Activity In Human Subjects Research Articles

Low dose aminophylline selectively increases upper airway motor activity in normals

Because certain pharmacologic agents differentially influence upper airway and diaphragm motor activity, we postulated that the adenosine antagonist theophylline might preferentially increase alae nasi activity in human subjects. Using a double-blinded, randomized, placebo controlled design, we studied the effect of low dose aminophyline (1–2 mg/kg) on alae nasi and diapragm surface electromyographic (EMG) activity. Seven healthy volunteers served as subjects for two trials on separate days. Subjects breathed from a closed circuit while end tidal P CO 2 was held constant in the eucapnic range. During each trial we recorded EMG signals from the alae nasi and diaphragm before and after intravenous infusion of either aminophylline or placebo. After the administration of aminophylline, the mean alae nasi EMG signal increased 87 ± 31 (SD)% ( P<0.005) while the mean diaphragmatic EMG signal did not change. There was no significant change in either the alae nasi or diaphragmatic EMG signal after placebo. There was no change in minute ventilation, tidal volume, or respiratory frequency after either aminophylline or placebo. We speculate that low dose aminophylline produced a selective increase in upper airway muscle activity through stimulation of the reticular activating system.

Effect of thyrotropin-releasing hormone (TRH) on gastric motility in man

The effect of TRH on gastric antral motor activity was examined in human subjects. Antral motor activity was assessed by balloon-kymography and electromyography (EMG). A balloon and an electrode were introduced into the gastric antrum through 2 channel fiberscope. When TRH was administered iv bolus at a dose of 250 or 500μg, gastric peristalsis was completely inhibited for 5-10min. Time of occurrence of rhythmic contraction during recovery was not modulated by previous TRH injection. When TRH was infused iv at a rate of 4μg/min, gastric peristalsis was inhibited completely for as long as the subjects were receiving TRH. Reinfusion of TRH after a short period of cessation similarly inhibited gastric peristalsis. The inhibitory effect of TRH on gastric motor activity was also confirmed by endoscopy and polysogram of the stomach.These results demonstrate that TRH administered iv exerts a potent inhibitory effect on gastric motor activity in human subjects and that the phenomenon of desentization and/or tachylaxis were not observed. Thus, TRH can be considered a useful adjunct to endoscopic and roentgenographic examinations of the stomach.

Phase relations between carotid pressure and ongoing electrocortical activity

The behavioral significance of changes in the cardiovascular system has been a major source of controversy in psychophysiology. In view of this, it is surprising that so few studies have examined the relationship between cardiac events and electrocortical (EEG) activity in human subjects. In the present study, this relationship was examined by comparing phase, amplitude and frequency of EEG activity sampled during systolic and diastolic pressure recorded from the carotid artery of resting subjects. The results indicated that rhythmic oscillations of the EEG (particularly those in the alpha range) were time-locked to the carotid pressure wave, and EEG samples taken during systolic and diastolic pressure were distincly out of phase. In addition, EEG activity sampled during systolic pressure was comprised of slower frequencies than EEG activity sampled during diastolic pressure. It was suggested that the relationship between cardiac events and behavior may be mediated in part by influences of the cardiovascular system on electrocortical rhythms.

Antineoplastic effect of 5-fluorocytosine and cytosine deaminase on brain tumor (author's transl)

The antifungal drug, 5-Fluorocytosine (5-FC) which is a derivative of 5-Fluorouracil (5-FU), lacks antineoplastic activity in human subjects because of the absence of cytosine deaminase (CDase) in mammalian cells. Therefore, intratumoral conversion of 5-FC to 5-FU by extrinsic CDase could be expected to induce antineoplastic effects at a local site with minimal systemic toxicity. The effects of combined administration of 5-FC and CDase in in vitro and in vivo were investigated. CDase was extracted from the E-Coli K-12 strain and purified. In vitro studies resulted in a significant inhibition of cell proliferation on cultured glioma cells (EA-285 cells) with 5-FC concentration over 10 μg/ml. Fluorocytographic studies of the tumor cell cycle progression showed synchronization in the early S phase at lower concentrations and complete blocking at the G1 and the early S phase with over 25 μg/ml. In in vivo studies, tissue concentrations of 5-FC and converted 5-FU were serially measured by a bioassay method after simultaneous intratumoral injection of CDase and systemic administration of 150 mg/kg of 5-FC to brain tumor bearing rats. The maximum concentrations of the drugs in the tumor tissue were 85 μg/g 5-FC at 1 hour and 9.6 μg/g 5-FU at 2 hours, which were sufficient to kill tumor cells. They were kept at higher levels in the tumor tissue than in the normal brain. In comparison, the maximum 5-FU concentration in the serum was only 0.4 μg/ml. The survival times and histological examinations of the experimental brain tumor models by this combined therapy were evaluated. The median survival time of the treated group was significantly prolonged (38.3 days) when compared with that of the control group (28.2 days). No side effects were recognized. Histological studies of the animal brains 2 weeks after the therapy revealed necrosis in the treated tumor. This combined treatment of 5-FC and CDase could be an ideal therapy for brain tumor in the future.

Metabolic mapping of functional activity in human subjects with the [18F]fluorodeoxyglucose technique.

The 2-[18F]fluoro-2-deoxy-D-glucose technique was used to measure regional cerebral glucose utilization by human subjects during functional activation. Normal male volunteers subjected to one or more sensory stimuli (tactile, visual, or auditory) exhibited focal increases in glucose metabolism in response to the stimulus. Unilateral visual hemifield stimulation caused the contralateral striate cortex to become more metabolically active than the striate cortex ipsilateral to the stimulated hemifield. Similarly, stroking the fingers and hand of one arm with brush produced an increase in metabolism in the contralateral postcentral gyrus, compared with the homologous ipsilateral region. The auditory stimulus, which consisted of a monaurally presented factual story caused an increase in glucose metabolism in the auditory cortex in the hemisphere contralateral to the stimulated ear. These results demonstrate that the technique is capable of providing functional maps in vivo related to both body region and submodality of sensory information in the human brain.

Influence of contingent responding on schedule-induced activity in human subjects

Contingent response requirement as well as payoff contingencies were manipulated to assess their influence upon schedule-induced activity in human subjects. Conditions which included various fixed-interval response topographies and a constant probability variable-interval reinforcement schedule were utilized to affect observation responding during a contingent detection task. Results obtained by the various manipulations indicated that the rates of schedule-induced activity in human subjects were inversely related to observation responding during fixed-interval detection intervals, while the variable-interval detection condition reduced the rates of schedule-induced activity to baseline levels. The time-course of schedule-induced activity in human subjects was demonstrated to be similar to that of infrahuman species.

Validation of 13CO 2 breath analysis as a measurement of demethylation of stable isotope labeled aminopyrine in man

Interval sampling of expired breath as a simple, non-invasive assessment of the effect of liver disease upon hepatic microsomal drug metabolism, has been demonstrated with [ 14C]dimethylaminoantipyrine (aminopyrine). In order to eliminate radiation risk we have validated the use of aminopyrine labeled with the stable, non-radioactive isotope 13C. Simultaneous oral administration of both [ 14C]- and [ 13C]aminopyrine to five adult subjects without liver disease as well as five patients with known liver disease, resulted in the excretion of label at nearly identical rates in both individual time collections ( r = 0.94) as well as cumulative excretion for three hours ( r = 0.97). An oral dose of 2-mg/kg of [ 13C]aminopyrine resulted in rates of production of 13CO 2 significantly greater than baseline variations in 13CO 2 production in the fasting, resting subject. Measurements of a single peak value at one half hour correlated closely with the determination of cumulative appearance over three hours ( r = 0.96). A consistent reproducible increase in the peak production of 13CO 2 was observed when five patients received phenobarbital. Stable isotope labeled aminopyrine may be used to detect the effects of disease and treatment upon hepatic N-demethylation activity in human subjects without incurring any risk from radiation. Furthermore, the availability of another isotopic carbon label should make possible the study of direct drug-drug interaction utilizing CO 2 analysis.

Jejunal Adenylate Cyclase Activity in Human Subjects During Viral Gastroenteritis

The histopathological changes that occur in the jejunal mucosa of humans infected with the Norwalk or Hawaii agent of acute infectious nonbacterial gastroenteritis ("viral" gastroenteritis) have ben well characterized. The pathogenesis of diarrhea in this syndrome remains unknown; however, recent reports have suggested a possible role for the adenylate cyclase system. In this combined paper, two groups of investigators working independently and employing slightly different techniques report that: (1) there is marked interindividual variation in the apparent specific activity of adenylate cyclase in human jejunal biopsy tissue; (2) such variation can be minimized by expressing enzyme activity as a fraction of maximal that can be stimulated by 10(-2) M sodium fluoride; and (3) adenylate cyclase activity in jejunal mucosa is not increased during diarrhea or illness in human viral gastroenteritis, therefore suggesting no role for the adenylate cyclase system in the pathogenesis of diarrhea in this common clinical entity.

On the interpretation and potential diagnostic value of the measurements related to lecithin:cholesterol acyltransferase activity

At least one reliable method is available for measuring LCAT activity in human subjects(25), and this assay may help to probe even subtle changes in plasma lipids and lipoproteins. Since plasma lipids and lipoproteins are known to be present in abnormal amounts in a large number of metabolic diseases, the method of measuring the rate of cholesterol esterification in plasma could assume a substantial role in the diagnosis and (or) monitoring of treatment of pathologic states.

Correlation of serum aspirin esterase activity and half-life of salicylic acid.

An inverse correlation was found between the serum aspirin esterase activity in human subjects and the biological half-life of salicylic acid in serum and a direct relationship between the values of the elimination rate constant and the activity of this enzyme. The rate of acetylsalicylic acid breakdown may be one of the factors which influences the biological half-life of salicylates in the organism and may participate also in determining the individual response to the administered drug.

Modifications of thyroid function induced by chronic administration of iodide in the presence of "autonomous" thyroid tissue.

ABSTRACT Fourteen patients were studied before and during administration of a daily supplement of 0.5 mg of iodide over a period of 3 to 10 months. Only a slight increase in PBI was observed in three patients with a non-toxic goitre and in two myxoedematous patients under treatment. The same supplements of iodine induced a marked rise in PBI in four euthyroid patients with a typical thyroid »hot« nodule. In the four cases, the PBI values reached the thyrotoxic range after only a few weeks. These elevated values were maintained throughout the period of iodine administration; data for the thyroxine content of the serum were strictly correlated with the PBI values. The T3-resin test measurements also gave values characteristic of hyperthyroidism. Later on, three of these patients developed definite symptoms of hyperthyroidism, although not until several months after the appearance of the biological picture. Finally a definite increase in PBI was also observed, albeit to a lesser extent, in five thyrotoxic patients previously treated with radioiodide or with methimazole. A progressive fall in the PBI was found in four patients after iodine supplements were discontinued. These observations indicate that chronic iodine supplementation leads to marked over-production of thyroid hormones in two pathological conditions characterized by the presence of autonomous thyroid tissue. It is concluded that, in the absence of an adequate feed-back control mechanism, the amount of dietary iodine may be one of the main regulatory factors involved in thyroid activity in human subjects.

A Comparative Study of Lung Compliance and Pulmonary Surfactant Activity in Human Subjects

Twenty-seven patients were studied by measuring dynamic lung compliance and lung extract surface activity to investigate a theoretical correlation. Fifteen patients were without respiratory symptoms or diffuse pulmonary disease. They were classified Group I (9 patients) with normal ventilation, normal lung compliance, and normal pulmonary surfactant activity, or Group II (6 patients) with either obstructed or restricted ventilation, low lung compliance (2 of 6 patients), and normal pulmonary surfactant activity. The other 12 patients, who made up Group III, were studied because they had radiographically apparent diffuse pulmonary disease. Their ventilatory impairment was consistent with the histopathology; however, lung compliance was normal in all but 1 patient, whereas pulmonary surfactant activity was abnormal in 4 including the patient with low compliance. It is concluded that (1) dynamic lung compliance may be independently abnormal in patients with obstructive ventilation; (2) pulmonary surfactant activity may be independently abnormal in lungs with parenchymal pathology; and (3) the I case of dynamic lung compliance and pulmonary surfactant found in this investigation does not constitute sufficient evidence to establish a correlation between these entities.

Measurement of Motor Activity in Human Subjects

A behavior recorder was developed to measure the types and duration of specific aspects of the behavior of human Ss. This instrument makes possible a more quantitative analysis of Ss' motor activity.

Serum "Angiotensinase activity" and female steroidal hormones.

Angiotensinase activity was measured in the third trimester of normal pregnancy (15) and preeclampsia (6) in women taking taking contraceptive pills (Oracon) (21) in males who also took these pills (3) and in serum and uterine tissue from pregnant and nonpregnant rabbits serving as controls. The findings of decreased angiotensin II amide survival and increased alpha-L-aspartyl-beta-naphthylamide hydrolysis in women during the third trimester of normal pregnancy suggests a possible relationship between serum angiotensinase activity and female steroidal hormones. Confirmatory evidence was provided by similar results with the latter substrate in women receiving contraceptive pills. Synthetic estrogen but not progestogen induced increased serum naphthylamidase activity in male volunteers. Starch gel electrophoresis was similar in normal women pregnant women and women on contraceptives in the patterns of proteins and this enzyme activity. Electrophoretic studies of enzyme activity in serum and uterine tissue extracts were not demonstrated in the electrophoresis studies and increased enzyme activity in human subjects could not be correlated with plasma renin activity blood pressure or liver cell damage it seems likely that the increased aspartic naphthylamidase hydrolysis is part of a nonspecific naphthylamidase increase induced by estrogens.(Authors modified)

Cardioglobulin. Assay methods.

The principles and procedural details for assay of the biological activity of cardioglob ulin A, B and C are presented. In the Methods section are described the construction of the frog heart cannula, and the technique for can nulating the heart and cauterizing the atria. The principle and methods for assaying car dioglobulin B are described. The use of rat plasma as a source of eardioglobulin A and C in the assay is discussed. The basis for the cardioglohulin C assay is described. The prep aration of cardioglobulin B for use in the assay is described in detail. The procedure used in the cardiogl.obulin C assay is given, with a discussion of certain factors which must be controlled. The assay for cardio globulin A is outlined, and the method for preparing cardioglobulin C for use in the assay is also given. A comparison between cardioglobulin A and C activity in human subjects is made.

The glycogen index in the menopause: A study of certain estrogen functions based on a new method of staining vaginal smears

The iodine vapor method of staining vaginal smears is presented as a rapid and simple means for determining the specific glycogen response to estrogen activity in the human subject. This method of clinical investigation is based upon observations that normal vaginal glycogen content parallels estrogen sufficiency, whereas diminution of glycogen (glycopenia) is indicative of estrogen deficiency.To determine the incidence of glycogen poverty in postmenopausal women, vaginal smears from 130 climacteric women (after staining by the iodine vapor procedure) were graded according to glycogen content. The incidence of the four glycogen grades was calculated according to age, duration of the menopause, and the nature of the climacteric, whether spontaneous or artificially induced. The significance of the findings, in terms of other reports of postmenopausal estrogen elaboration, is discussed. The possible “anti-hormonal” effects of various systemic and local disorders (febrile states and vaginitis) upon estrogenic activity, are suggested by observations in tuberculous women.Experience to date has established the usefulness of the glycogen index in estimating therapeutic response of estrogen therapy in juvenile gonorrheal and senile atrophic vaginitis. Evidence of its further value as a simple and sensitive indicator of estrogen activity in human subjects is presented in potency determinations of several commercial products.