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Biomedical subjects

R D Pratt

Publications and source records attributed to R D Pratt.

At least 19 recordsLinked to original sources
PubMed2003

Donepezil in vascular dementia: a randomized, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and tolerability of donepezil in patients with vascular dementia (VaD). METHODS: Patients (n = 616; mean age, 75.0 years) with probable or possible VaD, according to National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche en l'Enseignement en Neurosciences criteria, were randomized to receive donepezil 5 mg/day (n = 208), donepezil 10 mg/day (after 5 mg/day for the first 28 days) (n = 215), or placebo (n = 193) for 24 weeks. RESULTS: Seventy-six percent of the patients enrolled had probable VaD. A total of 75.3% of the 10 mg donepezil group and 80.8% of the 5 mg group completed the study compared with 83.4% of the placebo group. Both donepezil-treated groups showed improvements in cognitive function on the Alzheimer's Disease Assessment Scale-cognitive subscale compared with placebo, with a mean endpoint treatment difference, as measured by the change from baseline score, of approximately 2 points (donepezil 5 mg, -1.65 [p = 0.003]; 10 mg, -2.09 [p = 0.0002]). Greater improvements on the Clinician's Interview-Based Impression of Change-plus version were observed with both donepezil groups than with the placebo group (overall donepezil treatment vs placebo p = 0.008); 25% of the placebo group showed improvement compared with 39% (p = 0.004) of the 5 mg group and 32% (p = 0.047) of the 10 mg group. Withdrawal rates due to adverse events were low (placebo, 8.8%; donepezil 5 mg, 10.1%; 10 mg, 16.3%). CONCLUSIONS: Donepezil-treated patients demonstrated significant improvements in cognition and global function compared with placebo-treated patients, and donepezil was well tolerated.

Adult↗
PubMed2002

Donepezil: tolerability and safety in Alzheimer's disease.

The tolerability and safety of donepezil HCI in patients with mild to moderate Alzheimer's disease (AD) were examined in an integrated analysis of phase II/III placebo-controlled trials. Patients with mild to moderately severe AD (n=1,920) were randomised to receive donepezil (n=1,291) or placebo (n=629). Adverse events, physical examinations and clinical laboratory tests were assessed. A high completion rate (79%) was achieved in these trials. Of the 1,291 patients receiving donepezil only, 142 (11%) withdrew because of an adverse event compared with 43 of the 629 (7%) placebo patients. The most common adverse events included nausea, diarrhoea, headache, insomnia, dizziness, rhinitis, vomiting, asthenia/fatigue and anorexia. Donepezil had no clinically significant effect on any laboratory evaluations and was not associated with hepatotoxicity. These results demonstrate that donepezil is well tolerated and has a favourable safety profile at clinically effective, once-daily doses of 5 mg and 10 mg.

Aged↗
PubMed2001

A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients.

OBJECTIVE: To examine the effects of donepezil compared with placebo on the preservation of function in patients with AD over a 1-year period. METHODS: This was a prospective, 54-week, double-blind, placebo-controlled, survival to endpoint study. Patients were required to have at entry: a diagnosis of probable AD (National Institute of Neurological and Communicative Disorders and Stroke criteria); Mini-Mental State Examination score of 12 to 20; Clinical Dementia Rating of 1 or 2; modified Hachinski ischemia score < or =4; and capability of performing 8 of 10 instrumental activities of daily living and 5 of 6 basic activities of daily living. Patients (n = 431) were randomized to placebo or donepezil (5 mg/day for 28 days, 10 mg/day thereafter). Outcome measures were the AD Functional Assessment and Change Scale, the Mini-Mental State Examination, and Clinical Dementia Rating scale. At each visit, investigators determined whether predefined criteria for clinically evident decline in functional status had been met. Patients who met the endpoint criteria were discontinued per protocol. RESULTS: Donepezil extended the median time to clinically evident functional decline by 5 months versus placebo. The probability of patients treated with donepezil remaining in the study with no clinically evident functional loss was 51% at 48 weeks, compared with 35% for placebo. The Kaplan-Meier survival curves for the two treatment groups were different (p = 0.002, log-rank test). CONCLUSIONS: Patients with AD continue to show detectable disease progression over time, but treatment with donepezil for 1 year was associated with a 38% reduction in the risk of functional decline compared with placebo.

Aged↗
PubMed2001

Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease.

BACKGROUND: Donepezil hydrochloride is a selective acetylcholinesterase inhibitor approved for the symptomatic treatment of mild to moderately severe Alzheimer disease (AD). Controlled clinical trials of up to 24 weeks have demonstrated that donepezil treatment (5 and 10 mg/d) significantly improves cognition and global function. OBJECTIVE: To investigate the long-term benefits of donepezil treatment in patients with AD. DESIGN: Multicenter, open-label, 144-week extension of 2 US phase 3, double-blind, placebo-controlled clinical trials: a 15-week study (12 weeks of treatment followed by a 3-week placebo washout) and a 30-week study (24 weeks of treatment followed by a 6-week placebo washout). INTERVENTIONS: All patients (N = 763) initially received donepezil, 5 mg/d, for 6 weeks, after which an increase to 10 mg/d was encouraged. MEASURES: Primary efficacy measures were the Alzheimer's Disease Assessment Scale-cognitive subscale and the Clinical Dementia Rating-Sum of the Boxes. RESULTS: After the shorter 3-week placebo washout, donepezil-associated benefits remained above original baseline values for an additional 24 weeks of open-label treatment. Benefits on Alzheimer's Disease Assessment Scale-cognitive subscale scores for patients who received 10 mg/d in the double-blind study were evident compared with the other groups for 108 weeks of open-label treatment. In contrast, donepezil-associated benefits were lost after the 6-week placebo washout, and scores decreased below original baseline values for all patient groups. Although scores improved relative to the new open-label study baseline scores after drug use was restarted, patients remained below original baseline values. The most common adverse events were associated with the nervous and digestive systems and were generally mild and transient; 17% of patient discontinuations were associated with adverse events. CONCLUSIONS: Donepezil is an effective and safe drug for the long-term symptomatic treatment of mild to moderately severe AD for up to 144 weeks (2.8 years), and sustained treatment may confer some advantages.

Aged↗
PubMed2001

An assessment of thimerosal use in childhood vaccines.

BACKGROUND: On July 7, 1999, the American Academy of Pediatrics and the US Public Health Service issued a joint statement calling for removal of thimerosal, a mercury-containing preservative, from vaccines. This action was prompted in part by a risk assessment from the Food and Drug Administration that is presented here. METHODS: The risk assessment consisted of hazard identification, dose-response assessment, exposure assessment, and risk characterization. The literature was reviewed to identify known toxicity of thimerosal, ethylmercury (a metabolite of thimerosal) and methylmercury (a similar organic mercury compound) and to determine the doses at which toxicity occurs. Maximal potential exposure to mercury from vaccines was calculated for children at 6 months old and 2 years, under the US childhood immunization schedule, and compared with the limits for mercury exposure developed by the Environmental Protection Agency (EPA), the Agency for Toxic Substance and Disease Registry, the Food and Drug Administration, and the World Health Organization. RESULTS: Delayed-type hypersensitivity reactions from thimerosal exposure are well-recognized. Identified acute toxicity from inadvertent high-dose exposure to thimerosal includes neurotoxicity and nephrotoxicity. Limited data on toxicity from low-dose exposures to ethylmercury are available, but toxicity may be similar to that of methylmercury. Chronic, low-dose methylmercury exposure may cause subtle neurologic abnormalities. Depending on the immunization schedule, vaccine formulation, and infant weight, cumulative exposure of infants to mercury from thimerosal during the first 6 months of life may exceed EPA guidelines. CONCLUSION: Our review revealed no evidence of harm caused by doses of thimerosal in vaccines, except for local hypersensitivity reactions. However, some infants may be exposed to cumulative levels of mercury during the first 6 months of life that exceed EPA recommendations. Exposure of infants to mercury in vaccines can be reduced or eliminated by using products formulated without thimerosal as a preservative.

Animals↗
PubMed2001

Thiomersal in vaccines: is removal warranted?

The mercury-based vaccine preservative thiomersal has come under scrutiny in recent months because of its presence in certain vaccines that provide the foundation of childhood immunisation schedules. Over the past decade new vaccines have been added to the recommended childhood schedule, and the relatively smaller bodyweight of infants has led to concern that the cumulative exposure of mercury from infant vaccines may exceed certain guidelines for the human consumption of mercury. In the US, government agencies and professional societies have recently recommended that thiomersal be removed altogether from vaccines. Some involved in developing vaccine policy feel that the evidence to support these safety concerns has not risen to the level required for such a response. This apparent divergence of opinion has left healthcare professionals and the public with uncertainty about the potential health effects from low level exposure to thiomersal as well as the necessity of removing thiomersal from vaccines. At present, scientific investigation has not found conclusive evidence of harm from thiomersal in vaccines. As a precautionary measure, efforts are under way to remove or replace thiomersal from vaccines and providers should anticipate the availability of more vaccine products that are thiomersal-free over the coming years.

Child↗
PubMed2000

Long-term efficacy and safety of donepezil in the treatment of Alzheimer's disease: final analysis of a US multicentre open-label study.

This multicentre, open-label study evaluated the long-term efficacy and safety of donepezil in the treatment of patients with mild to moderately severe Alzheimer's disease (AD). The 133 patients who entered the study had previously completed a 14-week randomized, double-blind, placebo-controlled study with donepezil. In this open-label study, patients were treated initially with 3 mg per day donepezil, which could be increased to 5, 7 and 10 mg per day in a step-wise fashion. Patients attended the clinic for assessments at 3-week intervals for the first 12 weeks, then subsequently at 12-week intervals for up to 240 weeks (254 cumulative weeks). Efficacy was assessed using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Clinical Dementia Rating-Sum of the Boxes scale (CDR-SB), and data were compared with those predicted for historical untreated AD patients. During the first 6-9 months of the study, mean ADAS-cog and CDR-SB scores showed evidence of clinical improvement from baseline. After this time scores gradually deteriorated. Overall the decline was less than that estimated if this cohort of patients had not been treated. The most common adverse events were related to the nervous and digestive systems, and were generally mild and transient, resolving without the need for dose modifications. There was no evidence of hepatotoxicity. In conclusion, these data demonstrate that donepezil is a well-tolerated, realistic symptomatic treatment for AD over a period of up to 4.9 years. An interim report of the first 98 weeks of the study has been published previously.

Aged↗
PubMed1996

Virologic markers of human immunodeficiency virus type 1 in cerebrospinal fluid of infected children.

To identify virologic correlates associated with central nervous system (CNS) abnormalities in children infected with human immunodeficiency virus type 1 (HIV-1), cerebrospinal fluid (CSF) was examined for virologic markers and correlated with neurodevelopmental status and neuroimaging abnormalities. Of 30 children, 18 (60%) had at least 1 culture-positive CSF sample; in total, 21 (55%) of 38 CSF specimens were culture-positive. CSF white blood cell counts were higher in specimens that were culture-positive (P = .01). HIV-1 RNA was detected in 90% of CSF samples, and RNA levels > or = 10,000 copies/mL were found in 6 (75%) of 8 children with severe neurocognitive impairment (P = .08) and 11 (73%) of 15 children with a cognitive index < or = 85 (P = .04). Higher RNA levels were associated with abnormal brain imaging scans (P = .04) and with neurocognitive deficits (P = .04). Thus, HIV-1 is present within the CNS of most infected children, and neurocognitive impairment appears to be associated with increased HIV-1 replication.

Adolescent↗
PubMed1995

Rapidly recurrent enteroviral meningitis in non-immunocompromised infants caused by different viral strains.

Repeated episodes of enteroviral meningitis occurring within a 1-month period in two non-immunocompromised infants were investigated using molecular techniques to distinguish persistent or recrudescent infection from new infection. Viral RNA from cerebrospinal fluid was amplified by polymerase chain reaction, cloned, and the nucleic acid sequences determined. This analysis demonstrated that both infants had recurrent episodes of meningitis caused by new infection with a distinct enterovirus strain. The molecular methods that were employed should prove useful in similar clinical settings as well as for the study of enteroviral outbreaks. These cases also illustrate the potential for rapid reinfection of infants with different viruses of the same genus.

Base Sequence↗
PubMed1995

Rhabdomyolysis associated with acute varicella infection.

We report two cases of intense, generalized rhabdomyolysis complicating varicella-zoster virus (VZV) infections, one in an adolescent and one in a young adult male. In both cases, myoglobinuria and weakness of large muscle groups developed within 5 days of the onset of vesicular lesions. A muscle biopsy from one of the individuals showed muscle fiber necrosis in the absence of acute inflammatory infiltrates or vasculitis. Culture of the muscle biopsy specimen for VZV was negative; however, the VZV genome was detected by the polymerase chain reaction. Both patients recovered fully after treatment with hydration therapy alone.

Acute Disease↗
PubMed1995

Virologic characterization of primary human immunodeficiency virus type 1 infection in a health care worker following needlestick injury.

A health care worker (HCW) was infected via needlestick with human immunodeficiency virus (HIV) type 1 from a subject with AIDS who harbored a zidovudine-resistant, syncytium-inducing (SI) HIV strain. The phenotypic characteristics of the HIV-1 isolates obtained from the HCW and markers of virus load were followed for 20 months. Although the HCW was initially infected with an SI strain, within 75 days of infection the isolate became non-SI and remained so for > or = 635 days. Even though the AIDS patient had a zidovudine-resistant virus, the HCW was infected with a zidovudine-sensitive virus. Plasma RNA levels peaked 20 days after infection, declined rapidly within 2 weeks, and remained stable for the duration of follow-up. Similarly, the HCW's CD4 lymphocyte count remained stable throughout the study. Thus, selection for non-SI and zidovudine-sensitive virus occurred in the HCW, who, after initial symptomatic infection associated with high levels of plasma HIV-1 RNA, developed low plasma RNA copy numbers and stable CD4 lymphocyte counts.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Pediatric human immunodeficiency virus infection in a low seroprevalence area.

Although increasing information is available regarding human immunodeficiency virus (HIV) infections of children in high seroprevalence areas, few data are available describing trends in low seroprevalence populations. In San Diego County approximately 1 in 1450 live births are to women infected with HIV as identified by nonlinked heel stick testing. Seventy-seven HIV-infected children were identified and followed in our clinics during the period 1983 to 1991, of whom 32 (42%) were infected perinatally, 32 (42%) were hemophiliacs and 13 (17%) were infected by blood transfusions. During the last 4 years of the study period (1988 to 1991), most (28 of 37, 76%), newly identified HIV-infected children less than 13 years old were perinatally infected. Of the 32 perinatally infected children 50% were Hispanic, 34% were Caucasian and 16% were African-American. The prospective vertical transmission rate was 16%. Twenty-nine (38%) of the HIV-infected children have a diagnosis of acquired immunodeficiency syndrome and 17 (22%) have died. Comparatively few of the HIV-infected hemophiliac patients (4 (12%)) have progressed to an acquired immunodeficiency syndrome diagnosis. The number of acquired immunodeficiency syndrome diagnoses declined in the last 2 years of the study as a result of fewer cases of Pneumocystis carinii pneumonia; 11 cases of P. carinii pneumonia were diagnosed in 1988 to 1989 compared with 4 cases in 1990 to 1991. Survival analysis for the perinatally infected group yielded a median survival of 9.2 years. The apparent trend in our data toward improved outcomes of children infected with HIV suggests the beneficial effects of early identification, antiretroviral treatment, and P. carinii pneumonia prophylaxis.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Mitochondrial phosphate transport. Import of the H+/Pi symporter and role of the presequence.

The rat liver mitochondrial phosphate transporter contains a 44-amino acid presequence. The role of this presequence is not clear since the ADP/ATP carrier and the brown fat uncoupling protein, related members of a family of inner membrane anion transporters, lack a presequence and contain targeting information within the mature protein. Here, we present evidence that the rat liver mitochondrial phosphate transporter can be synthesized in vitro, imported into mitochondria, and processed to a protein of Mr 33,000. Import requires the membrane potential and external nucleotide triphosphate. The presequence inserts into the outer mitochondrial membrane, and import proceeds via a process similar to other proteins destined for the inner membrane or matrix. A mutant phosphate transporter lacking 35 amino acids at the NH2 terminus of the presequence has little capacity for mitochondrial import. The rat liver phosphate transporter is also imported and processed by rat kidney mitochondria and by mitochondria from the yeast Saccharomyces cerevisiae. A site-directed mutation of the N-ethyl-maleimide reactive cysteine 41 does not affect import or processing. The results presented show that optimal import of the mitochondrial phosphate transporter, unlike the ADP/ATP carrier and the brown fat uncoupling protein, is dependent on a presequence. As these carriers are believed to have evolved from a single gene, it seems likely that the H+/Pi carrier, known to be present in prokaryotes, appeared first and that subsequent evolutionary events leading to the other anion carriers eliminated the presequence.

2,4-Dinitrophenol↗
PubMed1990

Mitochondrial proton/phosphate transporter. An antibody directed against the COOH terminus and proteolytic cleavage experiments provides new insights about its membrane topology.

Molecular cloning and sequencing of a full-length cDNA encoding the rat liver mitochondrial phosphate transporter (H+/Pi symporter) has revealed its primary structure (Ferreira, G. C. Pratt, R. D., and Pedersen, P. L. (1989) J. Biol. Chem. 264, 15628-15633). To date, no experimental data pertinent to the membrane topology of this transporter are available. For this reason, four different peptides which represent different regions of the H+/Pi symporter were synthesized and used to raise polyclonal antibodies. Each of the antipeptide antibodies exhibits immunoreactivity with its synthetic peptide antigen, but only antiserum against a COOH-terminal peptide reacts with the native transporter, suggesting that the other peptides are either conformally restricted or located in the interior of the protein. Competitive radioimmunoassays, using intact "mitoplasts" (outer membrane-free mitochondria) and inverted inner membrane vesicles, show that the COOH-terminal antibodies bind only to the cytoplasmic surface of the inner membrane, indicating that the COOH terminus of the protein is normally exposed to the mitochondrial intermembrane space. In support of this conclusion, tryptic digestion of mitoplasts but not of the inside-out vesicles, cleaves the antigenic site for the COOH-terminal antibodies. In other experiments, it was shown that N-ethylmalemide, a sulfhydryl alkylating agent known to inhibit the mitochondrial phosphate transporter, markedly reduces the accessibility of the COOH terminus to trypsin. These studies provide the first direct experimental data relevant to the membrane topology of the mitochondrial H+/Pi symporter. In addition, they support the view that alkylation of a reactive cysteine residue induces a significant conformational change in the transporter.

Amino Acid Sequence↗
PubMed1990

Viruses associated with acute lower respiratory tract infections in children from the eastern highlands of Papua New Guinea (1983-1985).

This study, conducted at Goroka Hospital from January 1983 to June 1985, examined the viruses identified in nasopharyngeal aspirates (NPA) and urines collected from 716 hospitalised children with moderate or severe pneumonia, in NPA from 170 children with mild pneumonia treated as outpatients and in NPA from a control group of 428 children attending the outpatient department of Goroka Hospital suffering from minor ailments other than upper or lower respiratory tract infections. One or more viruses were identified from 68%, 51% and 43% of children with moderate or severe pneumonia, mild pneumonia and the control group, respectively. One-third of viruses were identified in conjunction with another virus in both control and sick children. Viral identification rates were highest in children under 1 year of age. Cytomegalovirus, adenoviruses, respiratory syncytial virus (RSV), measles and rhinoviruses were the most frequently identified viruses. RSV was associated with mild as well as moderate and severe disease. No virus was associated with an increased risk of death. Annual epidemics of RSV occurred during the wet season. An epidemic of influenza A virus and also influenza B virus and 3 epidemics of parainfluenza 3 virus occurred during the study period. The high viral identification rates in this study suggest a high frequency of transmission associated with the social structure and environment of Papua New Guinean highland villages and high population mobility.

Acute Disease↗
PubMed1989

Energy-linked anion transport. Cloning, sequencing, and characterization of a full length cDNA encoding the rat liver mitochondrial proton/phosphate symporter.

A full length cDNA clone encoding the precursor of the rat liver mitochondrial phosphate transporter (H+/Pi symporter) has been isolated from a cDNA library using a bovine heart partial length phosphate transporter clone as a hybridization probe. The entire clone is 1263 base pairs in length with 5'- and 3'-untranslated regions of 16 and 168 base pairs, respectively. The open reading frame encodes for the mature protein (312 amino acids) preceded by a presequence of 44 amino acids enriched in basic residues. The polypeptide sequence predicted from the DNA sequence was confirmed by analyzing the first 17 amino-terminal amino acids of the pure phosphate transporter protein. The rat liver phosphate transporter differs from the bovine heart transporter in 32 amino acids (i.e. approximately 10%). It contains a region from amino acid 139 to 159 which is 37% identical with the beta-subunit of the liver mitochondrial ATP synthase. Amino acid sequence comparisons of the Pi transporter with Pi binding proteins, other H+-linked symporters, and the human glucose transporter did not reveal significant sequence homology. Analysis of genomic DNA from both rat and S. cerevisiae by Southern blots using the rat liver mitochondrial Pi carrier cDNA as a probe revealed remarkably similar restriction patterns, a finding consistent with the presence in lower and higher eukaryotes of homologous Pi carrier proteins. This is the first report of the isolation, sequencing, and characterization of a full length cDNA coding for a protein involved in energy-coupled Pi transport.

Amino Acid Sequence↗