- Polypharmacological In Silico Bioactivity Profiling and Experimental Validation Uncovers Sedative-Hypnotic Effects of Approved and Experimental Drugs in Rat. [Journal Article]
- ACACS Chem Biol 2017 Apr 17
- In this work, we describe the computational ('in silico') mode-of-action analysis of CNS-active drugs, which is taking both multiple simultaneous hypotheses as well as sets of protein targets for eac...
In this work, we describe the computational ('in silico') mode-of-action analysis of CNS-active drugs, which is taking both multiple simultaneous hypotheses as well as sets of protein targets for each mode-of-action into account, and which was followed by successful prospective in vitro and in vivo validation. Using sleep-related phenotypic readouts describing both efficacy and side-effects for 491 compounds tested in rat, we defined an 'optimal' (desirable) sleeping pattern. Compounds were subjected to in silico target prediction (which was experimentally confirmed for 21 out of 28 cases, corresponding to 75%), followed by the utilization of decision trees for deriving polypharmacological bioactivity profiles. We demonstrated that predicted bioactivities improved classification performance compared to using only structural information. Moreover, DrugBank molecules were processed via the same pipeline and compounds in many cases not annotated as sedative-hypnotic (alcaftadine, benzatropine, palonosetron, ecopipam, cyproheptadine, sertindole and clopenthixol) were prospectively validated in vivo. Alcaftadine, ecopipam cyproheptadine and clopenthixol were found to promote sleep as predicted, benzatropine showed only a small increase in NREM sleep, whereas sertindole promoted wakefulness. To our knowledge, the sedative-hypnotic effects of alcaftadine and ecopipam have not been previously discussed in literature. The method described extends previous single-target, single-mode-of-action models, and is applicable across disease areas.
- New options and controversies in the management of chemotherapy-induced nausea and vomiting. [Journal Article]
- AJAm J Health Syst Pharm 2017 Apr 10
- CONCLUSIONS: Up to 80% of patients receiving chemotherapy have CINV. Current practice guidelines recommend that patients treated with highly emetogenic chemotherapy also receive a 3-drug antiemetic regimen initiated on the day of and continued for 3 days after chemotherapy administration, with the most commonly used 3-drug regimen consisting of an NK1 receptor antagonist, a 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, and dexamethasone. Developments in the area of CINV management in recent years include the use of olanzapine in combination with a 5-HT3 antagonist and dexamethasone; Food and Drug Administration (FDA) approval of the NK1 receptor antagonist rolapitant, which provides a longer duration of effect than aprepitant; FDA approval of a combination product containing palonosetron and the NK1 receptor antagonist netupitant; and revisions of U.S. practice guidelines ending palonosetron's status as the preferred 5-HT3 antagonist for prevention of CINV associated with moderately or highly emetogenic chemotherapy.Newer therapeutic options for the management of CINV are equivalent to standard-of-care regimens in terms of efficacy and toxicity. While the NK1 receptor antagonist rolapitant and a product combining palonosetron and netupitant have potential advantages over standard therapy in terms of convenience or pharmacologic properties, their relatively high costs must be considered.
- NEPA, a new fixed combination of netupitant and palonosetron, is a cost-effective intervention for the prevention of chemotherapy-induced nausea and vomiting in the UK. [Review]
- DCDrugs Context 2017; 6:212298
- CONCLUSIONS: Despite study limitations (study setting, time horizon, utility measure), the results suggest NEPA is cost effective for preventing CINV associated with HEC and MEC in the UK.
- Neurokinin-1 Receptor Antagonist-Based Triple Regimens in Preventing Chemotherapy-Induced Nausea and Vomiting: A Network Meta-Analysis. [Journal Article]
- JNCIJ Natl Cancer Inst 2017 Feb 01; 109(2):1-11
- CONCLUSIONS: Different NK-1RAs-based triple regimens shared equivalent effect on CINV control. Various triple regimens had superior antiemetic effect than duplex regimen in patients with HEC. Only aprepitant-based triple regimen showed better CINV control compared with duplex regimen in patients receiving MEC. Palonosetron and first-generation 5HT3RAs might share equivalent CINV control in the combination of NK-1RAs and dexamethasone. Lower doses of dexamethasone might be applied when used with NK-1RAs and 5HT3RAs.
- Antiemetic therapy for non-anthracycline and cyclophosphamide moderately emetogenic chemotherapy. [Review]
- MOMed Oncol 2017; 34(5):77
- Although antiemetic management in cancer therapy has improved, chemotherapy-induced nausea and vomiting remain common and troubling adverse events. Chemotherapeutic agents are classified based on the...
Although antiemetic management in cancer therapy has improved, chemotherapy-induced nausea and vomiting remain common and troubling adverse events. Chemotherapeutic agents are classified based on their emetogenic effects, and appropriate antiemetics are recommended according to this categorization. Chemotherapy categorized as moderately emetogenic is associated with a wide spectrum of emetic risks. Combined anthracycline and cyclophosphamide regimens have been recently reclassified as highly emetogenic chemotherapy regimen. This review focuses on antiemetic pharmacotherapy in patients receiving non-anthracycline and cyclophosphamide-based moderately emetogenic chemotherapy regimens. Combination therapy with a 5-hydroxytryptamine-3 receptor agonist, preferably palonosetron, and dexamethasone is the standard therapy in moderately emetogenic chemotherapy, although triple therapy with add-on neurokinin-1 receptor antagonist is used as an alternative treatment strategy. Among moderately emetogenic chemotherapy regimens, carboplatin-containing chemotherapy has considerable emetic potential, particularly during the delayed phase. However, the additional of a neurokinin-1 receptor antagonist to the standard antiemetic therapy prevents carboplatin-induced nausea and vomiting. For regimens including oxaliplatin, the benefit of adding neurokinin-1 receptor antagonist requires further clarification.
- Action of Bacopa monnieri to antagonize cisplatin-induced emesis in Suncus murinus (house musk shrew). [Journal Article]
- JPJ Pharmacol Sci 2017 Mar 12
- Bacopa monnieri (BM, family Scrophulariaceae) is used in several traditional systems of medicine for the management of epilepsy, depression, neuropathic pain, sleep disorders and memory deficits. The...
Bacopa monnieri (BM, family Scrophulariaceae) is used in several traditional systems of medicine for the management of epilepsy, depression, neuropathic pain, sleep disorders and memory deficits. The present study investigated the potential of BM methanol (BM-MetFr) and BM n-butanol fractions (BM-ButFr) to reduce chemotherapy-induced emesis in Suncus murinus (house musk shrew). Cisplatin (30 mg/kg, i.p.) reliably induced retching and/or vomiting over a 2 day period. BM-MetFr (10-40 mg/kg, s.c.) and BM-ButFr (5-20 mg/kg, s.c.) antagonized the retching and/or vomiting response by ∼59.4% (p < 0.05) and 78.9% (p < 0.05), respectively, while the 5-HT3 receptor antagonist, palonosetron (0.5 mg/kg, s.c.), reduced the response by ∼71% (p < 0.05). The free radical scavenger/antioxidant, N-(2-mercaptopropionyl)-glycine (30-300 mg/kg, s.c.) reduced the retching and/or vomiting response occurring on day one non-significantly by 44% (p > 0.05). In conclusion, the n-butanol fractions of BM have anti-emetic activity comparable with palonosetron and MPG. BM may be useful alone or in combination with other anti-emetic drugs for the treatment of chemotherapy-induced emesis in man.
- Comparison of Ramosetron with Palonosetron for Prevention of Postoperative Nausea and Vomiting in Patients Receiving Opioid-Based Intravenous Patient-Controlled Analgesia after Gynecological Laparoscopy. [Journal Article]
- BRBiomed Res Int 2017; 2017:9341738
- We aimed to compare the effects of ramosetron and palonosetron in the prevention of postoperative nausea and vomiting (PONV) in patients that received opioid-based intravenous patient-controlled anal...
We aimed to compare the effects of ramosetron and palonosetron in the prevention of postoperative nausea and vomiting (PONV) in patients that received opioid-based intravenous patient-controlled analgesia (IV-PCA) after gynecological laparoscopy. We reviewed the electronic medical records of 755 adults. Patients were classified into two groups, ramosetron (group R, n = 589) versus palonosetron (group P, n = 166). Based on their confounding factors, 152 subjects in each group were selected after the implementation of propensity score matching. The overall incidence of PONV at postoperative day (POD) 0 was lower in group R compared to group P (26.9% versus 36.8%; P = 0.043). The severity of nausea was lower in group R than in group P on postoperative day (POD) 0 (P = 0.012). Also, the complete responder proportion of patients was significantly higher in group R compared to that in group P on POD 0 (P = 0.043). In conclusion, ramosetron showed a greater efficacy in the prevention of postoperative nausea at POD 0 compared to palonosetron in patients after gynecological laparoscopy.
- Compatibility and Stability of Rolapitant Injectable Emulsion Admixed with Intravenous Palonosetron Hydrochloride. [Journal Article]
- IJInt J Pharm Compd 2017 Jan-Feb; 21(1):76-82
- Neurokinin-1 receptor antagonist, 5-hydroxytryptamine-3 RA, and dexamethasone combination therapy is standard of care for the prevention of chemotherapy-induced nausea and vomiting. Herein we describ...
Neurokinin-1 receptor antagonist, 5-hydroxytryptamine-3 RA, and dexamethasone combination therapy is standard of care for the prevention of chemotherapy-induced nausea and vomiting. Herein we describe the physical and chemical stability of rolapitant injectable emulsion 166.5 mg in 92.5 mL (185 mg hydrochloride salt) admixed with palonosetron injection 0.25 mg in 5 mL (0.28 mg hydrochloride salt). Admixtures were prepared and stored in two types of container closures (110-mL Crystal Zenith plastic and glass bottles) and four types of intravenous administration sets (or intravenous tubing sets). Assessment of the physical and chemical stability was conducted on the admixtures in the ready-to-use container closure systems as supplied by the manufacturer, stored at room temperature (20°C to 25°C under fluorescent light), and evaluated at 0, 1, and 6 hours; 1 and 2 days; and under refrigeration (2°C to 8°C protected from light) after 1, 3, and 7 days. For admixtures in intravenous tubing sets, the assessment of physicochemical stability was performed after 0 and 7 hours of storage at 20°C to 25°C initially, and then after 20 hours (total 27 hours) at 2°C to 8°C protected from light. Physical stability was assessed by visual examination of the container contents under normal room light, and measuring turbidity and particulate matter. Chemical stability was assessed by measuring the pH of the admixture and determining drug concentrations and impurity levels with high-performance liquid chromatographic analysis. The results indicated that all samples were physically compatible throughout the duration of the study. The pH, turbidity, and particulate matter of the admixture stayed within narrow and acceptable ranges. Rolapitant admixed with palonosetron was chemically stable when admixed in glass and Crystal Zenith bottles for at least 48 hours at room temperature and for 7 days under refrigeration, as well as in the four selected intravenous tubing sets for 7 hours at 20°C to 25°C and then for 20 hours at 2°C to 8°C. No loss of potency of any admixed components occurred in the samples stored at the two temperature ranges and time period studied.
- Efficacy of NEPA (netupitant/palonosetron) across multiple cycles of chemotherapy in breast cancer patients: A subanalysis from two phase III trials. [Journal Article]
- BBreast 2017 Mar 09; 33:76-82
- CONCLUSIONS: NEPA+DEX administered as a single dose is an effective option for preventing CINV in BC patients receiving AC and non-AC, across multiple chemotherapy cycles.
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- Intravenous palonosetron compared with a combination of ramosetron and dexamethasone in preventing post operative nausea and vomiting in patients undergoing gynaecological surgeries under spinal anaesthesia, a randomised study. [Journal Article]
- IJIndian J Anaesth 2017; 61(2):144-149
- CONCLUSIONS: Combination of ramosetron and dexamethasone is more effective than palonosetron alone in preventing PONV in patients undergoing gynaecological surgeries under SA.