Liujunanwei decoction attenuates cisplatin-induced nausea and vomiting in a Rat-Pica model partially mediated by modulating the gut micsrobiome.

Studies show that traditional Chinese medicine (TCM), such as Liujunanwei (LJAW) decoction, can play important roles in alleviating side effects of chemotherapy. The purpose of this study was to understand how LJAW can counter chemotherapy-induced emesis via alteration of gut microbiota. We evaluated the effect of LJAW on cisplatin (DDP)-induced nausea and vomiting using a rat-pica model. Rats react to emetic-producing stimuli with increased kaolin consumption, a phenomenon called pica. The rats were injected with cisplatin and then randomly assigned to the control (DDP), Ondansetron or LJAW. The intake of kaolin and chow diet as well as body weights were recorded every 24 hours. Fecal samples were collected prior to, after three and seven days of treatment. The expression of proteins was measured by western blot. The concentration of cytokines and serotonin was evaluated using ELISA assay kits. Kaolin consumption in rats induced by cisplatin was reduced by 16.5%, 22.5%, and 30.1% in the LJAW group compared to the DDP group at 24 hours, 48 hours and 72 hours, respectively (p>0.05). LJAW significantly increased the food intake of the rats (13.94 ± 4.73 g) during the first 24 hours as opposed to the DDP (9.23 ± 3.77 g) (p<0.05). 16S rRNA gene sequencing showed the abundance of Bacteroidetes increased in cisplatin treated rats. In addition, cisplatin injection caused an enrichment of Escherichia-Shigella and Enterococcus at the genus level. While, enrichment of Blautia and Lactobacillus was presented in LJAW treated rats. Serotonin decreased in LJAW treated intestine and medulla oblongata tissues. Further, the protein expression of tryptophan hydroxylase 1 (TPH1) a rate limiting enzyme of serotonin was inhibited in LJAW treated rat's jejunum compared with cisplatin only treated rats. In addition, LJAW downregulated chemotherapy induced elevated inflammation. The results of this study indicated that LJAW is capable of decreasing cisplatin-induced kaolin intake in rat-nausea model (pica), which might be mediated through gut microbiome-induced anti-inflammation and anti-serotonin synthesis functions.

A rare case report of teen-onset pica in a female patient with a clinical high risk for psychosis.

AIM: We aimed to further elucidate the under-researched, underdiagnosed and misunderstood comorbid pica in the context of psychosis. METHOD: We report a case of teen-onset plastophagia in an antipsychotic-naïve girl at ultra-high risk (UHR) for psychosis. RESULTS: HA is a 17-year-old unmarried girl who had a history of good premorbid functioning, no personal psychiatric history and an uncle with schizophrenia. She was referred to our psychiatry department with the complaint of having the habit of eating plastic for about 2 years. A thorough clinical history revealed that she developed, since more than a year, difficulty in school and interpersonal functioning. After clinical evaluation, a diagnosis of UHR with major depressive disorder, iron deficiency anaemia and pica was made. CONCLUSION: We draw attention to the possibility of an overlap between the pathogenesis of pica and psychosis, and we highlight the importance of early diagnosis and management of both pica and UHR since they can lead to serious medical and mental consequences.

Pica y traumatismo craneoencefálico en un paciente adolescente: recuperación <> con paliperidona / Pica and traumatic brain injury in an adolescent: complete improvement with paliperidone

Presentamos el caso clínico de un adolescente varón de 15 años derivado a Psiquiatría Infanto-Juvenil por realizar ingestas repetitivas de sustancias no nutritivas como gomas de borrar, escamas psoriásicas o incluso pintura de la pared. Entre sus antecedentes somáticos de interés, conviene destacar la Enfermedad de Kawasaki y psoriasis, además de haber sufrido un traumatismo craneoencefálico (TCE) tras lo cual presentó una exacerbación del cuadro. Tras el fracaso en el manejo conductual realizado por parte de su madre y teniendo en cuenta sus rasgos de personalidad caracterizados por una elevada suspicacia y desconfianza hacia los demás, se decide iniciar tratamiento con paliperidona oral produciéndose una rotunda mejoría clínica. Durante todo el seguimiento posterior hasta su mayoría de edad, se ha mantenido la desaparición de la pica. Presentamos el primer caso clínico publicado en la bibliografía actual de un adolescente con el diagnóstico de pica y un TCE previo y una adecuada respuesta a paliperidon

We present a case report of a 15-year-old male adolescent who was referred to our consultation of Children and Adolescent Psychiatry due to persistent eating of non-nutritive substances like rubber, psoriatic scale or wall paint. The patient had the previous diagnostic of Kawasaki Disease and psoriasis. In addition, he had suffered a traumatic brain injury, after which he presented an exacerbation of the clinic. After behaviour therapy failure realized by his mother and taking into account his personality features with high suspicion and distrust of others, he was prescribed paliperidone oral treatment and pica disappeared. During all subsequent follow-up until the age of majority, the disappearance of pica has been maintained. We describe the first case report in the current bibliography of an adolescent with the diagnosis of pica, a previous traumatic brain injury and a good response to oral paliperidone.

Drug repositioning of antipsychotic drugs for cisplatin-induced pica behavior in mice.

We aimed to clarify whether various antipsychotics ameliorate cisplatin-induced pica behavior in mice using a drug repositioning approach. Mice were administered cisplatin (12.5 mg/kg, i.p.) with or without olanzapine (1 mg/kg, i.p.), asenapine (4 mg/kg, i.p.), mirtazapine (5 mg/kg, i.p.) or standard three-drug antiemetics (granisetron [0.5 mg/kg, i.p.], fosaprepitant [25 mg/kg, i.p.], and dexamethasone [3 mg/kg, i.p.]). Kaolin, food, and water intake, and spontaneous motor activity on the day before and seven consecutive days after the cisplatin administration were measured using a telemetry system. At the primary endpoint, kaolin intake was significantly higher at day three in the cisplatin group than in the pre-treatment and saline groups ( p < 0.05). Additionally, kaolin intake was not significantly higher in cisplatin with olanzapine, asenapine, and mirtazapine groups for seven days than in the pre-treatment group. At the secondary endpoint, cisplatin decreased the food and water intake, and spontaneous motor activity in a time-dependent manner. Three antipsychotics failed to improve the cisplatin-induced decrease in food and water intake, and spontaneous motor activity. The findings suggest that prophylactic administration of antipsychotics besides olanzapine may improve cisplatin-induced nausea and vomiting in a delayed phase and de-escalate standard 3-drug antiemetics.

Pica: Treatment with Punica Granatum extract.

Pica is an eating disorder characterized by craving for nonfood items, such as dirt, clay, detergents, soap, stone, and paper. It occurs in children who start feeling the world with the oral cavity. The exact etiology of this disorder is still unknown; nonetheless, its treatment and prevalence vary according to patients' behavior and characteristics. We aim to present a case report of a patient with pica who was treated with Persian Traditional Medicine. This treatment was performed using four doses of 15 ml Punica granatum extract after every meal for 3 weeks while fasting before breakfast. The patient's appetite improve within 3 weeks, with remarkable improvement in pica symptoms. Punica granatum extract seems to be effective in controlling pica.

[6]-Gingerol Ameliorates Cisplatin-Induced Pica by Regulating the TPH/MAO-A/SERT/5-HT/5-HT3 Receptor System in Rats.

PURPOSE: [6]-gingerol is a bioactive compound extracted from ginger, a traditional anti-emetic herb in Chinese medicine. Previous studies have demonstrated that [6]-gingerol can ameliorate chemotherapy-induced pica in rats, although the underlying mechanism has not been elucidated. This study is designed to investigate [6]-gingerol's antiemetic mechanism focusing on the 5-hydroxytryptamine (serotonin, 5-HT) system by evaluating the synthesis, metabolism and reuptake of 5-HT, as well as the mechanism of 5-hydroxytryptamine type 3 receptor (5-HT3 receptor), in a cisplatin-induced pica model of rats. METHODS: Rats were randomly divided into control group (vehicle + saline, Con), [6]-gingerol control group (50 mg/kg [6]-gingerol + saline, G-con), ondansetron control group (2.6 mg/kg ondansetron + saline, O-con), cisplatin model group (vehicle + cisplatin, Model), ondansetron-treated group (2.6 mg/kg ondansetron + cisplatin, O-treated), high dosage of [6]-gingerol-treated group (100 mg/kg [6]-gingerol + cisplatin, GH-treated), and low dosage of [6]-gingerol-treated group (50 mg/kg [6]-gingerol + cisplatin, GL-treated). The rats were administered with [6]-gingerol, ondansetron, and vehicle (3% Tween-80) by gavage twice (7:00 AM and 7:00 PM). One hour after the first treatment (8:00 AM), rats in groups Model, O-treated, GH-treated and GL-treated were injected intraperitoneally (i.p.) with 6 mg/kg cisplatin, and the other groups were injected i.p. with saline of equal volume. The consumption of kaolin of the rats were measured. All the rats were anesthetized by i.p. injection of pentobarbital sodium at 24 h post-cisplatin. After blood samples were taken, medulla oblongata and ileum were removed. The levels of 5-HT and its metabolite 5-HIAA in ileum, medulla oblongata and serum were determined using high-performance liquid chromatography with electrochemical detection (HPLC-ECD). The mRNA expression levels of 5-HT3 receptor, tryptophan hydroxylase (TPH), monoamine oxidase A (MAO-A) and serotonin reuptake transporter (SERT) were detected by real-time PCR. The protein expression levels and distribution of 5-HT3 receptor, TPH and MAO-A in the medulla oblongata and ileum were measured by Western blotting and immunohistochemistry, respectively. RESULTS: [6]-gingerol treatment significantly reduced the kaolin ingestion and the increase in 5-HT concentration in rats induced by cisplatin. TPH, MAO-A, SERT, and 5-HT3 receptor are important in 5-HT metabolism, and cisplatin-induced alterations in the associated protein/mRNA levels were restored when treated with [6]-gingerol. CONCLUSION: This suggests that the antiemetic effect of [6]-gingerol against cisplatin-induced emesis may be due to 5-HT attenuation via modulating the TPH/MAO-A/SERT/5-HT/5-HT3 receptor system.

RNA-Seq reveals inflammatory mechanisms of Xiao-Ban-Xia-Tang decoction to ameliorate cisplatin-induced emesis in a rat pica model.

OBJECTIVES: Xiao-Ban-Xia-Tang decoction (XBXT), an antiemetic formula in traditional Chinese medicine, has been proved to be a potential treatment for chemotherapy-induced nausea and vomiting (CINV), but the underlying mechanisms are not adequately understood. This study aimed to investigate changes in the ileum transcriptome after cisplatin and XBXT treatment and to reveal whether the antiemetic mechanisms of XBXT are related to its anti-inflammatory effect. METHODS: The pica model was established by a single intraperitoneal injection of 6 mg/kg cisplatin in Wistar rats. Tissues from the gastric antrum and ileum were stained with hematoxylin-eosin to observe gastrointestinal tract pathological changes. Based on the differentially expressed genes (DEGs) which were altered by cisplatin and reversed by XBXT, the transcriptome data of rat ileum were analyzed by GO, KEGG, and PPI analyses. Several inflammatory DEGs were validated by RT-PCR. RESULTS: XBXT could reduce kaolin intake up to 72 h after modeling and alleviate the inflammatory damage of gastric antrum and ileum induced by cisplatin. According to the transcriptome profile, there were 75 DEGs down-regulated by cisplatin and up-regulated by XBXT and 343 DEGs up-regulated by cisplatin and down-regulated by XBXT. XBXT could blunt the overexpression of tryptophan hydroxylase 1 (the rate-limiting enzyme of serotonin synthesis) in ileum. Enrichment analysis showed that inhibiting overexpression of several conventional inflammation pathways and pro-inflammation cytokines were related to the antiemetic effectiveness of XBXT. CONCLUSIONS: This study implies that inhibiting inflammatory signaling pathways and synthesis of serotonin might be potential mechanisms of XBXT's antiemetic effect against CINV.

Effects of ondansetron and [6]-gingerol on pica and gut microbiota in rats treated with cisplatin.

PURPOSE: [6]-gingerol is one of the main components of ginger with many biological activities. In this study, the effects of ondansetron and [6]-gingerol on pica and gut microbiota in rats injected with cisplatin were evaluated. MATERIALS AND METHODS: Rat model of cisplatin-induced pica was established, and the effects of ondansetron and [6]-gingerol on the gut microbiota were further studied by 16S rDNA gene analysis. RESULTS: The results showed that the total intake of kaolin of the rats injected with cisplatin was significantly increased, and treatment of ondansetron and [6]-gingerol in advance could significantly ameliorate the pica induced by cisplatin. The body weight of the rats injected with cisplatin was decreased compared with the control group. The 16S rDNA gene analysis has shown that ondansetron, [6]-gingerol and cisplatin could increase the relative abundance of Bacteroidetes and decrease Firmicutes on phylum level. CONCLUSION: [6]-gingerol was as effective as ondansetron in the treatment of pica induced by cisplatin in rats, and it seemed that [6]-gingerol had the potential to ameliorate the alteration of gut microbiome, but it needs further study.

Effect of orexin-A in the arcuate nucleus on cisplatin-induced gastric side effects in rats.

The most common side effects of the cancer chemotherapy drug cisplatin are nausea and vomiting. These effects are heavily influenced by orexigenic and anorexigenic peptides. We explored the effects of orexin-A on the cisplatin-treated rats and a possible mechanism for its effects on cisplatin-induced side effects. Quantitative real-time PCR was used to measure the change of prepro-orexin mRNA in the hypothalamus following cisplatin treatment. The effect of orexin-A and cisplatin on the firing rate of arcuate nucleus neurons was recorded. The effect of administration of orexin-A and a neuropeptide Y1 receptor antagonist to the arcuate nucleus on food intake, pica, and gastric motility on cisplatin treated rats were also measured. The relative expression of prepro-orexin mRNA in the hypothalamus was reduced by cisplatin. Exogenous orexin-A altered cisplatin-induced changes to the neuronal firing of gastric distension-responsive neurons, alleviated the cisplatin-induced anorexia, pica and improves the weakened gastric motility in the arcuate nucleus of rats. These effects could be partially blocked by intracerebroventricular injection (i.c.v.) of a neuropeptide Y1 receptor antagonist. These results suggest that orexin-A signaling ameliorates the gastric disorder induced by cisplatin in rats, and may act through neuropeptide Y neurons in the arcuate nucleus.

Parapheromones Suppress Chemotherapy Side Effects.

The cytotoxic drugs used in chemotherapy are often accompanied by nausea and vomiting. Despite the use of antiemetic drugs, chemotherapy-induced nausea and vomiting (CINV) remain significant side effects for cancer patients and are associated with serotonin type 3 receptor (5-HT3R) activation in the brainstem. Farnesol and nerolidol are sesquiterpene alcohols found in essential oils of plants such as roses, citronella, and lemon grass and are used as antiemetic parapheromones. Medicinal plants often are effective in treating gastrointestinal disorders, including CINV, although the mechanism of action remains unclear. In the current work, the antiemetic efficacy of the naturally occurring racemic mixture of farnesol (m-farnesol) and nerolidol (m-nerolidol) against cisplatin CINV was tested using the pica behavior (consumption of nonnutritive substances) of rats. Animals treated with m-farnesol or m-nerolidol consumed a smaller amount of kaolin than of saline-treated control animals. This result is consistent with the antiemetic efficacy of farnesol and nerolidol. Compared with controls, m-farnesol- but not m-nerolidol-treated animals consumed more food and lost less body weight. Thus, farnesol effectively reduced appetite suppression and weight loss induced by cisplatin. In separate experiments, isomers of farnesol and nerolidol were tested on 5-HT-induced responses of acutely isolated nodose neurons using patch-clamp methods. All the tested constituents inhibited 5-HT3R-mediated current in a noncompetitive manner. Thus, both farnesol and nerolidol may exert antiemetic efficacy by inhibiting 5-HT signaling in cranial visceral afferents, resulting in interruption of emetogenic signaling; however, nerolidol failed to suppress cisplatin-induced anorexia and weight loss, suggesting that additional mechanisms may contribute.

Enhancement of ghrelin-signaling system by Rikkunshi-To attenuates teriparatide-induced pica in rats.

Teriparatide is clinically used for the treatment of osteoporosis; however, nausea is often observed in patients. Its insufficient control affects the ability to continue teriparatide therapy. Rikkunshi-To (RKT), a traditional Japanese herbal medicine, improves the gastrointestinal function via activation of the ghrelin-signaling system. We investigated the therapeutic effects of RKT on teriparatide-induced nausea in rats and the involvement of ghrelin in these effects. We previously reported that ovariectomized rats showed pica (kaolin ingestion), a behavior that can be used to assess nausea in rats, after the subcutaneous administration of teriparatide; thus, the behavior was used as an index of nausea. Ovariectomized rats were fed diets with or without RKT (1%) for 2 weeks, and then they received the subcutaneous injection of teriparatide (400 µg/kg). Teriparatide significantly increased the incidence of pica, while suppressing intestinal motility and plasma ghrelin levels in rats fed normal diets; however, rats fed diets with RKT showed improvements in all of the teriparatide-induced adverse reactions. These therapeutic effects were antagonized by a ghrelin receptor antagonist ([D-Lys3]-GHRP-6; 200 nmol/rat). These findings suggest that the enhancement of ghrelin-signaling is involved in RKT's therapeutic effect, and that RKT is a potentially useful treatment for teriparatide-induced nausea.

Cisplatin increases the number of enterochromaffin cells containing substance P in rat intestine.

We previously reported that cisplatin potentiated ileal 5-hydroxytryptamine (5-HT) metabolism and caused pathological changes with an inflammatory response in the delayed phase (72 h) after administration to rats. In the present study, we further investigated the time-dependent effect of cisplatin on ileal 5-HT metabolism and the effects of combining cisplatin and anti-inflammatory drugs on ileal tryptophan hydroxylase expression and pica (the consumption of non-nutritive materials such as kaolin). Cyclooxygenase-2 (COX-2) expression was significantly increased at 24 h after cisplatin (5 mg/kg, intraperitoneal) administration. Cisplatin significantly increased ileal 5-HT content at 48 h after administration and the number of L-tryptophan hydroxylase-expressing cells (i.e., enterochromaffin cells) in the ileal mucosa within 24 h after administration. It also caused a significant increase in the number of substance P-expressing cells. Immunohistochemical double staining revealed that most of the enterochromaffin cells contained substance P. Neither daily treatment with dexamethasone (1 mg/kg, subcutaneous) nor meloxicam (3 mg/kg, subcutaneous), a selective COX-2 inhibitor, affected the cisplatin-induced increase in the number of enterochromaffin cells. Meloxicam had no effect on cisplatin-induced pica, although dexamethasone almost completely inhibited it. This study demonstrated that cisplatin administration induced COX-2 expression and increased the number of enterochromaffin cells in the acute phase (i.e., within 24 h). However, COX-2 expression in the ileum seems to have little direct effect on the mechanism of the induction of enterochromaffin cells and pica.

Remote treatment of sleep-related trichotillomania and trichophagia.

We used a biobehavioral treatment consisting of melatonin and a standardized bed and wake time to decrease one girl's head and mouth touches associated with sleep-related trichotillomania and trichophagia. We remotely coached the girl's caregiver to implement all procedures and monitored response to treatment using a DropCam Pro video camera equipped with night-vision capabilities. Head and mouth touches decreased, and her sleep pattern improved with the combination of treatment strategies. We discuss our use of a novel mode of service delivery to treat sleep-related problem behavior.

Qualitative assessment of pica experienced by frequent blood donors.

BACKGROUND: Pica, the compulsive consumption of ice or other nonnutritious substances, is associated with iron deficiency, a common negative consequence of frequent blood donation. Because of this, blood donors, such as those participating in the Strategies to Reduce Iron Deficiency (STRIDE) study, are an ideal population to explore pica and iron deficiency. STUDY DESIGN AND METHODS: STRIDE was a 2-year intervention trial to assess the effectiveness of iron supplementation for mitigating iron deficiency in frequent blood donors. Subjects completed baseline and follow-up questionnaires that included questions about pica symptoms. In-depth telephone interviews were conducted with 14 of these subjects reporting pica symptoms and eight presumed controls (casual ice chewers) to gain a deeper understanding of pica symptoms and their impact on daily life and to make a final determination on the presence of pica. RESULTS: Pica was confirmed in five of the 14 subjects reporting symptoms and in two of eight controls. Outcome misclassification based on the questionnaire was attributed to inadequate assessment of several pica symptoms identified during the interview. Comparison of subjects' repeated quantitative iron measurements taken throughout STRIDE with subjects' final adjudicated pica status revealed a positive relationship between development of pica and worsening iron status; the opposite was found in those whose pica symptoms resolved. CONCLUSION: Continued refinement of pica symptom questions will allow for rapid and accurate detection of pica in frequent blood donors and confirmation of successful treatment with iron supplements.

Sevoflurane-induced pica in female rats.

We examined the effects of volatile anesthetics on pica, which can be used to assess nausea and vomiting in rats. We found that inhalation anesthesia with sevoflurane significantly induced pica in female but not male rats. Among the female rats, young rats (8 weeks old) were more susceptible to its induction than adult rats (20 weeks old) with ovariectomy or sham-surgery. Anti-emetic drugs that are used to prevent postoperative nausea and vomiting (PONV) inhibited the pica. These results suggest that sevoflurane-induced pica in young female rats has the potential to be an animal model of PONV in humans.

Hindbrain GLP-1 receptor mediation of cisplatin-induced anorexia and nausea.

While chemotherapy-induced nausea and vomiting are clinically controlled in the acute (<24 h) phase following treatment, the anorexia, nausea, fatigue, and other illness-type behaviors during the delayed phase (>24 h) of chemotherapy are largely uncontrolled. As the hindbrain glucagon-like peptide-1 (GLP-1) system contributes to energy balance and mediates aversive and stressful stimuli, here we examine the hypothesis that hindbrain GLP-1 signaling mediates aspects of chemotherapy-induced nausea and reductions in feeding behavior in rats. Specifically, hindbrain GLP-1 receptor (GLP-1R) blockade, via 4th intracerebroventricular (ICV) exendin-(9-39) injections, attenuates the anorexia, body weight reduction, and pica (nausea-induced ingestion of kaolin clay) elicited by cisplatin chemotherapy during the delayed phase (48 h) of chemotherapy-induced nausea. Additionally, the present data provide evidence that the central GLP-1-producing preproglucagon neurons in the nucleus tractus solitarius (NTS) of the caudal brainstem are activated by cisplatin during the delayed phase of chemotherapy-induced nausea, as cisplatin led to a significant increase in c-Fos immunoreactivity in NTS GLP-1-immunoreactive neurons. These data support a growing body of literature suggesting that the central GLP-1 system may be a potential pharmaceutical target for adjunct anti-emetics used to treat the delayed-phase of nausea and emesis, anorexia, and body weight loss that accompany chemotherapy treatments.

GSK356278, a potent, selective, brain-penetrant phosphodiesterase 4 inhibitor that demonstrates anxiolytic and cognition-enhancing effects without inducing side effects in preclinical species.

Small molecule phosphodiesterase (PDE) 4 inhibitors have long been known to show therapeutic benefit in various preclinical models of psychiatric and neurologic diseases because of their ability to elevate cAMP in various cell types of the central nervous system. Despite the registration of the first PDE4 inhibitor, roflumilast, for the treatment of chronic obstructive pulmonary disease, the therapeutic potential of PDE4 inhibitors in neurologic diseases has never been fulfilled in the clinic due to severe dose-limiting side effects such as nausea and vomiting. In this study, we describe the detailed pharmacological characterization of GSK356278 [5-(5-((2,4-dimethylthiazol-5-yl)methyl)-1,3,4-oxadiazol-2-yl)-1-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine], a potent, selective, and brain-penetrant PDE4 inhibitor that shows a superior therapeutic index to both rolipram and roflumilast in various preclinical species and has potential for further development in the clinic for the treatment of psychiatric and neurologic diseases. GSK356278 inhibited PDE4B enzyme activity with a pIC50 of 8.8 and bound to the high-affinity rolipram binding site with a pIC50 of 8.6. In preclinical models, the therapeutic index as defined in a rodent lung inflammation model versus rat pica feeding was >150 compared with 0.5 and 6.4 for rolipram and roflumilast, respectively. In a model of anxiety in common marmosets, the therapeutic index for GSK356278 was >10 versus <1 for rolipram. We also demonstrate that GSK356278 enhances performance in a model of executive function in cynomolgus macaques with no adverse effects, a therapeutic profile that supports further evaluation of GSK356278 in a clinical setting.