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At least 937 records · Page 52Linked to original sources
PubMed2004

Chemokine mRNA levels in mononucleated cells of HIV-infected patients before and after initiation of PI- versus NNRTI-containing HAART.

To compare CC chemokine mRNA levels from native peripheral blood mononucleated cells (PBMCs) before and 6 months after the initiation of two different regimens of highly active antiretroviral therapy (HAART), we treated group 1 (n = 11) with two nucleoside analogues and the protease inhibitor (PI) indinavir boosted by ritonavir (800/100 mg b.i.d.); group 2 (n = 8) was treated with the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz instead of PI. CC chemokine mRNA levels (regulated upon T cell activation expressed secreted [RANTES], macrophage inhibitory protein [MIP]-1alpha, MIP-1beta, monocyte chemotactic protein [MCP]-1, MCP-2) were quantified from PBMCs before and 6 months after the initiation of HAART using a reverse transcription/real-time polymerase chain reaction (PCR) assay. The mRNA levels of MCP-1 and MCP-2 were significantly decreased in both groups (P < 0.05), while MIP-1alpha and MIP-1beta were decreased significantly only in the PI-treated group, but not in the NNRTI group. A moderate decrease of RANTES was observed in both treatment groups. The data suggest that HAART regimens containing either NNRTI or PI are not equivalent with regard to modification of CC chemokine mRNA profiles.

Adult↗
PubMed2006

[Drug-induced renal calculi].

Drug-induced renal calculi represent 1-2% of all renal calculi. They include two categories: those resulting from the urinary crystallisation of a highly excreted, poorly soluble drug or metabolite, and those due to the metabolic effects of a drug. Indinavir, used in HIV-infected patients, sulfonamides, especially sulfadiazine, and triamterene, which is less prescribed today, are the most frequent. Besides these drugs, about twenty other molecules, among them silicate-containing drugs and some antibiotics have been reported in patients receiving high doses or long-term treatments. Calculi analysis by physical methods such as infrared spectroscopy or x-ray diffraction can demonstrate the presence of the drug or its metabolites inside the calculi. In those calculi due to the metabolic effects of a drug, diagnosis relies on both stone analysis and clinical inquiry. Incidence of such calculi is probably underestimated, especially those due to calcium/vitamin D supplements or carbonic anhydrase inhibitors. Drug-induced calculi occur more often during high-dose or long term treatments, but there are also patient-related risk factors in relation to urine pH, urine output and other parameters, which can provide a basis for preventive treatment of such calculi. A better knowledge of these lithogenic complications of treatments and of solubility characteristics of drugs should reduce the incidence of drug-induced nephrolithiasis, especially in patients with identified risk factors.

HIV Protease Inhibitors↗
PubMed2005

Antileishmanial activity of HIV protease inhibitors.

The proteasomes of some protozoa are possible targets for chemotherapy. Leishmaniasis is a major health problem in human immunodeficiency virus (HIV) co-infected subjects. Two HIV protease inhibitors (PI), indinavir and saquinavir, have been shown to block proteasome functions; we therefore investigated their effects on the growth of two Leishmania spp. (Leishmania major and Leishmania infantum). After 24 h of treatment, both drugs exhibited a dose-dependent antileishmanial activity, with 50% lethal dose (LD50) values of, respectively, 8.3 microM and 7 microM on L. major; minor activity was observed on L. infantum. These results add new in vitro insights into the wide-spectrum efficacy of PI and suggest studying their action on amastigote forms of leishmania within macrophages in order to validate their potential contribution against opportunistic infections in treated seropositive patients.

Animals↗
PubMed2006

An isocratic liquid chromatography method for determining HIV non-nucleoside reverse transcriptase inhibitor and protease inhibitor concentrations in human plasma.

An efficient, isocratic high performance liquid chromatography (HPLC) method for determining human immunodeficiency virus (HIV) non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) in plasma is advantageous for laboratories participating in clinical trials and therapeutic drug monitoring (TDM) programs, or conducting small animal research. The combination of isocratic reversed phase chromatography using an S-3, 3.0 mm x 150 mm column along with low plasma volume (200 microl), rapid liquid-liquid extraction, and detection at a single wavelength (212 nm) over a short run time makes this method valuable. Within and between assay variability ranges from 0.8 to 3.5% and 1.2-6.2%, respectively. Accuracy ranges from 91.0 to 112.8% for four quality controls (50, 100, 1000, and 10,000 ng/ml) for all drugs measured (efavirenz, nevirapine, amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir).

Alkynes↗
PubMed2006

Mechanism of drug resistance revealed by the crystal structure of the unliganded HIV-1 protease with F53L mutation.

Mutations in HIV-1 protease (PR) that produce resistance to antiviral PR inhibitors are a major problem in AIDS therapy. The mutation F53L arising from antiretroviral therapy was introduced into the flexible flap region of the wild-type PR to study its effect and potential role in developing drug resistance. Compared to wild-type PR, PR(F53L) showed lower (15%) catalytic efficiency, 20-fold weaker inhibition by the clinical drug indinavir, and reduced dimer stability, while the inhibition constants of two peptide analog inhibitors were slightly lower than those for PR. The crystal structure of PR(F53L) was determined in the unliganded form at 1.35 Angstrom resolution in space group P4(1)2(1)2. The tips of the flaps in PR(F53L) had a wider separation than in unliganded wild-type PR, probably due to the absence of hydrophobic interactions of the side-chains of Phe53 and Ile50'. The changes in interactions between the flaps agreed with the reduced stability of PR(F53L) relative to wild-type PR. The altered flap interactions in the unliganded form of PR(F53L) suggest a distinct mechanism for drug resistance, which has not been observed in other common drug-resistant mutants.

Catalytic Domain↗
PubMedDate not supplied

Adhesive capsulitis of the shoulder in human immunodeficiency virus-positive patients during highly active antiretroviral therapy.

Many adverse events have been described in patients treated with highly active antiretroviral therapy (HAART). Recently, among these, adhesive capsulitis of the shoulder has been described in some patients using protease inhibitors. We report our experience with 6 human immunodeficiency virus-positive patients in whom adhesive capsulitis of the shoulder developed during HAART. All 6 patients were treated with the same antiretroviral drug combination (HAART) including nucleoside reverse transcriptase (stavudine and lamivudine) and protease inhibitors (indinavir). The clinical pattern of adhesive capsulitis during HAART is similar to the classical form of adhesive capsulitis. Examining our case studies, we postulate a correlation between HAART and adhesive capsulitis. Discontinuation or reduction of the dosage of protease inhibitors associated with conventional conservative treatment is effective in reducing the symptoms and resolving the disease.

Adult↗
PubMed2004

Development of a microtiter plate fluorescent assay for inhibition studies on the HTLV-1 and HIV-1 proteinases.

The proteinase of human T-cell leukemia virus type-1 (HTLV-1), similar to the proteinase of human immunodeficiency virus type-1 (HIV-1), is a potential target for chemotherapy, since the virus is associated with a number of human diseases. A microtiter plate fluorescent assay was developed for the HTLV-1 and HIV-1 proteinases for direct comparison of the inhibition profiles of the enzymes. It was established that, except for Indinavir, none of the inhibitors designed against the HIV-1 proteinase were able to inhibit the HTLV-1 proteinase in the studied concentration range, while two reduced peptide bond-containing peptides having the sequence of HTLV-1 cleavage sites were inhibitors of the HTLV-1 proteinase. One of these was potent enough to be used for active site titration of the HTLV-1 proteinase.

Aspartic Acid Endopeptidases↗
PubMed2006

Secretory aspartyl peptidase activity from mycelia of the human fungal pathogen Fonsecaea pedrosoi: effect of HIV aspartyl proteolytic inhibitors.

Fonsecaea pedrosoi is the principal causative agent of chromoblastomycosis, which is a chronic, often debilitating, suppurative and granulomatous mycosis. Very little is known about the hydrolytic enzymes produced by this human fungal pathogen. In the present study, we have identified extracellular proteolytic activity from F. pedrosoi mycelial forms when grown in chemically defined conditions. Secretory aspartyl peptidase activity was measured during 15 days of fungal growth in vitro using bovine serum albumin (BSA) as the soluble substrate and extreme acidic pH (2.0). This activity was totally inhibited by pepstatin A, a classic aspartyl peptidase inhibitor. Conversely, metallo (o-phenanthroline), cysteine (E-64) and serine (PMSF) proteolytic inhibitors failed to restrain proteolytic activity. We also evaluated the effect of four distinct HIV aspartyl peptidase inhibitors on the secretory proteolytic activity of F. pedrosoi mycelia. Indinavir, ritonavir and nelfinavir powerfully inhibited extracellular aspartyl proteolytic activity by approximately 97, 96 and 87%, respectively, whereas saquinavir did not significantly interfere with BSA hydrolysis. Mycelial-derived secretory aspartyl peptidase activity cleaved other proteinaceous substrates, including human albumin, fibrinogen, fibronectin, laminin and type I collagen. As previously reported by our group, conidia also produce secretory aspartyl peptidase. In this sense, we investigated the effect of pepstatin A on F. pedrosoi development. Pepstatin A was able to inhibit the growth of conidium and its transformation into mycelium. Taken together, our results suggest a possible participation of aspartyl peptidases in the essential fungal processes, such as growth, differentiation, nutrition and cleavage of relevant host proteinaceous components.

Ascomycota↗
PubMed1999

Crystal-induced acute renal failure.

Several medications--notably acyclovir, sulfonamides, methotrexate, indinavir, and triamterene--are associated with the production of crystals that are insoluble in human urine. Intratubular precipitation of these crystals can lead to acute renal insufficiency. Many patients who require treatment with these medications have additional risk factors, such as true or effective intravascular volume depletion and underlying renal insufficiency, that increase the likelihood of drug-induced intrarenal crystal deposition. Acute renal failure in this setting may be preventable if it is anticipated by appropriate drug dosing, volume expansion with high urinary flow, and alkalinization of the urine when appropriate. Renal failure may be reversible if the drug is discontinued, and by volume repletion and alkalinization of the urine when appropriate. Management of established renal insufficiency includes volume repletion, dialytic support if necessary, adjustment of drug doses, and avoidance of further exposure to nephrotoxins.

Acute Kidney Injury↗
PubMed2001

Resolution of microsporidial keratoconjunctivitis in an AIDS patient treated with highly active antiretroviral therapy.

PURPOSE: To report the outcome of microsporidial keratoconjunctivitis in a patient with acquired immunodeficiency syndrome (AIDS) after highly active antiretroviral therapy without any specific treatment for microsporidiosis. METHODS: Case report. A 42-year-old woman diagnosed with AIDS and severe immunodepression (CD4+ of 9 cells/mm(3) and viral load of 460,000/mm(3)), antiretroviral naive, presented with cerebral toxoplasmosis and microsporidial keratoconjunctivitis in the right eye documented by conjunctival scraping and electron microscopy. RESULTS: The patient was treated with a combination of indinavir, stavudine, and lamivudine, besides sulfadiazine and pyrimethamine. No specific treatment for the microsporidial keratoconjunctivitis was attempted. One month later, the keratoconjunctivitis had disappeared. CONCLUSION: This case suggests that microsporidial keratoconjunctivitis in the setting of AIDS and severe immunodepression can be effectively managed with highly active antiretroviral therapy alone.

AIDS-Related Opportunistic Infections↗
PubMed1997

Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy.

BACKGROUND: In previous natural history studies and clinical trials, AIDS-related cytomegalovirus (CMV) retinitis has occurred primarily in patients with absolute CD4 counts of 50 cells/microL or less (0.05 x 10(9)/L) at the time of diagnosis. METHODS: We report five patients identified from our clinical practices who were diagnosed with CMV retinitis while their CD4 counts were above 195 cells/microL. We also analysed, based on CD4 counts, 76 AIDS patients with newly diagnosed CMV retinitis whose CD4 lymphocyte enumerations were done in laboratories that maintained certification in a common external quality control programme. FINDINGS: 5-24 weeks before retinitis was diagnosed, all five patients had had absolute CD4 lymphocyte counts of less than 85 cells/microL, and 4-7 weeks before diagnosis, all five patients had started taking highly active antiretroviral treatment (HAART) regimens. Only one (4%) of 27 patients enrolled in the trial between July, 1995, and February, 1996, had an absolute CD4 count of more than 50 cells/microL, and none of 27 had an absolute CD4 count of more than 100/microL on entry to the trial. However, from March, 1996 (when indinavir and ritonavir were approved by the FDA for marketing in the USA), to August, 1996, 14 (29%) of 49 patients had CD4 counts of more than 50/microL and seven (14%) of 49 had a CD4 count of more than 100 cells/microL on entry. INTERPRETATION: These findings suggest that the early immunological effects of HAART may not provide sufficient protection to prevent CMV retinitis in patients who have very low CD4 counts when therapy is started. Clinicians should note that CMV retinitis may now occur in patients who have CD4 counts of more than 100 cells/microL.

AIDS-Related Opportunistic Infections↗
PubMed2000

HIV protease inhibitors block adipogenesis and increase lipolysis in vitro.

AIDS therapies employing HIV protease inhibitors (PIs) are associated with changes in fat metabolism. However, the cellular mechanisms affected by PIs are not clear. Thus, the affects of PIs on adipocyte differentiation were examined in vitro using C3H10T1/2 stem cells. In these cells the PIs, nelfinavir, saquinavir, and ritonavir, reduced triglyceride accumulation, lipogenesis, and expression of the adipose markers, aP2 and LPL. Histological analysis revealed nelfinavir, saquinavir and ritonavir treatment decreased oil red O-staining of cytoplasmic fat droplets. Inhibition occurred in the presence of the RXR agonist LGD1069, indicating the inhibitory effects were not due to an absence of RXR ligand. Moreover, these three PIs increased acute lipolysis in adipocytes. In contrast, two HIV PIs, amprenavir and indinavir, had little effect on lipolysis, lipogenesis, or expression of aP2 and LPL. Although, saquinavir, inhibited ligand-binding to PPARgamma with an IC(50) of 12.7+/-3.2 microM, none of the other PIs bound to the nuclear receptors RXRalpha or PPARgamma, (IC(50)s>20 microM), suggesting that inhibition of adipogenesis is not due to antagonism of ligand binding to RXRalpha or PPARgamma. Taken together, the results suggest that some, but not all, PIs block adipogenesis and stimulate fat catabolism in vitro and this may contribute to the effects of PIs on metabolism in the clinic.

Adipocytes↗
PubMed2000

The cumulative occurrence of resistance mutations in the HIV-1 protease gene is associated with failure of salvage therapy with ritonavir and saquinavir in protease inhibitor-experienced patients.

Salvage therapy with ritonavir (RTV) and saquinavir (SQV) failed to achieve virological and immunological improvement in 24 HIV-infected patients who discontinued triple therapy with RTV or indinavir (IDV) because of failure or intolerance to treatment. Changes in the HIV-1 protease gene sequence were analyzed prospectively in 14 patients. No primary protease mutation was found prior to the use of protease inhibitors. After 7 months of treatment with IDV or RTV, primary resistance mutations at codons pol 46 and/or pol 82 were observed in 11 of 13 patients. After 16 weeks on RTV-SQV, novel primary mutations related to SQV emerged in 7 of 13 patients, together with an increase in the number of secondary resistance mutations. Our observations indicate that the cumulative occurrence of resistance mutations in the protease gene was associated with failure of antiretroviral therapy. The presence of mutations to a first protease inhibitor may represent a risk factor for the failure of a subsequent treatment with a second line protease inhibitor.

Adult↗
PubMed1998

Highly active antiretroviral therapy results in a decrease in CD8+ T cell activation and preferential reconstitution of the peripheral CD4+ T cell population with memory rather than naive cells.

OBJECTIVE: Highly active antiretroviral therapy (HAART) can produce marked increases in peripheral blood CD4+ T cells and decreases in HIV plasma RNA copy numbers. However, it is not clear whether these absolute changes will be accompanied by a recovery in the known naive CD4+ T cell depletion or a decrease in the marked CD8+ T cell activation. DESIGN: Twenty-nine patients were enrolled in studies of either nucleoside therapy alone or nucleoside therapy combined with a protease inhibitor (zidovudine + lamivudine + indinavir). One hundred and ninety-one examinations were carried out at three baseline time points and during 40 weeks of follow-up to evaluate the effect of HAART on CD4+ memory/naive phenotype and CD8+ T cell activation. METHODS: CD4+ and CD8+ T cell number, CD62L/CD45RA expression on CD4+ T cells and CD38 expression on CD8+ T cells were measured by three-color flow cytometry. RESULTS: Most protease inhibitor treated patients had a significant rise in CD4+ numbers. The marked rise in the CD4+ T cells seen in individuals in this study was not accompanied over a 40-week period by a change in the abnormally low CD4+ naive compartment, and thus was almost completely of memory phenotype. The CD38 expression on CD8+ cells fell during treatment, and decreased to a greater degree than the comparable rise in CD4+ T cell counts. This decrease continued in many patients after the CD4+ T cell rise or viral load decline had plateaued. CONCLUSION: HAART results in changes in activation to a greater extent than absolute changes in CD4+ T cell numbers, but is not accompanied by an increase in naive CD4+ T cells. Measurements of CD4+ T cell numbers alone may not allow appropriate interpretation of immune activation or immune competence in patients receiving those drugs.

Anti-HIV Agents↗
PubMed1999

[HIV protease inhibitors: drug interactions].

INTRODUCTION: Management of HIV infection considerably improved over the past few years. Factors that contributed to this improvement are the following: better knowledge of the dynamics of viral replication and immune response, plasma viral load quantitation, use of new combinations with more potent antiretroviral drugs, simultaneous progress in treatment of opportunistic infections. As a result, potential for drug interactions increased. CURRENT KNOWLEDGE AND KEY POINTS: Due to changes in hepatic metabolism, protease inhibitors may interact with concurrent treatment. The most relevant known drug interactions with each of the protease inhibitor (saquinavir, indinavir, ritonavir and nelfinavir) are summarized. Due to toxicity risks, co-administration is contraindicated for various interacting drugs, whereas dosage adjustments may only be required for others. Such interactions have relevant consequences in clinical practice for the choice of the combination that should be prescribed. However, they may have direct therapeutical benefit to the patient, particularly in the case of protease inhibitors. FUTURE PROSPECTS AND PROJECTS: Though potential drug interactions require careful monitoring in clinical practice, they should not limit the use and therefore therapeutical benefit conferred by these highly active drugs. To better define the value of combinations of protease inhibitors and treatment with non-nucleosidic reverse transcriptase inhibitor, further studies are required. As the number of drugs increases, experience and clinical practice in treatment of HIV infection will allow better knowledge of drug interactions and thereby optimal management of HIV-infected individuals.

Anti-HIV Agents↗
PubMed2002

Synthesis and activity of novel HIV protease inhibitors with improved potency against multiple PI-resistant viral strains.

Substitution of the t-butylcarboxamide substituent in analogues of the HIV protease inhibitor (PI) Indinavir with a trifluoroethylamide moiety confers greater potency against both the wild-type (NL4-3) virus and PI-resistant HIV. The trifluoroethyl substituent also affords a slower clearance rate in vivo (dogs); however, this may be due to more potent inhibition of at least two P450 isoforms.

Animals↗
PubMed2003

The design, synthesis and evaluation of novel HIV-1 protease inhibitors with high potency against PI-resistant viral strains.

Replacement of the pyridylmethyl moiety in indinavir with a pyridyl oxazole yielded HIV-1 protease inhibitors (PI) with greatly improved potency against PI-resistant HIV-1 strains. A meta-methoxy group on the pyridyl ring and a gem-dimethyl methyl linkage afforded compound 10 with notable in vitro antiviral activity against HIV-1 viral strains with reduced susceptibility to the clinically available PIs. Compound 10 also demonstrated favorable in vivo pharmacokinetics in animal models.

Animals↗