PubMed Health⌕ Search

Biomedical subjects

K L Melmon

Publications and source records attributed to K L Melmon.

At least 19 recordsLinked to original sources
PubMed1991

Histamine and its congener derivatives as immune modulators.

Our knowledge of the function of histamine as an immunoregulatory autacoid is expanding. The presence of histamine in many tissues in which the immune response takes place and its release during immune response lend credibility to the notion that histamine's role in the immune response could be an important one. In this report we present data that demonstrate the immune modulatory role of histamine. We also describe the synthesis and novel pharmacologic effects of congener derivatives of histamine. These new lymphocyte specific histamine H1 and/or H2 agonists make it feasible to assess the potential of histamine as a selective in vivo immune modulator.

Animals↗
PubMed1990

Abnormal T suppressor cell function in juvenile rheumatoid arthritis.

The purpose of this study was to analyze T suppressor cell function in juvenile rheumatoid arthritis (JRA). JRA is a chronic inflammatory childhood disease of unknown etiology that is characterized by arthritis and immunoregulatory abnormalities. T suppressor cell precursors (CD8+, CD28-) were purified from the peripheral blood of 24 JRA patients, using a combination of monoclonal antibodies. These cells were treated with histamine or concanavalin A, agents that are known to induce suppressor activity. They were also tested for their ability to inhibit the proliferative response of autologous T cells to phytohemagglutinin. In some experiments, the accumulation of intracellular cAMP following histamine treatment was also measured. Twelve of 13 patients with clinically active JRA showed abnormal histamine-inducible T suppressor cell function, characterized by the failure of CD8+, CD28- T cells to mediate any detectable suppression. The failure of these cells to accumulate intracellular cAMP after histamine treatment was observed in 5 of 5 patients tested who had active disease. In contrast, 11 of 11 patients with clinically inactive JRA, 5 of 5 patients with cystic fibrosis, and 9 of 9 pediatric control subjects had normal histamine- and concanavalin A-inducible T suppressor cell function, and a normal cAMP response to histamine. These results suggest that patients with clinically active JRA have a reversible defect in T suppressor cell function that is associated with a failure of T suppressor cell precursors to accumulate intracellular cAMP following their exposure to selected immune stimuli.

Adolescent↗
PubMed1990

Effects of histamine-trifluoromethyl-toluidide derivative (HTMT) on intracellular calcium in human lymphocytes.

We have studied the effects of histamine trifluoromethyl-toluidide derivatives on calcium mobilization in human peripheral blood lymphocytes using spectrofluorometric analysis. HTMT (compound 1) induced two phases of increase in intracellular calcium concentration--a rapid intracellular calcium concentration peak (10-60 sec), partial recovery (1-3 min) and a sustained moderate elevation that persisted for more than 5 min. The EC50 value was 1.9 X 10(-5) M. Pretreatment of lymphocytes with the agonist resulted in receptor desensitization that recovered after 15 min when the cells were drug free. The presence of extracellular ethylene glycol bis(beta-aminoethyl ether)N,N'-tetraacetic acid did not abrogate the early phase of the calcium rise, suggesting that the calcium appearing in the cytosol during the early phase was derived from intracellular stores. The increase in intracellular calcium concentration by this compound was competitively antagonized by high concentrations of histamine but not by classic histamine receptor antagonists (H1, H2 or H3). Other cyclic AMP elevating agents, with the exception of prostaglandin E2, did not affect the increase in calcium levels induced by compound 1. Compound 1 caused phosphatidylinositol metabolism resulting in inositol phosphate production, suggesting that inositol triphosphate may be the second messenger for the mobilization of intracellular Ca2+ by compound 1. The data imply a specific binding site for histamine trifluoromethyl toluidide derivative on lymphocytes that is different than the classic H1, H2 or H3 receptors.

Calcium↗
PubMed1989

Tissue selectivity of propranolol derivatives in vivo. A confirmation of in vitro findings.

The beta-adrenergic antagonist activities of a p-toluidide and a p-trifluoromethylanilide derivative of propranolol were tested in intact rats to determine whether the unusual in vitro profiles on myocardium and adipose tissue were found in vivo. The relative potencies of p-toluidide derivatives studied in pithed rats were 1.3 for the rate of change in left ventricular pressure with respect to time (dP/dt) and 4.6 for heart rate (HR) compared to propranolol. The values for p-trifluoromethylanilide were 2.5 (dP/dt) and 4.6 (HR). The SR-isomer of the p-toluidide derivative was 81 times more potent than propranolol in inhibiting effects on dP/dt and 27 times more effective than propranolol on HR, whereas the SS-isomer was 0.17 times (dP/dt) and 0.16 times (HR) as potent as the parent compound. In fasted rats, infusion of isoproterenol resulted in an increase of 10.6 +/- 3.1 mg/dl in plasma non-esterified fatty acid (NEFA) and an increase of 46 +/- 9 mg/dl in glucose. Unlike propranolol, neither the p-toluidide nor the p-trifluoromethylanilide derivative blocked the increase in plasma NEFA, although they both blocked the increase in plasma glucose. It appeared that the p-toluidide and p-trifluoromethylanilide derivatives of propranolol were more selective for the beta 1-adrenergic receptors on the heart as opposed to the beta 1-like adrenoceptors on adipose tissue. These findings were qualitatively and generally quantitatively in agreement with our previous findings in vitro. Therefore, the in vitro data may be useful in predicting atypical and tissue selective in vivo effects of these types of compounds.

Adipose Tissue↗
PubMed1989

Histamine regulates the generation of human cytolytic T lymphocytes.

Human cytolytic T lymphocytes (CTL) were generated in the presence and absence of histamine in order to define the role of this autacoid in immune regulation. Histamine (10(-8)-10(-4) M) suppressed the generation of class I specific CTL but, at 10(-4) M, actually increased class II specific cytolysis. Histamine acted at the level of CTL generation; histamine was not present in the cytolytic assay. When histamine was added to the cytolytic assay with CTL grown without histamine, the lytic ability of the effector cells was similar to that of controls. Histamine-induced suppression of class I specific cytolysis was blocked by continuous culture with the H2 antagonist ranitidine but not with the H1 antagonist pyrilamine. These data suggest that suppression was mediated by the H2 receptor. Continuous culture with histamine had no effect on T cell proliferation or the expression of cell surface molecules. Histamine-induced suppression of class I specific cytolysis was reversed by the addition of PHA to the cytotoxicity assay, showing that the cytolytic machinery was intact. These data provide evidence that histamine is involved in regulation of cytolytic T cells.

Antibodies, Monoclonal↗
PubMed1989

A subset of human rosetted lymphocytes contains previously unidentified histamine.

By sequential solid-phase immunoadsorption (panning) steps, we have isolated a subset of lymphocytes (comprising 3-7% of rosetted cells) that contains high concentrations of histamine. We have used a radioenzymatic assay for the determination of histamine and have located 117 ng of histamine/1 x 10(6) cells in Leu-5+ (OKT-11), Leu-15+ cells. This subset did not contain basophils and was negative for Leu-4 (OKT-3), Leu-3 (OKT-4), Leu-2 (OKT-8), and 9.3 antigens. The function of this subset of rosetted cells has not been determined.

Antigens, Differentiation↗
PubMed1989

Prothrombin time ratio and other factors associated with bleeding in patients treated with warfarin.

We previously showed that the risk of major hemorrhage in patients with venous thromboembolism treated with warfarin was strongly related to duration of anticoagulant therapy. We here report the results of a more detailed analysis of factors other than duration of warfarin therapy associated with the risk of hemorrhage in these patients. Almost 7% of patients had a major hemorrhage on warfarin and an additional 23.7% had at least one minor bleeding episode. Age, female sex, and congestive heart failure were associated with small increases in the risk of major hemorrhage but not with the risk of minor bleeding. A prothrombin time ratio greater than 2.5 was associated with a fourteen-fold increase in the risk of a major hemorrhage (95% CI 5.1, 42.7), but major hemorrhages occurred in patients on warfarin at all measured values of the prothrombin time ratio. Taken together with the findings from our previous analysis, the study suggests that prevention of bleeding in patients on warfarin would best be accomplished by minimizing the duration of warfarin therapy, by scrupulous monitoring of the prothrombin time ratio, and by considering the "therapeutic range" for the prothrombin time ratio to be somewhat less than 2.0-2.5.

Adult↗
PubMed1989

In vitro pharmacological properties of a series of isoprenaline derivatives.

The p-trifluoromethylanilide congener of isoprenaline, tert-butyl N-[(S)[( 4-[(R)-6-[2-(3,4-dihydroxyphenyl-2- hydroxyethyl]amino]heptanamido]phenyl]methyl][(N-methylcarbamoy l) methyl]carbamoyl]methyl]carbamate (1S,4R)-4,7,7-trimethyl-3-oxo-2- oxabicyclo[2.2.1]heptane-1-carboxylate (1:1) (Ro 17-2218) was investigated for its effects in various pharmacological tests in vitro and compared to the parent compound. As Ro 17-2218 represented a mixture of four diastereomers, the pure isomers were synthesized. They had a purity of 97-98%. By pharmacological testing of the diastereomers the highest potency was found in the 6R,2'R-isomer Ro 17-8648, while the potency of the 6S,2'S-isomer, Ro 17-9651 was lower by three orders of magnitude. The amorphous hydrochloride Ro 17-8648/001 had 1/10 the potency of the respective crystalline camphanate Ro 17-8648/003. (R)-6-[(R)-[2-(3,4-Dihydroxyphenyl)-2-hydroxyethyl]amino]-N-[4- (trifluoromethyl) phenyl]heptan amide (Ro 17-8648/003) was found to have potent beta-agonist properties with clear beta 1-selectivity in radioligand binding studies. It exerted an extremely tight binding to membrane receptors. As a full beta-agonist it elicited positive inotropic effects in isolated cardiac tissues, with a potency 10-360 times that of isoprenaline and an extremely long duration of action. Electrophysiological studies in isolated guinea-pig papillary muscles confirmed the beta 1-receptor-mediated effects of the compound.

Animals↗
PubMed1988

Suppressive characteristics of the cultured umbilical cord blood lymphocytes: enhanced suppression of non specific MLR by short term cultured peripheral blood and rosetted lymphocytes.

We have used the mixed leukocyte reaction assay (MLR) to compare the non-specific suppressor activity of fresh and short-term cultured peripheral blood rosetted lymphocytes from human umbilical cord blood. To a one way MLR between adult responders and irradiated adult stimulator cells, we added adult or cord blood mononuclear cells. Cord-blood derived mononuclear cells were more potent suppressors of the MLR than the adult peripheral blood mononuclear cells. When the fresh cord blood T cell fraction was separated from non-T cells by rosetting, the frequency and capacity of suppression fell, suggesting a role of non-T cells in this phenomenon. However, short-term culture (up to nine days) of cord blood derived T cells in the absence of mitogen resulted in a significant increase in their suppressive characteristics. Maternal cells were not used in any of these assays and the suppression was non specific. There was no HLA restriction to the response. The cord blood lymphocytes responded poorly to alloantigen when compared to the adult lymphocytes. In addition, there was a correlation between the allogeneic proliferative response and the suppressive capacity of the cord blood cells. Such a correlation was not found with the adult peripheral blood lymphocytes.

Adult↗
PubMed1987

Characterization of histamine type 1 receptors on natural suppressor lymphoid cells.

Using the radioligand H1 antagonist [3H]pyrilamine, we have characterized the histamine type 1 receptor on cloned murine natural suppressor cells (NS). A single, specific binding site for [3H]pyrilamine exists on these cells. The binding was saturable and reversible by various specific H1 receptor antagonists. The rank order of potency for displacement of [3H]pyrilamine binding from the H1 receptor by H1 receptor antagonists was promethazine = pyrobutamine greater than pyrilamine greater than diphenhydramine greater than chlorpheniramine. The histamine type-2 agonists, impromidine and dimaprit, and antagonists, cimetidine and ranitidine, as well as selected non-histamine agonists, did not displace [3H]pyrilamine from its binding sites on the natural suppressor cells. The data indicate that the theoretical KD was 1.1 +/- 0.3 X 10(-7) M while the measured KD of binding for [3H]pyrilamine was 6.0 +/- 0.8 X 10(-8) M; the maximum binding was 4.13 nM and the number of binding sites/cell was 2.14 +/- 0.29 X 10(6) (N = 3).

Animals↗
PubMed1987

In vitro pharmacologic activity of congener derivatives and model conjugates of propranolol and practolol.

Previous studies in our laboratory suggested that synthetized derivatives of isoproterenol and histamine could create agonists more potent and receptor and/or tissue selective than the parent compound. In the present study we have evaluated the hypothesis that our results with isoproterenol and histamine derivatives could be extended to include beta-adrenergic antagonists. With this purpose in mind, fourteen derivatives of propranolol and practolol were synthesized and tested in four in vitro systems. The congeners and conjugates were tested using biologic assays (blocking of cAMP accumulation) and/or radioligand binding assays in S-49 lymphoma cells and in rat adipocytes, heart and lung which contain beta 1 and/or beta 2 receptors. Our results indicate that structural modifications distant from the pharmacophore alter the pharmacologic profile of the parent compound. The relative potencies of the derivatives were dependent upon several key factors including the length of the methylene spacer chain and the nature of the substituents on the aromatic ring. The presence of a spacer group with four methylenes resulted in the most active compound in each series when tested on S-49 cells. The derivatives with a paramethyl toluidide group were more potent than the derivatives with a trifluoromethyl toluidide group. The dipeptide derivatives were more potent on adipocyte than S-49 cells, suggesting a preference for beta 1 receptors. Some of the same modifications that led to altered potency and which resulted in an increased receptor and/or tissue selectivity using the progenitors isoproterenol or histamine did extrapolate to the beta blockers. Our data suggest that alterations in receptor and/or tissue selectivity must be imparted by the carrier moiety of the drug and may be related to the biochemical microenvironment of the receptors.

Adipose Tissue↗
PubMed1987

Congener derivatives and conjugates of histamine: synthesis and tissue and receptor selectivity of the derivatives.

A series of 19 congener derivatives and conjugates of histamine was synthesized and tested to determine whether the ligands would alter the conventional histamine activity in various tissues. The derivatives, which contained either branched or unbranched aliphatic groups, aromatic amide groups, or dipeptides, exhibited affinities for histamine type 1 and/or type 2 receptors that were widely different from the progenitor. The p-trifluoromethyl derivative of histamine with an intermediate chain length of four methylenes (compound 13) was the most potent lymphocytes H2 receptor agonist but was inactive on guinea pig myocardium H2 receptors. The deletion of a single methylene chain (compound 12) from this compound resulted in total loss of its H2 activity on lymphocytes and its H1 activity on aorta. Compound 12 became an exclusive H1 agonist on lymphocytes H1 receptors. The dipeptide conjugate (compound 17) and the aliphatic congener derivative (compound 18), both with four methylenes, retained some of the activity on guinea pig myocardium H2 receptors, but lost their activity on lymphocytes H2 receptors. Therefore, histamine can be modified at sites that are at a distance from the imidazole moiety, resulting in tissue selective histamine receptor agonists.

Animals↗
PubMed1987

Conjugates of catecholamines. VII. Synthesis and beta-adrenergic activity of peptide catecholamine conjugates.

A series of novel catecholamine derivatives has been prepared in which one of the N-methyl substituents of isoproterenol has been extended by a spacer consisting of a chain of four methylenes which terminates with an amide linkage to a peptide, the point of attachment being via the aromatic amino group of p-aminophenylalanine. In one of the derivatives, two catecholamines are attached to the same peptide in this manner. The peptides, which range in size from three to eight amino acid residues and contain phenylalanine, glycine, and L-alpha-amino-delta-hydroxyvaleric acid, were synthesized via stepwise and fragment condensation techniques. The beta-adrenergic agonist activities of the derivatives were evaluated in vitro by measuring the intracellular accumulation of cyclic AMP in S49 mouse lymphoma cells.

Adrenergic beta-Agonists↗
PubMed1987

Pharmacokinetics and excretion of unique beta-adrenergic agonists.

beta-Adrenergic agonist analogs (congeners) of isoproterenol in which the N-isopropyl group has been linked to a p-methyl- (119) or p-trifluoromethyl- (143) anilide moiety through a four carbon methylene spacer have been investigated with respect to their plasma pharmacokinetic profiles and biliary and urinary elimination characteristics in rats. In spite of the differences in selectivity of pharmacologic effects and durations of action between these unique beta-adrenergic agonists and isoproterenol, no differences were observed in their pharmacokinetic parameters in plasma after intravenous administration. Plasma clearances were rapid (67-78 ml/min) and the compounds were widely distributed. In contrast to the known elimination characteristics of isoproterenol, biliary excretion was the major pathway for elimination of 119 and 143. Parent drug and 'one' major metabolite peak appeared in HPLC chromatograms of bile collected from rats that received 119 and 143 by intravenous administration. Preliminary evidence suggests that this metabolite peak consists of one or more glucuronide and/or sulfate conjugates. Urinary excretion appears to be of lesser quantitative importance for 119 and 143 than for isoproterenol. The protracted duration of residence of the derivatives in the heart may help to explain the unusual effects and tissue-specific pharmacological properties of these unique beta-adrenergic agonists.

Adrenergic beta-Agonists↗
PubMed1986

The effects of derivatives of histamine on natural suppressor cells.

Histamine is an impressive modulator of immune functions at least via its effects on lymphoid cells. Its in vivo effects will not be used practically as long as they produce the profound cardiovascular and pulmonary effects for which the drug is known. A series of 13 congener derivatives and conjugates of histamine was constructed and was tested to investigate whether chemical alterations would result in pharmacologic actions on leukocytes that were more potent and effect specific than histamine. The new compounds, which contained spacer groups of varying lengths between ligand and carrier and with various aromatic modifying groups, showed potencies widely different from histamine when tested in natural suppressor cells. Some compounds showed selective effects on natural suppressor cells in that they were inactive on myocardial tissue, whereas other compounds were selectively active on the myocardium. Some compounds augmented the suppressive capacity of natural suppressor cells in mixed leukocyte reactions via H1 receptors. Our scheme might be more widely extrapolated to other low m.w. immune modulators in an attempt to make them lymphocyte specific. The data also encourage the in vivo testing of selected histamine analogues as selective modulators of immunity. Some of these modulators might be experimentally useful in vivo because they may lack actions in other tissues.

Adenylyl Cyclases↗
PubMed1986

Beta-adrenergic receptors on human suppressor, helper, and cytolytic lymphocytes.

Using the radioligand beta-adrenergic blocker [125I]cyanopindolol (ICYP), we have characterized the beta-adrenergic receptors on Leu 3+ (T helper [TH]), Leu 2+, 9.3- (T suppressor [Ts]) and Leu 2+, 9.3+ (T cytolytic [Tc]) subsets of human lymphocytes. Peripheral blood T cells were isolated by rosetting, and then subsets were purified by their affinities to monoclonal antibodies against their Leu 3 and 9.3 markers. ICYP binding to the subsets was saturable with time and with concentration; the binding was stereoselective and reversible by beta-adrenergic antagonists. A biological response produced by beta agonists increased intracellular concentrations of cAMP and corresponded to the number of binding sites. Each subset of cells had a number of binding sites, which was characteristic for the given subset. The data indicate that the density of distribution of beta-adrenergic receptors was not homogeneous on the precursors of phenotypically and functionally distinct T cells (Ts approximately 2900, Tc approximately 1800 and TH approximately 750 binding sites). The displacement studies using beta-adrenergic agonists were performed on the cytolytic and suppressor T cell subsets, suggesting that the receptors were mainly of the beta-2 type. The immunobiological significance of such selective distribution of numbers and subtypes of beta-adrenergic receptors on distinct T cell subsets is under investigation.

Epinephrine↗