Treatment of subcutaneous nodules after infusion of apomorphine; a biopsy-controlled study comparing 4 frequently used therapies.

This study aimed to provide clinical evidence for existing treatments of subcutaneous nodules after subcutaneous infusion of apomorphine, using a biopsy-controlled prospective crossover design of four treatments. We demonstrated that dilution of apomorphine significantly improved patient satisfaction, while subcutaneous hydrocortisone reduced nodule size, however with no differences in the histopathology.

[Continuous and advanced treatment strategies in the old to very old parkinsonian population]. / Place des traitements continus et de seconde ligne dans la population des parkinsoniens âgés à très âgés.

Parkinson's disease (PD) is a neurodegenerative disorder with an incidence and a prevalence increasing with age, predicted to increase drastically in the next 10 years among the geriatric population aged above 80 in France. There are two distinct groups of patients in which therapeutic issues are different. On the one hand, old to very old patients in which PD started at a late age above 80. These patients present with a more severe PD with earlier onsets of cognitive defects and dopa-resistant axial signs, and more comorbidities needing to be taken into account while treating them. Because of their limited life expectancy, these patients would not likely need second line treatments over their disease course. On the other hand, patients presenting with advanced PD, in which fluctuations and dyskinesia induced by dopamine replacement therapy and dopa-resistant axial symptoms impede patient's daily life. These patients are often treated with multiple antiparkinsonian medications, sometimes at high doses. Some patients will also be treated with advanced therapies such as continuous subcutaneous apomorphine infusion, continuous levodopa-carbidopa intestinal gel or, more rarely, even subthalamic or pallidal deep brain stimulations. Because of the specificities of the old to very old parkinsonian patients, tolerance and efficacy of these treatments can be decreased. What is at stake is to aim for the best motor state possible while limiting iatrogenic adverse events. New emerging, potentially less invasive, techniques, such as gamma knife thalamotomy or high-intensity focused ultrasound thalamotomy or sub-thalamotomy, are also discussed here.

Antipsychotic-like activity of scopoletin and rutin against the positive symptoms of schizophrenia in mouse models.

In an earlier report, we demonstrated an antipsychotic-like activity of a methanolic extract of Morinda citrifolia Linn fruit in mouse models and postulated the contribution of its bioactive principles, scopoletin and rutin. Moreover, the antidopaminergic activities of scopoletin and rutin were reported in isolated vas deferens preparations. In the present study, scopoletin and rutin were assessed for antipsychotic-like activity using apomorphine-induced climbing behavior and methamphetamine-induced stereotypy in mice. The results of this study revealed that scopoletin and rutin (0.05, 0.1, 0.5, and 1 mg/kg, p.o.) had a "U-shaped" dose-dependent effect on climbing and stereotyped behaviors induced by apomorphine and methamphetamine, respectively, in mice. A significant reduction in climbing and stereotyped behaviors caused by scopoletin and rutin was observed only at a dose 0.1 mg/kg. This study suggests that scopoletin and rutin can alleviate positive symptoms of schizophrenia only at a specific dose. Further studies evaluating the effects of scopoletin and rutin on animal models for negative symptoms of schizophrenia are required for a novel drug discovery in the treatment of neuropsychiatric diseases.

Magnetic Resonance Imaging as a Noninvasive Method for Longitudinal Monitoring of Infusion Site Reactions Following Administration of a Novel Apomorphine Formulation.

Infusion site reactions are common following subcutaneous infusion of drugs. Such reactions can lead to discontinuation of the treatment. Therefore, assessment of such reactions is essential during preclinical safety studies, and magnetic resonance imaging (MRI) can assist in evaluation. Here, in vivo and ex vivo MRI evaluations were used in addition to classical histopathology to assess the infusion site reaction to ND0701, a novel formulation of apomorphine base developed for the treatment of Parkinson's disease, in comparison to the commercial apomorphine hydrochloride (HCl) formulation. Both formulations, each at two concentrations, were continuously administered subcutaneously for 20 hr to each of 3 male and 3 female domestic pigs. Based on MRI evaluations, there was a gradual decrease in the volume of the subcutaneous lesions over 4 weeks, with smaller lesions and quicker resolution with ND0701 at concentrations 2.5- to 5-fold higher when compared to the commercial apomorphine HCl formulation. Histopathological evaluation of ND0701 revealed only minimal inflammation at the sites of infusion, whereas the commercial apomorphine HCl caused persistent inflammatory reactions and necrosis. This study provides support to the use of MRI in preclinical testing of subcutaneous drugs when evaluating local site reactions.

Synthesis and biological evaluation of novel flavanone derivatives as potential antipsychotic agents.

In this study, a series of novel flavanone derivatives were designed and synthesized, and the antipsychotic activities of the target compounds were evaluated in vitro and in vivo. The results showed that synthesized compounds 7a-7g decreased the activity of dopamine D2 receptors in HEK293 cells co-transfected with D2 receptor/G protein α16a, with IC50 values of 0.051-0.35 µm. Compounds 7a-7g inhibited the over-production of nitric oxide stimulated by lipopolysaccharide/interferon-γ in BV-2 microglial cells. In mice, intragastric administration of 7d, 7e, and 7g reversed the increase in locomotor activity induced by MK-801 (an antagonist of NMDA receptors) and decreased the hyperactivity of climbing behavior induced by apomorphine (a dopamine receptor agonist). These results suggest that some of the novel flavanone derivatives have potential antipsychotic effects and may be useful in the treatment of schizophrenia.

Comparison of three preclinical models for nausea and vomiting assessment.

INTRODUCTION: Nausea is a subjective sensation often preceding emesis in humans. Drug-induced nausea remains difficult to predict in preclinical tests. The aim of this study was to compare the effects of emetic agents in rats (pica behavior), ferrets (acute and delayed phases of emesis) or dogs (emesis and cardiovascular endpoints). METHODS: Rats and ferrets were administered cisplatin (±aprepitant/ondansetron or aprepitant) or apomorphine (±domperidone). Telemetered dogs were administered apomorphine (±domperidone). Food and kaolin intake was measured in rats whereas the number of emetic events was counted in ferrets and dogs. Cardiovascular changes were also monitored in dogs. RESULTS: In rats, cisplatin (6mg/kg, i.p.) increased kaolin intake (+2257%, p<0.001). The cisplatin effects were not reversed by the combination of aprepitant/ondansetron (2mg/kg, p.o./2mg/kg, i.p.) or by aprepitant (30mg/kg, p.o.). Apomorphine (10mg/kg, i.p.) did not induce pica behavior. In ferrets, cisplatin (8mg/kg, i.p.) induced acute and delayed emesis (371.8±47.8 emetic events over 72h) which was antagonized by aprepitant (1mg/kg, p.o.). Apomorphine (0.25mg/kg, s.c.) induced acute emesis (38.8±8.7 emetic events over 2h) which was abolished by domperidone (0.1mg/kg, s.c.). In dogs, apomorphine (100µg/kg, s.c.) induced emesis and tachycardia which were decreased by domperidone (0.2mg/kg, i.v.). CONCLUSIONS: The assessment of emesis in the ferret or in the dog displays a strong predictive value. In contrast, assessing nausea remains challenging in all animal species and the use of pica behavior remains questionable in the context of antiemetic drug development.

The role of endogenous neurotensin in psychostimulant-induced disruption of prepulse inhibition and locomotion.

The neuropeptide neurotensin (NT) is closely associated with dopaminergic and glutamatergic systems in the rat brain. Central injection of NT into the nucleus accumbens (NAcc) or peripheral administration of NT receptor agonists, reduces many of the behavioral effects of psychostimulants. However, the role of endogenous NT in the behavioral effects of psychostimulants (e.g. DA agonists and NMDA receptor antagonists) remains unclear. Using a NTR antagonist, SR142948A, the current studies were designed to examine the role of endogenous NT in DA receptor agonist- and NMDA receptor antagonist-induced disruption of prepulse inhibition of the acoustic startle response (PPI), locomotor hyperactivity and brain-region specific c-fos mRNA expression. Adult male rats received a single i.p. injection of SR142948A or vehicle followed by D-amphetamine, apomorphine or dizocilpine challenge. SR142948A had no effect on baseline PPI, but dose-dependently attenuated d-amphetamine- and dizocilpine-induced PPI disruption and enhanced apomorphine-induced PPI disruption. SR142948A did not significantly affect either baseline locomotor activity or stimulant-induced hyperlocomotion. Systemic SR142948A administration prevented c-fos mRNA induction in mesolimbic terminal fields (prefrontal cortex, lateral septum, NAcc, ventral subiculum) induced by all three psychostimulants implicating the VTA as the site for NT modulation of stimulant-induced PPI disruption. Further characterization of the NT system may be valuable to find clinical useful compounds for schizophrenia and drug addiction.

Lesions of the entopeduncular nucleus in rats prevent apomorphine-induced deficient sensorimotor gating.

Dopamine-induced hyperactivity and deficient sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR), are used as animal models for neuropsychiatric disorders such as schizophrenia and Tourette's syndrome. We here investigated whether excitotoxic lesions of the rat entopeduncular nucleus (EPN), the equivalent to the human globus pallidus internus (GPi), would improve apomorphine-induced PPI-deficits and hyperactivity. Additionally, we investigated the effect of EPN lesions on cognition, motivation and motor skills. In male Sprague Dawley rats bilateral EPN lesions were induced by stereotactic injection of ibotenate (4 µg in 0.4 µl phosphate buffered saline, PBS) or sham-lesions by injection of vehicle PBS. After one week, rats were tested for learning and memory (continuous and delayed alternation, T-maze), for motivation (progressive ratio test with breakpoint of 3 min inactivity, Skinner box), and for motor skills (rotating rod). Thereafter, rats were tested for PPI of ASR (startle response system) after subcutaneous injection of apomorphine (1.0mg/kg and vehicle) and for locomotor activity (0.5mg/kg and vehicle). Ibotenate-induced EPN lesions did not affect learning and memory, motivation or motor skills. Basal locomotor activity and PPI was also not affected, but EPN lesions ameliorated apomorphine-induced hyperlocomotion and deficient PPI. This work indicates an important role of the EPN for the modulation of dopamine agonist-induced deficient sensorimotor gating and hyperlocomotion, without affecting normal behavioral function.

A water extract of Mucuna pruriens provides long-term amelioration of parkinsonism with reduced risk for dyskinesias.

Dopaminergic anti-parkinsonian medications, such as levodopa (LD) cause drug-induced dyskinesias (DID) in majority of patients with Parkinson's disease (PD). Mucuna pruriens, a legume extensively used in Ayurveda to treat PD, is reputed to provide anti-parkinsonian benefits without inducing DID. We compared the behavioral effects of chronic parenteral administration of a water extract of M. pruriens seed powder (MPE) alone without any additives, MPE combined with the peripheral dopa-decarboxylase inhibitor (DDCI) benserazide (MPE+BZ), LD+BZ and LD alone without BZ in the hemiparkinsonian rat model of PD. A battery of behavioral tests assessed by blinded investigators served as outcome measures in these randomized trials. In experiment 1, animals that received LD+BZ or MPE+BZ at high (6mg/kg) and medium (4mg/kg) equivalent doses demonstrated significant alleviation of parkinsonism, but, developed severe dose-dependent DID. LD+BZ at low doses (2mg/kg) did not provide significant alleviation of parkinsonism. In contrast, MPE+BZ at an equivalent low dose significantly ameliorated parkinsonism. In experiment 2, MPE without any additives (12mg/kg and 20mg/kg LD equivalent dose) alleviated parkinsonism with significantly less DID compared to LD+BZ or MPE+BZ. In experiment 3, MPE without additives administered chronically provided long-term anti-parkinsonian benefits without causing DID. In experiment 4, MPE alone provided significantly more behavioral benefit when compared to the equivalent dose of synthetic LD alone without BZ. In experiment 5, MPE alone reduced the severity of DID in animals initially primed with LD+BZ. These findings suggest that M. pruriens contains water-soluble ingredients that either have an intrinsic DDCI-like activity or mitigate the need for an add-on DDCI to ameliorate parkinsonism. These unique long-term anti-parkinsonian effects of a parenterally administered water extract of M. pruriens seed powder may provide a platform for future drug discoveries and novel treatment strategies in PD.

Electro-acupuncture stimulation improves motor disorders in Parkinsonian rats.

Electro-acupuncture (EA) is believed to be effective for alleviating motor symptoms in patients with Parkinson's disease. In a rat hemiparkinsonian model induced by unilateral transection of the medial forebrain bundle (MFB), the effects of EA stimulation were investigated. EA stimulation at a high frequency (100 Hz) significantly reduced apomorphine-induced rotational behavior. Tyrosine hydroxylase immunohistochemical staining revealed that EA at 100 Hz protected axotomized dopaminergic neurons from degeneration in the substantia nigra (SN). Moreover, high frequency EA reversed the axotomy-induced decrease in substance P content and increase in glutamate decarboxylase-67 (GAD 67) mRNA level in the midbrain; however, it did not affect the axotomy-induced increase in enkephalin content in the globus pallidus. These results suggest that the effects of high frequency EA on motor symptoms of Parkinsonian rats may involve restoration of the homeostasis of dopaminergic transmission in the basal ganglia circuit.

Comparison of apomorphine and levodopa infusions in four patients with Parkinson's disease with symptom fluctuations.

BACKGROUND: Motor fluctuations in patients with advanced Parkinson's disease may be successfully treated with subcutaneous apomorphine infusion or intraduodenal levodopa/carbidopa infusion. No comparative trials of these two alternatives were performed. AIMS OF THE STUDY: We present a subanalysis from a randomized crossover clinical trial where levodopa infusion as monotherapy was compared with any other combination of pharmacotherapy in fluctuating patients. Four patients used apomorphine infusion and oral levodopa in the comparator arm. The results of these four patients are presented in detail. METHODS: The duration of the trial was 3 + 3 weeks. Patients were video-recorded half-hourly on two non-consecutive days of both treatment arms. Blinded video ratings were used. Patient self-assessments of motor function and quality-of-life (QoL) parameters were captured using an electronic diary. RESULTS: Ratings in moderate to severe "off" state ranged 0-44% on apomorphine infusion and 0-6% on levodopa infusion. Moderate to severe dyskinesias were not recorded in any of the treatments. QoL was reported to be improved in all patients on duodenal levodopa infusion. CONCLUSIONS: Monotherapy with duodenal infusion of levodopa was more efficacious and brought greater QoL than combination therapy with apomorphine infusion in these fluctuating patients.

Comparative efficacy of maropitant and selected drugs in preventing emesis induced by centrally or peripherally acting emetogens in dogs.

Maropitant (Cerenia; a novel, selective neurokinin(1) receptor antagonist), chlorpromazine, metoclopramide and ondansetron were compared in two randomized, placebo-controlled studies for efficacy in preventing emesis induced by emetogens acting centrally (apomorphine; Study 1) or peripherally (syrup of ipecac; Study 2) in dogs. In each study, ten male and ten female beagles were treated in a five-treatment, five-period crossover design. The five treatments were 0.9% saline (0.1 mL/kg), maropitant (1 mg/kg), metoclopramide (0.5 mg/kg), or chlorpromazine (0.5 mg/kg) all administered subcutaneously, or ondansetron (0.5 mg/kg) administered intravenously. One hour posttreatment dogs were challenged with apomorphine at 0.1 mg/kg intravenously (Study 1) or syrup of ipecac at 0.5 mL/kg orally (Study 2). Following emetogen challenge, dogs were observed for 30 min (Study 1) or 1 h (Study 2) for emesis. No clinical signs, other than those related to emesis, were observed. Efficacy of maropitant in preventing emesis induced centrally by apomorphine was not different (P > 0.05) from metoclopramide or chlorpromazine but was superior (P < 0.0001) to ondansetron. Efficacy of maropitant in preventing emesis induced by syrup of ipecac was not different (P > 0.05) from ondansetron but was superior (P

High frequency stimulation of the subthalamic nucleus has beneficial antiparkinsonian effects on motor functions in rats, but less efficiency in a choice reaction time task.

Chronic subthalamic nucleus high frequency stimulation (STN HFS) improves motor function in Parkinson's disease. However, its efficacy on cognitive function and the mechanisms involved are less known. The aim of this study was to assess the effects of STN HFS in hemiparkinsonian awake rats performing different specific motor tests and a cognitive operant task. Unilateral STN HFS applied in unilaterally DA-depleted rats decreased the apomorphine-induced circling behaviour and reduced catalepsy induced by the neuroleptic haloperidol. DA-depleted rats exhibited severe deficits in the operant task, among which the inability to perform the task was not alleviated by STN HFS. However, in a few animals showing less impairment, STN HFS significantly reduced the contralateral neglect induced by the lesion. These results are the first to demonstrate a beneficial effect of STN HFS applied in awake rats on basic motor functions. However, STN HFS appears to be less effective on impaired cognitive functions.

New 1-aryl-4-(biarylmethylene)piperazines as potential atypical antipsychotics sharing dopamine D(2)-receptor and serotonin 5-HT(1A)-receptor affinities.

This paper describes the syntheses of several 1-aryl-4-(biarylmethylene)piperazines and the results of the determination of their affinity for D(2) and 5-HT(1A) receptors. A selection of these compounds was evaluated in vivo, resulting in the identification of a drug candidate which is being clinically evaluated as a potential atypical antipsychotic with reduced extrapyrimidal side effects.

[Parkinson therapy 2001, especially apomorphine in idiopathic Parkinson syndrome]. / Parkinson-Therapie 2001, speziell Apomorphin beim idiopathischen Parkinsonsyndrom.

Today (2001) most strategies for Parkinson's disease (PD) are symptomatic. The etiology of the disease is not known. There exists no possibility to inhibit the degeneration of dopaminergic neurons in the substantia nigra. There are hints (but no proofs) for neuroprotection. Beside levodopa a variety of alternative treatment options exists which enable a good and longer lasting control of symptoms (e.g. dopamine agonists, COMT-inhibitors etc.). Apomorphine can reduce off-periods and fluctuations remarkably, even in more advanced stages of PD. Some patients may take profit from neurosurgical procedures (especially deep brain stimulation of subthalamic nucleus and globus pallidus internus). Rehabilitative/supportive approaches complete the medical regime, but there is no proof of efficacy.

Entopeduncular lesions facilitate and thalamic lesions depress spontaneous and drug-evoked motor behavior in the hemiparkinsonian rat.

Pallidotomy is a neurosurgical procedure designed to ameliorate the akinesia and bradykinesia associated with Parkinson's disease. In the present study, the effects of pallidal-like lesions on motor behavior in the hemiparkinsonian rat were compared to the effects of lesions in the ventrolateral thalamus, a target of entopeduncular projections feeding motor-related information to motor cortex. Six aspects of spontaneous and evoked behavior induced by amphetamine and apomorphine in the hemiparkinsonian rat with either bilateral electrolytic entopeduncular lesions or bilateral electrolytic ventrolateral thalamic lesions were measured for 60 min. Saline or amphetamine, 5 mg/kg, or apomorphine, 0.3 mg/kg, were administered IP 5 min before the tests. The results show that on all measures except time spent resting the hemiparkinsonian rats with the entopeduncular lesions were more active than the hemiparkinsonian rats with the thalamic lesions. The asymmetrical rotation responses to dopamine receptor stimulation evoked by amphetamine and apomorphine were influenced by the general effect on gross motor behavior, as shown by the response being very large in the entopeduncular group and very small in the thalamic group. These results are consistent with current thinking about the functional organization of the basal ganglia according to which damage of the entopeduncular nucleus reduces its inhibitory control of the thalamic motor regions, thereby promoting thalamic facilitation of motor cortex, and damage to the thalamic motor regions has the opposite effect. These effects of the lesions translate, respectively, into hyperactivity and hypoactivity without blocking the asymmetrical rotation response of the hemiparkinsonian rat.

[Apomorphine therapy versus deep rain stimulation. Clinical and economic aspects in patients with advanced Parkinson disease]. / Apomorphintherapie versus tiefe Hirnstimulation. Klinische und ökonomische Aspekte bei Patienten mit fortgeschrittenem Morbus Parkinson.

Long-term dopaminergic treatment of Parkinson's disease is complicated by the occurrence of dyskinesia and motor fluctuations and is responsible for increasing the costs of treatment. In these patients, continuous subcutaneous therapy with the dopamine agonist apomorphine or deep-brain stimulation represents a promising strategy. While the costs for the treatment with apomorphine are covered by health insurance, separate reimbursement for deep-brain stimulation does not exist in Germany. The case reports (n = 3) presented here emphasize that deep-brain stimulation is less cost-intensive than subcutaneous treatment with apomorphine in selected patients. Even in the first postoperative year costs for medication and hospital stays were reduced by approximately 60%. Moreover, in all three patients, motor complications improved after deep-brain stimulation in comparison to previous subcutaneous application of apomorphine. Thus, to further ensure deep-brain stimulation in parkinsonian patients it is mandatory to find a mode of reimbursement for the institutions concerned.

Apomorphine test: a predictor for motor responsiveness to deep brain stimulation of the subthalamic nucleus.

The value of the apomorphine test as a predictor of the clinical outcome of deep brain stimulation of the subthalamic nucleus (STN) was evaluated in patients with advanced idiopathic Parkinson's disease (IPD) or multiple system atrophy (MSA). Thirteen IPD patients with severe diurnal fluctuations and one MSA patient not responding to dopaminergic drugs were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) and the timed finger tapping test (FTT), measured preoperatively on and off apomorphine and postoperatively on and off STN stimulation. UPDRS motor items 20-25 were assessed intraoperatively on and off STN stimulation when the clinically effective target was approached. The motor response to immediate intraoperative and long-term STN stimulation was correlated with results of the apomorphine test. The response to immediate intraoperative STN stimulation was accurately predicted by apomorphine challenge in all 13 IPD patients. Clinical outcome following long-term STN stimulation was correlated significantly with preoperative changes due to apomorphine measured with the UPDRS motor scores (r = 0.7125, P < 0.01) and FTT (r = 0.9276, P < 0.001). Moreover, comparison of long-term STN stimulation to preoperative drug treatment displayed a significant reduction in the duration of off-phases and a significant increase in the duration of on-phases. However, in the single patient with MSA no beneficial response was obtained either to apomorphine or to STN stimulation intraoperatively and during the postoperative externalized test period. Our results indicate that the apomorphine test can predict the outcome of immediate and long-term STN stimulation and may help in the selection of candidates for surgery.

Continuous subcutaneous waking day apomorphine in the long term treatment of levodopa induced interdose dyskinesias in Parkinson's disease.

OBJECTIVES: To determine whether continuous waking day dopaminergic stimulation with the dopamine agonist apomorphine can reduce levodopa induced dyskinesias in Parkinson's disease METHODS: 19 patients with severe unpredictable refractory motor fluctuations and functionally disabling levodopa induced dyskinesias were treated with continuous subcutaneous apomorphine monotherapy for a minimum duration of 2.7 years RESULTS: A mean 65% reduction in dyskinetic severity and a mean 85% reduction in frequency and duration occurred. On discontinuing levodopa a concomitant reduction in off period time was also seen (35% of waking day "off" reduced to 10%) CONCLUSION: Continuous waking day dopaminergic stimulation with apomorphine reset the threshold for dyskinesias and led to a pronounced reduction in their frequency. Apomorphine should be considered as a less invasive alternative to pallidotomy or deep cerebral stimulation in controlling levodopa induced interdose dose dyskinesias.

The effects of hange-shashin-to on gastric function in comparison with sho-saiko-to.

The effects of "Hange-shashin-to (TJ-14)" on gastric function were examined in comparison with "Sho-saiko-to (TJ-9)". Oral treatment with TJ-14 (125-500 mg/kg) caused dose-dependent suppression of ethanol-induced gastric injury, while it did not suppress gastric lesions induced by water-immersion stress. TJ-9 (125-500 mg/kg, p.o.) suppressed both water-immersion stress-induced gastric lesions and ethanol-induced gastric injury in a dose-dependent manner. Intraduodenal administration of TJ-14 even at 500 mg/kg did not affect gastric juice secretion, while TJ-9 at 125 to 500 mg/kg dose-dependently suppressed gastric juice secretion. TJ-14 (125-500 mg/kg, p.o.) accelerated gastric emptying in normal rats and improved the delayed gastric emptying induced by BaCl2 in a dose-dependent manner, whereas such effect was not noted with TJ-9. Oral treatment with TJ-14 at 500 mg/kg significantly suppressed apomorphine-induced vomiting, but it did not affect copper sulfate-induced vomiting. These results suggest that TJ-14 exhibits an anti-ulcer action (probably based on its ability to protect the gastric mucosa), improvement of gastric emptying and an anti-emetic action. TJ-9 also showed anti-ulcer effects, probably based on its ability to suppress gastric secretion and to protect the gastric mucosa. Thus, the present study demonstrated the effectiveness of TJ-14 and TJ-9 against gastric disease, and provided basic data which explain the differences in clinical application between these two kampo medicines.