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PubMed2004

Side-chain conformational restriction in template-competitive inhibitors of E. coli DNA polymerase I Klenow fragment: synthesis, structural characterization and inhibition activity.

Nucleotide triphosphate alpha-(4-azidophenyl)-1,N6-etheno-dATP 3 and its monophosphate 3m were synthesized by condensation of 2-halo-2-(4-azidophenyl)acetaldehyes with dATP and dAMP, respectively. Structure analysis shows that the azidophenyl side chain is attached to the alpha-position of the etheno ring (i.e., the carbon attached to N1 of the purine), and conformation calculations show minima in the etheno-phenyl bond rotation at 50 and 130 degrees where the bulk of the phenyl ring projects out from the plane of the etheno group. Like DNA Pol inhibitor 2-(4-azidophenacyl)thio-2'-deoxyadenosine 5'-triphosphate 1, nucleotide 3 is a template-competitive DNA polymerase inhibitor (TCPI), with a competitive Ki for Pol I KF of 3.41 microM, but has only weak activity as an HIV RT inhibitor relative to the template-competitive reverse transcriptase inhibitor 2-(4-azidophenacyl)thio-1,N6-etheno-2'-deoxyadenosine 5'-triphosphate 2. Additionally, 3 photoinactivates KF in a time-dependent manner, confirming the kinetic data that 3 binds to the free form of KF. The TCPI activity of 3 provides evidence for an extended side chain conformational preference in the combined substrate polymerase inhibitors.

Adenosine↗
PubMed1998

[Anti-HIV drugs and drug delivery system].

A number of candidate drugs for therapy of HIV-1 infection which show significant activity against the virus in vitro were reported; however, many of them have been dropped from drug development due to (i) insufficient intracellular activation in certain human target cells (particularly in case of nucleoside reverse transcriptase inhibitors), (ii) poor pharmacokinetic profiles, or (iii) intolerable in vitro and/or in vivo toxicities. To circumvent some of these problems, certain drug delivery systems have been applied and several candidate drugs including two novel nucleoside reverse transcriptase inhibitors, abacavir and adefovir, have acquired favorable properties in the clinical setting. This paper reviews several avenues for developing prodrugs of anti-HIV-1 agents to overcome their inherent limitations.

Acquired Immunodeficiency Syndrome↗
PubMed2004

The pipeline: three to watch.

Four antiretroviral drugs were approved in 2003: emtricitabine (FTC, Emtriva), and nucleoside reverse transcriptase inhibitor (NRTI); the protease inhibitors (PIs) atazanavir (Reyataz) and fosamprenavir (Lexiva); and T-20 (enfuvirtide, Fuzeon), the first of a new anti-HIV drug class, entry inhibitors.

CD4 Lymphocyte Count↗
PubMed1988

Reverse transcriptases from human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIVMAC) are susceptible to inhibition by foscarnet and 3'-azido-3'-deoxythymidine triphosphate.

Reverse transcriptases from human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV) were investigated with respect to susceptibilities to the reverse transcriptase inhibitors foscarnet and 3'-azido-3'-deoxythymidine triphosphate (AZTTP). The different reverse transcriptases had the same sensitivity to foscarnet (50% inhibition at 0.10 to 0.16 microM). The Ki values for AZTTP were 0.01 to 0.02 microM for HIV-1 reverse transcriptase and 0.02 to 0.03 microM for HIV-2 and SIVMAC reverse transcriptases.

Animals↗
PubMed2005

Adefovir dipivoxil: focus on its use in the treatment of chronic hepatitis B.

Adefovir is classified as a nucleotide reverse transcriptase inhibitor because it acts by inhibiting hepatitis B virus DNA polymerase (reverse transcriptase) and causing DNA chain termination after its incorporation into the viral DNA. Adefovir dipivoxil is indicated for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (alanine [ALT] or aspartate [AST]) or histologically active disease. It is useful in the treatment of patients with either hepatitis B e antigen-positive or -negative chronic hepatitis B. The recommended adefovir dipivoxil dose in the treatment of chronic hepatitis B in patients with adequate renal function is 10 mg once daily. Adefovir dipivoxil therapy can reduce viral load, improve ALT, and produce histologic improvement in patients with chronic hepatitis B. Improvements are generally seen within the first few weeks of therapy and have shown persistence up to at least 3 years with continued therapy. Therapy with adefovir dipivoxil is generally well tolerated. However, nephrotoxicity is a risk with adefovir therapy, especially in patients receiving higher doses (30-120 mg/d). Patients should have their renal function monitored closely throughout therapy and may require an adjustment in dose relative to changes in the creatinine clearance. Lactic acidosis and severe hepatomegaly with steatosis may also occur during therapy.

Adenine↗
PubMed1997

The thiocarboxanilide nonnucleoside UC781 is a tight-binding inhibitor of HIV-1 reverse transcriptase.

The thiocarboxanilide nonnucleoside inhibitor (NNI) UC781 inhibited HIV-1 reverse transcriptase (RT) DNA polymerase activity at a 1:1 molar ratio of inhibitor to enzyme. Inhibition was linear uncompetitive with respect to template/primer (T/P) and mixed noncompetitive with respect to deoxynucleoside triphosphate (dNTP), typical of NNI. When the RT-T/P binary complex was incubated with UC781 and then separated from unbound inhibitor, recovery of enzyme activity was slow, with only about 60% activity recovered after 25 min. The inactivation of the RT-T/P complex was prevented by the presence of a large excess of UC84, another carboxanilide NNI that interacts with this RT mechanistic form. UC781 protected the RT-T/P-dNTP ternary complex from irreversible inactivation by a photoactivatable azido analog of nevirapine, implying that UC781 binds to the NNI pocket of this RT mechanistic form. UC781 did not photoprotect either the free enzyme or the RT-T/P binary complex; however, protein fluorescence quenching studies indicated that UC781 interacted with all RT mechanistic forms, with the order of affinity being RT-T/P-dNTP ternary complex > RT-T/P binary complex > free RT. Reaction progress curve analysis showed that the binding of UC781 to RT is rapid (k(on) approximately 1.7 x 10(6) M(-1) s(-1)), but that dissociation is slow (k(off) approximately 1.6 x 10(-3) s(-1)). UC781 is therefore a rapid tight-binding inhibitor of HIV-1 RT, the first NNI to demonstrate this property.

Anilides↗
PubMed2000

[Current HIV therapy and its clinical problems].

HIV-specific protease inhibitors(PI) have been available in Japan since 1997. Since then, highly active anti-retroviral therapy(HAART) including two reverse transcriptase inhibitors combined with PI became the main strategy of HIV treatment. After introducing HAART, incidence of most opportunistic infections dramatically decreased, resulted a steep decline of AIDS death in Japan as well as in the United States. However, several unexpected problems related to HAART have been coming up. One is a lipodystrophy syndrome(LDS) which is a novel side effect caused by PI. Lipid disposition was noted associated with hyperlipidemia and/or hyperglycemia. Ischemic heart diseases will emerge in patients with LDS in future. Another one is inflammatory reactions to some opportunistic pathogens, such as Mycobacteria, Pneumocystis carinii, cryptococcus, and so on, occurred during course of immune reconstitution after HAART. This reaction is sometimes too severe to continue HAART and corticosteroid is often required to control the reaction. How to diagnose and how to manage the reaction are to be determined in future.

Drug Therapy, Combination↗
PubMed1999

Drug interactions of HIV protease inhibitors.

All the currently available protease inhibitors are metabolised by the cytochrome P450 (CYP) enzyme system. All are inhibitors of CYP3A4, ranging from weak inhibition for saquinavir to very potent inhibition for ritonavir. Thus, they are predicted to have numerous drug interactions, although few such interactions have actually been documented either in pharmacokinetic studies or in clinical reports. This article reviews the published literature with an emphasis on the magnitude of interactions and on practical recommendations for management. Many of the drugs commonly taken by patients with HIV have a strong potential to interact with the protease inhibitors. In particular, the non-nucleoside reverse transcriptase inhibitors are also metabolised by CYPand have been shown to interact with protease inhibitors. Delaviridine is an inhibitor of CYP3A4, but nevirapine and efavirenz are inducers of CYP3A4. The protease inhibitors also interact with each other, and these interactions are being explored for their potential therapeutic benefits. Other commonly used drugs are also known to affect protease inhibitor metabolism, including inhibitors such as clarithromycin and the azole antifungals and inducers such as the rifamycins. Drugs that are known to be significantly affected by the protease inhibitors include ethinylestradiol and terfenadine; many other drugs have lesser or potential interactions. Although little specific data is available on the drug interactions of protease inhibitors, this lack of data should not be interpreted as a lack of interaction. Retrospective chart reviews have demonstrated that potentially severe drug interactions are frequently overlooked. Much more clinical data is needed, but pharmacists and physicians must always be vigilant for drug interactions, both those that are already documented and those that are predictable from pharmacokinetic profiles, in patients receiving protease inhibitors.

Anti-Infective Agents↗
PubMed1995

Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors.

The mechanism of inhibition of HIV-1 reverse transcriptase by three nonnucleoside inhibitors is described. Nevirapine, O-TIBO, and CI-TIBO each bind to a hydrophobic pocket in the enzyme-DNA complex close to the active site catalytic residues. Pre-steady-state kinetic analysis was used to establish the mechanism of inhibition by these noncompetitive inhibitors. Analysis of the pre-steady-state burst of DNA polymerization indicated that inhibitors blocked the chemical reaction, but did not interfere with nucleotide binding or the nucleotide-induced conformational change. Rather, in the presence of saturating concentrations of the inhibitors, the nucleoside triphosphate bound tightly (Kd, 100 nM), but nonproductively. The data suggest that an inhibitor combining the functionalities of a nonnucleoside inhibitor and a nucleotide analog could bind very tightly and specifically to reverse transcriptase and could be effective in the treatment of AIDS.

Antiviral Agents↗
PubMed1999

P-glycoprotein, secretory transport, and other barriers to the oral delivery of anti-HIV drugs.

Orally administered anti-HIV drugs must be adequately and consistently absorbed for therapy to be successful. This review discusses the barriers to achieving oral bioavailability for the currently available anti-HIV drugs. Most reverse transcriptase inhibitors have good oral bioavailabilities. Didanosine bioavailability could be reduced by acid instability, first-pass hepatic metabolism, and possibly poor intestinal permeation. Bioavailability of zidovudine is also reduced by first-pass metabolism. The non-nucleoside reverse transcriptase inhibitors have oral bioavailabilities most probably limited by poor aqueous solubility. For each of the currently marketed HIV protease inhibitors, solubility, intestinal permeability, and first-pass metabolism could contribute to reducing oral bioavailability. The intestinal permeabilities of these agents is influenced by secretory transport. In vitro, secretory transport, which appears to be P-glycoprotein-mediated, is much greater than permeation in the absorptive direction for indinavir, nelfinavir, ritonavir, and saquinavir. The mechanisms of secretory intestinal transport are reviewed, and the factors that may influence the impact of secretory transport in vivo are considered.

Journal Article↗
PubMed1999

[Anti-HIV drugs].

Anti-HIV drugs act by blocking intracellular replication of the virus by inhibiting viral enzyme either reverse transcriptase or protease. Reverse transcriptase inhibitors belong to 3 different categories: nucleoside analogues, which active forms are the triphosphorylated intracellular compound, non nucleoside inhibitors and the more recent nucleotide analogues. Protease inhibitors are very active in vitro but besides their digestive side effects, have numerous drug interactions because they are metabolised through P450 liver cytochromes, and are associated with long-term toxicity.

Anti-HIV Agents↗
PubMed2002

Effect of delavirdine on plasma lipids and lipoproteins in patients receiving antiretroviral therapy.

Plasma lipid and lipoprotein levels were measured at baseline and after 8 weeks of highly active antiretroviral therapy among patients receiving delavirdine with or without a protease inhibitor (PI). In patients receiving nucleoside reverse transcriptase inhibitors (NRTI) plus delavirdine, there was a statistically significant increase in cholesterol and HDL levels, whereas those receiving NRTI plus a PI had no significant change in their HDL levels. When delavirdine was combined with a PI, there was a more dramatic increase in both cholesterol and HDL concentrations.

Anti-HIV Agents↗
PubMed2005

Low density lipoprotein apolipoprotein B metabolism in treatment-naive HIV patients and patients on antiretroviral therapy.

BACKGROUND: Dyslipidaemia and lipodystrophy have been described in treated HIV patients and in a small percentage of untreated HIV patients. Lipodystrophy in these patients has been shown to be associated with a lower expression of low density lipoprotein (LDL) receptors. METHODS: We have investigated the effect of antiretroviral treatment with either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) on body fat distribution and LDL apolipoprotein B (apoB) kinetics in 12 HIV-negative controls and 52 HIV-infected patients, including antiretroviral treatment-naive (TN) patients (n=13) and patients taking two nucleoside analogues plus either a PI (n=15) or an NNRTI (n=24). RESULTS: LDL cholesterol was not different between groups. Compared with the controls, LDL apoB absolute synthetic rate (ASR) and fractional catabolic rate (FCR) were lower and residence time (RT) was higher in the PI and NNRTI groups (P<0.05). In the TN patients, LDL ASR was lower (P<0.05) and there was a trend for a lower FCR and higher RT compared with the controls (P=0.07). LDL apoB pool size was greater in the PI group compared with the controls (P<0.05). In the PI group, patients on ritonavir (RTV)-containing regimens had a lower LDL apoB ASR (P=0.009) and a trend to a lower LDL apoB FCR and increased RT compared with non-RTV-containing PI regimens (P=0.05). There was a positive correlation between LDL apoB FCR and limb fat/lean body mass (P=0.004) in all subjects. CONCLUSIONS: Decreased LDL FCR, despite unchanged LDL cholesterol, was demonstrated in both treated and untreated HIV patients. It was more marked with RTV-containing regimens and was associated with reduced limb fat. The increased LDL RT may lead to an increased risk of atherogenesis thus contributing to the risk for cardiovascular disease in these patients.

Adult↗
PubMed1997

Antiviral chemotherapy.

Over the last few years, several new antiviral agents have been added to the chemotherapeutic armamentarium. This review discusses advances in the treatment of HIV disease in children and adults. More pronounced antiviral effects have been achieved through the study of new agents such as the protease inhibitors as well as through a better understanding of previously approved drugs, such as reverse transcriptase inhibitors.

Adult↗
PubMed2002

The interaction between antiretroviral agents and tacrolimus in liver and kidney transplant patients.

Solid organ transplantations have been performed successfully in selected HIV-positive patients with highly active antiretrovirus therapy (HAART). However, some of the medications in the HAART regimen require metabolism via the cytochrome P4503A, the same enzyme complex responsible for clearance of the calcineurin inhibitors cyclosporine and tacrolimus. Several case reports have described significant interactions between the agents used in HAART and immunosuppressive drugs. The goal of this report is to examine the extent of potential drug interactions between antiretroviral agents and tacrolimus after liver and kidney transplantation. Seven liver transplant (LTx) patients (M = 6, F = 1) and four kidney transplant (KTx) patients (M = 4) infected with HIV underwent surgery between September 1997 and January 2001. Initial immunosuppression consisted of tacrolimus and steroids for LTx patients or tacrolimus, steroids, and mycophenolate mofetil for KTx recipients. Their current baseline immunosuppression and HAART regimen were examined retrospectively. Of the seven liver recipients, one (case 4) died 2 weeks after LTx and never received HAART therapy posttransplantation. The remaining six patients were placed on a regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTI) and one protease inhibitor (PI) (nelfinavir in 5, indinavir in 1) based on known viral sensitivities or history of a previous clinical response. Kidney recipients received NRTI and nonnucleoside reverse transcriptase inhibitors (NNRTI). The mean dose of tacrolimus in liver recipients was 0.6 mg/d, with mean trough concentration of 9.7 mg/mL. Compared with historic controls (liver transplant patients not on HAART), the average tacrolimus dose was 16-fold lower in patients on HAART. In contrast to liver recipients, HIV-positive kidney recipients not on PI therapy required a mean tacrolimus dose of 9.5 mg/d to maintain a mean trough concentration of 9.6 ng/mL. Of the two protease inhibitors used, nelfinavir seems to have a more profound effect than indinavir. When patients on nelfinavir alone (n = 5) were compared with a control group not on antiretroviral therapy, the need for a tacrolimus dose was 38 times lower (mean dose, 0.26 mg/d). Profound drug interactions between PI and tacrolimus have been observed requiring up to 50-fold reductions in dosage. This effect seems to be most pronounced with the use of nelfinavir as opposed to indinavir, although further experience is required to confirm this observation. In contrast, HAART using NRTI and NNRTI without the use of PI, as shown in kidney recipients, produces less significant effects on tacrolimus metabolism. Great caution and frequent drug level monitoring are necessary when HAART is introduced or withdrawn in HIV-positive recipients of organ transplants.

Adult↗
PubMedDate not supplied

Sex differences in adverse reactions to antiretroviral drugs.

There have been recent increases in the number of female participants in HIV clinical trials and the number of studies addressing the influence of sex on HIV infection. The findings of some studies indicate a potential sex differences in the frequency and severity of adverse reactions to antiretroviral drugs. This article reviews the available data on the incidence and characteristics of potential sex differences in adverse reactions to certain nucleoside and nonnucleoside reverse transcriptase inhibitors and protease inhibitors. Adverse effects for which a sex difference has been reported include lactic acidosis, rash, elevation in liver enzymes, dyslipidemia, and insulin resistance. The reasons for these sex differences in adverse drug events are unclear but may include differences between men and women in body mass index and fat composition, hormonal effects on drug metabolism, or the effects of genomic constitutional differences on the levels of various enzymes. These differences warrant further study.

Anti-HIV Agents↗
PubMed2002

Inhibitory effects of triterpene-azidothymidine conjugates on proliferation of human immunodeficiency virus type 1 and its protease.

The conjugates of some dicarboxylic acid hemiesters of triterpenes which show potent inhibition against human immunodeficiency virus type 1 protease (HIV-1 PR) with a reverse transcriptase inhibitor azidothymidine (AZT) or anti-HIV alkaloid FK 3000 were prepared, and their inhibitory activities were investigated against HIV-induced cytopathic effects (CPE) and HIV-1 PR. Most of the triterpene-AZT conjugates showed potent anti-HIV activity as well as moderate to potent PR inhibitory activity, though AZT itself showed no PR inhibitory activity at all. However, the triterpene-FK 3000 conjugates showed neither PR inhibitory activity nor anti-HIV activity.

Anti-HIV Agents↗
PubMed2002

Therapeutic management of HIV.

Highly active antiretroviral therapy (HAART) has been used to treat HIV for several years with a reduction in mortality and morbidity. However, some patients fail to achieve complete viral suppression. Durability of therapy cannot be guaranteed and cross-resistance may arise, making second-line therapy a complex issue. Toxicity and pharmacokinetic interactions with other drugs may complicate long-term efficacy of regimens. The reduction of viral burden can prevent progressive immunodeficiency and may decrease the risk of selecting resistant viruses. Triple therapy with a protease inhibitor showed a decrease in morbidity, mortality and durability, but protease-sparing therapies might yield fewer side-effects. Lipid-related toxicity of protease inhibitors has resulted in the use of nonnucleoside reverse transcriptase inhibitors (NNRTI) in HAART. However, a single mutation for an NNRTI can confer cross-class resistance that limits further options for second-line therapy. When choosing HAART it is crucial to achieve durability and to structure doses to suit the patient's lifestyle, and it is important for patients to initiate therapy when they are ready. The decision to change drug regimens following treatment failure or rebound will depend on the initial choice of HAART. Viral load reduction occurs rapidly in most patients on HAART but immune reconstitution is slow and occurs almost unaided. Therefore prophylaxis against opportunistic infections should not be stopped prematurely.

AIDS-Related Opportunistic Infections↗