Slow acoustic surface modes through the use of hidden geometry.

The acoustic surface modes supported by a partly covered periodic meander groove structure formed in an assumed perfectly rigid plate are investigated. This allows one to create a slower acoustic surface wave than can be achieved with the same uncovered meander structure. By changing the size of the uncovered section the phase and group speeds can be tuned. When the uncovered section of the meander structure is centred along the grooves then the distance along the grooves between neighbouring holes is the same on both sides of the structure so no band gap is observed at the first Brillouin zone boundary due to glide symmetry. This then gives quite linear dispersion. As the uncovered section's position is moved away from the centre of the meander structure a band gap opens at the Brillouin zone boundary.

Technical considerations when designing a gene expression panel for renal transplant diagnosis.

Gene expression analysis is emerging as a new diagnostic tool in transplant pathology, in particular for the diagnosis of antibody-mediated rejection. Diagnostic gene expression panels are defined on the basis of their pathophysiological relevance, but also need to be tested for their robustness across different preservatives and analysis platforms. The aim of this study is the investigate the effect of tissue sampling and preservation on candidate genes included in a renal transplant diagnostic panel. Using the NanoString platform, we compared the expression of 219 genes in 51 samples, split for formalin-fixation and paraffin-embedding (FFPE) and RNAlater preservation (RNAlater). We found that overall, gene expression significantly correlated between FFPE and RNAlater samples. However, at the individual gene level, 46 of the 219 genes did not correlate across the 51 matched FFPE and RNAlater samples. Comparing gene expression results using NanoString and qRT-PCR for 18 genes in the same pool of RNA (RNAlater), we found a significant correlation in 17/18 genes. Our study indicates that, in samples from the same routine diagnostic renal transplant biopsy procedure split for FFPE and RNAlater, 21% of 219 genes of potential biological significance do not correlate in expression. Whether this is due to fixatives or tissue sampling, selection of gene panels for routine diagnosis should take this information into consideration.

Broadband, slow sound on a glide-symmetric meander-channel surface.

The acoustic surface waves supported by hard surfaces patterned with repeat-period, meandering grooves are explored. The single, continuous groove forms a glide-symmetric surface, inhibiting the formation of a bandgap at the first Brillouin-zone boundary. Consequently, the acoustic surface waves exhibit an almost constant, sub-speed-of-sound, group velocity over a broad frequency band. Such slow, broadband modes may have applications in controlling the flow of noise over surfaces.

Empathy in hippocampal amnesia.

Empathy is critical to the quality of our relationships with others and plays an important role in life satisfaction and well-being. The scientific investigation of empathy has focused on characterizing its cognitive and neural substrates, and has pointed to the importance of a network of brain regions involved in emotional experience and perspective taking (e.g., ventromedial prefrontal cortex, amygdala, anterior insula, cingulate). While the hippocampus has rarely been the focus of empathy research, the hallmark properties of the hippocampal declarative memory system (e.g., representational flexibility, relational binding, on-line processing capacity) make it well-suited to meet some of the crucial demands of empathy, and a careful investigation of this possibility could make a significant contribution to the neuroscientific understanding of empathy. The present study is a preliminary investigation of the role of the hippocampal declarative memory system in empathy. Participants were three patients (1 female) with focal, bilateral hippocampal (HC) damage and severe declarative memory impairments and three healthy demographically matched comparison participants. Empathy was measured as a trait through a battery of gold standard questionnaires and through on-line ratings and prosocial behavior in response to a series of empathy inductions. Patients with hippocampal amnesia reported lower cognitive and emotional trait empathy than healthy comparison participants. Unlike healthy comparison participants, in response to the empathy inductions hippocampal patients reported no increase in empathy ratings or prosocial behavior. The results provide preliminary evidence for a role for hippocampal declarative memory in empathy.

Electrophoretic karyotype analysis in fungi.

The resolution of chromosomal-sized DNAs by PFGE has many applications that include karyotyping, strain identification of similar species, characterization of transformed strains, building of linkage maps, and preparation of DNA for genomic analysis. Successful electrophoretic separation of chromosomes is an empiric process in which the initial concentration of intact chromosome-sized DNA and the optimization of electrophoretic parameters are the most important experimental variables. Nonetheless, inherent attributes of the genome architecture of certain species may thwart success. When a karyotype contains numerous chromosomes of the same size and/or many large (greater than 8 Mb) chromosomes, no amount of manipulation of the electrophoretic parameters will resolve individual chromosome bands using present technology. Further, fungi display a surprising amount of intraspecific variation in both chromosome number and size, making it difficult to establish a standard "reference" karyotype for many species. Although PFGE is not a panacea for bringing genetics to species that lack classical genetic systems, it often does provide a way for developing a molecular linkage map in the absence of a formal genetic system. It is far faster than parasexual analysis in the discovery of linkage relationships. For genomics projects, DNA can be recovered from pulsed field gels and used to prepare chromosome-specific libraries. Where whole genome sequencing strategies are used, chromosomes separated by PFGE provide an anchor for sequencing data. Electrophoretic karyotypes can be probed with anonymous pieces of DNA from bacterial artificial chromosome (BAC) contigs, thereby facilitating the building of physical maps. In conclusion, despite its shortcomings, the PFGE technique underlies much of our current understanding of the physical nature of the fungal genome.

Comparison of four different backpacks intended for school use.

Four backpacks were evaluated for their desireability for use as school bags. Three of the four backpacks were specifically designed for school use based on previous research and ergonomic principles while the fourth (standard) backpack was chosen from two backpacks that their manufacturer considered to be the most likely to be used as a school bag. Twelve school students evaluated each of the backpacks firstly by examining them, again after donning them and again after walking with them on a treadmill by completing a questionnaire asking about the appearance, function and comfort of each backpack. On initial examination, the standard backpack was the most favoured but as functionality became increasingly important during the treadmill walk, the backpack which was designed specifically for school use and had two major compartments, substantial back padding and side compression straps became the most favoured. This particular design of backpack was reported as having the greatest practicality, being the least physically demanding and allowing the greatest balance and ease of walking. The results of this study suggest that school student's preference of backpack may change from when they first examine a prospective backpack to when they have used it. The study also shows that school students' preferred attributes in a backpack may shift over this time from 'style and image' to 'function and fit'.

In vitro and in vivo activity of 1-O-hexadecylpropanediol-3-phospho-ganciclovir and 1-O-hexadecylpropanediol-3-phospho-penciclovir in cytomegalovirus and herpes simplex virus infections.

Human cytomegalovirus (HCMV) and herpes simplex virus (HSV) can cause a wide variety of clinical manifestations in man. Ganciclovir (GCV) is effective against HCMV infection when administered by the intravenous route and may be used orally in large doses for prophylaxis of HCMV infections in organ transplantation patients and in AIDS patients. In previous studies with acyclovir (ACV), we found that covalent attachment of an alkyl glycerol phosphate moiety greatly increased oral bioavailability and increased antiviral activity against hepatitis B virus. Adducts of ACV with alkyl propanediol phosphate were more active than the alkyl glycerol phosphate analogue in vitro in 2.2.15 cells, which constitutively produce hepatitis B virus. To see if this strategy would work for two other poorly absorbed nucleoside analogues, we synthesized 1-O-hexadecylpropanediol-3-phospho-GCV (HDP-P-GCV) and 1-O-hexadecyl-propanediol-3-phospho-penciclovir (HDP-P-PCV), and evaluated the in vitro antiviral activity, selectivity and oral antiviral activity of both compounds versus GCV or PCV in mice infected with HSV-1 or HDP-P-GCV versus murine cytomegalovirus (MCMV). HDP-P-GCV is orally active in both MCMV and HSV-1 infection in mice with antiviral activity equivalent to (HSV-1) or greater than oral GCV (MCMV). Oral HDP-P-PCV was more active than PCV orally versus intranasal HSV-1 infection in mice.

Alkylglycerol prodrugs of phosphonoformate are potent in vitro inhibitors of nucleoside-resistant human immunodeficiency virus type 1 and select for resistance mutations that suppress zidovudine resistance.

Phosphonoformate (foscarnet; PFA) is a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), but its use for the treatment of HIV-1 infection is limited by toxicity and the lack of an orally bioavailable formulation. Alkylglycerol-conjugated prodrugs of PFA (1-O-octadecyl-sn-glycero-3-PFA [B-PFA]) having sn-2 substituents of hydrogen (deoxybatyl-PFA [DB-PFA]), methyl (MB-PFA), or ethyl (EB-PFA) are more-potent inhibitors of wild-type HIV-1 in vitro than unmodified PFA and are orally bioavailable in mice. We have evaluated the activities of these compounds against a panel of nucleoside-resistant HIV-1 variants and have characterized the resistant variants that emerge following in vitro selection with the prodrugs. Except for an HIV-1 variant encoding the K65R mutation in RT that exhibited 3.3- to 8.2-fold resistance, the nucleoside-resistant viruses included in the panel were sensitive to the PFA prodrugs (<3-fold increase in 50% inhibitory concentration), including multinucleoside-resistant variants encoding the Q151M complex of mutations or the T69S[SA] insert. Viruses resistant to the PFA prodrugs (>10-fold) were selected in vitro after 15 or more serial passages of HIV-1 in MT-2 cells in escalating prodrug concentrations. Mutations detected in the resistant viruses were S117T, F160Y, and L214F (DB-PFA); M164I and L214F (MB-PFA); and W88G and L214F (EB-PFA). The S117T, F160Y, and M164I mutations have not been previously identified. Generation of recombinant viruses encoding the single and double mutations confirmed their roles in prodrug resistance, including 214F, which generally increased the level of resistance. When introduced into a zidovudine (AZT)-resistant background (67N 70R 215F 219Q), the W88G, S117T, F160Y, and M164I mutations reversed AZT resistance. This suppression of AZT resistance is consistent with the effects of other foscarnet resistance mutations that reduce ATP-dependent removal of AZT monophosphate from terminated template primers. The favorable activity and resistance profiles of these PFA prodrugs warrant their further evaluation as clinical candidates.

The effect of vitamin C supplementation on coagulability and lipid levels in healthy male subjects.

Although dietary intake and plasma levels of vitamin C have been inversely associated with cardiovascular disease, the mechanism through which it may exert its effect has not been fully explained. Since thrombosis plays an important role in the onset of cardiovascular disease, we investigated the effect of vitamin C on measures of hemostasis that have been associated with cardiovascular risk. The effect of vitamin C on lipid levels was also evaluated. In a randomized, placebo-controlled, crossover study, we determined the effect of 2 g daily of vitamin C supplementation on platelet adhesion and aggregation, levels of tissue plasminogen activator antigen, plasminogen activator inhibitor, fibrinogen, plasma viscosity, von Willebrand factor, and lipid levels in 18 healthy male volunteers with low normal vitamin C levels. No striking effects of vitamin C on the hemostatic measures were observed, although tissue plasminogen activator antigen levels were inversely related to Vitamin C levels. Von Willebrand factor levels were slightly higher with vitamin C, although within the normal range. Total cholesterol levels were 10% lower when subjects were receiving vitamin C compared to placebo (167+/-7 mg/dL vs. 184+/-7 mg/dL), P=0. 007), although the total cholesterol/HDL ratio was not significantly different. Higher levels of tissue plasminogen activator antigen, which in the present study were associated with lower vitamin C levels, have been shown in prospective studies to convey an increased risk of cardiovascular events. Further studies of the effect of vitamin C on hemostatic measures are required in higher risk populations or those with known cardiovascular disease.

In vitro anti-HIV-1 activity of sn-2-substituted 1-O-octadecyl-sn-glycero-3-phosphonoformate analogues and synergy with zidovudine.

Monoalkyl ether lipid analogues of foscarnet (phosphonoformate, PFA) exhibit substantially greater in vitro antiviral activity than unmodified PFA against human immunodeficiency virus type 1 (HIV-1). Our previous studies indicate that the length of the alkyl chain must be 14-22 carbons for optimal antiviral activity. To further evaluate the structure-activity relationship, we prepared 1-O-octadecyl-sn-glycerol analogues of PFA with various substitutions at the sn-2 position of glycerol and determined the effect of structure on in vitro antiviral activity and selectivity against HIV-1 in MT-2 and CD4-expressing HeLa cells (HT4-6C). We also studied combinations of zidovudine with PFA, 1-O-octadecyl-2-O-methyl-sn-glycero-3-PFA, or 1-O-octadecyl-sn-glycero-3-PFA and calculated their combination index values against HIV-1 in HT4-6C cells. Alkyl substitutions of one to four carbons at the sn-2 position of glycerol showed optimal antiviral activity. Both alkyl ether lipid analogues were strongly synergistic with zidovudine over a wide range of drug ratios and concentrations. 1-O-octadecyl-sn-glycerol analogues of PFA have selective antiviral properties and warrant further evaluation as potential antiretroviral drugs.

Antiviral activities of oral 1-O-hexadecylpropanediol-3-phosphoacyclovir and acyclovir in woodchucks with chronic woodchuck hepatitis virus infection.

Acyclovir triphosphate is a potent inhibitor of hepatitis B virus DNA polymerase, but acyclovir treatment provides no benefit in patients with hepatitis B virus infection. This is due in part to the fact that hepatitis B virus, unlike herpes simplex virus, does not code for a viral thymidine kinase which catalyzes the initial phosphorylation of acyclovir. We synthesized 1-O-octadecyl-sn-glycero-3-phospho (3-P)-acyclovir and found that it was highly active in reducing hepatitis B virus replication in 2.2. 15 cells, while acyclovir was inactive. The greater antiviral activity of 1-O-octadecyl-sn-glycero-3-P-acyclovir appeared to be due to liver cell metabolism of the compound to acyclovir monophosphate (K. Y. Hostetler et al., Biochem. Pharmacol. 53:1815-1822, 1997). However, a closely related compound without a hydroxyl group at the sn-2 position of glycerol, 1-O-hexadecylpropanediol-3-P-acyclovir, was more active and selective in 2.2.15 cells in vitro. In this study, we treated woodchucks chronically infected with woodchuck hepatitis virus with increasing oral doses of 1-O-hexadecylpropanediol-3-P-acyclovir and assessed the response to therapy versus acyclovir or a placebo. At a dosage of 10 mg/kg of body weight twice a day, the test compound significantly inhibited viral replication in vivo, as indicated by a 95% reduction in serum woodchuck hepatitis virus DNA levels and by a 54% reduction in levels of woodchuck hepatitis virus replicative intermediates in the liver. Higher doses were somewhat less effective. In contrast, 20 mg of acyclovir/kg twice daily, a 5. 3-fold-higher molar dosage, had no demonstrable activity against woodchuck hepatitis virus. Oral 1-O-hexadecylpropanediol-3-P-acyclovir appeared to be safe and effective in chronic woodchuck hepatitis virus infection.

Intravitreal toxicology and duration of efficacy of a novel antiviral lipid prodrug of ganciclovir in liposome formulation.

PURPOSE: To evaluate the intraocular safety and antiviral treatment efficacy of the sustained lipid prodrug of ganciclovir, 1-O-hexadecylpropanediol-3-phospho-ganciclovir (HDP-P-GCV), as an intravitreal injectable drug system for viral retinitis. METHODS: HDP-P-GCV was synthesized by coupling 1-O-hexadecyl-propanediol-3-phosphate to either free hydroxyl of ganciclovir in pyridine with dicyclohexylcarbodiimide as catalyst. The compound was formulated into liposomes. The antiviral activity was assessed by DNA reduction in vitro, and intraocular safety was assessed by ophthalmoscopy, electrophysiology, and histology after intravitreal injections, with resultant intravitreal concentrations of 0.2, 0.632, 1.12, and 2 mM. The treatment efficacy was evaluated by simultaneous intravitreal injection of HDP-P-GCV and herpes simplex virus type 1 (HSV-1) or by intravitreal injection of HDP-P-GCV at various times before HSV-1 intravitreal inoculation. Retinitis was scored with ophthalmoscopy and compared with controls. RESULTS: In vitro, the IC50 of HDP-P-GCV against HSV-1 and human cytomegalovirus (HCMV) infected cells was 0.02 and 0.6 microM, respectively. In rabbits in vivo, HDP-P-GCV dispersed evenly and maintained a good vitreous clarity at all doses except 2 mM final intravitreal concentration. Although cataracts were observed in some eyes at the higher doses, they were not observed in eyes with 0.2 mM final intravitreal concentration. No other indications of ocular toxicity were observed. Intravitreal injection of HDP-P-GCV with resultant 0.2 mM intravitreal concentration in the HSV-1 retinitis rabbit model demonstrated a complete protection of the retina with the simultaneous treatment strategy and a 4 (P = 0.03) to 6-(P = 0.058) week significant protection of retina with the pretreatment strategies when compared with ganciclovir or blank liposome controls. CONCLUSIONS: In the rabbit model of HSV-1 retinitis HDP-P-GCV acts as a long-lasting intravitreal injectable anti-CMV or anti-HSV compound. This self-assembling liposome system could be applicable for many compounds available for intraocular diseases.

Synthesis and antiviral evaluation of 1-O-hexadecylpropanediol-3-P-acyclovir: efficacy against HSV-1 infection in mice.

We synthesized, 1-O-hexadecylpropanediol-3-P-acyclovir, an orally bioavailable lipid prodrug of acyclovir and evaluated it for in vitro and in vivo activity against herpes simplex virus infections. Although 1-O-hexadecylpropanediol-3-P- acyclovir was less active in vitro than acyclovir, on a molar basis it was 2.4 times more active orally in preventing mortality from acute HSV-1 infection in mice. In vitro, 1-O-hexadecylpropanediol-3-P-acyclovir was also more active than acyclovir in a thymidine kinase negative mutant strain of HSV-1 (DM21) and had somewhat higher activity in cytomegalovirus infection in vitro due to it's ability to bypass thymidine kinase.

Intravitreal toxicology and therapeutic efficacy of the carboxymethyl ester of the 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA-O-Me), a novel lipid antiviral prodrug for intraocular drug delivery.

This study was conducted to evaluate the vitreous clarity and intraocular therapeutic index of three preparations ofthe carboxymethyl ester of 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA-O-Me), a long acting lipid derivative of foscarnet with potent anti-CMV activity. Twenty-six New Zealand white rabbits were intravitreally injected with one of three preparations of ODG-PFA-O-Me or control diluent. The vitreous clarity was graded after injection using indirect ophthalmoscopy and fundus photography. Drug intraocular toxicity was evaluated by electroretinography and by post-sacrifice tissue pathology using light and electron microscopy. Intravitreal injection of micellar ODG-PFA-O-Me showed variable local retinal toxicity and vitreal compound aggregates in eyes with the middle and high doses. The intraocular therapeutic index was lower than 465:1. Intravitreal injection of liposomal ODG-PFA-O-Me, either free acid or sodium salt, revealed clear vitreous for the 0.632 and 0.84 mM final intravitreal concentrations. No retinal toxicity was confirmed for the 1.12 mM final intravitreal concentration at the eight week observation following injection. The intraocular therapeutic index was between 585-1037:1. ODG-PFA-O-Me possesses better vitreous compatibility than ODG-PFA. Liposomal ODG-PFA-O-Me can be intravitreally injected with a resulting clear vitreous and high intraocular therapeutic index. Liposomal ODG-PFA-O-Me could be a long acting nontoxic intravitreous injectable drug for CMV retinitis.

Alkylthioglycerol prodrugs of foscarnet: synthesis, oral bioavailability and structure-activity studies in human cytomegalovirus-, herpes simplex virus type 1- and human immunodeficiency virus type 1-infected cells.

In a previous study, we reported that 1-O-octadecyl-sn-glycero-3-foscarnet (ODG-PFA) was 40 to 93 times more potent than free foscarnet (PFA) in human cytomegalovirus (HCMV)-, herpes simplex virus type 1 (HSV-1)- and human immunodeficiency virus type 1 (HIV-1)-infected cells. To evaluate the effect of substituting a 1-S-alkyl thioether for a 1-O-alkyl ether, we synthesized a series of PFA conjugates of 1-S-alkyl-sn-thioglycerols with varied 1-S-alkyl chain lengths. To establish structure-activity relationships we measured the in vitro antiviral activity of liposomal formulations of the drugs in cells infected with HCMV, HSV-1 or HIV-1. The optimum 1-S-alkyl chain length in the series was 16 to 18 carbon atoms. We compared the antiviral activity of 16- and 18-carbon alkyl thioglycerol versus alkylglycerol prodrugs and did not observe any significant differences in their antiviral activities. The series' most active member, 1-S-octadecyl-sn-glycero-3-foscarnet (ODSG-PFA) was 56-, eight- and 45-fold more active than PFA in HCMV-, HSV-1- and HIV-1-infected cells in vitro. The oral absorption of PFA and 1-S-octadecyl-sn-thioglycero-3-PFA was compared in mice by measuring plasma levels of 14C after oral administration of radiolabelled compounds. The peak plasma level of 14C was sevenfold higher following administration of [14C]ODSG-PFA than following an equimolar dose of [14C]PFA. Area-under-the-curve was 23-fold greater for ODSG-PFA than for PFA. Like previously reported alkyloxyether-lipid PFA conjugates, alkylthioether conjugates provided enhanced antiviral activity and oral bioavailability. However, S-ether conjugates may be metabolized differently than O-ether conjugates. More detailed in vivo pharmacokinetic evaluation of the alkyl-thioether-PFA conjugates is required.

Alkoxy propane prodrugs of foscarnet: effect of alkyl chain length on in vitro antiviral activity in cells infected with HIV-1, HSV-1 and HCMV.

The identification of more effective and less toxic foscarnet (PFA) analogs for antiviral therapy would be useful. We recently synthesized 1-O-octadecyl-sn-glycero-3-phosphonoformic acid (ODG-PFA) and noted a 93-fold increase in its anti-HCMV activity relative to PFA. In addition, the antiviral activity of ODG-PFA in herpes simplex virus type-1 (HSV-1) and human immunodeficiency virus type-1 (HIV-1) infected cells was increased 40-fold relative to PFA (Hostetler et al., 1996. Antiviral Res. 31, 59). To evaluate structure-activity relationships further, we synthesized alkoxypropyl esters of foscarnet with varying alkyl chain lengths and degrees of saturation. These compounds were tested in vitro for activity and selectivity in comparison with PFA and ODG-PFA in cells infected with HCMV, HSV-1 or HIV-1. Antiviral activity was strongly dependent on chain length with alkyl ethers 14-18 carbon atoms long exhibiting the greatest antiviral activity against HCMV and HSV-1. In HIV-infected HT4-6C cells, optimal activity was observed at 18-22 carbon chain lengths. The antiviral activities of 1-octadecyloxypropane-3-PFA and 1-docosyloxypropane-3-PFA were 135- and 338-fold greater than that of PFA in HT4-6C cells infected with HIV-1. This also represents a 2.6-6-fold improvement in antiviral activity over ODG-PFA, the previously reported analog.

Enhanced oral absorption and antiviral activity of 1-O-octadecyl-sn-glycero-3-phospho-acyclovir and related compounds in hepatitis B virus infection, in vitro.

Acyclovir (ACV) triphosphate and azidothymidine (AZT) triphosphate inhibit the DNA polymerase of human hepatitis B virus (HBV) by 50% at submicromolar concentrations, but no effects of ACV or AZT treatment have been noted on the clinical manifestations of hepatitis B. We synthesized 1-O-octadecyl-sn-glycero-3-phospho-acyclovir (ODG-P-ACV), 1-O-hexadecylpropanediol-3-phospho-acyclovir (HDP-P-ACV), and 1-O-octadecyl-sn-glycero-3-phospho-azidothymidine (ODG-P-AZT), and evaluated their antiviral activity in human hepatoma cells that constitutively produce HBV (2.2.15 cells). ACV and AZT up to 100 microM caused only slight inhibition of HBV replication in 2.2.15 cells. However, HDP-P-ACV and ODG-P-ACV inhibited viral replication by 50% at 0.5 and 6.8 microM, respectively. ODG-P-AZT also showed increased antiviral activity, with a 50% reduction in HBV replication at 2.1 microM. Based on the EC50, HDP-P-ACV, ODG-P-ACV, and ODG-P-AZT were > 200, > 14.7, and > 48 times more active than their free nucleosides in reducing HBV replication in 2.2.15 cells. To evaluate the biochemical basis for the increased antiviral activity, we studied the uptake and metabolism of 1-O-octadecyl-sn-glycero-3-phospho-[3H]acyclovir (ODG-P-[3H]ACV) in HepG2 cells. Cellular uptake of ODG-P-[3H]ACV was found to be substantially greater than that of [3H]ACV, and cellular levels of ACV-mono-, -di-, and -triphosphate were much higher with ODG-P-ACV. ODG-P-[3H]ACV was well absorbed orally. Based on urinary recovery of tritium after oral or parenteral administration of the radiolabeled compounds, oral absorption of ODG-P-ACV in mice was 100% versus 37% for ACV. ODG-P-ACV plasma area under the curve was more than 7-fold greater than that of ACV. Lipid prodrugs of this type may be useful orally in treating viral diseases.

Synthesis and antiviral activity of 1-O-octadecyl-2-O-alkyl-sn-glycero-3-foscarnet conjugates in human cytomegalovirus-infected cells.

A series of new lipid prodrugs with the general structure, 1-O-octadecyl-2-X-sn-glycero-3-PFA were synthesized and evaluated for antiviral activity in HCMV-infected human lung fibroblasts (X is -H, -OH or an O-alkyl group of increasing chain length) in order to study structure-activity relationships of PFA lipid prodrugs. The EC50 values for the 2-O-octyl, 2-O-butyl, 2-H, 2-OH, 2-O-methyl and 2-O-ethyl substituted analogs were 1.96, 0.36, 1.0, 0.7, 0.53 and 0.18 microM respectively versus 40 microM for PFA, representing increases in antiviral activity of 20-220 fold. We also synthesized the enantiomer of ODG-PFA, 3-O-octadecyl-sn-glycero-1-PFA, and found that the antiviral activity of both enantiomers as well as the racemate were not significantly different, with EC50 values in the range of 0.67-0.71 microM.