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Biomedical subjects

P Ward

Publications and source records attributed to P Ward.

At least 37 records · Page 2Linked to original sources
PubMed2000

Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group.

BACKGROUND: Use of some antiviral drugs for influenza infection is limited by potential rapid emergence of resistance. We studied the efficacy and safety of oseltamivir, the oral prodrug of the neuraminidase inhibitor GS4071, in adults with naturally acquired laboratory-confirmed influenza. METHODS: We did a randomised controlled trial of 726 previously healthy non-immunised adults with febrile influenza-like illness of up to 36 h duration. Patients were assigned oral oseltamivir 75 mg (n=243), oseltamivir 150 mg (n=245), or placebo (n=238) twice daily for 5 days. We assessed recovery by questionnaire and temperature recordings. The primary endpoint was time to resolution of illness in influenza-infected patients. FINDINGS: 475 (66%) patients had confirmed infection. Duration of illness was significantly shorter by 29 h (25% reduction, median duration 87.4 h [95% CI 73.3-104.7], p=0.02) with oseltamivir 75 mg and by 35 h (30%, 81.8 h [68.2-100.0], p=0.01) with oseltamivir 150 mg than with placebo (116.5 h [101.5-137.8]). The effect of oseltamivir was apparent within 24 h of the start of treatment. In patients treated within 24 h of symptom onset, symptoms were alleviated 43 h (37% reduction) and 47 h (40%) earlier with oseltamivir 75 mg and 150 mg, respectively, compared with placebo (75 mg 74.5 h [68.2-98.0], p=0.02; 150 mg 70.7 h [54.0-89.4], p=0.01; placebo 117.5 h [103.0-143.8]). Oseltamivir was associated with lower [corrected] symptom scores, less viral shedding, and improved health, activity, and sleep quality, and was well tolerated. INTERPRETATION: Oseltamivir was effective and well tolerated in the treatment of natural influenza infection in adults. The efficacy, tolerability, and ease of administration warrant further investigation in children, elderly patients, and at-risk patients.

Acetamides↗
PubMed2000

Increased levels of expression of an NMDARI splice variant in the superior temporal gyrus in schizophrenia.

Expression patterns of mRNAs for the NMDARI subunit (NRI) carboxy-terminus isoforms were investigated in postmortem brain tissue using isotopic in situ hybridization. Three brain regions (superior temporal, middle frontal and visual cortices) were examined in patients with schizophrenia (n = 6) and control subjects (n = 6). A 22% higher level of expression of the NRI isoform that contains neither spliced exon was observed in the superior temporal gyrus of patients with schizophrenia compared with controls (p = 0.01). No differences were observed in the expression of the other isoforms in the three regions studied. These data suggest that NRI alternative splicing might be abnormal in schizophrenia and reinforce previous findings implicating the superior temporal gyrus as a site of neural dysfunction in schizophrenia.

Adult↗
PubMed2000

Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group.

CONTEXT: Previous studies have shown oseltamivir, a neuraminidase inhibitor, to be effective in preventing influenza and treating experimental influenza. OBJECTIVE: To evaluate the efficacy and safety of oseltamivir in the treatment of naturally acquired influenza infection. DESIGN: Randomized, placebo-controlled, double-blind study conducted January through March 1998. SETTING: Sixty primary care and university health centers throughout the United States. PARTICIPANTS: A total of 629 healthy nonimmunized adults aged 18 to 65 years with febrile respiratory illness of no more than 36 hours' duration with temperature of 38 degrees C or more plus at least 1 respiratory symptom and 1 constitutional symptom. INTERVENTIONS: Individuals were randomized to 1 of 3 treatment groups with identical appearing pills: oral oseltamivir phosphate, 75 mg twice daily (n = 211) or 150 mg (n = 209) twice daily, or placebo (n = 209). MAIN OUTCOME MEASURES: Duration and severity of illness in individuals infected with influenza. RESULTS: Two individuals withdrew before receiving medication and were excluded from further analyses. A total of 374 individuals (59.6%) were infected with influenza. Their duration of illness was reduced by more than 30% with both oseltamivir, 75 mg twice daily (median, 71.5 hours; P < .001), and oseltamivir, 150 mg twice daily (median, 69.9 hours; P = .006), compared with placebo (median, 103.3 hours). Severity of illness was reduced by 38% (median score, 597 score-hours; P < .001) with oseltamivir, 75 mg twice daily, and by 35% (median score, 626 score-hours; P < .001) with oseltamivir, 150 mg twice daily, vs placebo (median score, 963 score-hours). Oseltamivir treatment reduced the duration of fever and oseltamivir recipients returned to usual activities 2 to 3 days earlier than placebo recipients (P < or = .05). Secondary complications such as bronchitis and sinusitis occurred in 15% of placebo recipients compared with 7% of combined oseltamivir recipients (P = .03). Among all 629 subjects, oseltamivir reduced illness duration (76.3 hours and 74.3 hours for 75 mg and 150 mg, respectively, vs 97.0 hours for placebo; P = .004 for both comparisons) and illness severity (686 score-hours and 629 score-hours for 75 mg and 150 mg, respectively, vs 887 score-hours for placebo; P < .001 for both comparisons). Nausea and vomiting occurred more frequently in both oseltamivir groups (combined, 18.0% and 14.1%, respectively; P = .002) than in the placebo group (7.4% and 3.4%; P < .001). CONCLUSIONS: Our data suggest that oral oseltamivir treatment reduces the duration and severity of acute influenza in healthy adults and may decrease the incidence of secondary complications.

Acetamides↗
PubMed2000

Brain uptake and receptor binding of two [11C]labelled selective high affinity NK1-antagonists, GR203040 and GR205171--PET studies in rhesus monkey.

Two high affinity and selective NK1-receptor antagonists, GR203040 and GR205171, were labelled with 11C and used in a series of experiments in rhesus monkeys. The purpose of these studies was to evaluate the brain uptake pattern and to explore the potential use of these compounds as PET ligands to characterise NK1-receptor binding. Seventeen studies were carried out with [11C]GR205171 and five experiments with [11C]GR203040, including baseline studies and studies performed after a 5 min infusion of cold compound at doses between 0.05 and 1 mg/kg. Both compounds demonstrated a significant and rapid uptake in the brain, but the uptake of [11C]GR205171 was more than double the uptake of [11C]GR203040. At tracer doses of [11C]GR205171 and all doses of [11C]GR203040 the uptake reached a plateau with no washout during the examination time, whereas [11C]GR205171 after pre-treatment with cold GR205171 showed a significant washout. Using a model with the cerebellum as reference, a method for quantitation was applied to the studies with [11C]GR205171 and the results indicated that the highest specific binding was in the striatum. The pre-treatment dose of cold GR205171 needed for 50% inhibition of binding was less than 0.04 mg/kg. The studies indicated that [11C]GR205171 could be used for the in vivo characterisation of NK1-receptor binding.

Animals↗
PubMed2000

Molecular identification of potentially probiotic lactobacilli.

The rRNA-targeted oligonucleotide probes are useful for the identification of Lactobacillus acidophilus, L. gasseri, L. johnsonii, L. crispatus, and L. amylovorus. However, the oligonucleotide probe designed for L. helveticus hybridized with nucleic acids of type strains of L. gallinarum and L. helveticus. Hence, the similarity among the 73 strains of lactobacilli was evaluated on the basis of their randomly amplified polymorphic DNA (RAPD) profiles derived from five single-primer reactions. These strains were grouped into seven clusters at a similarity level of 30%, which corresponded to six separate species of the L. acidophilus complex (L. johnsonii, L. gallinarum, L. amylovorus, L. crispatus, L. acidophilus, and L. gasseri, respectively) and L. helveticus. For the first time, strains of L. gallinarum were characterized by RAPD and PFGE analyses. The genome length in that species was estimated to be near 1.45 Mb with the summation of ApaI fragments, and near 1.95 Mb with the summation of SmaI fragments.

Bacterial Typing Techniques↗
PubMed2000

Hartshill rectangle: failure of spinal stabilisation in acute spinal cord injury.

A high rate of failure of the internal fixation of unstable spinal fractures in complete cord injured patients was noted in patients referred to the Salisbury Spinal Centre who had been stabilised with a Hartshill rectangle. This prompted a review of the operative notes, radiographs and clinical outcomes of all patients referred to the centre with a Hartshill rectangle in situ. All patients identified with a complete spinal cord injury and Hartshill rectangle were identified. Forty-three such patients referred from 13 different centres were found. Pre- and postoperative radiographs were assessed for fracture pattern and for spinal correction. Operative outcome in terms of pain and complications relating to surgery were identified. The most recent radiographs were assessed for signs of loss of reduction or stabilisation. Follow-up averaged 84 months (range 36-132 months). Of the 43 identified patients, 19 were found to have unsatisfactory stabilisation. Persistent pain, broken implants and worsening kyphosis were the main complications. The failure to use bone graft at the time of stabilisation was significantly (P < 0.001) related to risk of failure. The application and use of the Hartshill is not a technically challenging procedure; however, if the system is to be used, it must be used correctly. Failure to correctly apply the rectangle and to use bone graft will lead to an unacceptably high rate of failure.

Adolescent↗
PubMed2000

Migration of a transjugular intrahepatic portosystemic shunt (TIPS) stent: evaluation by transesophageal echocardiography.

Transjugular intrahepatic portosystemic shunting (TIPS) is a procedure for end-stage liver disease that involves angiographically guided placement of an intrahepatic expandable metal stent. Mechanical complications of intrahepatic stent placement have been reported, including stent migration to the central venous circulation. This report describes a patient who had embolization of a stent after a TIPS procedure, with subsequent failed percutaneous attempts at stent removal. Transesophageal echocardiography documented the stent caught in the tricuspid valve and apparatus, with its distal end projecting into the right ventricular cavity.

Echocardiography, Transesophageal↗
PubMed2000

Tumor-specific, replication-competent adenovirus vectors overexpressing the adenovirus death protein.

We have constructed two novel adenovirus (Ad) replication-competent vectors, named KD1 and KD3, that may have use in anticancer therapy. The vectors have two key features. First, they markedly overexpress the Ad death protein (ADP), an Ad nuclear membrane glycoprotein required at late stages of infection for efficient cell lysis and release of Ad from cells. Overexpression of ADP was achieved by deleting the E3 region and reinserting the adp gene. Because ADP is overexpressed, KD1 and KD3 are expected to spread more rapidly and effectively through tumors. Second, KD1 and KD3 have two E1A mutations (from the mutant dl1101/1107) that prevent efficient replication in nondividing cells but allow replication in dividing cancer cells. These E1A mutations preclude binding of E1A proteins to p300 and pRB. As a result, the virus should not be able to drive cells from G(0) to S phase and therefore should not be able to replicate in normal tissues. We show that KD1 and KD3 do not replicate well in quiescent HEL-299 cells or in primary human bronchial epithelial cells, small airway epithelial cells, or endothelial cells; however, they replicate well in proliferating HEL-299 cells and human A549 lung carcinoma cells. In cultured A549 cells, KD1 and KD3 lyse cells and spread from cell to cell more rapidly than their control virus, dl1101/1107, or wild-type Ad. They are also more efficient than dl1101/1107 or wild-type Ad in complementing the spread from cell to cell of an E1(-) E3(-) replication-defective vector expressing beta-galactosidase. A549 cells form rapidly growing solid tumors when injected into the hind flanks of immunodeficient nude mice; however, when A549 cells were infected with 10(-4) PFU of KD3/cell prior to injection into mice, tumor formation was nearly completely suppressed. When established A549 tumors in nude mice were examined, tumors injected with buffer grew 13.3-fold over 5 weeks, tumors injected with dl1101/1107 grew 8-fold, and tumors injected with KD1 or KD3 grew 2.6-fold. Hep 3B tumors injected with buffer grew 12-fold over 3.5 weeks, whereas tumors injected with KD1 or KD3 grew 4-fold. We conclude that KD1 and KD3 show promise as anticancer therapeutics.

Adenovirus E3 Proteins↗
PubMed2000

A role for single-stranded templates in cell-free adeno-associated virus DNA replication.

Assays have been described in which duplex adeno-associated virus (AAV) DNA can be replicated in HeLa cell extracts with exogenous AAV Rep protein. These assays appear to mimic the AAV DNA replication that occurs in the cell, including the ability of extracts from adenovirus (Ad)-infected cells to replicate duplex AAV DNA templates more efficiently than extracts from uninfected cells can. We showed previously that the Ad-infected extract was able to support a more processive replication than the uninfected extract. When the Ad single-stranded DNA binding protein (Ad-DBP) was added to an uninfected extract, DNA replication became processive. Based on a strand displacement replication model, we hypothesized that the Ad-DBP was stabilizing the displaced single-stranded DNA during strand displacement replication. In this report, we show that in Ad-infected extracts most of the newly replicated duplex DNA is converted into a single-stranded form shortly after synthesis. Using the results of assays for the replication of single-stranded AAV DNA, we show that these single-stranded molecules serve as templates for additional replication. In addition, we identify a class of molecules which are likely to be intermediates of replication on single-stranded templates. We discuss a possible role for replication of single-stranded molecules in the infected cell.

Camptothecin↗
PubMed2000

The pharmacokinetics and tolerability of the oral neuraminidase inhibitor oseltamivir (Ro 64-0796/GS4104) in healthy adult and elderly volunteers.

The tolerability and pharmacokinetics of Ro 64-0802, a potent, selective inhibitor of influenza neuraminidase, and its oral prodrug oseltamivir were investigated in three double-blind, placebo-controlled studies. Two studies involved healthy adult volunteers (18-55 years) (n = 48) who received single (20-1000 mg) or bid doses (50-500 mg) (n = 32) of oseltamivir or placebo for 7 days. Healthy elderly volunteers (> or = 65 years) (n = 24) received oseltamivir 100 to 200 mg bid or placebo for 7 days in a third study. Measurable plasma concentrations of the active metabolite appeared rapidly in plasma and were significantly higher and longer lasting than those of oseltamivir. Pharmacokinetics of both compounds were linear. Multiple-dose exposure was predictable from single-dose data, and steady-state plasma concentrations were achieved within 3 days of bid drug administration. Oseltamivir was well tolerated at single doses of up to 1000 mg and twice-daily doses of up to 500 mg. Adverse events were mild in intensity. Exposure to both prodrug and active metabolite was increased in elderly patients by approximately 25%. However, due to the wide safety margin of both compounds, no dose adjustment is necessary for elderly patients.

Acetamides↗
PubMed2000

Oral oseltamivir in human experimental influenza B infection.

Oseltamivir is the prodrug of Ro64-0802 (GS4071), a potent and selective inhibitor of influenza A and B virus neuraminidases. Three randomized, double-blind, placebo-controlled, parallel-group studies evaluated oral oseltamivir for early treatment (75 or 150 mg twice daily for 5 days) or prevention (75 mg once or twice daily for 7 days) of experimental influenza B virus infection in healthy susceptible adults. Treatment study A (n=60) demonstrated similar trends to treatment study B (n=117), in which 75 mg doses of oseltamivir introduced 24 h after inoculation reduced median area under curve (AUC) virus titre (oseltamivir, 22.7; placebo, 131.1 log10 TCID50 x h/ml; P=0.002) and duration of viral shedding (oseltamivir, 23.9 h; placebo, 95.8 h; P=0.0005). In prevention study C (n=58), oseltamivir did not reduce infection rates (85 versus 84%) but significantly reduced median AUC virus titre (10.0 versus 66.9 log10 TCID50 x h/ml; P=0.03) and duration of viral shedding (36 versus 84 h; P=0.03) compared with placebo. Oseltamivir was well tolerated. No emergence of drug-resistant variants was detected by testing last-day isolates (n=112) in neuraminidase inhibition assays. These results indicate that oseltamivir has significant antiviral activity in experimental human influenza B virus infection when used for prophylaxis or early treatment.

Acetamides↗
PubMed1999

Neo-striatal rCBF correlates of psychomotor slowing in patients with major depression.

Psychomotor slowing is a fundamental clinical feature of severe depression and is thought to reflect dysfunction within prefrontal-subcortical circuits. This study utilised a split-dose single photon emission computerised tomography (SPECT) scanning technique in association with a two-stage test of psychomotor speed. Twenty-five patients with primary depressive disorders were injected with technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO) whilst performing each component of a two-stage psychomotor task. The first stage, 'simple reaction time' (RT) and the second stage, 'choice reaction time' (CRT), were each followed by 30-min SPECT scans. Regions of interest (ROIs) corresponding to the left and right neo-striatum (caudate-putamen) were drawn, and regional cerebral blood flow (rCBF) values were calculated. Importantly, the change in rCBF measure in the left neo-striatum was inversely correlated with RT (r = -0.48, P < 0.05). That is, the patients with the greatest psychomotor slowing initially showed the least increase in rCBF during the CRT condition. This effect was independent of age. The study demonstrates that a simple two-stage motor paradigm can be used to elicit rCBF correlates of psychomotor slowing in patients with primary depression. Such rCBF findings may implicate the neo-striatum in the neurobiology of major depression.

Adult↗
PubMed1999

Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza.

BACKGROUND: Safe and effective antiviral agents are needed to prevent infection with influenza A and B virus. Oseltamivir (GS4104), which can be administered orally, is the prodrug of GS4071, a potent and selective inhibitor of influenzavirus neuraminidases. We studied the use of oseltamivir for long-term prophylaxis against influenza in two placebo-controlled, double-blind trials at different U.S. sites during the winter of 1997-1998. METHODS: We randomly assigned 1559 healthy, nonimmunized adults 18 to 65 years old to receive either oral oseltamivir (75 mg given once or twice daily, for a total daily dose of 75 or 150 mg) or placebo for six weeks during a peak period of local influenzavirus activity. The primary end point with respect to efficacy was laboratory-confirmed influenza-like illness (defined as a temperature of at least 37.2 degrees C accompanied by at least one respiratory and at least one systemic symptom). RESULTS: In the two studies combined, the risk of influenza among subjects assigned to either once-daily or twice-daily oseltamivir (1.2 percent and 1.3 percent, respectively) was lower than that among subjects assigned to placebo (4.8 percent; P<0.001 and P=0.001 for the comparison with once-daily and twice-daily oseltamivir, respectively). The protective efficacy of oseltamivir in the two active-treatment groups combined was 74 percent (95 percent confidence interval, 53 to 88 percent) at all the sites combined and 82 percent (95 percent confidence interval, 60 to 93 percent) at sites in Virginia, where the rate of influenza infection was higher than the overall rate. For culture-proved influenza, the rate of protective efficacy in the two oseltamivir groups combined was 87 percent (95 percent confidence interval, 65 to 96 percent). The rate of laboratory-confirmed influenza infection was lower with oseltamivir than with placebo (5.3 percent vs. 10.6 percent, P<0.001). Oseltamivir was well tolerated but was associated with a greater frequency of nausea (12.1 percent and 14.6 percent in the once-daily and twice-daily groups, respectively) and vomiting (2.5 percent and 2.7 percent, respectively) than was placebo (nausea, 7.1 percent; vomiting, 0.8 percent). However, the frequency of premature discontinuation of drug or placebo was similar among the three groups (3.1 to 4.0 percent). CONCLUSIONS: Oseltamivir administered daily for six weeks by the oral route is safe and effective for the prevention of influenza.

Administration, Oral↗
PubMed1999

Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment.

CONTEXT: Influenza virus neuraminidase is thought to be essential for virus replication in humans; however, to date, available neuraminidase inhibitors are limited to zanamivir, which is topically administered. OBJECTIVE: To determine the safety, tolerability, and antiviral activity of oral neuraminidase inhibitor oseltamivir (GS4104/Ro64-0796) for prevention and the early treatment of influenza in experimentally infected humans. DESIGN: Two randomized, double-blind, placebo-controlled trials conducted between June and July 1997. SETTING: Individual hotel rooms; 2 large US university medical schools. PARTICIPANTS: A total of 117 healthy adult volunteers (aged 18-40 years; median age, 21 years) who were susceptible (hemagglutination-inhibition antibody titer < or =1:8). INTERVENTIONS: All subjects were inoculated intranasally with influenza A/Texas/36/91 (H1N1) virus. For the prophylaxis study, oral oseltamivir (100 mg once daily [n = 12], 100 mg twice daily [n = 12], or matching placebo [n = 13], starting 26 hours before virus inoculation) was administered. For the treatment study, the same drug was given (20 mg, 100 mg, or 200 mg twice daily, 200 mg once daily, or matching placebo [n = 16], in each group starting 28 hours after inoculation). All regimens were continued for 5 days. MAIN OUTCOME MEASURES: Comparing placebo groups with pooled treatment groups, for prophylaxis, outcomes included frequency of infection and viral shedding; for treatment, viral shedding in titers. RESULTS: In the prophylaxis study, 8 (67%) of 12 placebo and 8 (38%) of 21 oseltamivir recipients became infected (P = .16; efficacy, 61%); 6 (50%) placebo compared with 0 oseltamivir recipients shed virus (P<.001; efficacy, 100%), and 33% of placebo but no oseltamivir recipient had infection-related respiratory illness (P<.01). Among infected subjects in the treatment study (n = 69), the viral titer area under the curve of the combined oseltamivir groups (n = 56) was lower (median [interquartile range [IQR]], 80 [23-151] vs 273 [79-306] log10 tissue culture-infective doses50 per milliliter x hour; P = .02) than the placebo group (n = 13), and the median (IQR) duration of viral shedding with therapy was reduced from 107 (83-131) to 58 (35-59) hours (P = .003). Oseltamivir treatment also reduced symptom scores (median [IQR] score-hours, 225 [97-349] vs 400 [189-645]; P = .05), and nasal proinflammatory cytokine levels. Transient mild to moderate nausea after dosing was observed in 15 (17%) of 88 oseltamivir and 2 (7%) of 29 placebo recipients (95% confidence interval for difference, -11% to 68%), which was largely prevented by ingestion with food. CONCLUSIONS: In these trials, prophylaxis and early treatment with oral oseltamivir were both associated with significant antiviral and clinical effects in experimental human influenza.

Administration, Oral↗
PubMed1999

Reported pica behavior in a sample of incident dialysis patients.

In a prospective study, pica behavior was investigated during baseline interviews with a cohort of incident patients (n = 226) who began chronic dialysis therapy in metropolitan Atlanta, GA, during 1996 to 1997. Pica, defined as current pica behavior and/or reported history of pica behavior, was reported by 16% of the sample. Patients reporting pica were significantly more likely to be African American women and were significantly younger than the remainder of the sample. Approximately two thirds of patients who reported pica behaviors craved and excessively consumed ice; the remainder craved and consumed starch, dirt, flour, or aspirin. Among patients reporting pica, average serum albumin values were low and average phosphorus was increased. The average hematocrit of patients reporting ice pica was low. Over half of the hemodialysis patients reporting pica behavior had excessive usual interdialytic weight gain. Potential symptoms/problems affecting quality of life among patients practicing pica, eg, cramps, are shown in a case report. The data indicate the need for targeted education and support for dietitians' increased interaction with dialysis patients involved in pica behaviors.

Adult↗
PubMed1999

Comparative characterization of rep proteins from the helper-dependent adeno-associated virus type 2 and the autonomous goose parvovirus.

Adeno-associated viruses (AAVs) are nonautonomous human parvoviruses in that they are dependent on helper functions supplied by other viruses or on genotoxic stimuli for conditions permissive for replication. In the absence of helper, AAV type 2 enters latency by integration into a specific site on human chromosome 19. This feature of AAV, in combination with a lack of pathogenicity, makes AAV an attractive candidate vector for human gene therapy. Goose parvovirus (GPV) is both autonomous and pathogenic yet is highly homologous to AAV. To address the molecular bases for the different viral lifestyles, we compare the AAV and GPV nonstructural proteins, Rep78 and Rep1, respectively. We find that Rep78 and Rep1 possess several biochemical activities in common, including (i) high-affinity DNA binding for sequences that constitute the minimal DNA replication origin; (ii) nucleoside triphosphate-dependent DNA helicase activity; and (iii) origin-specific replication of double-stranded linear DNA. These experiments also establish a specific 38-bp DNA sequence as the minimal GPV DNA replication origin. It is noteworthy that although the proposed Rep binding sites of GPV and AAV are highly similar, Rep1 and Rep78 show a high degree of specificity for their respective origins, in both binding and replication assays. One significant difference was observed; with the minimal replication origin in adenovirus-uninfected extracts, Rep78-mediated replication exhibited low processivity, as previously reported. In contrast, Rep1 efficiently replicated full-length template. Overall, our studies indicate that GPV Rep1 and AAV Rep78 support a comparable mode of replication. Thus, a comparison of the two proteins provides a model system with which to determine the contribution of Rep in the regulation of dependence and autonomy at the level of DNA replication.

Animals↗
PubMed1999

Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802.

Oseltamivir is an ethyl ester prodrug of Ro 64-0802, a selective inhibitor of influenza virus neuraminidase. Oral administration of oseltamivir delivers the active antiviral Ro 64-0802 to the bloodstream, and thus all sites of influenza infection (lung, nasal mucosa, middle ear) are accessible. The pharmacokinetic profile of oseltamivir is simple and predictable, and twice daily treatment results in effective antiviral plasma concentrations over the entire administration interval. After oral administration, oseltamivir is readily absorbed from the gastrointestinal tract and extensively converted to the active metabolite. The absolute bioavailability of the active metabolite from orally administered oseltamivir is 80%. The active metabolite is detectable in plasma within 30 minutes and reaches maximal concentrations after 3 to 4 hours. After peak plasma concentrations are attained, the concentration of the active metabolite declines with an apparent half-life of 6 to 10 hours. Oseltamivir is eliminated primarily by conversion to and renal excretion of the active metabolite. Renal clearance of both compounds exceeds glomerular filtration rate, indicating that renal tubular secretion contributes to their elimination via the anionic pathway. Neither compound interacts with cytochrome P450 mixed-function oxidases or glucuronosyltransferases. The pharmacokinetic profile of the active metabolite is linear and dose-proportional, with less than 2-fold accumulation over a dosage range of oseltamivir 50 to 500 mg twice daily. Steady-state plasma concentrations are achieved within 3 days of twice daily administration, and at a dosage of 75mg twice daily the steady-state plasma trough concentrations of active metabolite remain above the minimum inhibitory concentration for all influenza strains tested. Exposure to the active metabolite at steady state is approximately 25% higher in elderly compared with young individuals; however, no dosage adjustment is necessary. In patients with renal impairment, metabolite clearance decreases linearly with creatinine clearance. A dosage reduction to 75mg once daily is recommended for patients with creatinine clearance <30 ml/min (1.8 L/h). The pharmacokinetics in patients with influenza are qualitatively similar to those in healthy young adults. In vitro and in vivo studies indicate no clinically significant drug interactions. Neither paracetamol (acetaminophen) nor cimetidine altered the pharmacokinetics of Ro 64-0802. Coadministration of probenecid resulted in a 2.5-fold increase in exposure to Ro 64-0802; however, this competition is unlikely to result in clinically relevant effects. These properties make oseltamivir a suitable candidate for use in the prevention and treatment of influenza.

Acetamides↗