The virology of AIDS.
Explore the source record for details and available documents.
Acquired Immunodeficiency Syndrome↗
Biomedical subjects
N R Hall
Publications and source records attributed to N R Hall.
Behavioral tolerance and sensitization to CGS 19755, a competitive N-methyl-D-aspartate receptor antagonist.
Competitive N-methyl-D-aspartate (NMDA) receptor antagonists, including CGS 19755, have the ability to antagonize NMDA-induced convulsions, to cause ataxia and, at high doses, to increase spontaneous locomotor activity. It was of interest to determine whether or not repeated treatment with CGS 19755 would induce tolerance to some or all of these effects. CGS 19755 was administered to mice twice daily for 14 days at 54 mg/kg i.p. per injection. One day after the last repeated injection, mice were challenged with vehicle or one of several doses of CGS 19755 (10, 30, 54 and 100 mg/kg) and were tested for evidence of motor impairment (using righting reflex and traction tests), for spontaneous locomotor activity and for the threshold dose of NMDA required to induce convulsions. When challenged with CGS 19755, mice that had previously received only vehicle showed reduced motor activity in response to doses of 54 and 100 mg/kg. In contrast, mice that had received the repeated treatment regimen of CGS 19755 increased motor activity in response to challenge doses of 30 and 54 mg/kg. These effects resembled those reported previously by some investigators for phencyclidine. However, repeated treatment with CGS 19755 induced only slight tolerance to the ability of this drug to cause ataxia. In mice treated repeatedly with CGS 19755, the threshold dose of NMDA to induce convulsions did not differ significantly from that in mice treated repeatedly with vehicle, indicating no demonstrable tolerance to the apparent anticonvulsant effects of CGS 19755 over this time period.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Measures of poor early growth are correlated with lower adult levels of thymosin-alpha 1: results from the Normative Aging Study.
Explore the source record for details and available documents.
Aging↗
Thymosin fraction 5 stimulates the release of prolactin from cultured GH3 cells.
Thymosin fraction 5, a bovine thymus preparation, has recently been implicated in the regulation of neuroendocrine function. The purpose of the present study was to investigate the effects of thymosin fraction 5 treatment upon the GH3 rat pituitary cell line. Thymosin fraction 5 stimulated prolactin (PRL) release from these cells in a dose and time dependent manner. These results suggest that a product of the endocrine thymus may regulate the release of PRL.
Dose-Response Relationship, Drug↗
Thymosin fraction 5 stimulates secretion of immunoreactive beta-endorphin in mouse corticotropic tumor cells.
In addition to reconstituting immune competence, the thymus gland preparation, thymosin fraction 5 (TSN-5), has recently been shown to stimulate secretion of hormones from the hypothalamic-pituitary adrenal axis in vivo and from pituitary corticotropes in vitro. The purpose of the present study was to investigate the effects of TSN-5 on secretion of immunoreactive beta-endorphin (i beta-E) by mouse corticotropic tumor cells. The release of i beta-E by AtT-20 pituitary tumor cells was increased in a dose-dependent manner by concentrations of 30-600 micrograms/ml of TSN-5, whereas concentrations greater than 1,000 micrograms/ml were increasingly less effective in stimulating secretion. TSN-5 (600 micrograms/ml) significantly stimulated i beta-E release within 7 min; maximal secretory responses (up to 275% of control release) occurred by 4 hr. The secretory response of AtT-20 cells to 600 micrograms/ml TSN-5 (37.9 +/- 2.0 vs. 16.1 +/- 1.0 ng i beta-E/ml/4 hr, mean +/- SE) was similar in magnitude to release evoked by 0.1 microM corticotropin-releasing factor (CRF). Combining TSN-5 and CRF treatments increased secretion of i beta-E to nearly 600% of control levels, an effect greater than an additive influence of the two independent treatments. Whereas CRF treatment reduced the levels of i beta-E in AtT-20 cell extracts after 24-hr treatment by 45% (231.8 +/- 24.7 vs. 417.2 +/- 17.8 ng i beta-E/mg protein, CRF vs. vehicle treatments, respectively), TSN-5 did not significantly alter cellular hormone content. Neither TSN-alpha 1 nor TSN-beta 4, two of the component peptides of TSN-5, affected basal or CRF-stimulated release of i beta-E, indicating that an unidentified constituent(s) is corticotropic.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Stimulation of in vivo antibody production and concanavalin-A-induced mouse spleen cell mitogenesis by prolactin.
Regulation of the immune system by neuroendocrine hormones is receiving increased attention. Prolactin, a hormone normally associated with lactation, has been shown recently to reconstitute immunosuppressed hypophysectomized rats. The present studies demonstrate that prolactin administration to normal mice results in a biphasic stimulation of antibody production to sheep red blood cells. While 100 and 200 micrograms bovine prolactin/animal stimulated antibody production, 400 micrograms had no effect. Potentiation of lectin-induced T-cell mitogenesis by prolactin was also biphasic. As the concentration of prolactin increased the incorporation of [3H]thymidine into the cells first increased and then decreased. Decreasing serum prolactin levels with the dopaminergic agonist bromocriptine resulted in a reduction of antibody titers to sheep erythrocytes and a modulation of thymic weight. These data show that prolactin can stimulate the immune system in a biphasic manner and that a reduction in the basal levels of this hormone results in an attenuated immune response.
Animals↗
Thymic extracts and lymphokine-containing supernatant fluids stimulate the pituitary-adrenal axis, but not cerebral catecholamine or indoleamine metabolism.
Injection of thymosin fraction 5 (TF5) or the supernatant fluid from concanavalin A-stimulated rat spleen cells into mice significantly increased plasma concentrations of corticosterone at 1 or 3 h. However, measurement of the concentrations of the catecholamines, norepinephrine and dopamine, the indoleamine, serotonin, and their major metabolites, in prefrontal cortex, parietal cortex, nucleus accumbens, septum, caudate-putamen, hypothalamus, and brain stem did not indicate any statistically significant changes. Nor was there any alteration in splenic norepinephrine content. These data suggest that TF5 and lymphokines do not cause a generalized stress response, but rather a selective activation of the pituitary-adrenal axis, probably by causing release of adrenocorticophic hormone from the pituitary. There was no evidence that the corticotropin-releasing activity of TF5 was related to an effect on hypothalamic biogenic amines. These data are discussed in the light of previous results obtained with lymphokine-containing supernatant fluids.
3,4-Dihydroxyphenylacetic Acid↗
Effects of Newcastle disease virus administration to mice on the metabolism of cerebral biogenic amines, plasma corticosterone, and lymphocyte proliferation.
Newcastle disease virus (NDV) administration to mice increased concentrations of plasma corticosterone, with a maximal effect at 8 h. This elevation of plasma corticosterone concentrations was not observed in hypophysectomized animals in which the completeness of the hypophysectomy was verified by functional tests. NDV administration consistently increased concentrations of free tryptophan in all brain regions examined (prefrontal cortex, hypothalamus, and brain stem). It also caused an activation of cerebral catecholamine and indoleamine metabolism as determined by measurement of the amines and their catabolites. 3-Methoxy,4-hydroxyphenylethyleneglycol (MHPG), the major catabolite of norepinephrine (NE), homovanillic acid (HVA), a major catabolite of dopamine (DA), and 5-hydroxyindoleacetic acid (5-HIAA), the major catabolite of serotonin (5-HT), were all increased in both hypothalamus and brain stem. Ratios of catabolites to the parent amine, considered to be an index of utilization of the neurotransmitters, were increased for NE, DA, and 5-HT in the hypothalamus and for DA and 5-HT in the brain stem. This pattern of changes resembles that observed following stressors such as footshock or restraint. There were also significant increases of tryptophan, HVA, dihydroxyphenylacetic acid (DOPAC), and 5-HIAA in hypophysectomized relative to sham-operated mice. The NDV treatment also increased thymus weights and markedly decreased the proliferative responses of isolated spleen cells to phytohemagglutinin, concanavalin A, pokeweed mitogen, and Escherichia coli lipopolysaccharide. These changes were not caused by increased circulating corticosterone because they were present at equal magnitude in hypophysectomized mice. Thymosin alpha 1 concentrations in the plasma were not altered by NDV or hypophysectomy. These results indicate that administration of NDV to mice can initiate neurochemical and endocrine responses like those observed during stress and can also cause immunosuppression. They are thus consistent with the hypothesis that a virus can be a stressor.
Animals↗
Biology and chemistry of thymosin peptides. Modulators of immunity and neuroendocrine circuits.
Explore the source record for details and available documents.
Adjuvants, Immunologic↗
Poor growth prior to early childhood: decreased health and life-span in the adult.
Previous studies in animal populations have shown that stunted neural and thymolymphatic growth early in development may result in permanently impaired neural and immune function, decreased body growth, vertebral wedging, and decreased life-span. In the human adult, small vertebral neural canal (VNC) diameters may reflect early stunted neural and immune development and impaired function that leads to decreased health (inferred by greater vertebral wedging) and life-span in the adult. VNC, which complete their growth by early childhood (age 4), are markers of early development in adults. On the other hand, features following general body growth, such as height, weight (represented here by vertebral body height) continues to grow until young adulthood. They are less reliable, because they readily experience catch-up growth (even in chronically stressed populations) and, unlike VNC, may mask poor early growth. To test associations between early growth and adult health and life-span in humans, we measured 2,060 VNC, vertebral heights, vertebral wedging, nerve-root tunnel lengths, severity of vertebral osteophytosis, and ages at death in 90 adult (aged 15-55 years) prehistoric skeletons (950-1300 A.D.). Tibial lengths were also measured in a subsample (n = 30). Multivariate, bivariate, and nonparametric analyses showed that small VNC are significantly associated with greater vertebral wedging and decreased life-span (P less than 0.05-0.00001). VNC are independent of vertebral body heights and tibial lengths (general body growth). VNC, but not statural components, are useful in predicting adult health, presumably because they reflect neural and immune development and do not readily experience catch-up growth. Thus, longitudinal retrospective measures of early growth and adult health were systematically linked within individuals regardless of confounding factors operating over the 350-year time period. Since this research was completed, this model has repeatedly been independently confirmed in four living urban industrial populations. Longitudinal retrospective analysis was employed together with direct measures of VNC, neural and immune function. Together these results suggested that it may be essential to improve growth prior to early childhood in order to maximize adult health and life-span.
Adolescent↗
Thymosins and anti-thymosins: properties and clinical applications.
For years, scientists have searched for ways to trigger the body's own defenses against cancer and other diseases associated with abnormal immunity. This search has led to the discovery of a number of important new biological and chemical substances that augment, direct or restore many of the normal defenses of the body. These substances are in essence the natural drugs of the body that endow us with immunity and resistance to disease. Now called biological response modifiers (BRMs), most of these 'new medicines', such as thymosins, lymphokines, and interferons, occur naturally in the body, while others, synthetic immunomodulators and thymomimetic agents (drugs that mimic thymic function) have been created in the laboratory. Previously, therapeutic drug development in this area relied upon chemical synthesis or introduction of bacterial adjuvants, or modified viral compounds and substances, which were foreign to the body. Therefore, they did not and do not rely upon or use the body's natural immune and biological response systems for protection against disease, function and response to the environment. Although scientists have known about BRMs for years, isolating and purifying them so that they could be used to treat diseases has been extremely difficult. Many of these substances, such as the lymphokines, occur in the body in minute amounts and normally do not circulate in the blood. The development of new technologies for isolation and large scale synthesis, e.g. solid phase peptide synthesis, high-pressure liquid chromatography microsequencing and genetic engineering, has now permitted scientists to isolate, purify, and synthesize BRMs in sufficiently large quantities to allow human clinical trials. In this paper we will focus on the potential clinical applications of the thymosins and anti-thymosins.
Acquired Immunodeficiency Syndrome↗
Antinociceptive profile of sulfated CCK-8. Comparison with CCK-4, unsulfated CCK-8 and other neuropeptides.
The antinociceptive activity of sulfated cholecystokinin octapeptide (CCK-8-S) was characterized by comparison with two other endogenous forms, unsulfated CCK-8 (CCK-8-U) and the carboxyl tetrapeptide fragment (CCK-4) and two other peptides present in the gut and brain: bombesin and neurotensin. By the intracerebroventricular (i.c.v.) route, CCK-8-S was antinociceptive in the hot plate and phenylquinone-induced writhing assays, but CCK-8-U and CCK-4 were active only in the latter test. By systemic administration, CCK-8-S retained anti-writhing activity but CCK-8-U and CCK-4 did not. Therefore, CCK receptors in brain may be involved in the apparent antinociception produced by CCK-8-U and CCK-4. Bombesin produced potent antinociceptive activity, along with a distinct, head-scratching syndrome, in both the writhing and hot plate tests. Naloxone reversed bombesin-induced elevation of latencies of mouse jump but not the head-scratching syndrome, indicating that the analgesic effect in the hot plate test was independent of the scratching behaviour. Neurotensin, unlike CCK-8-S, elevated tail-flick latencies, and was more potent in the writhing than in the hot plate test. Several differences between CCK-8-S and opioid substances included the need for relatively large doses of naloxone to block the effects of CCK-8-S in the phenylquinone-induced writhing test and the lack of effect of CCK-8-S in the tail-flick test. Global sedation can account for some, but not all, of the effects of CCK-8-S.(ABSTRACT TRUNCATED AT 250 WORDS)
Analgesics↗
Bioequivalence of carbamazepine chewable and conventional tablets: single-dose and steady-state studies.
Single-dose and steady-state studies were carried out on separate occasions to examine the bioequivalence of the newly formulated carbamazepine chewable tablet. In the single-dose study, the plasma levels resulting from 2 X 200-mg conventional tablets (CT), 4 X 100-mg chewable tablets swallowed whole (SW), and 4 X 100-mg chewable tablets chewed before swallowing (CHEW) were compared. A randomized 3 X 3 Latin-square design balanced for residual effects, with a 3-week washout period, was used (n = 6). Plasma samples were analyzed by a specific GC method for carbamazepine. The following parameters were used for evaluation: AUC, Cmax, tmax, and t1/2. None of the parameters were significantly different except Cmax and t1/2 values for CHEW and CT. The Cmax was 25% higher and t1/2 was 11% shorter for CHEW than CT. The impact of differences in the peak plasma levels at steady state were examined by pharmacokinetic projection (400 mg b.i.d.) based on the single-dose data and with simulated induction equal to a 50% reduction in t1/2. The projected steady-state CT and CHEW plasma concentrations were similar, with a difference of only 4%. The results demonstrate the bioequivalence of the dosage forms with respect to the extent of absorption, and similar steady-state concentrations of carbamazepine in plasma can be expected. To test the conclusion from the projected study, a separate bioequivalence study to compare CHEW relative to CT was performed at steady state in normal volunteers (200 mg b.i.d.).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Immunomodulatory peptides and the central nervous system.
Explore the source record for details and available documents.
Adrenal Cortex↗
Evidence that thymosins and other biologic response modifiers can function as neuroactive immunotransmitters.
An increasing amount of data supports the hypothesis that there are bidirectional circuits between the central nervous system (CNS) and the immune system. Soluble products that appear to transmit information from the immune compartment to the CNS include thymosins, lymphokines, and certain complement proteins. Opioid peptides, adrenocorticotropic hormone (ACTH), and thyroid-stimulating hormone (TSH) are additional products of lymphocytes that may function in immunomodulatory neuroendocrine circuits. It is proposed that the term "immunotransmitter" be used to describe molecules that are produced predominantly by cells that comprise the immune system but that transmit specific signals and information to neurons and other cell types. Examples would include thymosin alpha 1 and beta 4, lymphocyte-derived ACTH, TSH, and beta-endorphin, interleukin 1, interferon as well as certain other lymphokines and cytokines. The evidence that certain thymosin peptides can serve as immunotransmitters by modulating the hypothalamic-pituitary-adrenal and gonadal axes will be discussed.
Adrenocorticotropic Hormone↗
Elevated levels of gamma amino butyric acid (GABA) in the thymus gland during the immune response.
Innervation of the mammalian thymus gland by both cholinergic and catecholaminergic neuronal projections has been documented. The present results reveal that the inhibitory neurotransmitter, gamma amino butyric acid is also present in the mouse thymus and that it is significantly elevated following challenge with a T-cell dependent antigen. A possible immunomodulatory role for the neurotransmitter is discussed.
Adjuvants, Immunologic↗
Thymosin fraction 5 causes increased serum corticosterone in rodents in vivo.
In these studies it was found that i.p. injection of thymosin fraction 5 (TF5) caused a dose-dependent increase in serum corticosterone in male Swiss Webster mice and in male Wistar rats. The maximum responses were seen at 1 and 2 hr, respectively. There was no effect on serum corticosterone in mice when Thymosin alpha 1 (a 28 amino acid peptide isolated from TF5) was injected i.p. at doses up to 100 micrograms. The steroidogenic effects of TF5 were seen only when the basal levels of serum corticosterone were low (less than 80 ng/ml). In studies in which the baseline levels in the animal colony were elevated (greater than 80 ng/ml), there were no steroidogenic effects, or they were minimal. These results suggest that some component of TF5 may influence pituitary adrenal function.
Animals↗
Comparative effects of beta 2-adrenoceptor agonists on intracranial self-stimulation, Sidman avoidance, and motor activity in rats.
The effects of beta-adrenoceptor agonists were compared in various operant behavioral tasks, particularly intracranial self-stimulation (ICSS). Clenbuterol, salbutamol, and terbutaline all reduced responding by rats that lever-pressed for low stimulation intensities. The effects of clenbuterol in this test were completely reversed by propranolol, and those of salbutamol were partly reversed. Intermediate doses of clenbuterol and salbutamol slowed the initiation of rewarding brain stimulation in a shuttlebox but had little or no effect on the termination latencies. However, higher doses of both drugs lengthened the termination latencies. Motor activity was reduced at doses that attenuated ICSS responding. Complete tolerance occurred within 4 days to the effects of clenbuterol and salbutamol on lever-pressing ICSS and to the effects of clenbuterol on motor activity. The apparent performance deficits induced by these drugs were overcome by more intense motivation. For example, even at high doses, clenbuterol reduced ICSS lever-pressing only partially when animals bar-pressed for high rather than low stimulation intensities. Furthermore, all three drugs failed to alter Sidman avoidance responding at doses up to 100 times those that attenuated ICSS responding. It is concluded that although beta-adrenoceptor agonists cause apparent sedation in rats, this sedation is limited and shows rapid tolerance.
Adrenergic beta-Agonists↗