Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IL-6 is a 26-kDa protein cytokine with pleiotropic activities in both hematopoietic and immune systems. It is one of the major mediators of the acute phase inflammatory response. Recently it has been demonstrated that pharmacological doses of human recombinant IL-6 (rhIL-6) inhibit certain murine tumors as well as stimulate thrombopoiesis in mice, dogs, nonhuman primates, and humans. The purpose of our study was to evaluate the effects and toxicity of rhIL-6 administration in nonhuman primates with particular reference to subject age. We treated 10 female monkeys of two age groups (midle-aged and old) with rhIL-6 (15 micrograms/kg/day) for 28 days. The monkeys were observed to be somewhat lethargic and lost an average of 10% of their body weights. The white blood cell count rose transiently whereas the levels of hemoglobin and hematocrit fell significantly and remained depressed for the same period. Importantly, platelet count rose and remained elevated for the duration of treatments. Serum alkaline phosphatase levels increase significantly and certain parameters of clinical immune competence were altered by IL-6 treatment. Treatment effects were similar in both age groups, but the changes in immune functions were different between the midle-aged and old monkeys. We observed a pattern in which the middle-aged group had a significant decrease in immune functions as a result of IL-6 administration and recovered to pretreatment level despite continuous treatment, whereas the old monkeys had a more protracted but less significant decline in these same immune functions during the trial.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The influence of recombinant human interleukin-6 on blood and immune parameters in middle-aged and old rhesus monkeys. 812 61

Nonhuman primates have been used as models for testing the role of interleukin-1 (IL-1) in inflammatory diseases, including endotoxemia. The objective of this investigation was to develop a reproducible and rapid method for in vivo evaluation of IL-1 antagonists using cynomolgus monkeys. IL-1 alone can induce many of the symptoms of endotoxemia in monkeys including fever, loss of appetite, and lethargy, however, test animals are slow to recover and may become desensitized to IL-1. We have developed an ex vivo method using whole blood for analysis of IL-1 antagonists administered in vivo to the monkeys and report here results for the naturally occurring IL-1 receptor antagonist, IL-1ra. In this procedure, animals are given an i.v. infusion of IL-1ra, and blood samples are taken preinfusion and during the infusion. The samples are incubated with or without IL-1 beta and the subsequent ex vivo induction of IL-6 determined. This allows analysis of the effects of in vivo pharmacodynamics on the efficacy of antagonists without exposing the test animals to IL-1. In this ex vivo protocol, each animal serves as its own control, eliminating from the assessment the large animal to animal variation observed with in vivo responses. By testing various doses, we estimate that 50% inhibition of IL-1 induced IL-6 can be achieved with an infusion of IL-1ra at 5 micrograms/kg/15 min. This method allows simple and efficient analysis of inhibitors and antagonists of IL-1 and, potentially, other effectors.
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PMID:An ex vivo method for studying inflammation in cynomolgus monkeys: analysis of interleukin-1 receptor antagonist. 895 81

In addition to the commonly reported ocular signs, Chlamydia psittaci infection of kittens resulted in fever, lethargy, lameness and reduction in weight gain following ocular instillation of virulent organisms. The appearance of these systemic signs was late with respect to the appearance of ocular symptoms and occurred simultaneously with increasing levels of chlamydia-specific IgG. Measurement of acute phase reactants and IL-6 in plasma indicated that both became elevated concurrent with or slightly after the appearance of fever and remained elevated after the fever began to resolve. Preliminary data also indicated that infectious C. psittaci was present in the blood stream during this time period. The results of ocular instillation of three different levels of C. psittaci (10(3.8), 10(2.8) and 10(1.5) TCID50) indicated that the frequency of infection and the severity of ocular signs were diminished in the group receiving the lowest dose. However, the magnitude of systemic disease was similar in all animals which exhibited clinical signs, irrespective of the dose administered. The immune response to infection included elementary body (EB)-specific lymphocyte proliferation as well as the development of EB-specific IgG and IgM antibodies. The predominant antibody response was to a 45 kDa protein, the major outer membrane protein (MOMP), lipopolysaccharide (LPS), a 58 kDa doublet and 32 and 16-19 kDa proteins.
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PMID:Characterization of the systemic disease and ocular signs induced by experimental infection with Chlamydia psittaci in cats. 955 58

Sleeping sickness (SS; African trypanosomiasis) is an anthropozoonosis transmitted by the tsetse fly. Infection with Trypanosoma brucei in humans is associated with adynamia, lethargy, anorexia, and more specifically amenorrhea/infertility in women and loss of libido/impotence in men. Recent evidence suggests that experimental infection in animals with Trypanosoma brucei species causes polyglandular endocrine failure by local inflammation of the pituitary, thyroid, adrenal, and gonadal glands. In a cross-sectional study we investigated the prevalence and significance of neuroendocrine abnormalities in 137 Ugandan patients with SS. In the untreated stage of the disease, there was a high prevalence of adrenal insufficiency (27%), hypothyroidism (50%) and hypogonadism (85%). Pituitary function tests suggested an unusual combined central (hypothalamic/pituitary) and peripheral defect in hormone secretion. Specific therapy resulted in a rapid recovery of adrenal/thyroid function, whereas hypogonadism persisted for years in a substantial portion of patients. We did not detect pituitary, thyroid, adrenal, and gonadal autoantibodies in patients with endocrine dysfunction, ruling out an autoimmune origin of the endocrine abnormalities. However, the presence of hypopituitarism correlated with high cytokine concentrations (TNF-alpha, IL-6) which--together with direct parasitic infiltration of the endocrine glands--are involved in the pathogenesis of SS-associated endocrine dysfunction.
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PMID:Neuroendocrine dysfunction in African trypanosomiasis. The role of cytokines. 962 7

High doses of adenotk were injected into the cerebrospinal fluid of rats and nonhuman primates (Macaca mulatta). Vector administration was followed by ganciclovir administration for 14 days. Despite the absence of clinical symptoms, analysis of the cerebrospinal fluid (CSF) and histopathological examination of the central nervous system (CNS) of the monkeys (3 weeks after vector injection) were consistent with a viral meningitis. Immunohistochemical analysis of the inflammatory infiltrates in the monkeys revealed the presence of T and B lymphocytes, indicating a combined cellular and humoral immune response to the vector. This latter was supported by the finding of intrathecal anti-adenovirus antibody synthesis. Rats receiving high intrathecal adenotk doses showed a transient and dose-dependent clinical toxicity consisting of lethargy, hyperemic eyes and weight loss. Histopathological examination of the meninges showed a shift from polymorphonuclear infiltrates during the first post-injection days to clusters of mononuclear cells after 7 days. Acute toxicity is probably related to the early, innate immune response to the vector. In a separate experiment, high levels of IL-8 and IL-6, were measured during the first 2-3 post-injection days in the CSF of two monkeys which received intrathecal adenoLacZ. Therefore, these cytokines seem to play an important role in initiating the nonspecific immune response. In one monkey which received adenotk, recombinant adenovirus was cultured from serum samples obtained at the 7th post-injection day. At this time-point, no vector could be isolated from CSF samples. Based on these preclinical data, we recommend careful dose finding for clinical studies that aim to treat patients with leptomeningeal metastases.
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PMID:Intra-CSF administered recombinant adenovirus causes an immune response-mediated toxicity. 1098 67

Hantaviruses cause two severe human diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Approximately 200,000 cases are reported annually, and there is to date no specific treatment available. A major obstacle in studying the medical aspects of HFRS and HPS has been the lack of an adequate animal model. Here we show that infection of cynomolgus macaques by wild-type Puumala hantavirus resulted in typical signs of HFRS including lethargy, anorexia, proteinuria, and/or hematuria, in addition to cytokine (interleukin 6 [IL-6], IL-10, and tumor necrosis factor alpha), C-reactive protein, creatinine, and nitric oxide responses. Viral RNA was detected in plasma from days 3 to 7 postinoculation until days 24 to 28 postinoculation, infectious virus was recovered, and the virus-specific immune responses (immunoglobulin M [IgM], IgG, and neutralizing antibodies) mimicked those seen in humans. The results indicated that the monkey model will provide a valuable tool for studies of pathogenesis, candidate vaccines, and antivirals for hantavirus disease.
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PMID:Wild-type Puumala hantavirus infection induces cytokines, C-reactive protein, creatinine, and nitric oxide in cynomolgus macaques. 1173 12

Neurons do not have receptors to detect bacteria or viruses, yet the presence of these microorganisms can cause a sickness behavior syndrome that includes, e.g., fever, anorexia, and lethargy. Because the immune system has receptors capable of detecting these non-cognitive stimuli, how the immune system transmits a message to the brain has been studied to understand why behavior is altered in sick animals. The focus has been on several cytokines secreted by leukocytes; these include interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha). These cytokines are secreted by activated mononuclear phagocytic cells, and numerous studies show that both peripheral and central injection of IL-1beta, IL-6, and TNF-alpha induce sickness behavior. Moreover, these cytokines and their receptors are present in the brain and inhibiting the secretion of cytokines or blocking their receptors in the brain blocks or abrogate the behavioral responses induced by inflammatory stimuli. Because the sickness behavior syndrome modulates the immune system and enhances recovery, the interplay between the immune system and central nervous system is an essential part of the overall host defense against pathogenic microorganisms. The purpose of this brief paper is to provide a chronological description of four critical advances that have led to the current understanding of how the immune system communicates with the brain to induce sickness behavior. Results from several key studies will be discussed, which showed that: (1) sickness behavior is a motivational state; (2) sickness behavior is a well-organized adaptive response to infection; (3) cytokines produced by activated leukocytes induce sickness behavior; and (4) cytokines transmit messages from the periphery to the brain using humoral and neural pathways.
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PMID:The concept of sickness behavior: a brief chronological account of four key discoveries. 1207 71

The objective of this study was to define the role of complement activation in the acute and transient toxicities associated with administration of phosphorothioate oligonucleotides in monkeys. In the absence of complement inhibitor, complement activation blocker-2 (CAB-2), i.v. infusion of 20 mg/kg ISIS 2302 produced increases in the concentrations of the complement split products Bb and C5a (100- and 7-fold, respectively). Monkeys also experienced marked changes in bloodpressure (hypertension and hypotension), clinical signs of toxicity (lethargy and periorbital edema), fluctuations in circulating neutrophil counts, and elevations in serum cytokine levels (45-, 12-, and 4-fold increases in IL-6, MCP-1, and IL-12, respectively). Changes occurred at or near the end of infusion and returned to normal over time. One of the three animals died approximately 4 h following infusion of 20 mg/kg ISIS 2302 alone. In contrast, prior treatment with CAB-2 effectively blocked complement activation, as well as the ISIS 2302-induced hemodynamic and clinical responses. Importantly, plasma concentration of ISIS 2302 were unaffected by CAB-2 pretreatment. Thus, the protection afforded by CAB-2 was due to its inhibition of complement activation rather than to any impact on the disposition of ISIS 2302. These results clearly demonstrate the causal relationship between activation of the alternative complement pathway and the hemodynamic and clinical responses associated with rapid infusion of phosphorothioate oligonucleotides. Demonstration of this relationship underscores the importance of avoiding complement activation in patients to ensure the continued safe use of phosphorothioate oligodeoxynucleotides.
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PMID:Complement activation is responsible for acute toxicities in rhesus monkeys treated with a phosphorothioate oligodeoxynucleotide. 1246 40

Smoking causes a variety of adverse effects on organs that have no direct contact with the smoke itself such as the liver. It induces three major adverse effects on the liver: direct or indirect toxic effects, immunological effects and oncogenic effects. Smoking yields chemical substances with cytotoxic potential which increase necro-inflammation and fibrosis. In addition, smoking increases the production of pro-inflammatory cytokines (IL-1, IL-6 and TNF- alpha) that would be involved in liver cell injury. It contributes to the development of secondary polycythemia and in turn to increased red cell mass and turnover which might be a contributing factor to secondary iron overload disease promoting oxidative stress of hepatocytes. Increased red cell mass and turnover are associated with increased purine catabolism which promotes excessive production of uric acid. Smoking affects both cell-mediated and humoral immune responses by blocking lymphocyte proliferation and inducing apoptosis of lymphocytes. Smoking also increases serum and hepatic iron which induce oxidative stress and lipid peroxidation that lead to activation of stellate cells and development of fibrosis. Smoking yields chemicals with oncogenic potential that increase the risk of hepatocellular carcinoma (HCC) in patients with viral hepatitis and are independent of viral infection as well. Tobacco smoking has been associated with suppression of p53 (tumour suppressor gene). In addition, smoking causes suppression of T-cell responses and is associated with decreased surveillance for tumour cells. Moreover, it has been reported that heavy smoking affects the sustained virological response to interferon (IFN) therapy in hepatitis C patients which can be improved by repeated phlebotomy. Smoker's syndrome is a clinico-pathological condition where patients complain of episodes of facial flushing, warmth of the palms and soles of feet, throbbing headache, fullness in the head, dizziness, lethargy, prickling sensation, pruritus and arthralgia.
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PMID:Heavy smoking and liver. 1703 78

Sickness behaviour (SB) consists of the set of adaptive responses of the host to severe infections and inflammation. It includes, among others, the thermoregulatory responses such as regulated increase (fever) and/or decrease (anapyrexia) of body temperature (T(b)), decrease of motor activity (lethargy), and loss of appetite (hypophagia) resulting in a transient loss of body weight. It is thought that SB is partially induced by the immune-derived mediators such as cytokines and prostaglandins acting on the central nervous system. It has repeatedly been shown, on the other hand, that severe infections (pneumonia, tissue septicemia) can impair processes of the gases exchange both in the lungs and in distal tissues including brain, which may lead to hypoxia of the affected organs. Therefore, we have tested the hypothesis that hypoxia may also provoke SB. The study was conducted on freely moving biotelemetered mice kept at 28 degrees C ambient and 12/12 h light/dark cycle. We demonstrate that mice exposed for 7 days to hypoxia (11%O(2)) displayed all symptoms of SB. Interleukin-6 deficient mice (IL-6 KO) revealed reduced SB symptoms under hypoxic conditions. Recovery of the hypoxia-exposed mice to a normal rhythm in T(b), motor activity and feeding was unaffected by mepacrine, a phospholipase A(2) blocker. The recovery, however, was significantly impaired by indomethacin, a cyclooxygenase inhibitor. Exposure to hypoxemia resulted in significant elevation of plasma IL-6 in both untreated and treated with lipopolysaccharide (LPS) mice. It inhibited, however, a generation of blood prostaglandins (PGE(2)) in mice. Based on these data we conclude that IL-6 and accumulation of free arachidonic acid in biomembranes contribute to hypoxemia- induced SB.
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PMID:Hypoxia-induced sickness behaviour. 1724 71


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