Biomedical subjects

M Nakashima

Publications and source records attributed to M Nakashima.

At least 325 records · Page 18Linked to original sources

PubMed1994

A prospective study for validation of Bayesian prediction approach to adjust individual lidocaine dosage.

A Bayesian approach, in which the estimates of the population pharmacokinetic parameters of lidocaine reported by Vozeh et al. [1984 a and b] and one measurement of serum lidocaine concentration as feedback information were utilized, was prospectively evaluated in 20 Japanese patients. The concentration of lidocaine in serum sampled from each patient at 1.5 to 3 hours after the commencement of i.v. lidocaine therapy was measured and the most likely pharmacokinetic parameters of that patient were predicted by the Bayesian program for microcomputer. Having the predicted parameters, we got the concentrations of lidocaine at 12 and 24 hours (C12 and C24) after starting the therapy within the recommended therapeutic range (2-5 micrograms/ml) by adjusting the individual dosage. As a result, the values of C12 and C24 remained within the therapeutic range in all patients and in all except one, respectively. The mean % prediction error (measured minus predicted concentration standardized by measured one) and its 95% confidence interval were 1.8% and -11.4 to 14.7% for C12, and -2.3% and -11.9 to 7.4% for C24, showing that the prediction of both C12 and C24 was not biased. The correlation coefficients between the measured and predicted concentrations were 0.574 for C12 and 0.721 for C24 (p < 0.01). From these findings, the present Bayesian method implemented with the estimates of pharmacokinetic parameters in a Swiss patient population is useful for sufficiently accurate and precise assessment of individual dosage requirement within a few hours after starting lidocaine therapy.

Acute Disease↗

PubMed1993

Clinical evaluation of low-molecular-weight heparin (FR-860) on disseminated intravascular coagulation (DIC)--a multicenter co-operative double-blind trial in comparison with heparin.

This study was evaluated the effectiveness, safety and utility of FR-860 and to compare those with heparin in patients with Disseminated intravascular coagulation (DIC). A diagnosis of DIC was made based on the criteria proposed by the Research Committee on DIC in the Ministry of Health and Welfare of Japan. FR-860 (FR group, 75 anti-factor Xa international units/kg/day) and Heparin (HP group, 240 units/kg/day) were administered for 5 days by continuous intravenous infusion. The total number of enrolled patients was 126 cases, and after excluding 1 case a total of 125 cases. Moderate or higher improvement of bleeding symptoms was 33.3% in the FR group and 18.5% in the HP group. On the organic symptoms, FR group showed a significantly higher improvement rate than the HP group, 20.5% and 8.2% respectively. On the overall efficacy of cases with pretreatment plasma AT III levels of less than 21 mg/dl or less than 70%. FR group showed a significantly higher improvement rate than the HP group. The safety rate of FR-860 (93.4%) was a significantly higher than that of the HP group (79.7%). Our report demonstrates that FR-860, as a therapeutic agent for the treatment of patients with DIC, is significantly higher safety and clinical utility as compared with heparin.

Adult↗

PubMed1993

Characterization of slow postsynaptic K+ current of Aplysia LUQ neurons in culture.

We have characterized the slow inhibitory synaptic connection between an left upper quadrant (LUQ) neuron and neuron L10, L12 or L13 in culture. A slow postsynaptic outward current in the LUQ neuron was elicited by repetitive firing of the co-cultured cholinergic neuron L10 as well as neuron L12 or L13 which were not cholinergic but FMRFamide synthesizing neurons. This outward current was due to an increase in K+ conductance and was relatively insensitive to external application of tetraethylammonium and 4-aminopyridine. We also investigated the effects of injection of a guanosine 5'-triphosphate (GTP) analogue into the LUQ neuron and extracellular application of serotonin and an adenosine 3',5'-cyclic monophosphate (cAMP) analogue on the current. In all the investigated properties, no significant difference was found among neuron L10, L12 and L13 as a presynaptic neuron. The slow postsynaptic current appeared to be virtually identical to the FMRFamide or acetylcholine (ACh)-induced K+ current reported in vivo, which resembled the 'S' current in Aplysia sensory neurons. We performed experiments to see the effect of phenyltrimethylammonium, an ACh antagonist, on the postsynaptic, ACh-, and FMRFamide-induced currents, clearly indicating that the neurotransmitter used in the cultured synapses was not ACh.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1993

Effect of a Ca2+ entry blocker, nilvadipine, on hearing disturbances and equilibrium dysfunction caused by microcirculatory disorders of the rat inner ear.

We evaluated the effects of Ca2+ entry blockers, nilvadipine and flunarizine, on microcirculatory disorders of the inner ear and on blood flow in the inner ear of rats. Under sodium pentobarbital anesthesia, the middle ear was opened by a ventrolateral approach. A green light (wave length 540 nm) was applied to the cochlea or the vestibule to induce a hearing disturbance or equilibrium dysfunction as a result of inner ear microcirculatory disorders, while rose bengal solution was infused intravenously. In a hearing disturbance model, a compound cochlear nerve action potential was recorded by electrocochleography every minute after the beginning of illumination. The sound stimulus was an 8 kHz sine wave 100 dB normal hearing level. The action potential was calculated 128 times. The action potential disappeared about 12 min after the beginning of illumination. In another model of equilibrium dysfunction, the photoillumination was applied for 40 min under the infusion of rose bengal. The behavior of rats was observed in the swimming test and nystagmus was recorded 24 h after the completion of photoillumination. In a separate experiment, blood flow in the inner ear was measured with a laser Doppler flowmeter under sodium pentobarbital anesthesia. In this study, both nilvadipine and flunarizine prolonged the time required for complete suppression of the action potential, prevented equilibrium dysfunction in the swimming test and reduced the occurrence of nystagmus. Flunarizine significantly increased inner ear blood flow and nilvadipine failed to decrease blood flow in the inner ear, despite a reduced systemic blood pressure. In conclusion, Ca2+ entry blockers may prevent microcirculatory disorders of the inner ear in rats.

Acoustic Stimulation↗

PubMed1993

Roles of platelet-activating factor, thromboxane A2, ADP and thrombin in thrombogenesis in the guinea pig.

The mediators of photochemically induced thrombosis in the femoral artery of guinea pig were investigated. The femoral artery was occluded by a thrombus about 7 min after the initiation of photochemical reaction between rose bengal and green light. Pretreatment with a specific thromboxane (TX) A2 receptor antagonist, vapiprost, a platelet-activating factor (PAF) antagonist, WEB-2086, and ADP-induced platelet aggregation inhibitor, ticlopidine, prolonged the time to occlusion. Within the range of doses used, platelet aggregation in whole blood, which was induced by U-46619, PAF and ADP ex vivo, was inhibited by vapiprost, WEB-2086 and ticlopidine, respectively. In contrast, argatroban, a thrombin inhibitor, had no effect on the time to occlusion, although the dose of argatroban was sufficient to delay the prothrombin time and the activated partial thromboplastin time and to inhibit thrombin-induced platelet aggregation ex vivo. These results suggest that TXA2, PAF and ADP are involved in photochemically induced thrombosis of the guinea pig femoral artery, although the coagulation cascade does not play an important role.

Adenosine Diphosphate↗

PubMed1993

Aldose reductase inhibitory and uricosuric activities of FK366 in healthy volunteers.

The pharmacokinetics, and aldose reductase (AR) inhibitory and uricosuric activities of FK366 were studied in healthy volunteers given a single oral dose of 150, 300, or 600 mg after fasting, 600 mg after a meal, or 300 mg twice a day for 8 days after meals. The AR inhibition was assessed by the percent reduction from the predrug dulcitol values in red blood cells converted from exogenous galactose by AR. Aldose reductase inhibition paralleled the plasma concentrations of FK366, with maximum inhibitions of 31.6, 48.0, and 56.9% at doses of 150, 300, and 600 mg, respectively. With multiple dosing, the inhibition scarcely differed between the first (41.8%) and last doses (41.5%). Serum uric acid decreased dose dependently, with a minimum concentration of 4.0 mg/dL (predrug: 5.5 mg/dL) 8 hours after receiving 600 mg. With multiple dosing, serum uric acid levels declined rapidly and remained at a concentration of 3.1 mg/dL beginning at day 3. Urinary excretion of uric acid was high on day 1 (879 mg/day), but decreased significantly to 654 mg/day on day 2 and then stabilized. The pharmacokinetics of FK366 were linear over the dose range studied, with an elimination half-life of 8.2 hours and urinary recovery of 27.2% as unchanged drug. FK366 was well tolerated by all subjects.

Adult↗

PubMed1993

Phase I study of DQ-2556, a new parenteral 3-quaternary ammonium cephalosporin antibiotic.

The safety and pharmacokinetic properties of DQ-2556, a new parenteral cephalosporin, were evaluated using healthy volunteers after 5-minute intravenous infusion of doses of 250, 500, 1000, or 2000 mg and a 1-hour infusion of 2000 mg, and an intramuscular dose of 500 mg. The half-lives of DQ-2556 ranged from 1.64 to 2.15 hours. The peak serum concentrations and area under the curve values were linearly correlated to the doses. The mean urinary recoveries were 80.0 to 85.5% of a dose within 24 hours. Salivary concentrations of the drug were low. There was no accumulation of DQ-2556 after 9 administrations every 12 hours. DQ-2556 was well tolerated.

Adult↗

PubMed1993

An animal model for hearing disturbance due to inner ear ischemia: photochemically induced thrombotic occlusion of the rat anterior inferior cerebellar artery.

A photochemical reaction between intravenous rose bengal and xenon light was used to induce a selective thrombus in the rat anterior inferior cerebellar artery (AICA). Compound action potentials (CAPs) were recorded by electrocochleography and cochlear blood flow (CBF) was monitored by laser Doppler flowmetry. Photothrombotic occlusion of the AICA caused inner ear ischemia to various degrees with or without alterations of the CAP. With use of this model we investigated the critical range of the CBF for preserving cochlear function, represented by the CAPs induced with 8 kHz half-wave of sinusoid at 100 dB SPL. Results then showed that a CBF range between 26.7% and 42.9% of baseline was somewhat critical for maintenance of cochlear function in an acute phase of ischemia. Pretreatment with heparin significantly delayed thrombotic occlusion of the AICA in a dose-dependent manner. Further use of our model for inner ear ischemia may be useful for studying pathophysiology and pharmacological therapy of cochlear disturbances subsequent to circulatory disorders.

Action Potentials↗

PubMed1993

Role of thromboxane A2 in a microcirculation disorder of the rat inner ear.

Since thromboxane (TX) A2 causes vasoconstriction and platelet aggregation, we evaluation the effect of a TXA2 receptor antagonist (vapiprost) and a TXA2 synthetase inhibitor (Y-20811) on a microcirculation disorder in the rat inner ear that was induced by a photochemical reaction between an intravenous injection of rose bengal (RB) and green light. A gradual decrease of the cochlear action potential (CAP) to an 8 kHz sound stimulus was measured with an electrocochleogram and occurred after the RB injection. The CAP then disappeared 5 min after the injection of RB. Both vapiprost and Y-20811 significantly prolonged the time required to complete suppression of the CAP as compared with saline as control. These findings indicate that TXA2 may play an important role in microcirculation disorders in the rat inner ear.

Action Potentials↗

PubMed1993

Information theoretic analysis of action potential trains. I. Analysis of correlation between two neurons.

A crosscorrelational method of action potential trains has been proposed, based on information theory. Two information theoretic quantities, mutual information and channel capacity, were calculated from a pair of action potential trains for detecting a crosscorrelation and estimating synaptic connectivity. The method was compared with conventional ones, using action potential trains obtained by the simulation of a neuron model. This method was shown to have the advantages to more easily find a weak but significant crosscorrelation and to give better estimation of synaptic connectivity independent of the firing probability of a presynaptic neuron.

Action Potentials↗

PubMed1993

Changes in plasma and urinary 11-dehydrothromboxane B2 in healthy subjects produced by oral CS-518, a novel thromboxane synthase inhibitor.

When 50 mg CS-518, a novel thromboxane (TX) A2 synthase inhibitor, was orally administered to healthy male volunteers, the plasma concentration of CS-518 peaked after 0.5 h and then decreased with a half-life of 0.44 h. There was no significant change in the plasma concentration of circulating TXB2, whereas that of circulating 11-dehydrothromboxane B2 (11-dhTXB2), an enzymatic metabolite of TXB2, was significantly decreased from 0.5 h to 24 h after administration; the maximal decrease to about 25% of the pre-dose value was found at 6 h. After CS-518 100 mg b.d. for 4.5 days, plasma 11-dhTXB2 was suppressed to the same extent as after the single dose of 50 mg from 6 h after the initial dose throughout the administration period. The urinary excretion of 11-dhTXB2 corrected for the creatinine level was significantly decreased by 70-84% throughout the treatment. These results suggest that CS-518 causes long-lasting inhibition of TXA2 synthase despite its rapid elimination from plasma, and that circulating 11-dhTXB2 in plasma and its urinary excretion can serve as a quantitative index of TXA2 synthase inhibition in vivo by CS-518.

Administration, Oral↗

PubMed1993

Chlorpromazine in human scalp hair as an index of dosage history: comparison with simultaneously measured haloperidol.

The concentration of chlorpromazine (CPZ) in hair was measured to demonstrate its value as an index of individual dosage history and compliance. An animal study using pigmented rats was conducted to confirm the dose-dependent accumulation of CPZ in hair. The concentration of CPZ in hair, newly regrown on a denuded area of the back after the administration of CPZ for 3 weeks, was 4.6, 8.5 and 16.6 ng.mg-1 hair after daily doses of 1.25, 2.5 and 5 mg.kg-1.day-1, respectively, significantly correlated with the daily dose. The concentration of CPZ in black hairs collected from 23 Japanese patients, who had been taking CPZ in fixed daily doses (30-300 mg/day), ranged from 1.6 to 27.5 ng.mg-1, and was significantly correlated both with the daily dose and with the trough plasma concentration at steady state. Several strands of hair collected from each of 5 patients, whose doses of CPZ had been changed within several months before sampling, were cut into 1-cm pieces successively from the scalp end and the concentration of CPZ in each piece was measured. With the assumption of a hair growth rate of 1 cm per month, the individual history of CPZ doses in all patients could be deduced from the distribution of CPZ along the hair shaft. In 5 patients with grizzled hair the concentration of CPZ in white hairs was much lower (< 10%) than in black hairs, suggesting that the strong affinity of CPZ for hair melanin may explain the accumulation of CPZ in black hair.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1993

The pharmacokinetics of the beta 2-adrenoceptor agonist, tulobuterol, given transdermally and by inhalation.

We have studied the pharmacokinetics of tulobuterol given transdermally or by aerosol inhalation in healthy male volunteers. Tulobuterol was rapidly absorbed after inhalation, with a tmax of 0.8-1.5 h. The Cmax and the AUC increased linearly with dose. Tulobuterol was well absorbed after transdermal administration, with an absorption lag-time of about 4 h. The Cmax and AUC increased linearly with dose and the tmax was about 9-12 h. The mean percentage of drug absorbed during the application of a patch for 24 h was 82-90% after a single dose and 82-85% during repeated dosing. The mean urinary recoveries as unchanged drug after a single inhalation and patch application were 3-4% and 5-6% respectively. Tulobuterol did not accumulate during repeated inhalation or transdermal application. It was well tolerated, except for an increase in heart rate of 10-20 beats.min-1 after five repeated applications of a 4 mg patch.

Administration, Cutaneous↗

PubMed1993

A simple and reproducible cerebral thrombosis model in rats induced by a photochemical reaction and the effect of a plasminogen-plasminogen activator chimera in this model.

In this study a new model of cerebral ischemia, based on a middle cerebral artery (MCA) thrombosis in rats is described. Furthermore, the effect of the novel plasminogen activator (SUN9216), a plasminogen-plasminogen activator chimera, comprising the fibrin kringle 1 domain of a plasminogen, and the two kringles, and the serine protease domains of wild-type tissue plasminogen activator (t-PA), including a modification of the mannose glycosylation site on the kringle 1 of t-PA (PK1de1FE1X), was studied in this model. In the newly described model of thrombotic cerebral ischemia, an occlusive thrombus occurred usually within 8 min in the MCA as a consequence of an endothelial injury subsequent to a photochemical reaction between a systemically administered photosensitive dye (rose bengal) and a transillumination of the MCA with a high-intensity green light with a wavelength of 540 nm. The study was quantitated by means of pathological examination of the MCA and the brain. A platelet-rich thrombus was observed in the MCA using electron microscopical analysis based on ion beam bombardment. At 24 hr after induction of the thrombus, the brain was removed from 13 control animals, nine coronal sections were stained from each brain with triphenyltetrazoliumchloride (TTC), and the ischemic area was quantitated. A constant area of infarction was observed in the cortex and the lateral part of the basal ganglia. In a second group (n = 8), at 1 or 8 weeks after induction of the thrombosis in the MCA, the coronal sections were stained with hematoxylin and eosin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Endothelins and membrane potential of vascular smooth muscle of the canine coronary artery.

We investigated the effects of endothelins on the membrane potential of vascular smooth-muscle cells of canine coronary artery, using glass microelectrodes. In tissues with endothelium, endothelin-1 (ET-1), from 10(-12) to 10(-9) M, did not alter the membrane potential. Higher concentrations of the peptide produced sustained depolarization without detectable hyperpolarization. Endothelin-3 (ET-3, 10(-11) to 10(-8) M) did not produce significant membrane hyperpolarization in tissues with endothelium. Prostaglandin F2 alpha (10(-5) M) depolarized the cell membrane by about 6 mV. ET-1 (10(-9) M) did not evoke detectable hyperpolarization in the presence of prostaglandin F2 alpha. In tissues incubated with BQ123 (10(-6) M, a selective ETA-receptor antagonist), which attenuated the depolarization evoked by ET-1, both isopeptides did not produce detectable hyperpolarization. These findings suggest that ET-1 and ET-3 do not evoke the release of endothelium-derived hyperpolarizing factor in the canine coronary artery.

Animals↗

PubMed1993

Age-dependent decrease in endothelium-dependent hyperpolarizations to endothelin-3 in the rat mesenteric artery.

The present study was designed to investigate the effects of age on the endothelium-dependent hyperpolarizing effect of endothelin-3 (ET-3) in the mesenteric artery of the rat. Main superior mesenteric arteries, with endothelium of young (7-9 weeks), adult (20-24 weeks), and old (40-50 weeks) male Wistar-Kyoto rats were studied. The cell membrane potential of the vascular smooth-muscle cells was measured with glass microelectrodes in the presence of indomethacin (inhibitor of cyclooxygenase) and NG-nitro-L-arginine (NLA, inhibitor of nitric oxide synthase). In preparations with endothelium from young rats, ET-3 produced transient hyperpolarizations in a concentration-dependent (10(-8) to 10(-9) M) manner. In tissues from adult rats, only a small hyperpolarization to the peptide was observed at 10(-7) M, whereas no detectable membrane potential changes were observed in tissues from old animals. In tissues of all groups, acetylcholine produced concentration-dependent hyperpolarizations, the maximal amplitude of hyperpolarization was reduced in the old rats but no significant differences were observed in the threshold concentration for hyperpolarization to acetylcholine. These data suggest that aging decreases endothelium-dependent hyperpolarizations evoked by both ET-3 and acetylcholine.

Acetylcholine↗

PubMed1993

Analysis of nicotine content of hair for assessing individual cigarette-smoking behavior.

The concentration of nicotine in hair was measured by a capillary gas chromatograph with a nitrogen-phosphorus detector after hair was dissolved in 2.5 N sodium hydroxide and nicotine was extracted using diethyl ether. In hair samples obtained from 36 smokers, who had smoked > or = 3 years, there was a significant positive correlation between the concentration of nicotine and the number of cigarettes consumed daily (r = 0.685; p < 0.001). The nicotine content of white hair was much less than that of black hair collected from the same subjects with grizzled hair. The above findings were confirmed by an animal experiment, in which nicotine (0.2, 0.6, and 2 mg/kg/day for 2 weeks) was administered intraperitoneally to pigmented rats whose hair had been removed beforehand by plucking from an area of the back of each rat. The hair which grew back in the denuded area was plucked and collected one week after the last administration of nicotine. The nicotine concentration in the brown hair of the back correlated with the given dose (r = 0.824; p < 0.001). In a separate experiment, hairs were removed from areas of back and thorax, and nicotine delivered to the rats for 4 weeks by an osmotic pump implanted under the skin, showing that the concentration in the whitish hair was much lower than that in brown hair. Finally, hair samples were collected from 14 subjects who had participated in a smoking cessation program over 6 months and who abstained from cigarette smoking. The axial distribution of nicotine along the hair shafts was determined for each subject.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

The measurement of a new antimicrobial quinolone in hair as an index of drug exposure.

1. Scalp hair samples were obtained at 1 month intervals up to 5 months from healthy male volunteers participating in a phase I study of a new antimicrobial quinolone, OPC-17116. 2. Hair was sectioned into 1 cm lengths from the scalp end. Corresponding portions from five pieces of hair were dissolved in 1 N NaOH and assayed for OPC-17116 by h.p.l.c. 3. In all subjects taking a single dose (400 mg, n = 5) or repeated doses (400 mg day-1, twice daily, for 6.5 days, n = 6), the drug was detected in the portions of hair corresponding to the administration period, assuming a hair growth rate of 1 cm/month. 4. OPC-17116 (300 mg day-1, three times daily, for 2 days) was given to four healthy male volunteers, from whom hair samples were obtained at 1 month and 3 months. The drug was detected in 1 to 4 consecutive 2.5-mm long portions of a single hair and there was no significant axial diffusion of the agent along the hair shaft with time. 5. These findings indicate the utility of measuring this quinolone derivative in hair as an index of exposure, and as a time-marker for the hair analysis of other drugs.

Adult↗