Cannabinoids: the lows and the highs of chemotherapy-induced nausea and vomiting.

Despite remaining one of the most widely abused drugs worldwide, Cannabis sativa exhibits remarkable medicinal properties. The phytocannabinoids, cannabidiol and Δ-9-tetrahydrocannabinol, reduce nausea and vomiting, particularly during chemotherapy. This is attributed to their ability to reduce the release of serotonin from enterochromaffin cells in the small intestine, which would otherwise orchestrate the vomiting reflex. Although there are many preclinical and clinical studies on the effects of Δ-9-tetrahydrocannabinol during nausea and vomiting, little is known about the role that cannabidiol plays in this scenario. Since cannabidiol does not induce psychotropic effects, in contrast to other cannabinoids, its use as an anti-emetic is of great interest. This review aims to summarize the available literature on cannabinoid use, with a specific focus on the nonpsychotropic drug cannabidiol, as well as the roles that cannabinoids play in preventing several other adverse side effects of chemotherapy including organ toxicity, pain and loss of appetite.

Corticotrophin-releasing factor mediates vasoactive intestinal peptide-induced hypophagia and changes in plasma parameters.

Vasoactive intestinal peptide (VIP) and corticotrophin-releasing factor (CRF) are anorexigenic neuropeptides that act in the hypothalamus to regulate food intake. Intracerebroventricular (ICV) microinjection of VIP promotes increased plasma adrenocorticotrophic hormone (ACTH) and corticosterone, indicating that VIP activates hypothalamic-pituitary-adrenal axis. The aim of this study was to evaluate the interaction between VIP and CRF, by verifying the effects of ICV administration of VIP on the activity of neurons and CRF mRNA expression in paraventricular nucleus of hypothalamus (PVN). In addition, it was evaluated the effects of pretreatment with CRF type 1 receptor (CRFR1) antagonist (Antalarmin, ANT) or CRF type 2 receptor (CRFR2) antagonist (Antisauvagine-30, AS30) on VIP-induced changes on food intake and plasma parameters of male rats. Compared to Saline group, VIP increased not only the number of Fos-related antigens (FRA)-immunoreactive neurons in the PVN but also CRF mRNA levels in this nucleus. Both ANT and AS30 treatment attenuated the inhibition of food intake promoted by VIP, ANT showing a more pronounced effect. Both antagonists also attenuated VIP-induced reduction and enhancement of free fatty acids and corticosterone plasma levels, respectively, and only AS30 was able to attenuate the hyperglycemia. These results suggest that CRF is an important mediador of VIP effects on energy balance, and CRFR1 and CRFR2 are involved in these responses.

Delayed neuropsychiatric syndrome in a child following carbon monoxide poisoning.

Here, we report the case of a five-year-old boy with carbonic monoxide (CO) poisoning. The patient initially recovered after the initiation of hyperbaric oxygen (HBO) therapy, but lethargy as well as visual and gait disturbances appeared two days later. Left hemiparesis and mood lability also subsequently appeared. Slow frontal activity was noted on electroencephalography, while fluid-attenuation inversion recovery and diffusion-weighted magnetic resonance imaging (MRI) revealed high signal-intensity lesions in the hippocampus and deeper layers of the occipital and frontal cerebral cortex. The neurological symptoms subsided gradually during the 10-day course of HBO therapy, but the left-hand paresis and quadrantic hemianopsia persisted, in association with impaired attention, slow mental processing, and incontinence. Lesions in the globus pallidum were noted on follow-up MRI at 14 days, and cortical lesions became evident as linear, low signal-intensity areas on T1-weighted imaging 4 months after presentation. Delayed neuropsychiatric syndrome in CO poisoning is rare in childhood, although children should be carefully monitored after CO exposure. The finding of cortical laminar necrosis in this patient is quite atypical in CO poisoning, and suggests a broader and previously nonpredicted pathomechanism in this condition.

Symptom monitoring and dependent care during cancer treatment in children: pilot study.

Symptom monitoring by parents/caregivers of children with cancer and what the caregiver and child did to help alleviate symptoms during chemotherapy were studied. The Therapy-Related Symptom Checklist (TRSC) child version was administered to parents/caregivers of 11 children and adolescents (mean age, 10.4 years; SD, 6.1 years; range, 2-18 years; 45% were boys). The Karnofsky scale was completed by clinicians to rate the child's functional status. The TRSC child version and functional status scores were inversely related. All children experienced nausea; the most frequent symptoms reported were in TRSC subscales: fatigue, nausea, eating, fever, oropharynx, pain, and hair loss. Care strategies that helped were distraction, massage, mouth rinses, and vitamins; some reported that their child received medications for pain, nausea, and vomiting. Using complementary medicine categories, the care strategies were diet/nutrition/lifestyle change (eg, more high-fat, high-calorie foods; new foods; any food the child likes; and much sleep and rest); mind/body control (eg, play, video games, television, reading, activity puzzle, breathing exercises, relaxation methods, and prayer); manual healing method (massage and skin-to-skin contact); and biologic treatments (vitamins). The first 2 categories were the most used. Systematic assessment with a self-report checklist enables the provider to identify and prioritize (according to reported severity) those symptoms needing intervention.

Síndrome de realimentación / Refeeding syndrome

El síndrome de realimentación es un cuadro clínico frecuente que ocurre en pacientes con desnutrición previa, expuestos a tratamiento nutricional, bien sea oral, enteral o parenteral. La administración de glucosa intravenosa es la causa más frecuente que precipita el cuadro. En la actualidad es más frecuente en la renutrición de pacientes con anorexia nerviosa o en colectivos de tercera edad, en quienes las carencias nutricionales permanecen ocultas. La prevención del síndrome de realimentación es la base del tratamiento, ya que cuando las complicaciones aparecen las consecuencias son graves. La hipofosfatemia y la hipopotasemia son los aspectos clínicos más llamativos y requieren tratamiento con administración de los iones deficitarios, preferentemente por vía intravenosa (AU)

2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced anorexia and wasting syndrome in rats: aggravation after ventromedial hypothalamic lesion.

Long-term regulation of body weight and food intake were studied after rats were subjected to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which causes hypophagia and body weight loss, and to ventromedial hypothalamic lesion, which causes hyperphagia, metabolic changes and obesity. These two factors appeared to have an interaction, as ventromedial hypothalamic lesion initially aggravated the effects of TCDD on body weight and food intake. This was seen in both TCDD-resistant and TCDD-susceptible rat strains. In contrast, if TCDD was given several weeks before the lesion and body weight had stabilized to a low level, no aggravation was seen, but TCDD completely blocked the effects of ventromedial hypothalamic lesion. Thus, TCDD seems to affect the same regulation chain that is involved in the lesioning of the ventromedial hypothalamus. TCDD might serve as a tool in studying different mechanisms of long-term food intake and body weight regulation.

d-Fenfluramine and d-norfenfluramine hypophagias do not require increased hypothalamic 5-hydroxytryptamine release.

d-Fenfluramine (2.5 mg/kg i.p.) caused marked hypophagia in food-deprived rats and significantly increased medial hypothalamic extracellular 5-hydroxytryptamine (5-HT) as indicated by in vivo microdialysis. When the drug was given after the 5-HT synthesis inhibitor p-chlorophenylalanine (150 mg/kg per day x 3) the hypophagic response was unimpaired but dialysate 5-HT concentration no longer rose. The d-fenfluramine metabolite d-norfenfluramine (1.5 mg/kg i.p.) caused slightly greater hypophagia than the parent drug and completely blocked feeding in animals pretreated with p-chlorophenylalanine, but dialysate 5-HT was increased in neither circumstance. The results provide evidence against mediation of the hypophagic effects of d-fenfluramine and d-norfenfluramine by increased availability of 5-HT to receptors.

[Clinical evaluation of aiconol side effects]. / Klinicheskaia otsenka pobochnykh éffektov preparata éikonol.

In the study of 164 patients with atherogenic dyslipidemia the authors studied side effects of aiconol, concentrated cod liver oil. Its lipid component contains not less than 18% of omega-3 polyunsaturated fatty acids (PUFA). All the patients were divided into 4 groups: 51 subjects of group 1 received aiconol in the form of oil, 35 subjects of group 2 had protein dietetic caviar prepared from animal proteins with addition of 3% aiconol, 38 subjects of group 3 were given protein-oil emulsion containing 20% aiconol and 40 patients of group 4 took gelatin aiconol in capsules. Side effects of the above food ingredients enriched with omega-3 PUFA were found to be of metabolic nature. These manifested most evidently in patients on oil aiconol incorporating both maximal doses of omega-3 PUFA and the largest amounts of inert constituents acting as additional fat load on the liver and pancreas. Group 1 patients also suffered from aggravated chronic gastrointestinal, hepatic and pancreatic disorders. Because of reduced quantities of omega-3 PUFA in the diets of group 2, 3 and 4 patients, they displayed much less severe side effects.

Ipecac myopathy and cardiomyopathy.

Two cases of ipecac myopathy, one with associated cardiomyopathy are reported. Both patients were young women with eating disorders who came to medical attention because of diffuse muscle weakness. Clinical and electromyographic data suggested ipecac myopathy and muscle biopsies confirmed this diagnosis. One patient had associated clinical and echocardiographic evidence of significant cardiomyopathy. The myopathy resolved and the echocardiogram returned to normal after discontinuing the use of ipecac.

Interleukin-1, anorexia, and dietary fatty acids.

IL-1 and other cytokines mediate several components of both acute and chronic pathological processes observed in patients with cancer and chronic infection. Cachexia ranks as one of the more prominent aspects of several diseases and the present studies demonstrate that recombinant forms of either IL-1 beta or IL-1 alpha reduce food intake in experimental animals. In meal-fed rats, a single injection of IL-1 induces a 40% reduction [table: see text] in food intake, whereas daily injections slow normal weight gain. The anorexic response to IL-1 is prevented by cyclooxygenase inhibitors, although this is unlikely due to a central nervous system effect. Reduced production of cyclooxygenase products such as PGE2 also occurs in rats fed supplemental N-3 fatty acids, and this was associated with a decreased anorexic response to IL-1. Therefore, one mechanism by which IL-1 induces anorexia appears to require cyclooxygenase metabolites, such as PGE2. N-3 fatty acid supplements also reduce the severity of host responses to inflammation and infection. Part of this is due to decreased cyclooxygenase products; however, part also may be due to reduced synthesis of IL-1. Blood leukocytes from human subjects taking oral N-3 supplements produce 60% less IL-1. The ability of N-3 fatty acids to reduce IL-1 synthesis appears to be via the lipoxygenase pathway. Therefore, N-3 fatty acids may be beneficial to patients with anorexia, since such supplements would decrease both the anorexic response to IL-1 via reduced cyclooxygenase metabolites and the production of IL-1, via altered lipoxygenase metabolites.

Abdominal pain, indigestion, anorexia, nausea and vomiting.

Non-specific abdominal complaints are a very frequent cause of discomfort. Even if only comparatively few are brought to the attention of the physician, they account for a considerable portion of the reasons for seeking medical care, both in acute and chronic conditions. On the other hand, few drugs are free of the suspicion of causing abdominal complaints, which make up between one-tenth and one-third of reported adverse reactions. A wide variety of possible alternative or concomitant causes makes a clear causative attribution to suspected drugs very difficult. This holds especially true for the ill-defined conditions of indigestion and anorexia. For nausea and vomiting, specific scales have been developed which facilitate differentiation between drugs causing these effects most frequently and most intensively. They have been applied in cytostatic therapy, where this is one of the most frequently encountered problems, but nausea and vomiting can seriously affect compliance in many other treatments. Somatic abdominal pain results in most instances from the irritation of the parietal peritoneum and is usually the effect of a lesion. This may or may not be caused by a drug, but this cause should be the first consideration. Visceral pain may result from functional disturbance of secretory glands or of the muscular coat, from drug action on bowel content or from irritation of the mucosa, all of which are frequently interrelated. Most frequently suspected pharmacological causes are drugs with anticholinergic action, antibiotics, potassium supplements and non-steroidal, anti-inflammatory agents. Drug-induced hyperinsulinism and porphyria are rare cases. Abuse of laxatives should always be considered because of its prevalence. A great number of other untoward drug effects have been described in the literature, but rarely merit first consideration. With the exception of promptly occurring or persistent emesis, gastrointestinal symptoms usually are not pathognomonic for drug effects and are the result of several factors. The usual approach to identifying an adverse drug effect is to delineate the functional or structural disorder, and to associate this diagnosis with possible pharmacodynamic aetiologies.

Transient hyperphagia after sodium selenite injection in mice.

Injection (s.c.) of Na2SeO3 (SS, 20-30 mumol/kg) into male mice initiated eating, which began about 20 min after injection and continued for about 3 h. This initiation effect was observed for mice of different ages and at different times of the day. Other findings of this study were: (1) early morning injection (30 mumol/kg) caused increased food intake, as examined by gastric content 3 h after injection, compared to daytime injection; and (2) SS-induced transient hyperphagia was observed at ambient temperatures of 10 and 22 degrees C, but not at 37 degrees C. This paper discusses these results in relation to SS-induced hypothermia.

Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity.

Neuropeptide Y (NPY), a putative neurotransmitter abundant in the brain, has recently been shown to act within the hypothalamus, inducing a powerful eating response and a specific appetite for carbohydrates. In the present study, NPY (235 pmol) injected bilaterally in the paraventricular nucleus three times a day for 10 days caused approximately a two-fold increase in daily food intake, a six-fold increase in the rate of body weight gain and a three-fold increase in the body fat of female rats. Subsequently, the food intake and body weight of these subjects decreased precipitously, reaching control levels 20 days postinjection. These findings, demonstrating that exogenous NPY is capable of overriding mechanisms of satiety and body weight control, suggest that disturbances in NPY function may play a role in some disorders of eating behavior and body weight regulation.

Anorexia induced in rat by D-glucosamine deoxidized at C-1.

The effects of D-glucosamine (2-amino-2-deoxy-D-glucose), an endogenous glucose analogue, and 1-deoxy-D-glucosamine on feeding behavior were clarified. Test solutions (24 mumol) were infused into the third cerebroventricle of the rat. Glucosamine induced a feeding episode within 30 min after infusion and then prolonged the ensuing postprandial intermeal interval for the first 4 h of the dark period, while glucose suppressed feeding by decreasing meal size. Ventricular injection of 1-deoxyglucosamine potently suppressed feeding in a dose-related manner by affecting all meal parameters, and oral administration of 2,400 mumol also induced anorexia. Changes in activity of glucose-sensitive neurons in the lateral hypothalamus and glucoreceptor neurons in the ventromedial hypothalamus after electrophoretic application of glucosamine and 1-deoxyglucosamine were compatible with behavior changes. The results indicate that replacement of a hydroxyl group by an amino group at C-2 of the glucose molecule affects feeding behavior and deoxidation of C-1 potently induces anorexia.

Components of hypothalamic obesity: bipiperidyl-mustard lesions add hyperphagia to monosodium glutamate-induced hyperinsulinemia.

Rats with bilateral electrolytic lesions in the general region of the ventromedial hypothalamic (VMH) nucleus develop hyperinsulinemia, excessive food intake and obesity. Monosodium glutamate (MSG) destroys neurons of the arcuate hypothalamic (AH) nucleus and produces hyperinsulinemic but hypophagic obesity. Bipiperidyl mustard (BPM) primarily destroys VMH neurons, but has produced only a slight obesity even when rats were maintained on high-fat diets. In the present study, rats treated with MSG (AH lesion) were hyperinsulinemic, moderately obese and hypophagic; BPM rats (primarily VMH lesion) were not different from controls when fed standard chow diets. However, MSG/BPM rats (AH + VMH lesion) were hyperinsulinemic, massively obese and hyperphagic. Thus, two components of the electrolytic lesion syndrome previously attributed to VMH damage (hyperinsulinemia and obesity) were reproduced simply by MSG treatment alone. The third component (hyperphagia) occurred only when both AH and VMH were lesioned, suggesting that neurons in both nuclei may perform a satiety function and may be able to substitute for one another in this respect. Since MSG treatment is required for all components of both obesity syndromes described here, this underscores the importance of MSG-sensitive neurons in mechanisms of obesity. The combined treatment approach also represents the first rat model of hyperinsulinemic, hyperphagic obesity that can be entirely produced by systemic administration of neurotoxins.

Tolerance pattern to amphetamine anorexia after selective lesions in the hypothalamic dopaminergic projection.

Tolerance to the anorexic effect of d-amphetamine was studied in rats with selective dopamine lesions in the forebrain by means of 6-hydroxy dopamine, and measuring the food intake during two consecutive 2 h periods. Lesions placed in the perifornical hypothalamus (PFH) strongly antagonised the anorexic effect, whereas, lesions produced via intraventricular injections affected the anorexia only marginally. Amphetamine anorexia observed in the first 2 h in control and lesioned groups remained persistently, without any evidence of tolerance, up to 2 weeks of treatment. The second 2 h food intake exhibited a progressive increase which contributed to the apparent tolerance seen in total 4 h food intake in the control and lesioned animals. The onset and completion of this apparent tolerance was markedly delayed in the dopamine depleted group; lesions placed in the relatively medial areas delayed the tolerance development more effectively than that of PFH lesions. The stimulant effect of amphetamine on locomotion was abolished in lesioned animals. The results indicate that an apparent tolerance to amphetamine anorexia still developed in animals with forebrain dopamine loss. Although both the beta adrenergic and dopaminergic systems act together in mediating AMPH anorexia, the onset and the rate of completion of tolerance appear to be under the influence of hypothalamic dopaminergic system.

Amphetamine-induced hyperphagia and obesity caused by intraventricular or lateral hypothalamic injections in rats.

Overeating and obesity relative to controls was produced by multiple bilateral injections of 0.5 mg of amphetamine in the lateral ventricles of female rats eating a palatable, high fat diet. This behavioral and physiological rebound following the expected period of anorexia was accompanied by long-term depletion of dopamine in the striatum and of norepinephrine in the hypothalamus. This suggested the next experiment in which 50 micrograms of amphetamine were injected repeatedly in the lateral hypothalamus; again a brief period of anorexia was followed by hyperphagia and chronic obesity. This suggests that amphetamine acts in the lateral hypothalamus not only to suppress feeding, but in high doses it may also have local neurotoxic effects that cause an upward shift in body weight maintained by overeating.