Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The acyclic nucleoside phosphonates [HPMPC (cidofovir), PMEA (adefovir) and PMPA] have proved to the effective in vitro (cell culture systems) and in vivo (animal models, clinical studies) against a wide variety of DNA virus and retrovirus infections: i.e., HPMPC against herpesvirus (herpes simplex virus type 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus types 6, 7, and 18), polyoma-, papilloma-, adeno-, and poxvirus (vaccinia virus, molluscum contagiosum virus) infections; PMEA against herpesvirus, hepadnavirus (human hepatitis B virus) and retrovirus (human immunodeficiency virus type 1 and 2, simian immunodeficiency virus, and feline immunodeficiency virus) infections; and PMPA against both hepadna- and retrovirus infections.
 ...
PMID:Acyclic nucleoside phosphonates in the chemotherapy of DNA virus and retrovirus infections. 967 35

Adefovir dipivoxil [9-(2-(bispivaloyloxymethyl)phosphonylmethoxyethyl)adenine (bis-POM PMEA)], an oral prodrug of adefovir (PMEA), is currently in phase III clinical testing for the treatment of human immunodeficiency virus-1 (HIV-1) infection. Previous in vitro experiments have shown that HIV-1 recombinant viruses expressing either a K65R or a K70E mutation in reverse transcriptase (RT) have reduced sensitivity to PMEA and that the K70E mutant also has impaired replication capacity in vitro. Genotypic analyses of samples from patients enrolled in a phase I/II clinical trial of adefovir dipivoxil demonstrated that the K70E RT mutation developed in two of 29 patients during extended therapy. To further investigate the molecular mechanisms involved in the resistance to PMEA, we cloned, expressed, and purified HIV-1 RT enzymes carrying either the K65R or K70E and, for comparison, the M184V mutation. The Km values of dNTPs for these mutant enzymes were not significantly altered from wild-type RT. The Ki values for the K65R mutant were increased from wild-type by 2-5-fold against a variety of inhibitors, whereas the Ki values for the M184V mutant were increased 12-fold specifically for 2', 3'-dideoxy-3'-thiacytidine (3TC) triphosphate. The Ki values for the K70E mutant were increased for PMEA diphosphate and 3TC triphosphate by 2-3-fold. These results are in agreement with antiviral drug susceptibility assay results. The three recombinant enzymes were also evaluated for their specific activities and processivities. All mutants were reduced in specific activity with respect to wild-type RT. In single-cycle processivity studies, the M184V mutant was, as expected, notably impaired. The K70E mutant was also slightly impaired, whereas the K65R mutant was slightly more processive than wild-type. These results with recombinant K70E RT are consistent with the reduced in vitro replication capacity of the K70E RT mutant of HIV-1 and further demonstrate that the K70E mutation confers minor PMEA and 3TC resistance to HIV-1.
 ...
PMID:Human immunodeficiency virus type 1 reverse transcriptase expressing the K70E mutation exhibits a decrease in specific activity and processivity. 968 70

LP-BM5 murine leukemia virus (MuLV) infection causes severe immunodeficiency termed murine AIDS (MAIDS). The acyclic nucleoside phosphonates, (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA) were examined, in comparison with zidovudine (AZT), for their inhibitory effect on the development of MAIDS. Although no significant difference in inhibition of LP-BM5 MuLV replication was identified between PMPA and PMEA in cell cultures, PMPA was obviously less cytotoxic to the host lymphocytes. None of the mice treated in vivo with 5 or 25 mg/kg of PMPA or 25 mg/kg of PMEA developed MAIDS at 5 weeks after viral infection. However at 9 weeks, none of the 25 mg/kg PMPA-treated mice progressed to MAIDS, except for one that developed mild MAIDS, whereas PMEA, even at 100 mg/kg, could not prevent disease progression. MAIDS-associated activation of lymphocytes and viral replication were drastically inhibited by PMPA treatment. These results indicate that PMPA is a highly effective antiretroviral agent in vivo.
 ...
PMID:Prevention of murine AIDS development by (R)-9-(2-phosphonylmethoxypropyl)adenine. 970 36

Nucleoside and nucleotide analogues, which are inhibitors of human immunodeficiency virus reverse transcriptase, are highly active inhibitors of visna virus replication in cell cultures. One such analogue, the acyclic nucleoside phosphonate PMEA, has also been found to have a prophylactic effect on visna virus infection in lambs. In the present study, lambs were injected subcutaneously with 10 mg/kg PMEA three times a week starting 4 weeks after inoculation with visna virus, when brain infection had been established. After 3 weeks of treatment there was a reduction in the amount of virus isolated from blood cells of PMEA-treated lambs compared to controls and during the remaining 7 months of drug treatment there was significantly less virus isolated from the blood cells of treated lambs than of controls. Antibody response against visna virus was also slower in the treated than in the untreated control group. On the other hand, there was no difference in the amount of virus isolated from various organs of the two groups and the severity of CNS lesions in sheep treated with PMEA for 8 months was comparable to that found in untreated controls, even though PMEA reached concentrations in the cerebrospinal fluid which were well in excess of the EC50 value of the drug for visna virus.
 ...
PMID:Treatment of visna virus infection in lambs with the acyclic nucleoside phosphonate analogue 9-(2-phosphonylmethoxyethyl)adenine (PMEA). 987 3

Intracellular delivery of novel macromolecular drugs against human immunodeficiency virus type-1 (HIV-1), including antisense oligodeoxynucleotides, ribozymes and therapeutic genes, may be achieved by encapsulation in or association with certain types of liposomes. Liposomes may also protect these drugs against nucleases. Low-molecular-weight, charged antiviral drugs may also be delivered more efficiently via liposomes. Liposomes were targeted to HIV-1-infected cells via covalently coupled soluble CD4. An HIV-1 protease inhibitor encapsulated in conventional negatively charged multilamellar liposomes was about 10-fold more effective and had a lower EC90 than the free drug in inhibiting HIV-1 production in human monocyte-derived macrophages. The drug encapsulated in sterically stabilized liposomes was as effective as the free drug. The EC50 of the reverse transcriptase inhibitor 9-(2-phosphonylmethoxyethyl)adenine (PMEA) was reduced by an order of magnitude when delivered to HIV-1-infected macrophages in pH-sensitive liposomes. A 15-mer antisense oligodeoxynucleotide against the Rev response element was ineffective in free form against HIV-1 replication in macrophages, while delivery of the oligonucleotide in pH-sensitive liposomes inhibited virus replication. The oligodeoxynucleotide encapsulated in sterically stabilized pH-sensitive liposomes with prolonged circulation in vivo, which were recently developed in the laboratories of the authors, was also highly effective. A ribozyme complementary to HIV-1 5'-LTR delivered in pH-sensitive liposomes inhibited virus production by 90%, while the free ribozyme caused only a slight inhibition. Cationic liposome-mediated co-transfection of the HIV-regulated diphtheria toxin A fragment gene and a proviral HIV clone into HeLa cells completely inhibited virus production, while the frame-shifted mutant gene was ineffective. Co-transfection of the proviral genome and a gene encoding a Rev-binding aptamer into HeLa cells via transferrin-associated cationic liposomes inhibited virus production. These studies indicate that liposomes can be used to facilitate the intracellular delivery of certain anti-HIV agents and to enhance their therapeutic effects. These properties may be particularly advantageous in the development of novel macromolecular drugs, which may be necessary because of the emergence of virus strains resistant to the currently available drugs.
 ...
PMID:Liposome-mediated delivery of antiviral agents to human immunodeficiency virus-infected cells. 1033 45

We assessed the effects of hydroxyurea (HU) at a concentration of 50 microM on the in vitro activities of 2',3'-dideoxyinosine (ddI), 9-[2-(phosphonylmethoxy)ethyl]adenine (PMEA), and 9-[2-(phosphonylmethoxy)propyl]adenine (PMPA) against a wild-type human immunodeficiency virus (HIV) type 1 (HIV-1) laboratory isolate and a panel of five well-characterized drug-resistant HIV isolates. Fifty micromolar HU significantly increased the activities of ddI, PMEA, and PMPA against both the wild-type and the drug-resistant HIV-1 isolates. In fixed combinations, both ddI and PMEA were synergistic with HU against wild-type and drug-resistant viruses.
 ...
PMID:Hydroxyurea enhances the activities of didanosine, 9-[2-(phosphonylmethoxy)ethyl]adenine, and 9-[2-(phosphonylmethoxy)propyl]adenine against drug-susceptible and drug-resistant human immunodeficiency virus isolates. 1042 34

Adefovir dipivoxil (bis-POM PMEA) is an adenine nucleotide analogue with activity against retroviruses and herpesviruses, and in vitro activity against hepatitis B virus (HBV). This study was conducted to evaluate its safety and antiviral activity in patients with chronic HBV infection. Twenty patients (13 co-infected with human immunodeficiency virus, HIV) were randomized in a phase I/II, double-blind, placebo-controlled study. Patients who had been hepatitis B surface antigen (HBsAg)/hepatitis B e antigen (HBeAg) positive for > or = 6 months, with elevated hepatic transaminases and serum HBV DNA > or = 50 pg ml-1, were randomized to adefovir dipivoxil 125 mg (n = 15) or placebo (n = 5) as a single, daily, oral dose for 28 days. Antiviral activity was assessed by changes in serum HBV DNA (using the Digene Hybrid Capture assay) and HBeAg/hepatitis B e antibody (HBeAb) status. HBV DNA levels fell rapidly by > 1 log10 in all active drug recipients (median fall 1.8 log10 pg ml-1) but increased by 0.01 log10 pg ml-1 in controls (P = 0.002). Reductions were sustained during treatment. HBV DNA returned to baseline over 1-6 weeks following discontinuation of active drug. HBeAg became transiently undetectable in one patient on treatment and, in another, sustained seroconversion to HBeAb occurred 12 weeks after treatment ended. Liver transaminase elevations > 300 U l-1 were observed in three patients during therapy (leading to protocol-specified treatment discontinuation or dose reduction) and in four patients during follow-up. On-treatment transaminase elevations were associated with HIV status, occurring in three of six HIV-uninfected patients compared with none of nine who were HIV infected. In addition, a slower return to baseline of serum HBV DNA levels was observed in the non-HIV-infected patients. Treatment for chronic hepatitis B as a once-daily oral dose was well tolerated and associated with significant and sustained reductions in serum HBV DNA levels during treatment. Transaminase elevations, which may be related to the therapeutic effect, were observed during and after treatment. Further studies are warranted to investigate the safety, and optimum dose and duration, of adefovir dipivoxil treatment for chronic hepatitis B.
 ...
PMID:A placebo-controlled phase I/II study of adefovir dipivoxil in patients with chronic hepatitis B virus infection. 1060 55

The compound 9-(2-phosphonylmethoxyethyl)adenine (adefovir; PMEA) is a potent inhibitor of a number of viruses in vitro, such as human immunodeficiency virus (HIV) type 1 and 2, herpes simplex virus (HSV) type 1 and 2, human papillomavirus virus (HBV) and Epstein-Barr virus (EBV). Adefovir also proved to be effective in vivo against feline immunodeficiency virus (FIV) in cats and simian immunodeficiency virus (SIV) in rhesus monkeys. In an open, non-placebo-controlled trial the antiviral activity of weekly doses of adefovir in nine patients with AIDS or AIDS-related complex was studied for a period of 11 weeks. CD4 cell counts at baseline were between 10 and 450 cells/mm3, HIV-1 RNA levels at baseline were between 24,210 copies/ml and 406,197 copies/ml. The drug was administered intravenously at a dose of 1000 mg every week and plasma viral load was assessed at multiple points during the study. Administration of adefovir was tolerated well and no severe side effects were seen. The response to adefovir treatment differed widely between patients. The increase in CD4 cell count at end point ranged from -40 to 120 cell/mm3. The lowest HIV RNA levels were measured after 3-5 days, showing an increase thereafter. The nadir in viral load was achieved after 2 weeks, with a mean viral load decline of 0.7 from baseline. The decrease of the HIV RNA level at end point ranged from -0.3 log10 to 1.8 log10 with a mean decrease of 0.4 log10. Our results indicate that adefovir given intravenously once weekly has a short-lasting initial antiviral effect. The effect of more frequent dosing requires further evaluation. If adefovir is to be useful clinically, it needs to be combined with other antiviral agents.
 ...
PMID:Effect of weekly adefovir (PMEA) infusions on HIV-1 virus load: results of a phase I/II study. 1068 55

Adefovir is a nucleotide analog with anti-human immunodeficiency virus (HIV) activity that has been extensively studied in clinical trials. While on prolonged anti-HIV therapy with adefovir, some patients may develop drug-associated nephrotoxicity manifested by changes in laboratory markers of renal tubular functions that are reversible upon drug discontinuation. It has been recently shown that adefovir is efficiently transported by the human renal organic anion transporter 1 (hOAT1), a membrane transport protein localized in the kidney, that presumably mediates the accumulation of adefovir in renal proximal tubules. In an effort to look for novel inhibitors of this transport process, we used a cell line stably expressing hOAT1 to demonstrate that nonsteroidal anti-inflammatory drugs (NSAIDs) efficiently inhibit hOAT1-specific transport of adefovir at clinically relevant concentrations. Diflunisal, ketoprofen, flurbiprofen, indomethacin, naproxen, and ibuprofen were equally or more effective (IC(50) = 0.85-8 microM) than probenecid or betamipron, two known potent inhibitors of hOAT1 (IC(50) = 8 and 6 microM, respectively) with in vivo nephroprotective effects. Importantly, NSAIDs significantly reduced the shift in adefovir cytotoxicity observed upon hOAT1 expression with ketoprofen and naproxen being 2- to 3-times more effective than probenecid. Transport experiments with [(3)H]ketoprofen and [(3)H]ibuprofen revealed that NSAIDs themselves were not efficiently transported by hOAT1. None of the NSAIDs tested showed any interference with the anti-HIV activity of adefovir. In conclusion, these observations suggest that NSAIDs may reduce or delay the emergence of adefovir nephrotoxicity.
 ...
PMID:Nonsteroidal anti-inflammatory drugs efficiently reduce the transport and cytotoxicity of adefovir mediated by the human renal organic anion transporter 1. 1099 54

We report that simian immunodeficiency virus (SIV) infection in macaques is a valuable animal model for studying post-exposure chemoprophylaxis (PECP). PECP with the acyclic nucleoside reverse transcriptase inhibitors 9-(2-phosphonylmetho-xyethyl)adenine (PMEA) and (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) at early viral infection can provide long-term protection against subsequent heterologous SIV challenge. Eight macaques previously treated with PECP (called PECP macaques) and four naive controls were challenged intravenously with the most virulent form of SIV, SIV(PBj14). All controls showed signs of SIV(PBj14)-induced acute disease syndrome on days 6 and 7 post-inoculation (PI). One had a fatal viral infection and two surviving controls had persistent infection and decreased CD4+ cell count. Virologic studies of the three surviving controls revealed SIV in multiple lymphoid tissues and peripheral blood mononuclear cells (PBMCs) at necropsy. In contrast, the PECP macaques showed none to mild signs of acute disease syndrome at day 9 PI and exhibited only transient SIV infection in PBMCs between weeks 1 and 8 PI. In virologic studies of five PECP macaques necropsied, two macaques were SIV-negative and the other three were SIV-positive only in either lymph node or bone marrow. Three SIV(PBj14)-challenged PECP macaques, that were randomly reserved for a follow-up study for > 4.0 years PI showed extremely low to undetectable levels of PBMC-associated viremia and normal to increased levels of CD4 + and CD8 + cell counts throughout the study. Our results indicate that early PECP could activate immune responses to protect against subsequent infection with heterologous challenge virus.
 ...
PMID:Post-exposure chemoprophylaxis (PECP) against SIV infection of macaques as a model for protection from HIV infection. 1108 87


<< Previous 1 2 3 4 5 6 7 8 9 Next >>