Anorexia Nervosa Treatment Overview

Breaking Bulimia

Breaking Bulimia

We have all been there: turning to the refrigerator if feeling lonely or bored or indulging in seconds or thirds if strained. But if you suffer from bulimia, the from time to time urge to overeat is more like an obsession.

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Bulimia Help Method

Endorsed by University Professors, Eating Disorders Specialists, Doctors and former bulimics, the Bulimia Help Method is a proven & trusted approach to lifelong recovery from bulimia. The Bulimia Help Method home treatment program gives you the insight, skills and tools needed to break free from bulimia and to make peace with food and your body. You are guided step-by-step along the way so you always know what to expect and what to do next. A powerful audio program will help to reprogram your old eating habits at a sub-conscious level, speed up your recovery and help you feel more calm and grounded.

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Pathogenesis of Anorexia

The pathogenesis of anorexia is multifactorial and related to disturbances of the central physiological mechanisms controlling food intake. The precise neurochemical mechanisms are still matter of debate however, by understanding how energy intake is physiologically controlled, insights might be obtained. the hypothalamus transduces these inputs into neuronal responses and, via second-order neuronal signalling pathways, into behavioural responses. Intuitively, anorexia may be secondary to defective signals arising from the periphery, due to an error in the transduction process, or to a disturbance in the activity of second-order neuronal signalling pathways.

Cytokines and Anorexia General

Several proinflammatory cytokines, including interleukin-1 (IL-1), IL-2, IL-6, IL-8, tumour necrosis factor-a (TNF-a) and interferon-y (IFN-Y), reduce food intake after peripheral or central administration in laboratory animals 3, 4 . Some cytokines suppress feeding synergistically 3, 4 . The anorectic effects of cytokines are pathophysi-ologically relevant because acute antagonism of particular cytokines and or their receptors often attenuates anorexia in various diseases or models of disease 5 . Furthermore, several immune challenges reduce food intake less in mice that are genetically deficient in a particular cytokine or cytokine receptor than in control animals (see below). Failure to establish a role for a particular cytokine in disease-related anorexia with genetic knock-out (KO) mice 5 is presumably due to the redundant and overlapping actions of cytokines, which allow for developmental compensation. Interestingly, the feeding-suppressive effect of proinflammatory cytokines...

Central Neural Mediation of Cytokine Induced Anorexia

The major hypothalamic detection site for blood-derived signals. Yet, severing the ARC from PVN or its connections with the PVN only slightly attenuated peripheral IL-1p-induced anorexia 35 , indicating that the ARC is involved but not necessary for peripheral IL-1p-induced anorexia. Several lines of evidence 20 implicate activation of hindbrain to forebrain aminergic neurons in the feeding suppression and hypermetabolic effects of circulating IL-1 p. IL-1p-induced anorexia may in part be mediated through prostaglandin E2-dependent activation of serotoninergic neurons originating in the raphe nuclei and projecting to the hypothalamus 36 . In line with this idea, systemic administration of a serotonin (5-HT2c) receptor antagonist and microinjection of the 5-HT1A autoreceptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) directly into the raphe nucleus both markedly attenuated the feeding-suppressive effect of peripherally injected IL-1-p 3 . Interestingly, anorexia...

Ghrelin and Anorexia Nervosa

Anorexia nervosa is a psychiatric disorder characterised by patient-induced and maintained weight loss that leads to progressive malnutrition and specific pathophysiological signs (disturbance of body image and fear of obesity). Based on the presence or not of bulimic symptoms, anorexia nervosa appears in two specific subtypes, restricting and binge-eating purging 70 . Complications in many organ systems can occur, including cardiovascular, gastrointestinal, haematological, renal, skeletal, endocrine and metabolic systems. These alterations are not only related to the state of malnutrition, but also to the behaviour of these patients to control their weight. The endocrine disturbances include hypothalamic amenorrhoea, hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis, low T3 syndrome and alterations in the activity of the GH IGF-1 axis 71-73 . Exaggerated GH secretion coupled with reduced IGF-1 levels are common findings in anorexia nervosa as well as in other catabolic...

Leptin and Anorexia in Ageing

Ageing appears to be associated with leptin resistance. It has been found that the relatively hyper-leptinaemic state of ageing animals blunts the sensitivity of the hypothalamic energy regulatory system, thus decreasing appetite even during episodes of negative energy balance. It has been found that age-associated decreased levels of orexigenic signalling through AgRP and NPY neurons in the arcuate nucleus of the hypothalamus are accompanied by increased levels of anorexi-genic signalling through POMC CART neurons. This pattern of neuropeptide gene expression may contribute to the loss of appetite and anorexia associated with ageing 56 .

Leptin and Cancer Anorexia Cachexia

The persistence of anorexia and the onset of cachexia in cancer patients, therefore, implies a failure of this adaptive feeding response 86 . Leptin, a member of the gp 130 family of cytokines, induces a strong T helper-1 lymphocyte response and is regarded as a proin-flammatory inducer 87 . Several data suggested a role of leptin in inflammatory diseases. Proinflammatory cytokines up-regulate leptin expression in white adipose tissue and increase plasma leptin levels in hamsters and mice 88 . However, in many common diseases associated with cachexia, such as chronic obstructive pulmonary disease and chronic inflammatory bowel disease, there is an inflammatory status caused by high proinflammatory cytokine levels, whereby leptin concentrations are decreased related to body fat mass. In patients with advanced non-small-cell lung cancer, serum leptin levels were lower than in controls and lower still in those who were cachectic who also showed an increase of...

Cancer Cachexia and Anorexia

The most common problems are cancer cachexia and anorexia, particularly when the tumor is already in a progressive stage. In a large study, DeWrys and co-workers reported that more than 50 of patients suffered from weight loss (21). About 15 lost more than 10 of their weight during the course of the disease. Signs of cancer cachexia are anemia, anorexia, lack of energy, and increasing weight loss. The latter is caused by a decrease in body fat and muscle mass (56-58). There is no clear correlation between the extent of malnutrition, the tumor's size,

Proinflammatory Cytokines and Anorexia

Another cause of CACS which, due to its particular aspects and appearance, may be considered specific for the syndrome is decreased food intake. Malnutrition may be considered a hallmark of cancer cachexia and it is associated with anorexia - that is, loss of appetite and or decreased food intake. Nutrition is a complex function resulting from the contribution of peripheral and central nervous afferents in the ventral hypothalamus. Stimulation of the medial hypothalamic nucleus inhibits feeding, while stimulation of the lateral nucleus promotes food intake. Among peripheral afferents, oral stimulation by pleasant tastes elicits eating, whereas gastric distension inhibits it. There is evidence that while the proinflammatory cytokines IL-1, IL-6, and TNF-a are involved in cancer-related anorexia and decreased food intake (see below), they are probably not the only mediators of CACS. Since multiple factors are involved in the control of food intake, it is possible that there are also...

Cytokines in Cancer Anorexia

Cytokines play a key role in the activation of the immune system and the inflammatory response typical of the catabolic state 39-41 . Different experimental approaches have demonstrated that cytokines are able to induce weight loss. They initiate a cascade of events that ultimately leads to a state of wasting, malnourishment, and eventually death. A number of pro-inflammatory cytokines, including IL-1, TNF-a, and interferon (IFN)-y, have been isolated in tumours, as shown in Fig. 4 7 . These cytokines together with IL-6, leukaemia inhibitory factor (LIF), and ciliary neurotrophic factor (CNTF) are also implicated in the aetiology of cancer anorexia-cachexia syndrome 6,7 . A variety of tumours and peri-tumour cells release these cytokines into the circulation 42 . Elevated serum concentrations of IL-1, IL-6, and TNF- a occur in cancer patients and the concentrations of these cytokines correlate with tumour progression 4, 42, 43 . Furthermore, peripherally circulating cytokines...

Neuropeptides and Cancer Anorexia

Food intake in tumour-bearing rats (TB-R) and control groups before and after tumour resection and sham operation, respectively. In the TB-R group, food intake decreased with the onset of anorexia. When rats were defined as anorectic, tumours were resected, while their controls underwent sham operation. Food intake continued to be measured until it normalised in TB-R, at which time rats in both groups were killed to harvest their brains. (From 59 ) Fig. 7. Food intake in tumour-bearing rats (TB-R) and control groups before and after tumour resection and sham operation, respectively. In the TB-R group, food intake decreased with the onset of anorexia. When rats were defined as anorectic, tumours were resected, while their controls underwent sham operation. Food intake continued to be measured until it normalised in TB-R, at which time rats in both groups were killed to harvest their brains. (From 59 ) ferent neuropeptides in cancer anorexia-cachexia syndrome, our knowledge...

Mechanisms of Cancer Related Anorexia Cachexia

The anorexia cachexia syndrome is one of the most common causes of death among patients with cancer and is present in 80 at death 1 . The term 'cachexia' derives from the Greek kakos, which means 'bad', and hexis, meaning 'condition'. The characteristic clinical picture of anorexia, tissue wasting, loss of body weight accompanied by a decrease in muscle mass and adipose tissue, and poor performance status that often precedes death has been named cancer-related anorexia cachexia (CAC) 2-5 . Since the 1980s, the previous concepts explaining CAC were replaced by a more complex insight, which stresses the interaction between metabolically active molecules produced by the tumour itself and the host immune response. One of the main features of the cachectic syndrome is anorexia, which may be so significant that spontaneous nutrition is totally inhibited. The pathogenesis of anorexia is most certainly multi-factorial but not yet well understood. It seems to be attributable, in part, to...

Treatment of Symptoms and Constipation as Causes for Secondary Anorexia Cachexia

In patients with advanced, progressive, incurable disease, the causes of anorexia, decreased oral intake and loss of weight are complex. Besides the primary (paraneoplastic) catabolic processes, a number of important causes for loss of appetite or weight may occur, such as severe symptoms (i.e. pain, shortness of breath, depression), syndromes (i.e. constipation, mucositis, bowel obstruction) or prolonged bed rest 12 . Poor assessment of interfering symptoms (see Chp. 9.11) by not acknowledging risk factors for symptom expression and insufficient symptom management (i.e. pain, depression, social distress), or negligence of the syndromes constipation 13 or sedation 14 can lead to sub-standard management.

Role of Brain Serotonin in Disease Associated Anorexia

Considering disease-associated anorexia as a pathological and persistent form of satiety, it is intuitive to speculate that the pathogenesis of anorexia could be related to a derangement of the physiological mechanism mediating satiety. As a consequence, much scientific effort has been devoted to clarify the involvement of hypothalam-ic appetite-suppressing circuits in the onset of anorexia. Many studies have been conducted in animal models of cancer anorexia, but it is reasonable to translate the results obtained to other diseases. Therefore, it appears that disease-associated anorexia is related to the inability of the hypothalamus to respond appropriately to consistent peripheral signals, primarily due to the hyperacti-vation of the melanocortin system. This derangement could be triggered by cytokines. The mechanisms by which cytokines negatively influence energy intake are currently under investigation. As proposed by Inui, cytokines may play a pivotal role in long-term inhibition...

Antiserotonergic Therapies Targeting Anorexia and Cachexia

Disease-associated anorexia might be therapeuti-cally approached by interfering with the neuro-chemical events downstream of cytokine activation. Serotonergic hypothalamic neurotransmission represents a suitable example, and it is therefore tempting to speculate that by interfering with hypothalamic serotonin release, food intake might be improved. Hypothalamic serotonin synthesis strictly depends on the brain availability of its precursor, the amino acid tryptophan 10 . An increase of plasma and brain tryptophan levels, leading to increased brain serotonergic activity, has been demonstrated in different diseases and linked to the presence of anorexia and reduced food intake. Tryptophan crosses the blood-brain barrier via a specific transport mechanism shared with the other neutral amino acids, including the branched-chain amino acids (BCAA). Thus, by artificially increasing the plasma levels of the competing amino acids, a reduction of tryptophan brain entry could be achieved,...

Role of Brain Monoamines in Disease Associated Anorexia Cachexia

More data support a role for hypothalamic neurotransmission as an effective therapeutic target in the treatment of anorexia. Using in vivo microdial-ysis, Blaha et al. showed that intrahypothalamic serotonin concentrations are increased in anorec-tic tumour-bearing rats 22 . In the same study, they also showed a more complex derangement of hypothalamic monoaminergic neurotransmission, since dopamine levels were also found to be depressed 22 . This evidence may give the neurochemical explanation for the results obtained in anorectic cancer patients, whose food intake has been restored and quality of life improved by the administration of dopamine (L-DOPA) at a dosage ranging from 375 750 mg day 23, 24 . Although not obtained in prospective randomised clinical trials, these data are very intriguing and further support the 'monoaminergic' approach to the treatment of anorexia. The nitric oxide system and the production of eicosanoids might be of importance for the pathogenesis of...

The Impetus Behind Studying and Treating the Cancer Anorexia Weight Loss Syndrome

Experienced oncologists acknowledge that the cancer anorexia weight loss syndrome predicts a shorter survival for patients with advanced, incurable disease. Several powerful, well-conducted studies have borne out this clinical impression. DeWys et al. focused on weight loss in a multi-institutional, retrospective review of 3047 cancer patients and observed that loss of more than 5 of premorbid weight predicted an early demise 1 . This prognostic effect occurred independently of tumour stage, tumour histology and patient performance status. Weight loss was also associated with a trend towards lower chemotherapy response rates. Anorexia carries this same prognostic effect. Chang recently reviewed the predictive capability of various cancer symptoms and found that, similar to weight loss, anorexia, or loss of appetite, also predicts an early demise for the cancer patient 2 . Thus, the impetus for studying the cancer anorexia weight loss syndrome rests in part in the hope that effective...

Brief Overview of Mechanisms To Explain the Cancer Anorexia Weight Loss Syndrome

Recent strategies for treating the cancer anorexia weight loss syndrome have relied heavily on an improved understanding of mechanisms of disease. How does cancer cause weight loss, debility and anorexia A variety of different mediators have been described. Todorov et al. have discovered a 24-kilodalton proteoglycan derived from the MAC16 tumour line 9 and have labelled this mediator proteolysis-inducing factor (PIF). Although only a few studies have focused on PIF, antibodies to this substance appear to prevent weight loss in tumour-bearing animal models. Clinical data suggest that PIF is specific to cancer-associated wasting, as it is not found in cancer patients without weight loss nor in patients who are losing weight as a result of other diseases. To our knowledge, no clinical studies that have specifically focused on PIF inhibition have been reported thus far. In addition to this mediator, other mediators that appear to play an active role in cancer-associated anorexia weight...

Eating Disorders

Although the name of this diagnostic class focuses on the fact that the disorders in this section are characterized by abnormal eating behavior (refusal to maintain adequate body weight in the case of anorexia nervosa and discrete episodes of uncontrolled eating of excessively large amounts of food in the case of bulimia nervosa), of near equal importance is the individual's pathological overemphasis on body image. A third category, which is being actively researched but has not been officially added to the DSM-IV-TR, is binge-eating disorder (included in the appendix of Criteria Sets and Axes Provided for Further Study). Like bulimia nervosa, individuals with binge-eating disorder have frequent episodes of binge-eating. However, unlike bulimia nervosa, these individuals do not do anything significant to counteract the effects of their binge-eating (i.e., they do not purge, use laxatives or diet pills, or excessively exercise). All three disorders are described in Chapter 38.

Anorexia Nervosa

Anorexia nervosa (AN) is characterised by a deliberate reduction of food intake in order to achieve an 'ideal' body weight and due to constant fear of getting fat. People affected by this disorder are constantly concerned with their body weight they try to reduce their body size and do not consider their weight loss as abnormal. AN patients have an altered way of experiencing their own body they 'feel they are fat,' even though they are underweight, and believe that some parts of their body are 'too fat,' even if they are objectively underweight. Table 1 lists the main criteria for the diagnosis of AN. Table 1. Diagnostic criteria for anorexia nervosa (DSM-IV)

Cancer Anorexia

Cancer anorexia is defined as the loss of the desire to eat, and several factors are involved in its pathogenesis. Anorexia and reduced food intake are physiological responses prompted by the growing tumour, and persistent anorexia compromises host defences, which ultimately delays recovery. Anorexia contributes to the development of malnutrition and cachexia, since it reduces the oral intake of calories, thus promoting skeletal-muscle wasting 13 . In the methylcholanthrene-induced sarcoma (MCA)-bearing Fischer rat, anorexia develops with progression of tumour growth, so that a characteristic feeding pattern is observed with the onset of anorexia (Fig. 1,11).A decrease in food intake occurs, first via a decrease in meal number associated with a simultaneous partial compensatory increase in meal size that lasts for approximately 24-48 h. Thereafter, meal size also decreases, and anorexia becomes apparent and profound 30-33 , leading ultimately to the rats' demise 32 . The decrease in...

Anorexia and Bulimia

Eating disorders that make you underweight cause health problems as severe as those caused by overweight. Anorexia, or self-starvation, is rampant on college campuses. Estimates suggest that one in five college women, and one in 20 college men restrict their intake of Calories so severely that they are essentially starving themselves to death. Others allow themselves to eat, sometimes very large amounts of food (called binge eating), but prevent the nutrients from being turned into fat by purging themselves, often by vomiting. Binge eating followed by purging is called bulimia. Anorexia has serious long-term health consequences. Anorexia can starve heart muscles to the point that it develops altered rhythms. Blood flow is reduced and blood pressure drops so much that the little nourishment that is present cannot get to the cells. The lack of fat that accompanies anorexia can also lead to the cessation of menstruation, amenorrhea. Amenorrhea occurs when Health problems resulting from...

Infantile Anorexia

This initial intensive phase of the intervention can be followed up by a telephone call and by a few visits spaced three to four weeks apart. The intervention focuses primarily on the mother because in infantile anorexia, the mother's feeding relationship with the infant is seen as central. Nevertheless, the other relationships, such as with the father, should not be overlooked.

Other thoracic malignancies

A Phase I study has been underway at the M.D. Anderson Cancer Center for patients with advanced unresectable gastric, gastroesophageal, or esophageal cancer (48). Patients must not have had previous treatment, and eligibility criteria regarding a baseline hema-tologic and liver function tests are standard. Previous treatment with irinotecan or topotecan (Hycamtin) or prior radiotherapy were exclusion criteria. The treatment plan consisted of a Phase I dose-escalation study beginning at 30 mg m2 and extending to a dose of 70 mg m2. A weekly dose of irinotecan was modified according to blood counts. Radiotherapy treatment consisted of 45-50 Gy in 1.8 Gy fractions for a total of 2528 fractions delivered over 5 wk. The irinotecan was administered 1 h prior to administration of radiation therapy on d 1 of each week of radiotherapy. In 18 patients enrolled between January and November of 1998, there were 12 patients evaluable for toxicities and response. There was a male predominance of 16...

General Symptom Data on Children at the End of Life

A retrospective chart review examined the signs and symptoms occurring at the end of life in 28 children dying from cancer in Japan. All children experienced anorexia, 82.1 had dyspnea, and 75 had pain. Other symptoms included fatigue (71.4 ), nausea vomiting (57.1 ), constipation (46.4 ), and diarrhea (21.4 ) (4). This symptom profile parallels that of the North American reviews of the symptoms of dying children (2,5,6).

General Symptom Data in the Context of Life Limiting Illness

The pattern of symptoms based on the self-report of US children aged 10-18 years treated for cancer was studied (7). This study included children across the spectrum of illness and included newly diagnosed patients, those receiving a bone marrow transplant, and those receiving palliative care. It showed that children with cancer are very symptomatic and are often highly distressed by their symptoms. A prevalence rate greater than 35 was noted for the symptoms of pain, drowsiness, nausea, cough, anorexia, lack of energy, and psychological upset. Inpatients reported being more symptomatic than their outpatient cohort, as evidenced by comparing their mean number of symptoms of 12.7 4.9 and 6.5 5.7, respectively. Recent administration of chemotherapy is associated with significant symptomatology in children with cancer (7). Children with solid tumors were more symptomatic than children with other malignancies. Pain, nausea, and anorexia were clustered as highly distressing symptoms (7)....

Chronic Obstructive Pulmonary Disease

In COPD patients, the prevalence of anorexia is particularly high, since most patients suffer from breathlessness, which affects food intake. Recent data indicate that 67 of chronic lung disease patients experience anorexia during the last year of life. This figure is not much different from the prevalence of 76 found among lung cancer patients 12 . More striking, however, are data showing that although COPD patients have physical and psychosocial needs at least as severe as those of lung cancer patients, their symptoms, including anorexia, receive much less attention from health care professionals 12 .

Second Order Neuronal Signalling

The hypothalamic arcuate nucleus, where peripheral signals mainly converge, projects to other hypothalamic areas, thus interacting with a number of neuronal populations 20 . Many pathways serving as second-order neuronal signalling pathways, including those of orexins A and B, have been described but their involvement in the pathogenesis of anorexia has so far received little attention, although it cannot be excluded. In a recent study, Li et al. showed that a loss of renal function in Wistar rats reduced hypothalamic orexin A, a prophagic mediator 33 , which in turn may have contributed to the development of anorexia in these animals. Evidence exists suggesting that disease-associated metabolic changes, and particularly alterations of protein turnover, impact on the neu-rochemistry in localised brain areas 34 . However, they also appear to have a role in sustaining and corroborating anorexia, while its onset seems to be secondary to the inability of the hypothalamus to recognise and...

Signs and Symptoms of the Arteritic Form of AION j Note

The average age at the onset of anterior ischemic optic neuropathy in patients with temporal arteritis (AAION) is about 75 years. Arteritis can also present with branch retinal vessel occlusions, choroidal infarctions, or retinal ischemia, as indicated by the presence of numerous cottonwool spots. Ischemic pareses of the extraocular muscles may be present, and ischemia of the scalp, sufficient to cause patchy areas of hair loss, have been known to appear. Even myocardial infarctions, hemispheric strokes, and cranial nerve palsies can be caused by severe forms of arteritic disease. Temporal arteritis (also called giant cell arteritis, cranial arteritis, or Horton's cephalgia a now-obsolete term ) has the following typical signs and symptoms headache, jaw claudication, scalp pain when combing or brushing the hair, malaise, fatigue, low-grade fever, anorexia, migratory myalgias, weight loss, and thickened, cord-like enlargements of the superficial, subcutaneous arteries of the scalp (...

Frontotemporal Lobar Dementias

A selective degeneration of the frontal and temporal lobes is the distinctive feature of a group of dementias estimated to comprise 15 to 20 of all dementia cases. Frontotemporal lobar dementias (FTLD) are not common, but their incidence is increasing as more cases are recognized. Individuals from early to late midlife are affected, and the clinical course averages from 5 to 15 years. Most diseases are sporadic, but familial examples with autosomal dominant inheritance also have been identified. The clinical presentation varies greatly among the diseases but all share neuropsychiatric symptoms, cognitive decline, and neurologic disorders. Neuropsy-chiatric symptoms in various combinations are usually in the foreground of the clinical picture, including behavioral and personality changes, emotional lability, depression, anxiety, restlessness, agitation, social disinhibition, and lack of initiative, planning, organizing (executive functions), insight, and judgment. Adding to the...

Glucose Metabolism Changes in CACS

In cancer patients, glucose intake is severely compromised by the presence of symptoms such as nausea, vomiting and anorexia. The reduced glucose intake induces the activation of gluconeo-genesis from lactate, muscle amino acids and free fatty acids, finally leading to depletion of fat and protein stores. The cycle converting lactate to pyruvate and glucose is named the Cory cycle. The Cory cycle activity is increased from 20 (value observed in healthy subjects) to 50 in cancer patients with CACS.

Changes in Intermediary Metabolism During the Acute Phase Response

Low-density lipoproteins, decreased lipoprotein lipase activity, increased de novo triglyceride synthesis and esterification, increased release of free fatty acid from the periphery, and a futile cycle of fatty acids between the liver and adipose tissue beds. These changes, which are promoted by a variety of cytokines, maintain serum lipid concentrations despite the presence of anorexia 4 .

Cytokine Regulation of the Acute Phase Response

The realisation that the response to illness and injury is an endogenous, not exogenous, process was a milestone in the understanding of cachexia. Our understanding that cytokines regulate the acute-phase response and cachexia resulted from several observations. For example, studies of hypertriglyceridaemia in experimental infections suggested indirect, or endogenous, control the degree of hypertriglyceridaemia was not necessarily correlated with infectious or tumour burden, and metabolic effects of infection could be reproduced with dead organisms or even with supernatants of macrophage cultures stimulated in vitro. The responsible protein was sought, isolated, and named cachectin, and its sequence was found to be identical to that reported for tumour necrosis factor (TNF) 5 . These studies concluded that this molecule was the mediator of cachexia. At approximately the same time, other investigators demonstrated that proteolysis in animals occurred after infusion of a...

Cytokines in Chronic Inflammation

With the tremendous increase in scientific knowledge about cytokines and their immune functions, it has also become clear that cytokines have systemic and local effects that are only partly related to their coordinating functions in the immune system. Thus, proinflammatory cytokines are the major endogenous mediators of anorexia and cachexia during chronic diseases. They have substantial hypermetabolic effects, which are at the core of the organism's fever reaction, and, last but not least, they are implicated in the metabolic disturbances and several other comorbidities of obesity, in particular by contributing to insulin resistance. This chapter summarises current knowledge of these effects it describes studies including different levels of scientific analysis, from the molecular through cellular to the systemic and behavioural levels, which reveal interesting features of the role of cytokines in these phenomena.

Early Childhood Developmental Social and Family History

A history of trauma is significant in evaluating for trauma sequelae including dissociative phenomena, hyperarousal, depression, eating disorders, substance use disorders, psychiatric disorders (especially posttrau-matic stress disorder), domestic violence, and commercial sex work. Specific questions about posttrau-matic stress disorder include those about dissociation, intrusive thoughts, flashbacks, nightmares, easy startle, hypervigilance, insomnia, and a sense of a foreshortened future.

Physiological Control of Ghrelin Secretion

In agreement with the major influence of nutrition on ghrelin secretion, circulating ghrelin levels are inversely related to body mass index (BMI), i.e. increased in anorexia and cachexia while reduced in obesity and overfeeding, a notable exception being patients with Prader-Willi syndrome (PWS) 3, 32, 33 . In particular, ghrelin hypersecretion has been suggested to be responsible for the hyperphagia and weight excess commonly present in this syndrome 32,33 . In both anorexia and obesity, ghrelin secretion is normalised by recovery of ideal body weight 18,34,35 . These changes are opposite to those of leptin, suggesting that both ghrelin and leptin are hormones signalling the metabolic balance and managing the neuroendocrine and metabolic response to starvation 3,35,36 .

Medical Complications Of Alcoholism Gastrointestinal Tract and Pancreas

Alcohol decreases gastric emptying and increases gastric secretion. As a result, the mucosal barrier of the gastrium is disrupted, allowing hydrogen ions to seep into the mucosa, which release histamine and may cause bleeding. Acute gastritis is characterized by vomiting (with or without hematemesis), anorexia, and epigastric pain. It remains unclear whether chronic alcohol abuse increases the risk of ulcer disease.

Identifying key symptoms

Sometimes more than one symptom may be important. For instance, patients may present with a complex mixture of symptoms which the treatment should palliate. In this situation a combination score or an algorithm maybe considered. In a trial assessing the value of mitoxantrone and prednisone in twenty-seven patients with hormonally resistant prostate cancer, Moore etal. 40 pre-defined a palliative response as a decrease in analgesic score by 50 per cent or a decrease in 'present pain intensity' by 2 points without an increase in analgesic score. In this phase II study nine patients were considered 'palliated' using this trial-specific definition, compared with only one who showed a traditional partial response. In an MRC Lung Cancer Working Party trial 41 comparing oral chemotherapy versus standard intravenous chemotherapy in patients with small cell lung cancer, QL was considered to be a primary outcome. In order to be considered 'equivalent' the oral treatment was required 'to achieve...

Cytokines General Comments

Multiple classes of cytokines have been proposed to participate in the induction and development of wasting and cachexia including via brain mechanisms. These comprise IL-1, IL-6 subfamily members including CNTF and leukaemia inhibitory factor, IFN-y, TNF-a and BDNF, which in many cases also induce anorexia 9,11,14, 28 . Studies have shown that intratumoral administration of IL-1 receptor antagonist significantly

Neurophysiology Responses

The behavioural mode of action of cytokines has been found to be consistent with the neurophysio-logical pattern induced by a cytokine 11, 27 . For instance, IL-1p activates specifically and reversibly the glucosensitive neurons in the ventromedial hypothalamic nucleus or VMN (a site involved in the integrative control of meal termination). This would predict changes of meal size and meal duration as those induced by IL-1p. Based on the data of IL-1p-induced inhibition of the inward calcium channel current (and hence calcium permeability), a model has been proposed that would be consistent with an IL-1p long-lasting VMN neuronal activity modulation that may be associated with the long-term anorexia induced by the cytokine. A decrease of calcium influx in VMN glucose-sensitive neurons may inhibit the defined calcium-dependent potassium conductance in these neurons, leading to maintenance of intracellular potassium, depolarisation and increase in neuronal activity.

Cytokine Peptide Interactions

Modulation of the neuroendocrine system by cytokines is robust and has been discussed previously in multiple elegant papers. Cytokine-neuropeptide interactions can also be antagonistic. IL-1p blocks neuropeptide Y-induced feeding and neuropeptide Y blocks IL-1p-induced anorexia IL-1p stimulates vasopressin release and vasopressin inhibits IL-lp-induced fever. In cancer models, a CNS dysregulation of neuropeptide Y mechanisms associated with an enhanced IL-1 activity and serotonin concentrations has been proposed 8,9,22 . Other endogenous cytokine-peptide interactions relevant to wasting, cachexia and the cachexia-anorexia syndrome include reciprocal cytokine-leptin (a member of the long-chain helical cytokine family)-neuropeptide Y-corti-cotropin-releasing hormone-glucocorticoid interactions, and perhaps also among cytokines and other CNS neuropeptide regulators involved in the control of energy balance including cocaine- and amphetamine-regulated transcript, melanin-concentrating...

Transducing Mechanisms and Functional Antagonism

And is indirect since IL-1 receptors are not G-pro-tein coupled. Receptors coupled to GaO that respond to feeding-stimulatory signals include receptors for galanin, endogenous opioids, and neuropeptide Y. Thus, IL-1p-induced modulation of GaO protein may be involved in IL-1p-induced brain activities and anorexia including antagonism of neuropeptide Y action. The consequence of this cytokine mode of action is broad. G-protein-coupled receptors that have been associated with energy balance regulation by the brain include receptors for cate-cholamines, serotonin, histamine, neuropeptide Y, hypocretins orexins, melanin-concentrating hormone, agouti-related protein, a-melanocyte stimulating hormone, IL-8 and other chemokines intercrines, cholecystokinin, opioids, glucagon and others. Cytokines have the ability to modulate mechanisms associated with all of these endogenous substances, and therefore, the potential of cytokine-induced modulation of G-proteins - the interface between...

Diabetic Neuropathy and Digestive System Dysfunction

Thesias over the limbs and trunk with spontaneous resolution usually occurring within a year. In 1974, Ellenberg reported on six patients with diabetic neuropathy who complained of profound weight loss and severe neuropathic pain. These patients were all males, chiefly in the sixth decade of life, had bilateral symmetrical peripheral neuropathy, severe emotional disturbance, anorexia, impotence, mild diabetes, simultaneous onset of neuropathy and diabetes, the absence of other specific diabetic complications, and a uniformly spontaneous recovery in about 1 year. Neurologic examination revealed severe muscle wasting and atrophy in all patients. Motor nerve conduction velocity studies and electromyographic studies corroborated the presence of neuropathy in all cases. Biopsies of muscle and nerve showed neu-rogenic atrophy in muscle and marked involvement of the nerves, with decrease of axon fibres. Ellenberg coined the term 'diabetic neuropathic

Ectopic ACTH Syndrome and Weight Loss

Most patients affected by ectopic ACTH syndrome have malignant tumours, half of them being small-cell lung carcinoma. The metabolic manifestations appear suddenly and progress rapidly while the typical Cushing's habitus is absent. Anorexia, weight loss, and anaemia are frequent and comprise the picture of neoplastic cachexia 30,31 .

Use in Prevention and Therapy

During increased physiologic stress, body requirements for BCAAs are greatly increased relative to other amino acids. Supplemental BCAAs are important in conserving body stores of protein in chronic illness, anorexia nervosa, very low-calorie diets, injury, surgery, burns, or infection.3 Anorexia. Appetite and food intake are increased when serotonin levels in the brain are low. By reducing brain uptake of tryptophan (the precursor of serotonin), BCAAs may increase appetite and food intake in disorders where appetite is lost (chronic infection, AIDS, cancer).

Hypothalamic Diseases and Weight Loss

Besides pituitary dysfunction, diseases of the hypothalamus can cause abnormal mental function and behavioural disorders, including hyper-phagia which leads to marked obesity or anorexia with weight loss 36 . Indeed, the hypothalamus is involved in the regulation of diverse functions and behaviours -in particular, social behaviours, sleep, sexuality, body temperature, and eating patterns. The abnormal eating pattern in subjects affected by hypothalamic lesions include exaggerated and uncontrolled food intake (binge eating, or bulimia) or profound anorexia with cachexia, as in Simmond's disease 37 . These are analogous to syndromes of hyperphagia produced in rats by destruction of the ventromedial nucleus or of connections to the paraventricular nucleus, while lateral hypothalamic damage causes profound anorexia 36 .

Effects On The Fetus And Neonate

Although maternal poliomyelitis in the first two trimesters can be associated with spontaneous abortion or stillbirth and can predispose to intrauterine growth retardation and premature delivery, poliovirus infection of the fetus was an infrequent occurrence in the prevaccine era (2-7). Maternal poliovirus infection was not linked to an increased incidence of congenital anomalies (8). Neonatal poliomyelitis was a complication of maternal infection, however. Cases presented from birth to 28 days of age, with most cases occurring between days 5 and 21. The incubation period of neonatal poliomyelitis was often shorter (

Protein Energy Malnutrition

The main cause of protein-energy malnutrition in Crohn's disease patients is anorexia, probably resulting from postprandial abdominal pain, diarrhoea, dietary restriction, and the side effects of medications 5,6 . In addition, animal studies have shown that anorexia can result from increased levels of tumour necrosis factor (TNF)-a, interleukin (IL)-1, and other cytokines 7, 8 . These weight-loss-inducing cytokines increase the expression of leptin mRNA in adipose tissue as well as plasma levels of leptin, despite the decrease in food intake that normally suppresses leptin expression 1011 . Thus, leptin may also be involved in anorexia accompanying Crohn's disease. In contrast, Lanfranchi and Geerling showed that energy intake was not decreased, but tended to increase in patients with Crohn's disease in the stage of remission or low activity 13, 14 . These results suggest that the amount of dietary intake in patients with Crohn's disease depends on the activity of the disease.

Client And Clinician Selection

In selecting clients, in general, the goal is to be as inclusive as possible, with a plan to monitor clients over time and evaluate whether the model appears helpful to them. As noted earlier, although most of the empirical studies on Seeking Safety were conducted on clients formally and currently diagnosed with both disorders, in clinical practice the range has been much broader. It has included clients with a history of trauma and or SUD, clients with serious and persistent mental illness, clients with just one or the other disorder, and clients with other disorders (e.g., eating disorders). An important consideration is clients' own preference. Given the powerlessness inherent in both PTSD and SUD, empowerment is key. It appears best to describe the

Regulation of Appetite in the Elderly

Regulation of appetite is a sophisticated process that involves feedback from peripheral sensory endings and the interaction of a variety of neurotransmitters in the central nervous system 1 . Numerous studies have shown that food intake declines over the human lifespan, with males having a greater decrease in food intake than females. A large part of the anorexia of aging seems to be related to the changes in gastrointestinal activity that occurs with aging 1 . Starvation (Anorexia of aging) The hormone leptin is released from adipose tissue 18 and exerts its effects by decreasing food intake and increasing the metabolic rate. Circulating leptin levels increase in older men and decrease in older women 19 . The increase in lep-tin levels in men is related to the decrease in testosterone that occurs with aging 1 , which, in turn, is associated with muscle loss 20 and an increase in body fat 21 . Testosterone replacement in older men leads to a decline in leptin levels 1 . The increase...

Nonsurgical Therapy 1781 Adjuvant therapy 17811 Interferon

Despite the evidence that adjuvant HDI is effective in patients with high-risk melanoma, the use of HDI is associated with significant toxicity, including anorexia and weight loss, neuro-psychiatric symptoms, myelo-suppression, and hepatotoxicity 92-94 . There are limited data on the use of this interferon regimen in patients under age 18 years. At the MD Anderson Cancer Center, 11 patients under aged 18 years have been treated with HDI, 1 patient was lost to follow-up after completion of the IV interferon (age 4 years), 6 completed the regimen with no problems (ages 916 years), and 4 had therapy discontinued early due to toxicity, 2 liver (age 6 and 11 years), 1 each neuro-cog-nitive (age 5 years) and pancreatic (age 2 years). At St. Jude Children's Hospital, 11 patients have been treated with HDI. It was well tolerated during induction, with only two grade 4 hematologic events and one grade 4 liver event (WL Furman, personal communication).

Tumour Necrosis Factor

Depend on the site of production 40 . This was demonstrated by intracerebral injection of TNF-a-secreting cells, which resulted in body weight loss and anorexia, while TNF-a-producing cells inoculated into peripheral tissue triggered cachexia, including weight loss, depletion of lipid and protein stores, and anaemia but without significant anorexia 39,40 .

Role of Ghrelin in Cachexia

The infusion of ghrelin stimulates eating and produces obesity in rats 79 , and a study in humans showed that ghrelin infusion led to short-term increase in hunger 80 . Maintenance of weight reduction after gastric bypass surgery was suggested to be due to markedly low levels of ghre-lin 76 . It has also been shown that ghrelin levels are elevated in cachectic patients with chronic heart failure or anorexia nervosa 78 . Several studies are currently underway to explore the effects of ghrelin and its agonists on cachexia.

Pathophysiology of Cachexia Mechanisms of Cachexia

Lack of protein-caloric nutrients due to famine, voluntary refusal, nervous anorexia, or poor diets, causes slimming. Infectious diseases, cancer, burns, traumas, or surgery induce hyperca-tabolism, which, by means of very similar metabolic responses (e.g. acute-phase response APR ) leads to self-cannibalism and to cachexia 35, 36 . Self-cannibalism is, in the short-term, the physiological strategy for coping with a pathogenic noxa. It can be advantageous because it immediately supplies amino acids to repair tissue damage and for the synthesis of acute-phase proteins in the liver 32,37 .

Symptoms and Complications

The incubation period is approx 6 weeks to 6 months. As the name suggests, the virus primarily affects the liver. Typical symptoms include malaise, anorexia, nausea, mild fever, and abdominal discomfort and may last from 2 days to 3 weeks before the insidious onset of jaundice. Joint pain and skin rashes may also occur as a result of immune complex formation. Infections in the newborn are usually asymptomatic.

Pancreatic cancer 31 Background

Specifically, the pain is constant and radiates to the middle and upper back, and it is due to invasion of the celiac and mesenteric plexuses (31-33). Obstructive jaundice occurs in approx 50 of all patients and up to 90 of those having cancer in the head of the pancreas (34). However, obstructive jaundice may represent less advanced cancer because patients seek medical attention early. Nausea, anorexia, weight loss, and fatigue also occur frequently.

Endocrine Abnormalities and Cytokines

The clinical symptoms of anorexia, nausea, fever, asthenia, fatigue, lethargy, myalgia, sickness, diarrhoea, anaemia, leucocytopaenia, tachycardia, headache, neurovegetative disturbances, etc., can be attributed to the release of cytokines by macrophages and activated inflammatory cells. Lipid metabolism disturbances, anorexia, and weight loss together lead to cachexia and are caused by the combined action of TNF, IL-1, IL-6, and IFN-y, the production of each being stimulated by infections and cancer 82, 83 . We demonstrated 84 high levels of TNF-a in HIV patients who had lost more than 10 of their ideal weight (Table 3).

Mechanism of Action

MDMA is a dirty drug, affecting many neurotransmitter systems. It is primarily serotonergic, and its principal mechanism of action is as an indirect seroto-nergic agonist (Ames & Wirshing, 1993 Rattray, 1991 Sprague et al., 1998). The drug's effects, and side effects (an arbitrary distinction), including anorexia, psychomotor agitation, difficulty in achieving orgasm, and profound feelings of empathy, can be explained as a result of the flooding of the serotonin system (Beck & Rosenbaum, 1994). After ingestion, MDMA is taken up by the serotonin cells through active channels, effecting the release of serotonin stores. MDMA also blocks reuptake of serotonin, and this contributes to its length of action. Although it inhibits the synthesis of new serotonin, this does not contribute to the intoxication phase, but it may contribute to sustained feelings of depression reported by some users and to a diminished magnitude of subjective effects when the next dose is taken within a few days of...

Gallbladder and biliary system cancers 41 Background

Gallbladder cancers are often diagnosed incidentally or in late stages. The symptoms can include pain, vomiting, fatty food intolerance, anorexia, jaundice, and weight loss. Unlike gallbladder cancer, however, the most common symptom of bile duct cancer is painless jaundice, especially in patients having cancer involving the proximal bile duct. Nonspecific symptoms also can be manifested.

Amylin Analogs Pramlintide

Pramlintide is the first amylin analog commercially available and received FDA approval in March 2005 for therapy in both T1DM and T2DM. Pramlintide, studied as an adjunctive therapy to insulin, has been shown to improve postprandial and overall glycemic control in individuals with both T1DM and T2DM (improvements in HbA1C of 0.67 82 and HbA1C of 0.62 ,83 respectively) without increasing the incidence of hypoglycemia or weight gain. The glycemic improvements with pramlintide had no significant effects on lipid concentrations or blood pressure and showed no evidence of cardiac, hepatic, or renal toxicity. The most frequent adverse side effects associated with pramlintide therapy include transient mild to moderate nausea and anorexia. In its current formulation, pramlintide is administered via subcutaneous injection separately from insulin.

Medroxyprogesterone Acetate and Megestrol Acetate Clinical Experiences

Medroxyprogesterone Acetate In two clinical studies 22, 66 , we used MPA(1 g day, os) and a hypercaloric diet to correct anorexia and cachexia occurring in HIV-infected patients. In the first study 22 , MAP was administered to 74 AIDS patients. The control group of 96 The progestogenic synthesised derivative MA has been successfully used in the treatment of neoplas-tic cachexia, anorexia, and in AIDS patients 24,56, 81-83 , but the optimal dosage of the drug remains to be defined. Also, the mechanism of action of MA is many-sided and not yet completely understood. It is thought that the stimulation of appetite by progestogens takes place at the hypo-thalamic level 84-86 . A second effect of MA, which has been demonstrated in vitro, is the promotion of fibroblast transformation into adipocyte. Finally, evidence has emerged showing anti-TNF and anti-IL-1 action 83 . may be achieved with a dose of 320 mg day. We designed a controlled study to evaluate the safety and efficacy of MA at...

CASE 4 Hypothalamic Amenorrhea Case Description

This 28-yr-old Asian-American female presented for the evaluation of secondary amenorrhea at age 24. Menarche began at 13 yr of age and was followed by several years of irregular periods. At age 16, her menses stopped and she remained amenorrheic until her presentation. She denied any significant change in lifestyle or activity. There was no antecedent weight loss or illness. She was not depressed and denied a history of eating disorders or anosmia. Her examination was significant for Tanner stage 4 breast development and Tanner stage 5 axillary and pubic hair development. Her vagina, however, was severely atrophic, suggesting long-term hypoestrogenism. There was no indication of other endocrine disorders.

Cachexia and Melatonin

Among the possible mediators involved in the pathophysiology of cancer anorexia-cachexia, the increased production of tumour necrosis factor (TNF)-a has long been implicated 45 as one of the major cytokines inducing wasting syndrome and enhancing REE. Melatonin was demonstrated to be able, both in vitro and in animals, to inhibit the lipopolysaccharide-induced TNF production in an endotoxic shock model 46 . In a preliminary study 47 , we found evidence of feedback systems between the pineal release of melatonin and TNF secretion other studies on the clinical use of mela-tonin in the palliation of symptoms suggested a role for melatonin activity in the improvement of the clinical conditions of patients with advanced-stage cancer 48 .

Historical Context

Cancer is a leading cause of death in Americans, second only to heart disease. While breast cancer kills the most women, many gynecological cancers are part of the overall cancer statistic. Ovarian cancer, the so-called whispering disease because of its insidious nature, is detected in one in 70 predominantly perimenopausal and postmenopausal American women and often metastasizes undetected. Risk factors include family history of ovarian and breast cancer, high dietary fat, delayed menopause, and no or late childbearing. The use of oral contraceptives appears to decrease risk. Ovarian cancer often presents itself with a cluster of three persistent and severe symptoms a swollen abdomen, a bloated feeling, and urgent urination. Other symptoms associated with the disease include gas pains, anorexia, backache, and indigestion. Unfortunately most women seek medical advice when their ovarian cancer is in the advanced stage because the symptoms might be associated with other gynecological...

Nutrition in the Palliative Care Context

The goal of palliation is to alleviate the suffering of patients and their relatives that is caused by distressing symptoms and complications. Treatment is based on active assessments that take into account multidimensional (physical, psychological emotional, social, spiritual existential) aspects 6 . Palliative nutrition aims to primarily improve subjective well-being of patients and their relatives, rather than to improve weight or nutritional intake per se (for further discussion of this concept, see the chapter 'Palliative Management of Anorexia Cachexia and Associated Symptoms').

Symptom Assessment Close to the Patients Endof Life Multidimensional Issues

Eating-related symptoms may also carry a more multidimensional meaning, one that reflects the suffering. The concept of 'total anorexia' has not been defined, although attempts have been made to define 'total pain.' Likewise, a staging system for eating-related symptoms, in order to identify refractory eating-related symptoms, has not yet been developed.

The Meaning of Eating in Terminally Ill Patients Importance of Carers

Mc Clement et al. observed three patterns of family interactions with patients and health-care providers around the issue of nutritional care in the Palliative Care Unit setting 14 . The authors used a qualitative systematic approach with repeated interviews until saturation. The first pattern was 'fighting back.' Family interactions were driven by expectations to reverse anorexia and cachexia, which were perceived as the cause, not as a consequence of the terminal illness. Substantial conflict between family members and health-care providers was reported. The second pattern, 'letting nature take its course,' was characterised by desire-driven care. Nutrition was understood not to stave off the inevitable and so family members found other ways to care ('being there,' 'simply be'). They appreciated the opportunities to say goodbye and to express feelings. In the third pattern, 'waffling,' family members were ambivalent, shifting between fighting back and letting nature take its course....

Assessment Instruments for Eating Related Distress

Traditional instruments, such as the FAACT (Functional Assessment of Anorexia Cachexia Therapy) for anorexia cachexia, or widely used quality-of-life instruments, such as the EORTC-QlQ-c30, carry some items related to distress, but they were not specifically developed for the purpose of assessing distress. The FAACT 19 , as an example, asks at least three distress-related questions 'I am worried about my weight' (item 3), 'I am concerned how thin I look' (item 5), and 'my family or friends are pressuring me to eat' (item 8). In the general section of the FACT, there is a question regarding the impact of physical function on social contacts (item 3). In the EORTC-QlQ-c30, questions assessing interference with (physical) function (items 6, 7) or social contacts (items 26, 27) may depict issues related to cachexia and weakness, but not directly to eating. As a solitary symptom, only the impact of pain on daily life (item 19) is included in the EORTC-QLQ-C30, but there are no items...

Nonsteroidal Anti Inflammatory Drugs

Inhibiting PG production by the rate-limiting enzymes known as cyclo-oxygenases (COX). Because traditional NSAIDs inhibit both COX-1 and COX-2, these drugs induce adverse effects such as gastrointestinal injury up to ulceration, reduced appetite and consequent reduced body weight indeed, these drugs may be considered a potential cause of anorexia in patients with cancer.

The Diagnosis of Cancer Cachexia and its Implications

However, not all patients will conform to the stereotypical image of 'cachexia' for example, they may still be technically overweight despite having lost a substantial mass of lean tissue or they may be relatively weight-stable despite significant physiological change.

Nutritional Therapy Background

Patients with advanced cancer may have an inadequate nutritional intake and fail to increase appropriately their intake in response to increased resting energy demands 18 . Intake may be reduced by 'primary' mechanisms induced by the cachexia syndrome (and manifesting as anorexia or early satiety) or may be 'secondary' to problems such as mechanical gut obstruction or impaired swallowing, nausea, constipation, depression, gastrointestinal fungal infection and treatment side-effects (e.g. opiates, antibiotics, chemotherapy, radiotherapy). Such secondary problems should be proac-tively sought and appropriately managed. In addition, the medical team should also be alert to the risk of deteriorating nutritional status when patients are hospitalised 19,20 . The pathogenesis of 'primary' anorexia early satiety and the control of human appetite are incompletely understood. At the present time,

Conventional Nutritional Support

The broad aims of nutritional support for cachectic cancer patients are to improve function and well-being, to reduce morbidity and mortality and to strengthen patients for further challenges that may be imposed upon them. A number of trials have studied conventional nutritional support in cancer patients, several in patients receiving anti-tumour therapy. These therapies may themselves be regarded as 'stressors' that can continue for weeks or months. Furthermore, many cancer interventions may exacerbate reductions in energy and nutrient intake. Surgical patients may be fasted for prolonged periods perioperatively and both chemotherapy and radiotherapy may induce side-effects such as anorexia, nausea, vomiting, mucosi-tis, taste change or lethargy (depending of course on the drugs being used and the location, treatment volume and dose of radiotherapy) 27 . Current understanding as to how nutrition and chemotherapy interact is incomplete 28-30 . Intuitively a nutritionally replete...

Appetite Stimulants Progestational Agents

Originally used as a therapy in hormone-sensitive tumours, the observation that in a substantial number of patients appetite and weight increased led to it being studied in cancer cachexia 81 . It has been widely promoted as a therapy for cachexia and anorexia, although whether patient function or quality of life is improved is less clear. Appetite can be increased after only a short period of treatment 82 . Improvements in well-being may also occur in some patients without obvious changes in nutritional status 83 . Although it has not been assessed in all studies, there appears to be little impact on lean body mass, which is currently thought to be the most important body compartment in modulating function. In fact, a detrimental effect on muscle has been demonstrated in elderly males 84 and the weight gain seems largely secondary to increased fat and some fluid 85 . This is consistent with observations in AIDS patients 86, 87 . Megestrol acetate has...

First Clinical Study Of Immune Gene Therapy For Patients With

The intravenous infusion of transduced cells was well tolerated. None of the patients experienced immediate toxicity or adverse events. The patients in groups 1, 2, and 3 commonly experienced flu-like symptoms. These included fever, fatigue, and anorexia, which began within

Cachexia Cachexia Therapy and Protein Nutrition

A large fraction of patients with advanced cancer develop cachexia 1 , a wasting syndrome characterised by anorexia, asthenia, and profound losses of adipose tissue and skeletal muscle mass. The association of cachexia syndrome with poor prognosis, loss of functional status and poor quality of life has motivated researchers to develop therapeutic strategies for this problem 2 .

Other Antiinflammatory Agents

One of the most promising studies to look at anti-inflammatory agents was a landmark trial from Lundholm et al. 27 . In a placebo-controlled trial, these investigators found that indomethacin resulted in an improvement in survival in advanced cancer patients with the anorexia weight loss syndrome. Since then, other studies have suggested that non-steroidal anti-inflammatory agents may play a role in treating this syndrome 28 . Although direct antineoplastic effects may be at work in achieving these benefits, the implication that the cancer anorexia weight loss syndrome is mediated by inflammation suggests that these agents might also be directly treating this syndrome. Further confirmatory clinical studies and further mechanistic studies with these agents in this setting are indicated.

Mechanism of Action of High Dose Progestins in CACS

The first question has been answered in a trial on a group of 65 patients with non-hormone-sensitive tumours, undergoing treatment with 2000 mg day of MPA (Fig. 1, bottom) appetite (anorexia) improved in 62 of patients, while body weight increased significantly (more than 0.5 kg) in 63 4 .

Controlled Trials on MPA

Placebo-controlled trials 9-13 on the effect of MPA treatment on anorexia and body weight generally confirmed an improvement in both parameters (Table 2). It is important to remark that in three studies 9-11 MPA was administered during chemotherapy, and that in the same studies an improvement in quality of life was reported. Nevertheless, in contrast with our previous experience, those authors 13 who analysed body composition demonstrated that the bulk of the weight gain was due to increased body fat, while fat-free mass was not significantly influenced by the treatment. Anorexia

Biological Rationale of Medical Treatment of Cancer Cachexia

This kind of approach has recently been evaluated in clinical research, and some preliminary results seem promising, but it would be hasty to state that the treatment of cancer cachexia as a 'target approach' is possible 57, 67 . Indeed, the reasons limiting a 'target approach' are various, and not well known. Besides the role of cytokines (interleukin 1, interleukin 6, interferon gamma and tumour necrosis factor alpha) in the patho-genesis of cachexia, some other mechanisms might play a pathogenetic role together with or instead of the cytokine cascade, favouring a low activity of an 'anti-cytokines' approach, or a mechanism of 'escape' in some patients 1,68 . However, the possible variables occurring in the 'cytokine-mediat-ed' anorexia-cachexia syndrome probably represent one of the main reasons supporting a target approach. An improvement in clinical results might be achievable by selecting patients using biological predictive factors of response, when we are able to detect...

Outcomes of a Palliative Treatment of Cancer Cachexia

Moreover, the main outcomes and the surrogate outcomes of a medical approach should be defined in clinical research, and the relationship between main and surrogate outcomes represents an open question not yet fully answered 74-79 . Indeed, there are no definitive data distinguishing main and surrogate end-points in quality-of-life assessment, and the relationship between symptom control and quality of life in an outcome analysis is still unclear. Symptom assessment surely represents the core of the validated instruments for quality-of-life assessment, but it cannot represent by itself a validated instrument for quality-of-life assessment. It follows that symptom assessment can be an index of activity of a treatment, or a surrogate end-point of quality of life, but quality of life must be considered either the main outcome of a treatment in palliative care, or the main index of efficacy of the treatment 74 . If we assume that symptom assessment represents an index of activity, and...

Corticosteroids or High Doses of Progestagens The Best Choice in Clinical Practice

In the previous paragraphs we have reviewed the evidence supporting the use of corticosteroids or progestagens in the treatment of cancer anorexia-cachexia, supplying either the evidence of activity and efficacy (if any), or the limits of their use in clinical practice. The next step is the evidence-based analysis of the reasons for selecting one approach rather than another in clinical practice. Most reviews suggest some assumptions that are worthy of critical analysis

TNFa and Cancer Cachexia

TNF-a was originally named 'cachectin' when identified as a circulating mediator of wasting in an animal model of chronic parasitic infection 22, 23 . In subsequent studies it was found that continuous infusions of TNF-a in rats resulted in the development of anorexia, loss of body weight, protein, lipid and cell mass, leading to death 24-26 . Oliff et al. established an animal model using a tumour cell line that continually produced low concentrations of TNF-a. When this cell line was transplanted into nude mice, 80 of the animals developed severe, progressive weight loss and ultimately died with the pathological and his-tological characteristics of cancer-induced

Objectives for a Clinical Trial

There is concordance of opinion amongst physicians, clinical scientists and regulatory health authorities on the value of multicentre, randomised, controlled clinical trials, with adequate statistical power and preferably double-blinded, to determine the true effects of an intervention with therapeutic intent. To evaluate treatment of a complex syndrome such as cachexia, rather than a distinct or singular abnormality, those design features may be considered requisite. Restrictive protocol eligibility criteria and stratification on prognostic factors must be used to limit the impact of various co-morbidities, concomitant medications, patient histories and physicians' treatment patterns and skills. Patients with eating disorders, infections, maldigestion, malabsorption or diarrhoea, adrenal or thyroid diseases should be excluded. Efforts to limit disparities among the patients may reduce confounding variables but also will limit the validity of generalisations about the results from the...

Diagnosing Psychiatric Disorders In Patients With Substance Use Disorders

Given these considerations, one could ideally establish diagnostic rules to assist in determining whether a psychiatric syndrome is due to substance use or represents a separate and independent disorder. For example, some clinicians may establish a rule that a patient must be abstinent from alcohol and drugs for at least 4 weeks before they can make a diagnosis. Unfortunately, one does not always have the luxury of observing such lengthy abstinent periods (either by historical report or in the present) to assess this. In such circumstances, guidelines, as opposed to strict rules, can be helpful. For example, several studies have indicated that for alcoholics with major depression, treating the depression can have a positive impact on drinking (Cornelius et al., 1997 Greenfield et al., 1998). Thus, while DSM-IV-TR (American Psychiatric Association, 2000) criteria for substance-induced mood disorder suggest at least 4 weeks of observation during abstinence before a clinician can...

Table 92 Symptoms of Depression

Psychiatrists use the symptoms of insomnia and decreased appetite (also referred to as anorexia) in order to identify the most severe form of depression, which is called melancholia. This used to be called endogenous depression, because it comes on suddenly without any pr cipitants and seems to grow from within (endo inside, genous to grow) for no apparent reason. In addition to terminal insomnia and anorexia, people with melancholia complain of other symptoms. One is a pervasive loss of interest or pleasure, including a subjective sense that their change in mood is different from normal (e.g., different from feelings that occur in response to a personal loss). Another indicator of melancholia is a change in mood state during the day, with a tendency to feel worse in the morning and better as the day goes on (known as diurnal variation). Other symptoms of melancholia include excessive guilt and severe psychomotor retardation or agitation. People with melancholia usually are able to...

Treatment with Appetite Stimulants Megestrol Acetate

Von Roenn et al. found that treating patients with MA for AIDS-related anorexia cachexia not only increased weight, but also improved body image, sense of well-being, and pleasure from eating 45-47 . The Food and Drug Administration (FDA) has approved the use of MA for the treatment of anorexia, cachexia, and or an unexplained significant weight loss in patients with a diagnosis of AIDS. A few studies have shown that treating cachexia in the elderly with MA improved quality of life and weight gain 48-51 . Lambert et al. found that MA appears to have an anti-anabolic effect on muscle size, even when combined with testosterone replacement. Resistance exercise attenuated this reduction in muscle mass 52 . patients improved with MA. In addition, cytokine levels in these patients decreased with MA treatment, but not with chemotherapy alone. They 57-60 also found that medroxyprogesterone acetate reduces the in vitro production of pro-inflammatory cytokines (IL-1, IL-6, TNF-a, and serotonin)...

N3 Fatty Acids and Fish

N-3 fatty acids, mainly from fish oils, interfere with the cyclooxygenase (PGE2 production) and lipooxygenase metabolic pathways. They also inhibit cytokine synthesis and activity 151, 152 . Dinarello 153 and Endres 154 found that N-3 fatty acids improved food intake in rats with IL-1-induced anorexia. Tisdale and Dhesi also reported that using omega-3 fatty acids stopped the weight loss in an experimental cachexia model 155 . While the role of N-3 fatty acids in the treatment of cancer cachexia remains unclear 156 , their potential role in the treatment of cancer cachexia is promising 157,158 .

Prevention Strategies

Physical symptoms compound psychological distress and can precipitate death by suicide. Providing symptomatic relief and palliation of nociceptive and neuropathic pain, pruritus, diarrhea, nausea, emesis, and anorexia can avert a suicidal crisis in persons with HIV infection.

Clinical Presentation and Diagnosis

The symptoms associated with HCC are usually of short duration, and most often patients present with an enlargement of the abdomen and an associated palpable right upper quadrant mass. Anorexia, weight loss, and abdominal pain are frequently seen in association with advanced disease. Rarely, it may present as an acute abdominal crisis secondary to tumor rupture. Jaundice, vomiting, fever, and pallor are rare. On physical examination, hepatomegaly is common, and a palpable hard mass is frequently found. If the tumor is associated with pre-existing inflammatory or metabolic diseases of the liver, signs associated with cirrhosis of the liver can be found, including splenomegaly and spider angiomata. Most frequently there is extensive involvement of the liver by the tumor, and often the tumor is multifocal in origin. The presence of ascites may suggest intraabdominal extension, and at least one-third of patients present with metastatic involvement, with the lungs being the most common...

Clinical Disease Manifestations Of Hivassociated Cognitive Impairments

May present with a mild influenza-like illness and rarely a mononucleosis-like syndrome (Martin et al., 1992 Beckett and Forstein, 1993 Huang et al., 2005). A portion of these individuals will develop headaches, fever, myalgia, anorexia, rash, and or diarrhea within the first 2 weeks (Schacker et al., 1996 Lindback et al., 2000 Tyrer et al., 2003 Pilcher et al., 2004). Prior to seroconversion, the acute phase of viral infection is characterized by a rapid HIV-mediated loss of memory CD4+CCR5+ T cells within the mucosal tissues that results in potentially irreversible immune suppression (Veazey et al., 1998 Brenchley et al., 2004 Mehandru et al., 2004 Derdeyn and Silvestri, 2005). During this acute HIV infection, high levels of vire-mia and viral shedding at mucosal sites occur. Genital and oral ulcers, cancers, and coinfections with a number of sexually transmitted microbial pathogens, including herpes simplex and hepatitis viruses, syphilis, and gonorrhea, can also manifest during...

Proteasome Dependent Protein Degradation

Cachexia is frequently accompanied by elevated levels of proinflammatory cytokines 1-5 . Indeed, tumour necrosis factor-a (TNF-a) appears to play a key role in the development of this perturbation 6 . TNF-a was first described in 1975 and termed cachectin for its ability to induce weight loss and anorexia in mice 7 . This syndrome, however, was reversed when the injection of TNF-a was discontinued. In chronic heart failure, for example, which often leads to cardiac cachexia, TNF-a leads to reduced peripheral blood flow 8 , increased apop-

Chronic Inflammation as a Cause of Cachexia in CKD Patients

A recent study of 331 maintenance haemodial-ysis patients showed a strong association between anorexia and high levels of pro-inflammatory cytokines 41 . In this study, an appetite questionnaire was used, and the subjectively reported appetite was scored from 1 to 4, corresponding to normal to poor appetite. Inflammatory markers including serum concentrations of high-sensitivity C-reactive protein (hs-CRP), tumour necrosis factor (TNF)-a and interleukin-(IL)-6 were measured. Markers of inflammation were progressively higher in association with declining grades of appetite. There were statistically significant negative correlations between appetite score and serum CRP and TNF-a, and these correlations remained significant after case-mix multivariate adjustment for age, sex, race, and diabetes. After dichotomising the appetite score, the odds ratio (OR) of anorexia, controlled for case mix and other pertinent covariates, for each 10 pg increase in serum TNF-a ml was 1.75 (confidence...

Malnutrition Inflammation Complex Syndrome

Inflammatory processes in patients with renal insufficiency 26,98-100 . Thus, chronic inflammation may be the missing link that causally ties protein-energy malnutrition to morbidity and mortality in these individuals. The following arguments have been proposed to indicate that the development of protein-energy malnutrition is secondary to inflammation (1) Pro-inflammatory cytokines such as TNF-a not only promote catabolic processes, engendering both protein degradation and suppression of protein synthesis, but also induce anorexia 101-103 . Low appetite has been shown to be associated with increased inflammatory markers in haemodialysis patients 41, 72 . (2) Dialysis patients with signs of inflammation are reported to develop weight loss and a negative protein balance even with an intact appetite, since there may be a shift in protein synthesis from muscle to acute-phase proteins as renal function declines 100 . (3) In both CKD and ESRD patients, albumin synthesis is suppressed when...

Dose administration malaise myalgias fatigueDLT for lowdose administration

-mucocutaneous effects (stomatitis, mucositis) -cardiovascular effects (arrhythmias, hypotension) -anorexia -anorexia, nausea and vomiting -alopecia Dexamethasone -corticosteroid -leukocytosis -nausea and vomiting -anorexia or increased appetite -CNS effects (psychosis, confusion) -fluid retention -hyperglycemia -osteoporosis

Demonstration of a Structure Toxicity Relationship A Strategy for Lead Progression

The drug-sparing 30-day toxicology protocol designed by Piper required that my laboratory need only prepare 8-12 g of each test compound. The use of such limited drug quantities was feasible, as the protocol would involve the dosing of only three rats per sex. As the rationale of the study was to enable the expeditious identification of oxazolidinones having at least a 10-fold therapeutic index in the rat, the test compounds were dosed orally, twice daily (b.i.d.), at a dosage level 10-fold the ED50 (the effective dose (mgkg_ 1) that protected 50 of the mice from death after an injection of a lethal dose of S. aureus). As the comparative study progressed, the toxicologists reported several distinct toxicological findings that were readily apparent by clinical observation in the group of rats dosed orally with ( + )-DuP-721 at 100mgkg_ 1 day_ 1. Those findings included alopecia, severe anorexia, ataxia, and the death of one of the six animals another two animals observed in a moribund...

Semaxanib SU5416 SU6668 and Sunitinib SU11248

But there were mild-moderate side effects included nausea, diarrhea and fatigue. Median time on study was 13 weeks (range 2-86 weeks), and no maximal tolerated dose (MTD) was reached. In a dose-escalation pharmacological study, SU6668 was administered at 100 or 200 mg kg to 16 patients with advanced solid tumors. No significant toxicities were observed. SU6668 was extensively bound to plasma proteins. A three-times daily dose regime suggested an MTD of 100 mg kg when administered with food. Half-life was 3.6 h. A dose of 300 mg kg administered with food was well tolerated among 35 patients, with adverse effects including fatigue and joint pains. DLT was 400 and 800 mg kg with grade III thrombocytopenia. Four patients had stable disease for more than 6 months. Phase I data were presented at the 39th ASCO meeting, June 2003. A group of 24 patients with advanced solid tumors were given between 200 and 500 mg kg day of SU6668 for 28 days. Grade I and II toxicities were edema, nausea,...

Strategies To Fight Cachexia Based on Cytokines and Transcriptional Factors

Since both anorexia and metabolic disturbances are involved in cancer cachexia, the development of different therapeutic strategies has focused on these two factors. Unfortunately, counteracting anorexia either pharmacologically or nutritionally has led to rather disappointing results in the treatment of cancer cachexia. It is basically for this reason that the strategies mentioned below rely on neutralising the metabolic changes induced by the tumour, which are ultimately responsible for the weight loss. Therefore, taking into account the involvement of cytokines in cachexia, therapeutic strategies have been aimed at blocking either their synthesis or their action.

Neovastat Ae941 structure unknown

A US open-label, multicenter phase I II study suggested that Neovastat was efficacious in the treatment of refractory metastatic lung cancer 215,302,303 . The study did not demonstrate any serious adverse events. Analysis of data from a group of 48 patients with unresectable late-stage NSCLC from phase I II dose-tolerance trial showed that those receiving more than 2.6 mg kg day Neovastat were 50 less likely to die than those who received less than 2.6 mg kg day 302,304 . Neovastat has now been monitored in over 800 patients, some ofwhom have taken the drug for over 4 years. Overall, Neovastat has an excellent safety profile with few side effects. Although one serious adverse event (hypoglycemia) was noted in type II diabetic patients, other grade III to IV toxicities have not been observed. Phase I II trial of Neovastat (30-240 mL day) conducted in 331 solid-tumor patients demonstrated the most frequent adverse events of nausea (7 ), vomiting (3 ), dyspepsia (2 ) and anorexia (2 )...

Immunological Parameters of Nutrition

4.1 Anorexia 8.2 Treatment of AIDS Anorexia-Cachexia Syndrome and Lipodystrophy 9.9 Omega-3 Fatty Acids, Cancer Anorexia, and Hypothalamic Gene Expression Eduardo J.B. Ramos, Carolina G. Goncalves, Susumu Suzuki,Akio Inui, 10.4 Palliative Management of Anorexia Cachexia and Associated Symptoms 10.9 An Update on Therapeutics The Cancer Anorexia Weight Loss Syndrome in Advanced Cancer Patients Pharmaco-nutritional Support, Progestagen and Anti-COX-2 Showing Efficacy and Safety in Patients with Cancer-Related Anorexia-Cachexia and Oxidative Stress

First Line Agents Selective Serotonin Reuptake Inhibitors

SSRIs have been studied in elderly depressed patients and have been shown to be effective and generally well tolerated and to have few side effects (New-house 1996). Some side effects, such as mild anorexia, nausea, gastrointestinal upset, jitteriness, and headache, typically diminish within the first few days to weeks of initiation of therapy others, such as sexual dysfunction (including inhibited desire, delayed ejaculation, and anorgasmia) and later-onset weight gain, may not diminish at all.

Consequences of Altered Glucose Metabolism Oxidative Stress

An inadequate detoxification due to altered glucose metabolism in addition to symptoms such as anorexia cachexia, nausea, and vomiting, that prevent a normal nutrition and thereby a normal supply of nutrients such as glucose, proteins and vitamins, leading to accumulation of ROS 53 . In a series of our recently published studies