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Biomedical subjects

L Bush

Publications and source records attributed to L Bush.

At least 19 recordsLinked to original sources
PubMed2006

Limited generation of activated protein C during infusion of the protein C activator thrombin analog W215A/E217A in primates.

Anticoagulation with activated protein C (APC) reduces the mortality of severe sepsis. We investigated whether the circulating protein C (PC) pool could be utilized for sustained anticoagulation by endogenous APC. To generate APC without procoagulant effects, we administered the anticoagulant thrombin mutant W215A;E217A (WE) to baboons. In preliminary studies, administration of high dose WE (110 microg kg(-1) i.v. bolus every 120 min; n = 2) depleted PC levels by 50% and elicited transient APC bursts and anticoagulation. The response to WE became smaller with each successive injection. Low dose WE infusion (5 microg kg(-1) loading + 5 microg kg(-1) h(-1) infusion; n = 5) decreased plasma PC activity by 15%, from 105% to 90%, to a new equilibrium within 60 min. APC levels increased from 7.5 ng mL(-1) to 86 ng mL(-1) by 40 min, then declined, but remained elevated at 34 ng mL(-1) at 240 min. A 22-fold higher dose WE (n = 5) decreased PC levels to 60% by 60 min without significant further depletion in 5 h. The APC level was 201 ng mL(-1) at 40 min and decreased to 20 ng mL(-1) within 120 min despite continued activator infusion. Co-infusion of WE and equimolar soluble thrombomodulin (n = 5) rapidly consumed about 80% of the PC pool with significant temporal increase in APC generation. In conclusion, low-grade PC activation by WE produced sustained, clinically relevant levels of circulating APC. Limited PC consumption in WE excess was consistent with the rapid depletion of cofactor activity before depletion of the PC zymogen. Reduced utilization of circulating PC might have similar mechanism in some patients.

Amino Acid Substitution↗
PubMed2000

Responses of the extrapyramidal and limbic substance P systems to ibogaine and cocaine treatments.

Ibogaine is an indolamine found in the West Africa shrub, Tabernanthe iboga, and has been proposed for the treatment of addiction to central nervous system (CNS) stimulants such as cocaine and amphetamine. The mechanism of ibogaine action and its suitability as a treatment for drug addiction still remains unclear. Since previous studies demonstrated differential effects of stimulants of abuse (amphetamines) on neuropeptide systems such as substance P, we examined the impact of ibogaine and cocaine on extrapyramidal (striatum and substantia nigra) and limbic (nucleus accumbens and frontal cortex) substance P-like immunoreactivity. Ibogaine and cocaine treatments altered substance P systems by increasing striatal and nigral substance P-like immunoreactivity concentration 12 h after the last drug treatment. However, substance P-like immunoreactivity content was not significantly increased in nucleus accumbens after treatment with either drug. The ibogaine- and cocaine-induced increases in substance P-like immunoreactivity in striatum and substantia nigra were blocked by coadministration of selective dopamine D(1) receptor antagonist (SCH 23390; R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride) or dopamine D(2) receptor antagonist (eticlopride; S(-)-3-Chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2- methoxy-benzamide hydrochloride). Most of the responses by substance P systems to ibogaine administration resembled those caused by cocaine, except in cortical tissue where multiple administration of cocaine, but not ibogaine increased substance P-like immunoreactivity. These data suggest that substance P systems may contribute to the effects of ibogaine and cocaine treatment.

Animals↗
PubMed2000

Selective antagonism of nigral neuropeptide responses to methamphetamine by conantokin G, a naturally occurring conopeptide.

Some conopeptides derived from cone snails act on specific subunits of the NMDA receptor and thus, exert an influence on the dopamine system. In this study, one such conopeptide, conantokin G, was administered i.c.v. in conjunction with methamphetamine, a potent central nervous system stimulant known to cause dopamine release and changes in tissue levels of neurotensin and dynorphin A in some brain structures. Both single and multiple administrations of the conantokin G preferentially attenuated the methamphetamine-induced increases in tissue levels of these neuropeptides in the substantia nigra. Conantokin G also enhanced the behavioral effects of the methamphetamine.

Animals↗
PubMed1999

Enhanced cell motility and invasion of chicken embryo fibroblasts in response to Jun over-expression.

Malignant tumor cells exhibit a number of distinct properties involved not only with deregulated cell proliferation but also enhanced migration and invasion. The Jun oncogene has been well studied in regard to its role in cell proliferation. Many of the target genes deregulated by Jun encode matrix metalloproteases (MMPs) such as MMP1, MMP3 and MMP9. These targets implicate a prominent role for Jun in tumor cell invasion, in addition to its role in growth transformation. To investigate this possibility, we have examined the effect of over-expression of transforming and non-transforming versions of Jun on motility and invasion of chicken embryo fibroblasts (CEFs). We found that over-expression of either form of Jun results in elevated intrinsic cellular motility as well as increased motility in response to several different chemo-attractants, including 3T3-conditioned media, basic fibroblast growth factor, hepatocyte growth factor and Matrigel. The capacity of these cells to invade through Matrigel is also elevated as a result of Jun over-expression. In addition to these effects, CEFs expressing Jun secrete factors that stimulate the motility of a human tongue carcinoma cell line. Our results suggest that Jun plays an important role in the potentiation of cell motility and invasion through multiple mechanisms.

3T3 Cells↗
PubMed1998

Apolipoprotein A-1 is a negative target of v-Jun overexpression.

The product of the Jun oncogene influences a variety of processes including cell proliferation and differentiation. Jun exerts its influence by binding to the promoter and enhancer regions of a number of different target genes resulting in their activation or repression. We describe here the isolation and characterization of a gene differentially downregulated upon overexpression of v-Jun but not c-Jun. DNA and amino acid homology search analysis revealed this gene to be identical to chicken apolipoprotein A-1, the major component of high density lipoprotein (HDL). The half life of apolipoprotein A-1 RNA remains constant in the presence or absence of v-Jun overexpression suggesting downregulation by v-Jun is at the level of promoter activity. Consistent with this hypothesis, apolipoprotein A-1 upstream promoter fragments active in normal and c-Jun expressing CEF are inactive in v-Jun transformed CEF. Analysis of expression of apolipoprotein A-1 in CEF overexpressing other oncogenes revealed a similar downregulation by Myc and v-Src but not c-Fos, v-Ha-Ras, c-Src or c-Ski. Our findings point to a potential regulatory affect on cholesterol metabolism by v-Jun, as a result of altered levels of apolipoprotein A-1 message expression.

Animals↗
PubMed1998

The formulation of recombinant factor IX: stability, robustness, and convenience.

A lyophilized recombinant factor IX (rFIX) formulation has been developed that is stable and contains no preservatives. No blood or plasma products are used in the production or formulation of rFIX. The formulation contains 10 mmol/L histidine, 0.26 mol/L glycine, 1% sucrose, and 0.005% polysorbate-80 (pH 6.8). Polysorbate-80 acts as a protectant for the protein from freezing-induced damage (eg, aggregation). Sucrose provides protection to the protein in the freeze-dried state. Glycine provides for a high-quality cake morphology. Histidine provides optimal buffering stability at the desired pH and minimizes aggregate formation upon storage in the lyophilized state. This optimized combination of excipients provides a high degree of long-term stability, as demonstrated by a variety of analytical methods, including clotting assays, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), isoelectric focusing (IEF), size-exclusion chromatography (SEC), peptide mapping, oligosaccharide fingerprinting, and reverse-phase high-performance liquid chromatography (HPLC). The rFIX product is easy to reconstitute and demonstrates excellent stability in solution after reconstitution.

Chemistry, Pharmaceutical↗
PubMed1997

Exacerbation of methamphetamine-induced neurochemical deficits by melatonin.

Methamphetamine (METH), administered in large, repeated doses, compromises the dopaminergic and serotonergic systems as indicated by prolonged suppression of tyrosine hydroxylase and tryptophan hydroxylase activity and concurrent decreases in the content of dopamine and 5-hydroxytryptamine. Because dopamine is necessary for these dopaminergic and serotonergic deficits we postulated that dopamine and/or its reactive metabolites are responsible for these degenerative alterations. Because we previously demonstrated that in vitro reducing conditions reverse the decrease in tryptophan hydroxylase activity, we reasoned that melatonin, a purported endogenous antioxidant, may alter this response. Rats were treated with METH and/or melatonin and trytophan hydroxylase activity and 5-hydroxytryptamine content were assessed; tyrosine hydroxylase activity and dopamine content were also measured. Not only did melatonin not prevent METH-induced deficits in serotonergic and dopaminergic parameters, but coadministration of melatonin with METH actually enhanced most of the monoaminergic effects of METH. This enhancing effect could not be attributed to alteration of body temperature. Because METH abuse causes insomnia and melatonin is promoted in some countries for insomnia, the implications of the interaction between these two drugs could be clinically important.

Animals↗
PubMed1995

Evaluation of recombinant human factor IX: pharmacokinetic studies in the rat and the dog.

The pharmacokinetics of intravenously administered recombinant human factor IX (rhFIX) were studied in Sprague-Dawley rats and Beagle dogs. Rats received rhFIX (50 IU/kg once daily) for 28 days, and the plasma half-life was 5 h. Anti-Human Factor IX serum antibody levels were found in only 1 of 12 rats. The pharmacokinetic profiles of rhFIX or Mononine, a purified human plasma-derived factor IX, after single 100 IU/kg i.v. doses in dogs, were similar. Peak plasma concentrations of rhFIX and Mononine were 4-5 micrograms/ml. The mean plasma half-lives were 13.2 +/- 1.6 h for rhFIX and 13.3 +/- 1.6 h for Mononine. Dogs also received rhFIX (40 IU/kg i.v., daily) for 28 days or Mononine (40 IU/kg i.v. daily) for 14 days. Anti-human Factor IX serum antibody levels were determined for each compound. Pharmacokinetic half-lives decreased in these treated dogs which developed antihuman Factor IX antibodies. The antibody responses in 28 day rhFIX (40 IU/kg) dogs were similar to 14 day Mononine (40 IU/kg) dogs.

Animals↗
PubMed1992

Response of monoaminergic and neuropeptide systems to 4-methylaminorex: a new stimulant of abuse.

4-Methylaminorex is an amphetamine analog which has recently gained attention due to its potential as a stimulant of abuse and the ease with which it is synthesized. Administration of acute and multiple doses of 4-methylaminorex caused rapid (3-h) and long-term (7-day) declines in striatal tryptophan hydroxylase activity with few changes in other serotonergic parameters. The acute response by tryptophan hydroxylase to this drug was reversed by incubating the tissues in a reducing environment suggesting that 4-methylaminorex alters this enzyme through oxidative mechanisms. The 4-methylaminorex-induced long-term reduction in tryptophan hydroxylase activity might be due to neurotoxic action on serotonergic systems. In contrast, although a decline in striatal tyrosine hydroxylase occurred 3 h following a single dose of 4-methylaminorex, no changes in this enzyme were observed at 7 days after acute or multiple dosing with this drug. This result suggests that 4-methylaminorex is not neurotoxic to the dopaminergic neurons. Even though this amphetamine analog apparently does not have long-term effects on dopaminergic systems, it does appear to enhance substantially dopaminergic activity. Evidence for increased dopamine activity resulting from 4-methylaminorex administration included dramatic but temporary rises in the levels of nigral neurotensin, dynorphin A and substance P following multiple drug administration. Similar peptide changes have been observed with other amphetamine-related stimulants and are mediated by increases in dopaminergic activity. In summary, 4-methylaminorex has significant impact on monoaminergic pathways. In general, its spectrum of effects on these systems is like that of the ring-substituted amphetamines, such as methylenedioxymethamphetamine.

Animals↗
PubMed1992

Responses of limbic and extrapyramidal neurotensin systems to stimulants of abuse. Involvement of dopaminergic mechanisms.

In summary, we have observed that drugs of abuse, which can cause schizophrenia-like paranoia, alter striatal and accumbens NT systems in a similar, dramatic fashion. The NT responses to these drugs, in particular METH, are mediated by activation of DA D1 receptors. We have observed that NMDA-type glutamate receptors are essential for the D1-NT interaction. NMDA receptors are selective, since they do not contribute to the antagonistic effects of DA D2 receptors on NT activity. This observation suggests that NT responses to D1 and D2 regulation are mediated through separate and distinct mechanisms. Finally, we found that the presence of METH dramatically reduces striatal NT release, which most likely leads to NT accumulation in nerve terminals and the observed increase in NT tissue level. The blockade of NT release by a psychotogenic drug, such as METH, is consistent with the hypothesis that NT has antipsychotic activity and a decrease in its release may contribute to some forms of schizophrenia similar to that caused by intense use of the stimulants of abuse.

Animals↗
PubMed1991

Response of extrapyramidal and limbic neuropeptides to fenfluramine administration: comparison with methamphetamine.

The responses of extrapyramidal and limbic neuropeptide and striatal dopamine and serotonin systems were evaluated after treatment with fenfluramine in rats. After multiple administrations of fenfluramine, its active metabolite, norfenfluramine, and methamphetamine (METH), striatal neurotensin (NT) content was similarly increased to approximately 200% of control. In contrast, nigral NT levels were unaltered by fenfluramine, intermediately increased by norfenfluramine (148% of control) and maximally increased by METH (267% of control). Striatal and nigral substance P (SP) and dynorphin A (Dyn) systems were unaltered by fenfluramine, whereas norfenfluramine caused an intermediate increase in striatal Dyn content but did not significantly alter striatal SP or nigral SP and Dyn levels. However, METH significantly elevated striatal and nigral Dyn and SP concentrations to 280 to 425% (Dyn) and 140% (SP) of control. For the most part, the response of the limbic peptides was similar to that seen in the striatum with a couple of notable differences. Further investigation of the striatal NT system showed that the increases induced by fenfluramine were completely blocked by the D1 antagonist, SCH 23390, and the noncompetitive N-methyl-D-aspartate antagonist, MK801. Depletion of 5-hydroxytryptamine with pretreatment by parachloroamphetamine did not alter the response of the striatal NT system to fenfluramine. The present results demonstrate common and unique features in the response of peptide systems to fenfluramine and methamphetamine, which might explain some of the similarities and differences between these two drugs.

Animals↗
PubMed1991

Effects of the fungal endophyte Acremonium coenophialum in fescue on pregnant mares and foal viability.

Effects of the endophyte Acremonium coenophialum in tall fescue on pregnant mares and foal viability were evaluated. Twenty-two mature pregnant mares were randomly chosen to graze either Kentucky-31 tall fescue that was free from A coenophialum (endophyte-free, EF) or tall fescue infected with A coenophialum (endophyte-present, EP) after the first 90 days of pregnancy through parturition. Concentrations of pyrrolizidine and ergopeptine alkaloids were significantly greater in EP grass, compared with EF pasture. Ten of 11 mares grazing EP pasture had obvious dystocia. Mean duration of gestation was significantly greater for the EP group, compared with the EF group. Foal survivability was severely reduced among mares grazing EP fescue with only 1 foal surviving the natal period. Udder development and lactation were low in mares grazing EP grass. The absence of clinical problems in mares grazing EF grass implicated the endophyte as the causative agent of reproductive problems and perinatal foal mortality in pregnant mares grazing endophyte-infected fescue grass. Caution should be exercised in allowing pregnant mares to graze pastures infected with the endophyte A coenophialum.

Acremonium↗
PubMed1990

Importance of neutralizers in the stripping fluid in a simulated healthcare personnel handwash.

The Food and Drug Administration (FDA) healthcare personnel handwash procedure allows for the use of a non-neutralizing stripping fluid after washing with an antimicrobial handwash product. The antimicrobial in the handwash product can remain active up until the time of neutralization or plating. A modified healthcare personnel handwash procedure using a pigskin substrate and a 4% chlorhexidine gluconate handwash product was used to demonstrate the need for a neutralizer in the stripping fluid. When tests were run with and without neutralizers in the dilution blanks, but with adequate neutralizers in the stripping fluid, there were no significant differences (p greater than .05) between results obtained after five washes or after each wash. When tests were run with a non-neutralizing stripping fluid, significant differences were noticed in the first and the fifth wash (p less than .05), and in the presence or absence of neutralizers in the dilution blanks (p less than .05). The data generated indicate that in order to determine the true activity of an antimicrobial handwash product, an adequate neutralizer should be incorporated into the stripping fluid and not just the dilution media. They also suggest that neutralizer carry-over from the stripping fluid is not a valid concern.

Chlorhexidine↗
PubMed1990

The effects of surfactant systems and moisturizing products on the residual activity of a chlorhexidine gluconate handwash using a pigskin substrate.

A series of handwashing experiments using a pigskin substrate and Serratia marcescens as the contaminant compared the residual activity of a chlorhexidine detergent handwash product alone and in combination with anionic and nonionic-based moisturizing products and surfactant systems. The anionic based moisturizing products and the anionic surfactant system almost completely destroyed the residual antibacterial activity of the chlorhexidine, while the nonionic-based products had minimal effect.

Administration, Topical↗