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K M Johnson

Publications and source records attributed to K M Johnson.

At least 37 records · Page 2Linked to original sources
PubMed2001

The child PTSD Symptom Scale: a preliminary examination of its psychometric properties.

Reports on the development and preliminary validation of the Child PTSD Symptom Scale (CPSS) for children and adolescents. The CPSS is a new instrument that was developed to assess the severity of Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994) posttraumatic stress disorder symptoms in children exposed to trauma. The CPSS was administered to 75 school-age children approximately 2 years after the 1994 Northridge, California, earthquake. The psychometric properties of the CPSS show high internal consistency and test-retest reliability for both the total score and the three subscales. Convergent validity with the Child Post-Traumatic Stress Disorder Reaction Index (CPTSD-RI) was established. As expected, the correlations of the CPSS with depression and anxiety measures were lower than those with the CPTSD-RI, providing some support for discriminant validity of the CPSS. These results suggest that the CPSS is a useful tool for the assessment of posttraumatic stress disorder (PTSD) severity and for the screening of PTSD diagnosis among traumatized children.

Adolescent↗
PubMed2001

Pharmacological characterization of locomotor sensitization induced by chronic phencyclidine administration.

Phencyclidine (PCP) administration in rats acutely in high doses or chronically in lower doses causes neurotoxicity characterized by neuronal vacuolization and apoptotic neuronal death, respectively. The purpose of this study was to determine whether drugs that previously had been reported to prevent either type of neurotoxicity were also able to prevent locomotor sensitization following chronic PCP administration. PCP (5 or 20 mg/kg) was administered once a day for 5 days following drug pretreatment. After withdrawal, rats were challenged with 3.2 mg/kg PCP and locomotor activity was assessed. Haloperidol and clozapine significantly attenuated sensitization elicited by PCP (20 mg/kg). The D(1)-like antagonist SCH23390 was much less effective than clozapine, showing a marginal inhibition. Risperidone, a D(2)/serotonin (5-HT(2)) antagonist, also resulted in a marginal attenuation of 15%. Ketanserin, a 5-HT(2) antagonist, had no effect. Atropine retarded sensitization by 35% and (+)-sulpiride caused a 50% reduction. The AMPA/kainate antagonist, 6,7-dinitroquinoxaline-2,3-dione, had no effect, but barbital sodium reduced sensitization by 54%. These data suggest that gamma-aminobutyric acid A, D(2), and muscarinic receptors play a major role in the complex pathway underlying sensitization to PCP, whereas D(1), 5-HT(2) and AMPA receptors have little or no relevance in the behavioral sensitization produced by 20 mg/kg PCP. In a model using 5 mg/kg PCP, the effects of sulpiride and SCH23390 replicated those observed with 20 mg/kg PCP and further showed that acute locomotor activation is not a strict requirement for the development of sensitization. These data argue that there is overlap, but nonidentity, between the mechanisms underlying PCP-induced sensitization and neurotoxicity.

Animals↗
PubMed2001

Surrogate end-point biomarkers in chemopreventive drug development.

Relevant and feasible surrogate end-points are needed for the evaluation of intervention strategies against cancer and other chronic, life-threatening diseases. Carcinogenesis can be viewed as a process of progressive disorganization. This process is characterized by the accumulation of genotypic lesions and corresponding tissue and cellular abnormalities, including loss of proliferation and apoptosis controls. Potential surrogate end-points for cancer incidence include both phenotypic and genotypic biomarkers of this progression. In the US National Cancer Institute chemoprevention programme, histological modulation of a precancer (intraepithelial neoplasia) has so far been the primary phenotypic surrogate end-point in chemoprevention trials. Additionally, high priority has been given to biomarkers measuring specific and general genotypic changes correlated with the carcinogenesis progression model for the targeted cancer (e.g., progressive genomic instability as measured by loss of heterozygosity or amplification at specific microsatellite loci). Other potential surrogate end-points include proliferation and differentiation indices, specific gene and general chromosome damage, cell growth regulatory molecules, and biochemical activities (e.g., enzyme inhibition). Serum biomarkers thought to be associated with cancer progression (e.g., prostate-specific antigen) are particularly appealing surrogate end-points because of accessibility. Potentially chemopreventive effects of the test agent may also be measured (e.g., tissue and serum estrogen levels in studies of steroid aromatase inhibitors). To establish chemopreventive efficacy, prevention of virtually all biomarker lesions, or of those lesions with particular propensity for progression, may be required. Ideally, the phenotype and genotype of any new or remaining precancers in the target tissue of chemopreventive agent-treated subjects would show less, and certainly no greater, potential for progression than those of placebo-treated subjects.

Anticarcinogenic Agents↗
PubMed2000

AIDA reduces glutamate release and attenuates mechanical allodynia after spinal cord injury.

Spinal cord injury (SCI) leads to an increase in extracellular excitatory amino acid (EAA) concentrations, resulting in glutamate receptor-mediated excitotoxicity and central sensitization. To test contributions of group I metabotropic glutamate receptors (mGluRs) in SCI induced release of glutamate and in behavioral outcomes of central sensitization following injury, we administered 1-aminoindan-1,5-dicarboxylic acid (AIDA; 0.1 nmol intraspinally), a potent group I mGluR antagonist, to rats immediately after spinal cord contusion injury. EAAs were collected by microdialysis and quantified using HPLC. AIDA significantly decreased extracellular glutamate but not aspartate concentrations and significantly attenuated the development of mechanical but not thermal allodynia. These results suggest mGluRs play an important role in injury-induced EAA release and in central sensitization following SCI.

Animals↗
PubMed2000

Chemical synthesis and pharmacology of 6- and 7-hydroxylated 2-carbomethoxy-3-(p-tolyl)tropanes: antagonism of cocaine's locomotor stimulant effects.

In our efforts to identify molecules that might act as cocaine antagonists or cocaine partial agonists, efforts were made to further capitalize on our earlier finding regarding the ability of a 7-methoxylated pseudococaine analogue to act as a weak cocaine functional antagonist. Herein, a series of the 6- and 7-hydroxylated WIN analogues possessing a boat or chair conformation of the tropane ring were prepared and tested for their ability to displace [(3)H]mazindol binding and to inhibit high-affinity monoamine uptake into rat brain nerve endings. These 6- and 7-hydroxylated WIN analogues were readily prepared by use of a classical Willstätter synthesis to construct an appropriately functionalized tropane ring followed by use of a Suzuki coupling reaction to introduce the aryl group at position 3. Reduction of the resulting tropene by use of SmI(2) or by catalytic hydrogenation followed by deprotection delivered the final target compounds. Some of these compounds were found to retain considerable affinity as inhibitors of the dopamine transporter (DAT) and the norepinephrine transporter (NET), but they were less potent inhibitors of the serotonin transporter (SERT). None of the compounds of the present series revealed any substantial potency difference in [(3)H]mazindol binding versus [(3)H]DA uptake, and failed to show "cocaine antagonism" when tested for their ability to prevent cocaine's inhibition of DA transport. However, one of these hydroxylated WIN analogues, namely 12b, which possesses nanomolar potency at the DAT and NET and micromolar potency at the SERT, when tested in vivo, was found capable of attenuating cocaine's locomotor activity (AD(50) = 94 mg/kg). Taken together, this work provides further support for our hypothesis that drugs that lack the ability to inhibit transport by all three monoaminergic transporters may exhibit "partial" cocaine-like properties, but act as cocaine antagonists. Consequently, it may prove valuable to examine the behavioral activity of other 6- and 7-substituted tropanes in animal behavioral paradigms in the search for a cocaine medication.

Animals↗
PubMed2000

An enantioselective synthesis and biobehavioral evaluation of 7-fluoro-3-(p-fluorophenyl)-2-propyltropanes.

Optically pure 7-fluorotropanes 3a-c, were synthesized as structural probes of the dopamine transporter. The synthesis of these compounds was accomplished through the asymmetric 1,3-dipolar cycloaddition reaction of the oxidopyridinium betaine 4 with the chiral dipolarophile (R)-p-tolyl vinyl sulfoxide. In the preliminary analysis, tropane 3a was found to reduce the rewarding effects of cocaine in the brain stimulation reward paradigm.

Animals↗
PubMed2000

Novel conformationally constrained tropane analogues by 6-endo-trig radical cyclization and stille coupling - switch of activity toward the serotonin and/or norepinephrine transporter.

A novel class of tricyclic tropane analogues has been synthesized by making use of radical cyclization technology in combination with the Stille coupling reaction. As hybrids between tropanes and quinuclidines, these tropaquinuclidines represent a significant structural departure from many of the other classes of tropane ligands synthesized to date. This structure class is characterized by the boat conformation of the tropane ring and the orientation of the additional bridge (and therefore of the nitrogen lone pair) together with the unusual placement of the aromatic moiety. All compounds were tested for their ability to inhibit monoamine reuptake under identical conditions. The ability to inhibit reuptake of dopamine in comparison to cocaine is generally decreased in this series but for one compound. (1S,3R, 6S)-(Z)-9-(thienylmethylene)-7-azatricyclo[4.3.1.0(3, 7)]decane-2beta-carboxylic acid methyl ester (5h) exhibits reasonable activity at the dopamine transporter (DAT) (K(i) = 268 nM) and good activity at the norepinephrine transporter (NET) (K(i) = 26 nM). The potency and selectivity shown by some of these ligands for the NET, serotonine transporter (SERT), or NET/SERT is striking, particularly in view of the displacement of the aromatic ring in this series from its usual position at C-3 in the WIN analogues. Thus, (1S,3R,6S)-(Z)-9-(4-biphenylylmethylene)-7-azatricyclo[4.3.1 . 0(3,7)]decane-2beta-carboxylic acid methyl ester (5a) is a selective inhibitor of norepinephrine reuptake (K(i) = 12 nM). Its p-methoxy analogue 5c is a mixed inhibitor of norepinephrine and serotonin reuptake (K(i) = 187 nM at the NET and 56 nM at the SERT). The most active and selective compound we found in the present series is compound 8b [(1S,3R,6S)-2-(acetoxymethyl)-(Z)-9-(3, 4-dichlorophenylmethylene)-7-azatricyclo[4.3.1.0(3,7)]decane ]. This compound is a potent (K(i) = 1.6 nM) and selective inhibitor of serotonin reuptake into rat midbrain synaptosomes. Its selectivity is about 400-fold over the NET and about 1000-fold over the DAT. The results of this study further demonstrate the possibility of tuning the selectivity of tropane analogues toward the SERT or NET binding site. The ligands disclosed herein provide additional pharmacological tools of use in attempting to correlate structure and transporter selectivity with in vivo studies of behavioral outcomes.

Animals↗
PubMed2000

Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors.

The synthesis and monoamine transporter activity of additional members of a series of 3,4-disubstituted piperidines (truncated analogues of the WIN series) are described. All members of this series were prepared from arecoline hydrobromide in optically pure form and were evaluated for their ability to inhibit high affinity uptake of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) into rat brain nerve endings (synaptosomes). Most of the compounds prepared in this series are reasonably potent DAT inhibitors (K(i) values of 4-400 nM) and have selectivity for the 5-HT transporter relative to both the NE transporter (3-9-fold) and to the DAT ( approximately 25-fold). In the present series, (-)-methyl 1-methyl-4beta-(2-naphthyl)piperidine-3beta-carboxylate (6) was found to be the most potent piperidine-based ligand, exhibiting K(i)'s of 21 nM and 7.6 nM at the DAT and 5-HTT, respectively. While the 5-HTT activity of compound 6 is comparable to that of the antidepressant medication fluoxetine, it is less selective. As is apparent from the data presented, the naphthyl substituted piperidines 6-9, which differ in their stereochemistry, show different degrees of selectivity for the three transporters. Consistent with results reported in the literature for the tropane analogues, removal of the methyl group from the nitrogen atom of 9 leads to a further enhancement in 5-HTT activity. To examine the in vivo effects of these piperidines, preliminary behavioral screening was carried out on piperidine 14. Despite its 2.5-fold greater DAT activity compared to cocaine, piperidine 14 was found to be about 2. 5-fold less potent in increasing distance traveled in mice. However, consistent with its DAT activity, piperidine 14 was found to be about 2.5-fold more potent than cocaine in enhancing stereotypic movements. Further studies of these piperidine-based ligands may provide valuable insights into the pharmacological mechanisms underlying the enhancement in distance traveled versus stereotypic movements. The present results have important implications for better understanding the structural motifs required in the design of agents with specific potency and selectivity at monoamine transporters.

Animals↗
PubMed2000

Discovery of a novel dopamine transporter inhibitor, 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone, as a potential cocaine antagonist through 3D-database pharmacophore searching. Molecular modeling, structure-activity relationships, and behavioral pharmacological studies.

A novel, fairly potent dopamine transporter (DAT) inhibitor, 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone (3, K(i) values of 492 and 360 nM in binding affinity and inhibition of dopamine reuptake, respectively), with significant functional antagonism against cocaine and a different in vitro pharmacological profile from cocaine at the three transporter sites (dopamine, serotonin, and norepinephrine) was discovered through 3D-database pharmacophore searching. Through structure-activity relationships and molecular modeling studies, we found that hydrophobicity and conformational preference are two additional important parameters that determine affinity at the DAT site. Chemical modifications of the lead compound (3) led to a high affinity analogue (6, K(i) values of 11 and 55 nM in binding affinity and inhibition of dopamine reuptake, respectively). In behavioral pharmacological testing, 6 mimics partially the effect of cocaine in increasing locomotor activity in mice but lacks cocaine-like discriminative stimulus effect in rats. Taken together, these data suggest that 6 represents a promising lead for further evaluations as potential therapy for the treatment of cocaine abuse.

Animals↗
PubMed2000

Intravascular susceptibility agent effects on tissue transverse relaxation rates in vivo.

Since vascular architecture differs among tissues, it was hypothesized that the change in transverse relaxation rate produced by a given tissue concentration of susceptibility contrast agent also varies by tissue. This is relevant to strategies to map regional blood volume by MRI using indicator dilution techniques. R*(2) was measured in rat organs over a range of susceptibility agent concentrations at 1.5 T. Rat red blood cells loaded with dysprosium-DTPA-BMA served as an intravascular susceptibility agent. Tissue samples were frozen in vivo and dysprosium concentrations were independently measured using inductively coupled plasma atomic emission spectroscopy. The slope (k) of R*(2) vs. tissue dysprosium concentration in sec(-1) mM(-1) for myocardium was 97.1 (95% C.I. 77. 0-117.2), liver 122.6 (108.3-136.9), spleen 22.5 (8.8-36.3), kidney 68.1 (58.6-77.6), and skeletal muscle 77.9 (4.1-151.6); k was significantly different (P < 0.05) for all pairings except those with skeletal muscle. Therefore, relative values of tissue blood volume derived from dynamic images of first pass contrast effects may be in error because k is not constant for different conditions.

Acetylcysteine↗
PubMed2000

Differences in tobacco assessment and intervention practices: a regional snapshot.

BACKGROUND: This research describes tobacco attitudes and practices of health care providers in the Upper Midwest. A baseline measure of preventive practices by providers was needed to plan effective tobacco intervention education programs. METHODS: Health care providers in a 16-county region received a mailed survey regarding tobacco assessment practices, intervention practices, attitudes, skills/knowledge, barriers, and desire for tobacco education. The survey was sent to all chiropractors, dentists, nurse practitioners/physician assistants, physicians (primary care and specialist), and public health nurses in the region. A total of 51.9% (n = 614) of all providers returned usable surveys. RESULTS: Significant differences were found between provider groups on all measured concepts. Primary care physicians, nurse practitioners/physician assistants, and public health nurses were more likely than specialist physicians, dentists, and chiropractors to assess, intervene, be supportive of tobacco cessation, have skills/knowledge about cessation, perceive fewer barriers, and want further education. CONCLUSIONS: In this region, provider groups differed in tobacco use assessment and treatment. All provider groups desired education regarding tobacco intervention. Region-wide tobacco cessation educational initiatives need to take into account differences between provider groups.

Adult↗
PubMed2000

Growth protocols for etiolated soybeans germinated within BRIC-60 canisters under spaceflight conditions.

As part of the GENEX (Gene Expression) spaceflight experiment, protocols were developed to optimize the inflight germination and subsequent growth of 192 soybean (Glycine max cv McCall) seeds during STS-87. We describe a method which provided uniform growth and development of etiolated seedlings while eliminating root and shoot restrictions for short-term (4-7 day) experiments. Final seedling growth morphologies and the gaseous CO2 and ethylene levels present both on the last day in space and at the time of recovery within the spaceflight and ground control BRIC-60 canisters are presented.

Carbon Dioxide↗
PubMed2000

Single dose pharmacokinetics of pleconaril in neonates. Pediatric Pharmacology Research Unit Network.

BACKGROUND: Pleconaril is an orally active, broad spectrum antipicornaviral agent with activity against nonpolio enteroviruses. Pleconaril phamacokinetics was evaluated in 16 neonates (16.4 +/- 8.7 days postnatal age) with suspected enteroviral infection. METHODS: Pleconaril (5 or 7.5 mg/kg) was administered orally to study subjects and plasma pleconaril concentrations quantified from serial blood samples obtained during 24 h after a single oral dose by gas chromatography with electrochemical detection. Pharmacokinetic parameter estimates were determined by noncompartmental methods and compared between doses and with similar data obtained from a previous study of pleconaril disposition in children (n = 18, 2 to 12 years). RESULTS: Pleconaril was well-tolerated in all neonates without discernible adverse events. Comparison between the 5.0- and 7.5-mg/kg doses revealed no significant differences in peak plasma concentration (Cmax 686.7 vs. 617.1 ng/ml), elimination half-life (t 1/2; 4.6 vs. 6.6 h), area under the plasma concentration vs. time curve (AUC; 5162.6 vs. 5523.9 ng/ml/h), apparent steady state volume of distribution (V(dss)/F; 9.3 vs. 17.1 liters/ kg) and apparent oral clearance (Cl/F; 1.3 vs. 1.7 liters/h/kg). In addition, no correlation was observed between postconceptional age and AUC, V(dss)/F, t 1/2 or Cl/F for pleconaril. Comparison of pleconaril pharmacokinetics between neonates and children suggested a significant difference in V(dss)/F (9.3 vs. 4.7 liters/kg), dose-normalized Cmax, (686.7 vs. 1272.5 ng(ml) and AUC (5125.6 vs. 8131.2 ng/ml/h). In contrast, the mean elimination t 1/2 between neonates and children was not appreciably different. CONCLUSIONS: The apparent age-dependent differences in the pharmacokinetics of pleconaril may in part be related to increased bioavailability of the drug in older children and adults than in neonates. Our data appear to support the use of a 5.0-mg/kg dose given every 8 to 12 h in future studies of pleconaril in neonatal patients with enteroviral infection.

Administration, Oral↗
PubMed2000

HCF-1 amino- and carboxy-terminal subunit association through two separate sets of interaction modules: involvement of fibronectin type 3 repeats.

When herpes simplex virus infects permissive cells, the viral regulatory protein VP16 forms a specific complex with HCF-1, a preexisting nuclear protein involved in cell proliferation. The majority of HCF-1 in the cell is a complex of associated amino (HCF-1(N))- and carboxy (HCF-1(C))-terminal subunits that result from an unusual proteolytic processing of a large precursor polypeptide. Here, we have characterized the structure and function of sequences required for HCF-1(N) and HCF-1(C) subunit association. HCF-1 contains two matched pairs of self-association sequences called SAS1 and SAS2. One of these matched association sequences, SAS1, consists of a short 43-amino-acid region of the HCF-1(N) subunit, which associates with a carboxy-terminal region of the HCF-1(C) subunit that is composed of a tandem pair of fibronectin type 3 repeats, a structural motif known to promote protein-protein interactions. Unexpectedly, the related protein HCF-2, which is not proteolyzed, also contains a functional SAS1 association element, suggesting that this element does not function solely to maintain HCF-1(N) and HCF-1(C) subunit association. HCF-1(N) subunits do not possess a nuclear localization signal. We show that, owing to a carboxy-terminal HCF-1 nuclear localization signal, HCF-1(C) subunits can recruit HCF-1(N) subunits to the nucleus.

Amino Acid Sequence↗
PubMed2000

Perspectives on surrogate end points in the development of drugs that reduce the risk of cancer.

This paper proposes a scientific basis and possible strategy for applying surrogate end points in chemopreventive drug development. The potential surrogate end points for cancer incidence described are both phenotypic (at the tissue, cellular, and molecular levels) and genotypic biomarkers. To establish chemopreventive efficacy in randomized, placebo-controlled clinical trials, it is expected that in most cases it will be critical to ensure that virtually all of the biomarker lesions are prevented or that the lesions prevented are those with the potential to progress. This would require that both the phenotype and genotype of the target tissue in agent-treated subjects, especially in any new or remaining precancers, are equivalent to or show less progression than those of placebo-treated subjects. In the National Cancer Institute chemoprevention program, histological modulation of a precancer (intraepithelial neoplasia) has thus far been the primary phenotypic surrogate end point in chemoprevention trials. Additionally, we give high priority to biomarkers measuring specific and general genotypic changes correlating to the carcinogenesis progression model for the targeted cancer (e.g., progressive genomic instability as measured by loss of heterozygosity or amplification at a specific microsatellite loci). Other potential surrogate end points that may occur earlier in carcinogenesis are being analyzed in these precancers and in nearby normal appearing tissues. These biomarkers include proliferation and differentiation indices, specific gene and general chromosome damage, cell growth regulatory molecules, and biochemical activities (e.g., enzyme inhibition). Serum biomarkers also may be monitored (e.g., prostate-specific antigen) because of their accessibility. Potentially chemopreventive drug effects of the test agent also may be measured (e.g., tissue and serum estrogen levels in studies of steroid aromatase inhibitors). These initial studies are expected to expand the list of validated surrogate end points for future use. Continued discussion and research among the National Cancer Institute, the Food and Drug Administration, industry, and academia are needed to ensure that surrogate end point-based chemoprevention indications are feasible.

Antineoplastic Agents↗
PubMed2000

Mechanisms of N-methyl-D-aspartate-induced apoptosis in phencyclidine-treated cultured forebrain neurons.

Chronic administration of phencyclidine (PCP) to rats has been demonstrated to produce a sensitized locomotor response to PCP challenge that is associated with apoptotic cell death and an up-regulation of the N-methyl-D-aspartate (NMDA) receptor. To determine the underlying mechanisms, dissociated forebrain cultures were treated for 2 days with 3 microM PCP. After washout of PCP, NMDA was added (in the presence of Mg(2+)) for 20 h. The uptake of a vital dye and the release of lactate dehydrogenase measured cell viability. Apoptosis was assessed by an enzyme-linked immunosorbent assay that was specific for fragmented (histone-associated) DNA and an in situ assay for nicked DNA, terminal dUTP nick-end labeling. These assays showed that the effect of a nontoxic concentration of NMDA (30 microM) became lethal to approximately one-third of the neurons after chronic (48-h) PCP treatment. This treatment also resulted in a 47% increase in NR1 subunit mRNA, suggesting that NMDA-induced neuronal cell death after chronic PCP is due to NMDA receptor up-regulation. Furthermore, exposure of PCP-treated cultures to NMDA led to increased expression of Bax and decreased expression of Bcl-X(L). The Bcl-X(L)/Bax ratio was markedly decreased by 30 microM NMDA in the PCP-treated, but not control, cultures. Addition of superoxide dismutase and catalase prevented the decrease in Bcl-X(L)/Bax. This study suggests that NMDA-induced changes in Bax and/or Bcl-X(L) involve the formation of reactive oxygen species. By extrapolation, these data suggest that PCP-induced apoptosis in vivo may involve similar mechanisms and that cultured neurons may be a suitable model for the mechanistic study PCP toxicity in vivo.

Animals↗