Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Antiviral activities of nucleotide heterodimers against human immunodeficiency virus type 1 in vitro. 879 15

In summary, DLV has been well-tolerated in > 1,000 HIV-1 infected patients. Skin rash is the most prevalent medical event associated with DLV therapy. The rash can be successfully dosed through or rechallenged in > 85% of patients. The pharmacokinetics are non-linear as DLV is metabolized primarily by cytochrome P4503A in the liver. Serum levels of DLV +/- 10 microM can easily be achieved in most HIV-1 patients, which are 100 fold above the in vitro IC90 activity. In clinical trials, DLV inhibits viral replication as demonstrated by positive surrogate marker responses (CD4 counts, P24 antigen concentration, PMBC and plasma virus titers, and plasma HIV RNA concentration). Susceptibility of HIV-1 strains to DLV decrease over time in a majority of subjects in which virus can be cultured. However, HIV strains from about 80% of subjects had a DLV IC50 < 10 microM (the trough DLV concentration in plasma) throughout the Upjohn trial. In HIV strains from about 20% of subjects, susceptibility to DLV remained unchanged in the first 8 months of DLV combination therapy, or HIV-1 was not recovered at all or most timepoints. In contrast, development of resistance to nevirapine or L-697,661 monotherapy or combination therapy with ZDV has occurred in the first eight weeks of therapy. The most common genotypic mutations seen to date are K103N and P236L. The clinical significance of the phenotypic, genotypic and surrogate marker changes associated with DLV remain to be elucidated. The surrogate marker responses in clinical trials suggest that DLV has clinical synergy with ZDV +/- ddI as evidenced by a better and more sustained surrogate marker response when a subject is sensitive to or naive to the nucleoside RTI combined with DLV. Future therapy with DLV will likely be in combination with one or more nucleoside or non-nucleoside RTIs, protease inhibitors and/or immunomodulatory agents.
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PMID:Delavirdine mesylate, a potent non-nucleoside HIV-1 reverse transcriptase inhibitor. 881 92

Two trials of subjects inoculated with the inactivated, gp120-depleted HIV-1 Immunogen are reported. In one study, in which 19 subjects received ZDV and 8 subjects received ddI, treatment with the HIV-1 Immunogen did not affect the pharmacokinetic parameters of the antiviral drugs. In another study, 65 subjects who were previously immunized with the HIV-1 Immunogen over a mean period of 4.0 years (range, 1.2-5.4 years) received inoculations at 0 and 6 months. At some point during this 48-week study, 72% of the subjects (47/65) were receiving antiviral drug therapy. The HIV-1 DNA load in CD4 cells and CD4 percentage were found to be stable over the 48-week period. Delayed-type hypersensitivity to HIV-1 antigens increased after two inoculations with the HIV-1 Immunogen. In these two trials, no serious treatment-related adverse events were documented in the subjects. The two studies presented herein are the first to suggest that an immune-based therapy such as the HIV-1 Immunogen can be combined safely with antiviral drugs, supporting further study to evaluate the clinical utility of this approach.
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PMID:Viral load, CD4 percentage, and delayed-type hypersensitivity in subjects receiving the HIV-1 immunogen and antiviral drug therapy. 888 95

9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA) is an acyclic nucleotide with potent in vitro activity against human immunodeficiency virus type 1 (HIV-1). The present study was undertaken to determine whether HIV-1 resistance to PMEA could be generated by in vitro selection and if so, to determine which mutations in reverse transcriptase (RT) were responsible. HIV-1LAI was serially passaged for 10 months in the presence of increasing concentrations of PMEA up to a maximum of 40 microM. After 40 passages, the 50% inhibitory concentration (IC50) of PMEA had increased almost 7-fold from 4.45 to 30.5 microM. Some cross-resistance to 2',3'-dideoxycytidine (ddC, zalcitabine), 2',3-dideoxyinosine (ddI, didanosine), and 3'-thiacytidine (3TC, lamivudine) was also observed, but no cross-reactive resistance to 3'-azido-3'-thymidine (AZT, zidovudine). Sequencing of the RT encoding region of each of eight pol clones from resistant isolates revealed a Lys-65-->Arg (K65R) substitution. HIV with the K65R mutation inserted by site-directed mutagenesis also had decreased sensitivity to PMEA in H9 cells and a similar cross-resistance profile. Thus, HIV can develop decreased sensitivity to PMEA after long-term in vitro exposure and this change is associated with a K65R substitution. Additional studies will be needed to determine whether a similar mutation in HIV RT develops in patients receiving PMEA or its orally bioavailable prodrug adefovir dipivoxil (bis-POM PMEA).
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PMID:In vitro selection and molecular characterization of human immunodeficiency virus type 1 with reduced sensitivity to 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA). 889 Nov 68

A series if 2',3'-dideoxy-3'-C-hydroxymethyl purine nucleosides were prepared based on the photochemical ring expansion of a chiral cyclobutanone precursor, (2S)-trans-2,3-bis[(benzoyloxy)methyl]cyclobutanone, in the presence of a 6-substituted purine. Both alpha- and beta-anomers are produced in this transformation. Deprotection was effected by reaction of the photoadducts with saturated methanolic ammonia. Nine purine nucleosides were tested for their inhibitory effect of HIV IIIB virus on H9 cells. The 6-hexyloxy and adenine derivatives 4e,c, respectively, appeared to be most effective at inhibiting viral reproduction with 4c comparable in activity to ddI and AZT.
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PMID:Synthesis and HIV inhibition activity of 2',3'-dideoxy-3'-C-hydroxymethyl nucleosides. 897 56

Retrovirally encoded proteases are responsible for the maturation of immature viral particles yielding mature, infectious virus. This is done by apparent (auto)-processing and self-activation of the protease (PR) from a larger viral gag-PR-(pol) protein (zymogen) precursor and subsequent processing of the viral reverse transcriptase (RT) and integrase (IN), and the gag protein precursor into mature gag proteins. Only the matured components are capable of forming capsids for intact, infectious viruses. Blocking this proteolytic process results in production of immature, non-infective virions. All retroviral proteases are aspartic-type proteases. Determination of the three-dimensional structure revealed retroviral proteases as small, nearly symmetric homodimers. This prompted de novo design of inhibitors for the HIV protease taking advantage of the unique symmetric structure of the active center, unparalleled by cellular proteases. The novel substances inhibit in vitro the HIV protease at nanomolar/subnanomolar concentrations and exhibit very low toxicity. They are inactive against human proteases such as renin or pepsin. The HIV protease inhibitors (PI) represent a promising alternative to the reverse transcriptase (RT) inhibitors (AZT, ddC, ddI) hitherto used with limited success for HIV chemotherapy. Clinical studies confirmed the low toxicity but revealed a pharmacological pattern typical for these hydrophobic compounds, such as low water solubility, poor oral bioavailibility, and short plasma half-life. Typical for antimicrobial agents, also a resistance phenomenon became evident. Latest clinical results show, however, promisingly that both problems might be overcome by application of the PI in combination with RT inhibitors (such as AZT, ddI or ddC) exerting a remarkable synergistic antiviral effect with lasting restoration of the CD4-T-cell level.
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PMID:Retroviral proteases: structure, function and inhibition from a non-anticipated viral enzyme to the target of a most promising HIV therapy. 899 87

The pharmacokinetics of didanosine and ciprofloxacin were evaluated following the administration of multiple oral doses of each drug as a single agent or in combination. Didanosine was dosed as the Videx chewable/dispersible tablet, which contains the antacids dihydroxyaluminum sodium carbonate and magnesium hydroxide. Sixteen HIV-seropositive male subjects were randomly assigned to two groups of eight each. Group A received didanosine (200 mg q 12h) for 3d, followed by didanosine (200 mg q 12h) and ciprofloxacin (750 mg q 12h) for 3d, and finished with another course of didanosine (200 mg q 12h for 3 d). Group B began with ciprofloxacin, followed by the combination, and finished with ciprofloxacin using the same doses and schedule as utilized in group A. During the combination phase of the study, ciprofloxacin was administered 2 h prior to didanosine. Serial blood and urine samples were collected on study days 4, 8, and 12 for the quantitative determination of didanosine and ciprofloxacin using validated HPLC methods. The plasma and urine data were subjected to noncompartmental pharmacokinetic analysis. A statistically significant decrease in the average AUC and UR values of ciprofloxacin was noted when it was given with didanosine, relative to administration as a single agent. However, the magnitude of the decrease in these parameters, approximately 26 and 29%, respectively, was not considered clinically significant. The apparent decrease in the bioavailability of ciprofloxacin was probably due to the formation of a chelation complex between it and the aluminum- and magnesium-containing antacids found in the didanosine tablet. Other than an approximately 16% decrease in AUC, ciprofloxacin did not alter the pharmacokinetics of didanosine. The data from the present study demonstrate that didanosine or ciprofloxacin can be added to a treatment regimen consisting of the other single agent and that cessation of treatment with one agent does not have an impact on the pharmacokinetics of the other drug. The dose of ciprofloxacin must be taken at least 2h prior to didanosine to avoid a clinically significant interaction with the antacids present in the didanosine formulation.
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PMID:A multiple-dose pharmacokinetic interaction study between didanosine (Videx) and ciprofloxacin (Cipro) in male subjects seropositive for HIV but asymptomatic. 900 70

Dideoxyinosine (ddI) is a widely used antiretroviral agent in treatment of HIV infection. Pancreatitis is a serious side effect. Two cases are reported, one with rapid development of a pseudocyst.
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PMID:Dideoxyinosine-induced pancreatitis in human immunodeficiency virus-infected children. 902 60

Several synthetic nucleoside analogues, including AZT(RETROVIR), ddC (HIVID), ddI (VIDEX), and d4T (ZERIT), are currently being used in the treatment of HIV infection. Unfortunately, in clinical use the appearance of severe and sometimes debilitating peripheral neuropathy and pain has been associated with the long-term use of several of these drugs (i.e., ddC, ddI and d4T), although not with AZT. To date, standard pre-clinical animal toxicity studies have failed to reveal any adverse neurologic effects of these compounds. However, previously reported preliminary findings suggest that ddC may alter several neuro-behavioral parameters (including locomotor activity, acoustic startle responding, and aggression) in rats and mice following presentation in the animals' drinking water for 7 days. The current series of experiments examined effects of acutely administered ddC and AZT on spontaneous locomotor activity and acoustic startle responses (with and without pre-pulse) in female Sprague-Dawley rats. Following intragastric administration, ddC reduced locomotion at all but the highest dose, whereas AZT had no significant effect on locomotor activity. Acutely administered ddC had no effect on ASR, whereas AZT increased ASR at the highest stimulus intensity. These data support the use of behavioral testing in the development of the antiviral nucleoside analogues, as behavioral testing may be more effective in identifying the neurologically active agents than is standard toxicity testing.
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PMID:Effects of ddC and AZT on locomotion and acoustic startle. I: Acute effects in female rats. 905 78

A lymphoblastoid cell line, CEM, was rendered resistant to zidovudine (AZT) in vitro by exposure to low but gradually increasing concentrations of the drug. This type of cellular resistance seems to be due to a defect of thymidine kinase (TK) activity that is acquired by cells grown in the presence of AZT. In fact, enzymatic studies with extracts from AZT-resistant cells (CEMazt), have shown that the value of the maximum velocity (Vmax) of TK activity measured with AZT and for deoxythymidine (dThd) is decreased as compared to sensitive CEM cells. Furthermore, the enzyme affinity for AZT and dThd is reduced in CEMazt. Further experiments have shown that such cells do not show resistance to other nucleoside analogs, such as ddI, ddC, AraT and D4T, suggesting that the phosphorylation pathways different from those involving TK are unaltered. Ex vivo experiments performed by using peripheral blood mononuclear cells (PBMC) from HIV infected individuals revealed that a prolonged treatment with AZT may modify the affinity of TK for dThd, thus suggesting that the aforementioned phenomenon may occur also in vivo.
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PMID:Alteration of thymidine kinase activity in cells treated with an antiviral agent. 912 32


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