Evidence map›Paper›PMID 19425198›Full record

Trial reportAntiviral research2009

Alkoxyalkyl prodrugs of acyclic nucleoside phosphonates enhance oral antiviral activity and reduce toxicity: current state of the art.

Karl Y Hostetler

Open access · greenAbstract readClinical Trial, Phase IRandomized Controlled Trial
In one paragraph

Trial report in Antiviral research, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 124 papers.

0numbers the graph read from it
0cells of the map it votes in
124citing papers in PubMed
11.3field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

124 citing papers in PubMed, 236 citations in OpenAlex.

  1. A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Oral Brincidofovir for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation.Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation · 2019
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64 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

1 author at 1 institution in 1 country.

Karl Y HostetlerDepartment of Medicine, Division of Infectious Disease, University of California, San Diego, La Jolla, CA 92093-0676, USA. khostetler@ucsd.edu
Veterans Medical Research Foundation of San Diego · US

Funding

Orally Active Nucleoside Phosphonates for Hepatitis C VirusR01AI076558 · NIAID · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI SCHOOLEY, ROBERT TURNER · 2009 to 2013
$2.8M
Optimization of HPMPA and CDV Analogs for Treatment of SmallpoxR01AI074057 · NIAID · VETERANS MEDICAL RESEARCH FDN/SAN DIEGO · PI HOSTETLER, KARL Y · 2008 to 2011
$2.2M
ANALOGS OF HPMPA FOR TREATMENT OF SMALLPOXR01AI066499 · NIAID · VETERANS MEDICAL RESEARCH FDN/SAN DIEGO · PI HOSTETLER, KARL Y · 2005 to 2005
$1.4M
POTENT NEW NUCLEOSIDE ANALOGS FOR DRUG RESISTANT HIVR01AI071803 · NIAID · VETERANS MEDICAL RESEARCH FDN/SAN DIEGO · PI HOSTETLER, KARL Y · 2007 to 2010
$1.3M
Lung-Targeted Poxvirus AntiviralsR21AI064615 · NIAID · VETERANS MEDICAL RESEARCH FDN/SAN DIEGO · PI HOSTETLER, KARL Y · 2005 to 2006
$571k
NIAID NIH HHS AI064615NIAID NIH HHS AI066499NIAID NIH HHS AI074057NIAID NIH HHS AI076558NIAID NIH HHS R01 AI066499NIAID NIH HHS R01 AI071803NIAID NIH HHS R01 AI074057NIAID NIH HHS R01 AI076558NIAID NIH HHS R21 AI064615
6 · The paper itself

Abstract

Although the acyclic nucleoside phosphonates cidofovir, adefovir and tenofovir are approved for treating human cytomegalovirus, hepatitis B and HIV infections, respectively, their utility is limited by low oral bioavailability, renal toxicity and poor cell penetration. Research over the past decade has shown that these undesirable features can be eliminated by esterifying the compounds with an alkoxyalkyl group, in effect disguising them as lysophospholipids. In this modified form, the drugs are readily taken up in the gastrointestinal tract and have a prolonged circulation time in plasma. The active metabolite also has a long half life within cells, permitting infrequent dosing. Because these modified drugs are not recognized by the transport mechanisms that cause the accumulation of acyclic nucleoside phosphonates in renal tubular cells, they lack nephrotoxicity. Alkoxyalkyl esterification also markedly increases the in vitro antiviral activity of acyclic nucleoside phosphonates by improving their delivery into cells. For example, an alkoxyalkyl ester of cyclic-cidofovir, a less soluble compound, retains anti-CMV activity for 3 months following a single intravitreal injection. Two of these novel compounds, hexadecyloxypropyl-cidofovir (CMX001) and hexadecyloxypropyl-tenofovir (CMX157) are now in clinical development. This article focuses on the hexadecyloxypropyl and octadecyloxyethyl esters of cidofovir and (S)-HPMPA, describing their synthesis and the evaluation of their in vitro and in vivo activity against a range of orthopoxviruses, herpesviruses, adenoviruses and other double-stranded DNA viruses. The extension to other nucleoside phosphonate antivirals is highlighted, demonstrating that this novel approach can markedly improve the medicinal properties of these drugs.

Indexed as

AnimalsAntiviral AgentsDrug DesignHumansOrganophosphonatesProdrugsStructure-Activity RelationshipVirus DiseasesVirusesAntiviral AgentsOrganophosphonatesProdrugs

Identifiers

PMID19425198
PMCPMC2768545
OpenAlexW2062597360

What OpenQuestion holds

Textmetadata
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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.