My husband has cirrhosis and is waiting for a transplant but. He gets really nauseated and doesn't want to eat. What can i do or give him

[Chuyo57-chula18]

His really gets tired and could barely walk. He slurs and his voice changed is that common.

[Hidden]

There’s still a lot of confusion across the nation about whether or not marijuana is effective for cancer patients. Odds are you’ve heard something about it but weren’t sure whether the information was reliable or definitive. So, in order to help clear things up, here is a list of 34 studies showing that marijuana cures cancer, categorized by the type of cancers being cured in each study. As you sort through the articles, note that the consistent theme between them is that cannabis shrinks tumors and selectively targets cancer cells. As bills and voter initiatives to legalize medical marijuana spread from state to state, remember that we’re not just talking about mitigating the side effects of chemo (though this is another viable use), we’re talking about curing the cancer itself as well as preventing its spread. I’ve taken the liberty of only including articles from credible scientific journals, removing any biased or otherwise improperly cited studies. Enjoy!

Cures Brain Cancer

nature.com/bjc/journal/v95/...

ncbi.nlm.nih.gov/pubmed/114...

jneurosci.org/content/21/17...

jpet.aspetjournals.org/cont...

mct.aacrjournals.org/conten...

Cures Mouth and Throat Cancer

ncbi.nlm.nih.gov/pubmed/205...

Cures Breast Cancer

ncbi.nlm.nih.gov/pubmed/208...

ncbi.nlm.nih.gov/pubmed/180...

ncbi.nlm.nih.gov/pubmed/219...

jpet.aspetjournals.org/cont...

molecular-cancer.com/conten...

ncbi.nlm.nih.gov/pubmed/227...

pnas.org/content/95/14/8375...

Cures Lung Cancer

ncbi.nlm.nih.gov/pubmed/221...

ncbi.nlm.nih.gov/pubmed/210...

nature.com/onc/journal/v27/...

Cures Uterine, Testicular, and Pancreatic Cancers

cancer.gov/cancertopics/pdq...

cancerres.aacrjournals.org/...

Cures Prostate Cancer

ncbi.nlm.nih.gov/pubmed/127...

ncbi.nlm.nih.gov/pmc/articl...

ncbi.nlm.nih.gov/pubmed/225...

Cures Colorectal Cancer

ncbi.nlm.nih.gov/pubmed/222...

Cures Ovarian Cancer

aacrmeetingabstracts.org/cg...

Curse Blood Cancer

ncbi.nlm.nih.gov/pubmed/120...

ncbi.nlm.nih.gov/pubmed/169...

onlinelibrary.wiley.com/doi...

molpharm.aspetjournals.org/...

Cures Skin Cancer

ncbi.nlm.nih.gov/pubmed/125...

Cures Liver Cancer

ncbi.nlm.nih.gov/pubmed/214...

Cures Biliary Tract Cancer

ncbi.nlm.nih.gov/pubmed/199...

Cures Bladder Cancer

medscape.com/viewarticle/80... (Sign-up required to view study)

Cures Cancer in General

ncbi.nlm.nih.gov/pubmed/125...

ncbi.nlm.nih.gov/pubmed/153...

ncbi.nlm.nih.gov/pubmed/153...

source:

wakingtimes.com/2013/07/27/...

very best

Steve

[Hidden]

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IV. Endocannabinoid System in the Modulation of Energy Balance

Two notions highlight the importance of the endocannabinoid system in the regulation of food intake and energy metabolism. The first is the finding of a high degree of evolutionary conservation of the role of this system in the regulation of feeding responses (212). The second is the observation that high levels of endocannabinoids in maternal milk are critically important for the initiation of the suckling response in newborns (213).

A. Animal studies before the discovery of endocannabinoids

Animal models are ideal tools for elucidating the putative mechanism(s) of cannabinoids in the control of energy metabolism. The studies performed in different species to test the orexigenic properties of Δ9-THC up to the discovery of endocannabinoids are summarized in Table 2⇓ (214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244). From a general point of view, one can say that rather contradictory results were obtained in these experiments. The ambiguous data could likely be attributed to differences in the animal model and in the experimental procedures used. Moreover, in early studies using marijuana extracts, comparisons between various experimental data sets are extremely difficult due to the variability of the activity of cannabis derivatives, the dosages, and the routes of administration. In general, early studies using low doses of cannabinoids showed a reliable increase in food intake. When doses of Δ9-THC above 10 mg/kg were used, a concomitant decrease in food intake was observed due to the confounding factors given by the sedative effect of the drug. Studies employing high amounts of Δ9-THC should thus be viewed with caution in terms of effects on appetite and body weight. This is also the reason why, in reviewing the studies published between 1965 and 1975, Abel reported an increased food intake after cannabinoid administration only in 3 of 25 experiments (245). In 1998, Williams et al. (246) provided a very convincing and well-performed experiment to characterize the orexigenic property of Δ9-THC. The authors maximized the ability to detect hyperphagia by adopting a prefed paradigm in which the animals were characterized by low baseline food intake before drug administration. In this experimental setting, Δ9-THC was given orally at increasing dosage before unrestricted access to a standard diet. The authors observed that the maximum effect of the drug (1.0 mg/kg) was far greater than previously reported results, showing a 4-fold increase in food consumption over 1 h. Importantly, this hyperphagic effect was largely attenuated by pretreatment with the CB1 receptor antagonist SR141716, strongly supporting the notion that CB1 receptor activation mediates the hyperphagic effect of Δ9-THC (247). In this experiment, it was also reported that at doses of Δ9-THC higher than 1.0 mg/kg, the rats become unable to overeat due to the presence of motoric and sedative side effects (246). These results strongly suggest that the anorectic effect of Δ9-THC shown by many previous reports was indirectly due to the sedated state induced by high doses of the drug.

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TABLE 2.

Summary of the effects of exogenous cannabinoids on food intake

B. Studies in humans with exogenous cannabinoids before the discovery of endocannabinoids

Abel (245) also critically reviewed the studies aimed at proving the stimulating effect of cannabis on hunger in humans. However, the lack of scientific thoroughness of these earlier studies led Abel to conclude that the putative cannabis-induced hunger effect was still far from being proven (245). Greenberg et al. (248) were the first to systematically assess, under rigorous experimental conditions, the effect of a well-defined amount of Δ9-THC in terms of changes in feeding behavior and in body weight in humans. Both parameters increased after the first few days of the experiment. However, after this period, body weight continued to rise, averaging 2.3 kg across the whole 21-d period study, whereas a stabilization of energy intake was observed. This pioneer study already suggested that the ability of cannabinoids to stimulate hunger may vanish with time, whereas a possible metabolic effect of the drug may remain active longer (248). Nonetheless, later studies did not investigate the metabolic idea further, preferring to concentrate interest on the ability of cannabis to stimulate hyperphagia and overconsumption of highly palatable food at the central level. In 1986, Foltin et al. (249) noted a relevant increase in frequency and consumption of snack foods induced by marijuana only in the periods of social facilitation and environmental familiarity and not when the subjects were alone, indicating on the one hand a strong link between recreational use of the drug and its orexigenic properties and, on the other hand, the ability of marijuana to drive the tendency for palatable food. This hypothesis was further substantiated by the same group a few years later when increased total food intake particularly related to consumption of palatable food (sweet solid snacks) was observed as a main effect of smoked marijuana (250).

The stimulating effect of cannabinoids on appetite observed in healthy subjects promoted assessment of the efficacy of a cannabinoid treatment for clinical syndromes featuring loss of appetite or weight, such as cancer or AIDS-associated anorexia (251, 252, 253), or as adjuvant therapy to limit nausea and vomiting symptoms associated with most chemotherapeutic drugs (254). In 1985, the U.S. Food and Drug Administration officially approved the use of Δ9-THC (commercially named Dronabinol) for the treatment of chemotherapy-induced nausea and vomiting refractory to other drugs. In 1992, Dronabinol was approved for the treatment of patients with HIV-induced wasting syndrome. Recently, Dronabinol was also proposed as an orexigenic drug in patients suffering from Alzheimer’s disease (255).

The most comprehensive data are those obtained when Dronabinol was administered in HIV patients with wasting syndrome (252, 256, 257, 258, 259). To varying degrees, the drug was able to mildly increase appetite and energy intake in all studies. However, a marked improvement in mood was also documented, raising the question of whether the positive effect in energy balance may derive from a specific action of cannabinoids in the brain areas controlling food intake or may be simply due to a generalized change in the sense of well-being. Intriguingly, in some reports, a significant gain was found in body fat mass associated with minimal changes in appetite rating and food intake (255, 258). At that time, this finding remained unexplained. However, with the current knowledge of CB1 receptor expression at the level of the adipose tissue (58, 59), we can hypothesize that the increase in fat mass of HIV patients was probably due to a direct lipogenic action of Δ9-THC. In this context, it is still unknown, and it would be of great relevance to investigate whether the administration of Dronabinol can improve the pathological changes in fat distribution induced by the concomitant retroviral therapy in patients with AIDS (260).

C. Endocannabinoid functions at mesolimbic level to regulate rewarding properties of food

After the finding of the hyperphagic effect of Δ9-THC mediated by CB1 receptor activation, Williams and Kirkham (261) reported that endocannabinoids were also able to stimulate hunger in a dose-dependent manner. The degree of overeating induced by 1 mg/kg AEA was only a 2-fold increase over a 3-h test, therefore less than that obtained with the same dosage of Δ9-THC. However, Δ9-THC-induced hyperphagia was restricted to the first hour of testing, whereas the AEA effect was evident later when the inhibitory effects of the prefeed started to wane (261). The authors speculated that administration of AEA may represent an amplification of endocannabinoid activity associated with the normal, episodic pattern of meal-taking in rats (261).

Importantly, the effect of AEA was completely blocked by pretreating the animals with SR141716, confirming the pivotal role of CB1 receptor activation in the hyperphagic effects of endocannabinoids (247, 262). Similar conclusions were derived from other studies in which AEA was able to exert an appetite-stimulating effect even at very low doses in mice (0.001 mg/kg) (263) and 2-AG was capable of promoting feeding behavior (264). These data therefore make it possible to attribute the endocannabinoid system with an important role in the processes underlying the motivation to obtain food. It is suggested that endocannabinoids gradually increase during intermeal intervals, reaching a critical level where motivation to eat is triggered. Accordingly, the longer the time since the last meal, the greater the activity in relevant endocannabinoid circuits, and consequently the higher the motivation to eat (265). The findings of increased levels of AEA and 2-AG in the fasting condition in the nucleus accumbens and a decline of 2-AG concomitant with the feeding state strongly support this hypothesis (264). Interestingly, unchanged levels of endocannabinoids were shown in the cerebellum, a region not involved in the control of feeding, further confirming the notion that endocannabinoids are produced in situ and on demand (264).

With the advent of CB1 receptor-specific antagonists (Table 3⇓), it became clear that, even when injected alone, these compounds are able to modify ingestive behavior. An ip injection of SR141716 was found to significantly reduce sucrose or alcohol intake and craving in rodents (266, 267, 268) and in marmosets (269), leading to the hypothesis that the activation of the endocannabinoid system may alter the appetitive value of ingested substances. This idea is consistent with the evidence in favor of a facilitatory function of the endocannabinoid system on brain reward circuits (266, 269). Evidence therefore suggests that endocannabinoids bring forward the onset of eating in satiated animals and increase the incentive value of the food regardless of the quality of the macronutrients (“incentive hypothesis”) (270). Other findings, however, resembling the “marshmallow effect” in marijuana smokers (245), have been interpreted in terms of an endocannabinoid action toward a preference to eat highly palatable food (“orosensory reward hypothesis”) (271). In favor of this latter hypothesis, there are several reports indicating the ability of CB1 receptor blockade to decrease the rewarding properties of addictive drugs (186, 272, 273, 274). It is now clear that the endocannabinoid system participates in the modulation of “reward/reinforcement” circuitries and its manipulation is able to influence reward-related behaviors (275). The high expression of CB1 receptor in areas involved in reward constitutes a strong indication that the endocannabinoid system is directly involved in various physiological functions controlled in these brain regions, including feeding (43). The reward/reinforcement circuitry of the mammalian brain consists of a series of synaptically interconnected brain nuclei associated with the medial forebrain bundle, linking the VTA, the nucleus accumbens, and the ventral pallidum (275). This circuit is implicated in the pleasure produced by natural rewards, such as food, addictive drugs, and sex, and it is the neural substrate of drug addiction and addiction-related phenomena, such as craving and dysphoria induced by withdrawal (275). In such a framework, food intake acts on dopamine, opioid, serotonin, and noradrenaline neuronal fibers, which connect the hindbrain and midbrain to the hypothalamus to modulate the action of feeding and satiety factors (276).

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TABLE 3.

Summary of the effect of CB1 antagonist treatment on food intake in different rodent models

The most relevant reward pathway is represented by the mesolimbic dopaminergic system. It has been shown that increased levels of extracellular dopamine and its metabolites are found within the nucleus accumbens after ingestion of highly palatable food (277). Moreover, administration of a dopamine D1 agonist reduces food intake (278). Both CB1 receptor and endocannabinoids were found in the rat limbic forebrain (279), in which colocalization with dopamine D1 and D2 and CB1 receptor were described (280). Psychoactive drugs such as marijuana, ethanol, and also pleasant stimuli or palatable food are known to induce the release of dopamine in specific brain regions (281). A correlation between limbic endocannabinoid/dopamine levels and craving for tasty food is thus presumed to occur (275). Verty et al. (282) recently substantiated the hypothesis of the existence of cannabinoid-dopamine interactions in feeding behavior, demonstrating that the dopamine D1 antagonist SCH 23390 attenuated feeding induced by Δ9-THC. The endocannabinoid system also provides retrograde control of synaptic transmission onto the VTA dopaminergic neurons, where the postsynaptic synthesis of endocannabinoids is under the control of somatodendritically released dopamine (108).

A relevant interplay also exists between the endocannabinoid system and the endogenous opioid peptides (283). Both systems are linked to central reward processes, and there is increasing evidence supporting an important functional cross-talk between the two systems, in relation to a wide range of physiological processes, including appetite. Several reports indicate that opioid receptor agonists increase food intake (284, 285, 286), whereas opioid antagonists induce anorectic effects (287). Gallate and McGregor (267) found that the facilitatory effects of a cannabinoid agonist on responding to palatable solutions were reversed not only by CB1 receptor antagonism but also by naloxone, an opioid receptor antagonist. The existence of cross-talk between the endocannabinoid and opioid systems in controlling food intake was also confirmed by several studies in which naloxone and SR141716 synergistically depress food intake at doses that do not alter food intake on their own (287, 288). However, a recent finding seems to localize the interaction between opioids and endocannabinoids involved in feeding behavior not at the mesolimbic system level but, preferentially, at the level of the PVN of the hypothalamus. In fact, SR141716 was able to attenuate morphine-induced feeding only when the opioid was directly injected in the PVN and not in the nucleus accumbens. According to this last finding, the endocannabinoid system appears to participate in the opioid-mediated enhancement of rewarding properties of food in the hypothalamus and not in the nucleus accumbens (286).

According to the involvement of serotonin in the control of feeding behavior (289), the interaction of the endocannabinoid system with the serotoninergic system has also been investigated. However, the administration of a CB1 receptor antagonist in rats combined with dexfenfluramine, an anorectic drug stimulating the release of serotonin, led to additional but not synergistic effects on reducing food intake, which is consistent with the hypothesis that the two pathways work via independent mechanisms of action (288). This notion is important, because it makes it possible to exclude a synergistic effect in a possible future combination of antiobesity drugs such as those inhibiting serotonin reuptake, like sibutramine (290) and CB1 receptor antagonists.

D. The endocannabinoid system as a new hypothalamic player in the regulation of food intake

A complex and redundant neuronal hypothalamic network provides high levels of adaptability of feeding behavior to various central and peripheral stimuli (291). Redundancy in appetite-stimulating signaling is conceivable in view of the vital importance of feeding for survival (291). Whereas defects in anorexigenic signaling pathways almost always lead to obesity, loss of orexigenic signals rarely results in a lean phenotype. An example of this redundancy in orexigenic hypothalamic signaling systems is provided by mice lacking neuropeptide Y (one of the most important appetite-stimulating neuropeptides) where compensatory mechanisms are likely to be activated (292). Signals coming from various peripheral organs, such as the liver, gastrointestinal tract, and adipose tissue, are conveyed mainly at the hypothalamic level to constantly inform the brain about the state of nutrition (291, 293). An example of such peripheral control is the adipocyte-derived hormone leptin, which acts on receptors located in the hypothalamus (291). A milestone in the identification of the endocannabinoid system as a new player in the regulation of food intake at hypothalamic level was the finding that leptin is a strong modulator of hypothalamic endocannabinoid levels (294). Di Marzo et al. showed that acute leptin treatment reduced AEA and 2-AG not only in the hypothalami of normal mice but also in mice lacking leptin signaling. They also described the defect in leptin signaling as being constitutively associated with elevated hypothalamic levels of endocannabinoids. In these animals, SR141716 was able to reduce food intake, confirming the anorectic properties of the compound (294). These findings suggest that, at least in genetically modified animal models, obesity is associated with a chronic hypothalamic overactivation of the endocannabinoid system, which may in turn explain the hyperphagic behavior of the animals having leptin signal impairment. However, before giving a general value to this assumption, the intrahypothalamic amount of endocannabinoid levels during the development of obesity in normal rodents eating a high-fat diet must be investigated. Nevertheless, endocannabinoids are variably produced in the hypothalamus of normal animals. In fact, 2-AG levels increase during acute fasting, decline as the animals are refed, and return to normal values in satiated animals (264, 295). However, a long period of diet restriction (12 d) was found to be associated with reduced levels of 2-AG in the hypothalamus (295). The authors interpreted these data observing that the decrease of 2-AG levels in mice after a prolonged diet may represent a general psychobehavioral strategy for intermittent starvation when food is scarce (295).

As mentioned above, the hypothalamus is not the cerebral area where the highest levels of CB1 receptor expression are found (24, 36, 38). However, studies using [35S]GTPγS binding indicated that the hypothalamic CB1 receptor coupling to G proteins is more efficient than in other cerebral areas known to be a site of high CB1 receptor expression, such as the hippocampus or the entopeduncular nucleus (43). On the other hand, it is also evident that CB1 receptors are present at a very high density in the brain compared with other receptors. Therefore, even regions with a relatively lower density of CB1 receptors, such as the hypothalamus, contain a significant number of receptors. Both these factors thus probably explain the ability of hypothalamic CB1 receptors to strongly affect the functions of this brain region. Interestingly, no changes in CB1 receptor expression have been shown at the level of hypothalamus after diet modification (296). The direct involvement of the hypothalamus in the modulation of food intake operated by endocannabinoids was also demonstrated by the significant hyperphagic effects of AEA directly administered into the ventromedial nucleus and by the inhibition of this effect obtained by the injection of SR141716 via the same route (297).

It was only during the last few years that the interaction of CB1 receptor and endocannabinoids in feeding-regulating pathways started to be elucidated in detail. The CB1 receptor is expressed in key hypothalamic peptidergic systems, such as those producing CRH in the PVN, cocaine-amphetamine-related transcript in the dorsomedial nucleus, and melanin-concentrating hormone and orexins in the lateral hypothalamus-perifornical area (58). Importantly, these data were recently confirmed by the demonstration that CB1 receptor activation strongly augments the orexin-A-stimulated intracellular pathway (88). CB1−/− mice also possess increased CRH and reduced cocaine-amphetamine-related transcript expression, indicating that the genetic impairment of the endocannabinoid system may affect the pattern of gene expression of peptides involved in the regulation of food intake (58). Conversely, the neuropeptide Y/agouti-related protein system in the arcuate nucleus does not seem to be directly targeted by endocannabinoid action (58, 294). This fact confirms that orexigenic pathways are less critical (or at least functionally more redundant) in the chronic maintenance of energy balance (298). Functional cross-talk between CB1 receptor and melanocortin receptor type 4 (MCR4) has been recently highlighted by the finding of the synergistic action of subanorectic doses of SR141716 and of a MCR4 agonist administered together (299). Furthermore, the same authors showed that the orexigenic impulse given by the administration of CB1 receptor agonists is not blocked by the costimulation with MCR4 agonists, whereas CB1 receptor antagonists are able to inhibit the stimulation of food intake induced by MCR4 antagonists. Consequently, the authors hypothesized that the melanocortin receptor signaling in the hypothalamic regulation of food intake is upstream of the activation of the endocannabinoid system (299).

The mechanism(s) of action of the endocannabinoids at hypothalamic synaptic level are still a matter of debate. Great progress has recently been made by the finding that postsynaptically released endocannabinoids acting at presynaptic CB1 receptors are able to decrease glutaminergic transmission onto CRH-producing neurons, resulting in an inhibition of CRH release (103). This release of endocannabinoids from the parvocellular neurons is stimulated by a nongenomic effect of glucocorticoids. Therefore, it is conceivable that the well-known regulation of food intake by glucocorticoids may partly derive from functional cross-talk with the endocannabinoid system (300). The same inhibitory mechanism mediated by glucocorticoids through an activation of the endocannabinoid system has also been proposed for other hormones and neuropeptides such as oxytocin and vasopressin (103). In this sense, we may speculate that the recently described interaction between endocannabinoid and the oxytocin system in modulating food intake (301) may derive from the same fast feedback mechanism mediated by nongenomic glucocorticoid inhibition.

Despite the dogma that neurons do not utilize fatty acids for energy, a growing body of evidence points to a critical role for both fatty acid production and utilization in regulating hypthalamic neurons that regulate food intake (302). In fact, inhibitors of fatty acid synthase are capable of greatly affecting appetite in an anorexigenic manner (303, 304). In such a scenario, it has recently been proposed that via CB1 receptors, endocannabinoids may modulate the fatty acid synthetic pathway in the hypothalamus, and the inhibition of the hypothalamic expression by rimonabant may explain the anorexigenic properties of cannabinoid antagonists (62).

E. The peripheral effect of the endocannabinoid system in the modulation of metabolic functions

Several lines of evidence are currently converging, indicating that the effects of CB1 receptor blockade on food intake and body weight are not limited to a central mode of action. An early report describing the effect of CB1 receptor blockade on changes in food intake and in body weight was, in this sense, highly predictive of a mechanism of action not limited to the mesolimibic or hypothalamic circuits. In fact, Colombo et al. (305) were the first to demonstrate, in lean rats fed with a standard diet, that the tolerance to the anorectic effects of two different doses of SR141716 (2.5 and 10 mg/kg) develops rather rapidly (5 d). Nevertheless, the body weight loss in SR141716-treated rats persisted for 14 d, well beyond the drug effect on food intake. At that time, the authors were not able to explain this body weight loss that was not related to a decrease in food intake, and they merely hypothesized a stimulatory action of SR141716 on the energy expenditure (305). However, in the last 2 yr, the use of CB1−/− mice has represented an important tool to substantiate further the hypothesis of an additional effect of endocannabinoids in peripheral organs. Indeed, the lack of CB1 receptor in mutant mice causes hypophagia and body fat reduction. Importantly, pair-feeding experiments showed that in young CB1−/− mice, the lean phenotype is predominantly caused by decreased caloric intake, whereas in adult CB1−/− mice metabolic factors appear to be the major cause of the lean phenotype. These experiments therefore suggested that the endocannabinoid system might regulate central food intake-related mechanisms at young ages, but that this function diminishes with age (58). These observations converge on the idea that additional peripheral food intake-independent metabolic functions may participate, or even predominate, in the control of energy balance exerted by the endocannabinoid system (58). Even more prominent differences in terms of body weight regulation are obtained when a high-fat diet is administered to adult CB1−/− mice and wild-type littermates. In contrast to wild-type littermates, CB1−/− mice do not display hyperphagia or reduction of their relative energy intake and were resistant to diet-induced obesity (DIO) (306). Importantly, the obesity-prone diet induced a significant increase of fasting glycemia in the two genotypes, but the sensitivity to insulin remained unchanged in CB1−/− mice, whereas it was significantly reduced in the wild-type animals (306).

The expression of CB1 receptor in adipocytes and the ability of SR141716 to block lipogenesis stimulated by cannabinoids represent a first important step forward in understanding the peripheral mechanisms of action of the endocannabinoid system in regulating metabolic processes (58). Moreover, the presence of CB1 receptor is increased in mature adipocytes compared with preadipocytes (59, 60), indicating that CB1 receptor activation is likely needed more for metabolic processes than for differentiation. Importantly, a recent study shed further light on the mechanisms of action of the endocannabinoid system on adipose tissue. By using SR141716 in DIO mice, Jbilo et al. (307) were able to reverse the phenotype of obese adipocytes at both macroscopic and genomic levels. They showed that a major restoration of white adipocyte morphology similar to lean animals occurred in adipocytes derived from obese animals after CB1 antagonist treatment. More importantly, they found that the major alterations in gene expression levels induced by obesity in white adipose tissue were mostly reversed in SR141716-treated obese mice. Importantly, the transcriptional patterns of treated obese mice were similar to those obtained in the CB1−/− mice fed with a high-fat diet, supporting a CB1 receptor-mediated process. Functional analysis of these modulations indicated that the reduction of adipose mass by the drug was due to enhanced lipolysis through the induction of enzymes of the β-oxidation and tricarboxylic acid cycle; increased energy expenditure, mainly through futile cycling (calcium and substrate); and a tight regulation of glucose homeostasis. In particular, in this last context the SR141716-induced increased expression of glucose transporter 4, the insulin-responsive glucose transporter, appears very important (307). This finding makes it possible to hypothesize that cannabinoid antagonists may also be attractive drugs in fighting diabetes. Altogether, these data confirmed that the endocannabinoid system has a major role in the regulation of energy metabolism in adipocytes. Importantly, CB1 receptor expression has been found to be higher in adipocytes derived from obese animals compared with lean controls (59). Similar to the finding of higher levels of endocannabinoids in the hypothalamus derived from obese animals, the overexpression of CB1 receptor in adipocytes of obese rats seems to confirm the notion that hyperactivity of the endocannabinoid system is associated with the obesity state. However, this up-regulation of CB1 receptor expression in fat pads derived from rodents has not been confirmed in adipocytes derived from sc fat of obese women (60); on the other hand, a partial limitation of this study is that CB1 receptors have not been measured in visceral fat tissue that is supposed to be more prone to the endocannabinoid action. Finally, the increase in levels of adiponectin in Zucker obese rats chronically treated with SR141716 in vivo (59) and in 3T3 F442A adipocytes acutely stimulated with the CB1 receptor antagonist in vitro (59) points to a close relationship between CB1 receptor blockade and the production of this antiatherogenic and antidiabetic adipocyte-derived protein (308). The quick and strong improvement of hyperinsulinemia detected after a very short-term treatment with SR141716 (4 d) in obese Zucker rats was also attributed to an increase in adiponectin (59). However, the well-known reduction in food intake and the consequent body weight loss displayed at the beginning of SR141716 treatment may be the most obvious explanation for the changes in adiponectin levels. The ability of long-term treatment with SR141716 to enhance the circulating levels of adiponectin was further confirmed in DIO mice (309).

In the last few years, several studies using different CB1 receptor antagonists confirmed the hypothesis that a potential peripheral mode of action of pharmacological CB1 receptor blockade may play a relevant role in the final weight loss effect. Ravinet-Trillou et al. (310) found that long-term (40 d) treatment with two different dosages of SR141716 (3 and 10 mg/kg, respectively) produces a marked acute hypophagia in DIO mice only in the first few days of treatment, followed by the development of tolerance to the anorectic effect of the drug. However, the effect on body weight was sustained until the end of the 5-wk experiment compared with DIO mice treated with the vehicle. The significant difference in weight of white adipose pads between SR141716- and vehicle-treated animals confirmed that weight loss was accompanied by a decrease in adipose tissue. Similar data showed a rapid tolerance to the anorectic action despite a sustained and prolonged effect on body fat loss also being obtained when obese Zucker rats were treated for 14 d with SR141716 (59). Importantly, another CB1 receptor antagonist, AM-251, produced similar effects in DIO mice (311). Very recently, Poirier et al. (309) monitored weight and metabolic marker changes in three groups of mice after establishing a condition of obesity by a 5-month high-fat diet. Two groups of animals were maintained on a high-fat diet, but one was treated for 10-wk with 10 mg/kg SR141716 and the other one with a vehicle. A third group received a dietary switch to standard food after the 5 months on a high-fat diet. SR141716 induced a weight loss of approximately of 78% in comparison to the weight of the animals receiving the vehicle. More importantly, the antiobesity effect of the drug was equivalent (both in terms of time course and maximum effect) to that achieved by switching obese mice to a normal diet (309). Again, the authors demonstrated that the anorectic effect of the CB1 receptor antagonist vanished with time because the energy intake in the SR141716-treated animals was equivalent to animals on a high-fat diet during the last 6 wk of the experiment and significantly greater than in the group receiving standard diet. Consistent with a previous report (310), the SR141716-induced weight loss was accompanied by normalization of leptin, insulin, and glucose levels (309). Notably, SR141716 also normalized triglycerides and low-density lipoprotein-cholesterol. Moreover, the high-density lipoprotein (HDL)-cholesterol/low-density lipoprotein-cholesterol ratio after SR141716 treatment was significantly higher than in the other two groups (309). Whether this effect on lipid metabolism is indirectly related to an elevation of adiponectin is still a matter of

[Yarnie]

Hi there

A year ago I was exactly the same! I was told to eat little and often. But I still struggled, try shakes or soups like complan, they'll give your hubby the vitamins etc he'll need to get through transplant...I was told I wouldn't be strong enough to get through op if I didn't. I also had encephalopathy (confusion ), all I can say is I had transplant in Febuary this year and almost immediately those symptoms disappeared. I'm doing great now and am totally different than a year ago. I hope this helps and I wish you both the very best, good luck x

[Chuyo57-chula18 in reply to Yarnie]

Thank you for your reply. I'm so happy for you and your recovery. Hope my husband gets one soon. Yes his a total different person now I won't my husband back. What state do you live in?

[Hidden]

You could ask your GP for energy drinks: they are 300 calls each and make up for lost intake to some extent.

[Chuyo57-chula18 in reply to Hidden]

Thanks a lot for your reply. They really are helping me out.

[ancientadolescent]

I had a transplant last Christmas eve after a wait of 18 months. During that time I had the same symptoms as your husband. I was prescribed "Fresubin" which is a drink described as a protein and energy suppliment. This helped me. I wish you the very best of luck.

[Chuyo57-chula18 in reply to ancientadolescent]

Thank you for your reply I will find out about this drink. I really aim trying hard keep him strong for his op. What state do you live in?

[ancientadolescent in reply to Chuyo57-chula18]

I live in the uk and I agree with Yarnie, once your hubby has a transplant he will be a different person and be part of society again.

[Chuyo57-chula18 in reply to ancientadolescent]

I hope some but it's a longer wait in California then any where else in the world. But I have lots of faith. Happy for you !!

[Yarnie]

Hi there

I live in uk, but I can honestly say once hubby has transplant you will get him back. Wishing you luck x

[Chuyo57-chula18 in reply to Yarnie]

I dearly want him back. But it's a longer wait in California but that's when faith. Comes in strong. Im happy for you and your feeling your else once again

[lexuslove]

Hi my dad is the same way he wont eat cant talk rite and now they going put a feeding tube in. Theyvgive him 6-12 months live am sorry about u husband

[caseyliver]

use boost or other nutritional drinks with high protein content. I drank a lot of it pre tx