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Biomedical subjects

R A Lewis

Publications and source records attributed to R A Lewis.

At least 325 records · Page 18Linked to original sources
PubMed1983

Involvement of biogenic amines with the mechanisms of novel analgesics.

The analgesic activity of the kappa opioid agonist, U-50,488H, was markedly antagonized by pretreatment with reserpine, p-chlorophenylalanine, and ketanserin. Likewise, analgesic doses of U-50,488H enhance serotonin metabolism. These results suggest that kappa analgesia requires serotonin acting through 5-HT2 receptors. The non-opioid analgesic, nefopam HCl, though a blocker of biogenic amine uptake, displays an analgesic spectrum of action more similar to that of amphetamine than that of the tricyclic antidepressants or serotonin uptake blockers. Likewise p-chlorophenylalanine and ketanserin do not block nefopam analgesia nor do naloxone, atropine, yohimbine, propranolol or haloperidol. However, as reserpine does block nefopam analgesia, biogenic amines acting at other receptors may be involved. The observation that m-tyrosine causes behavioral effects similar to high doses of nefopam suggested that they might be acting through similar mechanisms. However, although m-tyrosine causes analgesia, it is blocked by yohimbine. This suggests that alpha2-adrenoreceptors are involved in m-tyrosine analgesia and that it differs in mechanism from nefopam analgesia.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1983

Optic disk and visual field correlations in primary open-angle and low-tension glaucoma.

If the amount of visual field loss is less than expected from the amount of optic disk cupping in low-tension glaucoma compared with primary open-angle glaucoma, it might imply a difference between the two conditions in the type of optic nerve lesion produced. To test this hypothesis, three observers independently examined, in a masked fashion, optic disk stereoscopic photographs of 127 eyes with primary open-angle glaucoma and 71 eyes with low-tension glaucoma. For each stereoscopic photograph the observer predicted whether the visual field loss would be mild, moderate, or severe. The visual field were then classified, according to the number of sectors defective on the Goldmann perimeter chart, as having mild (1 to 15 sectors), moderate (16 to 30 sectors), or severe (more than 30 sectors) visual field loss. For no observer did the frequency of underpredictions or overpredictions in the two conditions differ significantly. The results of this study, thus, did not support the theory that the optic disk damage in primary open-angle glaucoma differs from that in low-tension glaucoma.

Adult↗
PubMed1983

Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophils: predominant production of leukotriene C4.

5-Lipoxygenase pathway-derived products of arachidonic acid released by human eosinophils activated in vitro have been measured by using radioimmunoassays specific for leukotriene B4 (LTB4) and for sulfidopeptide leukotrienes including leukotriene C4 (LTC4). Eosinophil-enriched leukocytes (mean, 85% eosinophils) from five hypereosinophilic donors activated with 5.0 microM ionophore A23187 for 15 min at 37 degrees C in the presence of 50 mM L-serine released 69 +/- 28 and 1.5 +/- 0.8 (mean +/- SEM) ng of LTC4 and LTB4, respectively, per 10(6) cells; ratios of LTC4 to LTB4 ranged from 16 to 149. Eosinophils stimulated with ionophore (2.5 microM) or phorbol myristate acetate (1 microgram per ml) metabolized exogenously added LTC4 to products that coeluted on reverse-phase high-performance liquid chromatography with synthetic S-diastereoisomeric LTC4 sulfoxides and 6-trans-LTB4 diastereoisomers, and this metabolic inactivation was inhibited by L-serine or catalase. Ionophore-activated eosinophils purified from three normal donors also preferentially generated LTC4 (38 +/- 3 ng per 10(6) cells) relative to LTB4 (6.0 +/- 3.1 ng per 10(6) cells), whereas neutrophils from the same donors released LTB4 (48 +/- 21 ng per 10(6) cells) in a greater than 7-fold excess to LTC4. The predominant production by human eosinophils of LTC4 with its potent smooth muscle spasmogenic and vasoactive properties may contribute to the pathobiology of allergic and other diseases associated with eosinophilia.

Arachidonate Lipoxygenases↗
PubMed1983

Local effects of synthetic leukotrienes (LTC4, LTD4, LTE4, and LTB4) in human skin.

The local effects of intracutaneous injections into humans of 1-3 nmol of five products of arachidonic acid metabolism, leukotrienes (LT) C4, D4, E4, and B4 from the 5-lipoxygenase pathways and prostaglandin (PG) D2 from the cyclooxygenase pathway, were assessed clinically and histologically. In equimolar concentrations, LTC4, LTD4, and LTE4, elicited erythema and wheal formation, in which a wheal with central pallor was present up to 2 hr, and the erythema persisted as long as 6 hr. PGD2 elicited a wheal that lasted up to 1 hr and erythema that lasted up to 2 hr. The dermal vascular sites affected by LTD4 and PGD2 included capillaries, superficial and deep venules, and arterioles. LTB4 elicited a transient wheal and flare, followed in 3-4 hr by induration that was characterized by a dermal infiltrate comprised predominantly of neutrophils. The combination of LTB4 and PGD2 elicited tenderness and increased induration associated with a more intense neutrophil infiltration. Thus, the products of the 5-lipoxygenase pathway of arachidonic acid metabolism in nanomole amounts can induce cutaneous vasodilation with edema formation and a neutrophil infiltrate, and these responses are enhanced by a cyclooxygenase pathway product, PGD2.

Biopsy↗
PubMed1983

Dosage and delivery of nebulised beta agonists in hospital.

A questionnaire was sent to physicians with an interest in chest disease to determine the dose and method of delivery of nebulised beta agonists in hospital. All of the 67 physicians replying gave beta agonists by nebuliser, and all reported either salbutamol (72%) or terbutaline (10%) as the drug they prescribed most commonly (18% gave either drug). There was a fivefold difference in the dose of salbutamol they prescribed most commonly (range 2.5-12.5 mg, mode 5 mg), a 20 fold difference in the volume of diluent solution used (range 0.5-10 ml, mode 2 ml), and a 10 fold variation in the flow rates of gas driving the nebuliser (range 1-10 1/min, mode 4 1/min). There are therefore very large variations in the dose and method of delivery of beta agonists nebulised in hospital. Studies attempting to determine the optimum dose of beta agonist for use in a nebuliser need to take the type of nebuliser, diluent volume, and gas flow rate into account.

Adrenergic beta-Agonists↗
PubMed1983

Comparison of three techniques of inhalation on the airway response to terbutaline.

The relative efficiency of the metered dose inhaler (MDI), the MDI attached to a pear shaped extension tube (PET), and the Inspiron Mini-Neb nebuliser were assessed in eight normal and eight asthmatic subjects. Subjects inhaled the same increasing doses of terbutaline with each technique on different occasions and the response was measured as specific airway conductance (sGaw) and, in the asthmatic patients only, as FEV1. The PET produced greater bronchodilatation than either the MDI or the nebuliser in both normal and asthmatic subjects. Serum terbutaline concentrations were similar after the PET and MDI in the normal subjects, but were lower with the PET in the asthmatic patients. The nebuliser produced about the same amount of bronchodilatation as the MDI--slightly less in the normal subjects and slightly more when assessed as FEV1 in the asthmatic subjects. Serum terbutaline concentrations were lower after the nebuliser than after the MDI in both groups of subjects. For patients with moderately severe airways obstruction requiring large doses of beta agonist, the nebuliser will produce an amount of bronchodilatation similar to the MDI with lower blood levels. Overall, the PET produced greater bronchodilatation than either of the other two methods of inhalation, with low serum terbutaline concentrations similar to those produced by the nebuliser in the asthmatic patients.

Adult↗
PubMed1983

Systemic hemodynamic effects of leukotrienes C4 and D4 in the rat.

Although local administration of the sulfidopeptide leukotrienes into cutaneous and coronary vascular beds indicates that these naturally occurring metabolites of arachidonic acid are vasoconstrictors, their systemic administration has produced both pressor and depressor responses. The systemic hemodynamic effects of intravenous leukotriene C4 (LTC4) and leukotriene D4 (LTD4) were assessed in ether-anesthetized rats and compared with the effects produced by equimolar doses (2 X 10(-10) to 4 X 10(-8) mol/kg) of norepinephrine and angiotensin. Mean arterial pressure, right atrial pressure, and cardiac output (electromagnetic flowmetry) were recorded during bolus administrations of these vasoactive compounds. LTC4 and LTD4 had similar hemodynamic effects that were characterized by moderate pressure elevations produced by dose-dependent increases in total peripheral resistance, since cardiac output declined. Although the peak mean arterial pressure levels produced by LTC4 and LTD4 (135 +/- 7 and 129 +/- 5 mmHg, respectively) were less than those by norepinephrine (157 +/- 3 mmHg) and angiotensin (174 +/- 5 mmHg), the peak total peripheral resistance values of LTC4 and LTD4 (2.23 +/- 0.32 and 1.86 +/- 0.17 mmHg X ml-1 X min-1, respectively) were between those of the well-known vasopressors, norepinephrine (1.50 +/- 0.09) and angiotensin (2.72 +/- 0.41). The pressor response to LTC4 and LTD4 was less marked than that to norepinephrine and to angiotensin because of the concomitant reduction in cardiac output. These results indicate that LTC4 and LTD4 are systemic vasoconstrictors with potencies similar to those of norepinephrine and angiotensin.

Angiotensins↗
PubMed1983

Bioconversion of C-6 sulfidopeptide leukotrienes by the responding guinea pig ileum determines the time course of its contraction.

The naturally occurring sulfidopeptide leukotrienes, leukotriene (LT) C(4) (LTC(4)) [5(S)-hydroxy - 6(R) - S - glutathionyl - 7,9 - trans, 11,14 - cis - eicosatetraenoic acid] and its cysteinylglycine (LTD(4)) and cysteinyl (LTE(4)) analogs, which are derived by peptide cleavage, differ in the concentrations required to elicit comparable contractions of the guinea pig ileum, with respective potencies of 1.2:5:1. The effect of the ongoing bioconversion of LTC(4) and LTD(4) on the contractile response of the guinea pig ileum to each was determined by recording the pattern of the contraction and quantitating the initial agonist and its metabolic products. The contraction was elicited by radiolabeled agonist, and its conversion products were sampled at defined intervals and resolved by their retention times on reverse-phase high performance liquid chromatography. After a latent period of 60 s. LTC(4) initiated a linear response, followed by a slower, progressive response to a maximum level that was maintained without relaxation. The metabolic conversion of LTC(4) was <5% during the linear phase of contraction and complete inhibition of bioconversion of LTC(4) to LTD(4) by the presence of serine-borate complex did not alter the pattern of the spasmogenic response. As the maximum response in the presence of serine-borate complex was three-quarters of that obtained without the inhibitor of bioconversion, the predominant response was to LTC(4) itself. The spasmogenic response of the ileum to LTD(4) was immediate, linear to a maximum level, and immediately followed by a marked relaxation. That the failure of LTD(4) to sustain a contraction was due to its immediate, rapid, and quantitative conversion to the less potent LTE(4) was established by pharmacologically inhibiting and anatomically deleting the converting activity. In the presence of L-cysteine the conversion of LTD(4) to LTE(4) was largely inhibited and the maximum contractile response was well maintained. After anatomic removal of the mucosa that contained the LTD(4) dipeptidase activity, the longitudinal smooth muscle preparation gave a maximal response to LTD(4) that was fully maintained. Thus, bioconversion is not a prerequisite for the spasmogenic activity of LTC(4) and accounts for the transient response of the ileum to LTD(4).

Animals↗
PubMed1983

Specific receptors for leukotriene C4 on a smooth muscle cell line.

Specific receptors for leukotriene C4 (LTC4) have been identified on an intact smooth muscle cell line, DDT1 MF-2 cells derived from the Syrian hamster vas deferens. Specific [3H]LTC4 binding at a fixed input at 4 degrees C was rapid, reached a plateau at 86% of total binding at 60 min, and was reversible upon addition of excess homoligand. With incremental inputs of radioligand and a constant cell number, specific [3H]LTC4 binding reached a plateau indicative of saturable binding sites. LIGAND analysis of the Scatchard plot demonstrated a single high affinity binding site with a dissociation constant (Kd) of 5 nM. With incremental inputs of unlabeled LTC4, LIGAND analysis of the Scatchard plot demonstrated a single high affinity site with a Kd of 4.4 nM and in some experiments an additional low affinity site with a Kd of 634 nM. The myotonically active structural analogues of LTC4, 5(R),6(S)-LTC4, 11-trans-LTC4, and C1-monoamide-LTC4, competed effectively with radiolabeled LTC4 such that the relative Kd values of these heteroligands were within one log of that of the homoligand. In contrast, the other native sulfidopeptide leukotrienes, leukotriene D4 and leukotriene E4, exhibited relative Kd values that were 2-3 logs less than that of LTC4. Thus, the high affinity receptor on the DDT1 smooth muscle cell line is specific for a single constituent, LTC4, of slow reacting substance of anaphylaxis.

Animals↗
PubMed1983

Lymphocytic meningoradiculitis in the United States.

Lymphocytic meningoradiculitis (Bannwarth's syndrome) is a radicular neuralgia associated with a chronic lymphocytic pleocytosis in cerebrospinal fluid and frequently with unilateral or bilateral peripheral facial weakness. Most reported cases have occurred during the summer among adults living in central Europe. Lymphocytic meningoradiculitis has occurred in the United States in a few patients with Lyme disease and erythema chronicum migrans. However, it may occur independently. We describe a woman with no erythema chronicum migrans, in whom lymphocytic meningoradiculitis preceded a migratory oligoarthropathy by 5 months.

Cerebrospinal Fluid↗
PubMed1983

Ultrastructure and electrodiagnosis of peripheral neuropathy in Cockayne's syndrome.

Cockayne's syndrome is a multisystem disease that begins in infancy and is inherited as an autosomal recessive. We studied a 4-year-old girl with nystagmus, ataxia, motor weakness, peripheral neuropathy, deficient growth, and developmental delay. Nerve biopsy revealed segmental demyelination and granular lysosomal inclusions on ultrastructural examination.

Child, Preschool↗
PubMed1983

Conversion of leukotriene D4 to leukotriene E4 by a dipeptidase released from the specific granule of human polymorphonuclear leucocytes.

Leukotriene D4 (LTD4), the most active spasmogenic leukotriene constituent of the slow reacting substance of anaphylaxis was converted by suspended human polymorphonuclear leucocytes (PMNs) to a single, less polar metabolite which was not further catabolized. This product was identified as leukotriene E4 (LTE4) by its retention time during reverse phase-high performance liquid chromatography (RP-HPLC) and subsequent bioassay on the guinea-pig ileum. LTD4 with a retention time of 21 +/- 1.6 min (mean +/- SD) and a contractile activity of 5.0 +/- 0.4 u./pmol (mean +/- SD) was quantitatively converted extracellularly by PMNs to LTE4 with a retention time of 26 +/- 1.8 min and a contractile activity of 1.2 +/- 0.3 u./pmol. Subcellular fractionations of PMNs revealed the recovered LTD4-to-LTE4 converting activity, termed LTD4 dipeptidase, to be localized only in he granule fraction. There was a time- and calcium-dependent extracellular release of LTD4 dipeptidase in association with lysozyme (r = 0.97, n = 16, P less than 0.001), a constituent of both specific and azurophilic granules, in the absence of release of cytoplasmic lactate dehydrogenase (LDH) and of beta-glucuronidase from the azurophilic granule. Phorbol myristate acetate (PMA), which selectively induces secretion of specific granules, released lysozyme and the LTD4 dipeptidase in a constant dose-dependent manner from PMNs (r = 0.96, n = 8, P less than 0.001). Calcium ionophore A23187 at concentrations less than 10(-7) M stimulated the parallel secretion of LTD4 dipeptidase and lysozyme (r = 0.91, n = 9, P less than 0.005), dipeptidase and lysozyme (r = 0.91, n = 9, P less than 0.005), whereas higher concentrations resulted in secretion of beta-glucuronidase and additional lysozyme without further release of dipeptidase. Thus, human PMNs can convert LTD4 to LTE4, a less vasoactive and spasmogenic leukotriene, via the secretion of a dipeptidase associated with the specific granules.

Cells, Cultured↗
PubMed1983

Immunologic and ionophore-induced generation of leukotriene B4 from mouse bone marrow-derived mast cells.

Mouse bone marrow-derived mast cells differentiated in vitro and sensitized with monoclonal IgE respond to antigen-initiated activation-secretion with the generation of leukotriene B4 (LTB4), a highly potent chemotactic factor. The antigen-initiated net percent release of the secretory granule marker beta-hexosaminidase and the generation of immunoreactive LTB4 and of immunoreactive leukotriene C4 (LTC4) were not diminished by washing the cells before challenge, indicating that interaction of the antigen occurred with the IgE fixed on cell membranes and was not due to phagocytosis of immune complexes formed in the fluid phase. The parallel dose-response relationship for the antigen-induced release of the performed mediator and the generation of both leukotrienes along with the superimposable time courses of their extracellular appearance indicate the origin of these mediators from a common cell type with IgE receptors. Resolution by reverse phase-high performance liquid chromatography (RP-HPLC) of the leukotrienes released from unsensitized cells by ionophore A23187 and from sensitized cells by the specific antigen revealed that the generation of LTB4 was accompanied by the production of the two diastereoisomers of 6-trans-LTB4, which were not immunoreactive. The immunoreactive LTB4 eluted from RP-HPLC at the same retention time as synthetic LTB4 was present in similar nanogram quantities when measured by either radioimmunoassay or integrated absorbance at 269 nm and exhibited a chemotactic activity for human neutrophils on a weight basis comparable to that of synthetic LTB4. The overall recoveries after RP-HPLC of immunoreactive LTB4 released from ionophore A23187-activated, bone marrow-derived mast cells and of added tritiated synthetic LTB4 in separate experiments with ionophore-activated cells were comparable and greater than 78%. The maximum generation of LTB4 by ionophore A23187-activated cells of 7.9 +/- 2.5 ng/10(6) cells (mean +/- SD), occurring at 40 min, was greater than the maximum generation of 4.5 +/- 0.8 ng/10(6) cells, with immunologic stimulation occurring 5 min after antigen challenge of sensitized cells. The initial rate of LTB4 generation after perturbation of the IgE-Fc receptors, however, exceeded that following ionophore A23187 stimulation and may represent one important variable in establishing a significant chemotactic gradient.

Animals↗
PubMed1983

Antigen-initiated release of platelet-activating factor (PAF-acether) from mouse bone marrow-derived mast cells sensitized with monoclonal IgE.

Mouse bone marrow mast cells sensitized with monoclonal IgE and activated with specific antigen released 2.8 +/- 0.5 ng of platelet-activating factor (1-0-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine) (PAF-acether)/ 10(6) cells. The PAF-acether was identified by its ability to aggregate fully aspirin-treated washed rabbit platelets in the presence of an adenosine diphosphate (ADP)-scavenger complex, by its co-chromatography with [3H]-labeled semi-synthetic PAF-acether and synthetic 1-0-octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine, and by its inactivation by phospholipases A2, C, and D and not by lipase A1. The antigen-initiated release of PAF-acether, leukotriene C4 (LTC4), and leukotriene B4 (LTB4), and the secretion of the granule marker beta-hexosaminidase were not diminished by washing the cells before challenge, indicating that they were due to the interaction of antigen with the IgE fixed on the cell membrane and not to phagocytosis of immune complexes formed in the fluid phase. The parallel antigen-induced dose-response relationship, along with the superimposable time-course of the extracellular appearance, of beta-hexosaminidase, PAF-acether, and both leukotrienes indicated that the origin of these diverse mediators was from a common cell type with IgE-Fc receptors. Ethanol extraction of antigen-stimulated bone marrow-derived mast cells revealed the early transient appearance of a cell-associated platelet-aggregating activity, the action of which on platelets, like PAF-acether, was independent of ADP and arachidonic acid metabolism. The cell-associated activity contained a novel product that eluted at 13 min during high performance liquid chromatography (HPLC) (solvent hexane:n-propanol:water, 46:46:8), permitting resolution from PAF-acether and lyso-PAF-acether (1-O-alkyl-sn-glyceryl-3-phosphorylcholine), which eluted at 29 min and 30 min, respectively. The cell-associated material, which differs from lyso-PAF-acether, the putative precursor of PAF-acether, in being active in the bioassay on platelets may represent a newly recognized intermediate in the generation of PAF-acether. As the transiently present cell-associated intermediate has not been previously recognized, its detection may depend upon the relatively unique properties of the bone marrow-derived mast cell system in which IgE-dependent activation leading to product generation is complete within 5 min.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

Asthma and suggestion: psychological or physical?

The effect of suggestion on the airway response to ten inhalations of normal saline followed by doubling concentrations of isoprenaline was assessed in 12 normal and 30 asthmatic subjects. It was suggested that the first 5 saline solutions contained a bronchoconstrictor and the second 5 a bronchodilator, or vice-versa, and that the first four isoprenaline solutions were inert whilst the last was a bronchodilator. Nine asthmatic but no normal subjects bronchoconstricted after saline inhalation with a mean 40% fall in specific airway conductance (sGaw). This was dose-dependent and abolished when inhalations were carried out at 37 degrees C 100% relative humidity. Suggestion did not affect the airway response to saline or isoprenaline in either group. We conclude that bronchoconstriction following saline inhalation, previously attributed to the effect of suggestion, is caused by airway cooling.

Asthma↗
PubMed1982

Bronchoconstrictor effects of leukotriene C in humans.

Maximum expiratory flow rate at 30 percent of vital capacity above residual volume served as an index of airway obstruction in comparing the effects of leukotriene C and histamine administered by aerosol to five normal persons. Leukotriene C was 600 to 9500 times more potent than histamine on a molar basis in producing an equivalent decrement in the residual volume. The leukotriene C response was slow in onset and prolonged, reminiscent of the effects of aerosol allergen challenge in asthmatic allergic subjects.

Adult↗