Kenneth L. Melmon

Lindau's disease: Review of the literature and study of a large kindred

Abstract The history of Lindaus disease is reviewed, and current knowledge of the multisystemic involvement and the clinical, laboratory and roentgenologic features are outlined. Ten proved cases and two clinically unequivocal cases, occurring in three generations of a large kindred, are reported. One of these patients was asymptomatic and was detected in a routine screening program by the finding of an epididymal cyst. The success of craniotomy, if performed early, and the desirability of prompt diagnosis have been emphasized. Attention has been called to the need for vigorous screening of all relatives.

Lidocaine Pharmacokinetics in Advanced Heart Failure, Liver Disease, and Renal Failure in Humans

Abstract The pharmacokinetics of intravenously administered lidocaine were studied in 10 normal subjects, 11 patients with heart failure, 8 patients with alcoholic liver disease, and 6 chronic rena...

Modelling of individual pharmacokinetics for computer-aided drug dosage.

Abstract A conceptual scheme and associated statistical methodology is presented which is designed to provide the basis for a clinically useful computer program to suggest optimal dosage regimens for a number of drugs for individual patients. Routinely available clinical observations will be used to predict the parameters of a pharmacokinetic model, and subsequent blood level determinations used to refine these predictions, so that dosages can be designed to produce therapeutically desirable blood levels of agents. The system is intended to deal with most, if not all, of the influences on drug pharmacokinetics, to improve its performance by learning about the individual patient as well as the underlying population, and to modify its suggestions for an individual, should his clinical characteristics change. It may be used to discover new relationships between physiological states and drug pharmacokinetics. The system can exploit prior information in the form of theoretical and published data when its data base is small. An encouraging preliminary test of the system is reported.

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.

Long-Term Digitalis Therapy Improves Left Ventricular Function in Heart Failure

To clarify the controversy regarding the benefits of long-term oral digoxin in the treatment of heart failure, we evaluated hemodynamics at rest and during exercise in nine patients in sinus rhythm with symptomatic heart failure. Patients were studied during long-term digoxin therapy, after withdrawal of the drug, and six hours after readministration. Upon withdrawal of digoxin, pulmonary capillary-wedge pressure increased from 21 +/- 8 to 29 +/- 10 mm Hg, and cardiac index decreased from 2.4 +/- 0.7 to 2.1 +/- 0.6 liters per minute per square meter of body-surface area, suggesting a deterioration in left ventricular function. In addition, heart rate tended to increase and stroke-work index, stroke-volume index, and radioangiographic ejection fraction decreased. Acute readministration restored the hemodynamic values to those observed during long-term digoxin therapy. The improvement in hemodynamics during long-term digoxin administration was also observed during exercise. This improvement demonstrated the value of long-term oral digoxin therapy in congestive heart failure.

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.

Characterization of the human blood lymphocytes that produce a histamine-induced suppressor factor (HSF)

Abstract The cells which elaborate a soluble suppressor factor in vitro in response to histamine (histamine-induced suppressor factor or HSF) were partially characterized in the present studies. Human blood T- and B-cell populations were purified by affinity chromatography with rabbit anti-human F(Ab′)2 and examined for their ability to make HSF. Highly purified populations of T cells, but not B cells, produced HSF in response to varying concentrations of histamine (10−4 to 10−4M). The HSF-producing cells were characterized further by means of affinity chromatography with columns containing conjugates of insolubilized histamine as well as by rosette formation with IgG (Tγ)- or IgM (Tμ)-coated ox red blood cells. These studies revealed the following: (a) Cells that synthesize HSF are retained on histamine (but not control) columns; (b) cells with histamine receptors comprise approximately 50% of the Tγ subpopulation but are not found in the Tμ subpopulation; (c) cells not retained by histamine columns have a reduced capacity to develop into suppressor cells following stimulation by concanavalin A or specific antigen (compared to unfractionated or control column passed cells). In addition, it was shown that cells synthesizing HSF predominantly express histamine type 2 receptors: (d)4-Methyl histamine (H2 agonist), but not 2-methyl histamine (H1 agonist), was capable of inducing HSF production; (e) cimetidine (H2 antagonist) inhibited HSF production but chlorpheniramine (H1 antagonist) did not. Taken together, these experiments suggest that T lymphocytes capable of expressing suppressor function following activation by histamine, specific antigen, concanavalin A, or perhaps through their Fc receptors may either be heterogeneous within the same subpopulation or more likely be the same cell with the complement of receptors described above.

Contribution of Kinins to Endotoxin Shock in Unanesthetized Rhesus Monkeys

The effects of endotoxin (Escherichia coli and Pseudomonas pseudomallei) were studied in 18 unanesthetized rhesus monkeys restrained in primate chairs. Indwelling arterial and venous catheters were used for hemodynamic measurements and blood sampling. Whole blood kinin, plasma kininogen, lysosomal enzymes, complete blood counts, and blood gas tensions were measured. Within an hour of beginning the infusion of the endotoxin, the mean arterial pressure and systemic peripheral resistance decreased significantly in the 18 experimental monkeys compared to 13 control monkeys. These early changes were associated with significant elevation in whole blood kinin concentration and a decrease in plasma kininogen. All of these early changes were most marked in the animals that died. Granulocytopenia occurred within 15 minutes, and the concentration of free lysosomal enzyme in the plasma rose 2 hours after endotoxin infusion. The preterminal phase of shock was characterized by a low peripheral vascular resistance and decreasing cardiac output without elevation of kinin levels. These findings support the hypothesis that kinins play a pathogenetic role in the early phase of endotoxin-induced shock and that the severity of the early phase may influence the animals survival. The relation of kinins to other vasoactive substances released after endotoxin-induced shock is unknown.

Kinins: Possible Mediators of Neonatal Circulatory Changes in man

Bradykinin is a potent constrictor of the human umbilical artery and vein and the ductus arteriosus of the lamb in vitro at oxygen tensions above 40 mm Hg (comparable to those in the newborn infant). Bradykinin is also capable of producing remarkable dilatation of the pulmonary vasculature of the lamb. Theoretically, kinins are capable of effecting some of the rapid circulatory changes required of the neonate. The present study was undertaken to investigate the role of kinins as mediators of such changes. The concentration of bradykinin in the cord blood of 56 newborn infants at the time of birth was significantly higher than the blood level in adult subjects (12.8 +/- 4.3 ng/ml compared with 2.0 ng/ml or less). Cord arterial blood contained inactive kinin precursor (kininogen) and inactive kinin-releasing enzyme (kallikrein). Plasma kallikrein was activated, with subsequent kinin formation and kininogen depletion, by exposure to neonatal granulocytes or by a decrease in the temperature of cord blood from 37 to 27 degrees C. A comparable decrease in the temperature of umbilical arterial blood occurs at the time of birth. Activation of kallikrein by neonatal granulocytes was dependent on cell concentration and required oxygen tensions comparable to those in the neonate but above the range in the fetus. Granulocytes of the neonate, unlike those of adult subjects, lacked kininase activity.Thus, bradykinin can constrict and dilate vessels as required for the transition of fetal to neonatal circulation. Bradykinin can be produced in plasma of the newborn by decreases in temperature, such as occur in the umbilical blood at birth, and by exposure to granulocytes which are present in the circulation in increased numbers shortly after birth. We propose that bradykinin is produced at birth and may be a mediator of neonatal circulatory changes.

Lidocaine disposition kinetics in monkey and man; II. Effects of hemorrhage and sympathomimetic drug administration

Lidocaine disposition kinetics in normal and hemorrhaged rhesus monkeys was studied. During bleeding there was a reduction in distribution and clearance of lidocaine, along with an increase in half‐life, which was similar to that in human patients with congestive heart failure. In the monkey in shock there was impaired liver extraction of lidocaine. Sympathomimetic drugs, such as isoproterenol and norepinephrine, which influence hepatic blood flow, markedly altered clearance and steady‐state lidocaine concentrations in blood. A perfusion model that simulates blood and tissue levels during hemorrhage in monkey and man by using blood flow measurements during hemorrhagic shock is reported here. This perfusion model allowed a quantitative understanding of the interaction between lidocaine and sympathomimetic drugs and may be clinically useful in man simultaneously receiving a variety of cardioactive drugs ill suggesting appropriate ad;ustments of the dosages of the most critical drugs used.