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Biomedical subjects

H Mitsuya

Publications and source records attributed to H Mitsuya.

At least 163 records · Page 9Linked to original sources
PubMed1990

Immunologic issues in anti-retroviral therapy.

A number of drugs acting at different stages of viral replication have been shown to be effective anti-HIV agents in the laboratory, and several have been found to be active in patients. It has become evident that inhibition of viral replication in HIV-infected patients will result in an improvement in their immune function. However, as Robert Yarchoan, Hiroaki Mitsuya and Samuel Broder point out, complete immunoreconstitution generally does not occur in patients with established AIDS using currently available therapies. It is important to understand the factors that limit immunologic improvement in such patients so that more effective therapy can be devised.

Antiviral Agents↗
PubMed1990

Antiviral therapy against HIV infection.

The replication of human immunodeficiency virus (HIV) can be suppressed in vivo by drugs chosen on the basis of their selective in vitro antiviral activity. Such suppression can confer prolonged survival and improved quality of life in patients with already established HIV infection. The clinical benefits indicate that targeted therapy for acquired immunodeficiency syndrome based on the emerging knowledge of replicative cycle of HIV is an attainable goal.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Acid-stable 2'-fluoro purine dideoxynucleosides as active agents against HIV.

2',3'-Dideoxy purine nucleosides have anti-HIV activity in vitro and the inosine analogue is being clinically evaluated. The instability of these compounds toward acidic conditions complicates oral administration. The effect of the addition of a fluorine atom to the 2'-position was investigated by preparing the fluorine-containing 2'-erythro and 2'-threo isomers of ddA and the threo isomer of ddI. All fluorine-containing compounds were indefinitely stable to acidic conditions which completely decomposed ddI (1) and ddA (2) in minutes. While the fluorine-containing erythro isomer, 5, was inactive, the threo isomers, 2'-F-dd-ara-A (3) and 2'-F-dd-ara-I (4), were just as potent and active in protecting CD4+ ATH8 cells from the cytopathogenic effects of HIV-1 as the parent drugs. Exposure to pH 1 at 37 degrees C prior to testing destroyed the activity of ddA and ddI but left the anti-HIV properties of 3 and 4 unchanged. The fluorinated analogues also protected cells exposed to HIV-2 and inhibited gag gene product expression but not as effectively as the parent compounds. The fluorine-containing analogues appear to be somewhat more toxic in vitro to the antigen- and mitogen-driven proliferation of immunocompetent cells than their corresponding parent compounds.

Antiviral Agents↗
PubMed1990

Lipophilic halogenated congeners of 2',3'-dideoxypurine nucleosides active against human immunodeficiency virus in vitro.

Four 2-amino-6-halo- and four 6-halo-2',3'-dideoxypurine ribofuranosides (ddPs) were synthesized and tested for in vitro activity to suppress the infectivity, cytopathic effect, Gag protein expression, and DNA synthesis of human immunodeficiency virus (HIV). The comparative order of in vitro anti-HIV activity of the eight 6-halo-ddPs was as follows: 2-amino-6-fluoro, 2-amino-6-chloro, 6-fluoro greater than 2-amino-6-bromo greater than 2-amino-6-iodo, 6-chloro greater than 6-bromo greater than 6-iodo. 2-Amino-6-fluoro-, 2-amino-6-chloro-, and 6-fluoro-ddPs showed a potent activity against HIV comparable to that of 2',3'-dideoxyinosine (ddI) or 2',3'-dideoxyguanosine (ddG) and completely blocked the infectivity of HIV without affecting the growth of target cells. The lipophilicity order was as follows: 2-amino-6-iodo greater than 2-amino-6-bromo greater than 2-amino-6-chloro greater than 2-amino-6-fluoro much greater than ddG greater than ddI. All eight 6-halo-ddPs were substrates for adenosine deaminase (ADA; adenosine aminohydrolase, EC 3.5.4.4). The relative rates of hydrolysis by ADA were as follows: ddA, 2-amino-6-fluoro much greater than 2-amino-6-chloro, 2-amino-6-bromo greater than 2-amino-6-iodo. Taken together, these compounds may represent an additional class of lipophilic prodrugs for ddI and ddG and may also provide a strategy for endowing therapeutic purine nucleosides with desirable lipophilicity.

Antiviral Agents↗
PubMed1990

Quantitative analysis of HIV-1 proviral DNA in peripheral blood mononuclear cells from patients with AIDS or ARC: decrease of proviral DNA content following treatment with 2',3'-dideoxyinosine (ddI).

A rapid and simple method for determining the proviral DNA content in peripheral blood mononuclear cells (PBM) from patients with human immunodeficiency virus type 1 (HIV-1) infection was established by using the polymerase chain reaction (PCR) technique. We found that the majority of HIV proviral DNA copies detectable in unfractionated PBM resided in T cells, while B cells/monocytes contained lesser amounts of HIV DNA (93.9 +/- 3.5% for T cells vs. 6.1 +/- 3.5% for B cells/monocytes: p less than 0.05). When we compared the amount of HIV proviral DNA in PBM from 13 patients with AIDS or AIDS-related complex (ARC) before and during antiretroviral therapy with 2',3'-dideoxyinosine (ddI) which was given as an escalating dose in a Phase I clinical study, a significant decrease was observed in 9 of 12 evaluable patients receiving the drug for 8 to 14 weeks (p less than 0.02). The decrease appeared more pronounced in patients receiving relatively high doses of the drug. These data suggest that the quantitation of HIV viral DNA in PBM by PCR is feasible and may theoretically contribute to an overall monitoring of patients receiving experimental therapy. However, larger studies will be required to determine the sensitivity and specificity of this assay and further longitudinal studies will be essential.

AIDS-Related Complex↗
PubMed1990

Pharmacokinetic analysis of dextran sulfate in rats as pertains to its clinical usefulness for therapy of HIV infection.

We administered radiolabeled dextran sulfate (3H labeled on the reducing end, MW approximately 8000) [( 3H]DS) to rats. High-performance liquid chromatography (HPLC) analysis of plasma from animals that were given [3H]DS intravenously revealed an initial plasma half-life of about 30 min. Eleven percent of [3H]DS administered was recovered in the urine in 24 h; this material represented minor breakdown with a molecular weight of 4000 as determined by size exclusion HPLC analysis. When administered orally, the apparent bioavailability of [3H]DS was 6.8%, based on the recovered radioactivity; however, the molecular weight of the radioactive material obtained from the plasma was all less than 200, indicating that no detectable intact dextran sulfate was absorbed upon oral administration. Only 2% of orally administered [3H]DS was found in the 24-h urine; this material also had a molecular weight less than 200. Further less than 2300 had no anti-HIV effect and that in the presence of higher concentrations of human serum, more DS was required for antiviral effect. Although the pharmacokinetics of dextran sulfate in rats can differ from those in humans to some extent, these data suggest that oral administration of DS is unlikely to produce significant antiretroviral effect against HIV in vivo and higher plasma levels of DS may be necessary than those inferred from earlier in vitro data.

Administration, Oral↗
PubMed1990

Initial clinical experience with dideoxynucleosides as single agents and in combination therapy.

Several dideoxynucleosides, including 3'-azido-2',3'-dideoxythymidine (zidovudine, azidothymidine, AZT), 2',3'-dideoxycytidine (ddC), and 2',3'-dideoxyinosine (ddI), have been shown to be potent inhibitors of human immunodeficiency virus (HIV) replication in human T cells and macrophages. These compounds undergo anabolic phosphorylation within target cells to a 3'-triphosphate moiety; as triphosphates, they act at the level of HIV DNA polymerase (reverse transcriptase). AZT has been shown to reduce the morbidity and mortality of patients with severe HIV infection and to at least temporarily ameliorate certain cases of HIV-induced dementia. In phase 1 studies, ddC and ddI have been shown to induce immunologic and virologic improvements in patients with AIDS or related disorders; phase 2 studies of ddC and ddI are underway. The use of these drugs can be associated with toxicity. AZT can cause bone marrow toxicity or myositis with prolonged use, ddC can cause peripheral neuropathy at high doses, and ddI can cause sporadic pancreatitis and peripheral neuropathy at high doses. For each compound, however, a therapeutic window exists in which an anti-HIV effect can be attained without short-term toxicity in most patients. Dose-intensity appears to be an important determinant of the toxicity of dideoxynucleosides. Studies are underway to explore how the therapeutic profiles of these compounds may be enhanced by attention to scheduling or through the use of combination therapy.

Antiviral Agents↗
PubMed1990

In vitro inhibition of the infectivity and replication of human immunodeficiency virus type 1 by combination of antiretroviral 2',3'-dideoxynucleosides and virus-binding inhibitors.

We tested the in vitro inhibitory activities of three 2',3'-dideoxynucleosides and two inhibitors of viral binding in combinations against the infectivity and cytopathic effect of human immunodeficiency virus type 1. 3'-Azido-2',3'-dideoxythymidine, 2',3'-dideoxyinosine, or 2',3'-dideoxycytidine, combined with recombinant soluble CD4 (sCD4), brought about synergistic antiretroviral activity without toxicity at clinically achievable concentrations. Combinations of 2',3'-dideoxynucleosides plus dextran sulfate exerted similar synergistic antiviral effects without concomitant increases in toxicities. When sCD4 and dextran sulfate were combined, apparent antagonism was observed. We confirmed that no combination of sCD4 plus 3'-azido-2',3'-dideoxythymidine, 2',3'-dideoxyinosine, or 2',3'-dideoxycytidine significantly increased the inhibitory effect on colony formation of human myeloid-monocytic bone marrow cells in vitro at the concentrations used in this study. These data might have clinical relevance for the treatment of patients infected with human immunodeficiency virus.

Antiviral Agents↗
PubMed1990

Cyclobut-A and cyclobut-G, carbocyclic oxetanocin analogs that inhibit the replication of human immunodeficiency virus in T cells and monocytes and macrophages in vitro.

Two newly synthesized carbocyclic oxetanocin analogs, (+/-)-9-[(1 beta,2 alpha,3 beta)-2,3-bis(hydroxymethyl)-1-cyclobutyl]adenine (cyclobut-A) and (+/-)-9-[(1 beta,2 alpha,3 beta)-2,3-bis(hydroxymethyl)-1-cyclobutyl]guanine (cyclobut-G) were tested for activity against the infectivity of human immunodeficiency virus (HIV) in vitro. A number of other carbocyclic oxetanocin analogs failed to exert good antiretroviral effects. Both cyclobut-A and cyclobut-G protected CD4+ ATH8 cells against the infectivity and cytopathic effect of HIV type 1 (HIV-1) and suppressed proviral DNA synthesis in ATH8 cells exposed to HIV-1 in vitro at concentrations of 50 to 100 microM. These compounds also inhibited the in vitro infectivity of another human pathogenic retrovirus, HIV-2. Furthermore, both compounds completely suppressed the replication of a monocytotropic strain of HIV-1 in monocytes and macrophages at concentrations as low as 0.5 microM, as assessed by inhibition of HIV-1 p24 gag protein production. We also found that 2'-deoxyguanosine readily reversed the antiretroviral activity of cyclobut-G in our system, whereas the activity of cyclobut-A was hardly reversed by 2'-deoxyadenosine or 2'-deoxycytidine. We noted, however, that these compounds inhibited the proliferation of peripheral blood mononuclear cells at concentrations of greater than or equal to 100 microM in vitro. Although both cyclobut-A and cyclobut-G appear to have a certain level of in vitro toxicity, our observations may have theoretical and clinical implications in understanding the structure-activity relationships of antiretroviral agents active against HIV.

Adenine↗
PubMed1990

Synthesis and antiviral activities of carbocyclic oxetanocin analogues.

9-Cyclobutyladenine (4a), cis- and trans-9-[3- (hydroxymethyl)cyclobutyl]adenine (4b) and 9-[3,3-bis(hydroxymethyl)cyclobutyl]adenine(4d) were prepared from the corresponding cyclobutylamine derivatives (1a, 1b and 1d). Guanine congeners (9a, cis- and trans-9b and 9d) and carbocyclic oxetanocin G (1',2'-trans-9f) were also prepared. Carbocyclic oxetanocin A(1',2'-trans-4f), the preparation of which we have already published, and G were found to be active against herpes simplex virus (type 1 and 2) in vitro, while cis-4b and cis-9b showed an in vitro antiretroviral activity against human immunodeficiency virus (type 1).

Adenine↗
PubMed1990

[Masticatory area in the persons who become conscious of temporomandibular joint sound].

Using subjects conscious of temporomandibular joint sound and normal subjects, the ratio of the masticatory area to the mandibular border movement area was measured. Also, splints were fitted to subjects conscious of TMJ sound and changes of sound and masticatory areas were measured. 1. In normal subjects, the ratio tended to vary little with any of the test foods. 2. In subjects conscious of the TMJ sound, the ratio decreased in the case of all test foods when compared with the normal subjects. 3. In subjects conscious of TMJ sound, it was observed that the TMJ sound occurred in some subjects but not in others during mastication. 4. The decrease in the ratio of the subjects with no TMJ sound during mastication was more outstanding than that of subjects in which TMJ sound occurred during mastication. 5. After fitting splints, the change in the TMJ sound was accompanied by a change in the masticatory area. 6. These findings suggest that the decrease in the mastication area experienced by subjects conscious of TMJ sound, when compared with normal subjects, may be caused by the TMJ sound.

Humans↗
PubMed1990

Differences in the interaction of HIV-1 and HIV-2 with CD4.

Inhibition of infectivity, cytopathicity, and binding by soluble CD4 was determined for several human immunodeficiency virus (HIV)-1 and HIV-2 strains. Although infectivity and binding of both groups were blocked equally well by OKT4A, HIV-2 viruses were more refractory to inhibition by soluble CD4. Rates of envelope shedding, as determined by thermal stability, did not differ between HIV-1 and HIV-2; however, Scatchard plot analysis of radiolabeled virus binding revealed that fewer HIV-2 virions were bound to CD4+ cells under saturating conditions. The HIV-2 viruses also possessed consistently greater infectivity, whereas greater concentrations of gp120 were found in supernatants of HIV-1-infected cells and in HIV-2 virus pellets, suggesting that more envelope glycoprotein remains associated with HIV-2 virions. This factor may contribute to the observed in-vitro resistance of HIV-2 viruses to soluble CD4.

Antibodies, Monoclonal↗
PubMed1990

2'-Fluoro-2',3'-dideoxyarabinosyladenine: a metabolically stable analogue of the antiretroviral agent 2',3'-dideoxyadenosine.

In this report, we have compared the uptake, metabolism, and relevant enzymology of a novel anti-acquired immunodeficiency syndrome drug, 2'-fluoro-2',3'-dideoxyarabinosyladenine (2'-F-dd-ara-A) with the corresponding properties of its parent compound 2',3'-dideoxyadenosine (2',3'-ddAdo) in three human T cell lines, MOLT-4, ATH8, and CEM. In previous communications, we have reported that the primary route of metabolism of 2',3'-ddAdo in human T lymphoblasts is catabolic, i.e., deamination to 2',3'-dideoxyinosine (2',3'-ddlno). At this point, the metabolic pathway diverges, to result in either cleavage and inactivation of 2',3'-ddlno by purine nucleoside phosphorylase or in 5'-phosphorylation by a phosphotransferase, a reaction that generates 2',3'-inosine monophosphate and ultimately the putative active metabolite 2',3'-dideoxy-ATP. Studies with kinase-deficient mutant CEM lines indicate, however, that 2'-F-dd-ara-A favors a more direct anabolic route toward formation of 2'-fluoro-dideoxynucleotides, catalyzed initially by 2'-deoxycytidine kinase. In MOLT-4 cells, amounts of 2'-fluoro-dideoxyarabinosyladenine di- and triphosphate formed were approximately 20-fold and 5-fold greater than the respective accumulation of 2',3'-dideoxy-ADP and 2',3'-dideoxy-ATP over the same time of exposure. This metabolic profile was supported by enzymological studies, which revealed that 2'-F-dd-ara-A is deaminated 10 times less rapidly than ddAdo and that the resulting deaminated product is resistant to hydrolysis by purine nucleoside phosphorylase. Under similar conditions, ddAdo was rapidly degraded through cleavage of its deamination product ddlno. Like ddAdo, 2'-F-dd-ara-A was found to be transported by passive diffusion and does not enter cells via the purine nucleoside transport carrier system. However, the rate of entry of 2'-F-dd-ara-A was about half that of ddAdo (9.7 pmol/10(6) cells/min for 2'-F-dd-ara-A versus 18.4 pmol/10(6) cells/min for ddAdo). This investigation, therefore, demonstrates that, under the conditions studied, 2'-F-dd-ara-A and its deamination product 2'-fluoro-2',3'-dideoxyarabinosylhypoxanthine have metabolic properties that differ significantly from those of their parent compounds ddAdo and ddlno. These properties, combined with the previously reported resistance of the fluorinated nucleosides to acid degradation, make these compounds interesting candidates for further study as orally administered agents for the inhibition of human immunodeficiency virus replication in patients with acquired immunodeficiency syndrome.

AMP Deaminase↗
PubMed1990

[A case of urinary undiversion from ileal loop conduit].

A seventeen-year-old girl, who had had an ileal conduit urinary diversion at 5 years of age, underwent a urinary undiversion 12 years after the initial operation. She has been suffering from recurrent episodes of urinary tract infection with fever. The preoperative evaluation revealed dilatation of the bilateral pelvis and ureters on an excretory urography. Ileal conduitgraphy revealed urinary reflux from the ileal loop to the bilateral upper urinary tracts. Cyclic bladder hydrodilatation through a suprapubic cystostomy was performed and a precise urodynamic study was done on the lower urinary tract. The vesical capacity increased from 40 ml to 300 ml in a month. Cystometry and urethral pressure profile revealed a stable bladder with good detrusor contraction and preserved urethral continence. Voiding status was satisfactory with only a small amount of residue. The undiversion was undertaken as follows. The ureters were once isolated from the ileal loop and their distal ends were everted in length of 5 mm to be nipples in shape. The ureters were reanastomosed to the proximal end of the ileal loop with submucosal tunnels of 2 cm. The ileal loop was then tapered and implanted to the bladder with a submucosal tunnel of 5 cm. Eight months after the undiversion, she enjoys good urination, free from urinary tract infection. Although moderate hydronephrosis remains bilaterally, renal function is stable.

Adolescent↗