Search PubMed⌕ Search

Biomedical subjects

K L Melmon

Publications and source records attributed to K L Melmon.

At least 55 records · Page 3Linked to original sources
PubMed1985

Immunoregulatory T cells in man. Histamine-induced suppressor T cells are derived from a Leu 2+ (T8+) subpopulation distinct from that which gives rise to cytotoxic T cells.

One mechanism of histamine-mediated inhibition of the immune response in man is to activate T suppressor cells that bear the Leu 2 (OKT8) marker. The current study was undertaken to characterize the histamine-induced suppressor cell using a monoclonal antibody (9.3) shown previously to distinguish cytotoxic T cells from antigen-specific suppressor T cells. Leu 2+ cells isolated from peripheral blood were further separated with antibody 9.3 into Leu 2+, 9.3+, and Leu 2+, 9.3- subsets and each subset was incubated with different concentrations of histamine before determining their ability to suppress immune responses in vitro. The results indicate that the Leu 2+, 9.3- subpopulation includes all histamine-induced suppressor cells, that 10(-4) M histamine is the optimal concentration for suppressor cell induction, and that exposure of Leu 2+, 9.3- cells to histamine for 30 s is sufficient to initiate the induction process. After treatment with histamine these cells inhibit both phytohemagglutinin-induced T cell proliferation and pokeweed mitogen-induced B cell differentiation. The suppression of phytohemagglutinin-induced proliferation was resistant to x-irradiation with 1,200 rad, either before or after histamine exposure, suggesting that Leu 2+, 9.3- cells need not proliferate to become suppressor cells or exert suppression. Moreover, suppression by these cells was not due to altered kinetics of the response. Finally, a histamine type 2 receptor antagonist (cimetidine) but not a type 1 receptor antagonist (mepyramine) blocked the induction of suppressor cells. On the basis of these results and our previous studies of antigen specific suppressor cells, we conclude that Leu 2+ suppressor cells in man are derived from a precursor pool that is phenotypically distinct from cells that can differentiate into cytotoxic T cells.

Antibodies, Monoclonal↗
PubMed1985

Pharmacologic effects of autacoids on subsets of T cells. Regulation of expression/function of histamine-2 receptors by a subset of suppressor cells.

Autacoids (principally histamine, beta adrenergic catecholamines, and prostaglandins E and A) have only recently been recognized as substantive moderators of a number of immune functions. If autacoids are to be considered as potential therapeutic immunomodulators, it is necessary to understand their effects on subsets of T cells while they are and are not in contact with each other. This report demonstrates that autacoid receptors are nonrandomly distributed on phenotypically and functionally distinct subsets of human T cells. Each human T cell subset responded to both histamine and isoproterenol, but the dose response curve and maximal efficacy varied widely between the subsets. The suppressor T cells were more responsive to both histamine and isoproterenol than helper/inducer T cells (TH) or cytotoxic T cells (Tc). We found that after mitogenic stimulation the response to histamine, but not isoproterenol, was greatly increased only in TH (Leu 3+) and Tc (Leu 2+, 9.3+) subsets, and that this effect may be regulated by suppressor T cells (Leu 2+, 9.3-). The dramatic rise in cAMP accumulation in response to histamine in mitogen-treated TH and Tc was totally blocked by an H2 antagonist (cimetidine), but not by an H1 antagonist (mepyramine). These findings indicate interdependence of (a) immunologically uncommitted subsets in their response to selected drugs, and (b) control of basal- and autacoid-induced cAMP production, as well as (c) increased qualitative and quantitative selectivity, which is caused by mitogen. If we had performed these experiments only on unseparated cells we would not have observed the remarkable selectivity of autacoid effects on subsets of T cells.

Autacoids↗
PubMed1985

The effects of autacoids on cloned murine lymphoid cells: modulation of IL 2 secretion and the activity of natural suppressor cells.

The pharmacologic effects of histamine and isoproterenol (autacoids) were studied on clones of murine T helper (TH) and natural suppressor (NS) cells. The data are consistent with receptors for the autacoids being nonrandomly distributed on phenotypically and functionally distinct clones. The effects of histamine on IL 2 secretion by TH cells could be either inhibitory or stimulatory, depending on the conditions of incubation with the autacoid. When TH cells were pretreated with histamine, their secretion of IL 2 was augmented; conversely, if histamine was added to the TH cells in the presence of antigen, IL 2 secretion was inhibited. The suppressor function of NS cells was enhanced by preincubation with histamine (10(-4) M) for 4 hr before the washed NS cells were added to responder and stimulator cells in mixed lymphocyte cultures. Two H1 receptor antagonists, mepyramine (10(-6) M) and pyrobutamine (10(-7) M), each competitively blocked the histamine activation of the NS cells, but an H2 receptor antagonist cimetidine (10(-5) M) did not alter the suppressor-enhancing function of histamine. Activation of NS cells did not occur if histamine was added with responder, stimulator, and co-cultured cells in MLR. The effects of each autacoid were additive in cytolytic T cells alone. The adenylate cyclase pools that can be stimulated by isoproterenol and histamine in cytolytic T cells may be independent of each other, but further work will be needed to prove this point.

Animals↗
PubMed1984

Post-marketing studies of drug efficacy: how?

This report reviews the 100 most recently approved drugs in order to quantify the frequency with which post-marketing studies of drug efficacy can be performed experimentally and non-experimentally. These drugs represent 131 potential drug uses. Of them, the absolute efficacy of 89 (68 percent) could be evaluated from clinical observations. Of the remaining 42, six (14 percent) could be studied experimentally or non-experimentally, six (14 percent) only experimentally, one (2 percent) only non-experimentally, and 29 (69 percent) by neither technique. Answers to all questions of relative efficacy required formal research. Of these, 94 (72 percent) could be studied using either experimental or non-experimental techniques. The remaining 37 (28 percent) could be studied experimentally only. Thus, clinical observations and non-experimental research can contribute a large proportion of the information about drug efficacy still needed after marketing.

Drug Therapy↗
PubMed1983

Optimal therapy for the geriatric patient: the challenge to clinical pharmacology.

The elderly are an increasing proportion of the population. Their median life span should rise to 85 years, although in later life organs of drug distribution and elimination may deteriorate in function and 100 years will remain the general maximum. Progressive containment of chronic diseases will still leave them at lethal risk from acute infectious diseases because of depleted homeostatic reserves of vital systems (cardiovascular, hepatic, immunological and renal). A decline in chronic disease should lengthen the period of well-being and reduce medical needs and perhaps drug needs of older persons. To estimate further therapeutic requirements of the elderly, information is needed on the epidemiology of drug use and rates of efficacy and toxicity in the elderly. Implicit in the data gathering is a true need for systematic post-marketing surveillance (PMS) of drugs with particular respect to drug efficacy and unanticipated adverse or beneficial reactions in this age group. Observational, non-experimental techniques can be devised and should be tested as appropriate methods of establishing the rates of anticipated efficacy and unwanted effects of drugs. The application of such techniques may be one of the only feasible ways to establish utility functions for drugs used in the elderly.

Aged↗
PubMed1983

Conjugates of catecholamines. 1. N-alkyl-functionalized carboxylic acid congeners and amides related to isoproterenol.

A series of functionalized catecholamines (congeners) has been synthesized in which, formalistically, the N-isopropyl group of isoproterenol has been extended by a linear alkyl chain of varying length, terminated by a carboxy group or a substituted amide. The compounds were prepared generally via the reductive amination of norepinephrine with a keto acid or a preformed keto amide. An alternate synthesis of the model amide derivatives, involving activation of the carboxylic acid congeners and coupling with amines, was complicated in the case of short-chain derivatives by facile cyclization to lactams. In vitro evaluation of these compounds as potential beta-adrenergic agonists has shown that, while the carboxylic acid congeners have relatively low potencies, the model amide derivatives have potencies that are highly dependent on both the length of the alkyl chain and also the nature of the substituent on the amide. In general, aromatic amides are the most potent, although the nature and position of substituents on the aromatic group dramatically influences their potency. The implications of these studies, in terms of general beta-adrenergic drug design and also the attachment of the carboxylic acid congeners to carriers, are discussed.

Animals↗
PubMed1983

Conjugates of catecholamines. III. Synthesis and characterization of monodisperse oligopeptides conjugates related to isoproterenol.

A series of monodisperse oligopeptide conjugates related to the catecholamine, isoproterenol, has been synthesized. The peptide carrier molecules used were synthesized by stepwise and fragment condensation techniques and ranged in size from a single, blocked amino acid derivative to isomeric pentapeptides. The amino acid compositions and sequences of the carriers were chosen so as to provide specific information concerning the effects of molecular weight, hydrophilic/hydrophobic balance, charge, etc., on the biological activity of the final conjugates. The common point of attachment for the drug in all carriers was a p-aminophenylalanine residue. The peptide-catecholamine conjugates were prepared via the attachment of carboxyl-containing catecholamine congeners, to the peptide carriers by techniques described previously. The conjugates were purified rigorously by chromatographic techniques and characterized by high-field n.m.r. spectroscopy.

Catecholamines↗
PubMed1983

Conjugates of catecholamines. IV. In vitro and in vivo pharmacological activity of monodisperse oligopeptide conjugates.

Conjugates of low molecular weight amines with inert peptide carriers can be made to preserve some pharmacologic effects of the ligand. No previous studies of conjugates have systematically derivatized the ligand to optimize its activity or affinity to receptors; or have pharmacophores been selected for conjugation on the basis of their effects making them particularly interesting as ligands. Chemically pure and characterizable conjugates ranging from single blocked amino acid derivatives to isomeric pentapeptides were constructed and tested for beta adrenergic properties. Sixteen conjugates with varying water solubility, amino acid composition and sequence, charged groups and spacer length between ligand and carrier showed potencies and duration of action widely different from isoproterenol. In the in vitro S-49 mouse lymphoma assay a range of relative potencies (as compared to isoproterenol) from 10(-6) to 1 time as potent was obtained, whereas in the in vivo rat blood pressure assay these compounds were shown to be from one-fifth to 4 times as potent as isoproterenol. The most potent compound tested, Boc-Phe(NH)-Gly-NHCH3, was also tested in a guinea-pig atrial preparation as well as in an anesthetized cardiovascular dog preparation. The results indicated that the compound was approximately 3.5 times more potent in producing an inotropic response than isoproterenol. In some instances, ostensively trivial changes quite distant from the pharmacophores in amino acid sequence of the carrier made major changes in potency and efficacy of the compound.

Adrenergic beta-Antagonists↗
PubMed1983

Conjugates of catecholamines. II. In vitro and in vivo pharmacological activity of N-alkyl-functionalized carboxylic acid congeners and amides related to isoproterenol.

In this study, 10 congeners of isoproterenol were systematically synthesized and pharmacologically tested in both in vitro and in vivo systems. The aim was to produce compounds that were more potent and had effects different from those of the parent compound and that could ultimately be attached covalently to inert peptide carriers offering versatility in size, pK, and other physicochemical properties. The congeners synthesized were tested in the S49 mouse lymphoma assay for their ability to stimulate cyclic AMP accumulation and were shown to have potencies relative to isoproterenol ranging from 4 orders of magnitude less potent to 4 orders of magnitude more potent than isoproterenol in eliciting this response. Some of the congeners were also tested in a guinea pig isolated atrial preparation, a rat blood pressure assay, a guinea pig bronchodilation assay, and an anesthetized dog preparation. In these assays, the congeners were shown to have the same types of activities as in the S49 cell assay. The results of these studies indicate that structural modifications distant from the catecholamine moiety dramatically alter the pharmacological profile of the congeners versus the parent compound, resulting in a series of ligands with a wide range of activities.

Adrenergic beta-Antagonists↗