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Biomedical subjects

A Ohnishi

Publications and source records attributed to A Ohnishi.

At least 37 records · Page 2Linked to original sources
PubMed2000

Congenital neuropathy with the absence of large myelinated fibers.

Twelve patients with hereditary motor and sensory neuropathy with the absence of large myelinated fibers have been reported. All of these patients had central nervous system involvement. In this report, we describe the first patient with pure motor and sensory neuropathy with the absence of large myelinated fibers without central nervous system involvement. Morphometric analysis of the biopsied sural nerve specimen revealed extremely small myelinated fibers compared with previously reported patients. It is supposed that the cause of this disease might be the abnormal development of axons of the peripheral nerves.

Abnormalities, Multiple↗
PubMed2000

Effect of furanocoumarin derivatives in grapefruit juice on the uptake of vinblastine by Caco-2 cells and on the activity of cytochrome P450 3A4.

1. The presence of inhibitors of drug efflux transporters, such as P-glycoprotein (P-gp), in grapefruit juice (GFJ) was confirmed based on the uptake of [(3)H]-vinblastine (VBL) by Caco-2 cells. 2. The uptake of [(3)H]-VBL by Caco-2 cells was significantly increased by the ethyl acetate extract of GFJ as well as by cyclosporin A. The extract was separated on a Cosmosil column and the eluate with 60% methanol increased [(3)H]-VBL uptake, while the activity to inhibit CYP3A4 was greatest in the 70 and 80% eluates. 3. These results show that the major inhibitor of efflux transport of VBL is different from that of CYP3A4. 4. Further separation of the 60% methanol eluate afforded dihydroxybergamottin (DHBG). Both ethyl acetate extract of GFJ and DHBG increased steady-state [(3)H]-VBL uptake by LLC-GA5-COL300 cells. Besides DHBG, other furanocoumarins contained in GFJ, such as bergamottin, FC726, bergaptol and bergapten, increased the steady-state uptake of [(3)H]-VBL by Caco-2 cells. 5. The order of inhibitory potency of these compounds was FC726>DHBG>bergamottin>bergapten>bergaptol . While, the IC(50) values for inhibition of CYP3A4 were 0.075, 0.45, 1.0, 1.0 and >20 microM, respectively. Bergaptol specifically inhibited VBL efflux. 6. DHBG was thus identified as a candidate for inhibitors of VBL transport, together with other furanocoumarins. Moreover, partly involvement of the P-gp inhibition was suggested. 7. Therefore, the inhibition of efflux transport of drugs as well as of drug metabolism by CYP3A4 could be an important cause of drug-GFJ interaction.

3-O-Methylglucose↗
PubMed2000

Pharmacokinetics and adverse events following 5-day repeated administration of lenograstim, a recombinant human granulocyte colony-stimulating factor, in healthy subjects.

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) (lenograstim) was administered to healthy subjects at doses of 2, 5 and 10 micrograms/kg/day for 5 days (twice a day subcutaneously) to examine the optimal dose and schedule of lenograstim in mobilizing peripheral blood progenitor cells (PBSC) for allogeneic transplantation. Lenograstim administration significantly increased CD34+ cells in a dose-related manner. A significant correlation was observed between the maximal post-dosing counts and the pre-dosing baseline counts of CD34+ cells. Peripheral neutrophils increased markedly by seven to 13 times from the baseline to a peak of approximately 40,000/microliter on day 5 for the 5 and 10 micrograms/kg/day doses. After peak serum concentration (Cmax) was attained 4 h following administration, serum G-CSF declined with time in a log-linear fashion. The Cmax and 12 h area-under-the-curve increased dose dependently, but minimum drug level increased up to day 2 and then decreased until day 5. Clearance decreased with increasing dosage at the first dose, and increased significantly at the last dose. We found a highly significant correlation between absolute neutrophil counts and clearance for each dose. Adverse events most frequently occurred on day 6, with increases of alkaline phosphatase and lactate dehydrogenase and onset of bone pain. Increases of aspartate aminotransferase and alanine aminotransferase occurred as delayed events. Platelet count gradually decreased after the end of drug administration to 57% of the pre-dosing count on day 10, but was still within the normal range. These preliminary results suggest that repeated doses of lenograstim induce mobilization of PBSC in a dose-dependent manner and the pre-dosing baseline count of PBSC may predict the post-dosing maximal mobilization. The drug treatment may cause delayed-onset moderate thrombocytopenia and increased transaminase, and the drug clearance changes in a complex manner during repeated dosing.

Adult↗
PubMed2000

Pharmacokinetic analysis of felodipine-grapefruit juice interaction based on an irreversible enzyme inhibition model.

UNLABELLED: Aims Ingestion of grapefruit juice (GFJ) alters the pharmacokinetics of various orally administered drugs. Quantitative evaluation of this GFJ-drug interaction is required for the proper clinical management of patients. Methods Using felodipine as a model drug, we constructed a pharmacokinetic model based on irreversible inhibition of intestinal cytochrome P450 3A4 (CYP3A4) by GFJ. We fitted previously published data [5, 6] for felodipine ER (extended release formulation) to the ratio of CLGI,int before and after grapefruit juice ingestion by nonlinear least-squares regression analysis to estimate the reaction rate constant between GFJ and CYP3A4 (K) and the elimination rate constant of CYP3A4 (k ). RESULTS: The model gave a turnover rate of CYP3A4 of 0.0849 h-1, corresponding to a half-life of 8.16 h, in agreement with reported values. The AUC-time profiles of felodipine ER in the case of different amounts and schedules of GFJ ingestion were simulated using the parameter values estimated from the model. CONCLUSIONS: The modelling leads to the important conclusion that GFJ-felodipine interaction increases with increasing frequency and amount of GFJ ingestion, and that an interval of 2-3 days between GFJ intake and felodipine administration is necessary if GFJ-felodipine interaction is to be avoided.

Adult↗
PubMed2000

Relationship between time after intake of grapefruit juice and the effect on pharmacokinetics and pharmacodynamics of nisoldipine in healthy subjects.

A clinical study was performed in eight healthy volunteers to investigate the effect of various timing of grapefruit juice intake on nisoldipine pharmacokinetics and pharmacodynamics, and to validate our pharmacokinetic model. The subjects were given 10 mg oral nisoldipine with water (control), or 5 mg oral nisoldipine with 200 mL grapefruit juice (G0) or with water at 14 (G14), 38 (G38), 72 (G72) or 96 hours (G96) after a 7-day period of thrice-daily intake of grapefruit juice. Grapefruit juice ingestion did not affect heart rate or the effect area during the first 8 hours of heart rate after nisoldipine administration, although significant decreases of systolic and diastolic blood pressure were caused in G0 by coadministration of grapefruit juice with nisoldipine. Headaches were reported by 3, 2, and 1 persons in G0, G14, and G38, respectively, but no subjects in G72 and G96 reported headaches. Compared with the control group, the maximum plasma concentration of nisoldipine was significantly increased after grapefruit juice intake in G0 and G14, and the plasma concentration was significantly increased at each time in G0 to G72. Therefore the effect of grapefruit juice decreased time dependently and lasted for at least 3 days after intake. Furthermore, our model gave predicted values in good agreement with the observed values. It is therefore necessary to withhold grapefruit juice for at least 3 days before administration of the drug to prevent grapefruit juice-nisoldipine interaction.

Adult↗
PubMed2000

Usefulness and safety of theophylline injection form (Theodrip) for the treatment of acute asthma.

The effects of the speed of intravenous infusion on the pharmacokinetics of theophylline were studied in 9 healthy volunteers (Ex I). Subjects were intravenously administered either six 4.8 mg/kg theophylline (Theodrip, Nikken Chemicals Co., Ltd., Japan) or three matching placebo injections (4.8 ml/kg physiological saline) for 30 min (Step I) or for 15 min (Step II). In Steps I and II, Cmax was 10.8 +/- 1.1 and 10.8 +/- 0.8 micrograms/ml, respectively. These Cmaxs were concentrations yielding therapeutic effects in patients with acute asthma. Next, comparative pharmacokinetics between theophylline (Theodrip) and aminophylline were examined by a crossover method in 16 healthy volunteers (Ex II). The 90% confidence limits of the differences of mean values were within 80-120% and were 92.8-100.1% for Cmax, 99.7-105.3% for t1/2 and 100.2-104.4% for AUC. Thus, we concluded that the pharmacokinetics of the plasma theophylline after intravenous administration of Theodrip (theophylline at 4.8 mg/kg) were bioequivalent to those of aminophylline (6.0 mg/kg) for 30 min. In Ex I and II, no subjects had adverse effects and in Ex I no influence on ECG was seen. In addition, the convenience of Theodrip was compared with that of ampules of aminophylline among nurse volunteers (Ex III). The times required for set-up of Theodrip were significantly shorter than those of aminophylline ampules. On the other hand, the adverse reactions to aminophylline resulting from hypersensitivity reactions to its ethylenediamine component have been reported. Theodrip consists of 200 mg theophylline and 200 ml physiological saline in a plastic bag. Therefore, Theodrip, which does not contain ethylenediamine, is expected to have less adverse effects and be easier to handle than aminophylline.

Acute Disease↗
PubMed2000

A review of clinical use of theophylline in acute asthma: factors influencing kinetic disposition and drug interactions.

The clinical use of theophylline as a first line bronchodilator has declined during the last two decades. However, many therapeutic mechanisms for bronchial asthma have been discovered, and recent studies have suggested that theophylline therapy can play a beneficial role in the management of both chronic stable asthma and exacerbated disease treated in the emergency setting. In this article, the author describes the pharmacokinetics of theophylline and the major factors that influence the kinetics of the drug, such as physiopathological conditions and interactions with concomitantly administered drugs. Practical guidelines are then given on how to achieve optimal serum levels when planning theophylline therapy, including use of nomograms to decide loading and maintenance doses for nonsmoking adult asthmatic patients and adjustments for asthmatic patients with complications or on other drugs that may alter the kinetic disposition of theophylline.

Acute Disease↗
PubMed2000

Polymethoxylated flavones in orange juice are inhibitors of P-glycoprotein but not cytochrome P450 3A4.

The presence in orange juice of compounds that specifically inhibit the P-glycoprotein (P-gp) drug efflux transporter, but not the cytochrome P450 (CYP) isozyme CYP3A4, was investigated. The uptake of [(3)H]vinblastine, a substrate of P-gp, by Caco-2 cells was measured. An ethyl acetate extract of orange juice did not affect the initial uptake rate of [(3)H]vinblastine but significantly increased the steady-state uptake, as did cyclosporin A (20 microM), an inhibitor of P-gp. No significant effect on the uptake of 3-O-[(3)H]methylglucose or [(14)C]phenylalanine by Caco-2 cells was found, compared with the control. When the extract was separated on a Cosmosil column, the eluate with 70% methanol showed the most potent ability to increase [(3)H]vinblastine uptake. Additional separation of the 70% methanol eluate on a silica gel column with hexane-acetone (3:1) gave 3,3',4',5,6,7,8-heptamethoxyflavone (HMF) and 4',5,6,7,8-pentamethoxyflavone (tangeretin). HMF, tangeretin, and 3',4',5,6,7,8-hexamethoxyflavone (nobiletin), another methoxyflavone contained in orange juice, all increased the steady-state uptake of [(3)H]vinblastine by Caco-2 cells in a concentration-dependent manner. The order of potency of these compounds at the concentration of 50 microM was tangeretin > HMF > nobiletin. None of these methoxyflavones inhibited 6beta-hydroxylation of testosterone catalyzed by CYP3A4. The ethyl acetate extract of orange juice and these methoxyflavones also increased steady-state [(3)H]vinblastine uptake by LLC-GA5-COL300 cells (a cell line transfected with human MDR1 cDNA). We conclude that these methoxyflavones enhanced vinblastine uptake by specifically inhibiting drug efflux via P-gp. They may have potential as agents for reversing multidrug resistance or for recovering the bioavailability of certain drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

[Effect of lenograstim (glycosylated recombinant human granulocyte-colony stimulating factor) on peripheral blood stem cell mobilization in healthy volunteers].

The efficacy and safety of high-dose lenograstim on CD34 positive (CD34+) cell mobilization into peripheral blood were investigated in 18 healthy male volunteers. The volunteers were divided into 3 lenograstim dose groups of 6 subjects each. Lenograstim was administered at a dose of 2, 5, or 10 micrograms/kg/day, b.i.d. by subcutaneous injection for a total of 5 days. The median peak number of CD34+ cells/microliter of blood was 16.3, 53.9, and 96.6 in the 2, 5, and 10 micrograms/kg/day groups, respectively. A positive correlation was observed between the peak CD34+ level and dose of lenograstim (P = 0.002). The percentage of volunteers achieving more than 50 CD34+ cells/microliter of blood was significantly higher in the 10 micrograms/kg/day group (83.3%, P = 0.010) than in the 2 micrograms/kg/day group (0%). On the subject of safety, at least 1 adverse drug reaction (ADR) was observed in each of the volunteers, and a total of 12, 33, and 45 ADRs were observed in the 2, 5, and 10 micrograms/kg/day groups, respectively. A dose-dependent increase in the number of ADRs was also observed, including an elevation of LDH (P < 0.001), bone pain (P < 0.001), and fatigue (P = 0.008). However, no volunteers required symptomatic treatment or discontinuation of lenograstim. We concluded that administration of lenograstim at a dose of 10 micrograms/kg/day for 5 days is highly effective for CD34+ cell mobilization into peripheral blood and tolerable in healthy volunteers.

Adult↗
PubMed2000

[A case of Charcot-Marie-Tooth disease 1 B with Val 146Phe mutation of myelin protein zero showing a severe clinical phenotype].

A 15-year-old boy had complaints of progressive gait disturbance and foot deformity. He started to walk at the age of 18 months. Since two years of age, he had noticed unstable gait. He showed evident scoliosis and enlarged great auricular nerves. Moderate to slight degrees of muscular atrophy and weakness of distal upper, and proximal and distal lower limbs were observed. Pes equinovarus deformity of both feet was obvious. Muscle stretch reflexes were absent in both limbs except decreased triceps brachii reflex. Vibratory sensation was decreased severely in the toes and mildly in the fingers. In cerebrospinal fluid, protein was mildly elevated. Median nerve motor conduction velocity was 5.0 m/sec. On sural nerve biopsy, both demyelinated and remyelinated axons and onion-bulbs without hypomyelination were observed. Therefore, the diagnosis of Charcot-Marie-Tooth disease 1 was made. The direct sequencing of the genomic DNA encoding the Po gene revealed a mutant allele, a guanine to thymine substitution of nucleotide position 436, which caused a substitution of phenylalanine for valine at amino acid position 146. This type of Po mutation is different from any type of Po mutation reported in the literature.

Adolescent↗
PubMed1999

Identification of a new locus for autosomal recessive Charcot-Marie-Tooth disease with focally folded myelin on chromosome 11p15.

Autosomal recessive Charcot-Marie-Tooth disease type 4B (CMT4B) is a demyelinating hereditary motor and sensory neuropathy characterized by abnormal folding of myelin sheaths. A locus for CMT4B has previously been mapped to chromosome 11q23 in a southern Italian pedigree. We initially excluded linkage in two Tunisian families with CMT4B to chromosome 11q23, demonstrating genetic heterogeneity within the CMT4B phenotype. Subsequently, using homozygosity mapping and linkage analysis in the largest Tunisian pedigree, we mapped a new locus to chromosome 11p15. A maximum two-point lod score of 6.05 was obtained with the marker D11S1329. Recombination events refined the CMT4B locus region to a 5.6-cM interval between markers D11S1331 and D11S4194. The second Tunisian CMT4B family was excluded from linkage to the new locus, demonstrating the existence of at least a third locus for the CMT4B phenotype.

Charcot-Marie-Tooth Disease↗
PubMed1999

Myelinated fibers in Charcot-Marie-Tooth disease type 1B with Arg98His mutation of Po protein.

This study was undertaken to characterize the clinical, electrophysiologic, and histopathologic features of five presumably unrelated Japanese patients with Charcot-Marie-Tooth (CMT) disease type 1B and Arg98His substitution of Po protein and, in particular, to correlate Arg98His substitution to the ultrastructural abnormalities of the myelin sheath. Systematic morphometric studies of the sural nerve, where the CMT type 1B gene abnormality is expressed, have not been performed, especially on the basis of the type of mutation causing CMT type 1B. Electrophysiologic evaluation of limb nerves and morphometric analysis of sural nerves obtained at biopsy were performed. Ultrastructural myelin abnormalities were precisely examined. Clinical symptoms appeared from the second to the fifth decade. All probands presented with gait disturbance. Motor and sensory conduction velocities in the median and ulnar nerves ranged from 10 to 30 m/s. Segmental demyelination and remyelination and marked loss of myelinated fibers were the main findings. On electron microscopy, widening between major dense lines was found between the paired intraperiod lines, where the extramembranous portion of the Po protein resides. This widening is probably directly related to Arg98His substitution. Focal uncompaction of major dense lines coexisted with this widening. This uncompaction, which directly decreases the number of myelin lamellae, may be a secondary effect of Arg98His substitution on the intramembranous domain of Po protein. In conclusion, myelin changes at both extracellular and cytoplasmic appositions of Schwann cell membranes were found in association with Arg98His substitution of Po protein. This study contributes to a better understanding of myelin abnormalities in patients with CMT type 1B and Arg98His or other similar extramembranous amino acid substitutions of Po protein.

Adult↗
PubMed1999

[A family of hereditary neuropathy with liability to pressure palsies with a proband who developed right and left foot drop successively following the left radial nerve palsy].

A 41-year-old man developed multifocal mononeuropathies manifesting right and left foot drop successively, following the left radial nerve palsy as an initial symptom. Based on the neurological findings and the results of the genetic study of peripheral myelin protein (PMP) 22 gene and the histological study of the sural nerve on biopsy, the diagnosis of hereditary neuropathy with liability to pressure palsies (HNPP) was made. Two asymptomatic carriers were found among his family members based on the genetic study. The diagnosis of HNPP can be definitely established by the genetic study and this disease is relatively rare. In this report it is important to note that there are a few patients who show radial nerve palsy as an initial symptom, that we should carefully study the family members to obtain the prevalence of HNPP because asymptomatic carriers may be present, and that the carriers should be advised to avoid strenuous exercises and works which may produce excessive extension or compression of nerve trunks with the subsequent development of clinical symptoms.

Adolescent↗
PubMed1999

[A family of hereditary motor and sensory neuropathy type 1B showing a marked difference of neurological disability score among affected family members].

The proband was a 22-year-old man with a complaint of progressive weakness in his lower limbs. His clinical diagnosis of hereditary motor and sensory neuropathy (HMSN) type 1 was made based on the neurological findings and the results of peripheral nerve conduction studies and of histological studies of the sural nerve obtained on biopsy. The molecular genetic studies revealed arginine-to-histidine substitution at amino acid 98 of the Po protein in the proband. Therefore, the final diagnosis of HMSN type 1B was made. The same mutation was found in his mother and his two sisters. The neurological disability score of the proband was 69. It was 24 for his affected mother. The scores were 16 and 20 for the two affected sisters. The reason why the proband showed the highest score was considered to be the presence of the marked muscle weakness in the lower limbs found only in the proband. Therefore, it was concluded that the neurological disability score differs greatly among the affected members even with the same genetic abnormality in the same generation of the same family with HMSN type 1B. The affected family member with a low neurological disability score may be clinically undiagnosed.

Adolescent↗
PubMed1999

[Neurotoxicity of 1-bromopropane in rats].

Neurotoxicity of 1-bromopropane (1-BP) used as an alternative solvent of fluorocarbons was experimentally studied. Eight rats in the experimental group were exposed to 1-BP at 1500 ppm for six hours a day, five days a week for four weeks in an exposure chamber. Another eight rats in the control group were exposed to room air in a similar exposure chamber as those in the experimental group. During the latter half of the fourth week of exposure, all the rats in the experimental group showed a loss of body weight and ataxic gait compared with control rats. At the end of the fourth week, the rats in both groups were perfused through the ascending aorta and fixed. The cerebellum, medulla oblongata, spinal cord and peripheral nerve were processed for histopathological studies. No statistically significant difference in the frequency of axonal degeneration in both peroneal and sural nerves was found between the experimental and control groups. In the cerebellum, the frequency of degeneration of Purkinje cells in both the vermis and hemisphere was higher in the experimental group than in the control group (P < 0.05). There was no significant difference in the frequency of myelin ovoids in the fifth thoracic and in the third cervical posterior columns of the spinal cord between control and experimental groups. There was also no significant difference in the frequency of axonal swelling in the nucleus gracilis of the medulla oblongata between control and experimental groups. Ataxic gait was considered to be induced by degeneration of Purkinje cells in the cerebellum due to 1-BP exposure. However, degenerative findings of nerve fibers in the peripheral nerve, spinal posterior column and nucleus gracilis of the medulla oblongata due to 1-BP exposure were not evident. At the end of the fourth week of exposure, rats in the experimental group showed loss of body weight and markedly decreased motor activities, and it was considered that they would die if we continued the exposure into the fifth week. Therefore, we feel that our experimental schedule should be reconsidered before undertaking any further studies on the peripheral nerve toxicity of 1-BP.

Animals↗
PubMed1999

Solution structure of an insect growth factor, growth-blocking peptide.

Growth-blocking peptide (GBP) is an insect growth factor consisting of 25 amino acid residues that retards the development of lepidopteran larvae at high concentration while it stimulates larval growth at low concentration. In this study, we determined the solution structure of GBP by two-dimensional 1H NMR spectroscopy. The structure contains a short segment of double-stranded beta-sheet involving residues 11-13 and 19-21 and a type-II beta-turn in the loop region (residues 8-11), whereas the N and C termini are disordered. This is the first report of the three-dimensional structure of the peptiderigic insect growth factor, and the structure of the well defined region of GBP was found to share similarity with that of the C-terminal domain of the epidermal growth factor (EGF). Because GBP has been reported to stimulate DNA synthesis of not only insect cells but also human keratinocyte cells at the same level with EGF, the structural similarity between GBP and EGF may lead to the interaction of GBP to EGF receptor.

Amino Acid Sequence↗
PubMed1999

Apparent diffusion coefficient on rat brain and nerves intoxicated with methylmercury.

The effects of methylmercury chloride (MMC) on the degenerative changes in rat brain and cranial nerves were studied. Twelve Wistar rats were divided into two equal groups. The rat model of methylmercury intoxication (MMC group) was made by subcutaneously administering 10 mg mercury/g body weight daily for 7 days. Control group rats were infused with the same amount of normal saline during this period. Magnetic resonance imaging (MRI) measurements were performed before and 14 days after the first MMC administration, using a 4.7-T MR system. No significant focal changes were observed on T1- and T2-weighted MR images regarding the internal structures of the brains of the MMC-intoxicated rats, atrophy of the cerebellum, and dilatation of the arachnoid space around the brain stem of MMC-treated rats, but were demonstrated without edematous change. The apparent diffusion coefficients (ADC) of the cortex, caudate-putamen, and trigeminal nerve were not significantly different between the MMC-treated and control rats. However, the ADC parallel to the optic nerves were significantly increased in the MMC group, in contrast to the unchanged ADC perpendicular to the optic nerves. An electron microscopy study revealed a marked decrease of microtubules and moderate decrease of neurofilaments in the axons of myelinated fibers of optic nerves of the MMC-treated rats. We have thus demonstrated a disturbance in the integrity of microtubules and neurofilaments as a toxic action of MMC in the rat nervous system in vivo, particularly in the optic nerves. The use of ADC values calculated by diffusion-weighted MRI is a promising approach for the evaluation of changes in brains and nerves in methylmercury intoxication research.

Animals↗