Search PubMed⌕ Search

Biomedical subjects

K L Melmon

Publications and source records attributed to K L Melmon.

At least 73 records · Page 4Linked to original sources
PubMed1981

Autacoids as modulators of the inflammatory and immune response.

Once considered only mediators of inflammation, autacoids, (histamine, prostaglandins and beta-mimetic catecholamines) have been found to be generated during specific early and late phases of immunity. They need sufficient concentrations to affect immunocytes and can modulate immunity usually by inhibiting it. Receptors for the autacoids on the immunocytes are nonrandomly distributed. A small portion of T suppressor cells always appear to have receptors on them, but precursor B cells and precursors of T cells that produce lymphokines or are responsible for cytolysis do not. Instead, as these cells mature they develop their autacoid receptors. With one exception, the function of the immunocytes is inhibited by the effects of autacoids. Again, in all but one instance, that inhibitory modulating effect is mediated by and directly proportional to the intracellular concentrations of cyclic adenosine monophosphate (AMP) generated by the autacoid. The clinical implications of these observations are beginning to be appreciated. One of them is that pharmacologic antagonists of the autacoids can have predictable but hitherto unanticipated effects on immune functions. It is inconceivable that these effects will not have clinical value.

Animals↗
PubMed1980

Generation of antigen-specific suppressor cells during allergy desensitization.

We used a suppressor-cell assay to study a possible mechanism of allergy desensitization. Before specific immunotherapy, blood mononuclear cells from 20 patients with ragweed hayfever failed to exhibit suppressor activity in vitro after stimulation by ragweed antigen E. However, when the 10 patients with allergic rhinitis had been desensitized by injections of ragweed extract, their mononuclear cells specifically suppressed a ragweed proliferative response six and 12 months after desensitization was begun (31 per cent and 48 per cent suppression, respectively). Suppressor mononuclear cells were not detected in 10 control subjects of in 10 patients with ragweed hayfever who were not desensitized. When mononuclear cells taken from treated patients were passed over columns containing insolubilized histamine, antigen-specific suppressor cells that could be activated by ragweed antigen were depleted. These results indicate that antigen-specific suppressor cells, probably bearing histamine receptors, are generated during desensitization to allergy and may be partly responsible for the efficacy of this therapy.

Adult↗
PubMed1980

Synthetic and preliminary hemodynamic and whole animal toxicity studies on (R,S)-, (R)-, and (S)-2-methyl-3-(2,4,5-trihydroxyphenyl)alanine.

The synthesis, resolution, and absolute configuration assignment of 2-methyl-3-(2,4,5-trihydroxphenyl)alanine (6-OH-alpha-Me-Dopa) are reported. Hemodynamic studies in the rat have shown that this structural analogue and potential metabolite of the clinically useful drug (S)-alpha-Me-Dopa possesses weak hypotensive activity which resides in the R enantiomer. LD50 studies in mice have established that 6-OH-alpha-Me-Dopa is over four times more toxic than alpha-Me-Dopa. Chronic exposure to 6-OH-alpha-Me-Dopa leads to renal and hepatic lesions. The case of oxidation of this hydroquinone to the electrophilic quinone species may contribute to its enhanced toxicity compared to alpha-Me-Dopa.

Animals↗
PubMed1980

Renal excretion of pseudoephedrine.

A patient with renal acidosis developed unanticipated toxicity after ordinary doses of pseudoephedrine, prompting us to study renal determinants of its elimination. We presumed that our patient accumulated the drug because of her persistently alkaline urine, which would favor tubular resorption of this weak base (pKa = 9.4). We studied normal adults and children and one adult and one child with renal tubular acidosis. Increasing urine pH increased the serum elimination half-life from 1.9 to 21 hr. While urinary pH remained alkaline, renal excretion of pseudoephedrine and its metabolite, norpseudoephedrine, was directly correlated with the flow rate of urine in each subject. Both urine pH and flow are important determinants of the elimination of pseudoephedrine in man and could be critical determinants of unanticipated toxicity.

Ephedrine↗
PubMed1980

Antagonism of morphine by naloxone in pregnant ewes and fetal lambs.

We wanted to determine if naloxone antagonizes the direct effects of morphine transferred from the mother to her fetus and if this antagonism resembles fetal narcotic withdrawal. After continuous infusions of morphine into pregnant ewes, injections of naloxone into their fetuses produced increases in fetal arterial blood presure; decreases in fetal heart rate, arterial blood pH, and PO2; and defecation of meconium. There were no maternal responses. Injections of naloxone into the mothers produced the same fetal responses and narcotic withdrawal responses in the mothers. Naloxone, therefore, antagonized the direct effects of morphine in the fetus, and this antagonism produced responses resembling narcotic withdrawal.

Animals↗
PubMed1979

Can postmarketing surveillance help to effect optimal drug therapy?

Postmarketing drug surveillance (PMS) assesses the epidemiology of drug use and monitors beneficial or harmful effects of drugs following marketing. If used systematically, PMS can substantially improve drug therapy in the United States. This can be accomplished by generating information on drug use and effects otherwise unavailable, by enabling a more efficient drug approval process, and by educating drug prescribers. However, to be successful, any PMS system will need a good deal of input from such prescribers.

Animals↗
PubMed1979

Salicylate clearance, the resultant of protein binding and metabolism.

Steady-state plasma salicylate concentrations and protein binding were examined in 9 normal subjects to determine relationships among daily dose, total and unbound salicylate concentrations, and total and unbound clearances. Aspirin doses ranging from 0.66 to 4.0 mg/kg/hr were given to steady state. Free and total salicylate concentrations were measured with spectrophotometric, fluorimetric, and equilibrium dialysis techniques. Although unbound clearance decreased over the therapeutic range, total clearance was unchanged. The former is a consequence of saturable metabolism; the latter, of saturable plasma protein binding as well as saturable metabolism. The fraction unbound increased linearly with unbound concentration. Clearance determined at 1.8 mg/kg/hr was used to predict levels obtained at higher aspirin doses. Analysis of residuals was used to ascertain the accuracy of the prediction. The coefficient of variation from prediction among subjects was found to be +/- 14%. It is concluded that, in normal subjects, salicylate clearance changes relatively little over the therapeutic range because the increasing fraction unbound compensates for decreasing clearance of unbound drug.

Adult↗
PubMed1979

Augmentation of the in vitro humoral immune response by pharmacologic agents. I: An explanation for the differential enhancement of humoral immunity via agents that elevate cAMP.

Agents that elevate intracellular concentrations of cAMP in cultured spleen cells can augment the in vitro 19s humoral immune response to SRBC. DBcAMP and 8BrcAMP were more effective than MIX, CT, PGE1, or ISO in producing the enhanced PFC response, when they were present only during an early stage of immune induction. The thesis is presented that the differential ability of these agents to augment humoral immunity results from their relative ability to maintain elevated concentrations of intracellular cAMP. Studies on the cellular mechanism by which cAMP elevation produces immune enhancement reveal that DBcAMP effects are on a T-cell-deficient population of murine spleen cells (predominantly B cells and macrophages). In addition, we showed that DBcAMP cannot replace the need for helper T cells in the induction of the PFC response to SRBC. Taken collectively, these results suggest that cAMP may be an important immunoregulatory signal, and that a variety of pharmacologic agents that modulate the induction of the humoral immune response may operate via this as a final common biochemical pathway.

1-Methyl-3-isobutylxanthine↗
PubMed1979

Augmentation of the in vitro humoral immune response by pharmacologic agents. II: comparison of the effects of antiproliferative agents with DBcAMP.

We have compared the stimulatory activity of DBcAMP with various antiproliferative agents on the induction of the humoral immune response. When they are present only during an early stage of immune induction, DBcAMP, colcemid, cytosine-arabinoside, hydroxy urea, and high specific activity 3H-thymidine can all enhance the primary 19s antibody response to SRBC. In contrast, each of these agents inhibits the PFC response, when they are incubated with the cells during late stages of induction of humoral immunity. Because all of these agents can inhibit proliferation of cultured cells, the results suggested that DBcAMP and other agents that elevate cAMP could augment humoral immunity via their effects on cellular proliferation. However, we also found that although each agent could modulate induction of the immune response to SRBC, only DBcAMP produced a dose- and time-dependent augmentation of the response to DLF. We conclude that although antiproliferative effects of drugs may contribute to augmentation of some humoral antibody responses, this effect alone is insufficient to account for the mechanism by which agents that elevate intracellular levels of cAMP produce enhancement of humoral immunity.

Animals↗
PubMed1978

Studies of cyclic AMP action using mutant tissue culture cells.

S49 mouse lymphoma cell mutants, each with a specific defect in its ability to generate or respond to cyclic AMP, have been isolated. Analysis of the properties of these cells has begun to provide information on complex and significant biologic problems related to the cyclic AMP system.

Adenylyl Cyclases↗