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Biomedical subjects

H Machida

Publications and source records attributed to H Machida.

At least 55 records · Page 3Linked to original sources
PubMed1997

Allopurinol reduced hepatic ischemia-reperfusion injury exacerbated by inhalation of high-concentration oxygen in rats.

Exposure to high-concentration oxygen (O2) increases lipid peroxidation of the cellular membrane, leading to tissue injury which may involve hepatic ischemia-reperfusion (I/R) injury. We examined the effects of inhaling high-concentration O2 on hepatic I/R injury with allopurinol, which is a xanthine oxidase inhibitor. Partial hepatic ischemia was performed in rats with or without allopurinol under 21 or 100% O2 inhalation. Levels of lipid peroxide, serum liver enzymes, and hepatocellular oxidative stress in the 100% O2 group were significantly higher than in the 21% O2. Administration of allopurinol significantly inhibited those changes in the 100% O2 group. Severe degeneration of mitochondria were noted in the 100% O2 group, but appeared to be reduced by allopurinol. Results suggest that inhalation of high-concentration O2 during liver surgery may increase lipid peroxidation and exacerbate hepatic I/R injury, but those changes may be prevented by allopurinol.

Alanine Transaminase↗
PubMed1997

Synthesis of 2'-deoxy-2'-fluoro-4'-thioarabinonucleosides using the Pummerer rearrangement and their biological evaluation.

Searching for more effective antineoplastic and antiviral agents, we have prepared various 2'-deoxy-2'-fluoro-4'-thioarabinonucleosides. The glycosylation reaction of persilylated pyrimidine bases with a 4-thiosugar derivative was performed using SnCl4 as a catalyst. The same reaction between purines and the 4-thiosugar, catalyzed by TMSOTf, gave the corresponding purine 4'-thionucleosides. Pyrimidine derivatives (e.g., 5-ethyluracil, 5-iodouracil, and 5-iodocytosine) showed potent anti-HSV-1 activities, and guanine and 2,6-diaminopurine derivatives showed marked anti-HCMV activities.

Antimetabolites, Antineoplastic↗
PubMed1997

Characterization and transplantation of agarose microencapsulated canine islets of Langerhans.

The bioartificial pancreas was designed to incorporate islet tissues and a selectively permiable membrane that isolates islets from the immune system of the recipient. The efficacy of agarose, a nontoxic polysaccharide, has been evaluated as a material of microcapsules to prevent allo- and xenograft rejection in rodents. The aim of this study is to demonstrate the possibility of the agarose microcapsule containing allo-islets as a bioartificial pancreas in canine model. In vitro viability of islets was determined by glucose challenge during perifusion experiments (n = 4). Insulin secretion from both encapsulated (enc.) and non-encapsulated (non-enc.) canine islets rose from initial basal levels of 0.09 (encap.), 0.07 (non-encap.) to the peak of 0.2 (encap.), 0.1 (non-encap.) in microU/islet/min after 5 minutes, then decreased to the basal level when the glucose challenge was discontinued. Auto-transplantation was performed in two dogs to evaluated in vivo viability and biocompatibility of encapsulated islets implanted into the splenic sinus by venouse reflux. Two weeks after auto-transplantation, the plasma insulin levels in the splenic vein and artery of two dogs were assayed. In the first dog, serum insulin level was 1 microU/ml both in the vein and the artery and increased, after glucagon (1.0 mg) injection, to levels of 9 microU/ml in the vein, but still kept 1 microU/ml in artery, as well as in the second one. Histological and electron-microscopical examination of the spleen revealed that encapsulated islets remained morphologically intact and the surface of agarose capsules showed no significant adherence of fibroblasts and inflammatory cells. Functional efficacy of the microencapsulated islets was determined using five totally-pancreatectomized diabetic dogs as recipients without immunosuppression. Defined quantity of microencapsulated islets from outbred mongrel donors were grafted through the catheter into omental tissue of the pancreatectomized recipients. All dogs had various degrees of reduced insulin requirements. In three of five recipients, the average fasting glucose values were controlled under 120 mg/dl for 28, 42, 49 days without exogenous insulin, which received totally 4.3 x 10(3), 7.3 x 10(3) and 1.0 x 10(4) (IE/kg) of microencapsulated islets, respectively. In conclusion, the present study indicates that the agarose-based microencapsulated islets can function in large diabetic animals, resulting in the independence of exogenous insulin therapy for prolonged periods without the need for immunosuppression.

Animals↗
PubMed1996

Synthesis and antiviral activity of 5-substituted (2'S)-2'-deoxy-2'-C-methylcytidines and -uridines.

Synthesis of several 5-substituted (2'S)-2'-deoxy-2'-C-methylcytidines (8) and -uridines (6, 11) has been accomplished using radical deoxygenation of the 2'-tert-alcohols via their methyl oxalyl esters as a key reaction. Anti-herpes simplex virus type-1 and -2, and anti-varicella-zoster virus activities of the newly synthesized nucleosides were evaluated. Among them, the 5-iodouracil derivative 6e showed the most potent activity against herpes simplex virus type-1, with an EC50 of 0.14 micrograms/mL without showing cytotoxicity up to 100 micrograms/mL, but had a weak activity against herpes simplex virus type-2 and no activity against varicella-zoster virus up to 50 micrograms/mL in vitro. Although the 5-fluorocytosine derivative 8b had a potent anti-herpes simplex virus type-1 activity (EC50 = 0.22 micrograms/mL), it was rather cytotoxic to the CCRF-HSB-2 human T-cell line (IC50 > or = 1.0 microgram/mL).

Animals↗
PubMed1996

Antiviral activities of nucleotide heterodimers against human immunodeficiency virus type 1 in vitro.

Nucleotide heterodimers were synthesized and examined for their inhibitory effects on the replication of human immunodeficiency virus type 1 (HIV-1), including HIV-1 reverse transcriptase (RT) inhibitor-resistant mutants. 3'-Azido-3'-deoxythymidilyl-(5')-phospho-(5')-6-[(3', 5'-dimethylphenyl)thio]-5-ethyl-1-[(2-hydroxyethoxy)methyl]uracil (AZT-P-E-HEPU-dM) and 3'-azido-3'-deoxythymidilyl-(5')-phospho-(5')-2', 3'-dideoxyinosine (AZT-P-ddI) proved to be highly potent and selective inhibitors of HIV-1 (IIIB strain) in MT-4 cells. The mechanism of inhibition by these heterodimers may be attributed to their degradation and the formation of each constituent. AZT-P-E-HEPU-dM was also markedly inhibitory to an AZT-resistant mutant (HIV-1-IIIB/AZT) and an E-HEPU-dM-resistant mutant (HIV-1-IIIB-R). However, AZT-P-ddI was found to have a less inhibitory effect on HIV-1-IIIB/AZT than on HIV-1-IIIB. The heterodimers of (5',5') AZT and ribavirin (AZT-P-Ribavirin) and (5',5') ddI and ribavirin (ddI-P-Ribavirin) were also synthesized: AZT-P-Ribavirin inhibited HIV-1 replication, but ddI-P-Ribarvirin did not.

Anti-HIV Agents↗
PubMed1996

Right lung transplantation followed by left pneumonectomy in the rat.

OBJECTIVE: To develop a rodent lung transplant model which depends on graft function for survival, total microsutureless lung transplantation was carried out and followed by contralateral native pneumonectomy in the rat. METHODS: Total non-microsuture right lung transplantation was undertaken using a cuff technique with anastomotic areas twice as big as those for the left lung transplantation. Inbred rats received either right (n = 10) or left lung isograft (n = 10) with non-microsuture techniques and underwent contralateral native pneumonectomy 2 weeks later to test the function of the grafted lung. RESULTS: While none of the left lung recipients could be disconnected from the respirator after right pneumonectomy, eight of ten right lung recipients tolerated left pneumonectomy, increased body weight and regained exercise capacity (oxygen uptake 49 +/- 4 ml/kg per min) comparable to that of control rats undergoing right hilar stripping and left pneumonectomy. CONCLUSIONS: The results suggest that the grafted right lung, but not the left lung, allows survival, growth and exercise of the recipient. Right lung transplantation followed by native left pneumonectomy may serve as a physiologic model of lung transplantation in the rat.

Animals↗
PubMed1996

Elevated aminotransferase activity as an indication of muscular dystrophy: case reports and review of the literature.

Five male children are reported in whom incidental recognition of elevated serum alanine aminotransferase (ALT) activity initiated investigation to identity the cause of suspected hepatocellular injury. All five were later diagnosed with X chromosome-linked muscular dystrophy. The serum level of ALT, generally considered to be specific for hepatocellular injury, was increased two to 25 times above normal in all the reported cases. Paradoxically, the increase in ALT activity was greater than that of serum aspartate aminotransferase (three to 16 times normal), an enzyme whose elevation is generally recognized as being less specific and indicative of muscle, cardiac, kidney, pancreatic, red blood cell or hepatic injury. At presentation to the gastrointestinal service, one case, age 2.5 months, had no symptoms or signs of neuromuscular dysfunction, while the other four had previously unrecognized hypertrophy of the calves, proximal limb weakness, positive Gower's sign or delayed gross motor skills. All five patients had marked elevation of serum creatine kinase activity and histopathologically confirmed muscular dystrophy. The practical clinical implication of this report is that children with elevated serum ALT, in the absence of other signs and symptoms of hepatic injury, may have occult muscular disease--most frequently muscular dystrophy. Although the clinical signs of muscular dystrophy may be subtle or absent, early determination of creatine kinase will suggest the correct diagnosis and minimize extensive and invasive investigation focusing on hepatic injury.

Adolescent↗
PubMed1996

In vitro and in vivo antitumor activity of a novel nucleoside, 4'-thio-2'-deoxy-2'-methylidenecytidine.

The in vitro and in vivo antitumor activity of a novel nucleoside, 4'-thio-2'-deoxy-2'-methylidenecytidine (4'-thio-DMDC), was examined. 4'-Thio-DMDC inhibited the growth of various cell lines established from human solid cancers, particularly the growth of lung and bladder carcinomas and melanomas. 4'-Thio-DMDC exhibited potent antitumor activity against subcutaneously implanted murine sarcoma S-180 and human fibrosarcoma HT-1080 xenografts. It was shown that 4'-thio-DMDC suppressed cell growth by inhibiting cellular DNA synthesis, and phosphorylation of the 5'-position of its deoxyribose by deoxycytidine kinase was needed for its antitumor activity. 4'-Thio-DMDC is a poor substrate for cytidine deaminase, thus it is a promising agent for the treatment of malignant solid tumors because it will not be converted into its inactive uridine form.

Animals↗
PubMed1996

Prevention of human T cell lymphotropic virus type I infection in Japanese macaques by passive immunization.

Prophylaxis against human T cell lymphotropic virus type I (HTLV-I) is of primary importance for the eradication of adult T cell leukemia and other diseases associated with this virus. Hyperimmune globulin (H-IgG) prepared from healthy blood donors with high antibody titers for HTLV-I was evaluated for its prophylactic effect against HTLV-I in Japanese macaques (Macaca fuscata). Normal IgG (N-IgG) prepared from seronegative healthy blood donors was used as control. Both preparations contained 50 mg/ml IgG and H-IgG had a neutralizing antibody titer of 1:7100 by vesicular stomatitis virus (HTLV-I) pseudotype neutralization assay. Two macaques were infused with 2 ml/kg N-IgG and three macaques were immunized with 2-0.5 ml/kg H-IgG. They were immediately challenged by inoculation of 8 x 10(6)/kg cells from an HTLV-I-producing rabbit lymphoid cell line (Ra-1). Another macaque was immunized with 1 ml/kg H-IgG 24h after inoculation of 8 x 10(6)/kg Ra-1 cells. HTLV-I infection, as determined by seroconversion and verified by polymerase chain reaction, occurred in both of the N-IgG-injected macaques but in none of the four H-IgG-injected macaques. These results demonstrate the protective efficacy of H-IgG against HTLV-I infection in a primate model and provide an experimental basis for passive immunization trials in humans.

Animals↗
PubMed1995

Differential vasodilatory action of 2-octynyladenosine (YT-146), an adenosine A2 receptor agonist, in the isolated rat femoral artery and vein.

The vasodilatory action of 2-octynyladenosine (YT-146), an adenosine A2 receptor agonist, was investigated in the isolated rat femoral artery and vein. Exposure to YT-146 resulted in preferential vasodilatation; the vein was completely dilated at YT-146 concentrations as low as 10(-7) M; in contrast, a concentration of YT-146 greater than 10(-4) M was necessary to induce complete relaxation in the femoral artery. 2-[p-(2-Carboxyethyl)-phenethylamine]-5'-N-ethylcarboxamidoadenosine (CGS 21680) also evoked stronger dilation in the vein than in the artery. The vasodilatory action of N6-cyclopentyladenosine (CPA) was much weaker in the vein than that of YT-146. YT-146-induced vasodilation in the artery was antagonized by neither 10(-7) M 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) nor 3 x 10(-6) M (E)-8-(3,4-dimethoxystylyl)-1,3-dipropyl-7-methylxanthine (KF17837), while the vasodilation in the vein was only antagonized by KF17837, suggesting that the vasodilation may involve adenosine A2 receptor activation in the vein. However, the present study did not provide evidence of a link between adenosine agonist-induced vasodilation and adenosine A2 receptor activation in the artery. The addition of 10(-4) M N omega-nitro-L-arginine partially reversed YT-146-induced vasodilation in the artery, but not in the vein. The reversal of YT-146-induced vasodilation by N omega-nitro-L-arginine in the artery was attenuated by the addition of 10(-3) M L-arginine. Removal of the endothelium decreased YT-146-induced vasodilation in the artery, but not in the vein.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1995

Deglycosylation of antiherpesviral 5-substituted arabinosyluracil derivatives by rat liver extract and enterobacteria cells.

A number of antiherpesviral 5-substituted derivatives of 1-beta-D-arabinofuranosyluracil (araU) were significantly resistant to phosphorolysis by rat liver extract (S-9), but were gradually deglycosylated in a 2% enterobacteria cell suspension. The relative order of the resistance conferred by the different C-5 substituents was: 5-propynyl > 5-(E)-2-bromovinyl > 5-(E)-2-chlorovinyl > 5-methyl > 5-iodo. The 2'-fluoro derivatives of araU were completely resistant to phosphorolysis by both liver extract and enterobacteria, whereas the corresponding ribofuranosyl and 2'-deoxyribofuranosyl nucleosides were easily phosphorolysed by S-9, and were immediately cleaved in a 1% enterobacteria cell suspension. These findings suggest that antiherpesviral 5-substituted araU analogues can be relatively stable in vivo, when injected intravenously, and that degradation of 1-beta-D-arabinofuranosyl-5-(E-2-bromovinyl)uracil (sorivudine) following oral administration is due primarily to the action of enterobacteria.

Animals↗
PubMed1995

Vaccination of rabbits with recombinant vaccinia virus carrying the envelope gene of human T-cell lymphotropic virus type I.

Two groups of 3 rabbits each were immunized with either recombinant vaccinia virus, WR-SFB5env, carrying the human T-cell lymphotropic virus type I (HTLV-I) env gene at the site of the hemagglutinin gene of the WR strain, or control vaccinia virus, HA-WR, lacking the functional hemagglutinin gene. All 6 rabbits responded with anti-vaccinia virus antibodies. WR-SFB5env elicited anti-HTLV-I env antibodies but no vesicular stomatitis virus (HTLV-I) pseudotype neutralizing antibodies in all 3 rabbits. After 10 weeks, the animals were challenged by transfusion of blood from an HTLV-I-infected rabbit. Two of the 3 vaccinated rabbits and all 3 control rabbits became infected with HTLV-I, as indicated by seroconversion and detection of HTLV-I proviral sequences by polymerase chain reaction. The rabbit that had been protected from initial challenge became infected with HTLV-I upon rechallenge 12 weeks after the first challenge. In view of the proven prophylactic effect of passive immunization against HTLV-I, our vaccine trial failed because WR-SFB5env was incapable of inducing neutralizing antibodies against HTLV-I in the immunized animals. It remains to be studied whether cell-mediated immunity such as antibody-dependent cellular cytotoxicity was involved in the temporary protection of I vaccinated rabbit.

Animals↗
PubMed1995

Endothelium-derived hyperpolarizing factor does not contribute to the decrease in endothelium-dependent relaxation in the aorta of streptozotocin-induced diabetic rats.

1. We examined the contribution of endothelium-derived hyperpolarizing factor (EDHF) to the impairment of endothelium-dependent relaxation caused by acetylcholine (ACh) in the aorta of streptozotocin-induced diabetic rats, by using N omega-L-nitro-arginine methylester (L-NAME) and tetraethylammonium chloride (TEA) to inhibit nitric oxide (NO) and EDHF, respectively. 2. ACh-induced relaxation of the aorta decreased in diabetic rats. In contrast, sodium nitroprusside-induced relaxation was the same in diabetic rats and control rats. 3. Treatment with 5 x 10(-7) M L-NAME resulted in a right shift of the dose-response curves of ACh-induced relaxation in the aorta. The shift was greater in the control aorta. 4. Treatment with 5 x 10(-4) M TEA resulted in a similar right shift in both the control and diabetic aorta. 5. Therefore, while endothelium-derived NO appears to contribute to the impairment of ACh-induced endothelium-dependent relaxation in the aorta of diabetic rats, EDHF does not.

Acetylcholine↗
PubMed1995

Comparison of the selectivity of anti-varicella-zoster virus nucleoside analogues.

We compared the selectivity of six anti-varicella-zoster virus (VZV) drugs, which are clinically available or of which clinical efficacy for the treatment of VZV infections has been reported. Sorivudine (BV-araU) had the most potent anti-VZV effect in the plaque inhibition assay, followed by brivudine (BVDU) and 5-propynyl-arabinofuranosyluracil (Pry-araU). All test compounds, except vidarabine (AraA), had only a very weak effect on human embryonic lung cell growth. The selectivity indexes (ID50 for cell growth/ED50 for VZV plaque inhibition) of BV-araU, BVDU, and Pry-araU were > 1,000,000, 20,000, and > 10,000, respectively, while those of acyclovir and penciclovir ranged from 600 to 800. AraA was much less selective than any of the other drugs tested. We measured the amount of [3H] thymidine incorporated into the acid-insoluble fraction of VZV-infected cells to determine the ability of these drugs to selectively inhibit viral DNA synthesis. [3H]Thymidine incorporation was markedly inhibited by all anti-VZV compounds, except BVDU. Treatment of infected cells with drugs from 32 to 38 hr after infection inhibited the DNA synthesis to the same extent as VZV plaque formation, except that AraA inhibited the DNA synthesis at a lower dose than for VZV plaque formation. DNA synthesis in non-infected growing cells was inhibited to the same extent as cell growth. A particularly high selectivity index for the inhibition of DNA synthesis was noted for BV-araU, which was defined as the ratio of inhibitions of DNA synthesis in VZV-infected and non-infected. The highest selectivity indexes were recorded for BV-araU > Pry-araU > acyclovir > or = penciclovir > AraA.

Antiviral Agents↗
PubMed1995

The effects of anxiolytics and anxiogenics on evaluation of learning and memory in an elevated plus-maze test in mice.

We examined the effects of anxiolytics and anxiogenics on evaluation of learning and memory in the elevated plus-maze test in mice. Transfer latency (TL), the time mice took to move from the open arm to the enclosed arm, was used as an index of learning and memory. The TL on day 2 was shorter than that on day 1 with the maze at a height of 40 cm, and was not affected by anxiolytics and anxiogenics such as 8-OH-DPAT (0.4 mg/kg), picrotoxin (2 mg/kg), and FG-7142 (20 mg/kg), but was affected by diazepam (8 mg/kg). On the other hand, the TL on day 2 was prolonged by changing the experimental room between day 1 and day 2. TL on day 1 and day 2. TL on day 2 was prolonged by treatment with scopolamine before the trial on day 1 compared with vehicle-treated groups. This scopolamine-induced prolongation of TL was reversed by pretreatment with physostigmine and piracetam. The TL on day 2 was also prolonged by treatment with cycloheximide or normobaric hypoxia initiated immediately after the trial on day 1. The cycloheximide- and hypoxia-induced prolongation of TL were reversed by pretreatment with piracetam. These results indicate that disruption of learning and memory and its amelioration, induced by the treatments described above, can be detected using the plus-maze test, suggesting that the elevated plus-maze test could be used for evaluation of learning and memory without influence of anxiolytics and anxiogenics.

Animals↗
PubMed1995

A facile synthesis of 4'-thio-arabinonucleosides as potential antiviral agents from D-glucose.

As potential antiviral agents, 4'-thio-arabinonucleosides were synthesized. Methyl 3-O-benzyl-xylo-furanoside, readily obtained from D-glucose, was converted to 1,4-anhydro-4-deoxy-4-thio-arabinitol. The protection of hydroxyl groups and the Pummerer rearrangement, followed by Lewis acid induced glycosylation afforded 4'-thio-arabinonucleosides. The compounds showed anti HSV-1 activity.

Antiviral Agents↗
PubMed1994

Effects of 1-amino-5-bromouracil on the benzodiazepine-GABAA receptor complex.

We investigated the effects of 1-amino-5-bromouracil on the benzodiazepine-gamma-aminobutyric acid (GABA)A receptor complex to elucidate its central action. 1-Amino-5-bromouracil neither displaced nor enhanced [3H]muscimol, [35S]t-butylbicyclophosphorothionate (TBPS), or [3H]dehydroepiandrosterone sulfate binding to the rat brain synaptosomal membranes. The anesthesia induced by 1-amino-5-bromouracil was potentiated by diazepam, pentobarbital, and muscimol, and was antagonized by picrotoxin but not by bicuculline. 1-Amino-5-bromouracil protected mice from picrotoxin-induced seizure and slightly ameliorated TBPS-induced seizure, but did not antagonize bicuculline-induced seizure. Diazepam antagonized both the bicuculline- and the picrotoxin-induced seizure, and pentobarbital antagonized the picrotoxin- and the TBPS-induced seizure. Our in vivo studies suggest that part of the central action of 1-amino-5-bromouracil is concerned with the benzodiazepine-GABAA receptor complex including the chloride channel.

Anesthesia↗