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Theoretical considerations were advanced on the reaction rate of biological systems in a rocket accelerated at fractional levels of the velocity of light. The values of mass increase in reacting molecules and length contraction of space under these relativistic velocities attained by the hypothetical rocket were inserted in equations of the absolute reaction rate theory. The equations employed were for the frequency of collisions, and for the internal kinetic energy of molecular reactions. Results of both sets of equations indicated that reduction of reaction rates were correlated to the mass increase. This would imply a general slowing of all chemical, biochemical and biological processes taking place. A human would suffer a related decrease in metabolic rate. Contrary to what is generally accepted, the biological aging of the space traveler under velocities bearable by humans, namely under 0.50c, would follow a pace very similar to that of an observer remaining in the resting frame of reference. With increased increments of the velocity, the space traveler would display a more intense lowering of the metabolic rate, with signs and symptoms comparable to body core hypothermia. Metabolic rates at insufficient levels to maintain the vital functions would be attained at 0.70c and higher, leading swiftly to coma and death. The presence of an endocrine dysfunction such as hypothyroidism or obesity in the space traveler would aggravate the signs and symptoms. Space travel at efficient velocities would be unbearable for a warm-blooded animal.
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PMID:Theoretical considerations concerning the effect of relativistic velocities on the rate of biological processes. 973 67

In an effort to combat obesity, several medications have been developed. The nonamphetamine anorectics, such as phentermine, fenfluramine, and dexfenfluramine, have been recommended as first-line drug therapy for the treatment of obesity once diet and exercise alone have failed. Numerous studies have shown that these agents can promote weight loss when combined with diet restriction and exercise. Although fenfluramine and dexfenfluramine lack the abuse potential of amphetamine and its congeners, these agents are associated with drug interactions and adverse effects. Concomitant administration of fenfluramine or dexfenfluramine with medications that enhance serotonin levels (e.g., antidepressants, monoamine oxidase inhibitors, and migraine medications) can precipitate serotonin syndrome. Sudden discontinuation of fenfluramine or dexfenfluramine after prolonged administration can precipitate withdrawal depressive symptoms. Primary pulmonary hypertension, a potentially fatal disorder, has been reported to occur approximately 30 times more frequently in patients receiving anorectic agents for more than 3 months compared to the general population. More recently, the association of these popular anorectics with valvular heart disease has caused increased concerns about their use. The risks of primary pulmonary hypertension, valvular heart disease, and the occurrence of convulsions, coma, and death in overdose appear to be equally likely with dexfenfluramine and fenfluramine. In addition, many patients who lose weight while taking these anorectics rapidly regain it after the medication has been discontinued.
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PMID:A close look at fenfluramine and dexfenfluramine. 954 1

Based on 2000 census data, ethnic minorities constitute approximately 25% of the overall population of the United States, and the population of minority groups has been increasing at a faster rate than the general U.S. population. Compared with caucasians, persons from minority ethnic groups suffer disproportionately from type 2 diabetes and its long-term complications. Acute complications of diabetes occur with varying frequencies in the different demographic groups, but there are indications that the rate of hospitalization for diabetic ketoacidosis and nonketotic coma may be higher among certain minority populations. Genetic and lifestyle factors likely account for the increased prevalence of type 2 diabetes among ethnic minorities. However, the increase in morbidity and mortality from diabetes may be the result, in part, of socioeconomic factors. Pathophysiologically, several studies have documented a higher prevalence of insulin resistance in minority groups, even after correction for obesity and lifestyle factors. These findings underscore the need for a more aggressive approach to diabetes management in high-risk populations. Behavioral and pharmacologic interventions that reduce insulin resistance have profound beneficial effects in African-American patients and subjects with diabetes from other ethnic groups. Indeed, much of the ethnic difference in morbidity from diabetic complications disappears when caucasians and non-caucasians are treated to identical degrees of glycemic control.
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PMID:Ethnic disparities in type 2 diabetes: pathophysiology and implications for prevention and management. 1465 83

Monosomy 1p36 may result in a clinically recognizable chromosomal microdeletion syndrome. We report the unexpected death of a 12 year old boy with mildly dysmorphic facial features, short stature at 138 cm (3rd centile), moderate mental retardation and a history of seizures, obesity, transient muscle weakness of the right arm and leg and episodes of transient atonic hemiparesis of the right side of the body. Despite the relatively few congenital anomalies and normal karyotype, the 1p36 deletion was suspected on clinical grounds and was demonstrated by fluorescent in situ hybridisation (FISH). Two months after diagnosis and following a short history of a mild upper airway infection, high fever and severe diarrhea, the patient had a massive circulatory shock and asystolia, resulting in deep coma, brain edema, apallic syndrome and death. To our knowledge there has been no previous report of episodes of transient unilateral muscle weakness and atonic hemiparesis, circulatory shock and sudden death associated with monosomy 1p36.
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PMID:Unexpected death of a 12 year old boy with monosomy 1p36. 1508 95

Caffeine is a mild central nervous stimulant that occurs naturally in coffee beans, cocoa beans and tea leaves. In large doses, it can be profoundly toxic, resulting in arrhythmia, tachycardia, vomiting, convulsions, coma and death. The average cup of coffee or tea in the United States is reported to contain between 40 and 150 mg caffeine although specialty coffees may contain much higher doses. Over-the-counter supplements that are used to combat fatigue typically contain 100-200 mg caffeine per tablet and doses of 32-200mg are included in a variety of prescription drug mixtures. Fatal caffeine overdoses in adults are relatively rare and require the ingestion of a large quantity of the drug, typically in excess of 5 g. Over a period of approximately 12 months our office reported two cases of fatal caffeine intoxication. In the first case, the femoral blood of a 39-year-old female with a history of intravenous drug use contained 192 mg/L caffeine. In the second case, femoral blood from a 29-year-old male with a history of obesity and diabetes contained 567 mg/L caffeine. In both cases, the cause of death was ruled as caffeine intoxication and the manner of death was accidental.
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PMID:Fatal caffeine overdose: two case reports. 1593 84

Weight gain is associated with the use of many psychotropic medications, including antidepressants, mood stabilizers, antipsychotic drugs, and may have serious long term consequences: it can increase health risks, specifically from overweight (BMI = 25-29.9 kg/m2) to obesity (BMI > or =30 kg/m2), according to Body Mass Index (BMI), and the morbidity associated therewith in a substantial part of patients (hypertension, coronary heart desease, ischemic stroke, impaired glucose tolerance, diabetes mellitus, dyslipidemia, respiratory problems, osteoarthritis, cancer); according to patients, psychosocial consequences such as a sense of demoralization, physical discomfort and being the target of substantial social stigma are so intolerable that they may discontinue the treatment even if it is effective. The paper reviews actual epidemiological data concerning drug induced weight gain and associated health problems in psychiatric patients : there is a high risk of overweight, obesity, impaired glucose tolerance, diabetes mellitus, premature death, in patients with schizophrenia or bipolar disorder; and the effects of specific drugs on body weight: Tricyclic Antidepressants (TCA) induced weight gain correlated positively with dosage and duration of treatment, more pronounced with amitriptyline ; Selective Serotonin Reuptake Inhibitors (SSRI) decrease transiently bodyweight during the first few weeks of treatment and may then increase bodyweight; weight gain appears to be most prominent with some mood stabilizers (lithium, valproate); atypical antipsychotics tend to cause more weight gain than conventional ones and weight gain, diabetes, dyslipidemia, seem to be most severe with clozapine and olanzapine. Conceming the underlying mechanisms of drug induced weight gain, medications might interfere with central nervous functions regulating energy balance; patients report about: increase of appetite for sweet and fatty foods or "food craving" (antidepressants, mood stabilizers, antipsychotic drugs) and weight gain despite reduced appetite which can be explained by an altered resting metabolic rate (TCA, SSRI, Monoaminoxidase Inhibitors MAO I). According to current concepts, appetite and feeding are regulated by a complex of neurotransmitters, neuromodulators, cytokines and hormones interacting with the hypothalamus, including the leptin and the tumor necrosis factor system. The pharmacologic mechanisms underlying weight gain are presently poorly understood: maybe the different activities at some receptor systems may induce it, but also genetic predisposition. Understanding of the metabolic consequences of psychotropic drugs (weight gain, diabetes, dyslipidemia) is essential: the insulin-like effect of lithium is known; treatment with antipsychotic medications increases the risk of impaired glucose tolerance and diabetes mellitus. Several management options of weight gain are available from choosing or switching to another drug, dietary advices, increasing physical activities, behavioural treatment, but the best approach seems to attempt to prevent the weight gain : patients beginning maintenance therapy should be informed of that risk, and nutritional assessment and counselling should be a routine part of treatment management, associated with monitoring of weight, BMI, blood pressure, biological parameters (baseline and three months monitoring of fasting glucose level, fasting cholesterol and triglyceride levels, glycosylated haemoglobin). Psychiatrics must pay attention to concomitant medications and individual factors underlying overweight and obesity. Weight gain has been described since the discovery and the use of the firstpsychotropic drugs, but seems to intensify with especially some of the second generation antipsychotic medications ; understanding of the side effects of psychotropic drugs, including their metabolic consequences (weight gain, diabetes, dyslipidemia) is essential for the psychiatrics to avoid on the one hand a risk of lack of compliance, a discontinuation of the pharmacological medication and also a risk of relapse and rehospitalization, and on the other hand to avoid acute life threatening events (diabetic ketoacidocetosis and non ketotic hyperosmolar coma, long term risk complications of diabetes and overweight).
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PMID:[Psychotropic drugs induced weight gain: a review of the literature concerning epidemiological data, mechanisms and management]. 1638 18

Vagus nerve stimulation (VNS) is an established treatment for selected patients with medically refractory seizures. Recent studies suggest that VNS could be potentially useful in the treatment of resistant depressive disorder. Although a surgical procedure is required in order to implant the VNS device, the possibility of a long-term benefit largely free of severe side effects could give VNS a privileged place in the management of resistant depression. In addition, VNS appears to affect pain perception in depressed adults; a possible role of VNS in the treatment of severe refractory headache, intractable chronic migraine and cluster headache has also been suggested. VNS is currently investigated in clinical studies, as a potential treatment for essential tremor, cognitive deficits in Alzheimer's disease, anxiety disorders, and bulimia. Finally, other studies explore the potential use of VNS in the treatment of resistant obesity, addictions, sleep disorders, narcolepsy, coma and memory and learning deficits.
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PMID:Vagus nerve stimulation: indications and limitations. 1769 14

Thiopental is a barbiturate used in traumatic brain injuries (TBIs) to reduce intracranial pressure (ICP) and to manage cerebral ischemia. As thiopental follows Michaelis-Menten kinetics, therapeutic drug monitoring (TDM) has been used in practice to improve efficacy and reduce adverse effects. However, its role is still debatable, and TDM is not widely practiced. Current evidence suggests that thiopental therapy may improve mortality and functional outcome in a subpopulation of patients with severe TBI with elevated ICP refractory to conventional medical therapy. Several analytical methods are available to quantify thiopental concentrations. This review uses a previously published 9-step decision-making algorithm to determine whether TDM of thiopental in TBI is warranted. There seems to be poor correlation between thiopental concentration and pharmacological response in terms of neurological response, ICP, electroencephalography, and drug toxicity. There is no established therapeutic range for thiopental continuous infusion due to a wide range of plasma concentrations corresponding to efficacy (25-50 mg/L) and toxicity (30-70 mg/L) and the resulting overlap between the 2. Thiopental exhibits intrapatient and interpatient variability due to age, obesity, renal and hepatic dysfunction, Michaelis-Menten kinetics, and hepatic enzyme autoinduction. Available evidence suggests that TDM of thiopental continuous infusion is not beneficial in improving efficacy or avoiding toxicity. There are however 2 possible scenarios in which TDM may provide additional information to sound clinical judgment. The first is providing patient-specific plasma target concentration to guide titration of therapy. The second scenario is differentiating between brain death and barbiturate-induced coma.
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PMID:A critical review: does thiopental continuous infusion warrant therapeutic drug monitoring in the critical care population? 1917 32

Mitochondrial dysfunction is a major mechanism of liver injury. A parent drug or its reactive metabolite can trigger outer mitochondrial membrane permeabilization or rupture due to mitochondrial permeability transition. The latter can severely deplete ATP and cause liver cell necrosis, or it can instead lead to apoptosis by releasing cytochrome c, which activates caspases in the cytosol. Necrosis and apoptosis can trigger cytolytic hepatitis resulting in lethal fulminant hepatitis in some patients. Other drugs severely inhibit mitochondrial function and trigger extensive microvesicular steatosis, hypoglycaemia, coma, and death. Milder and more prolonged forms of drug-induced mitochondrial dysfunction can also cause macrovacuolar steatosis. Although this is a benign liver lesion in the short-term, it can progress to steatohepatitis and then to cirrhosis. Patient susceptibility to drug-induced mitochondrial dysfunction and liver injury can sometimes be explained by genetic or acquired variations in drug metabolism and/or elimination that increase the concentration of the toxic species (parent drug or metabolite). Susceptibility may also be increased by the presence of another condition, which also impairs mitochondrial function, such as an inborn mitochondrial cytopathy, beta-oxidation defect, certain viral infections, pregnancy, or the obesity-associated metabolic syndrome. Liver injury due to mitochondrial dysfunction can have important consequences for pharmaceutical companies. It has led to the interruption of clinical trials, the recall of several drugs after marketing, or the introduction of severe black box warnings by drug agencies. Pharmaceutical companies should systematically investigate mitochondrial effects during lead selection or preclinical safety studies.
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PMID:Mitochondrial involvement in drug-induced liver injury. 2002 Feb 67

Today, obesity is the most urgent unsolved medical problem, with the threat of a decreased life expectancy rate for the first time in medical history. Many obese subjects try to lose weight by dieting and exercising, without success on a long term basis. The only therapy with some effect is bariatric surgery with the impact of sustainable adverse effects only suitable in morbid obesity. Why are the therapies to treat obesity not working? Within the last years, we have become more aware of the role of the brain in energy homeostasis. The three main players within the brain controlling our weight are the cortex for cognition, hypothalamus for vital body functions and limbic-reward system for emotions. One hypothesizes that the failure of the cortex to inhibit the hypothalamus is the main cause of obesity. The evolutionary old hypothalamus constantly seeks for a positive energy balance, always in endeavor to avoid any energy shortage in the future. The hypothalamus is executing its tasks in a parallel mode. It can coordinate a set of vital routines independently, yet simultaneously. For e.g., energy balance, salt balance, body temperature and sleep are executed even in a coma. The hypothalamus is primitive but stable. The cortex in humans is, compared to rodents, much bigger and more complex, while the hypothalamus bears more similarities between these two species. The cortex in humans is evolutionary younger and represents higher cognition, an unique human feature. In contrast to the hypothalamus, the cortex focuses on one problem at a time, thus functioning on an attention-based manner. Due to this serial mode, the cortex uses a large part of its capacity for one problem at a time. Therefore, it can solve more complex calculations than the hypothalamus by thinking about one problem after another. It is even strong enough to veto the hypothalamus, if necessary. If the concentration on weight loss is distorted, the hypothalamus is free of inhibition by the cortex, and the subject will gain weight again. It is suggested that this is why diets do not work in the long term. In anorexic patients, the cortex is fully occupied to control the hypothalamus resulting in extreme weight loss. In obese subjects, the cortex is less disciplined and the hypothalamus will take control again to stimulate positive energy balance. From this viewpoint, the limbic-reward system interacts both with the hypothalamus and the cortex to achieve demands by emotional motivation. The last part of this paper describes a therapeutic strategy based on this hypothesis. We propose a dual approach to fight obesity. First, interventions should be implemented that remind the cortex to control the hypothalamus and second, to stimulate physiological feedback to the hypothalamus.
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PMID:To be, or not to be obese - that's the challenge: a hypothesis on the cortical inhibition of the hypothalamus and its therapeutical consequences. 2030 18


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