Department of Psychiatry, UCLA-Neuropsychiatric Institute, Los Angeles.
OBJECTIVE AND METHOD: A review of the literature on the serotonin syndrome in animals and human beings was conducted, and 12 reports of 38 cases in human patients were then analyzed to determine the most frequently reported clinical features and drug interactions, as well as the incidence, treatment, and outcome of this syndrome. FINDINGS: The serotonin syndrome is most commonly the result of the interaction between serotonergic agents and monoamine oxidase inhibitors. The most frequent clinical features are changes in mental status, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, and tremor. The presumed pathophysiological mechanism involves brainstem and spinal cord activation of the 1A form of serotonin (5-hydroxytryptamine, or 5-HT) receptor. The incidence of the syndrome is not known. Both sexes have been affected, and patients' ages have ranged from 20 to 68 years. Discontinuation of the suspected serotonergic agent and institution of supportive measures are the primary treatment, although 5-HT receptor antagonists may also play a role. Once treatment is instituted, the syndrome typically resolves within 24 hours, but confusion can last for days, and death has been reported. CONCLUSIONS: The serotonin syndrome is a toxic condition requiring heightened clinical awareness for prevention, recognition, and prompt treatment. Further work is needed to establish the diagnostic criteria, incidence, and predisposing factors, to identify the role of 5-HT antagonists in treatment, and to differentiate the syndrome from neuroleptic malignant syndrome.
PMID: 2035713 [PubMed - indexed for MEDLINE]
Senin, 11 Agustus 2008
International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin).
Sandoz Pharma Limited, Basel, Switzerland.
It is evident that in the last decade or so, a vast amount of new information has become available concerning the various 5-HT receptor types and their characteristics. This derives from two main research approaches, operational pharmacology, using selective ligands (both agonists and antagonists), and, more recently, molecular biology. Although the scientific community continues to deliberate about the hierarchy of criteria for neurotransmitter receptor characterisation, there seems good agreement between the two approaches regarding 5-HT receptor classification. In addition, the information regarding transduction mechanisms and second messengers is also entirely consistent. Thus, on the basis of these essential criteria for receptor characterisation and classification, there are at least three main groups or classes of 5-HT receptor: 5-HT1, 5-HT2, and 5-HT3. Each group is not only operationally but also structurally distinct, with each receptor group having its own distinct transducing system. The more recently identified 5-HT4 receptor almost undoubtedly represents a fourth 5-HT receptor class on the basis of operational and transductional data, but this will only be definitively shown when the cDNA for the receptor has been cloned and the amino acid sequence of the protein is known. Although those 5-HT receptors that have been fully characterised and classified to date (and, hence, named with confidence) would seem to mediate the majority of the actions of 5-HT throughout the mammalian body, not all receptors for 5-HT are fully encompassed within our scheme of classification. These apparent anomalies must be recognised and need further study. They may or may not represent new groups of 5-HT receptor or subtypes of already known groups of 5-HT receptor. Even though the cDNAs for the 5-ht1E, 5-ht1F, 5-ht5, 5-ht6, and 5-ht7 receptors have been cloned and their amino acid sequence defined, more data are necessary concerning their operational and transductional characteristics before one can be confident of the suitability of their appellations. Therefore, it is important to rationalise in concert all of the available data from studies involving both operational approaches of the classical pharmacological type and those from molecular and cellular biology.(ABSTRACT TRUNCATED AT 400 WORDS)
PMID: 7938165 [PubMed - indexed for MEDLINE]
It is evident that in the last decade or so, a vast amount of new information has become available concerning the various 5-HT receptor types and their characteristics. This derives from two main research approaches, operational pharmacology, using selective ligands (both agonists and antagonists), and, more recently, molecular biology. Although the scientific community continues to deliberate about the hierarchy of criteria for neurotransmitter receptor characterisation, there seems good agreement between the two approaches regarding 5-HT receptor classification. In addition, the information regarding transduction mechanisms and second messengers is also entirely consistent. Thus, on the basis of these essential criteria for receptor characterisation and classification, there are at least three main groups or classes of 5-HT receptor: 5-HT1, 5-HT2, and 5-HT3. Each group is not only operationally but also structurally distinct, with each receptor group having its own distinct transducing system. The more recently identified 5-HT4 receptor almost undoubtedly represents a fourth 5-HT receptor class on the basis of operational and transductional data, but this will only be definitively shown when the cDNA for the receptor has been cloned and the amino acid sequence of the protein is known. Although those 5-HT receptors that have been fully characterised and classified to date (and, hence, named with confidence) would seem to mediate the majority of the actions of 5-HT throughout the mammalian body, not all receptors for 5-HT are fully encompassed within our scheme of classification. These apparent anomalies must be recognised and need further study. They may or may not represent new groups of 5-HT receptor or subtypes of already known groups of 5-HT receptor. Even though the cDNAs for the 5-ht1E, 5-ht1F, 5-ht5, 5-ht6, and 5-ht7 receptors have been cloned and their amino acid sequence defined, more data are necessary concerning their operational and transductional characteristics before one can be confident of the suitability of their appellations. Therefore, it is important to rationalise in concert all of the available data from studies involving both operational approaches of the classical pharmacological type and those from molecular and cellular biology.(ABSTRACT TRUNCATED AT 400 WORDS)
PMID: 7938165 [PubMed - indexed for MEDLINE]
Jumat, 01 Agustus 2008
:: Angiogenesis in cancer
How angiogenesis complicates cancer
Angiogenesis performs a critical role in the development of cancer. Solid tumors smaller than 1 to 2 cubic millimeters are not vascularized. To spread, they need to be supplied by blood vessels that bring oxygen and nutrients and remove metabolic wastes.
Beyond the critical volume of 2 cubic millimeters, oxygen and nutrients have difficulty diffusing to the cells in the center of the tumor, causing a state of cellular hypoxia that marks the onset of tumoral angiogenesis.
New blood vessel development is an important process in tumor progression. It favors the transition from hyperplasia to neoplasia i.e. the passage from a state of cellular multiplication to a state of uncontrolled proliferation characteristic of tumor cells.
Neovascularization also influences the dissemination of cancer cells throughout the entire body eventually leading to metastasis formation.The vascularization level of a solid tumor is thought to be an excellent indicator of its metastatic potential.
The molecular factors involved in the stimulation of blood vessel growth are described in detail in The process of angiogenesis.
Shortcomings of standard therapies
Standard therapies to combat cancer are usually aimed at interfering with the cellular replication process which is accelerated in tumors. Despite the efforts made since 1971 to fight cancer -- the year the United States declared war on the disease -- new cases of most cancers have increased significantly. Ninety percent of all cancers are solid tumors and thus depend on angiogenesis to support their growth.
Resistance to treatment is a major issue in oncology. In hormone-dependent cancer for instance, after standard anti-hormonal therapy, it is common to see a recurrence of cancer. This occurs when a malignant cell is transformed a second time, thus making its replication independent of hormones. The same phenomenon takes place with cancers treated with chemotherapy. Often a transformed cell exposed to a powerful chemical agent goes through a mutation, giving it a selective advantage for growth, such as the production of a growth factor or resistance to chemotherapeutic agents.
It has also been shown that the resection of a primary tumor is often accompanied by metastases caused by a systemic disturbance of the angiogenic balance of the body. All these standard therapies could profit from a concomitant treatment that would restrict latent tumors in a prevascular phase.
Antiangiogenesis as a strategy against cancer
As early as the 1970s, Dr. Judah Folkman of the Harvard Medical School suggested inhibiting new blood vessel formation as a way to fight cancer.
The malignant tissue would be deprived of its oxygen and nutrient supply, as well as be unable to eliminate metabolic wastes. This in turn would inhibit tumor progression and metastatic progression that accompanies most advanced cancers. These are the main steps of the angiogenic process that can be interrupted:
Inhibiting endogenous angiogenic factors, such as bFGF (basic Fibroblast Growth Factor) and VEGF (Vascular Endothelial Growth Factor)
Inhibiting degradative enzymes (Matrix Metalloproteinases) responsible for the degradation of the basement membrane of blood vessels
Inhibiting endothelial cell proliferation
Inhibiting endothelial cell migration
Inhibiting the activation and differentiation of endothelial cells
However, the challenge is to develop an antiangiogenic factor that does not affect the existing vasculature.
Neovastat is an inhibitor of angiogenesis
A number of studies have shown Neovastat to have antiangiogenic properties. The mechanisms of action include:
Inhibiting degradative Matrix Metalloproteinases,
Blocking receptor sites for the angiogenic growth factor VEGF, which prevents endothelial cells from proliferating, migrating, and organizing to form new blood vessels in vitro.
As well, clinical and pre-clinical studies show Neovastat can be used alone or in combination with other therapies. Clinical experience with 540 patients, some of whom have been administered the drug for almost four years, have confirmed Neovastat’s excellent safety and tolerability profile in monotherapy and in concomitant chemotherapy and radiotherapy.
(Angio World)
Angiogenesis performs a critical role in the development of cancer. Solid tumors smaller than 1 to 2 cubic millimeters are not vascularized. To spread, they need to be supplied by blood vessels that bring oxygen and nutrients and remove metabolic wastes.
Beyond the critical volume of 2 cubic millimeters, oxygen and nutrients have difficulty diffusing to the cells in the center of the tumor, causing a state of cellular hypoxia that marks the onset of tumoral angiogenesis.
New blood vessel development is an important process in tumor progression. It favors the transition from hyperplasia to neoplasia i.e. the passage from a state of cellular multiplication to a state of uncontrolled proliferation characteristic of tumor cells.
Neovascularization also influences the dissemination of cancer cells throughout the entire body eventually leading to metastasis formation.The vascularization level of a solid tumor is thought to be an excellent indicator of its metastatic potential.
The molecular factors involved in the stimulation of blood vessel growth are described in detail in The process of angiogenesis.
Shortcomings of standard therapies
Standard therapies to combat cancer are usually aimed at interfering with the cellular replication process which is accelerated in tumors. Despite the efforts made since 1971 to fight cancer -- the year the United States declared war on the disease -- new cases of most cancers have increased significantly. Ninety percent of all cancers are solid tumors and thus depend on angiogenesis to support their growth.
Resistance to treatment is a major issue in oncology. In hormone-dependent cancer for instance, after standard anti-hormonal therapy, it is common to see a recurrence of cancer. This occurs when a malignant cell is transformed a second time, thus making its replication independent of hormones. The same phenomenon takes place with cancers treated with chemotherapy. Often a transformed cell exposed to a powerful chemical agent goes through a mutation, giving it a selective advantage for growth, such as the production of a growth factor or resistance to chemotherapeutic agents.
It has also been shown that the resection of a primary tumor is often accompanied by metastases caused by a systemic disturbance of the angiogenic balance of the body. All these standard therapies could profit from a concomitant treatment that would restrict latent tumors in a prevascular phase.
Antiangiogenesis as a strategy against cancer
As early as the 1970s, Dr. Judah Folkman of the Harvard Medical School suggested inhibiting new blood vessel formation as a way to fight cancer.
The malignant tissue would be deprived of its oxygen and nutrient supply, as well as be unable to eliminate metabolic wastes. This in turn would inhibit tumor progression and metastatic progression that accompanies most advanced cancers. These are the main steps of the angiogenic process that can be interrupted:
Inhibiting endogenous angiogenic factors, such as bFGF (basic Fibroblast Growth Factor) and VEGF (Vascular Endothelial Growth Factor)
Inhibiting degradative enzymes (Matrix Metalloproteinases) responsible for the degradation of the basement membrane of blood vessels
Inhibiting endothelial cell proliferation
Inhibiting endothelial cell migration
Inhibiting the activation and differentiation of endothelial cells
However, the challenge is to develop an antiangiogenic factor that does not affect the existing vasculature.
Neovastat is an inhibitor of angiogenesis
A number of studies have shown Neovastat to have antiangiogenic properties. The mechanisms of action include:
Inhibiting degradative Matrix Metalloproteinases,
Blocking receptor sites for the angiogenic growth factor VEGF, which prevents endothelial cells from proliferating, migrating, and organizing to form new blood vessels in vitro.
As well, clinical and pre-clinical studies show Neovastat can be used alone or in combination with other therapies. Clinical experience with 540 patients, some of whom have been administered the drug for almost four years, have confirmed Neovastat’s excellent safety and tolerability profile in monotherapy and in concomitant chemotherapy and radiotherapy.
(Angio World)
Process of Angiogenesis
Physiological and pathological angiogenesis
Almost all tissues develop a vascular network that provides cells with nutrients and oxygen and enables them to eliminate metabolic wastes. Once formed, the vascular network is a stable system that regenerates slowly.
In physiological conditions, angiogenesis occurs primarily in embryo development, during wound healing and in response to ovulation.
However, pathological angiogenesis, or the abnormal rapid proliferation of blood vessels, is implicated in over 20 diseases, including cancer, psoriasis and age-related macular degeneration.
The angiogenic sequence
The angiogenic process, as currently understood, can be summarized as follows:
A cell activated by a lack of oxygen releases angiogenic molecules that attract inflammatory and endothelial cells and promote their proliferation.
During their migration, inflammatory cells also secrete molecules that intensify the angiogenic stimuli.
The endothelial cells that form the blood vessels respond to the angiogenic call by differentiating and by secreting matrix metalloproteases (MMP), which digest the blood-vessel walls to enable them to escape and migrate toward the site of the angiogenic stimuli.
Several protein fragments produced by the digestion of the blood-vessel walls intensify the proliferative and migratory activity of endothelial cells, which then form a capillary tube by altering the arrangement of their adherence-membrane proteins.
Finally, through the process of anastomosis, the capillaries emanating from the arterioles and the venules will join, thus resulting in a continuous blood flow.
The normal regulation of angiogenesis is governed by a fine balance between factors that induce the formation of blood vessels and those that halt or inhibit the process. When this balance is destroyed, it usually results in pathological angiogenesis which causes increased blood-vessel formation in diseases that depend on angiogenesis.
More than 20 endogenous positive regulators of angiogenesis have been described, including growth factors, matrix metalloproteinases, cytokines, and integrins. Growth factors, such as vascular endothelial growth factor (VEGF), transforming growth factors (TGF-beta), fibroblast growth factors (FGF), epidermal growth factor (EGF), angiogenin, can induce the division of cultured endothelial cells thus indicating a direct action on these cells.
However, other factors have virtually no effect on the division of cultured endothelial cells or, in the case of TGF-beta and TNF-alpha, paradoxically inhibit their growth indicating that their angiogenic action is indirect.
Almost all tissues develop a vascular network that provides cells with nutrients and oxygen and enables them to eliminate metabolic wastes. Once formed, the vascular network is a stable system that regenerates slowly.
In physiological conditions, angiogenesis occurs primarily in embryo development, during wound healing and in response to ovulation.
However, pathological angiogenesis, or the abnormal rapid proliferation of blood vessels, is implicated in over 20 diseases, including cancer, psoriasis and age-related macular degeneration.
The angiogenic sequence
The angiogenic process, as currently understood, can be summarized as follows:
A cell activated by a lack of oxygen releases angiogenic molecules that attract inflammatory and endothelial cells and promote their proliferation.
During their migration, inflammatory cells also secrete molecules that intensify the angiogenic stimuli.
The endothelial cells that form the blood vessels respond to the angiogenic call by differentiating and by secreting matrix metalloproteases (MMP), which digest the blood-vessel walls to enable them to escape and migrate toward the site of the angiogenic stimuli.
Several protein fragments produced by the digestion of the blood-vessel walls intensify the proliferative and migratory activity of endothelial cells, which then form a capillary tube by altering the arrangement of their adherence-membrane proteins.
Finally, through the process of anastomosis, the capillaries emanating from the arterioles and the venules will join, thus resulting in a continuous blood flow.
The normal regulation of angiogenesis is governed by a fine balance between factors that induce the formation of blood vessels and those that halt or inhibit the process. When this balance is destroyed, it usually results in pathological angiogenesis which causes increased blood-vessel formation in diseases that depend on angiogenesis.
More than 20 endogenous positive regulators of angiogenesis have been described, including growth factors, matrix metalloproteinases, cytokines, and integrins. Growth factors, such as vascular endothelial growth factor (VEGF), transforming growth factors (TGF-beta), fibroblast growth factors (FGF), epidermal growth factor (EGF), angiogenin, can induce the division of cultured endothelial cells thus indicating a direct action on these cells.
However, other factors have virtually no effect on the division of cultured endothelial cells or, in the case of TGF-beta and TNF-alpha, paradoxically inhibit their growth indicating that their angiogenic action is indirect.
Langganan:
Postingan (Atom)
