PubMed Health⌕ Search

Biomedical subjects

J N Weinstein

Publications and source records attributed to J N Weinstein.

At least 145 records · Page 8Linked to original sources
PubMed1991

Effects of thymidine and uridine on the phosphorylation of 3'-azido-3'-deoxythymidine (zidovudine) in human mononuclear cells.

The effects of thymidine and uridine on the phosphorylation of 3'-azido-3'-deoxythymidine (AZT) were studied in various human mononuclear cell preparations. Thymidine suppressed [3H]AZT phosphorylation in the same concentration range (20 to 100 microM) in which it antagonizes the anti-human immunodeficiency virus activity of AZT. Uridine, in turn, had no influence on AZT phosphorylation, just as it has no effect on the anti-human immunodeficiency virus activity of AZT. These findings are consistent with a close relationship between the inhibition of AZT phosphorylation and the influence of physiological nucleosides on the antiviral activity of AZT.

Bone Marrow↗
PubMed1991

Differential inhibition of 2'-deoxycytidine salvage as a possible mechanism for potentiation of the anti-human immunodeficiency virus activity of 2',3'-dideoxycytidine by dipyridamole.

Dipyridamole, a commonly used coronary vasodilator and antithrombotic drug, was recently shown to potentiate the activity of 3'-azido-3'-deoxythymidine and 2',3'-dideoxycytidine against the human immunodeficiency virus type 1 (HIV-1) in human monocyte-macrophages in vitro. We report in the present paper that in uninfected monocyte-macrophages dipyridamole significantly inhibits cellular salvage of [3H]deoxycytidine, whereas it does not affect the salvage of [3H]dideoxycytidine. Similar differential inhibition by dipyridamole of the salvage of thymidine, as opposed to 3'-azido-3'-deoxythymidine, was reported previously (G. V. Betageri, J. Szebeni, K. Hung, S. S. Patel, L. M. Wahl, M. Corcoran, and J. N. Weinstein, Biochem. Pharmacol. 40:867-870, 1990). Taken together, these observations suggest that inhibition of the salvage of competing physiological nucleosides may explain or contribute to the potentiating effect of dipyridamole on these antiviral dideoxynucleoside drugs.

Antiviral Agents↗
PubMed1991

Immunohistochemical observations on spinal tissue innervation. A review of hypothetical mechanisms of back pain.

Immunohistochemical studies support earlier reports of a rich nerve supply to the posterior longitudinal ligament, a less developed innervation of the anterior ligament and the outermost annular ring, and a total lack of innervation in deeper parts of the intervertebral disc. Whether this pattern of innervation is altered when the disc becomes severely degenerated is presently uncertain. Recent studies have also revealed neuropeptide-immunoreactive nerves in the outermost parts of the annulus and adjacent peridiscal ligaments. These nerves are probably involved in discogenic back pain, and may become sensitized when disc tissue is injured. This sensitization appears to be coupled to an alteration of neuropeptide pools in the nearby dorsal root ganglion, the important site of neuropeptide production. Direct influences on the dorsal root ganglion, mechanical and/or chemical, may also be important, and may be involved in spinal segment degeneration.

Back Pain↗
PubMed1991

Dipyridamole binding to proteins in human plasma and tissue culture media.

Dipyridamole (Persantin), a commonly used coronary vasodilator and antithrombotic drug, has been intensively studied for its potential use in combination chemotherapy for cancer, and, recently, for acquired immunodeficiency syndrome. However, the strong binding of dipyridamole to proteins in human plasma complicates quantitative extrapolations from in vitro data to the clinic. To aid in such extrapolations, we incubated dipyridamole in human plasma and in tissue culture media containing 10% fetal calf serum (FCS), and determined the equilibrium levels of free drug. In human plasma, after addition of 2 to 10 mumol/L dipyridamole (i.e., in the therapeutically relevant concentration range), the fraction of free drug averaged between 1.9% and 3.5%. In 10% FCS, after addition of 0.08 to 5 mumol/L dipyridamole (i.e., the experimentally relevant concentration range), mean free fractions were in the 75% to 100% range. Relating various total dipyridamole levels in the therapeutically relevant range in human plasma to those in 10% FCS that provided identical fractions of free drug gave ratios in the 24 to 55 range. Thus, a multiplication factor in the above range is suggested for the interconversion of in vitro and in vivo dipyridamole concentrations that provide equivalent levels of free drug.

Blood Proteins↗
PubMed1990

Effect of dipyridamole on transport and phosphorylation of thymidine and 3'-azido-3'-deoxythymidine in human monocyte/macrophages.

Dipyridamole (DPM), a commonly used coronary vasodilator and antithrombotic drug, was shown recently to potentiate the antiviral effect of 3'-azido-3'-deoxythymidine (AZT) in HIV-1 infected human monocyte-derived macrophages (M/M) in vitro. We report in the present study that in uninfected M/M, DPM markedly inhibited cellular uptake of [3H]thymidine (dThd) and its incorporation into the nucleotide pools, particularly the dThd-triphosphate pool. In contrast, DPM did not affect cellular uptake and phosphorylation of [3H]AZT. Since dThd counteracts the phosphorylation and antiviral action of AZT, these findings support the hypothesis that the potentiation of the anti-HIV effect of AZT is due, at least in part, to differential inhibition of nucleoside salvage.

Biological Transport↗
PubMed1990

Mapping the binding site of the nucleoside transporter protein: a 3D-OSAR study.

The nucleoside transporter is an intrinsic membrane protein that mediates salvage of nucleosides from the extracellular medium. In this report, its binding sites have been characterized by a 3D-QSAR (three-dimensional structure-directed quantitative structure-activity relationships) receptor mapping technique. REMOTEDISC. The algorithm is applied to a set of 19 nucleoside analogues, each of which binds to the transporter. The methodology includes: (i) conformational analysis of each ligand; (ii) estimation of physicochemical properties of each ligand at the atomic level; (iii) structural comparison of the low energy conformation of each ligand in the series with a reference structure on the basis of physicochemical property matching; (iv) construction of a predicted binding site cavity from the alignments of step (iii); and (v) multiple regression analysis of the binding data with respect to the 3-dimensional physicochemical descriptors in different 'site-pockets' of the binding cavity. The pharmacophore model that emerges consists of the geometry of the binding site cavity and the relative weights of various properties in different pockets for each of the ligands considered. The study suggests that binding free energy is sensitive to the composition, size and hydrophobicity of the heterocyclic base in the ligand. Though both syn and anti conformations are tried as active forms, the anti conformation gives a better solution and is chosen for modeling the binding site cavity. The best model obtained divides the binding site into six pockets and uses nine independent variables, fitting the observed data with a correlation coefficient of 0.94, a standard deviation of 0.22 and an explained variance of 0.80. Results of our model are consistent with a hypothesis that the 5'-OH group hydrogen bonds with the receptor. This model provides tentative design criteria for development of new nucleoside drugs and transport inhibitors. The model will undoubtedly continue to evolve (i) as the 3D-QSAR algorithm is further refined, and (ii) as data on additional nucleoside analogues become available.

Algorithms↗
PubMed1990

Elimination of infectious human immunodeficiency virus from human T-cell cultures by synergistic action of CD4-Pseudomonas exotoxin and reverse transcriptase inhibitors.

We have previously described a recombinant protein, designated CD4(178)-PE40, consisting of the human immunodeficiency virus (HIV) envelope glycoprotein-binding region of human CD4 linked to the translocation and ADP-ribosylation domains of Pseudomonas aeruginosa exotoxin A. By virtue of its affinity for gp120 (the external subunit of the HIV envelope glycoprotein), the hybrid toxin selectively binds to and kills HIV-1-infected human T cells expressing surface envelope glycoprotein and also inhibits HIV-1 spread in mixed cultures of infected and uninfected cells. We now report that CD4(178)-PE40 and reverse transcriptase inhibitors exert highly synergistic effects against HIV-1 spread in cultured human primary T cells. Furthermore, combination treatment can completely eliminate infectious HIV-1 from cultures of human T-cell lines. This conclusion is based on protection of a susceptible cell population from HIV-induced killing, complete inhibition of virus protein accumulation, and elimination of HIV DNA (as judged by quantitative polymerase chain reaction analysis). The results highlight the therapeutic potential of treatment regimens involving combination of a virostatic drug that inhibits virus replication plus an agent that selectively kills HIV-infected cells.

ADP Ribose Transferases↗
PubMed1990

Secondary structure of the human membrane-associated folate binding protein using a joint prediction approach.

The secondary structures of the human membrane-associated folate binding protein (FBP) and bovine soluble FBP are assessed by a joint prediction approach that combines neural network models, information theory, homology modeling and the Chou-Fasman methods. Two new profile maps are used to characterize the non-regular secondary structure and to assist in assigning buried and exposed parts of secondary structure: (i) the loop potential profile and (ii) the long range contact profile. Approximately half of human FBP is predicted to form regular secondary structure (alpha-helices-35% or beta-sheets - 12%, excluding the transmembrane helices) and the rest is predicted to form coil, turns or loops. The bovine milk soluble FBP is predicted to have a similar secondary structure as expected because of the high degree of homology between the FBP's. Discriminant analysis predicts two transmembrane segments for the human FBP sequence, one at the amino terminus (a leader sequence) and the other at the carboxy terminus. These predicted transmembrane domains are absent in the bovine milk soluble FBP, further supporting these predictions. The present set of secondary structural predictions for human FBP is obtained by 'consensus' to aid in modeling the super-secondary structure of the protein.

Amino Acid Sequence↗
PubMed1990

Inhibition of HIV-1 in monocyte/macrophage cultures by 2',3'-dideoxycytidine-5'-triphosphate, free and in liposomes.

The antiviral effects of 2',3'-dideoxycytidine (ddC), 2',3'-dideoxycytidine-5'-triphosphate (ddCTP) and liposome-encapsulated ddCTP [L(ddCTP)] were compared in cultured human monocyte-macrophages (M/M) infected with HIV-1. These treatments inhibited virus replication at nanomolar drug levels with activities in the order ddC greater than ddCTP = L(ddCTP). Studies on drug stability and uptake suggest that a large part of the free ddCTP is dephosphorylated before entering the cells, whereas L(ddCTP) remains stable over days and is taken up, probably by endocytosis. The response to L(ddCTP) suggests that the capability of liposomes for targeting drugs to macrophages in vivo could potentially be exploited to improve the therapeutic index of dideoxynucleoside drugs.

Acquired Immunodeficiency Syndrome↗
PubMed1990

A new approach to the low-back physical examination. Behavioral assessment of mechanical signs.

UNLABELLED: A rationale for a new approach to the low-back physical examination was developed. A set of 21 tests, 17 assessing organic and four assessing nonorganic signs, were organized into an examination according to specified criteria, and the reliability of the patient-reported and examiner-observed measures within the examination assessed. Primary outcome measures included patient reports of their pain location, aggravation and examiner-observed pain behaviors resulting from the maneuvers. Two pain behavior composites, conceptualized as outcome measures, were developed, one based on the 17 organic tests and one based on the four nonorganic tests. DESIGN: The reliability of the physical examination was assessed using a short-term test-retest paradigm. Three raters, two experienced orthopaedic surgeons and an RN with no previous experience in administering physical examinations were trained in the examination methods. Patients were assigned to one of three rater pairs and examined twice within a single day. During each examination both raters evaluated each patient; however, rater role as examiner or observer was reversed across examination. RESULTS: Forty-two patients were examined. Average times of 13.9 and 11.6 minutes were required to complete examinations 1 and 2, respectively. In addition, the time required to complete the examination decreased as the examiners became more familiar with the procedure, suggesting that an experienced examiner would usually be able to complete the examination in approximately 10 minutes. Within-examination reliabilities for the patient-reported measures (pain location and aggravation) were universally high, as expected, since these rating required the rater only to correctly hear and code patient responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Back Pain↗
PubMed1990

Stimulation of dorsal root ganglia and degradation of rabbit annulus fibrosus.

The authors sought to determine whether narrowing of the intervertebral neural foramen, by itself and in association with vibration, would stimulate the mechanosensitive dorsal root ganglia and result in degradation of proteoglycan and collagen of the annulus fibrosus, as proposed in their working model of dorsal root ganglia-neuropeptide-mediated degeneration of the spinal motion segment. Degradation of proteoglycan and collagen of rabbit annulus was observed when there was narrowing of the neural foremen and the degradation process was accelerated by vibration. Vibration alone, in the absence of structural abnormalities of the spinal motion segment, did not induce matrix degradation probably because of a less pronounced stimulation of the dorsal root ganglia. Biological events similar to those postulated here, fomented by a combination of structural abnormalities and environmental factors, could be involved in human disc degeneration.

Animals↗
PubMed1990

A modeling analysis of monoclonal antibody percolation through tumors: a binding-site barrier.

For successful use of radiolabeled monoclonal antibodies (MAbs) for diagnosis and therapy, it is helpful to understand both global and microscopic aspects of antibody biodistribution. In this study, antibody distribution in a tumor is simulated by splicing together information on global pharmacokinetics: transport across the capillary wall, diffusive penetration through the tumor interstitial space, and antigen-antibody interaction. The geometry simulated corresponds to spherical nodules of densely packed tumor cells. This modeling analysis demonstrates that: 1) antigen-antibody binding in tumors can retard antibody percolation; 2) high antibody affinity at a given dose tends to decrease antibody percolation because there are fewer free antibody molecules. The result is a more heterogeneous distribution; 3) the average antibody concentration in the tumor does not increase linearly with affinity; and 4) increasing antibody dose leads to better percolation and more uniform distribution. This mathematical model and the general principles developed here can be applied as well to other biologic ligands.

Antibodies, Monoclonal↗
PubMed1990

Lumbar discography in normal subjects. A controlled, prospective study.

Major advances in the techniques of discography since 1968, in conjunction with major strides in the evaluation of pain in recent years, prompted a study in which Holt's work on the specificity of discography was replicated and extended. For the present study, seven patients who had low-back pain and ten volunteers who had been carefully screened, with a questionnaire and a physical examination, to ensure that they had no history of problems with the back, had an injection at three levels, and all sessions were videotaped. After each injection, the participant was interviewed about the pattern and intensity of the pain, and then the discs were imaged with computed tomography. Five raters, who were blind to the condition of the participant, graded each disc as normal or abnormal on the basis of findings on magnetic resonance images that had been made before the injection and computed tomography (discography) were done. There was only one disagreement between the ratings that were made on the basis of the magnetic resonance images and those that were made on the basis of the discograms. Each participant's pain-related response was evaluated independently by two raters who viewed the videotapes of the discography. Inter-rater reliability was 0.99, 0.93, and 0.88 for the evaluation of intensity of the pain, pain-related behavior, and similarity of the pain to pain that the subject had had before the injection. In the asymptomatic individuals, the discogram was interpreted as abnormal for 17 per cent (five) of the thirty discs and for five of the ten subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Modeling analysis of the global and microscopic distribution of immunoglobulin G, F(ab')2, and Fab in tumors.

In order to understand the pharmacology of monoclonal antibodies and their conjugates, one must consider both global and microscopic aspects of antibody distribution. Here we present an analysis of antibody distribution in tumors based on the following factors: (a) molecular weight and valence of the antibody; (b) global pharmacokinetic profile following i.v. bolus injection; (c) penetration through the vascular wall; (d) diffusive and convective transport through interstitial space in the tumor; (e) antigen-antibody interaction; (f) antibody metabolism. Partial differential equations were developed to incorporate these factors and then solved numerically using parameter values from animal experiments, from clinical protocols at our institution, from studies of antibody binding characteristics in vitro, and from the literature. Salient findings from this model are that (a) antigen-antibody interaction in the tumor can retard antibody percolation away from blood capillaries, thus constituting a "binding site barrier"; (b) high antibody affinity tends to decrease antibody penetration and result in a more heterogeneous distribution; (c) high molecular weight [IgG greater than F(ab')2 greater than Fab] slows percolation and results in less uniform spatial distribution; (d) the average antibody concentration in the tumor does not increase linearly with antibody dose; (e) raising the rate of antibody metabolism results in low concentration and poor percolation; (f) perhaps most interesting, there is predicted to be a range of antibody dose and affinity within which the specificity ratio and average concentration could be kept high while limiting the heterogeneity of distribution. PERC, the computer program package developed for these analyses, provides a convenient and flexible way to assess the impact of global and microscopic parameters on the distribution of immunoglobulin in tumors. For calculations presented here, the input data were obtained from experimental sources, and qualitative features of the output proved consistent with the few interpretable observations available. However, detailed validation would require much more data than are currently at hand. The mathematical findings should therefore be considered as aids to concept development and as a set of null hypotheses with which to guide experimentation. Experiments and simulations will continue in tandem. It should be noted that the PERC package (and also the general principles delineated here) can be applied as well to biological ligands other than antibodies.

Antibody Affinity↗
PubMed1989

Dipyridamole potentiates the inhibition by 3'-azido-3'-deoxythymidine and other dideoxynucleosides of human immunodeficiency virus replication in monocyte-macrophages.

Dipyridamole (DPM) is commonly used as a coronary vasodilator and inhibitor of platelet aggregation in the treatment of cardiovascular diseases. We report here that DPM potentiates the inhibitory effects of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine against human immunodeficiency virus type 1 (HIV-1) in human monocyte-macrophages. At the same concentrations, DPM does not potentiate the toxic effects of AZT on these cells or on human bone marrow (granulocyte-monocyte) progenitor cells. Since monocyte-macrophage lineage cells appear to be the major reservoir for HIV-1 in vivo, these findings suggest the possibility of using DPM or its analogues in combination chemotherapy of HIV infections.

Antiviral Agents↗