis in Our Hospital / 日本東洋医学雑誌

We surveyed side effect incidences with Kampo therapies in 2530 patients based on their Kampo diagnoses. The number of side effects seen, including taste disorder, was 569 in 503 patients. Side effects were noted in 64 (3.0%) of 2139 patients administered Glycyrrhizae radix. The average 63.4±13.8 age of these patients was statistically higher than the overall 54.9±18.1 year mean. Symptoms which led to diagnosis of side effects were high blood pressure in 45 patients, edema in 16 patients, and hypokalemia in only 5 patients. Glycyrrhizae radix dose as an extract was 2.0±1.0 (mean±SD) g/day in 34 patients, and as a decoction was 2.2±1.1 g/day in 29 patients. There was no difference in administration or recovery periods between these two groups. Liver dysfunction was noted in 13 (1.0%) of 1328 patients administered prescriptions containing Scutellaria radix. Scutellaria radix was administered as an extract at 2.3±0.5 g/day in 7 patients, and as a decoction at 2.8±0.8 g/day in 6 patients. Although there was no difference in administration periods, the 69.0±52.5 day recovery period from side effects in the extract group was longer than that of 22.7±16.0 days in the decoction group. Symptom improvement was had for a large portion of these side effects with the first visit, indicating that initial diagnoses were correct. Care should be exercised with regard to inducing side effects, with Kampo medicines, even when using traditional diagnostic standards.

Development of Pseudo-aldosteronism Depends on Amount of Glycyrrhizae Radix in Each Individual / 日本東洋医学雑誌

Two theories have been suggested for the etiology of pseudo-aldosteronism with Glycyrrhizae radix intake : 1) Differing sensitivities to Glycyrrhizae radix between patients, 2) Differing daily Glycyrrhizae radix dosages between patients.We treated two patients who were relieved of their pseudo-aldosteronism, through a reduction in their daily Glycyrrhizae radix dosage. These cases suggest that Glycyrrhizae radix intake, rather than individual metabolic differences, influences the development of pseudo-aldosteronism.

A case of Megacolon Successfully Treated by Re-dosage of Kobokusanmotsuto; After an Attack of Pseudoaldosterenism induced by Chukenchuto / 日本東洋医学雑誌

We present a case of megacolon successfully treated with Kampo medicine. A 65-year-old male diagnosed with megacolon in 1999, came to our department in July 2003 complaining of severe abdominal distention. We successively used different Kampo formulae, in accordance with the diagnostic standard known as “SHO” which were: Daikenchu-to, Koboku-sanmotsu-to, Chukenchu-to, and Koboku-sanmotsu-to again. Daikenchu-to was only partly effective. Koboku-sanmotsu-to made the abdominal distention worse, forcing a change of drug. Chukenchu-to relieved the symptoms for some time, but the patient had to be hospitalized because of pseudoaldosteronism caused by the drug. Koboku-sanmotsu-to, however, worked smoothly on the second occasion and the symptoms disappeared. The efficacy of Koboku-sanmotsu-to was completely different on the two occasions it was used. This suggests that the pathological conditions were in a state of change, and these changes were identical to changes of SHO. This case reinforces the importance of detecting changes of the SHO accurately.

Four Cases with Side Effects caused by Shakuyaku-kanzo-to / 日本東洋医学雑誌

Four cases which showed side effects caused by Syakuyaku-kanzo-to were reported. All the patients were women over 60 years old with “Chukan-sho” or “Kyo-sho”.<br>Hypopotassemia was noted in all 4 cases, muscular weakness in 3 and edema in 1. Treatment of side effects involved discontinuing administration of Syakuyaku-kanzo-to in all cases. Potassium administration was additionally required in 2 cases of severe hypopotassemia. Muscular weakness and edema disappeared with recovery from hypopotassemia.<br>Taking past reports into consideration, it is suggested that, in older woman, “Kyo-sho” and “Suidoku” are important risk factors for pseudoaldosteronism caused by Syakuyaku-kanzo-to.

Efficacy of Shakuyaku-kanzo-to Extract Granules in Cramp in the Calf with Cerebrovascular Disease / 日本東洋医学雑誌

We asked 50 ambulatory patients with cerebrovascular disease whether their sleep had been disturbed due to cramp in the calf while they were sleeping soundly at night. Their age ranged from 32 to 81 years. Eleven patients (22%) gave an affirmative answer, and eight of these answered that they had cramp from one to three times a week or more. These eight patients received Syakuyaku-kanzo-to extract granules (2.5g) daily for two weeks. Those who responded sufficiently remained on the same dose, and those who did not received double the dose for further two weeks before the efficacy was evaluated.<br>All five patients who were able to comply with the treatment for four weeks improved either markedly or slightly. The onset of its action was rapid. These results are comparable to those of muscle relaxants and minor tranquilizers and suggest that Syakuyaku-kanzo-to extract granules are beneficial for spasm of the calf in patients with cerebrovascular disease.<br>With regard to its side-effects, one patients who received the treatment for more than two weeks developed pseudoaldosteronism. This was the only negative point of the treatment, but this disappeared rapidly after treatment was discontinued.