Katsushi Furuno

Chronic nicotine treatment potentiates behavioral responses to dopaminergic drugs in rats

In the present study, the behavioral effects of apomorphine, methamphetamine, and haloperidol were examined in nicotine-treated rats. All animals were SC administered nicotine at a dose of 0.5 mg/kg or saline once daily for 14 days. Hyperlocomotion induced by apomorphine (0.2 mg/kg, IP) and methamphetamine (1.0 mg/kg, IP) was greater in nicotine-treated rats than in control rats. Stereotyped behaviors induced by apomorphine (1.0 mg/kg, IP) and methamphetamine (5.0 mg/kg, IP) were also potentiated in nicotine-treated rats. However, the incidence of catalepsy induced by haloperidol (0.25-1.5 mg/kg, IP) was slightly lower in nicotine-treated rats. These results suggest that chronic nicotine treatment may increase the susceptibility of the dopaminergic system to dopaminergic drugs.

Simple and rapid analysis of lamotrigine, a novel antiepileptic, in human serum by high-performance liquid chromatography using a solid-phase extraction technique

A simple and rapid method for the quantitation of concentrations of lamotrigine, a novel antiepileptic, in human serum was developed with high-performance liquid chromatography, using a solid-phase extraction technique. The mobile phase was composed of acetonitrile-10 mM phosphate buffer (pH 3.5) containing 5 mM sodium octanesulphonate (27:73, v/v), and components were detected at 265 nm. Retention times of acetanilide as an internal standard and lamotrigine were 3.4 and 10.3 min, respectively. The coefficients of variation were 3.1-4.5% and 4.4-9.8% for the within-day and between-day precision estimates, respectively. The extraction recovery of lamotrigine added to blank serum was 86-107%. The quantitation limit of lamotrigine was ca. 0.2 microgram/ml in 100 microliters of serum. These results suggest that the method employed in this study is useful for the routine monitoring of serum concentrations of lamotrigine in epileptic patients.

New cocaine-selective membrane electrode

Abstract The sensitivity and selectivity of a cocaine-selective membrane electrode have been improved with the use of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate as an ion-exchanger and tetrakis(2-ethylhexyl) pyromellitate (TEHPY) as a solvent mediator. The use of TEHPY suppressed the responses to lipophilic quaternary ammonium ions and strengthened the response to cocaine. The electrode exhibited a near-Nernstian response over a concentration range of 10 −2 to 10 −6 M cocaine with a slope of 56 mV per decade. The lower limit of detection was 4 × 10 −7 M cocaine. Interference by other drugs (morphine and codeine) and a stimulant (methamphetamine) was negligible. This electrode was applied for the determination of cocaine in a drug mixture containing cocaine and morphine, which is widely used to suppress acute pain in cancer patients. The concentration of cocaine, different in each patient, was measured precisely with an average recovery of 99.9% and a mean relative standard deviation of 0.56%.

Simple and sensitive assay of zonisamide in human serum by high-performance liquid chromatography using a solid-phase extraction technique

A rapid and sensitive method for the assay of zonisamide in serum was developed using a solid-phase extraction technique followed by high-performance liquid chromatography. A 20-microliter volume of human serum was first purified with a Bond-Elut cartridge column. Then, the methanol eluate was injected onto a reversed-phase HPLC column with a UV detector. The mobile phase was acetonitrile-methanol-distilled water (17:20:63, v/v) and the detection wavelength was 246 nm. The detection limit was 0.1 micrograms/ml in serum. The coefficients of variation were 4.2-5.6% and 5.1-9.1% for the within-day and between-day assays, respectively. This method can be used for clinical pharmacokinetic studies of zonisamide in serum even in infant patients with epilepsy.

Nicotine-induced tail-tremor and drug effects

Tail-tremor induced by repeated and daily administration (0.5 mg/kg SC x 6 times/day) of nicotine as well as effects of various drugs on this response were investigated in Wistar strain male rats. Daily administration of nicotine in doses of 0.5 mg/kg SC caused tail-tremors to appear beginning on the 3rd day. Tail-tremor induced by the first injection of each day gradually increased with the daily injections, however, the heightened effect of this first injection at the beginning of each day decreased during the day upon repeated administration of 6 times/day at 2-hr intervals. Basically, tail-tremor appeared about 5 min after SC administration of nicotine and reached a peak approximately 7-9 min after injection, declining to zero afterwards. Different drugs showed various effects on this response. While mecamylamine (0.5 and 1.0 mg/kg IP) abolished nicotine-induced tail-tremor, arecoline (0.5 and 1.0 mg/kg IP), atropine (2.5 and 5.0 mg/kg IP), scopolamine (1.0 and 2.0 mg/kg IP) and hexamethonium (0.5 and 1.0 mg/kg IP) showed no such effects. Furthermore, physostigmine (0.1 mg/kg IP) actually potentiated this action. These results suggest that tail-tremor induced by nicotine may be mediated through central nicotine receptor system.

Tail-tremor induced by exposure to cigarette smoke in rats.

Tremors appearing only in the tail (tail-tremor) induced by cigarette smoke and subcutaneous nicotine were investigated using a smoking machine and Wistar rats. Daily exposure (twice a day) to smokes of two commercial cigarettes (Mild-Seven Select for the first 7 days and Long-Peace for the next 6 days) caused the tail-tremor to appear even if it was slight. A single subcutaneous nicotine (0.5 mg/kg) administration to rats exposed to the cigarette smokes for 13 days markedly caused the tail-tremor. On the other hand, daily subcutaneous injection of nicotine (0.5 mg/kg/day) also caused the tail-tremor to appear beginning on the 4th day and the incidence of tremor increased to 100% by the 12th day. These results indicate that tail-tremor can be caused not only by daily subcutaneous administration of nicotine but also by daily exposure to cigarette smoke.

Effects of various antiepileptic drugs on plasma levels of lamotrigine, a novel antiepileptic, in rats.

The pharmacokinetics of lamotrigine (LTG) and effects of carbamazepine (CBZ), valproic acid (VPA) and zonisamide (ZNS) on LTG kinetics were investigated in rats. LTG plasma levels were measured by high-performance liquid chromatography (HPLC). A single oral administration of LTG at 2.5-10 mg/kg showed linear disposition kinetics. In the pharmacokinetic parameters of LTG when combined with CBZ, the maximal plasma concentration (Cmax) and the area under the plasma concentration curve (AUC0-36) values were significantly lower and the time to maximal plasma concentration (Tmax) value was significantly higher than those in LTG alone. Furthermore, the Cmax and AUC0-36 values of LTG when pretreated with CBZ for 7 days were significantly lower than those from simultaneous treatment with CBZ. The Cmax and AUC0-36 values of LTG when combined with VPA were significantly lower than those for LTG alone. There was no significant difference in the Tmax or time of elimination half-life (t1/2) values of LTG between simultaneous and pretreatment with VPA. Of the pharmacokinetic parameters of LTG with ZNS combination, the Cmax value of LTG after long-term dosings of ZNS decreased significantly, whereas no significant change in Cmax was observed after the combined single administration of LTG and ZNS. Single and chronic ZNS treatment did not significantly affect the Tmax, t1/2 and AUC0-36 values of LTG. The LTG trough level was significantly reduced by CBZ administration, reached the bottom level at 6 days after starting CBZ administration, and recovered gradually after withdrawal of CBZ. These results suggest that CBZ, VPA and ZNS causes changes in the plasma LTG level. They also suggest that in therapy combining LTG with one of these antiepileptics, especially CBZ, the LTG concentration in plasma should be monitored carefully.

Ion-selective electrode for procainamide determination in blood serum

Abstract A procainamide-selective electrode was constructed and applied for the determination of procainamide concentration in blood serum. The detection limit was 1.5 μg ml−1, but determination down to 0.5 μg ml−1 was possible with an appropriate calibration. The results correlated well with those obtained by a fluorescence polarization immunoassay which is widely used for the determination of serum procainamide concentration. The present method is simple, rapid, economical and is unaffected by common cations present in blood and only slightly by N-acetylprocainamide, a metabolite of the drug. It is therefore useful for therapeutic drug monitoring in a clinical setting.

Effect of Cigarette Smoking on Theophylline Pharmacokinetics in Rats

Abstract— The effect of acute cigarette smoke inhalation on the plasma levels of theophylline administered orally and parenterally to rats has been studied. The animals were exposed to smoke containing low‐ or high‐nicotine/tar concentration for 10 min immediately after oral, intraperitoneal (i.p.) or intravenous (i.v.) administration of theophylline. The plasma levels of theophylline when administered orally (20 mg kg−1) were lower in the two cigarette smoke‐inhaling groups than in the non‐smoking restrained control group, with the lowest values in the high‐nicotine/tar group. The plasma levels (8 and 12 h after administration) in the high‐nicotine/tar group when theophylline was administered i.p. (10 mg kg−1), were also slightly lower than in the non‐smoking restrained control group but this was not significant. When theophylline was administered i.v. (5 mg kg−1), there was no difference between the high‐nicotine/tar group and the nonsmoking restrained control group. These data indicate that cigarette smoke inhalation causes suppression or delay of theophylline absorption from the gastrointestinal tract.

Phenobarbital in Sera of Epileptic Mothers and Their Infants.

The phenobarbital (PB) transition from epiletpic mothers to their breast milks and offspring in cases of PB monopharmacy with other antiepileptic drugs was investigated in 26 epileptic mothers and 24 offspring who were taking the breast milk from epileptic mothers. The mothers serum PB concentration in monopharmacy was almost the same in various stages (stage I, with 5 days after the delivery; stage II, 6–10 days after; stage III, 1–2 months after; stage IV, 3–5 months after). However, the PB concentrations in polypharmacy were markedly higher than those in monopharmacy. Concerning the PB concentration in breast milk, a significant increase was found in polypharmcy in comparison with monopharmacy only in stage I. On the other hand, the offsprings PB concentration in polypharmacy was markedly higher than that in monopharmacy, particulary in stage I. In another stages, PB concentration in monopharmacy gradually decreased according to the increase of stages. These results indicate that pharmacokinetics of antiepileptic drugs in the perinatal may be considerably different in PB monopharmacy and polypharmacy.