bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical pharmacokinetics of irinotecan and its metabolites in relation with diarrhea
Authors: Xie Rujia , Mathijssen Ron H. J. , Sparreboom Alex , Verweij Jaap , Karlsson Mats O. 
Published: October 2002

ObjectivesOur objective was to build population pharmacokinetic models that describe plasma concentrations of irinotecan (CPT‐11) and its metabolites 7‐ethyl‐10‐hydroxycamptothecin (SN‐38) and SN‐38 glucuronide (SN‐38G) and to investigate the pharmacokinetic‐pharmacodynamic relationships between drug exposure and diarrhea, the major dose‐limiting toxicity.MethodsData were obtained from 109 patients (65 men and 44 women) who received 1.5‐hour (range, 0.75‐ to 2.25‐hour) intravenous infusions of irinotecan at doses that ranged from 100 to 350 mg/m2; 44 patients had a second course. The population pharmacokinetic models were developed to describe plasma concentration‐time profiles. The area under the concentration‐time curve from time zero to 60 hours [AUC (0–60)] was used as a measure of drug exposure to model the probabilities of diarrhea with use of a logistic regression model.ResultsA 3‐compartment pharmacokinetic model best described the disposition of irinotecan, whereas SN‐38 and SN‐38G showed 2‐compartmental characteristics. The population estimate of clearance for irinotecan was 31.6 L/h, and the volume of distribution at steady‐state (VSS) was 263 L. The clearance divided by formation fraction (Fm) was 712 L/h and 66.8 L/h for SN‐38 and SN‐38G, respectively. The VSS/Fm was 72,000 L for SN‐38 and 85.4 L for SN‐38G. The frequencies of diarrhea scores in this study were 46% (grade 0), 28% (grade 1), 20% (grade 2), 4% (grade 3), and 2% (grade 4). Significant correlations between AUC(0–60) and diarrhea scores were found for irinotecan (P < .05) and SN‐38G (P < .01) but not for SN‐38 or the biliary index.ConclusionsIn this population analysis, irinotecan and SN‐38G AUC values were appropriate predictors of the risk for diarrhea, and SN‐38G AUC showed the stronger relationship of the two. The developed population models may be useful in further clinical development of this agent.Clinical Pharmacology & Therapeutics (2002) 72, 265–275; doi: 10.1067/mcp.2002.126741
Cytochrome P450 phenotypic ratios for predicting herb‐drug interactions in humans
Authors: Gurley Bill J. , Gardner Stephanie F. , Hubbard Martha A. , Williams D. Keith , Gentry W. Brooks , Cui Yanyan , Ang Catharina Y. W. 
Published: October 2002

ObjectivesPhytochemical‐mediated modulation of cytochrome P450 (CYP) activity may underlie many herb‐drug interactions. Single‐time point phenotypic metabolic ratios were used to determine whether long‐term supplementation of St John's wort, garlic oil, Panax ginseng, and Ginkgo biloba affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity.MethodsTwelve healthy volunteers (6 females) were randomly assigned to receive either St John's wort, garlic oil, P ginseng, or G biloba for 28 days. For each subject, a 30‐day washout period was interposed between each supplementation phase. Probe‐drug cocktails of midazolam, caffeine, chlorzoxazone, and debrisoquin (INN, debrisoquine) were administered before supplementation (baseline) and at the end of supplementation. Presupplementation and postsupplementation phenotypic trait measurements were determined for CYP3A4, CYP1A2, CYP2E1, and CYP2D6 with the use of 1‐hydroxymidazolam/midazolam serum ratios (1‐hour sample), paraxanthine/caffeine serum ratios (6‐hour sample), 6‐hydroxychlorzoxazone/chlorzoxazone serum ratios (2‐hour sample), and debrisoquin urinary recovery ratios (8‐hour collection), respectively.ResultsComparisons of presupplementation and postsupplementation ratios indicated that St John's wort significantly induced the activity of CYP2E1 and CYP3A4 (P < .0001). Among female subjects, St John's wort produced significantly greater increases in CYP3A4 phenotypic ratios that appeared to be unrelated to body mass index. This finding is suggestive of a sexual dimorphism in CYP3A4 inducibility. Garlic oil reduced CYP2E1 activity by 39% (P = .030), whereas no significant effect on CYP activity was observed for P ginseng and G biloba.ConclusionsSingle‐time point phenotypic metabolic ratios may provide a practical means of predicting CYP‐mediated herb‐drug interactions in humans.Clinical Pharmacology & Therapeutics (2002) 72, 276–287; doi: 10.1067/mcp.2002.126913
Losartan and lercanidipine attenuate low‐density lipoprotein oxidation in patients with hypertension and type 2 diabetes mellitus: A randomized, prospective crossover study
Authors: Rachmani Rita , Levi Zohar , Zadok Bat‐Sheva , Ravid Mordchai 
Published: October 2002

ObjectivesLipoprotein oxidation, dyslipidemia, and hypertension are important underlying causes of accelerated atherosclerosis in patients with diabetes mellitus. The potential of antihypertensive medications to reduce lipid oxidation is, therefore, an important determinant in the choice of agents for patients with diabetes mellitus. The aim of this study was to compare the lowering effect of a new dihydropyridine calcium antagonist, lercanidipine, with that of the first angiotensin‐receptor blocker, losartan, on low‐density lipoprotein (LDL) oxidation.MethodsForty patients in metabolically stable condition who had type 2 diabetes mellitus with hypertension were studied in this single‐blind, randomized, prospective crossover study, comprising 2 treatment periods of 16 weeks each, separated by a 4‐week washout period. LDL oxidation was evaluated by dialdehyde analysis by means of the thiobarbituric acid‐reactive substances assay with and without cupric sulfate, as well as determination of conjugated dienes in the LDL lipid extract.ResultsLercanidipine and losartan both significantly reduced the propensity of the serum to oxidize LDL (P = .001). With one method of estimation (conjugated dienes), the effect of lercanidipine was superior to that of losartan (P = .04). Losartan lowered urinary albumin excretion but lercanidipine did not.ConclusionsBoth lercanidipine and losartan attenuate LDL oxidation in patients with type 2 diabetes mellitus and hypertension. This observation may offer insight into the mechanisms of the therapeutic effects of these agents in patients with diabetes mellitus.Clinical Pharmacology & Therapeutics (2002) 72, 302–307; doi: 10.1067/mcp.2002.127110
Ischemic stroke in a user of Thermadrene: A case study in alternative medicine
Authors: Kaberi‐Otarod Jila , Conetta Rick , Kundo Krzysztof K. , Farkash Arthur 
Published: October 2002

A case of a young user of Thermadrene (SportPharma USA, Inc, Concord, Calif), an herbal remedy for weight loss, was studied. We believe that Thermadrene can cause serious complications such as ischemic stroke. Because these remedies are available over the counter and are not regulated by the Food and Drug Administration or similar organizations, there is a need for critical scrutiny of their content and side effects, as is performed for other pharmaceuticals.Clinical Pharmacology & Therapeutics (2002) 72, 343–346; doi: 10.1067/mcp.2002.127942
Membrane Fusion Tropism and Heterotypic Functional Activities of theNipah VirusandHendra VirusEnvelope Glycoproteins
Authors: Bossart Katharine N. , Wang Lin-Fa , Flora Michael N. , Chua Kaw Bing , Lam Sai Kit , Eaton Bryan T. , Broder Christopher C. 
Published: October 2002

ABSTRACTNipah virus(NiV) andHendra virus(HeV) are novel paramyxoviruses from pigs and horses, respectively, that are responsible for fatal zoonotic infections of humans. The unique genetic and biological characteristics of these emerging agents has led to their classification as the prototypic members of a new genus within theParamyxovirinaesubfamily calledHenipavirus. These viruses are most closely related to members of the genusMorbillivirusand infect cells through a pH-independent membrane fusion event mediated by the actions of their attachment (G) and fusion (F) glycoproteins. Understanding their cell biological features and exploring the functional characteristics of the NiV and HeV glycoproteins will help define important properties of these emerging viruses and may provide new insights into paramyxovirus membrane fusion mechanisms. Using a recombinant vaccinia virus system and a quantitative assay for fusion, we demonstrate NiV glycoprotein function and the same pattern of cellular tropism recently reported for HeV-mediated fusion, suggesting that NiV likely uses the same cellular receptor for infection. Fusion specificity was verified by inhibition with a specific antiserum or peptides derived from the α-helical heptads of NiV or HeV F. Like that of HeV, NiV-mediated fusion also requires both F and G. Finally, interactions between the glycoproteins of the paramyxoviruses have not been well defined, but here we show that the NiV and HeV glycoproteins are capable of highly efficient heterotypic functional activity with each other. However, no heterotypic activity was observed with envelope glycoproteins of the morbillivirusesMeasles virusandCanine distemper virus.
Identification of the Orthopoxvirus
p4c
Gene, Which Encodes a Structural Protein That Directs Intracellular Mature Virus Particles into A-Type Inclusions
Authors: McKelvey Terry A. , Andrews Stanley C. , Miller Sara E. , Ray Caroline A. , Pickup David J. 
Published: October 2002

ABSTRACT

The orthopoxvirus gene
p4c
has been identified in the genome of the vaccinia virus strain Western Reserve. This gene encodes the 58-kDa structural protein P4c present on the surfaces of the intracellular mature virus (IMV) particles. The gene is disrupted in the genome of cowpox virus Brighton Red (BR), demonstrating that although the P4c protein may be advantageous for virus replication in vivo, it is not essential for virus replication in vitro. Complementation and recombination analyses with the
p4c
gene have shown that the P4c protein is required to direct the IMV into the A-type inclusions (ATIs) produced by cowpox virus BR. The
p4c
gene is highly conserved among most members of the orthopoxvirus genus, including viruses that produce ATIs, such as cowpox, ectromelia, and raccoonpox viruses, as well as those such as variola, monkeypox, vaccinia, and camelpox viruses, which do not. The conservation of the
p4c
gene among the orthopoxviruses, irrespective of their capacities to produce ATIs, suggests that the P4c protein provides functions in addition to that of directing IMV into ATIs. These findings, and the presence of the P4c protein in IMV but not extracellular enveloped virus (D. Ulaeto, D. Grosenbach, and D. E. Hruby, J. Virol. 70:3372-3377, 1996), suggest a model in which the P4c protein may play a role in the retrograde movement of IMV particles, thereby contributing to the retention of IMV particles within the cytoplasm and within ATIs when they are present. In this way, the P4c protein may affect both viral morphogenesis and processes of virus dissemination.
Tsg101, an Inactive Homologue of Ubiquitin Ligase E2, Interacts Specifically with Human Immunodeficiency Virus Type 2 Gag Polyprotein and Results in Increased Levels of Ubiquitinated Gag
Authors: Myers Erin L. , Allen Jane F. 
Published: October 2002

ABSTRACT
The final stages of budding and release of a retroviral particle from the cell require the late (L) domain of Gag. Recently, ubiquitin and ubiquitin ligases have been implicated in the late stages of retroviral budding. In a yeast two-hybrid screen of a T-cell cDNA library to identify cellular proteins that interact with human immunodeficiency virus type 2 (HIV-2) Gag polyprotein, we identified Tsg101, an inactive homologue of ubiquitin ligase E2. Tsg101 and HIV-2 Gag interact specifically in vitro and in vivo. The interaction requires the L domain PTAPP motif in the p6 domain of HIV-2 Gag and the N-terminal Ubc-conjugation homology domain of Tsg101. Tsg101 is incorporated into HIV-2 virions. Expression of the N-terminal Ubc-conjugation homology domain of Tsg101 inhibits the release of HIV-2 virus particles. Overexpression of Tsg101 results in an increase in the level of ubiquitination of HIV-2 Gag. Our results provide evidence for recruitment of the ubiquitination machinery of the cell during late stages of the viral life cycle, mediated by the viral Gag protein.
Proline Residues within Spacer Peptide p1 Are Important for Human Immunodeficiency Virus Type 1 Infectivity, Protein Processing, and Genomic RNA Dimer Stability
Authors: Hill Melissa K. , Shehu-Xhilaga Miranda , Crowe Suzanne M. , Mak Johnson 
Published: October 2002

ABSTRACT
The full-length human immunodeficiency virus type 1 (HIV-1) mRNA encodes two precursor polyproteins, Gag and GagProPol. An infrequent ribosomal frameshifting event allows these proteins to be synthesized from the same mRNA in a predetermined ratio of 20 Gag proteins for each GagProPol. The RNA frameshift signal consists of a slippery sequence and a hairpin stem-loop whose thermodynamic stability has been shown in in vitro translation systems to be critical to frameshifting efficiency. In this study we examined the frameshift region of HIV-1, investigating the effects of altering stem-loop stability in the context of the complete viral genome and assessing the role of the Gag spacer peptide p1 and the GagProPol transframe (TF) protein that are encoded in this region. By creating a series of frameshift region mutants that systematically altered the stability of the frameshift stem-loop and the protein sequences of the p1 spacer peptide and TF protein, we have demonstrated the importance of stem-loop thermodynamic stability in frameshifting efficiency and viral infectivity. Multiple changes to the amino acid sequence of p1 resulted in altered protein processing, reduced genomic RNA dimer stability, and abolished viral infectivity. The role of the two highly conserved proline residues in p1 (position 7 and 13) was also investigated. Replacement of the two proline residues by leucines resulted in mutants with altered protein processing and reduced genomic RNA dimer stability that were also noninfectious. The unique ability of proline to confer conformational constraints on a peptide suggests that the correct folding of p1 may be important for viral function.
Human Immunodeficiency Virus Type 1 Recombination: Rate, Fidelity, and Putative Hot Spots
Authors: Zhuang Jianling , Jetzt Amanda E. , Sun Guoli , Yu Hong , Klarmann George , Ron Yacov , Preston Bradley D. , Dougherty Joseph P. 
Published: October 2002

ABSTRACT
Previously, we reported that human immunodeficiency virus type 1 (HIV-1) recombines approximately two to three times per genome per replication cycle, an extremely high rate of recombination given the relatively small genome size of HIV-1. However, a recombination hot spot involving sequence of nonretroviral origin was identified in the vector system utilized, raising the possibility that this hot spot skewed the rate of recombination, and the rate of recombination observed was an overestimation. To address this issue, an HIV-1-derived vector system was used to examine the rate of recombination between autologous HIV-1 sequences after restricting replication to a single cycle in the absence of this hot spot. Viral DNA and RNA were analyzed by a combination of the heteroduplex tracking assay, restriction enzyme analysis, DNA sequencing, and reverse transcription-PCR. The results indicate that HIV-1 undergoes recombination at a minimum rate of 2.8 crossovers per genome per cycle. Again, this is a very high rate given the small size of the HIV-1 genome. The results also suggested that there might be local hot spots of recombination at different locations throughout the genome since 13 of the 33 strand transfers identified by DNA sequencing shared the same site of recombination with one or two other clones. Furthermore, identification of crossover segments also allowed examination of mutations at the point of recombination, since it has been predicted from some studies of cell-free systems that mutations may occur with a frequency of 30 to 50% at crossover junctions. However, DNA sequence analysis of crossover junctions indicated that homologous recombination during viral replication was not particularly mutagenic, indicating that there are other factors or conditions not yet reproduced in cell-free systems which contribute to fidelity during retroviral recombination.
Requirement of BAX for Efficient Adenovirus-Induced Apoptosis
Authors: Lomonosova Elena , Subramanian T. , Chinnadurai G. 
Published: October 2002

ABSTRACT

Infection of human epithelial cells with adenoviruses induces an apoptosis paradigm that is efficiently suppressed by the expression of viral E1B-19K protein, which is a functional homolog of the cellular antiapoptosis protein BCL-2. The mechanisms of adenovirus (Ad)-induced apoptosis appear to involve the cellular BCL-2 family proapoptotic proteins. Recent genetic studies with fibroblasts derived from mutant mouse embryos indicate that a class of the BCL-2 family proapoptotic proteins (designated BH-123 or multidomain proteins) such as BAX and BAK constitutes an essential component of the core apoptosis machinery in animal cells. We have examined the role of BAX in Ad-induced apoptosis in human epithelial cells using two colon cancer cell lines, HCT116Bax (Bax
+/−
) and HCT116BaxKO (Bax
−/−
) (L. Zhang, J. Yu, B. H. Park, K. W. Kinzler, and B. Vogelstein, Science 290:989-992, 2000). Infection of Bax
+/−
cells with an Ad type 2 mutant (
dl
250) defective in expression of the E1B-19K protein resulted in enhanced cytopathic effect, large plaques on cell monolayers, fragmentation of cellular DNA, and enhanced cell death. These mutant phenotypes were not efficiently expressed in Bax
−/−
cells, suggesting that BAX is essential for Ad-induced apoptosis. Infection of Bax
+/−
cells with
dl
250 induced increased levels of an N-terminally processed form of BAX. Cells infected with the 19K mutant also contained enhanced levels of truncated BAX in membrane-inserted form. Our results suggest that at least a part of the mechanism utilized by E1B-19K to suppress apoptosis during Ad infection may involve modulation of the activities of BAX.
Human Papillomavirus Type 31b Infection of Human Keratinocytes and the Onset of Early Transcription
Authors: Ozbun Michelle A. 
Published: October 2002

ABSTRACT
Human papillomaviruses (HPVs) cause a number of human tumors and malignancies, including cervical cancers. Epithelial differentiation is required for the complete HPV life cycle and can be achieved using the organotypic (raft) culture system. The CIN-612 9E cell line maintains episomal copies of HPV type 31b (HPV31b), an HPV type associated with cervical cancers. When grown in the raft system, CIN-612 9E cells form a differentiated epithelium such that infectious virions can be synthesized. Many aspects of the later stages of the HPV31b life cycle have been investigated in CIN-612 9E raft tissues. We used a biologically contained homogenization system for efficient virion extraction from raft epithelial tissues. Purified HPV31b virions were used to infect low-passage-number human foreskin keratinocytes and a variety of epithelial cell lines. Newly synthesized, spliced HPV31b transcripts were detected by reverse transcription and PCR (RT-PCR) following HPV31b infection. HPV31b infection was most efficient and reproducible in HaCaT cells. The onset of viral transcription following infection was also investigated using RT-PCR techniques. Spliced E1∗I,E2 RNAs were present as early as 4 h postinfection (p.i.), whereas the other major viral transcripts were detected by 8 to 10 h p.i. Furthermore, we characterized the structures and temporal expression of seven novel spliced early transcripts expressed following infection.
Porcine Endogenous Retrovirus Infects but Does Not Replicate in Nonhuman Primate Primary Cells and Cell Lines
Authors: Ritzhaupt Armin , van der Laan Luc J. W. , Salomon Daniel R. , Wilson Carolyn A. 
Published: October 2002

ABSTRACT
Porcine endogenous retroviruses (PERV) can infect human cell lines in vitro; hence, there is a presumed risk of viral exposure to a recipient when pig cells are transplanted into humans (xenotransplantation). Nonhuman primates (NHP) are considered a potential permissive animal model to study the risk of in vivo infection of PERV after xenotransplantation. We set out to determine whether PERV can infect and replicate in NHP primary cells or established cell lines from African green monkey, rhesus macaque, and baboon. We confirm that the NHP cell lines under investigation were infected with PERV as measured by detection of viral DNA and RNA by PCR and reverse transcription (RT)-PCR, respectively, indicating that a functional receptor must be present on the cell surface. However, the load of detectable viral DNA in infected NHP cells declined over time, and the cells never had detectable reverse transcriptase activity. Utilizing quantitative real-time TaqMan PCR we found detectable levels of unintegrated DNA intermediates, but the levels were approximately 100-fold lower compared to HEK 293 cells infected with PERV. Virions released from infected NHP cells could productively infect naïve human cell lines, HEK 293 and HeLa, as shown by RT-PCR and RT assay. However, naïve NHP cells remained negative in RT-PCR and RT assay after exposure to virions from infected NHP cells. Together our data demonstrate that NHP cells are not permissive to productive replication by PERV, presumably due to inefficient cell entry and replication. In light of these observations, the appropriateness of NHP as suitable animal models to study PERV infection in vivo needs to be reevaluated.
Genetic Analysis of High-Risk E6 in Episomal Maintenance of Human Papillomavirus Genomes in Primary Human Keratinocytes
Authors: Park Regina B. , Androphy Elliot J. 
Published: October 2002

ABSTRACT
Papillomaviruses possess small DNA genomes that encode five early (E) proteins. Transient DNA replication requires activities of the E1 and E2 proteins and a DNA segment containing their binding sites. The E6 and E7 proteins of cancer-associated human papillomavirus (HPV) transform cells in culture. Recent reports have shown that E6 and E7 are necessary for episomal maintenance of HPV in primary keratinocytes. The functions of E6 necessary for viral replication have not been determined, and to address this question we used a recently developed transfection system based on HPV31. To utilize a series of HPV16 E6 mutations, HPV31 E6 was replaced by its HPV16 counterpart. This chimeric genome was competent for both transient and stable replication in keratinocytes. Four HPV16 E6 mutations that do not stimulate p53 degradation were unable to support stable viral replication, suggesting this activity may be necessary for episomal maintenance. E7 has also been shown to be essential for episomal maintenance of the HPV31 genome. A point mutation in the Rb binding motif of HPV E7 has been reported to render HPV31 unable to stably replicate. Interestingly, HPV31 genomes harboring two of the three p53 degradation-defective E6 mutations combined with this E7 mutation were maintained as replicating episomes. These findings imply that the balance between E6 and E7 functions in infected cells is critical for episomal maintenance of high-risk HPV genomes. This model will be useful to dissect the activities of E6 and E7 necessary for viral DNA replication.