Biomedical subjects

H Machida

Publications and source records attributed to H Machida.

At least 37 records · Page 2Linked to original sources

PubMed1994

Retinal toxicity and ocular kinetics of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil in rabbits.

The intraocular penetration of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU), a new antiviral drug, after oral administration, the effects of non-toxic intravitreal doses of BV-araU, and the intraocular kinetics of BV-araU after intraocular injection were studied in rabbits. The intravitreal penetration of BV-araU after oral administration was very poor: 0.11 +/- 0.13 micrograms/ml and 0.20 +/- 0.02 microgram/ml respectively in albino and pigmented rabbits 2 h after 30 mg/kg. An intravitreal injection of 200 micrograms BV-araU caused transient electroretinographic (ERG) changes, whereas a 100-micrograms injection and intravitreal irrigation with 20 micrograms/ml BV-araU caused no ERG and histologic changes over the 4-week follow-up period. The half-life of the intravitreal concentration of BV-araU after an intravitreal injection was short (2.4 h). The results suggest that an intravitreal injection of 100 micrograms BV-araU or an intravitreal irrigating solution containing 20 micrograms/ml BV-araU is non-toxic to the retina and may be used for treatment of retinitis caused by varicella-zoster virus or herpes simplex virus type 1.

Administration, Oral↗

PubMed1994

Effect of 1-amino-5-bromouracil on brain monoamine metabolism in rats.

The effect of 1-amino-5-bromouracil (ABU), a novel central-acting agent, on monoaminergic neurotransmitter levels of rat brain was investigated. Under the nonstressed condition, ABU (20 and 30 mg/kg intraperitoneally [IP]) did not affect monoamine metabolism, whereas diazepam (5 mg/kg IP) increased the 3-methoxy-4-hydroxyphenylethylene glycol (MHPG)/noradrenaline (NA) ratio. One-hour immobilization stress increased the MHPG/NA ratio in various brain regions of drug-naive rats, but did not increase the homovanilic acid (HVA) plus 3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine (DA) ratio or the 5-hydroxyindole acetic acid (5-HIAA)/serotonin (5-HT) ratio. Pretreatment with ABU or diazepam suppressed the activation of noradrenergic neurons induced by immobilization stress. By contrast, electric foot shock stress increased the MHPG/NA and HVA+DOPAC/DA ratios. Pretreatment with ABU or diazepam suppressed the activation of noradrenergic and dopaminergic cortical neurons by electric foot shock stress. These results indicate that these two physiologic stresses affected monoaminergic neurons differently and that their effects were suppressed by ABU and diazepam.

Animals↗

PubMed1994

In vitro and in vivo anti-herpes viral activities and biological properties of CV-araU.

We compared the in vitro and in vivo antiviral effects against herpes simplex virus type 1 (HSV-1) and other biological properties of 1-beta-D-arabinofuranosyl-5-[(E)-2-chlorovinyl]uracil (CV-araU) and 1-beta-D-arabinofuranosyl-5-[(E)-2-bromovinyl]uracil (BV-araU, sorivudine). Both CV-araU and BV-araU exhibited antiviral activities against HSV-1 in the cell culture derived from mouse, though the activities were lower than those seen in human cells. For intraperitoneal and intracerebral infections in mice with HSV-1 strain WT-51, both compounds, administered twice daily, were effective in increase in the survival rate at doses of 15 mg/kg and 30 mg/kg, respectively. In pharmacokinetic analysis, both drugs were absorbed well in the rat gastrointestinal tract following oral administration. There was no difference between the metabolism of orally administered CV-araU and BV-araU in rats. High levels of the corresponding base were found in plasma after oral administration of CV-araU and BV-araU, but much lower base levels were seen after intravenous doses. Both drugs were resistant to degradation by rat liver enzymes.

3T3 Cells↗

PubMed1994

Effect of BV-araU and acyclovir on varicella-zoster virus replication with various length and timing of drug exposure.

We studied antiviral effects of 1-beta-D-arabinofuranosyl-5-[(E)-2-bromovinyl]uracil (BV-araU) and acyclovir against varicella-zoster virus (VZV) multiplication varying the length or timing of drug exposure. First, residual anti-VZV effect of drugs, exposed to cells for various periods followed by incubation in drug-free medium, was determined by the plaque inhibition assay. None of the drugs showed activity when removed within 24 hr of incubation. Weakened efficacy of BV-araU was seen in 2 days of treatment. When it was removed after 3 or 4 days, the ED50 was as low as that for cultures in which the drug was not removed. Still, plaque inhibition was not complete even at high concentrations. Acyclovir inhibited plaque formation only by 50% or less in 2 days of treatment. It gave a much higher ED50 in 3 days of treatment than that observed without drug removal. In the experiments, in which BV-araU was added to VZV-infected cells 1 day after infection, BV-araU immediately suppressed increase in the number of infective centers at a concentration of 0.001 microgram/ml, and reduced it at concentrations of 0.01 microgram/ml or higher. The reduction of infective centers was seen with a dose-dependent manner when added 2 or 3 days after infection. BV-araU stimulated the decrease in the number of infective centers when added 4 days after infection. This inhibitory effect of acyclovir was very weak. Microscopic observations supported the above results. BV-araU was still much superior to acyclovir in the anti-VZV effect when the length and timing of drug exposure were varied.

Acyclovir↗

PubMed1994

Discriminative stimulus properties of diazepam and the novel anxiolytic agent 1-amino-5-bromouracil in rats.

A stimulus cue of 1-amino-5-bromouracil (ABU, CAS 127984-93-4) was compared with that of diazepam (DZP) using a drug discrimination paradigm in rats. Groups of rats were trained to discriminate DZP (1 mg/kg i.p.) or ABU (20 mg/kg i.p.) from vehicle. Generalization of the cue of the trained drug to pentobarbital was shown in DZP- and ABU-trained rats at a dose of 5 mg/kg. The stimulus cue of ABU showed a tendency to generalize to DZP in ABU-trained rats but generalization of that of DZP to ABU in DZP-trained rats was only partial. Also partial generalization of that of DZP to imipramine and clonidine was found but not to 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) in DZP-trained rats. Full generalization of the stimulus cue of ABU to imipramine and partial generalization of that of ABU to clonidine and 8-OH-DPAT was observed in ABU-trained rats. The results suggest that the discriminative stimulus properties of ABU differ from those of DZP.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1994

Pharmacological profile of the novel putative anxiolytic agent 1-amino-5-bromouracil.

The newly synthesized compound, 1-amino-5-bromouracil (ABU, CAS 127984-93-4), showed unique anxiolytic activity in rats and mice. Its minimum effective dose was 10 mg/kg p.o. in the Geller type conflict test in rats, and it showed anxiolytic activity at a dose of 20 mg/kg i.p. in the Vogel type conflict test in mice. ABU also induced loss of the righting reflex in mice. The ED50, a dose level that induces loss of the righting reflex in 50% of mice, was 86.4 mg/kg p.o. On the other hand, ABU showed only weak activities both potentiating the drug-induced anesthesia and myorelaxing in comparison with diazepam. Furthermore ABU did not show an affinity for benzodiazepine receptor. Thus, the pharmacological profile of ABU is concluded to be different from that of diazepam.

Anesthetics↗

PubMed1994

A fully automated apparatus for a light/dark test measuring anxiolytic or anxiogenic effects of drugs in mice.

We developed a fully automated light/dark apparatus which detects locomotion, rearing and time spent in light and dark zones, and shuttle crossing of mice. This apparatus is controlled by a personal computer and detects these parameters by using infrared beamsensors. We used this apparatus to investigate the effects of the anxiolytics, diazepam (DZP) and pentobarbital (PB); the putative anxiolytic, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT); and the anxiogenics, picrotoxin, methyl-beta-carboline-3-carboxylate (beta-CCM), and ethyl-beta-carboline-3-carboxylate (beta-CCE), on each parameter measured by a light/dark test in mice. DZP (5 mg/kg) and 8-OH-DPAT (0.1 and 0.2 mg/kg) significantly increased the time spent in the light zone. PB (10 mg/kg) also significantly increased the number of shuttle crossings between the dark and light zones. Conversely, picrotoxin (1 and 2 mg/kg) significantly decreased locomotion, rearing and time spent in the light zone. beta-CCM (10 mg/kg) and beta-CCE (5 mg/kg) also significantly decreased rearing and time spent in the light zone. Although the same dose of beta-CCE significantly decreased shuttle crossing and rearing in the dark zone, beta-CCE did not change locomotion in either zone. Our results indicate that this apparatus is useful for the assessment of the anxiolytic and anxiogenic activities of drugs in mice.

Animals↗

PubMed1993

Metabolism of 5'-ether prodrugs of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil in rats.

1-beta-D-Arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU) is a selective antiherpesviral agent that has been shown to be metabolically stable in mice. However, E-5-(2-bromovinyl)uracil (BVU) is the major metabolite found after oral dosing in animals other than mice. When BV-araU was given orally to germ-free rats, only small amounts of BVU were found in the plasma, suggesting an important role of enterobacteria in the formation of BVU. Then, the metabolism of BV-araU prodrugs was studied in specific-pathogen free rats to select oral prodrugs of BV-araU with enhanced metabolic stability. 5'-O-Ethyl BV-araU (Et-BV-araU) gave about a 2-fold higher BV-araU blood concentration 3 and 6 hr after administration than after oral dosing of BV-araU, while the level of BVU was lower. Other aliphatic alkyl prodrugs also gave a lower level of BVU, but did not give the same elevation in blood concentration of BV-araU as did Et-BV-araU. Dosing of 5'-O-acetyl BV-araU resulted in blood concentrations of BV-araU and BVU similar to those after oral administration of BV-araU. 5'-O-Aromatic alkyl prodrugs showed poor bioavailability. A nearly 2-fold higher urinary recovery rate was seen for Et-BV-araU than for BV-araU or 5'-O-acetyl BV-araU. The conversion of Et-BV-araU to BV-araU was demonstrated in vitro using rat liver extract in the presence of co-factors, although the reaction was slow. The 5'-O-aliphatic alkyl prodrugs were completely resistant to degradation by enterobacteria, whereas the esters were partially degraded to BVU. Et-BV-araU may be a useful oral prodrug of BV-araU due to its increased metabolic stability and bioavailability.

Animals↗

PubMed1993

Complete avulsion of the papilla of Vater and gastroduodenal artery due to blunt abdominal trauma: report of a case.

A case of traumatic avulsion of the papilla of Vater and gastroduodenal artery successfully treated by pancreaticoduodenectomy is presented herein. The mechanism of this rare injury appeared to be a shearing force applied to the common bile duct and gastroduodenal artery. Thus, when the liver is driven cephalad by compression of the abdomen and by the deceleration force, the common bile duct and gastroduodenal artery are avulsed from the fixed duodenum and pancreas. The mechanism of this rare injury is postulated on the basis of operative and histological findings. Our case is thought to be the first of traumatic avulsion of the papilla of Vater and gastroduodenal artery to be reported in Japan.

Abdominal Injuries↗

PubMed1993

Topical treatment with BV-araU of immunosuppressed and immunocompetent shaved mice cutaneously infected with herpes simplex virus type 1.

Effect of topical treatments with BV-araU was tested in cutaneous infections of shaved Balb/c mice with herpes simplex virus type 1. Evolution of zosteriform skin lesions associated with infection with a low virulent KOS(S) strain was almost completely suppressed by treatments with 5% BV-araU cream given 4 times daily for 5 days starting 1 day after inoculation. This effect was equivalent to that of Zovirax Cream including 5% acyclovir. One percent BV-araU cream was also effective in inhibiting progression of symptoms, while 0.2% cream was not effective. Five percent BV-araU cream significantly suppressed progression of skin lesion even if initiation of treatment was delayed to 2 days after infection. However, the efficacy was diminished by further delay in starting treatment. The effect of BV-araU cream was also evident during infection of immunosuppressed mice. Virus titers in the skin tissue encompassing the inoculation site of mice decreased the day after the first treatment. In the lower flank site, virus replication was almost completely suppressed by the treatment beginning 1 day postinfection. Topical application of BV-araU may be useful therapy for HSV-1 infections in humans, including immunocompromised patients.

Administration, Topical↗

PubMed1993

Mechanism of inhibition of DNA synthesis by 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil.

The mechanism of the inhibitory action of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl) uracil triphosphate (BV-araUTP) on DNA synthesis by Escherichia coli DNA polymerase I Klenow fragment was studied. Acting as a chain terminator, BV-araUTP inhibited DNA synthesis by Klenow fragment more effectively than 2',3'-dideoxythymidine triphosphate (ddTTP). However, the incorporation sites of BV-araU monophosphate were restricted at consecutive dTMP sequence whereas ddTMP was incorporated at every dTMP site.

Antiviral Agents↗

PubMed1993

Acute pancreatitis in a child with sickle cell anemia.

A case of pancreatitis that occurred as a complication of a vaso-occlusive crisis in a child with sickle cell anemia is reported. We encourage others to consider pancreatitis as a cause for abdominal pain in children with multisystem diseases, particularly those that may cause ischemic organ injury such as sickle cell anemia.

Abdominal Pain↗

PubMed1992

Nucleosides and nucleotides. 107. 2-(cycloalkylalkynyl)adenosines: adenosine A2 receptor agonists with potent antihypertensive effects.

Adenosine receptor-binding profiles in rat brain tissues and antihypertensive effects in spontaneously hypertensive rats (SHR) of a series of 2-(cycloalkylalkynyl)adenosines (2-CAAs) and their congeners are described. The structure-activity relationship of this series of compounds is discussed, focusing on the length of the alkynyl side chain and bulkiness of the terminal cycloalkyl substituents in terms of binding activity and cardiovascular effects. All the 2-CAAs had a preferential affinity for A2 receptors. Of these derivatives, 2-(3-cyclopentyl-1-propyn-1-yl)adenosine (10b) exhibited the most selective affinity for A2 receptors (Ki ratio: A1/A2 = 70) on the basis of receptor binding. In the C-2 binding region of adenosine, compounds often have potent and/or selective A2 activity from introduction of an acetylenic group at the C-2 position followed by one methylene residue further followed by a hydrophobic substituent such as a cycloalkyl ring at the terminal position of the alkynyl side chain. Intravenous injection of 10b up to 100 micrograms/kg had a potent hypotensive effect without a marked decrease in heart rate in anesthetized SHR. Compounds 10j-s, with a hydroxyl group in the C-3" position of the alkynyl side chain, had a potent affinity for both A1 and A2 receptors, but they were not highly selective for A2 receptors. These compounds caused a marked bradycardia upon intravenous administration in anesthetized SHR. Oral administration of 10b (0.1-1 mg/kg) had a potent and long-lasting antihypertensive effect in conscious SHR.

Adenosine↗

PubMed1992

Analysis of toxic and mutagenic activities of antiherpesvirus nucleosides against HeLa cells and herpes simplex virus type 1.

The toxic and mutagenic activities of five antiherpesvirus agents to HeLa cells and herpes simplex virus type 1 (HSV-1) were investigated. 5-Iodo-2'-deoxyuridine (IDU) and 9-beta-D-arabinofuranosyl-adenine (araA) showed very potent inhibitory effects on cell growth and the cloning efficiency of HeLa cells, whereas 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU), E-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and 9-(2-hydroxyethoxymethyl)guanine (ACV) showed less inhibitory effect. 50% inhibitory doses of BV-araU and BVDU for cell growth were 657 and 253 micrograms/ml, respectively. Although the growth inhibitory activity of BVDU was very weak, as above, the mutagenic activity of this drug to the cells, estimated by induction of colchicine-resistant mutants, was observed to be 4 micrograms/ml, which was a markedly smaller dose than the inhibitory dose for cell growth, and the highest frequency of mutation of the cells was shown at 100 micrograms/ml of BVDU. This activity was more potent than that of IDU. No mutagenic activity of BV-araU, araA and ACV to cells was observed within the concentration range of 1-800 micrograms/ml. IDU showed high mutagenic activity to HSV-1 growing in human embryo lung fibroblasts, and IDU-resistant mutants were induced at a high frequency. BVDU also induced a small amount of BVDU-resistant mutant virus, although this drug induced many mutant cells. No mutagenic activity of BV-araU, araA and ACV to HSV-1 was observed.

Acyclovir↗

PubMed1992

Efficacy of oral treatment with BV-araU against cutaneous infection with herpes simplex type 1 in shaved mice.

The effect of oral BV-araU was tested in cutaneous model infections of shaved Balb/c mice with herpes simplex virus type 1 (HSV-1). Progression of cutaneous symptoms associated with cutaneous infection with HSV-1 F strain was inhibited by BV-araU at doses of 20 and 50 mg/kg twice daily, beginning one day post-infection, resulting in significant increase in the survival rate. Onset of disease was suppressed in most animals receiving 100 mg of BV-araU per kg. BV-araU (20 mg/kg or more) also significantly increased the survival rate of mice infected with HSV-1 WT-51 strain. The efficacy of BV-araU was not affected by gender or age (6-9 weeks) of the mice. BV-araU was effective even when the treatment was started 2.5 days post-infection. The efficacy of BV-araU against F strain infection was comparable to that of acyclovir, but acyclovir showed therapeutic effects at lower doses compared with BV-araU against WT-51 strain infection. Against infection of cyclophosphamide-treated immunosuppressed mice with HSV-1 KOS(S) strain, BV-araU decreased the morbidity rate and severity of symptoms at doses of 200 and 100 mg/kg, respectively, and all mice given 50 mg of BV-araU or more per kg survived, suggesting oral efficacy can be achieved against HSV-1 infections in immunosuppressed individuals.

Acyclovir↗

PubMed1992

In vitro drug combination of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil with anti-human immunodeficiency virus or anticancer nucleosides.

1-beta-D-Arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU) and E-5-(2-bromovinyl)uracil, a metabolite of BV-araU, did not affect either the anti-human immunodeficiency virus activity or the cytotoxicity of azidothymidine in MT-4 and MOLT-4 cells. Similarly, the bromovinyl compounds did not affect the in vitro antitumor activities of arabinosylcytosine, 5-fluorouracil, and 5-fluoro-2'-deoxyuridine. The anti-varicella-zoster virus activity of BV-araU was not influenced by azidothymidine, 2',3'-didehydro-2',3'-dideoxythymidine, or arabinosylcytosine, whereas relatively high concentrations of fluorinated antitumor agents enhanced the anti-varicella-zoster virus activity.

Antiviral Agents↗

PubMed1992

Effects of inline filtration on delivery of gentamicin at various flow rates.

The effects of inline filtration on delivery of gentamicin (GM) in the pediatric field were studied. The filter sets (Pall 0.20 micron. JMS 0.20 micron, and IVEX 2.022 micron) were studied using a simulated system. 10 mg of GM was injected into the system containing 5% dextrose in water (flow rate: 50 ml/hr, 10 ml/hr and 2 ml/hr) with horizontal and vertical settings of the inline filters. In case of 50 ml/hr, delivery of GM of Pall showed nearly the same delivery pattern as compared with no filter setting. However, JMS and IVEX 2 showed little differences. In case of 10 ml/hr and 2 ml/hr those differences became more significant. Delivery of GM was influenced by the priming volume of the filters, increasingly so at slow flow rates. Filter settings also influenced the delivery of GM. Furthermore, with regards to the results of the Vitamin K2 delivery and the technetium radiotracer method, JMS and IVEX 2 filters were observed to have some stagnation of drugs in the filter. Not only priming volumes of the filters affect delivery of drugs, filter designs also have an influence. The use of the inline filters is important in the pediatric field, but their charactaristics for drug delivery pattern should be considered.

Drug Contamination↗

PubMed1992

[Bezafibrate myopathy in two patients with chronic renal failure].

Case 1, a 60-year-old man and case 2, a 70-year-old man had several year history of chronic renal failure with hypertension and hyperlipidemia due to diabetes mellitus. Treatment of hyperlipidemia was started by oral bezafibrate intake 1,200 mg per day in case 1 and 400 mg per day in case 2 respectively. Three to fourteen days later, both patients noticed symmetrical muscle pain and weakness. Then the symptoms worsened and they were hospitalized. At the time of admission, both patients revealed weakness in the proximal muscles of their upper and lower limbs and the serum creatine kinase and myoglobin levels were remarkably elevated. Myoglobinuria was also noted. Routine light microscopic examination of biopsied quadriceps femoris muscles of two patients showed scattered necrotic muscle fibers, some of which were under phagocytosis. The symptoms of the patients were immediately resolved after the drug was discontinued. Serum concentration of bezafibrate was remarkably elevated during treatment. Thus the diagnosis was established as having bezafibrate induced myopathy and, as far as we know, this is the first report of bezafibrate induced myopathy in Japan. On the basis of the above description, bezafibrate may induce muscle damage if dose is excess over the renal capacity. Extreme caution is warranted when the patient is placed on bezafibrate and has renal dysfunction. Strict dose adjustment is necessary in taking account of renal function to avoid muscle damage including rhabdomyolysis.

Aged↗