Shigeaki Arai

Chronic inhibition of the norepinephrine transporter in the brain participates in seizure sensitization to cocaine and local anesthetics

The involvement of chronic inhibition of monoamine transporters (MAT) in the brain with respect to sensitization to cocaine- and local anesthetic-induced seizures was studied in mice. Repeated administration of subconvulsive doses of meprylcaine as well as cocaine, both of which inhibit MAT, but not lidocaine, which does not inhibit MAT, increased seizure activity and produced sensitization to other local anesthetics. The effects of five daily treatments of monoamine transporter inhibitors on lidocaine-induced convulsions were examined 2 or 3 days after the last dose of the inhibitors. Daily treatments of GBR 12935, a specific inhibitor of dopamine uptake, significantly increased the incidence and the intensity of lidocaine-induced convulsions at 20 mg/kg and decreased the threshold of the convulsions. Daily treatments of desipramine and maprotiline, selective norepinephrine uptake inhibitors, markedly increased the incidence and intensity of lidocaine-induced convulsions, and decreased the threshold in a dose-dependent manner at between 5 and 20 mg/kg. Daily treatments of citalopram, a selective serotonin uptake inhibitor, at 10 and 20 mg/kg, produced no significant increase in the incidence or intensity of lidocaine-induced convulsions, but decreased the threshold of the convulsions. These results suggest that the chronic intermittent inhibition of monoamine uptake increases susceptibility to cocaine- and local anesthetic-induced seizures, and the norepinephrine transporter is an integral component of this sensitization.

Inhibition of serotonin transporters by cocaine and meprylcaine through 5-TH2C receptor stimulation facilitates their seizure activities.

The present study examined whether the inhibition of serotonin transporters (SERT) contributes to cocaine- and other local anesthetics-induced convulsions, and which subtypes of 5-HT receptor are involved in the convulsions. For this purpose, cocaine, meprylcaine and lidocaine, all of which have different effects on SERT, were used as convulsants and the effects of serotonin reuptake inhibitors (SSRIs), specific agonists and antagonists for 5-HT receptor subtypes were evaluated in mice. Administration of SSRI, zimelidine, citalopram and fluoxetine, 5-HT(2A,2C) receptor agonist, R(-)-DOI and the 5-HT2C receptor agonists, mCPP, and MK212 resulted in a marked increase in incidence of convulsions and a reduction in the threshold of lidocaine-induced convulsions, while the 5-HT2B receptor agonist, BW723C86, had little influence. On the other hand, SSRI did not affect the measured parameters in meprylcaine- and cocaine-induced convulsions. R(-)-DOI, mCPP, and MK212 reduced the threshold of meprylcaine or cocaine with less extent than the reduction of lidocaine threshold. Incidence of cocaine- and meprylcaine-induced convulsions was significantly reduced by 5-HT(2A,2B,2C) antagonist, LY-53857, and 5-HT2C antagonist, RS 102221. The threshold of cocaine and meprylcaine was significantly increased by both antagonists. 5-HT2A antagonists MDL 11,939 and ketanserin, and 5-HT2B antagonist SB 204741 except at high doses had little effect on cocaine- and meprylcaine-induced convulsions. None of these antagonists altered the parameters of lidocaine-induced convulsions. Pretreatment with fluoxetine but not citalopram increased the plasma concentration of lidocaine. These results suggest that the increase of serotonergic neuronal activity through 5-HT2C receptor stimulation was responsible for increased activity of local anesthetics-induced convulsions and support the involvement of this mechanism in cocaine- and meprylcaine- but not in lidocaine-induced convulsions through their direct inhibitory action on central SERT.

The Changes in the Laboratory Values During Administration of Commercially Available Ready-to-use Basal Solutions for Total Parenteral Nutrition

Some differences are seen in the concentrations of glucose and electrolytes between commercially available ready-to-use basal solutions for total parenteral nutrition (R-TPN).In this study, we investigated the effects of the long-term administration of Unicaliq®, which contains relatively higher concentrations of chloride ions than other R-TPNs, on the clinical laboratory values. One hundred and nineteen patients, who received Unicaliq® for more than four weeks at Hiroshima University Hospital, participated in this study. The laboratory values of chloride ion (Cl-) and blood urea nitrogen (BUN) significantly increased after receiving Unicaliq® for 2 weeks, but all levels, except for BUN, returned to the pretreatment levels after 4 weeks of administration. However, these changes were slight and all were within the normal ranges.No changes were observed in other laboratory values during the 4-week administration period.These results suggest that the clinical laboratory values are not affected by the long-term administration of Unicaliq®, at least up until 4 weeks.

Effect of Age on High-Dose Methotrexate Infusion Therapy.

The effect of age on pharmacokinetics of MTX after high-dose MTX (HD-MTX) infusions was investigated. Fifty-nine patients (age: 18-83 years) received HD-MTX infusions (dosage: 1.9-3.8g/m3) for 6 hrs. All patients were divided into the following three groups according to their ages: young group (18-29 years), middle-aged group (31-57 years), and elder group (60-83 years). Mean residence time and clearance of MTX obtained by moment analysis showed a significant delay and decrease, respectively, in the elder group among patients, while there was no significance in the steady-state volume of distribution. In addition, a significantly higher concentration and slower elimination during the first 12 hr were observed in the elder group. Significant resultant decrease in renal and hepatic functions were demonstrated on days 2 and 7, respectively, indicating prompt renal damage and delayed hepatic damage in the elder patients.These results suggest that the pharmacokinetic differences among age groups were evoked by the decreased renal function at the early stage of infusions. Furthermore, drug monitoring in the early stage following the infusion is important for preventing the onset of the severe toxicity common with HD-MTX therapy in the elder patients.