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Biomedical subjects

K L Melmon

Publications and source records attributed to K L Melmon.

At least 109 records · Page 6Linked to original sources
PubMed1976

Control of immune responses by cyclic AMP and lymphocytes that adhere to histamine columns.

Mixed lymphocytes from human peripheral blood, murine spleens, lymph nodes or thymus glands have pharmacologically specific receptors for histamine, beta mimetic catecholamines and prostaglandins. When these cells are exposed to the panoply of drugs mentioned above, their intracellular cyclic AMP concentrations increase. The biologic consequences of such an increase were at first elusive. Now we know that the immune potential of some murine spleen cells may be modulated and the release of lysosomal enzymes and histamine from human leukocytes may be inhibited. This paper concentrates on the effects that manipulation of cells with amine receptors has on their immune function. Recent studies have revealed that a subpopulation of splenic suppressor T cells responds to increases in its cyclic AMP content by reversing its suppressive effects on the humoral antibody response. When these T cells are removed from the murine cell population by their differential adherence to insolubilized conjugates of histamine with albumin, the remainder of the cells are more responsive to sheep cell antigen, as tested by transferring the spleen cells together with the antigen into lethally irradiated recipient animals. The suppressor T cells that adhere to the insolubilized conjugates of histamine-albumin (called histamine-rabbit serum albumin-Sepharose, or HRS) are Ia positive, they appear to have receptors for histamine, beta adrenergic amines and prostaglandins of the E series, and when stimulated by these agents their in vivo and in vitro suppressor actions are reversed. The reversal seems quantitatively dependent on cyclic AMP accumulation. Receptors for the amines and prostaglandins are found on the T cell precursors of cell mediated immunity. They develop on some T effector cells in selected models of allogeneic target cell lysis. The receptors also appear to develop on selected B cells once these cells become committed to antibody production. The distribution of receptors on all leukocytes has not been adequately studied nor has their full potential in the immune response been studied in detail.

Animals↗
PubMed1975

Determinants of the renal clearance of digoxin.

The renal clearances of digoxin, creatinine, and urea nitrogen were determined simultaneously in each of 41 patients receiving digoxin, in most of whom there was prerenal azotemia. Mean plus or minus SD values were: blood urea nitrogen (BUN), 26.1 plus or minus 12.8 mg per 100 ml; creatine, 1.1 + 0.41 mg per 100 ml; creatinine clearance, 78 plus or minus 42 ml/min/1.73 m2; digoxin clearance, 66.6 plus or minus 42.1 ml/min/1.73 m2; urea nitrogen clearance, 27.8 plus or minus 19.2 ml/min/1.73 m2. Correlation analysis revealed that urea clearance is superior to creatinine clearance, and BUN is superior to serum creatinine concentration in the degree of relationship to renal digoxin clearance. Moreover, using partial correlation techniques, it is apparent that in these patinets digoxin clearance was significantly related to urine flow rate. These findings are compatible with the hypothesis that digoxin undergoes some degree of tubular reabsorption as well as filtration and secretion.

Adult↗
PubMed1975

Influence of congestive heart failure on blood vessels of lidocaine and its active monodeethylated metabolite.

The blood concentrations of lidocfaine and its active monodeethylated metabolite, monethylglycinexylidide (MEGX), were measured in 31 patients who were receiving infusiions of lidocaine intravenously. In 3 patients who were studied intensively, the elimination half-life of MEGX was 120 min, which was similar to the elimination half-life of lidocaine (139 min). An addition 3 patients demonstrated a higher ratio of the concentration in blood of MEGX to lidocaine, and the MEGX may have contributed, in 1 patient, to the central nervous system toxicity that occurred during the infusion. Elevated concentrations of MEGX in blood were associated with congestive heart failure (r equalto 0.5, p equal to 0.004). Our data suggest that the elimination of MEGX may be decreased in patients with depressed cardiac output and sympathomimetic compensation.

Adult↗
PubMed1975

Influence of acute viral hepatitis on phenytoin kinetics and protein binding.

Patients with liver disease are thought to have abnormal responses to drugs metabolized by the liver, although supportive evidence is sparse. The influence of acute viral hepatitis on the pharmacokinetics and protein binding of phenytoin (DPH) was examined in 5 patients. A longitudinal study design was used so that each patient acted as his own control. DPH clearance was unaffected by acute viral hepatitits over theconcentration range studie, but the percentage of unboudn DPH increased by an average of nearly one-third during acute viral hepatitis. A small decline in serum albumin concentration and elevated serum bilirubin levels may be responsible for the alterations in protein bindig. These results indicate that acute inflammatory liver disease has complex and perhaps paradoxical effects on durg disposition. Clinical and laboratory observations including plasma durg concentrations, still provide the best means for adjusting dosage regimens in patients with fluctuating hepatic function.

Bilirubin↗
PubMed1975

Interaction of leukocytes and endotoxin with the plasmin and kinin systems.

Leukocytes can generate a substance that, when added to some partially purified human kininogen, is capable of forming kinins. The addition of endotoxin or polystyrene latex particles to the incubated leukocytes doubled the amount of kinin generated. Certain preparations of kininogen, however, failed to allow kinin formation by the leukocytes. No evidence could be found that an activator of prekallikrein or a kallikrein was present in the granulocyte preparations. However, the addition of highly purified plasminogen to inactive kininogen preparations restored their ability to generate kinins in the presence of leukocytes. All the kininogen preparations that allowed kinin formation when incubated with leukocytes contained plasminogen. These data suggest that a plasminogen activator is present on the leukocyte surface. This activator activates plasminogen to form plasmin which in turn acts on kininogen to release a kinin and thus provides a mechanism for the formation of kinins in inflammatory exudates and during endotoxemia.

Endotoxins↗
PubMed1975

Cutaneous immediate hypersensitivity in man: effects of systemically administered adrenergic drugs.

In in vitro models of hypersensitivity, beta adrenergic drugs inhibit the antigen-induced release of histamine and other mediators from mast cells and basophils. Epinephrine, an agent with both beta and alpha adrenergic properties, is clinically useful for treating immediate hypersensitivity reactions. We examined the effects of intravenously administered adrenergic drugs on cutaneous wheal-and-flare reactions to antigens and histamine in 7 normal men. Both epinephrine and isoproterenol, a beta agonist, inhibited skin reactions produced by antigen or histamine. Phenylephrine, an alpha adrenergic agonist, produced no effect. These results suggest that epinephrine's inhibition of cutaneous immediate hypersensitivity in vivo is mediated by beta, rather than alpha, receptors. This inhibitory effect in vivo is probably not mediated solely in preventing allergic release of inflammatory mediators since the skin reactions to histamine were inhibited as well.

Adrenergic alpha-Agonists↗
PubMed1975

Hemodynimic effects of systemic and central administration of clonidine in the monkey.

Systemic and regional hemodynamic changes were measured in restrained, conscious rhesus monkeys with indwelling arterial and venous catheters before and after clonidine (5 and 15 mug/kg) was slowly infused intravenously or smaller doses (2 mug/kg) were injected into a lateral cerebral ventricle. Dye-dilution cardiac outputs and the complete distribution of cardiac output were obtained intermittently with the use of the radioactive microsphere method. After the higher intravenous dose and the intraventricular injection, systemic arterial pressure was significantly lowered for 30-45 min. Both of these groups had similar changes in the redistribution of cardiac output and blood flow that outlasted the hypotensive period. Blood flow was maintained or increased in the hepatic and renal arteries at the expense of skin; flow to skeletal muscle and brain also decreased during the first hour. These data support previous studies that indicate that the primary action of clonidine is in the central nervous system and, in addition, add new information about the regional blood flow changes evoked by clonidine.

Animals↗
PubMed1975

Improved computer-assisted digoxin therapy. A method using feedback of measured serum digoxin concentrations.

Automated feedback control methods were applied to a medical problem, in a computer program that used measured serum digoxin concentrations (as feedback) to predict future concentrations and to achieve desired concentrations. The system was validated by comparing its ability with the corresponding ability of physicians to regulate digoxin dosage. The prospective, randomized study included 51 patients. In the presence of varying amounts of feedback (serum digoxin concentration) information, the computer always predicted future digoxin concentrations as accurately as did physicians. For both computer and physician, the decrease in the prediction errors when two concentrations were known against that when no concentrations were known was significant: mean absolute error decreased from 0.40 to 0.25 ng/ml for the physicians and from 0.45 to 0.27 ng/ml for the computer. Thus the computer system is capable of simulating and reproducing a sophisticated aspect of physician behavior: "learning" about individual patient responses. The computer achieved desired concentrations more accurately than did physicians, especially when two or more previous digoxin concentrations were abailable (mean absolute achievement error for computer, 0.28 ng/ml; for physicians, 0.50 ng/ml).

Achievement↗
PubMed1975

Specific mitogenic activity of 8-Br-guanosine 3',5'-monophosphate (Br-cyclic GMP) on B lymphocytes.

8-Br-cyclic GMP has been found to be a specific B cell mitogen; it triggers athymic nude mice spleen cells and "B mice" spleen cells, nylon adherent, anti-theta and complement-treated cells to proliferate. It does not stimulate thymocytes or purified T cells. The kinetics of the response to Br-cyclic GMP and LPS are almost identical. The mitogenic effect of LPS and Br-cyclic GMP is additive when the two mitogens are given together to cells. Spleen cells (C3H/HeJ strain) that did not respond to LPS were triggered by Br-cyclic GMP to make DNA. In order to achieve maximal stimulation by Br-cyclic GMP, the drug had to be in contact with the cells for more than 24 hr. Br-cyclic GMP was found to be mitogenic for spleen cells from five different mouse strains, but not for human leukocytes. DB-cyclic AMP was found to inhibit the DNA synthesis of T lymphocytes after they interacted with Con A; DB-cyclic AMP had no effect on the ability of the B lymphocytes to be transformed by LPS. The differential effects of cyclic nucleotides on B vs. T lymphocytes are discussed.

Animals↗
PubMed1975

Metabolic disposition and cardiovascular effects of methyldopate in unanesthetized rhesus monkeys.

Methyldopate, the ethyl ester hydrochloride salt of alpha-methyldopa (alpha-MD), is used extensively in the treatment of severe hypertension. We have developed a high-pressure liquid chromatographic assay to determine the plasma-time concentrations of alpha-MD after intravenous administration of methyldopate and alpha-MD in the monkey in an effort to evaluate the bioavailability of alpha-MD and the extent of in vivo hydrolysis of the amino ester to the amino acid. The results establish that in this experimental situation methyldopate is not metabolically equivalent to alpha-MD.

Animals↗