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Keywords:

  • appetite loss;
  • elderly dementia patient;
  • ghrelin;
  • Rikkunshi-to;
  • side-effect

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Background:  Functional gastrointestinal symptoms are frequently found in elderly dementia patients. In such a case, we attempt treatment by the administration of antidepressants or second-generation antipsychotics. However, these medications have a risk of side-effects. In the present study, we carried out oral administration of Rikkunshi-to to elderly dementia patients with appetite loss, and examined its effects on food intake.

Methods:  Six elderly dementia patients were recruited from inpatients. They showed appetite loss, but no organic abnormalities of the gastrointestinal organs. These patients were given Rikkunshi-to, at 7.5 g per day, t.i.d. for 4 weeks. We examined the food intake, weight, total protein, albumin and potassium in plasma before administration and for 4 weeks after administration. In statistical analyses, the percentage of food consumed for 4 weeks was analyzed by anova. We also examined the side-effects of Rikkunshi-to.

Results:  In patient 3, we stopped investigation after 3 weeks because of the development of cholecystitis. The values of 4 weeks in patient 3 were calculated as the mean values of 4 weeks in the other five patients. anova and Tukey's multiple comparison showed a marginally significant difference in weight between before Rikkunshi-to was given and 4 weeks after. In change of food intake, there were no significant differences between before Rikkunshi-to was given and 1 day after, 1 day and 2 days after, 2 days and 3 days after, 3 days and 1 week after, and 1 week and 2 weeks after; however, there were significant increases in food intake between other times. With regard to the side-effects, mild lower limb oedema appeared in the two patients.

Conclusion:  In the present study, we showed the effect of Rikkunshi-to in improving appetite loss in elderly dementia patients. The present study suggests that Rikkunshi-to might be useful in improving functional appetite loss in elderly dementia patients, because there are no serious side-effects.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

It is generally conceded that the gastrointestinal motility of the elderly is weaker than that of the young. Gastrointestinal symptoms, such as appetite loss, nausea, stomach ache, diarrhoea and constipation, are frequently found in the elderly. Elderly dementia patients often do not complain of gastrointestinal symptoms specifically because of their cognitive impairment, therefore symptoms are sometimes identified quite late. Dehydration can result from appetite loss. Appetite loss can also lead to low nutrition, which results in decubitus and easy infection. If appetite loss is not caused by organic abnormalities including physical, metabolic and neurological abnormalities of the gastrointestinal organs as well as side-effects of administered medications, we suspect functional abnormalities including psychological abnormalities, such as depression, delirium and so on, and attempt treatment by the administration of a small dose of antidepressants or second-generation antipsychotics.1,2 However, these medications have a risk of serious side-effects including oversedation, extrapyramidal signs, ileus and aspiration pneumonia. If these medications are not effective, we finally carry out intravenous hyperalimentation, nasogastric-tube feeding or the creation of gastric fistula.

Rikkunshi-to (TJ-43) is a kampo preparation for unidentified complaints of the upper abdomen3–5 Recently, its other function that increases food intake has been focused on. Although the agents of this drug are gradually being analyzed, there are only a few case reports in clinical medicine. In the present study, we carried out oral administration of Rikkunshi-to (TJ-43) to elderly dementia patients with appetite loss, and examined its effects on food intake.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Six elderly dementia patients were recruited from inpatients at dementia wards of Juntendo Geriatric Medical Center during 2008. These patients had moderate to severe dementia caused by various diseases (Table 1). Patient 1 with Alzheimer's disease (AD) was hospitalized for increasing uneasiness, irritability, sleeplessness and appetite loss. We administered olanzapine 5 mg/day and sulpiride 50 mg/day for these symptoms. The psychological symptoms improved after 1 month, whereas appetite loss did not improve. Patient 2 had dementia with Lewy bodies (DLB) and was hospitalized for increasing uneasiness and appetite loss. We administered paroxetine 20 mg/day for these symptoms. The uneasiness improved after 2 weeks, whereas appetite loss deteriorated 1 month after the medication was started. Patient 3 had AD and was hospitalized for increasing sleeplessness, loitering in the night and appetite loss. We administrated trazodone 25 mg/day for these symptoms. The psychological symptoms improved after 1 month, whereas appetite loss did not improve. Patient 4 had AD and was hospitalized for increasing sleeplessness, aggression in the night and appetite loss. We administered quetiapine 50 mg/day for these symptoms. The psychological symptoms improved after 2 weeks, whereas appetite loss did not improve 1 month after the medication was started. Patient 5 had DLB and was hospitalized for increasing sleeplessness, aggression and appetite loss. We administrated quetiapine 50 mg/day for these symptoms. The psychological symptoms improved after 1 month, whereas appetite loss did not improve. Patient 6 with vascular dementia (VaD) was hospitalized for increasing uneasiness, sleeplessness and appetite loss. The psychological symptoms improved after 2 weeks without the medication, whereas appetite loss did not improve after 1 month.

Table 1.  Clinical data of six patients
PatientSexAge (years)Dementia duration (years)Dementia typeMMSEComplicationMedication/day
  1. AD, Alzheimer's disease; DLB, dementia with Lewy bodies; MMSE, Mini-Mental State Examination; VaD, vascular dementia.

1Female731AD12Myasthenia gravisolanzapine 5 mg sulpiride 50 mg
2Male765DLB5Prostatomegalydonepezil 5 mg paroxetine 20 mg
3Female772AD4Gallstonestrazodone 25 mg
4Female783AD5 quetiapine 50 mg
5Male796DLB4 donepezil 5 mg quetiapine 50 mg
6Female831VaD14Cerebral infarctionno medication

At the admission, any significant psychological abnormalities in the six patients, such as depression, delirium and so on, were ruled out by two experienced psychiatrists, although these patients showed unidentified psychological symptoms other than appetite loss. They had no organic abnormalities related to appetite loss, as determined using routine blood analysis, computed tomography, magnetic resonance imaging, ultrasound or endoscopic examinations of the gastrointestinal organs.

The six patients were given Rikkunshi-to, at 7.5 g per day, t.i.d. after meals 4 weeks. During these 4 weeks, we did not change the dose of Rikkunshi-to or the form and quantity of food given to the patients. We also did not change the type or dose of the combination of medications that the patients were receiving, except for the medications resolving side-effects of Rikkunshi-to. We examined the food intake, weight, total protein, albumin and potassium in plasma before administration and for 4 weeks after administration. Characteristics of the food provided were as follows: total energy 1700 kcal, carbohydrate 260 g, protein 70 g and lipid 45 g. The percentage of food consumed was calculated by nursing staff. The food intake before administration was defined as the average for the 3 days before the initiation of the examination.

In statistical analyses, each examined item for 4 weeks was analyzed by anova. The null hypothesis was rejected at a significance level of P < 0.05. In addition, we examined the side-effects of Rikkunshi-to.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

We showed the change of food intake, weight, total protein, albumin and potassium in plasma before administration and for 4 weeks after administration (Tables 2,3).

Table 2.  Change of four items
 Before1 week2 weeks4 weeksanova
  • *

    anova and Tukey's multiple comparison indicate a marginally significant difference between before administration and 4 weeks. After.

  • The values of 4 weeks in patient 3 are calculated as the mean values of 4 weeks in the other five patients. Mean (SD), Ns: not significant.

Change of weight (kg)41.4 (6.5)41.9 (5.6)42.2 (6.2)43.6 (7.0)P < 0.10*
Change of total protein in plasma (mg/dL)6.2 (0.8)6.0 (1.1)5.8 (1.0)6.2 (0.9)NS
Change of albumin in plasma (mg/dL)2.8 (0.6)2.8 (0.8)2.7 (0.6)3.0 (0.7)NS
Change of potassium in plasma (mg/dL)4.2 (0.4)4.1 (0.5)4.2 (0.5)4.1 (0.4)NS
Table 3.  Change of food intake
PatientBefore1 day2 days3 days1 week2 weeks4 weeksanova
  • *

    There are no significant differences between before administration and 1 day after, one day and two days after, two days and three days after, three days and one week after, and one week and two weeks after; however, there are significant increases in food intake between other times.

  • The value of 4 weeks in patient 3 is calculated as the mean value of 4 weeks in the other five patients. Food intake is shown as percentage (%).

110%20%40%50%80%80%80% 
250%50%30%60%80%80%100% 
330%30%45%50%45%50%Stopped 
40%5%20%40%60%70%80% 
510%10%60%30%60%70%100% 
615%25%30%20%25%20%40% 
Mean19.2%23.3%37.5%41.7%58.3%61.7%80.0%P < 0.05*
(SD)(18.0)(16.0)(14.1)(14.7)(21.1)(23.2)(24.5)

For patient 3, we stopped the administration of Rikkunshi-to after 3 weeks of the examination because of the development of cholecystitis. A relationship between the cholecystitis and the administration of Rikkunshi-to might be ruled out by a physician, because the patient had gallstones and a past history of cholecystitis. The values of 4 weeks in patient 3 were calculated as the mean values of 4 weeks in the other five patients (Tables 2,3). In six patients, anova showed no significant differences among total protein, albumin and potassium in plasma for the examination; however, anova and Tukey's multiple comparison showed a marginally significant difference in weight between before Rikkunshi-to was administered and 4 weeks after (Table 2). In change of food intake, there were no significant differences between before Rikkunshi-to was administered and one day after, one day and two days after, two days and three days after, three days and one week after, and one week and two weeks after; however, there were significant increases in food intake between other times (Table 3; Fig. 1,2).

image

Figure 1. Change in food intake after administration of Rikkunshi-to in six patients for 2 weeks. Before, before administration of Rikkunshi-to; 1 day to 2 weeks, after administration of Rikkunshi-to.

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image

Figure 2. Change in food intake after administration of Rikkunshi-to in five patients for 4 weeks. Before, before administration of Rikkunshi-to; 1 day to 4 weeks, after administration of Rikkunshi-to.

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With regard to the side-effects of Rikkunshi-to, mild lower limb oedema appeared a week after administration in patients 1 and 4, although the level of potassium in plasma only decreased in patient 4. The lower limb oedema and decreased potassium level were resolved soon by intravenous infusion of spironolactone and potassium aspartate.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Appetite loss is a common condition associated with a complex range of upper abdominal symptoms, such as abdominal discomfort or pain, feeling of abdominal fullness, early satiety, abdominal distention and bloating, and nausea. Patients with appetite loss should be carefully examined for the detection of possible organic abnormalities of the gastrointestinal organs. We should also take care of the malfunction of false teeth and the form of the meal. Particularly, we should be careful with elderly dementia patients, because they often do not complain of their symptoms specifically, because of their cognitive impairment. When such an examination fails to detect any organic abnormalities, these patients should be considered to have some functional abnormalities including psychological abnormalities, such as depression, delirium and so on, that lead to appetite loss. Appetite loss causes serious problems, such as weight loss and general weakness in elderly dementia patients,6 which become worse as their cognitive impairment and behavioural symptoms progress.7,8

Rikkunshi-to contains 4.0 g of dried extract obtained from mixed raw herbs in the following ratio: Atractylodes lancea rhizome, 4.0 g; Ginseng, 4.0 g; Pinellia tuber, 4.0 g; Poria sclerotium, 4.0 g; Jujube, 2.0 g; Citrus unshiu peel, 2.0 g; Glycyrrhiza, 1.0 g; and Ginger, 0.5 g. Rikkunshi-to is effective for improving gastric dysmotility.4 Recently, the mechanism by which Rikkunshi-to improves appetite has been clarified. Hayakawa et al.9 assumed that Rikkunshi-to elevates gastric accumulation by two types of mechanisms operating with a time lag. At the first receptive relaxation, stimulation occurs when food passes through the pharynx and oesophagus, and relaxes the fundus of the stomach. At the second adaptive relaxation, pressure stimulation occurs when food passes through the fundus of the stomach, which relaxes the fundus of the stomach even more in preparation for more food. These two types of mechanisms seem to be controlled by nitric oxide (NO).10,11 Rikkunshi-to contains L-arginine, which is a precursor of NO. Kido et al.12 showed that Rikkunshi-to ameliorates abnormalities of NO-mediated gastric functions, such as delayed gastric emptying, and hesperidin and L-arginine have been identified as two of the active ingredients contributing to the ability of Rikkunshi-to to facilitate gastric emptying. Rikkunshi-to also has beneficial effects on the gastric mucosa.13 Arakawa suggested that the protective effect of Rikkunshi-to for the gastric mucosa might be related to endogenous NO14. Recently, attention has been focused on Rikkunshi-to as an appetite stimulant. Takeda et al. showed that Rikkunshi-to causes an increase in ghrelin level in plasma, and suggested that antagonism of the 5HT2B/2C receptor might be related to an increase in ghrelin level.15 Ghrelin, a gastrointestinal hormone identified by Kojima et al.,16 is a factor that promotes appetite and gastrointestinal motility,17–19 and is a component of both fasting and satiety systems.20 Ghrelin accelerates the systolic function of the stomach and duodenum. When ghrelin is given, it changes the type of motion from the after-meal state to the before-meal state.21 This function with regard to fasting time also occurs in humans.22 Ghrelin and its receptor are also produced and expressed in the hypothalamus arcuate nucleus neurons as well as in the stomach, and ghrelin given to rodents peripherally or intracerebrally was found to cause an enhancement of gastrointestinal motility, and an increase in food intake.23

In the present study, we found that food intake significantly improved after administration of Rikkunshi-to in the six elderly dementia patients. Five out of six patients took a small dose of antidepressants or second-generation antipsychotics before administration of Rikkunshi-to. These medications were given for unidentified psychological symptoms with dementia, as well as appetite loss. Thereafter, these psychological symptoms improved within approximately 1 month, whereas appetite loss did not improve even after the improvement of psychological symptoms. We did not change the type or dose of the medications during the examination of Rikkunshi-to. Therefore, we assume that Rikkunshi-to itself improved food intake during the examination, although we cannot deny the possibility that these medications themselves or improvement of psychological symptoms as a result of the medications influenced food intake during the examination. Other items, such as weight and albumin in plasma, did not change significantly during the examination, although they slightly increased in some patients. The reason might be because we had to treat the patients for a short time, and therefore the examination period was too short to change weight and nutrition.

When we give Rikkunshi-to to patients with appetite loss, we have to be aware of possible side-effects, such as myopathy, pseudoaldosteronism and liver dysfunction, which are mentioned in the instructions that accompany Rikkunshi-to. It is unknown what kind of ratio a side-effect comes out in. These side-effects are more likely to occur in elderly patients than in young patients, because drug metabolism is slower in the elderly than in the young. In the present study, mild lower limb oedema appeared in two patients. It might be caused by pseudoaldosteronism, because one of the two patients showed a low level of potassium in their plasma. Rikkunshi-to contains Kanzou, as well as many other kampo preparations, and Kanzou has the possibility of causing pseudoaldosteronism. The lower limb oedema and decreased potassium level were resolved quickly by intravenous infusion of spironolactone and potassium aspartate. We should provide Rikkunshi-to to elderly patients accompanied by repeated blood analyses and neurological examinations.

The present study is a preliminary study with some critical limitations. First, the sample size was too small to show a significant general effect of Rikkunshi-to in improving appetite loss. Second, a long-term effect of Rikkunshi-to was unknown, because the patients left our hospital. Third, the possibility that a small dose of antidepressants or second-generation antipsychotics taken before and during the examination of Rikkunshi-to might influence the appetite cannot be denied. Fourth, the present study lacks an analysis of whether there is any relationship between the effect of Rikkunshi-to and the age of patients, duration and types of dementia, Mini-Mental State Examination or complications. However, the present study suggests that Rikkunshi-to might be more useful in improving functional appetite loss in elderly dementia patients than antidepressants or second-generation antipsychotics. Although there are several limitations, we hope that the present study attracts attention to the possibilities of Rikkunshi-to. We will carry out a further large controlled study supporting this conclusion.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES
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