Biomedical subjects

H Tanii

Publications and source records attributed to H Tanii.

At least 37 records · Page 2Linked to original sources

PubMed1998

Clinical pharmacology of UCN-01: initial observations and comparison to preclinical models.

UCN-01 (7-hydroxystaurosporine; NSC 638850) is a protein kinase antagonist selected for clinical trial based in part on evidence of efficacy in a preclinical renal carcinoma xenograft model. Schedule studies and in vitro studies suggested that a 72-h continuous infusion would be appropriate. In rats and dogs, maximum tolerated doses produced peak plasma concentrations of approximately 0.2-0.3 microM. However, concentrations 10-fold greater are well tolerated in humans, and the compound has a markedly prolonged T1/2. Specific binding to human alpha1-acidic glycoprotein has been demonstrated. These findings reinforce the need to consider actual clinical pharmacology data in "real time" with phase I studies.

Adult↗

PubMed1997

Relationship of anesthetic activity of alkyl acetates to hydrophobicity and in vivo effect on membrane fluidity in mice.

In vivo anesthetic activity of alkyl acetates in mice was studied in relation to hydrophobicity and the in vivo effect on membrane fluidity. The anesthetic potency (AD50) of alkyl acetates was determined; AD50 shows the i.p. dose required to anesthetize 50% of mice from the treated group. We used log P (n-octanol/water partition coefficient) as an operational definition of hydrophobicity. Membrane fluidity was determined using 1,6-diphenyl-1,3,5-hexatriene (DPH) as fluorescence probe. Log (1/AD50) was a parabolic function of log P, and the value of log P that corresponds to the minimum AD50 was estimated to be 2.08. Brain synaptosomal membranes were prepared from mice 30 min after dosing with each of the three alkyl acetates applied at 1.5-fold AD50: n-butyl, n-amyl, and n-hexyl acetate. In each alkyl acetate group, most of the animals were anesthetized (> 68%). Decreased membrane fluidity was observed for the animals that were anesthetized while no change in the fluidity was seen for the animals that were not anesthetized. The results suggest an involvement of decreased DPH fluidity in alkyl acetate-induced anesthesia.

Acetates↗

PubMed1997

Dantrolene sodium reverses the increase in cAMP response element and TPA responsive element DNA-binding activity in the rabbit brain following haloperidol administration and heat stress.

Using electrophoretic mobility-shift assay (EMSA), we examined DNA-binding activity of cAMP response element (CRE), onto its responsive element CRE, as well as TPA responsive element (TRE) in the medial hypothalamus and striatum of the experimental rabbits administered with haloperidol under heat stress exposure and studied the effects of dantrolene sodium to the transcriptional factor. In EMSA with nuclear extracts from the rabbit brain, the DNA-binding activities of CRE and TRE in medial hypothalamus and striatum increased following haloperidol and heat stress. These increases were maintained by coadministration with atropine. The treatment with dantrolene sodium markedly reversed such increases. The alterations of activities of these transcriptional factors may reflect the therapeutic effect of dantrolene sodium.

Animals↗

PubMed1997

Classification system of complications in neuroleptic malignant syndrome.

Our group treated 13 cases of neuroleptic malignant syndrome (NMS) over a period of 8 years. Based on the clinical severity of complications, the cases were classified into three types: mild, with no complications; moderate, with only respiratory disturbance; and severe, with respiratory disturbance and renal failure. The major complications affecting the prognosis of NMS are respiratory disturbance and renal failure. Renal failure is also associated with the occurrence of disseminated intravascular coagulation and rhabdomyolysis. The proposed classification system for NMS patients is useful in selecting the appropriate therapeutic strategy for this disorder. The clinical data were analyzed to determine the factors in the process of deterioration in NMS.

Adolescent↗

PubMed1996

Development of an animal model for neuroleptic malignant syndrome: heat-exposed rabbits with haloperidol and atropine administration exhibit increased muscle activity, hyperthermia, and high serum creatine phosphokinase level.

The neuroleptic malignant syndrome (NMS) is a life-threatening complication of neuroleptic treatment. To elucidate the pathogenesis of NMS, an animal model has been developed. Experimental rabbits treated with haloperidol (1 mg/kg) by intramuscular injection, were studied for the diagnostic symptoms of increased muscle rigidity, elevated body temperature, and high serum creatine phosphokinase (CPK) level. Administration of haloperiodol (1 mg/kg) and atropine (0.4 mg/kg), and exposure to high ambient temperature (35 degrees C) induced a significant increase in electromyographic activity with muscle rigidity similar to that observed in patients with NMS. Such rabbits also showed elevated body temperature and serum CPK value. In addition to the similarity of the signs and symptoms, all parameters measured (muscle rigidity, body temperature, and serum CPK level) were normalized by dantrolene treatment. The effectiveness of dantrolene in the experimental animal partially confirms the validity of this animal model for NMS. This experimental animal model for NMS may be useful to elucidate the pathogenesis of NMS.

Animals↗

PubMed1996

Anesthetic activity of monoketones in mice: relationship to hydrophobicity and in vivo effects on Na+/K+ -ATPase activity and membrane fluidity.

The in vivo anesthetic activity of monoketones in mice was examined in relation to their hydrophobicity and to the in vivo effects on Na+/K+ -adenosine triphosphatase (Na+/K+ -ATPase) activity and membrane fluidity. Anesthetic potency (AD50) of monoketones was determined; AD50 implys the dose required to anesthetize 50% of the animals from the treated group. The n-octanol/water partition coefficient (P) was used as an index of hydrophobicity. Membrane fluidity was determined by using 1,6-diphenyl-1,3,5-hexatriene (DPH) or 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH as fluorescence probes. Log (1/AD50) was the parabolic function of log P, log ((1/AD50) = -0.167(log P)2 + 0.698 log P - 1.365, and the log P that corresponds to the minimum AD50 was estimated to be 2.09. Brain synaptosomes were prepared from mice that were considered anesthetized with each of the 4 monoketones (1.5-fold AD50), methyl n-propyl, methyl n-amyl, methyl 3-methylhexyl and methyl n-octyl ketone. The Na+/K+ -ATPase activity was inhibited by methyl n-propyl ketone alone, membrane DPH fluidity was decreased by each of the 4 monoketones, and membrane TMA-DPH fluidity was decreased by methyl n-propylketone alone. These results suggest an involvement of the decreased DPH fluidity in monoketone-induced anesthesia.

Anesthetics↗

PubMed1995

In vitro influences of alcohols on mouse synaptosomes, and structure-activity relationships.

Little information is available on the structure-central nervous system membrane toxicity relationship of alcohols. The purpose of the present study was to study in vitro influence of alcohols (n = 20) on the activity of the toxic indicator Na+/K(+)-adenosine triphosphatase (Na+/K(+)-ATPase) and acetylcholinesterase (AchE), and membrane fluidity in mouse brain synaptosomes, in terms of the structure-activity relationship. The potency of inhibition for the enzymes (IC50) and the potency of increasing membrane fluidity (IC12.5) were determined experimentally, and n-octanol/water partition coefficient (P) and the steric constant Taft Es are cited from the literature. Regression analysis revealed that log 1/IC50 for Na+/K(+)-ATPase is a function of log P and Taft Es. The situation was true for AchE activity. The results indicate that the hydrophobicity expressed as log P and the steric effect of the alcohols play an important role in inhibiting both enzyme activities. A linear relationship between log 1/IC12.5 for membrane fluidity and log P is shown, indicating a significant effect of the alcohols on membrane fluidity. Based on these results, it is suggested that the alcohols inhibit the Na+/K(+)-ATPase and AchE activity through a direct action on the enzymes and/or through changing the membrane fluidity.

Acetylcholinesterase↗

PubMed1995

Structure-acute toxicity relationship of aromatic hydrocarbons in mice.

The structure-acute toxicity relationship of aromatic hydrocarbons was examined in mice. In all test compounds, the acute toxicity was determined under 2 conditions: control LD50 (LD50-cont) and carbon tetrachloride (CCl4)-pretreated LD50 (LD50-CCl4). The CCl4-pretreatment was done in order to evaluate the toxic potency of compound itself without the influence of metabolism. Both log (1/LD50-cont) and log (1/LD50-CCl4) were functions of the log P, n-octanol/water partition coefficient, i.e., log (1/LD50-cont) = 0.080 log P - 1.532 and log (1/LD50-CCl4) = -0.040(logP)2 + 0.157 log P - 1.373. Both equations were statistically significant (P < 0.01). The ratio of LD50-cont/LD50-CCl4 indicated that metabolic activation is more evident in hydrophobic compounds than in hydrophilic compounds. The results suggest that hydrophobicity of the aromatic hydrocarbons plays an important role in determining their acute toxicity.

Animals↗

PubMed1994

[The role of biochemical markers in peripheral body fluids in assessment of human neurotoxicity].

To date the evaluation of chemically-induced neurotoxic effects on humans has been dependent mostly on electrophysiological measurements, neurobehavioral tests and biological exposure assessment. However, recently attempts have been made to develop biochemical parameters in peripheral body fluids which can be easily obtained from humans and which can represent markers for the same parameters in nervous tissue. The approach of this kind is logically based on the following facts: 1) Blood cells (e.g., platelets and lymphocytes) possess some characteristics of monoaminergic neurons such as the existence of storage vesicles of monoamines, membrane neurotransmitter receptors, high affinity uptake sites and neurotransmitter-related metabolizing enzymes. 2) Leakage of nerve-specific markers from nervous tissue to peripheral body fluids may occur following damages of target neuronal cells or macromolecules. 3) Quantitative and/or qualitative alterations of peripheral biochemical markers (e.g. neurotransmitter receptors) can be induced by the regulation mechanisms of neuronal, endocrinal and immunologic interactions when the nervous functions are perturbed by various exogenous or endogenous factors. Erythrocyte acetyl cholinesterase (AChE), free erythrocyte protoporphyrin (FEP), lymphocyte neurotoxicity target enzyme (NTE), blood aminolevulinic acid dehydratase (ALA-D), and carboxyhemoglobin (CO-Hb) are well-known peripheral markers of the effects induced by organophosphates (AChE, NTE), lead (FEP, ALA-D) and carbon monoxide (CO-Hb). Many studies have been made on the effects of organic solvents, heavy metals and pesticides on neurotransmission parameters in blood cells such as neurotransmitter uptake, receptor binding and enzyme activity. This paper summarizes the present knowledge on the development and clinical applications of some peripheral biochemical markers such as neurotransmission parameters in blood cells and neuronal or glial cell marker proteins in CSF, blood and urine. The role of these peripheral biochemical markers in the assessment of environmental chemically-induced human neurotoxicity is also discussed.

Biomarkers↗

PubMed1994

[Structure-activity relationships of organic solvents and related chemicals].

The number of chemicals used in industry is increasing, and as a consequence workers in chemical industries are thought to have many opportunities for being exposed to chemicals. For organic solvents, although a number of studies have shown the toxicity of individual chemicals, there are a relatively small number of studies that have described their toxicity in terms of a quantitative structure-activity relationship (QSAR). In the present article I first introduced an outline of the method of QSAR (Hansch's method), and then reviewed the literature on QSAR of industrial chemicals, principally organic solvents and related chemicals as follows: 1) A review was made of the studies of general toxicity of chlorophenols, alcohols, amines, anilines, phenols, ethers, alkanes, ketones, acrylates, methacrylates and nitriles. In almost all cases, the general toxicity is related to log P, in which P is n-octanol/water partition coefficient, indicating the importance of the hydrophobicity of chemicals for their toxicities. 2) The QSARs of anesthetic organic solvents were reviewed. The chemicals analysed were ethers, alkanes, ketones, miscellaneous chemicals and anesthetic gases. It is shown that the relative anesthetic potency of anesthetic gases depends not only on the hydrophobicity expressed by log P but on a polar factor, while the potency of other chemicals depends largely on log P. 3) The relationship of the structure of organic solvents to skin penetration or absorption was reviewed. QSARs reveal that the potency of skin penetration or absorption of solvents is a function of water solubility, log P or hydrogen bond number, each relating to hydrophobicity. 4) Some organic solvents have an effect on the upper respiratory tract. The established QSAR models considerably resemble corresponding equations for gas/liquid partition coefficients into organic bases such as tricresylphosphate. 5) The ecotoxicity of chemicals including solvents was reviewed. Overall, the relative toxic potency of chemicals is related linearly to log P, indicating the importance of hydrophobicity in determining the toxicity of chemicals. 6) Although no QSAR has modeled the mutagenic activity of organic solvents, a few studies show the relationship between the structure and mutagenicity of haloalkenes. Finally, if QSAR could model the toxicity of a series of chemicals, it would serve our purpose of understanding the mechanism of toxicity and of predicting the toxic potency of chemicals in the same series tested.

Solvents↗

PubMed1993

Involvement of noradrenergic and 5-hydroxytryptaminergic systems in allylnitrile-induced head twitching.

Allylnitrile induces in rats persistent behavioral abnormalities, including head twitching, following a single administration. We studied the role of 5-hydroxytryptamine (5-HT) and noradrenaline (NA) systems in the brain of rats in inducing and maintaining the head twitching. Allynitrile (1.49 mmol/kg) induced 5-HT system activation in all areas of the brain studied 1-4 days after oral administration, and a reduction in the content of NA in the hippocampus, cortex and hypothalamus 1 day after dosing, in the hippocampus, cortex, hypothalamus and midbrain 2 days after dosing, and in the hypothalamus 4 days after dosing. Allylnitrile induced no change in the content of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) or NA 7-28 days after dosing. Pretreatment with 5,7-dihydroxytryptamine (5,7-DHT) suppressed the allylnitrile-induced head twitching, and decreased the contents of 5-HT and 5-HIAA in almost all areas of the brain throughout the observation period, as well as the ratio of 5-HIAA/5-HT in the medulla oblongata plus pons from 1 to 30 days after dosing with allylnitrile. No change in NA was observed in any areas of the brain. Pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) increased the head twitching induced by allylnitrile, and decreased the content of NA in all areas of the brain throughout the observation period, without any change in the contents of 5-HT or 5-HIAA or in the ratio of 5-HIAA/5-HT. The present results suggest the involvement of 5-HT and NA systems in allylnitrile-induced head twitching.

5,7-Dihydroxytryptamine↗

PubMed1993

Effect of carbon tetrachloride on allylnitrile-induced head twitching.

Allylnitrile is known to induce head twitching in rats and mice. Carbon tetrachloride (CCl4) impairs the hepatic mixed function oxidase system and lowers acute toxicity of nitriles. In the present study we examined the effect of CCl4 on the allylnitrile-induced head twitching to elucidate the mechanism of the abnormal behavior. In rats, CCl4 pretreatment inhibited the head twitching induced by allylnitrile (1.49 mmole/kg, po), the maximal and dose-dependent inhibition occurring when CCl4 was given just prior to the nitrile administration, while CCl4 post-treatment had no effect on the head twitching. A dose-dependent inhibition of cyanide formation arising from allylnitrile in the liver and a dose-dependent attenuation of acute toxicity of allylnitrile were observed when CCl4 was given just prior to the nitrile administration in rats and mice. Intracerebroventricular injection of allylnitrile (2.0 to 18 mumole/brain) induced no head twitching in rats. The results suggest that active metabolites of allylnitrile are responsible for the head twitching, and that CCl4 prevents the metabolic process in the liver by forming conjugates with allylnitrile, resulting in the inhibition of the head twitching.

Animals↗

PubMed1993

Neuron and glial cell marker proteins as indicators of heavy metal-induced neurotoxicity in neuroblastoma and glioma cell lines.

The sensitive and specific biochemical indicators for assessing chemical-induced neurotoxic insults in cell culture models have not been sufficiently explored. This study was designed to assess the usefulness of glia-specific beta-S100 protein and neuron-specific enolase (NSE) as indices of in vitro neurotoxicity of heavy metals. Glioma C6 and neuroblastoma N18TG-2 cells were grown in Dulbecco's modified Eagle's medium containing various concentrations of mercuric chloride (HgCl2) or cadmium chloride (CdCl2) for 5 days. Toxic response patterns of the neurospecific endpoints (beta-S100 and NSE), which were monitored with enzyme immunoassays, were compared with those of the non-neurospecific endpoints such as cell viability, total cellular protein, lactate dehydrogenase (LDH) activity, and cumulative glucose consumption in the two cell lines. Both HgCl2 and CdCl2 produced dose-dependent inhibition of neurospecific endpoints and non-specific endpoints. However, by ranking the EC50 values (effective concentration producing half-maximal inhibition) for various endpoints, the lowest values were found for beta-S100 in C6 cells, and for NSE in N18TG-2 cells. In lower and intermediate concentrations, the inhibitory effects of the heavy metals on the content of beta-S100 and NSE occurred in the absence of any detectable effect on intracellular LDH activity, and independently of total cellular protein inhibition. The sensitive and excess responses of the neurospecific endpoints relative to that of the non-specific endpoints may reflect the specific neurotoxic insults of the heavy metals on the cultured cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Structure-toxicity relationship of ethylene glycol ethers.

The ultimate purpose of the present study was to evaluate correlations between acute in vivo and in vitro toxicity and log P (P is n-octanol-water partition coefficient). The in vitro toxicity to cloned cells (neuroblastoma N18TG-2 and glioma C6) in culture (ED50) and the in vivo toxicity to mice (LD50) of ethylene glycol ethers were studied in terms of the structure-activity relationship. The test ethers showed a wide range of ED50 values in both cells. LD50 was determined under two conditions: LD50-cont. was estimated in mice pretreated with olive oil and LD50-CCl4 in CCl4-pretreated mice. Multiple regression analyses revealed a significant correlation between log 1/LD50 and log P as follows: log (1/LD50-cont.) = -0.120 (log P)2+0.487log P-1.182, and log (1/LD50-CCl4) = -0.128 (log P)2+0.566log P-1.157. There was no significant correlation either between ED50 and LD50 or between ED50 for N18TG-2 and ED50 for C6. The results suggest that metabolic activation might not occur during acute toxicity from the ethers, and that hydrophobicity, expressed as log P, plays an important role in acute toxicity.

Animals↗

PubMed1991

Behavioral syndrome induced by allylnitrile, crotononitrile or 2-pentenenitrile in rats.

A single oral administration of allylnitrile, crotononitrile or 2-pentenenitrile in rats induced behavioral abnormalities, such as head-twitching, head weaving, hindlimb abduction, backward pedaling and pivoting. The head-twitching, which was most consistently observed, was suppressed by serotonin (5-HT) antagonists, cyproheptadine or methysergide or by the 5-HT depleter, dl-p-chlorophenylalanine but was accentuated by the 5-HT releaser, dl-p-chloroamphetamine. The results suggest that the 5-HT system is involved in producing the behavioral abnormalities. To discover the effects of allylnitrile, crotononitrile and 2-pentenenitrile on the metabolism of 5-HT and dopamine, 6 areas of the brain of the rat were examined on days 1, 6, 15 and 30 after injection. Each of the nitriles caused significant increases in the level of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) and in the ratio of 5-HIAA/5-HT, one day after injection. The increase in 5-HIAA was most remarkable, suggesting an enhancement of the serotonergic system. The three nitriles had no effect on the metabolism of dopamine, over a period of 30 days.

Animals↗

PubMed1991

Alterations in the metabolism of serotonin and dopamine in the mouse brain following a single administration of allylnitrile, which induces long-term dyskinesia.

The effects of allylnitrile (ALN), which induces a long-term dyskinesia in mice, on the metabolism of serotonin (5-HT) and dopamine (DA) were studied after a single administration. One day after injection, ALN produced a significant increase in the levels of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA): 5-HT in the brain cortex, medulla oblongata plus pons, hypothalamus and midbrain; 5-HIAA in the cortex, medulla oblongata plus pons, striatum, hypothalamus and midbrain; the ratio of 5-HIAA/5-HT in the medulla oblongata plus pons, striatum and midbrain; HVA in the cortex and midbrain. These changes were not seen 10 and 35 days after injection when the animals were showing behavioral abnormalities. The present findings suggest that changes in 5-HT and DA metabolism are involved in the appearance of the dyskinetic syndrome.

Administration, Oral↗

PubMed1991

In vitro neurotoxicity study with dorsal root ganglia for acrylamide and its derivatives.

Acrylamide and 6 derivatives inhibited neurite growth from rat dorsal root ganglion in culture. The half-maximum inhibition concentration (I50) varied among test compounds, ranging from 0.8 mM for acrylamide and N-hydroxymethylacrylamide to 30 mM for methacrylamide. The value correlated well with the acute oral LD50 for rats, the linear regression equation being I50 = 2.74LD50-6.52 (r = 0.897, P less than 0.05), but did not correlate with in vivo neurotoxicity for mice. Log (1/I50) was a linear function of the rate constant with glutathione (K), i.e. log (1/I50) = 0.828logK + 0.056 (r = 0.938, P less than 0.05).

Acrylamides↗

PubMed1990

Alterations in the metabolism of serotonin and dopamine in the central nervous system of mice displaying a persistent dyskinesia due to crotononitrile or 2-pentenenitrile.

The effect of crotononitrile (4.22 mmol/kg, CRN) or 2-pentenenitrile (2.00 mmol/kg, 2-PN), which exhibit long-term dyskinesia, was examined on the metabolism of serotonin (5-HT) and dopamine (DA) in five brain regions of mice 1, 5, 12 and 35 days after dosing with CRN or 2-PN or vehicle (0.1 ml/25 g). One day after injection, CRN increased the level of the following substances and the ratio of 5-hydroxyindoleacetic acid (5-HIAA)/5-HT: 5-HT in medulla oblongata plus pons (144% of control); 5-HIAA in cortex (162%), striatum (166%), medulla oblongata plus pons (212%), hypothalamus (146%) and mid-brain (167%); 5-HIAA/5-HT in medulla oblongata plus pons (148%) and midbrain (133%). The changes caused by 2-PN were as follows: DA levels in cortex (176% of control, 35 days after dosing); HVA levels in striatum (136%, 1 day); 5-HT levels in hypothalamus (141%, 35 days); 5-HIAA levels in striatum (150%, 1 day), medulla oblongata plus pons (159%, 1 day) and midbrain (146%, 1 day); 5-HIAA/5-HT in striatum (153%, 1 day) and midbrain (134%, 1 day). The results suggest that changes in the 5-HT system are involved in the appearance of the dyskinetic syndrome which was seen in mice 1-2 days after dosing with CRN or 2-PN.

Animals↗