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PubMed1996

Clinically significant pharmacokinetic drug interactions with carbamazepine. An update.

Carbamazepine is one of the most commonly prescribed antiepileptic drugs and is also used in the treatment of trigeminal neuralgia and psychiatric disorders, particularly bipolar depression. Because of its widespread and long term use, carbamazepine is frequently prescribed in combination with other drugs, leading to the possibility of drug interactions. The most important interactions affecting carbamazepine pharmacokinetics are those resulting in induction or inhibition of its metabolism. Phenytoin, phenobarbital (phenobarbitone) and primidone accelerate the elimination of carbamazepine, probably by stimulating cytochrome P450 (CYP) 3A4, and reduce plasma carbamazepine concentrations to a clinically important extent. Inhibition of carbamazepine metabolism and elevation of plasma carbamazepine to potentially toxic concentrations can be caused by stiripentol, remacemide, acetazolamide, macrolide antibiotics, isoniazid, metronidazole, certain antidepressants, verapamil, diltiazem, cimetidine, danazol and (dextropropoxyphene) propoxyphene. In other cases, toxic symptoms may result from elevated plasma concentrations of the active metabolite carbamazepine-10,11-epoxide, due to the inhibition of epoxide hydrolase by valproic acid (sodium valproate), valpromide, valnoctamide and progabide. Carbamazepine is a potent inducer of CYP3A4 and other oxidative enzyme system in the liver, and it may also increase glucuronyltransferase activity. This results in the acceleration of the metabolism of concurrently prescribed anticonvulsants, particularly valproic acid, clonazepam, ethosuximide, lamotrigine, topiramate, tiagabine and remacemide. The metabolism of many other drugs such as tricyclic antidepressants, antipsychotics, steroid oral contraceptives, glucocorticoids, oral anticoagulants, cyclosporin, theophylline, chemotherapeutic agents and cardiovascular drugs can also be induced, leading to a number of clinically relevant drug interactions. Interactions with carbamazepine can usually be predicted on the basis of the pharmacological properties of the combined drug, particularly with respect to its therapeutic index, site of metabolism and ability to affect specific drug metabolising isoenzymes. Avoidance of unnecessary polypharmacy, selection of alternative agents with lower interaction potential, and careful dosage adjustments based on serum drug concentration monitoring and clinical observation represent the mainstays for the minimisation of risks associated with these interactions.

Analgesics, Non-Narcotic↗
PubMed1993

TAN-1120, a new anthracycline with potent angiostatic activity.

A potent angiogenesis-inhibitory compound TAN-1120 was found to be produced by a Streptomyces species isolated from a soil sample. The producing organism was characterized as a new subspecies of S. triangulatus and named S. triangulatus subsp. angiostaticus subsp. nov. due to its specific ability to produce the compound. This substance was isolated as a red powder by a combination of organic solvent extraction, silica gel column chromatography and preparative HPLC using an ODS column. Its structure was elucidated by chemical reactions and spectral analyses to be a new baumycin-group anthracycline. Reduction of TAN-1120 gave two compounds, a deoxy derivative and baumycin A1. TAN-1120 showed remarkably potent angiostatic activity in two conventional angiogenesis assay systems in vivo, while doxorubicin and daunomycin had far weaker activity. It strongly inhibited proliferation of vascular endothelial cells did not prevent capillary cord formation in vitro by the endothelial cells on extracellular matrix-coated plates. TAN-1120 is one of the most potent angiostatic agents reported.

3T3 Cells↗
PubMed2001

Defrosting the frozen approximation: PROSPECTOR--a new approach to threading.

PROSPECTOR (PROtein Structure Predictor Employing Combined Threading to Optimize Results) is a new threading approach that uses sequence profiles to generate an initial probe-template alignment and then uses this "partly thawed" alignment in the evaluation of pair interactions. Two types of sequence profiles are used: the close set, composed of sequences in which sequence identity lies between 35% and 90%; and the distant set, composed of sequences with a FASTA E-score less than 10. Thus, a total of four scoring functions are used in a hierarchical method: the close (distant) sequence profiles screen a structural database to provide an initial alignment of the probe sequence in each of the templates. The same database is then screened with a scoring function composed of sequence plus secondary structure plus pair interaction profiles. This combined hierarchical threading method is called PROSPECTOR1. For the original Fischer database, 59 of 68 pairs are correctly identified in the top position. Next, the set of the top 20 scoring sequences (four scoring functions times the top five structures) is used to construct a protein-specific pair potential based on consensus side-chain contacts occurring in 25% of the structures. In subsequent threading iterations, this protein-specific pair potential, when combined in a composite manner, is found to be more sensitive in identifying the correct pairs than when the original statistical potential is used, and it increases the number of recognized structures for the combined scoring functions, termed PROSPECTOR2, to a total of 61 Fischer pairs identified in the top position. Application to a second, smaller Fischer database of 27 probe-template pairs places 18 (17) structures in the top position for PROSPECTOR1 (PROSPECTOR2). Overall, these studies show that the use of pair interactions as assessed by the improved Z-score enhances the specificity of probe-template matches. Thus, when the hierarchy of scoring functions is combined, the ability to identify correct probe-template pairs is significantly enhanced. Finally, a web server has been established for use by the academic community (http://bioinformatics.danforthcenter.org/services/threading.html).

Benchmarking↗
PubMed1989

Systemic induction of cells mediating antibody-dependent cellular cytotoxicity following administration of interleukin 2.

We have previously demonstrated that incubation of murine cells in vitro in interleukin 2 (IL-2) induced antibody-dependent cellular cytotoxicity (ADCC) and that these cells were derived from the NK/LAK, FcR+ cell population. In the present study we show that in vivo administration of IL-2 to mice induces cells which exhibit ADCC activity in the peritoneal cavity, liver, lungs, and to a lesser degree in the bone marrow, spleen, mesenteric lymph nodes, and thymus. A gradual increase in ADCC activity and the number of Fc-receptor-positive cells was seen 1 to 3 days after starting IL-2 treatment. The cells mediating ADCC are closely related to LAK cells since they expressed Thy1.2 antigens and are derived from asialo GM1-positive, Lyt2/L3T4-negative, radiosensitive cells. These results demonstrate that IL-2 can systemically induce cells with ADCC activity and that this ability may be useful in the establishment of therapeutic models against disseminated cancer when combined with specific antitumor monoclonal antibodies.

Animals↗
PubMed1988

Failure or success in the restoration of virus-specific cytotoxic T lymphocyte response defects by dendritic cells.

C57BL/6 (B6, H-2b) mice are CTL responders to both Sendai virus and Moloney leukemia virus. In the former response the H-2Kb class I MHC molecule is used as CTL restriction element, in the latter response the H-2Db molecule. B6 dendritic cells (DC) are superior in the presentation of Sendai virus Ag to CTL in comparison with B6 normal spleen cells. Con A blasts have even less capacity to present viral Ag than NSC, and LPS blasts show an intermediate capacity to present viral Ag. H-2Kb mutant bm1 mice do not generate a CTL response to Sendai virus, but respond to Moloney leukemia virus, as demonstrated by undetectable CTL precursors to Sendai virus and a normal CTL precursor frequency to Moloney virus. Compared to B6 mice, other H-2Kb mutant mice show decreased Sendai virus-specific CTL precursor frequencies in a hierarchy reflecting the response in bulk culture. The Sendai virus-specific CTL response defect of bm1 mice was not restored by highly potent Sendai virus-infected DC as APC for in vivo priming and/or in vitro restimulation. In mirror image to H-2Kb mutant bm1 mice, H-2Db mutant bm14 mice do not generate a CTL response to Moloney virus, but respond normally to Sendai virus. This specific CTL response defect was restored by syngeneic Moloney virus-infected DC for in vitro restimulation. This response was Kb restricted indicating that the Dbm14 molecule remained largely defective and that a dormant Kb repertoire was aroused after optimal Ag presentation by DC. In conclusion, DC very effectively present viral Ag to CTL. However, their capacity to restore MHC class I determined specific CTL response defects probably requires at least some ability of a particular MHC class I/virus combination to associate and thus form an immunogenic complex.

Animals↗
PubMed1994

Magnetic resonance imaging in rheumatology. An overview.

Magnetic resonance (MR) imaging has revolutionized the assessment of pathology involving the musculoskeletal system. The soft tissue contrast, superb resolution, multiplanar acquisition potential, and the ability to monitor physiologic processes combine the best features of other imaging modalities. The sensitivity and specificity of MR imaging for a wide range of disease processes matches or supersedes conventional radiology, nuclear medicine, and clinical examination. This article provides a brief overview of the use of MR imaging for some of the more common clinical situations confronting the rheumatologist.

Diagnosis, Differential↗
PubMed1996

Effect of factor Xa inhibitors on thrombin formation and complement and neutrophil activation during in vitro extracorporeal circulation.

BACKGROUND: Even when large doses of heparin are administered during cardiopulmonary bypass, thrombin is produced. Thrombin is a powerful protease that is associated with the thrombotic and bleeding complications of open heart surgery and is produced by cleavage of prothrombin by factor Xa. This study assessed the ability of a specific inhibitor of factor Xa, recombinant tick anticoagulant peptide (rTAP), alone or in combination with standard heparin and a low-molecular-weight heparin, enoxaparin, to suppress thrombin formation and activity during in vitro extracorporeal circulation. METHODS AND RESULTS: Fresh, anticoagulated human blood was recirculated for 2 hours in an extracorporeal membrane oxygenator perfusion circuit at 37 degrees C. Four anticoagulant protocols were evaluated; porcine heparin (3.75 U/mL); enoxaparin (17.5 U/mL); rTAP (4 mumol/L); and porcine heparin plus rTAP (2 mumol/L). Blood samples were obtained for analysis from the donor, after anticoagulation, and after 5, 30, 60, and 120 minutes of recirculation. There were no significant differences between groups in platelet count, response to adenosine diphosphate, or prothrombin fragment (F1.2) production. rTAP plus heparin reduced beta-thromboglobulin release; fibrinopeptide A concentrations were significantly higher with rTAP alone. Enoxaparin strongly and significantly inhibited complement C5b9 production and neutrophil elastase release and was associated with significantly increased concentrations of C1-C1 inhibitor and kallikrein-C1 inhibitor complexes. CONCLUSIONS: rTAP does not reduce thrombin formation or activity during in vitro extracorporeal circulation. Enoxaparin markedly inhibits formation of the complement membrane attack complex and neutrophil elastase release, possibly by accelerating C1 inhibitor activity.

Adenosine Diphosphate↗
PubMed1999

Broad spectrum drug identification directly from urine, using liquid chromatography-tandem mass spectrometry.

BACKGROUND: Currently the rate-limiting step for mass spectrometric analysis of drugs in biological samples is sample preparation. Many gas chromatography/mass spectrometry (GC/MS) methods are specific for a certain class of compounds, requiring extraction and/or derivatization before analysis. The purpose of this study was to develop a broad spectrum liquid chromatography/mass spectrometry (LC/MS) procedure that allowed for direct analysis of urine specimens with potential for quantitative analysis. METHODS: We modified a commercially available column-switching instrument, the REMEDi HS from Bio-Rad Diagnostics, to make it compatible with atmospheric pressure ionization. The system we developed was based on electrospray ionization and used three LC columns to extract, purify, and separate drugs directly from urine specimens. Drugs and metabolites were tentatively identified on the basis of retention times and (M+H)(+) ions. Tandem mass spectrometry (MS/MS) was used to confirm the qualitative identification of suspected drugs, using data-dependent acquisition. For quantitative analysis, the cocaine metabolite benzoylecgonine was analyzed using isotope dilution and selected reaction monitoring. RESULTS: Seventeen basic drugs from a variety of classes of compounds were identified directly from urine without the need for prior sample extraction, using LC and MS/MS. Quantitative analysis was demonstrated for benzoylecgonine. When benzoylecgonine-d(3) was used as the internal standard, the method was linear from 30 to 10 000 microgram/L (range tested). At these concentrations, the within-run accuracy was +/- 10% of the target concentration, with CVs <10%. Analytical results by LC/MS/MS compared favorably with GC/MS values for 50 benzoylecgonine-containing specimens and for 25 negative specimens. CONCLUSIONS: The ability to directly analyze urine for a wide variety of drug classes, combined with the sensitivity and specificity of LC/MS/MS makes this technique attractive for many clinical, forensic, and biotechnology applications.

Chromatography, Liquid↗
PubMed2000

The relative value of fine-needle aspiration and imaging in the preoperative evaluation of parotid masses.

BACKGROUND: To establish the sensitivity, specificity, and accuracy of imaging and fine-needle aspiration (FNA), alone or in combination, in distinguishing benign from malignant histologic findings for parotid lesions. METHODS: Retrospective blinded review of preoperative imaging and FNA studies of parotid masses and comparison with histologic findings after excision. RESULTS: Forty-eight patients were identified (13 with CT, 35 with MRI); 23 (48%) of the lesions were malignant, 25 (52%) were benign. MRI, CT, and FNA misclassified 17%, 46%, and 21% of the lesions, respectively. The sensitivity/specificity/accuracy of these tests for detecting malignant lesions were as follows: MRI (88%,77%,83%), CT (100%,42%, 69%), and FNA (83%,86%,85%) and were not significantly different. Combinations of imaging and FNA were not significantly better in detecting malignancy. CONCLUSIONS: Imaging and FNA are comparable in their ability to correctly identify malignant parotid lesions preoperatively. Combining these two modalities yields no advantage in terms of specificity, sensitivity, or accuracy of a malignant diagnosis.

Biopsy, Needle↗
PubMed1999

Mutations to alter Aspergillus awamori glucoamylase selectivity. IV. Combinations of Asn20-->Cys/Ala27-->Cys, Ser30-->Pro, Gly137-->Ala, 311-4 loop, Ser411-->Ala and Ser436-->Pro.

Six previously constructed and nine newly constructed Aspergillus awamori glucoamylases with multiple mutations made by combining existing single mutations were tested for their ability to produce glucose from maltodextrins. Multiple mutations have cumulative effects on glucose yield, specific activity and thermostability. No general correlation between glucose yield and thermostability was observed, although mutations that presumably impede unfolding at high temperatures uniformly increase thermostability and generally increase glucose yield. Peak glucose yields decrease with increasing temperature. The best combination of high glucose yield, high specific activity and high thermostability occurs in Asn20-->Cys/Ala27-->Cys/Ser30-->Pro/Gly137-->Ala glucoamylase.

Aspergillus↗
PubMedDate not supplied

Interleukin-7 (IL-7): immune function, involvement in the pathogenesis of HIV infection and therapeutic potential.

Interleukin 7 (IL-7), which is constitutively produced particularly by stromal cells from the bone marrow and thymus, plays a crucial role in T cell homeostasis. This cytokine is implicated in thymopoiesis since it sustains thymocyte proliferation and survival. It regulates peripheral naive T cell survival by modulating the expression of the anti-apoptotic molecule Bcl-2, and sustains peripheral T cell expansion in response to antigenic stimulation. Infection by the human immunodeficiency virus (HIV) leads to severe T lymphopenia and general immune dysfunction. Increased IL-7 plasma levels are generally observed in HIV-infected patients. The existence of an inverse correlation between IL-7 plasma levels and the CD4+ T cell count suggests that a direct feedback mechanism is working to restore peripheral T cell counts in lymphopenic patients. Here, IL-7 plasma levels are a good predictive marker of CD4+ T cell restoration during therapy. Combinations of antiretroviral treatments considerably slow disease progression. They drastically decrease the viral load and, in most patients, significantly increase peripheral CD4+ T cell counts. However, despite their usual ability to reduce viral replication, such treatments often fail to reverse lymphopenia and do not restore specific antiviral immune responses. IL-7, based therapy, combined with efficient antiretroviral treatment, may be beneficial to HIV-infected patients by promoting thymic output, sustaining naive T cell counts and increasing memory T cell activation.

Antiretroviral Therapy, Highly Active↗
PubMed2005

Haplotype-dependent binding of nuclear proteins to the promoter of the neural tube defects-associated platelet-derived growth factor alpha-receptor gene.

We have previously shown that polymorphisms in the promoter of the human platelet-derived growth factor alpha-receptor (PDGFRA) gene can be grouped into five distinct haplotypes, designated H1, H 2 alpha, H 2 beta, H 2 gamma and H 2 delta, and that specific combinations of these promoter haplotypes predispose to neural tube defects (NTDs). These promoter haplotypes differ strongly in their ability to drive reporter gene expression in various human cell lines, with highest activity for H 2 alpha and H 2 beta. Here, we show that the haplotype-linked PDGFRA promoter region extends to 3.6 kb upstream from the transcription start site, and contains a total of ten polymorphic sites. For two of these polymorphic sites, i.e. -909 C/A and +68 GAins/del, we observed differential binding of nuclear proteins from human osteosarcoma (HOS) cells. The protein complex binding specifically to -909 C, which is present in all haplotypes except the low activity haplotype H 2 gamma, contained members of the upstream stimulatory factor (USF) family of transcription factors. Furthermore, we identified a protein complex of 125 kDa which bound specifically to the low activity haplotype H1 at position +68 GAdel and may represent an H1-specific PDGFRA transcriptional repressor. The current identification of cis-acting elements in the PDGFRA promoter and the transcription factors that bind them, provides a new strategy for the identification of genes that are potentially involved in neural tube defects.

Base Sequence↗
PubMed1987

Modifying role of dietary factors on the mutagenicity of aflatoxin B1: in vitro effect of vitamins.

19 vitamins including some derivatives have been tested for their ability to suppress mutagenic activity of aflatoxin B1 (AFB1) towards Salmonella typhimurium strain TA100 activated with a rat-liver metabolic activation system. Several vitamins have shown an ability to inhibit the mutagenic potency of AFB1. The values of ID50, i.e. the dose required to inhibit mutagenic activity by 50% calculated from dose-response curves for each vitamin show retinoids, riboflavin, folic acid, menadione, cyanocobalamin, ascorbic acid and pyridoxine to be significantly antimutagenic. Although inhibition by vitamins is apparent over a range of AFB1 concentrations, their effect is more pronounced at lower concentrations of AFB1. When combined data are expressed in terms of specific mutagenicity, riboflavin, retinol and menadione have been found to possess exceptional inhibitory ability in as much as, on a molar basis, only 15-40-fold excess vitamins can inhibit the mutagenic potency of AFB1 by 50%. Their action is possibly mediated through interaction with microsomal activating enzymes. Previous evidence from this laboratory about their inhibitory action on DNA-adduct formation and metabolic activation together with the present results suggest that certain vitamins notably retinoids and riboflavin may have potential anticarcinogenic activity against AFB1.

Aflatoxin B1↗
PubMed2000

Diagnosis of tuberculosis based on the two specific antigens ESAT-6 and CFP10.

Tests based on tuberculin purified protein derivative (PPD) cannot distinguish between tuberculosis infection, Mycobacterium bovis BCG vaccination, or exposure to environmental mycobacteria. The present study investigated the diagnostic potential of two Mycobacterium tuberculosis-specific antigens (ESAT-6 and CFP10) in experimental animals as well as during natural infection in humans and cattle. Both antigens were frequently recognized in vivo and in vitro based on the induction of delayed-type hypersensitivity responses and the ability to induce gamma interferon production by lymphocytes, respectively. The combination of ESAT-6 and CFP10 was found to be highly sensitive and specific for both in vivo and in vitro diagnosis. In humans, the combination had a high sensitivity (73%) and a much higher specificity (93%) than PPD (7%).

Animals↗
PubMed2005

Brief cognitive assessment for patients with cerebral small vessel disease.

BACKGROUND: Cerebral small vessel disease is a common cause of cognitive impairment and vascular dementia. The cognitive deficit differs from that in Alzheimer's disease, with greater executive/attentional dysfunction and relatively intact episodic memory. OBJECTIVE: To develop brief assessment tools that are better adapted to the neuropsychological profile of cerebral small vessel disease. METHODS: 32 subjects with ischaemic leukoaraiosis (history of lacunar stroke and leukoaraiosis on MRI), aged 50 to 84 years, and 17 age and education matched controls had a brief executive assessment, which took 20 minutes to administer, and a wide range of additional tests. The ability of the brief executive assessment to discriminate between groups-both individually and in combination-was evaluated and compared with that of the whole battery. RESULTS: The brief executive assessment provided good sensitivity and specificity for identifying subjects with ischaemic leukoaraiosis (sensitivity 88%, specificity 88%, using the optimal combination of scores). The best individual tests were trail making and digit symbol, which were both far more sensitive than the mini-mental state examination (MMSE). The ability to discriminate between groups was maintained in subjects with MMSE > 27 and across the whole age range. The brief executive assessment performed well compared with the whole battery, with additional tests accounting for only a further 12% of between-group variance. CONCLUSIONS: The brief executive assessment was sensitive to deficits found in ischaemic leukoaraiosis and discriminated them from the cognitive effects of healthy aging. The assessment has potential for bedside use and as a cognitive end point for clinical trials.

Aged↗
PubMed1992

Facilitation of specific tolerance induction in adult mice by RS-61443.

RS-61443 is an immunosuppressive agent that facilitates pancreatic islet allograft acceptance in two mouse strain combinations (BALB/c----CBA and C57Bl/6J----BALB/c). A remarkable feature of this agent is its ability to facilitate long-term graft acceptance after a short (30 days) period of treatment; following withdrawal of the agent 40-70% of islet allografts are maintained for an indefinite period. This long-term graft acceptance has been shown to result from specific tolerance induction in the recipient animal. The state of specific tolerance is an active rather than a passive form of tolerance, such as clonal deletion or anergy. Active tolerance induction is cyclosporine-sensitive, although cyclosporine enhances graft acceptance when used in combination therapy with RS-61443, this agent inhibits tolerance development under the influence of RS-61443.

Animals↗
PubMed2002

Primary acute myeloid leukaemia blasts resistant to cytokine-induced differentiation to dendritic-like leukaemia cells can be forced to differentiate by the addition of bryostatin-1.

Primary acute myeloid leukaemia (AML) blasts can be induced to differentiate into dendritic-like leukaemia cells (DLLC) by culture with certain cytokine combinations. DLLC offer potential for use as autologous vaccines based on their ability to present putative leukaemia-specific antigens to T cells. It has been reported, however, that in around 30-50% of AML cases the leukaemia cells are not capable of undergoing DLLC differentiation. The purpose of this study was to identify the features that represent successful DLLC differentiation and, for those cases shown to be resistant to cytokine-induced differentiation, to use differentiating agents in an attempt to overcome the differentiation block. Leukaemia cells derived from 42 patients with AML were cultured in vitro with cytokines GM-CSF, IL-4 and TNFalpha/CD40L. In 22 cases the leukaemic cells underwent DLLC differentiation based on characteristic morphological changes and expression of costimulatory and dendritic cell-associated molecules. Four cases were not evaluable because of poor viability over the culture period. The remaining 16 cases failed to show evidence of DLLC differentiation. Many of these differentiation resistant cases were associated with poor risk karyotypic features. Nine of the resistant cases were selected for further study. Differentiating agents trichostatin (TSA), azacytidine (AZA) and bryostatin (BRYO) were used in combination with cytokines for the first 96 h of the culture period. Bryostatin (BRYO) alone was shown to be capable of overcoming differentiation resistance and allowing DLLC differentiation to proceed.

Acute Disease↗
PubMed2004

Single-stranded DNA-binding protein facilitates gel-free analysis of polymerase chain reaction products in capillary electrophoresis.

It has been recently demonstrated that single-stranded DNA-binding protein (SSB) can facilitate quantitative analyses of DNA, RNA, and proteins in gel-free capillary electrophoresis (CE). Here, we report the application of SSB-mediated gel-free CE for analyses of polymerase chain reaction (PCR) products. The unique ability of SSB to bind ssDNA but not double-stranded DNA (dsDNA) allows efficient separation of three types of DNA molecules in the PCR reaction mixture: primers, products (amplified templates), and by-products, which originate from non-specific DNA hybridization. SSB-mediated gel-free CE analysis of PCR products combines simplicity, high sensitivity, and outstanding quantitative capabilities. The ability of the method to distinguish between products and by-products makes this method an indispensable tool in preparative PCR (e.g., in the development of nucleotide aptamers).

DNA Primers↗