Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice

Treatment with PAN-PDE4 inhibitors has been shown to produce hypothermia in multiple species. Given the growing body of evidence that links nausea and emesis to disturbances in thermoregulation in mammals, we explored PDE4 inhibitor-induced hypothermia as a novel correlate of nausea in mice. Using knockout mice for each of the four PDE4 subtypes, we show that selective inactivation of individual PDE4 subtypes per se does not produce hypothermia, which must instead require the concurrent inactivation of multiple (at least two) PDE4 subtypes. These findings contrast with the role of PDE4s in shortening the duration of α2-adrenoceptor-dependent anesthesia, a behavioral surrogate previously used to assess the emetic potential of PDE4 inhibitors, which is exclusively affected by inactivation of PDE4D. These different outcomes are rooted in the distinct molecular mechanisms that drive these two paradigms; acting as a physiologic α2-adrenoceptor antagonist produces the effect of PDE4/PDE4D inactivation on the duration of α2-adrenoceptor-dependent anesthesia, but does not mediate the effect of PDE4 inhibitors on body temperature in mice. Taken together, our findings suggest that selective inhibition of any individual PDE4 subtype, including inhibition of PDE4D, may be free of nausea and emesis.

Antiemetic Prophylaxis for Chemoradiotherapy-induced Nausea and Vomiting (C-RINV) in Locally Advanced Head and Heck Squamous Cell Carcinoma: a Prospective Phase Ⅱ Trial

Background There is sparse research reporting effective interventions for preventing nausea and emesis caused by concurrent chemoradiotherapy (CCRT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). This phase Ⅱ trial was conducted to provide the direct evidence for the current practice of prescribing antiemetic in patients with LA-HNSCC receiving CCRT.Methods Treatment-naïve LA-HNSCC patients received intensity-modulated radiotherapy with concomitant cisplatin 100 mg/m² every 3 weeks for two cycles. All patients were given orally aprepitant 125 mg once on d1, then 80mg once on d2-5; ondansetron 8 mg once on d1; and dexamethasone 12 mg once on d1, then 8mg on d2-5. The primary endpoint was complete response (CR). Pursuant to δ=0.2 and α=0.05, the expected CR rate was 80%. Results A total of 43 patients with LA-HNSCC were enrolled. The median age was 53 years old, and 86.0% were male. All patients received radiotherapy and 86.0% of patients completed both cycles as planned. The overall CR rate was 86.0% (95% CI: 72.1-94.7). The CR rates for cycles 1 and 2 were 88.4% (95% CI: 74.9-96.1) and 89.2% (95% CI: 74.6-97.0). The complete protection rate in the overall phase was 72.1% (95% CI: 56.3-84.7). The emesis-free response and nausea-free response in overall phase were 88.4% (95% CI: 74.9-96.1) and 60.5% (95% CI: 44.4-75.0), respectively. The adverse events related to antiemetics were constipation (65.1%) and hiccups (16.3%), but both were grade 1-2. There was no grade 4 or 5 treatment-related adverse event with antiemetic usage. Conclusion The addition of aprepitant into ondansetron and dexamethasone provided effective protection from nausea and emesis in patients with LA-HNSCC receiving radiotherapy and concomitant high-dose cisplatin chemotherapy. Randomised phase 3 studies are required to further define the potential role of NK1RA in chemoradiotherapy setting.Trial registration: ClinicalTrials.gov, number NCT03572829. Registered 28 June 2018, https://clinicaltrials.gov/ct2/show/NCT03572829?term=NCT03572829&draw=2&rank=1.

Comparative study of Prophylactic Intravenous Ondansetron in the Attenuation of Post Spinal Hypotension versus Dexamethasone in Parturient Undergoing Caesarean Delivery

Background Spinal anaesthesia (SA) is the preferred anaesthesia technique for Caesarean section. Hypotension and bradycardia are the most common side effects encountered and are more pronounced in pregnant patients, the incidence being as high as 52.6% and 2.5% in normal patients. The occurrence of hypotension can be dangerous as it compromises placental circulation and can have a detrimental effect on the foetus. Objectives The purpose of this study is to assess the efficacy of ondansetron versus dexamethasone in decreasing incidence of spinal induced hypotension in parturient undergoing cesarean surgery. Patients and Methods This study was conducted at Ain Shams University Hospitals between March 2019 till September 2019. After approval is obtained from the research ethics committee of faculty of medicine, Ain Shams University & patients’ informed consents consent from each patient after full explanation of the procedure possible side effects and complications., 75 healthy parturient, (ASA)physical status I and II undergoing elective cesarean delivery under spinal anesthesia. Results 8 mg ondansetron is more effective than 8 mg dexamethasone in the attenuation of post spinal hypotension. Also, that Dexamethasone 8 mg was as effective as ondansetron 8 mg in providing a simple, safe, cheap, and effective intra and postoperative nausea and emesis prevention method with the advantage of being cheaper decreasing the economic burden. Conclusion The present study demonstrated that, among patients who received spinal anesthesia with bupivacaine and fentanyl as adjuvant for elective for cesarean section, prophylactic intravenous 8 mg ondansetron compared to dexamethasone significantly decreases hypotension, HR fluctuation, yet the need for rescue doses for ephedrine were significantly higher in ondansetron.

Thyroid storm as an early presentation of hCG-producing metastatic choriocarcinoma: a case report and review of the literature

Human chorionic gonadotropin (hCG)-induced hyperthyroidism has been previously reported as a rare paraneoplastic syndrome in non-seminomatous germ cell tumours and usually presents with mild symptoms or subclinical thyrotoxicosis. We present a case of a young adult man who consulted with abdominal pain, nausea and emesis. On admission, he was found to be tachycardic, febrile, anxious and with icteric sclera and tenderness to palpation in the right upper abdomen. A right scrotal mass was also noted. Initial studies revealed transaminitis, hyperbilirubinaemia, suppressed thyroid-stimulating hormone and elevated free T4. Scrotal biopsy confirmed diagnosis of testicular choriocarcinoma with an elevated hCG level of 6074 mIU/mL, which was corrected to 6 760 713 mIU/mL when reassessed with dilution. The clinical scenario reflected hCG-induced thyrotoxicosis concerning for thyroid storm. Euthyroid state was restored after initiation of chemotherapy and a short course of methimazole. Unfortunately, the patient passed away due to progression of his malignant disease. This case suggests that when choriocarcinoma is suspected, the use of iodinated contrast agents should be limited to avoid precipitation of thyroid storm or worsening of hCG-induced hyperthyroidism. Moreover, if the clinical picture does not support a primary aetiology of hyperthyroidism and hCG is not concordantly elevated, reassessment of hCG by dilution should be considered as hCG assays are subject to prozone effect.

GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist Induced Nausea and Emesis in Preclinical Models

Glucagon-like peptide-1 receptor (GLP-1R) agonists decrease body weight and improve glycemic control in obesity and diabetes. Patient compliance and maximal efficacy of GLP-1 therapeutics are limited by side effects including nausea and emesis. In three different species (i.e., mice, rats, and musk shrews), we show that glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling blocks emesis and attenuates illness behaviors elicited by GLP-1R activation, while maintaining reduced food intake, body weight loss, and improved glucose tolerance. The area postrema and nucleus tractus solitarius (AP/NTS) of the hindbrain are required for food intake and body weight suppression by GLP-1R ligands and processing of emetic stimuli. Utilizing single-nuclei RNA-sequencing, we identified the cellular phenotypes of AP/NTS GIPR- and GLP-1R-expressing cells on distinct populations of inhibitory and excitatory neurons, with the greatest expression of GIPR in GABAergic neurons. This work suggests that combinatorial pharmaceutical targeting of GLP-1R and GIPR will increase efficacy in treating obesity and diabetes by reducing nausea and vomiting.

GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist Induced Nausea and Emesis in Preclinical Models

Glucagon-like peptide-1 receptor (GLP-1R) agonists decrease body weight and improve glycemic control in obesity and diabetes. Patient compliance and maximal efficacy of GLP-1 therapeutics are limited by side effects including nausea and emesis. In three different species (i.e., mice, rats, and musk shrews), we show that glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling blocks emesis and attenuates illness behaviors elicited by GLP-1R activation, while maintaining reduced food intake, body weight loss, and improved glucose tolerance. The area postrema and nucleus tractus solitarius (AP/NTS) of the hindbrain are required for food intake and body weight suppression by GLP-1R ligands and processing of emetic stimuli. Utilizing single-nuclei RNA-sequencing, we identified the cellular phenotypes of AP/NTS GIPR- and GLP-1R-expressing cells on distinct populations of inhibitory and excitatory neurons, with the greatest expression of GIPR in GABAergic neurons. This work suggests that combinatorial pharmaceutical targeting of GLP-1R and GIPR will increase efficacy in treating obesity and diabetes by reducing nausea and vomiting.

Emerging Potential of Naturally Occurring Molecules against Gastric Cancer: Insights Molecular Mechanism and Therapeutic Targets

Gastric cancer, also known as stomach cancer, is a cancer which develops from the lining of the stomach. Accumulated evidences and epidemiological studies have been indicated that natural products play an important role in gastric cancer prevention and treatment, although its mechanism of action did not elucidate yet. Particularly, experimental studies have been showed that natural products displayed a protective effect against gastric cancer via numerous molecular mechanisms such as suppression of cell metastasis, anti-angiogenesis, inhibition of cell proliferation, induction of apoptosis, and modulation of autophagy. Although chemotherapy remains the standard treatment for advanced gastric cancer along with surgery, radiation therapy, hormone therapy and immunotherapy, but its adverse side effects including neutropenia, stomatitis, mucositis, diarrhea, nausea, and emesis are well documented. Additionally, intake of naturally occurring phytochemicals could increase the efficacy of gastric chemotherapy and chemotherapeutics resistance. However, natural product structural stability and powerful bioactivity are important to develop novel treatments for gastric cancer that may minimize such adverse effects. Therefore, the purpose of this review is to summarize the potential therapeutic effects of natural products on prevention and treatment of gastric cancer with intensive molecular mechanisms of action, bioavailability, and safety efficacy.

Unusual Presentation of a Gastrointestinal Stromal Tumor in a Small Intestine Diverticulum

A 50-year-old female with no significant medical history initially presented to an urgent care center with symptoms of acute onset abdominal pain, nausea, and emesis. Chest and abdominal X-ray revealed free air under the diaphragm, prompting immediate transfer to the emergency department. Continued abdominal tenderness and pain were concerning for perforated viscus. The patient was transferred to the operating room, and diagnostic laparoscopy was performed. Inflammation and contamination were discovered in the right side of the abdomen and pelvis secondary to a small bowel (SB) perforation. Segmental SB resection revealed a perforated diverticulum. Pathological examination confirmed a diagnosis of gastrointestinal stromal tumor (GIST) at the perforated segment. On postoperative day 5, the patient was discharged home, and at 30-month follow-up, the patient continued to do well. Although rare, SB diverticula are commonly false (i.e., pseudodiverticula). The concomitant presence of a GIST in a true SB diverticulum presenting with perforation has not yet been reported.

Evaluation of an Oral Sodium Bicarbonate Protocol for High-Dose Methotrexate Urine Alkalinization

Purpose: Intravenous (IV) sodium bicarbonate is considered standard therapy for high-dose methotrexate (HDMTX) urine alkalinization. Due to a national IV sodium bicarbonate shortage, an oral (PO) sodium bicarbonate protocol was implemented by Alberta Health Services (AHS) for HDMTX urine alkalinization. This study aims to evaluate the efficacy and safety of the PO sodium bicarbonate protocol compared to IV sodium bicarbonate for HDMTX urine alkalinization. Methods: A retrospective chart review of adult patients who received HDMTX (>500 mg/m2) with sodium bicarbonate for urine alkalinization at 4 hospitals in Alberta was conducted. Patients who received IV sodium bicarbonate between January-June 2017 and PO sodium bicarbonate between July-December 2017 were compared for the primary outcome of time to methotrexate clearance. Results: A total of 84 and 78 HDMTX cycles were included in the IV and PO cohorts, respectively. No difference in time to methotrexate clearance was seen between the IV and PO cohorts, 91.6 (± 35.4) hours and 95.2 (± 44) hours respectively; p=0.5. The proportion of HDMTX cycles that experienced a >25% increase in serum creatinine was not statistically significant, IV protocol 12% and PO protocol 5%; p=0.13. Nausea and emesis occurred more frequently in the PO cohort than the IV cohort, though rarely resulted in refused doses or change to alternate sodium bicarbonate formulations.Conclusions: The results of this study indicate that the AHS PO sodium bicarbonate protocol was no different in time to methotrexate clearance or rates of increased serum creatinine when compared to IV sodium bicarbonate.