Further Research Table

It is quite clear that the availability of a 200-mg tablet has helped address the issue of pill count that has often limited the use of delavirdine in clinical practice. A more compact tablet (perhaps 400 mg) would be of even greater benefit, and efforts should be made to develop this. However, although logical, the generation of a 300-mg tablet would be more difficult, because delavirdine does not have regulatory approval for twice-daily administration, and this would be the only rationale to...

Emtricitabine In Pediatric Patients Pharmacokinetics Efficacy And Safety

The pharmacokinetic profile of emtricitabine was established in children in a phase I, multicenter, open-label trial (FTC-105) (39). Two dose levels of emtricitabine were studied in children younger than 18 yr of age 60 mg m2 and 120 mg m2, up to a maximum of 200 mg, in an oral solution formulation (10 mg mL). Children 6 yr of age and older who could swallow the solid oral dosage formulations also received a third dose of 120 mg m2 of emtricitabine (to the nearest 25 mg) in a capsule...

References

Pallela FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatients Study Investigators. N Engl J Med 1998 338 853-860. 2. Shevitz A, Wanke CA, Falutz J, Kotler DP. Clinical perspectives on HIV-associ-ated lipodystrophy syndrome an update. AIDS 2001 15 1917-1930. 3. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients...

Basic Understanding Of Mitochondria

The most important and critical mitochondrial function is oxidative phos-phorylation, a mechanism by which the energy derived from metabolism of nutrients in the presence of oxygen is transformed into adenosine triphosphate (ATP). Figure 1 describes the mitochondrial oxidative energy metabolism. The system of oxidative phosphorylation includes five multienzyme complexes, designated as electron-transport chain complexes I through V. These enzymes are encoded by either mitochondrial or nuclear...

What Laboratory Studies Are Needed For Initiation In Monitoring Of Therapy In Developing Countries

Laboratory tests in Western countries costing between 1000 and 2000 annually are used to provide serial CD4 counts, viral loads, occasional resistance tests, and other laboratory tests for initiating and monitoring HIV care. In many countries in Africa, few laboratory studies are available and most patients have no resources to pay for laboratory studies. As a result, the majority of patients are treated without Western-type laboratory support. Several initiatives need to urgently be taken....

Crystal Structure Of Hiv2 Rt

Until recently, there were no reports of a crystal structure of HIV-2 RT. HIV-2 is a less-widespread serotype than HIV-1 and is found most commonly in West Africa, although there is some evidence of the spread of the virus to other areas, including Europe and Asia. HIV-2 is considered less pathogenic than HIV-1 (81). HIV-2 RT forms a heterodimer that has different apparent molecular weights than HIV-1, reported as either p68 p55 or p68 p58 for HIV-2, compared with p66 p51 for HIV-1 (82)....

Management Of Neuropathy Associated With Nucleoside Reverse Transcriptase Inhibitor Therapy

Complaints of pain or paresthesias in the lower extremities of a patient taking ddI, ddC, or d4T suggests the possibility of a toxic neuropathy and warrants detailed evaluation. Compared with HIV-associated DSP, toxic neuropathies appear more abruptly and progress more quickly, thus, an individual who develops such progressive symptoms within several months after the introduction of a potentially neurotoxic antinucleoside agent is more likely to have a toxic neuropathy. The diagnosis, however,...

The Role Of Delavirdine In Clinical Practice Table

According to its package insert, delavirdine is indicated for the treatment of HIV infection in combination with at least two other agents when antiretroviral therapy is warranted from a clinical perspective. Of seven women who became pregnant while receiving delavirdine as part of a clinical trial, three had ectopic pregnancies, one delivered an infant with a small muscular ventricular septal defect, and three had normal deliveries. In light of this (along with limited animal data suggesting...

Index

Abacavir, 33-35, 56-67, 100, 101, 188192, 203-205, 214, 217, 218, 222-227, 442 arm, 63-65, 139 hypersensitivity, 59, 62-64, 66 monotherapy, 59, 64, 190, 191, 193 pharmacokinetics, 58 resistance, 65 toxicity, 66 ABC See Abacavir Academic Alliance, 511 Acetyl CoA, 282 Acetyl-L-carnitine, 254, 255, 260, 271 ACTG, 37, 41, 49, 63, 64, 84, 110, 111, 113, 304, 305, 363, 364, 382, 383, 390, 391. See also AIDS Clinical Trials Group Activation, 3, 22, 94, 157, 159, 209, 210, 212, 215-217, 219-222, 224,...

Emtricitabine Drug Interactions

The likelihood of drug-drug interactions with emtricitabine is quite low. In vitro data have shown emtricitabine's benign effect on many clinically relevant cytochrome P450 isoforms (3). In several single-dose healthy volunteer studies combining tenofovir disoproxil fumarate, indinavir, famciclovir, stavu-dine, or zidovudine with emtricitabine, negligible effects were observed, except for a 13 and 17 increase in zidovudine's AUC and Cmax, respectively (3,19). Although statistically...

Factors That May Influence Intracellular Phosphorylation

Because the NRTIs require intracellular activation for antiretroviral activity, influences on the enzymes responsible for activation can modulate drug activity. In vitro, cellular factors have been shown to alter antiretroviral activity. The activation state of the cell may change the relationship between drug triphos-phate and endogenous triphosphate. For instance, in activated cells, the ratios of ZDVTP to deoxythymidine triphosphate (dTTP) and of d4T triphosphate to dTTP are greater than in...

Toxicity

The spectrum and frequency of adverse events associated with nevirapine therapy have been extensively reviewed (47,48). Data from long-term clinical trials evaluated by Pollard et al. indicated that the safety profiles changed in comparison with short-term studies (47). Among adult subjects in long-term studies (time on therapy > 6 mo n 487), 15 of the subjects experienced nevirapine-related adverse events. However, among all subjects taking nevirapine in the pooled data set of the 22...

Didanosine

Didanosine (also known as ddI) is available in its original buffered formulations (Videx) and as a delayed-release formulation with enteric-coated beadlets Selected Laboratory and Hematological Abnormalities From Combination Studies of Stavudine (Pooled Data) (6)a Parameter n 467 ( of patients)c Total bilirubin (> 2.6 x ULN) 0 Neutropenia (ANC < 750 mm3) 5 Anemia (hemoglobin < 8 g dL) < 1 Thrombocytopenia (platelets < 50,000 cells mm3) 2 AST, aspartate aminotransferase ALT, alanine...

L74v

Codon 74 interacts directly with the template and the incorporating dNTP (32). The mutation L74V confers resistance by selectively reducing incorporation rates of specific nucleoside analogs (40). L74V is the most common mutation that arises in patients receiving didanosine monotherapy (109,154-156) and is often seen in patients receiving abacavir monotherapy (105,106). Combinations of didanosine plus lamivudine (157), didanosine plus emtricitabine (158), and abacavir plus lamivudine (110,147)...

Richard Ogden PhD

Pfizer Inc., San Diego, CA Foreword by Professor of Medicine Center for Poverty-Related Communicable Diseases Academic Medical Center, University of Amsterdam Amsterdam, The Netherlands 2006 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 humanapress.com All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without...

Info

NVP, nevirapine od, once daily bd, twice daily EFV, efavirenz lab, laboratory value Treatment failure defined as a less than 1 log10 copies mL decline in HIV RNA pVL in first 12 wk, two consecutive pVL levels greater than 50 copies mL from week 24 onwards, a new AIDS-defining illness or death, or a change of allocated treatment Percentage of patients with at least one grade 3 or 4 adverse events (AE) cGrade 3 or 4 elevations in AST, ALT, or total bilirubin levels Excluding isolated (-glutamic...

General Mechanisms Of How The Mutations Confer Drug Resistance

HIV RT converts genomic single-stranded RNA into double-stranded DNA to be integrated in the host DNA. HIV RT has RNA- and DNA-primed DNA polymerase activity as well as RNase H activity that degrade the DNA-RNA intermediates. DNA elongation exists as an equilibrium between a dominant Fig. 3. Sites of drug-resistant mutations in HIV-1 RT. The structure of HIV-1 RT in the region near the polymerase active site is shown. A template-primer is shown. The incoming dNTP (spheres) is bound at the N...

Nd

Vd, volume of distribution CSF, cerebrospinal fluid ND, not determined Pediatric patients (8-mo to 19-yr old) demonstrate a lower oral bioavailability (25 ), smaller Vd (28 L m2), and shorter half-life (0.8 h) (60,65) Vd, volume of distribution CSF, cerebrospinal fluid ND, not determined Pediatric patients (8-mo to 19-yr old) demonstrate a lower oral bioavailability (25 ), smaller Vd (28 L m2), and shorter half-life (0.8 h) (60,65) Buffered didanosine, the first available formulation of...

Clinical Manifestations Of Mitochondrial Toxicity

Symptomatic Forms of Hyperlactatemia Lactic acidosis is the most dramatic manifestation of NRTI-associated mitochondrial dysfunction. Lactic acidosis has been reported in HIV-infected patients since the early 1990s, but recent clusters of reports increased physicians' awareness about this potentially fatal syndrome. Fortunately, severe lactic acidosis remains a rare occurrence. The typical clinical presentation is one of precipitous occurrence of nausea, vomiting, abdominal pain, severe...

Therapeutic Interventions In The Prevention Of Vertical Hiv Transmission

The initial reports of HIV in children highlighted the fact that this emerging infection could be transmitted from an asymptomatic mother to her newborn child (51), that HIV-infected infants had faster disease progression, and that pediatric AIDS had a high mortality rate (52,53). The poor prognosis of pediatric AIDS led investigators to design strategies to reduce perinatal HIV-1 transmission. ZDV, the only Food and Drug Administration-approved antiretroviral drug in the mid-1980s, was the...

Hiv Rt Crystal Structures

The Architecture of the HIV-1 RT Heterodimer A number of crystal structures of HIV-1 RT have been published during the last 10 years mainly of the full RT heterodimer. In addition, structures of some RT domains have been determined, including the C-terminal HIV-1 RNase H (25) and N-terminal fragments from HIV-1 (26) and murine Moloney RTs (27). The HIV-1 RT heterodimer structures determined, to date, can be divided into three general categories 1. complexes containing nucleic acid, which...