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Biomedical subjects

C R Clark

Publications and source records attributed to C R Clark.

At least 127 records · Page 7Linked to original sources
PubMed1988

Highly selective kappa opioid analgesics. Synthesis and structure-activity relationships of novel N-[(2-aminocyclohexyl)aryl]acetamide and N-[(2-aminocyclohexyl)aryloxy]acetamide derivatives.

This paper describes the synthesis, structure-activity relationships (SAR) of mu and kappa opioid binding affinities, and analgesic properties of a series of novel highly selective kappa opioid N-[(2-aminocyclohexyl)aryl]acetamide and N-[(2-aminocyclohexyl)aryloxy] acetamide derivatives. Ten compounds, 14, 15, 31-37, and 39 (Tables I and II), show a marked kappa selectivity of greater than 100:1 over mu binding, with high affinity for the kappa opioid receptor (approximately 10(-8) - 10(-9) M). Compound 39, (S,S-trans)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-4-benzo[b] furanacetamide hydrobromide, has the highest mu/kappa selectivity, 780:1 (kappa Ki = 4.2 nM), reported to date. Four of these compounds, 14, 15, and their S,S-trans enantiomers, 37 and 39, respectively, produce effective analgesia by oral administration, as assayed by a rat-paw pressure test (RPP) (MPE50 = 24, 26, 8.3, and 12 mg/kg, respectively). The R,R-trans isomer, 38, was inactive in binding and RPP. The analgesic effect was reversed by administration of naloxone, confirming these effects are opioid in character. Optimal activity is produced when the basic nitrogen atom is in a pyrrolidine ring, the aryl group is a 10-pi-electron-rich aromatic system, such as 4-benzo[b]thiophene, 4-benzo[b]furan, or 4-chlorophenoxy, and overall lipophilicity lies within the range log P = 3.5-5.0.

Acetamides↗
PubMed1988

Liquid chromatographic determination of serum levels of d,l-4-amino-N-(alpha-methylbenzyl)-benzamide, a new benzamide anticonvulsant.

A method for the high-performance liquid chromatographic (HPLC) determination of serum concentrations of d,l-4-amino-N-(alpha-methylbenzyl)-benzamide and its N-acetylated metabolite is described. The compounds are isolated from a 50-microL sample of serum using solid phase extraction. The compounds and internal standard are eluted from the extraction column with acetonitrile. Quantitation is performed via UV detection at 275 nm following isocratic reversed-phase (C18) separation using a ternary solvent system. The assay procedure is useful for the determination of concentrations of parent compound from 0.63 to 87.9 micrograms/mL from 50 microL of serum.

Acetylation↗
PubMed1988

Liquid chromatographic and mass spectral analysis of N-substituted analogues of 3,4-methylenedioxyamphetamine.

The C1 to C3 N-alkyl, N,N-dimethyl, and N-hydroxy analogues of 3,4-methylenedioxyamphetamine (MDA) are identified by high performance liquid chromatographic (HPLC) and spectrometric techniques. The compounds are separated using reversed-phase procedures on C18 stationary phase with an acidic (pH 3) aqueous methanol mobile phase. The mass spectra of the compounds are distinctive and reference spectra are provided. The N-hydroxy derivative is unstable at high temperatures and decomposes to MDA and the oxime of 3,4-methylenedioxyphenyl-2-propanone.

3,4-Methylenedioxyamphetamine↗
PubMed1988

Comparison of psychologic and cognitive functions after general or regional anesthesia.

The behavior of 105 patients randomly assigned to receive either general or regional anesthesia and who underwent one of three types of surgery (hysterectomy, prostatectomy, or joint replacement) was assessed before, immediately after, and 3 mo after surgery. Psychologic status was assessed by the Sickness Impact Profile, the SCL-90-R, and a Metamemory Questionnaire. Cognitive functioning was measured by a battery of ten psychomotor, memory, and skilled performance tasks. Physical health was scored by the ASA classification of physical status, a health index, postoperative complications ratings, and a self-rated measure of the patient's health. There were cognitive differences across surgery groups due to age and gender variability among the patients; however, the type of anesthesia produced no difference in behavior. Both the physical and mental health indices showed improvement from the preoperative to the postoperative periods. General anesthesia appears to pose no risk to mental function and recovery beyond that associated with regional anesthesia and surgery.

Adult↗
PubMed1988

Radiographic evaluation of cervical spine injuries.

This study involves an evaluation of specific radiologic patterns of various cervical spine injuries on plain radiographs in order to determine a rational approach for further radiologic investigation and resultant treatment. We retrospectively reviewed 236 patients with 319 cervical spine injuries. Fractures included 50 of the dens, 21 hangman, 4 Jefferson, 29 burst, 24 compression, 32 corner/teardrop, 65 facet, 24 lamina, and nine pedicle. Dislocations included one occipitoatlantal, two atlantoaxial rotatory, and 28 facet. Pleuridirectional tomography performed in 137 cases and computerized tomography was performed in 26. The cases were divided into three groups according to the significance of their radiographic findings: Group I: no additional information was added by the additional radiographic studies compared to the plain radiographs. Group II: the additional radiographic studies changed the extent or type of injuries seen on the plain radiographs. Group III: plain radiographs were negative. The abnormalities were only found on the additional radiographic studies. Results of 137 patients undergoing tomography: 62 were in group I, 64 were in group II, and 11 were in group III. Of the 26 patients undergoing computerized tomography, 13 were in group I, 13 were in group II, and no patients were in group III. Specific fracture types were reviewed according to the distribution of the three groups. We concluded that pleuridirectional tomography appears to be particularly advantageous in patients with injuries involving the facets. Computerized tomography appears to add the most additional information in patients with laminar and posterior element fractures and C1 fractures. We feel that timely and accurate diagnosis of cervical spine injuries is essential.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Developing a sensation information message for femoral arteriography.

Sensation information is proposed as a way of decreasing the patient's distress during a threatening health care event. A first step in developing a sensation information message is to determine the content of the message. This study, using a systematic theory-based methodology, was conducted to describe and validate the common physical sensations experienced by patients undergoing the diagnostic procedure of femoral arteriography. (A conceptual framework based on how an individual perceives or senses a situation was used.) A three-stage survey design was used including: (1) tool development following observation of the procedure and pilot-testing of the interview schedule, (2) interview of patients who had undergone femoral arteriography about the sensations experienced during the procedure, and (3) validation of the responses. Twenty-one steps in the femoral arteriography procedure of which patients were aware were identified. Nine 'feeling' sensations commonly experienced during the procedure and the sights and sounds associated with the procedure were determined. The sequencing and duration of procedure steps were observed and the environment in which the procedure was performed was described.

Adult↗
PubMed1988

PD117302: a selective agonist for the kappa-opioid receptor.

1. A new nonpeptide kappa-opioid compound, a cyclohexyl benzeneacetamide derivative (PD117302), has been synthesized and its affinity for the different types of opioid receptor determined. The ability of PD117302 to modify the activity of the electrically-stimulated guinea-pig ileum and rabbit vas deferens has also been evaluated. 2. In binding studies using guinea-pig brain homogenates, unlabelled PD117302 had a high affinity (Ki = 3.7 nM) at [3H]-etorphine labelled kappa sites and a low affinity at [3H]-[D-Ala2, MePhe4, glyol5]-enkephalin ([3H]-DAGOL) labelled mu sites (Ki = 408 nM) and [3H]-SKF 10047 labelled sigma sites (Ki = 1.8 microM). In bioassay studies, PD117302 was a potent agonist, producing a maximum inhibition of the electrically-evoked contractions of the guinea-pig ileum (IC50 = 1.1 nM) and rabbit vas deferens (IC50 = 45 nM) which was naloxone-reversible. 3. In guinea-pig brain, [3H]-PD117302 bound to a high-affinity opioid binding site with a KD of 2.7 nM and a Bmax of 3.4 pmol g-1 wet weight. The Bmax was found to be less than 50% of the Bmax values for [3H]-etorphine and [3H]-bremazocine suggesting that [3H]-PD117302 may be a specific ligand for a subtype of kappa receptor. [3H]-PD117302 also bound with micromolar affinity to a non-opioid binding site. 4. Kinetic studies found that [3H]-PD117302-specific binding to the high affinity site was saturable, reaching equilibrium within 20 min at 4 degrees C, and reversible, with a half-life of dissociation of 3.9 min. 5. Several unlabelled compounds with high affinities for the ['H]-etorphine labelled K binding site, had comparable affinities when competing for the ['H]-PDl 17302-specific high affinity binding site. In contrast, DAGOL, [D-Ala', D-Leu'] enkephalin (DADLE) and [D-Pen2, D-Pen'] enkephalin (DPDPE) had no significant effect on ['H]-PD 1 17302 binding, suggesting minimal interaction with mu and delta binding sites. 6. In autoradiography studies ['H]-PD1 17302 binding sites were found throughout the brain with the greatest density in the striatum, cerebral cortex (layers V-VI), substantia nigra, and the molecular layer of the cerebellum. Lowest levels were found in the granular layer of the cerebellum, thalamus and cerebral cortex (layers I - IV).

Animals↗
PubMed1988

Macrophage progenitor cell and colony-stimulating factor production during granulomatous schistosomiasis mansoni in mice.

Schistosoma mansoni worm eggs stimulate a T-cell-mediated granulomatous response in which macrophages play important inflammatory and regulatory roles. Although much has been learned about the functions of the schistosome granuloma macrophages, their origin and replicative ability are unknown. In the present sequential study, macrophage progenitor cells in the bone marrow (GM-CFC) and liver granulomas (M-CFC) were enumerated, and macrophage colony-stimulating factor (CSF-1) in the circulation and culture fluid of explanted granulomas of infected mice was assayed. During the acute phase of the infection, when the granulomatous response was vigorous (weeks 8 to 12) GM-CFC numbers were high in the bone marrow and M-CFC numbers were low within granulomas. Circulating CSF-1 levels were elevated, but the vigorous granuloma-secreted CSF-1 level was low. During the chronic phase of the infection, the number of GM-CFC within the bone marrow and levels of circulating CSF-1 returned to normal. Conversely, a sharp increase in the number of M-CFC occurred within the small immunomodulated granulomas that also secreted high levels of CSF-1. The frequency of M-CFC that proliferated under exogenously added CSF-1 within the immunomodulated granulomas was significantly higher than that of cells in the vigorous granulomas. Adherent macrophage-rich cells obtained after dispersal of the granulomas appeared to be one source of CSF-1 production. These data indicate that during the infection the macrophage supply to and replicative ability within the granulomas is influenced by systemically and/or locally produced CSF-1.

Animals↗
PubMed1988

Comparative dermal carcinogenesis of shale and petroleum-derived distillates.

Ten test materials derived from petroleum or hydrotreated shale oils were applied 3 times/week for up to 105 weeks to the shaved skin of 25 male and 25 female C3H/HeN mice per group. Mineral oil and benzo(a) pyrene (0.15%) were control materials. Clinical observations were recorded during the study. At death, histopathologic examination was conducted on skin, internal organs and any gross lesions. Exposures to some materials were ended midway in the study due to severe irritation. Chronic toxicity of all materials was limited to inflammatory and degenerative skin changes. Significant increases over control incidence of skin tumors (squamous cell carcinoma and fibrosarcoma) occurred with both petroleum and shale-derived naphtha (21%, 50%), Jet A (26%, 28%), JP-4 (26%, 50%), and crude oils (84%, 54%). Severely hydrotreated shale oil and petroleum and shale-derived diesel distillates were not considered tumorigenic. Results indicate that toxicity of comparable petroleum and shale-derived fractions was qualitatively similar and confirm earlier findings that hydrotreating reduces or eliminates carcinogenicity of raw shale oil.

Animals↗
PubMed1988

Granulocyte/macrophage colony-stimulating factor stimulates monocyte and tissue macrophage proliferation and enhances their responsiveness to macrophage colony-stimulating factor.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a specific humoral growth factor that stimulates both neutrophilic granulocyte and macrophage production by bone marrow hematopoietic progenitor cells. GM-CSF also stimulates the proliferation and clonal growth of both tissue macrophages and blood monocytes. Although at low concentrations GM-CSF was unable to support the long-term growth of tissue macrophages, it greatly enhanced their responsiveness to macrophage CSF (M-CSF, or CSF-1). This effect was also observed by treating macrophages with GM-CSF for a short time. GM-CSF did not compete with M-CSF for binding to M-CSF receptors nor was it inactivated by treatment with anti-M-CSF antiserum. Treatment of tissue macrophages with GM-CSF led to a rapid but transient downregulation of M-CSF receptors; prolonged incubation at 37 degrees C, however, resulted in a restoration and upregulation of M-CSF receptors. Identical effects were observed with both native or recombinant GM-CSF. This study suggests that GM-CSF regulates tissue macrophage production by two modes of action: (a) direct stimulation of macrophage proliferation, and (b) enhancement of their responsiveness to M-CSF.

Animals↗
PubMed1987

Metabolism and binding of androgens in the spinal cord of the rat.

The binding of [3H]androgens and estrogens, and the metabolism of [3H]androgens, were studied in the spinal cord of the adult rat. High-affinity, specific binding sites for [3H]testosterone and [3H]estradiol were detected in cytosol fractions from the spinal cords of castrate animals. Equilibrium dissociation constants for reaction of these sites with their respective ligands were similar to those of androgen and estrogen receptors from other regions of the central nervous system. Nuclear binding of [3H]estradiol was observed in the spinal cord 1 h after intravenous administration of the isotope. Likewise, exchange assay demonstrated the presence of high-affinity androgen binding sites in spinal cord nuclei from orchidectomized, testosterone propionate treated animals. 5 alpha-Reductase activity in homogenates of the spinal cord was relatively high, approximately 3 times that in the pooled hypothalamus, preoptic area, septum and amygdala. However, in contrast to the latter brain regions, estrogen formation was not detectable in spinal cord tissue. No sex differences were observed in the metabolism of [3H]testosterone by spinal cord homogenates. These results confirm the presence of androgen and estrogen receptors in the rat spinal cord. The lack of detectable aromatase activity in the spinal cord is consistent with the hypothesis that the effects of circulating testosterone on spinal reflex function are mediated primarily through the androgen receptor system.

Androgens↗
PubMed1987

Anticonvulsant activity of some 4-aminophenylacetamides.

A series of 4-aminophenylacetamides was prepared and evaluated for anticonvulsant activity. These compounds were prepared during studies designed to determine the relationship between benzamide-like compounds and anticonvulsant effects. Unlike benzamides, these phenylacetamides have a methylene group between the aromatic ring and the amide carbonyl. Consequently, formal conjugation is lost, and the number of conformational degrees of freedom has increased. The compounds were tested in mice against seizures induced by electroshock and pentylenetetrazol, and in the rotorod assay for neurologic deficit. The more active and selective anticonvulsants prepared in this study were those having an additional aromatic ring as part of the substituent on the amide nitrogen. Compound 16, the 4-aminophenylacetamide derived from 2,6-dimethylaniline, was the most potent compound observed (ED50 = 50.50 mg/kg against electroshock-induced convulsions and ED50 = 93.20 mg/kg against pentylenetetrazol-induced convulsions).

Acetamides↗
PubMed1987

Purification of Black Moor goldfish melanophores and responses to epinephrine.

Two key modifications of the previously reported method for isolation of goldfish xanthophores allowed the isolation and establishment of primary cultures of terminally differentiated melanophores from the Black Moor goldfish (Carassius auratus). First, pretreatment with 10(-4) M epinephrine causing aggregation of the melanosomes and collapse of the dendrites, prevents damage to the melanophores during tissue dissociation and melanophore isolation. Second, maintenance of these cells in culture was successful only when the culture medium was supplemented with fish serum. The purified melanophores attached, flattened, and were maintained in culture for up to 3 mo. Although the morphology of the cultured melanophores is less dendritic than their in vivo counterparts, the melanophores translocate melanosomes in a normal manner except that they exhibit enhanced sensitivity to epinephrine. This epinephrine-induced pigment aggregation, as well as the redispersion of pigment after the removal of epinephrine, can occur in the presence of ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid and absence of Ca2+.

Animals↗
PubMed1987

Efficacy of morantel sustained release bolus against gastrointestinal nematodes in first season grazing Holstein calves.

The efficacy of the morantel sustained release bolus (MSRB) in reducing gastrointestinal parasitism in first season grazing calves was evaluated during the summer--autumn grazing seasons of 1982 and 1983 in western Oregon. Each of 38 calves (1982) and 40 calves (1983) were randomly assigned to either control or treatment groups which were given MSRB on the day of turnout onto pasture. Mean worm burdens from tracer calves grazed with treated animals in 1982 and 1983 showed overall reductions of 86.4% (P greater than 0.05) and 84.3% (P less than 0.01), respectively, compared to tracers grazed with controls. Ostertagia ostertagi, Cooperia oncophora and Nematodirus helvetianus were the primary nematodes collected at necropsy. Twelve full-season 1982 tracer animals (6 treated and 6 control) indicated an 88.1% (P less than 0.05) overall reduction in mean worm burdens. Mean fecal worm egg per gram (EPG) counts of treated animals reflected a reduction of 69% (P less than 0.05) in 1982 and 90% (P less than 0.05) in 1983. Autumn inhibition of O. ostertagi was observed. In the 1982 trial the control animals showed a slight mean weight gain advantage over the treated group from Day 84 until Day 160 (trial termination) when the mean difference was 7.9 kg. The final mean weight gain advantage of treated animals in 1983 was 13.5 kg (P less than 0.05). These trials demonstrated that the MSRB was an effective anthelmintic for reducing gastrointestinal parasitism in grazing calves and for decreasing pasture larval contamination.

Animals↗
PubMed1987

Liquid chromatographic determination of the pH-dependent degradation of eseroline--hydrolysis product of physostigmine.

The stability of eseroline, the hydrolysis product of physostigmine under aerobic conditions, was studied by liquid chromatography. A reversed-phase, ion-pair technique was used to separate eseroline from its degradation products. The degradation of eseroline in phosphate buffer solutions of pH 6.91, 7.40, 7.98, 8.41 and 8.94 appears to follow first-order kinetics; the rate constant increased with an increase in pH. The degradation appears to follow specific base catalysis.

Journal Article↗
PubMed1987

Catecholamines and attention. I: Animal and clinical studies.

One important function of the catecholamine innervation of the cerebral cortex may be the control of attention. Of particular interest are the catecholamine projections to the cerebral cortex from the reticular formation, namely the dopamine neurons of the ventral tegmentum of the midbrain and the noradrenergic neurons of the locus coeruleus in the upper pons. Animal studies implicate noradrenaline and dopamine in a wide range of attention-related behaviours involving search and exploratory activity, distractibility, response rate, discriminability and the switching of attention. Most human studies come from the clinical literature relating to schizophrenia, Parkinson's disease and attention deficit disorder. An association has been claimed in each of these conditions between abnormal catecholamine activity (in particular dopamine) and attentional dysfunction. In particular, difficulty with the attachment of appropriate responses to environmental stimuli, akin to those observed in animals with lesions to central dopamine pathways, indicates a role for dopamine in response selection processes. Overall, the animal and human studies reviewed indicate a role for central noradrenaline and dopamine in the early and late processing of information, respectively.

Animals↗