Effects of Magnesium Oxide on the Serum Duloxetine Concentration and Antidepressant-Like Effects of Duloxetine in Rats.

Duloxetine is a serotonin/noradrenaline reuptake inhibitor that is used as an antidepressant. However, it is known to cause constipation as a side effect. Magnesium compounds, such as magnesium oxide and magnesium hydroxide aqueous solution, are often combined with duloxetine to ameliorate the constipation caused by duloxetine. However, there is concern that these magnesium compounds might alter the effects of duloxetine via physicochemical interactions. In this study, we attempted to clarify the interactions that take place between duloxetine and magnesium oxide using in vivo and in vitro experiments. We evaluated the influence of magnesium oxide on in vitro duloxetine concentrations using HPLC. In addition, we examined the in vivo antidepressant-like effects and serum concentrations of duloxetine in rats. In the in vitro experiment, the duloxetine concentration was significantly decreased by co-treatment with magnesium oxide. In the in vivo experiment, the antidepressant-like effects of duloxetine were not affected by the combined oral administration of magnesium oxide and a duloxetine formulation although the serum duloxetine level was significantly decreased. However, the antidepressant-like effects of a duloxetine reagent were significantly attenuated by the co-administration of magnesium oxide. These results suggest that duloxetine and magnesium oxide directly interact and that such interactions affect the absorption and antidepressant-like effects of duloxetine.

[Monitoring of the Blood Concentrations of Antiepileptic Drugs (TDM)].

The incidence of epilepsy is high in infants/children and elderly persons. Patients with epilepsy account for approximately 1% of the population. This chronic cerebral disorder is characterized by repeated epileptic seizures related to excessive excitation of the brain, and it is important to reduce such seizures in life. Therapeutic drug monitoring (TDM) is useful for evaluating the treatment response and checking for adverse effects. When interpreting the results of measurement of the blood concentrations of antiepileptic drugs, the duplication of various factors must be understood. In this article, matters that clinical technologists face in routine work are presented/arranged so that the results of TDM may be adequately interpreted. In 270% of patients with epilepsy, as a nervous disease, seizures may be reduced by administering adequate therapy with antiepileptic drugs; the response rate is high. If measurements deviate from the reference range, clini- cal technologists should utilize their specialized knowledge and adequately evaluate the values obtained, con- tributing to drug therapy. [Review].

Photoinitiator-Initiated Estrogenic Activity in Human Breast Cancer Cell Line MCF-7.

A recent in vitro study reported that the photoinitiator 2-isopropylthioxanthone (2-ITX) is an endocrine-disrupting compound (EDC). However, it is not clear whether other photoinitiators such as 1-hydroxycyclohexyl phenyl ketone (1-HCHPK) and 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MTMP) produce endocrine-disrupting effects. The purpose of this study was thus to assess the association between estrogenic activity and exposure to photoinitiators. For estimation of the proliferative effect of the photoinitiators, the E-screen assay was used. Six photoinitiators, 2,2-dimethoxy-2-phenylacetophenone (2,2-DMPAP), 2-ethylhexyl 4-(dimethylamino)benzoate (2-EHDAB), 1-HCHPK, 2-ITX, methyl-2-benzoylbenzoate (MBB), and MTMP, significantly increased number of MCF-7 cells, an estrogen-sensitive human breast cancer cell line. In addition, pretreatment with estrogen receptor (ER) antagonists such as clomiphene, tamoxifen, or fulvestrant, significantly reversed the proliferative effect of each photoinitiator. Data demonstrated that the six photoinitiators produced endocrine-disrupting effects and that these photoinitiators interacted with ER as agonists. Evidence indicates that the six photoinitiators demonstrated estrogenic activity via ER as agonists.

Differential combined effect of COX inhibitors on cell survival suppressed by sorafenib in the HepG2 cell line.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib, a molecular-targeted drug, is a multi-target oral anti-neoplastic drug that is used as a first-line treatment for patients with advanced Human HCC. An increase in the expression of the cyclooxygenase-2 (COX-2) protein and sequential production of prostaglandin (PG) E2 were previously shown to significantly enhance carcinogenesis. Although the synergistic and/or additive effects of various COX inhibitors have been demonstrated in HCC, those of a combination of sorafenib and COX inhibitors remain unclear. The aim of the present study was to examine the antitumor effects of a combination of sorafenib and COX inhibitors on HCC HepG2 cells. Various COX inhibitors suppressed HepG2 cell survival, and exhibited a combined effect with sorafenib. However, COX-2 selectivity had little relevance. The co-administration of COX inhibitors and sorafenib increased the frequency of apoptosis. Moreover, the combination of sorafenib and diclofenac significantly increased Bax protein expression levels. The results of the present study indicate that COX inhibitors can be administered in combination with sorafenib for HCC therapy.

Characteristics of the runway model of intracranial self-stimulation behavior and comparison with other motivated behaviors.

Motivation incorporates several psychological aspects that produce reward-related and learning behaviors. Although reward-related behavior is reported to be mediated by the dopaminergic reward pathway, the involvement of dopaminergic systems in motivated behavior has not been fully clarified. Several experimental methodologies for motivational behavior have been reported, but pharmacological characteristics seem to vary among these methodologies. In this review, we attempt to summarize three main concepts:(1) the relationship of dopamine neuron physiology with motivated behavior, (2) the pharmacological characteristics of the runway intracranial self-stimulation model, and (3) the behavioral distinction of disparate motivated behaviors.

The polymerization agent, 2-methyl-4'-(methylthio)-2-morpholinopropiophenone induces caspases-3/7 in human blood mononuclear cells in vitro.

Our previous studies detected the presence of a photoinitiator 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MTMP) in an intravenous (i.v.) injection bag solution. Importantly, MTMP has demonstrated cytotoxicity for normal human peripheral blood (PB) mononuclear cells (MNC). Cell death pathways have two well-known modes, apoptosis and necrosis. But it has not been clear whether MTMP induced apoptosis or necrosis in normal human PB MNC. In the present in vitro study, we examined normal human PB MNC for the frequencies of apoptosis and necrosis and changes upon exposure to MTMP. We observed time-dependent changes in MNC viability with MTMP. We also assessed the activity of caspases-3/7. The results demonstrated that MTMP induced apoptosis in normal human PB MNC after 24 h. In addition, MTMP induced caspases-3/7 in a time-dependent manner. In conclusion, we suggest that MTMP induces apoptosis in a caspase-dependent pathway in vitro.

Cetuximab-induced skin reactions are suppressed by cigarette smoking in patients with advanced colorectal cancer.

BACKGROUND: Smoking is widely accepted as the most important risk factor for cancer in the modern world. Several constituents of cigarette smoke are known to interact with drug-metabolizing enzymes, potentially affecting the outcomes of drug treatment. Cetuximab (Erbitux(®); Merck Serono) is indicated for the treatment of colorectal cancer with respect to restoring chemosensitivity to irinotecan in irinotecan-resistant patients. The purpose of this study was to determine whether cigarette smoking adversely affects the actions of cetuximab in the treatment of colorectal cancer. METHODS: We studied 56 patients with colorectal cancer who were treated with cetuximab in our hospital during the time period from 2009 through 2010. We compared the adverse reaction rates of 16 patients who smoked (smokers) with those of 38 patients who did not smoke (non-smokers, including 16 patients who never smoked and 22 patients who were former smokers). RESULTS: The incidence of skin reactions after cetuximab treatment was lower in the smokers than in the non-smokers. In addition, the incidence of anorexia was higher in the smokers than in the non-smokers. Within the group of non-smokers, no statistically significant differences were observed between the never smokers and the former smokers with regard to adverse reactions. CONCLUSION: Our findings suggest that cigarette smoking during anticancer treatment with cetuximab-based regimens reduces the skin reaction, which leads to a reduction in the benefit of the treatment; therefore, patients should quit smoking, at least while receiving cetuximab-based treatment.

Cytotoxicity of the polymerization agent, 2-methyl-4'-(methylthio)-2-morpholinopropiophenone on human monocytes.

This is the first study to detect 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MTMP) from an intravenous injection bag solution by GC-MS. In previous studies, several other photoinitiators were reported to be very cytotoxic. Therefore, we theorized that photoinitiators such as MTMP might also have adverse cellular effects. The purpose of this study was to quantitate the amounts of contaminants from plastic containers such as those used for peripheral parenteral nutrition and to determine the cytotoxicity of such extracts on human monocytes. The sample extraction procedure for GC-MS analysis involved a liquid-phase extraction. The solvent was evaporated under a stream of nitrogen at 50°C. The residue was dissolved in n-hexane and injected into a GC-MS. Normal human peripheral blood mononuclear cells (PBMC), isolated from the buffy coat by centrifugation, were suspended in RPMI 1640 medium supplemented with 10% (v/v) heat-inactivated fetal calf serum. In the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cells (1×10(4)) were treated with MTMP for 24 h or 48 h at 37°C. From the GC-MS analysis, 5.62 ± 1.03 µg/mL of MTMP was found in the BFLUID(®) Injection 500 mL solution. In the MTT assay, MTMP decreased cell viability in a dose-dependent manner for both the 24 h and 48 h incubation periods. Our findings suggest that photoinitiators could promote adverse effects in patients. Future studies will clarify the possible health risks of photoinitiator accumulation in human cells.

Quantitation and human monocyte cytotoxicity of the polymerization agent 1-hydroxycyclohexyl phenyl ketone (Irgacure 184) from three brands of aqueous injection solution.

In this study, levels of the photoinitiator 1-hydroxycyclohexyl phenyl ketone (1-HCHPK) in aqueous injection solutions were analyzed by GC-MS. In our previous studies, photoinitiators such as 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MTMP) were detected in intravenous (i.v.) injection bag solution, and they were found to be cytotoxic to human monocytes. Therefore, we hypothesized that 1-HCHPK might display similarly cytotoxicity. The purpose of this study was to quantitate the amount of contaminants from plastic containers such as those used for peripheral parenteral nutrition and to determine the cytotoxicity of such extracts on human monocytes. The sample extraction procedure for GC-MS analysis involved a liquid-phase extraction. The solvent was evaporated under a stream of nitrogen at 50°C to yield a residue, which was dissolved in n-hexane and injected into a GC-MS. Normal human peripheral blood mononuclear cells (PBMC), isolated from the buffy coat by centrifugation, were suspended in RPMI 1640 medium supplemented with 10% (v/v) heat-inactivated fetal calf serum. In the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay, cells (1×10(4)) were treated with 1-HCHPK for 24 h or 48 h at 37°C. From the GC-MS analysis, 6.13-8.32 µg/mL of 1-HCHPK was found in 20 mL vials of water for injection solution. In the MTT assay, 1-HCHPK decreased cell viability for both the 24 h and 48 h incubation periods. In conclusion, our findings suggest that 1-HCHPK could promote adverse events in patients. Future studies will clarify the possible health risks of photoinitiator accumulation in human cells.

Involvement of dopaminergic receptor signaling in the effects of glutamatergic receptor antagonists on conditioned place aversion induced by naloxone in single-dose morphine-treated rats.

A better understanding of the neurochemical mechanisms mediating the aversive consequences of drug withdrawal is important for understanding drug addiction. We previously demonstrated that the inhibitory effect of glutamate receptor antagonists on the conditioned place aversion (CPA) induced by naloxone-precipitated withdrawal after a single morphine exposure could be blocked by dopamine receptor antagonists. Thus, a glutamatergic-dopaminergic interaction may participate in this phenomenon. The current study was undertaken to further characterize this interaction by employing both D(1) (SCH 23390) and D(2) (raclopride and eticlopride) dopamine receptor antagonists. The influence of these antagonists on the attenuation of CPA by MK-801 (NMDA receptor antagonist), GYKI 52466 (AMPA receptor antagonist), and MCPG (metabotropic glutamate receptor antagonist) was determined in rats receiving a single dose of morphine. The dopamine antagonists showed either a significant reversal or a tendency to reverse the effects of MK-801 on CPA. The effect of GYKI 52466 was also attenuated by the blockade of either D(1) or D(2) receptors. The effect of MCPG, however, was only blocked by D(2) antagonists and not by the D(1) antagonist SCH 23390. These results add evidence to the hypothesis that a glutamatergic-dopaminergic interaction may be involved in the CPA induced by naloxone-precipitated withdrawal following a single morphine exposure and suggest that both D(1) and D(2) dopamine receptor signaling mechanisms play a role in mediating the aversive aspects of acute dependence.

Three photoinitiators induce breast tumor growth in mouse xenografts with MCF-7 breast cancer cells.

Photoinitiators are utilized in the production of a wide range of commonly used products. However, some photoinitiators exert toxic effects. We previously demonstrated the endocrine-disrupting effects of photoinitiators in vitro. The present study investigated the estrogenic activities of three photoinitiators: 1-hydroxycyclohexyl phenyl ketone (1-HCHPK), methyl 2-benzoylbenzoate (MBB), and 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MTMP), which were subcutaneously injected into mouse xenografts with MCF-7 breast cancer cells. The results obtained showed that 1-HCHPK, MBB, and MTMP promoted breast tumor growth in these xenografts. A pretreatment with the estrogen receptor antagonist tamoxifen blocked the tumor growth-promoting effects of each photoinitiator. Collectively, the present results suggest that the three photoinitiators exhibit estrogenic agonist activities in vivo. Furthermore, as a factor for breast tumor growth, these photoinitiators potentially have estrogenic properties in vivo.

Development of an appropriate simple suspension method for valganciclovir medication.

BACKGROUND: Valganciclovir (VGC) is essential for preventing cytomegalovirus infections after transplants in adult and pediatric patients. In pediatric patients, VGC tablets have to be pulverized so that they can be delivered via nasogastric tubes. The "simple suspension method" is usually used to suspend tablets in hot water in Japan. However, the optimal suspension conditions and metering methods for preparing VGC suspensions using the simple suspension method are unclear. The purpose of this study was to clarify these issues. METHODS: VGC tablets were suspended in water (initial water temperature: 25 °C or 55 °C) using the simple suspension method. The residual rate of VGC after it had been suspended in hot water was determined using HPLC. In addition, the suspended solution was passed through 6, 8, and 12 Fr. gavage tubes. The VGC concentrations of suspensions produced using different preparation methods were also determined using HPLC. RESULTS: Cracking the surfaces of VGC tablets and suspending them in water at an initial temperature of 55 °C was effective at dissolving the tablets. The VGC concentration of the suspension remained stable for at least 80 min. Furthermore, the VGC concentration remained stable for 48 h during cold dark storage. Cracking the surfaces of VGC tablets could be a more effective metering method than preparing powder from VGC tablets. In addition, little VGC remained in 6, 8, or 12 Fr. gavage tubes after VGC solution was passed through them. CONCLUSION: The amount of VGC should be measured carefully when preparing VGC solutions using the simple suspension method.

[Study on insoluble microparticulate contamination at ampoule opening].

The hazardous effects due to the insoluble microparticles generated in the injections have been pointed out. To our knowledge, however, there have been no reports about insoluble microparticulate contamination at ampoule opening. Therefore, we performed this study to evaluate the relationship between time and glass particulate sedimentation to examine the effect of swabbing the ampoule neck on particle generation to clarify the relationship between the inner-diameter size of an ampoule and the amount of glass particulate sedimentation to find out the effect of methods for ampule opening, and compare particle contamination in glass ampoule and that of plastic, after ampoule opening and assessed the contribution of material of ampoule to the particle generation. We observed that the glass particulate contamination of accumulation value at a size over 2 mum increased significantly after 60 seconds, the swabbing the neck of the ampoule prior to opening had a negative effect on prevention of glass particulate contamination, the glass particulate contamination was positively influenced by the inner-diameter size of the ampoule, but not by the thickness of the ampoule walls, the particulate contamination derived from glass significantly increased by general method as well as using ampoule open adaptor compared with our method, and the insoluble microparticulate contamination in plastic ampoule was significantly lower than that in glass ampoule. The present findings might provide an useful information to reduce glass particules after ampoule opening performed in clinical practice.

[Involvement of the amygdala on place aversion induced by naloxone in single-dose morphine-treated rats].

Signs characteristic of opiate withdrawal symptoms can be precipitated by an opiate antagonist after short-term infusion or even a single dose of an opiate both in humans and in animals. This phenomenon has been referred to as acute dependence. In contrast to extensive studies on chronic dependence, less is known about the neural mechanisms mediating acute dependence. It will benefit the development of appropriate therapies to facilitate opiate abstinence and reduced craving to better understand the mechanisms underlying acute opiate dependence and to determine whether there are dissociation and similarity between the early and fully developed stages of dependence. In the present study, we examined the influence of c-Fos expression in the amygdala in acquisition of conditioned place aversion (CPA) induced by naloxone-precipitated withdrawal from a single morphine exposure 24 h earlier. The effect of microinjection into the central amygdaloid nucleus (CeA) of various kinds of glutamatergic neurotransmission inhibitors was also investigated. Findings showed that CeA displayed significant increase in c-Fos expression in the acquisition of CPA. Furthermore, CPA was attenuated significantly and dose-dependently by microinjection into CeA of all glutamatergic neurotransmission inhibitors (NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine maleate (MK-801), AMPA receptor antagonist 1-(4-aminophenyl)4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI52466), metabotropic glutamate receptor antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG), and glutamate release inhibitor riluzole). These findings suggest that CeA involves the acquisition of CPA induced by naloxone-precipitated withdrawal from a single morphine exposure, and the function of the glutamatergic system projected from the amygdala to nucleus accumbens plays a facilitative role in formation of morphine dependence.

UV-irradiated 2-methyl-4'-(methylthio)-2-morpholinopropiophenone-containing injection solution produced frameshift mutations in the Ames mutagenicity assay.

In previous studies, we detected the photoinitiators 1-hydroxycyclohexyl phenyl ketone (1-HCHPK), methyl 2-benzoylbenzoate (MBB), and 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MTMP) in intravenous injection solutions. In addition, we reported that 1-HCHPK, MBB, and MTMP exhibited cytotoxicity towards normal human peripheral blood mononuclear cells. A previous in vitro study reported that a free-radical photoinitiator introduced covalently bound purine residues into DNA. However, little is known about the in vitro mutagenicity of 1-HCHPK, MBB, and MTMP. In the present in vitro study, we evaluated the mutagenicity of 1-HCHPK, MBB, and MTMP using the Ames test. We found that untreated 1-HCHPK, MBB, and MTMP were not mutagenic in S. typhimurium strain TA97, TA98, TA100, TA102, or TA1535, regardless of the presence/absence of S9 activation. However, ultraviolet (UV) light-irradiated MTMP exhibited mutagenicity in S. typhimurium strain TA97 in the absence of S9 activation. In conclusion, we suggest that exposure to UV-irradiated MTMP, including in intravenous injection solutions, can result in frameshift mutations.

[Training 5th-Year Clinical Pharmacy Students to Collect and Evaluate Information from Original Articles].

　Pharmacists are required to contribute to evidence-based medicine (EBM) by providing drug information, which can be collected from various sources such as books, websites, and original articles. In particular, information from original articles is needed in some situations. For example, original articles by international researchers are used to aid the management of novel in-hospital preparations on which little knowledge is available. We introduced an information evaluation program, the Okayama University Hospital EBM Model, into the clinical training of 5th-year pharmacy students. It aims to enable students to evaluate the validity of novel in-hospital preparations using original articles. This program has improved students' knowledge of EBM, and the satisfaction level of those enrolled was high. In addition, customer satisfaction analysis revealed that the overall degree of student satisfaction was related to their understanding of the necessity for EBM and the difficulty of practical training. In addition, students' achievements were evaluated using rubrics, and that method allowed the achievements of each student to be assessed appropriately. We hope to revise this program with the aim of improving students' understanding of EBM.

The glutamate release inhibitor riluzole attenuates the formation of conditioned place aversion induced by naloxone in rats undergoing a single morphine exposure.

Acute morphine exposure has been hypothesized to produce long-lasting central changes that contribute to the withdrawal aversion. We have most recently demonstrated that those changes may involve the glutamatergic system, including multiple classes of receptors. The present study was undertaken to further determine the involvement of the glutamatergic system by examining the effect of riluzole, a glutamate release inhibitor, on the motivational component of withdrawal from acute morphine dependence. The role of the amygdala in the action of riluzole was also assessed. We investigated the effects of riluzole on the conditioned place aversion (CPA) induced by naloxone-precipitated withdrawal from a single morphine exposure 24 h before, and on c-Fos expression within the amygdala during the withdrawal period in rats. Riluzole (2, 4, 8 mg/kg) dose-dependently attenuated the CPA without producing place conditioning itself. This result provided further evidence that glutamatergic mechanisms may be recruited in adaptational changes following acute morphine exposure and play a role in withdrawal aversion. In addition, riluzole appeared to produce nonspecific effects on c-Fos expression by itself, without specifically modifying c-Fos expression following naloxone-precipitated withdrawal in any region of the amygdala examined, suggesting that the amygdala may not serve as a specific site of action for riluzole.

In vitro quantitative determination of the concentration of the polymerization agent methyl 2-benzoylbenzoate in intravenous injection solution and the cytotoxic effects of the chemical on normal human peripheral blood mononuclear cells.

In previous studies, we detected the photoinitiators 1-hydroxycyclohexyl phenyl ketone (1-HCHPK) and 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MTMP) in an intravenous injection solution. Importantly, 1-HCHPK and MTMP have been demonstrated to be cytotoxic to normal human peripheral blood (PB) mononuclear cells (MNC). Cell death (apoptosis) pathways can be classified into two modes, caspase-dependent and -independent pathways. However, it is unclear whether methyl 2-benzoylbenzoate (MBB) induces the caspase-dependent and/or -independent pathway in normal human PBMNC. In the present in vitro study, we examined the levels of MBB in a solution from an intravenous fluid bag and the cytotoxicity of MBB towards normal human PBMNC via the caspase-8-, caspase-9-, or apoptosis-inducing factor (AIF)-mediated apoptosis pathways. We found that extracts from the injection solution had been contaminated with approximately 80 µM of the photoinitiator MBB. In addition, MBB induced apoptosis in the high concentration range in normal human PBMNC in vitro. Moreover, we found that MBB-induced apoptosis occurs via the caspase-9 pathway, but not the AIF pathway. In conclusion, we suggest that MBB has cytotoxic effects on normal human PBMNC in vitro, which are mediated via the caspase-dependent pathway.

Effect of glutamate receptor antagonists on place aversion induced by naloxone in single-dose morphine-treated rats.

The neurobiological mechanism underlying the negative motivational component of withdrawal from acute opiate dependence is far from understood. Our objectives were to determine whether the glutamatergic system is involved in the motivational component of morphine withdrawal in acutely dependent rats and such an involvement is associated with dopaminergic neurotransmission. We examined the effects of various kinds of glutamate receptor antagonists on conditioned place aversion (CPA) induced by naloxone-precipitated withdrawal from a single morphine exposure 24 h before. Furthermore, the influence of pretreatment with the dopamine receptor antagonist haloperidol on those effects of glutamate receptor antagonists was also investigated. CPA was attenuated in a dose-dependent manner by all glutamate receptor antagonists examined including the NMDA receptor antagonists (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine maleate (MK-801) and phencyclidine hydrochloride (PCP), AMPA receptor antagonist 1-(4-aminophenyl)4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466), and metabotropic receptor antagonists (+/-)-2-amino-3-phosphonopropionic acid (AP-3) and (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG). The effects of MK-801, GYKI 52466 and MCPG were blocked by haloperidol. These results suggest that the glutamatergic system involving multiple classes of receptors plays a role in the motivational component of withdrawal from acute morphine dependence, and the function of the glutamatergic system would be closely associated with dopaminergic neurotransmission.

[Examination of the escape phenomenon in disease modifying antirheumatic drugs].

Although disease-modifying antirheumatic drugs (DMARDs) are used in the treatment of rheumatoid arthritis (RA), the selection of agents in the case of relapse (escape phenomenon) lacks clear-cut standards. Therefore we investigated the rate and conditions of escape as well as the agents used after escapes had occurred. Outpatients of the Matsubara Mayflower Hospital with a history of DMARD administration during the 4 years prior to May 2003 were studied. Those receiving salazosulfapyridine (SASP) had a high escape rate and those receiving methotrexate (MTX) and bucillamine (BC) had a low rate. The continuous duration of administration was long for MTX and BC, but short for sodium aurothiomalate (GST). BC and Actarit (AR) gradually elevated C-reactive protein (CRP) levels and the erythrocyte sedimentation rate (ESR). In patients receiving SASP and MTX, a high level of CRP and high ESR was seen 2 months prior to the occurrence of escape and remained unchanged after escape. With respect to the agents used after escape, SASP and BC were substituted with other DMARDs. A combination with other DMARDs was usually administered to patients who had been receiving MTX. Taken together, the present results clarified the characteristics of DMARD escape and will contribute to the appropriate pharmacotherapy for RA.