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Glycogen synthase kinase 3 (GSK-3) is a constitutively active multifunctional serine-threonine kinase which is involved in diverse physiological processes. GSK-3 has been implicated in a wide range of diseases including neurodegeneration, inflammation, diabetes and cancer. GSK-3 is a downstream target for protein kinase B (Akt) which phosphorylates GSK-3 and suppresses its activity. Based upon our preliminary findings, we postulated Akt's involvement in emesis. The aim of this study was to investigate the participation of GSK-3 and the antiemetic potential of two GSK-3 inhibitors (AR-A014418 and SB216763) in the least shrew model of vomiting against fully-effective emetic doses of diverse emetogens, including the nonselective and/or selective agonists of serotonin type 3 (e.g. 5-HT or 2-Methyl-5-HT)-, neurokinin type 1 receptor (e.g. GR73632), dopamine D 2 (e.g. apomorphine or quinpirole)-, and muscarinic 1 (e.g. pilocarpine or McN-A-343) receptors, as well as the L-type Ca 2+ channel agonist (FPL64176), the sarco/endoplasmic reticulum Ca 2+ -ATPase inhibitor thapsigargin, and the chemotherapeutic agent, cisplatin. We first determined if these emetogens could regulate the phosphorylation level of GSK-3 in the brainstem emetic loci of least shrews and then investigated whether AR-A014418 and SB216763 could protect against the evoked emesis. Phospho-GSK-3α/β Ser21/9 levels in the brainstem and the enteric nerves of jejunum in the small intestine were upregulated following intraperitoneal (i.p.) administration of all the tested emetogens. Furthermore, administration of AR-A014418 (2.5-20 mg/kg, i.p.) dose-dependently attenuated both the frequency and percentage of shrews vomiting in response to i.p. administration of 5-HT (5 mg/kg), 2-Methyl-5-HT (5 mg/kg), GR73632 (5 mg/kg), apomorphine (2 mg/kg), quinpirole (2 mg/kg), pilocarpine (2 mg/kg), McN-A-343 (2 mg/kg), FPL64176 (10 mg/kg), or thapsigargin (0.5 mg/kg). Relatively lower doses of SB216763 exerted antiemetic efficacy, but both inhibitors barely affected cisplatin (10 mg/kg)-induced vomiting. Collectively, these results support the notion that vomiting is accompanied by a downregulation of GSK-3 activity and pharmacological inhibition of GSK-3 protects against pharmacologically evoked vomiting., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We performed a systematic review and meta-analysis of the risk of gastrointestinal (GI) toxicities associated with MEK inhibitors. Eligible studies included randomized Phase II and III trials of cancer patients on the three MEK inhibitors (trametinib, selumetinib and cobimetinib), describing events of stomatitis, diarrhea and vomiting. Our search strategy yielded 250 potentially relevant citations from Pubmed/Medline, Google scholar and CENTRAL Cochrane registry. After exclusion of ineligible studies, a total of 16 clinical trials were considered eligible for the meta-analysis. The relative risks of all-grade stomatitis, diarrhea and vomiting were 2.03 (95% CI 1.41-2.96; p = 0.002), 1.92 (95% CI 1.48-2.50; p < 0.00001) and 1.35 (95% CI 1.06-1.71; p = 0.01). Subgroup analyses according to agent used (trametinib vs Selumetinib), the regimen used (monotherapy vs combination) and the cancer treated (melanoma vs nonmelanoma) did not reveal any significant difference between the subgroups. Our meta-analysis has demonstrated that MEK inhibitor-based treatment is associated with an increased risk of stomatitis, diarrhea and vomiting compared to control. Clinicians should be aware of this risk and perform regular assessment.

Complete control of emesis caused by cyclophosphamide (CPA) is of immense interest to both patients and physicians. Serotonin 5-HT3- and tachykinin NK1-receptor antagonists are widely used antiemetics in clinic, but they fail to completely control CPA-induced emesis. New antiemetic targets for the full control of CPA-induced vomiting are lacking. We therefore examined the effects of CPA on emetic targets downstream of 5-HT3- and NK1- receptors in an attempt to better understand the molecular bases of CPA-induced emesis. Acute CPA (200 mg/kg, i.p.) administration in the least shrew caused a biphasic pattern of emesis over a 40 h observation period, with maximal peak vomit frequency during the 1st hour of treatment (acute phase), followed by a delayed-phase which peaks at 27th hour. The NK1 receptor mRNA levels increased significantly at 8 h post-CPA treatment in the brainstem, and at 28 h in the whole intestine. Substance P mRNA levels tended to increase both in the brainstem and intestine at most time-points post-CPA injection, however due to large variability, they failed to attain significance. Likewise, protein expression profiles of both NK1- and 5-HT3 -receptors in the brainstem were unchanged at any time-point. However, phosphorylation levels of protein kinase A (PKA), but not of extracellular signal-regulated protein kinase 1/2 (ERK1/2), were increased at 2, 8, 22, 28, and 33 h time-points after the treatment with CPA. Moreover, brainstem but not frontal cortex cAMP tissue levels tended to be elevated at most time-points, but significant increases occurred only at 1 and 2 h post-CPA treatment. The phosphodiesterase inhibitor, rolipram, caused significant increases in shrew brainstem cAMP levels which were associated with its capacity to produce vomiting, while pretreatment with SQ22536, an inhibitor of adenylyl cyclase, prevented rolipram-induced emesis. The results demonstrate that accumulation of cAMP and subsequent activation of PKA in the brainstem may help to initiate and sustain emesis induced by CPA in the least shrew. Our findings suggest that suppression of the cAMP/PKA cascade may have antiemetic potential in the management of CPA-induced emesis.

Patients with bulimia nervosa are at high risk for dental erosion. However, not all bulimic patients suffer from erosion, irrespective of the severity of their eating disorder. It is often speculated that differences in the saliva are important, however, little is known about salivary parameters in bulimic patients, particularly directly after vomiting. The aim of the clinical trial was to compare different salivary parameters of subjects suffering from bulimia with those of healthy controls. Twenty-eight subjects participated (14 patients with bulimia nervosa, 7 of them with erosion; 14 matched healthy controls). Resting and stimulated saliva of all participants was analysed as well as saliva collected from bulimic patients directly and 30 min after vomiting. Parameters under investigation were flow rate, pH, buffering capacity and the enzyme activities of proteases in general, collagenase, pepsin, trypsin, amylase, peroxidase, and lysozyme. Regarding flow rate, pH and buffering capacity only small differences were found between groups; buffering capacity directly after vomiting was significantly lower in bulimic subjects with erosion than in subjects without erosion. Differences in enzymatic activities were more pronounced. Activities of proteases, collagenase and pepsin in resting and proteases in stimulated saliva were significantly higher in bulimic participants with erosion than in controls. Peroxidase activity was significantly decreased by regular vomiting. Proteolytic enzymes seem to be relevant for the initiation and progression of dental erosion directly after vomiting, maybe by both hydrolysis of demineralized dentine structures as well as modulation of the pellicle layer., (Copyright © 2012 S. Karger AG, Basel.)

This study investigated doxycycline-related side effects in a large population of dogs. Data from 386 dogs that had received doxycycline for the treatment of various infectious diseases were analysed retrospectively. Potential side effects that developed during treatment were documented, and correlations with signalment, dose, duration of treatment, frequency of application, doxycycline preparation and use of additional drugs were investigated. Vomiting was reported in 18.3 per cent of dogs, 7.0 per cent developed diarrhoea and 2.5 per cent developed anorexia. While being treated with doxycycline, 39.4 per cent of dogs showed an increase in alanine aminotransferase (ALT) activity and 36.4 per cent showed an increase in alkaline phosphatase (ALP) activity. There was a dose-related risk of an increase in ALP activity (P=0.011, odds ratio [OR]=1.27, 95 per cent confidence interval [CI] 1.06 to 1.53), and older dogs treated with doxycycline were more likely to develop an increase in ALT activity (P=0.038, OR=1.23, 95 per cent CI 1.01 to 1.50) and vomiting (P=0.017, OR=1.11, 95 per cent CI 1.02 to 1.21).

The authors investigated the significance of vomiting for hyperamylasemia and sialadenosis in patients with bulimia nervosa. Hyperamylasemia was found in 61% of the bulimics and in 20% of the restrictor anorectics but in no patients with binge-eating syndrome. In more than three fourths of the bulimics there was a close positive correlation between the frequency of vomiting and total serum amylase levels. Both frequency and type of vomiting seem to be relevant to the extent of salivary gland enlargement. The significance of vomiting for the etiopathology of hyperamylasemia and for the diagnosis of eating disorders will be discussed.

The paper reports four cases of idiopathic transient alkaline hyperphosphatasemia during episodes of acute infection of presumable viral etiology. It is interesting to note that one patient present a exanthematous febrile reaction to an anti-measles vaccination, which seems to confirm that the measles virus may be one of the possible causal factors of the pathology. The assay of alkaline phosphatase isoenzymes showed an increase in the three hepatic, bone and intestinal fractions, thus excluding a sectorial pathology (bone or hepatic). This will avoid the need to subject the child to superfluous diagnostic tests in this transient and benign condition of increased enzyme levels.