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Wensheng Zhang - One of the best experts on this subject based on the ideXlab platform.
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The preclinical pharmacological study on HX0969W, a novel water-soluble pro-drug of propofol, in rats.
PeerJ, 2020Co-Authors: Yujun Zhang, Hai-yan Wang, Jun Yang, Yingying Jiang, Bin Wang, Yi Kang, Jun Chen, Jin Liu, Wensheng ZhangAbstract:Background Propofol is the most widely used intravenous sedative-hypnotic anesthetic in clinical practice. However, many serious side effects have been related to its lipid emulsion formulation. The pro-drug design approach was used to develop the water-soluble propofol, which could effectively resolve the limitations associated with the lipid emulsion formulation. Thus, the new water-soluble pro-drug of propofol, HX0969W, was designed and synthesized. The objective of this study was to conduct preclinical pharmacological studies on this novel water-soluble pro-drug of propofol. Methods The assessment of the loss of the righting reflex (LoRR) was used for the pharmacodynamic study, and liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography- fluorescence were used for the pharmacokinetic study. Results The potency of HX0969W (ED50 [95% CI], 46.49 [43.89-49.29] mg/kg) was similar to that of Fospropofol disodium (43.66 [43.57-43.75] mg/kg), but was lower than that of propofol (4.82 [4.8-14.82] mg/kg). Administered with a dose of 2-fold ED50, propofol required a shorter time to cause LoRR than that of HX0969W and Fospropofol. However, the LoRR duration was significantly longer in response to the administration of HX0969W and Fospropofol disodium than that caused by propofol. In the pharmacokinetic study, the Cmax of Fospropofol was higher than that of HX0969W. HX0969W had a shorter mean residual time and a rapid clearance rate than that of Fospropofol disodium. There was no significant difference between the Tmax of the propofol whether it was released by HX0969W or Fospropofol disodium; the Cmax of propofol released by HX0969W was similar to that of propofol, which was higher than the propofol released by Fospropofol disodium.
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An improved water-soluble prodrug of propofol with high molecular utilization and rapid onset of action.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 2018Co-Authors: Zhang Weiyi, Jun Yang, Wensheng Zhang, Bin Wang, Yi Kang, Jin Liu, Jing Fan, Tao ZhuAbstract:Abstract Water-soluble prodrugs of propofol often carry an excess of propofol at the effective dose and have a slower onset of action. Sustained release of the original drug can result in propofol accumulation in the body after administration, causing delays in wakefulness. This situation causes the prodrug to lose the benefits of rapid onset and recovery from the effects of propofol. In the present study, HX0921 (sodium 2-(2-(2,6-diisopropylphenoxy)-2-oxoethoxy)acetate), an improved prodrug of propofol with high utilization of propofol and fast onset of action, was studied. The rate of propofol release from HX0921 was much faster than that from Fospropofol (a marketed propofol prodrug) in rat plasma. The 50% effective dose (ED50) of propofol, HX0921 and Fospropofol to induce anesthesia in rats was 5.78, 22.19 and 42.44 mg/kg, respectively. After administration at 2 × ED50, the onset time of anesthesia in the HX0921 group was significantly shorter than that in the Fospropofol group (0.26 ± 0.15 min vs. 2.24 ± 0.35 min, P
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Efficacy and Safety of FospropofolFD Compared to Propofol When Given During the Induction of General Anaesthesia: A Phase II, Multi-centre, Randomized, Parallel-Group, Active-Controlled, Double-Blind, Double-Dummy Study.
Basic & clinical pharmacology & toxicology, 2016Co-Authors: Rong Liu, Chao-zhi Luo, Jin Liu, Wensheng ZhangAbstract:The present phase II study aimed to compare the efficacy and safety of Fospropofol disodium for injection (FospropofolFD ) and propofol when given during the induction of general anaesthesia in patients scheduled for elective surgery. FospropofolFD is a water-soluble prodrug of propofol. Approved by the Ethical Committee, 240 participants aged 18-65 years were equally randomly allocated to receive an intravenous bolus of FospropofolFD 20 mg/kg or propofol 2 mg/kg without any anaesthetic pre-treatment. The primary efficacy end-point was the sedation success rate within 5 min. after administering investigational drugs (the sedation success is defined as obtaining Modified Observer's Assessment of Alertness/Sedation scale score of 1). All the participants completed the induction and intubation within 25 min. after administration. The sedation success rates within 5 min. after administration of FospropofolFD 20 mg/kg and propofol 2 mg/kg were 94.50% versus 100% in the intention-to-treat population and 95.10% versus 100% in the per-protocol population, respectively. The non-inferiority test obtained a p-value less than 0.025, and the lower limits of the one-sided 97.5% confidence interval were more than -0.09. This meant that FospropofolFD 20 mg/kg was considered non-inferior to propofol 2 mg/kg for the primary efficacy end-point. Compared with propofol 2 mg/kg, FospropofolFD 20 mg/kg had a slower sedation efficacy. No serious adverse events were observed in the two groups. The sedation success rate within 5 min. after administration of FospropofolFD 20 mg/kg was non-inferior to propofol 2 mg/kg, and FospropofolFD 20 mg/kg can be used for the induction of general anaesthesia safely.
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The sedative-hypnotic effects and safety of oral administrated propofol prodrugs hx0969w and Fospropofol disodiun in comparison with propofol emulsion in rats
Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition, 2015Co-Authors: Hai-yan Wang, Jun Yang, Wang Yin, Linghui Yang, Wensheng ZhangAbstract:Objective To estimate the median effective dose (EDs0) of oral administrated HX0969w, Fospropofol disodium and propofol emulsion in rats, and to compare the sedative-hypnotic effects and safety of the three drugs. Methods The ED50 of the three drugs were determined using sequential method. Thirty healthy adult Sprague-Dawley rats were divided into three groups randomly, being orally administered with HX0969w (n=10), Fospropofol disodium (n=10) and propofol emulsion (n=10), respectively. The neurobehavioral performance of the rats was observed. The time of loss of forepaw righting reflex (LRR) and the time of recovery of forepaw righting reflex (RRR) were recorded. Results The ED50 of oral HX0969w, Fospropofol disodium and propofol emulsion were 96.5 mg/kg, 130.0 mg/kg and 113.8 mg/kg, respectively. HX0969w, Fospropofol disodium and propofol emulsion had a mean LRR of (10.0 +/- 2.9) min,(7.5 +/- 2.8) min and (16.0 +/- 5.9) min; respectively; and a mean RRR of (66.9 +/- 21.5) min, (131.9 +/- 32.7) min and (198.9 +/- 110.0) min, respectively. Conclusion HX0969w, Fospropofol disodium and propofol emulsion can produce sedative-hypnotic effects and they are safe when administered by oral route. The two propofol prodrugs HX0969w and Fospropofol disodium have shorter LRR than propofol emulsion. HX0969w also has a shorter RRR than Fospropofol disodium and propofol emulsion.
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An improved design of water-soluble propofol prodrugs characterized by rapid onset of action.
Anesthesia and analgesia, 2014Co-Authors: Bing-chen Lang, Jun Yang, Yi Kang, Jin Liu, Yu Wang, Yun Luo, Wensheng ZhangAbstract:BACKGROUND:Phosphate ester prodrugs of propofol (Fospropofol, HX0969W) were designed to avoid the unsatisfactory water solubility of the parent drug. However, in previous clinical trials, there were reported prodrug side effects such as paresthesia and pruritus. The accumulation of a phosphate ester
Jürgen Schüttler - One of the best experts on this subject based on the ideXlab platform.
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A Randomized Open-Label Phase I Pilot Study of the Safety and Efficacy of Total Intravenous Anesthesia With Fospropofol for Coronary Artery Bypass Graft Surgery
Journal of cardiothoracic and vascular anesthesia, 2013Co-Authors: J. Fechner, Harald Ihmsen, Jürgen Schüttler, Christian JeleazcovAbstract:Objective To determine safety and efficacy of the water-soluble prodrug Fospropofol for anesthesia in cardiac surgery and to compare the pharmacodynamic profiles of Fospropofol and propofol. Design Pilot study and a prospective, phase I, open-label, single-center, randomized clinical trial. Setting University hospital; single institution. Participants Sixteen patients undergoing elective first-time coronary artery bypass surgery. Interventions Patients were randomized to receive total intravenous anesthesia with Fospropofol (n = 8) or propofol (n = 8) combined with alfentanil as total intravenous anesthesia. Bispectral index, arterial blood pressure, and heart rate were recorded continuously, and pulmonary artery catheter measurements were obtained. Plasma concentrations of formate, phosphate, and Ca2+ were monitored closely. Safety and tolerability were assessed by adverse events, neurologic examinations, clinical laboratory tests, and vital signs. Measurements and Main Results The total doses of Fospropofol and propofol during anesthesia were 11.3±2.5 and 4.4±1.0 mg/kg/h, respectively. According to the achieved bispectral index (BIS) values, Fospropofol was as effective as propofol in providing general anesthesia and sedation. There were no clinical signs of formate toxicity in the Fospropofol group. The only treatment-related adverse event after administration of Fospropofol was a transient burning sensation in the perineal and perianal region during induction of sedation or anesthesia. Conclusions Fospropofol could be used to provide general anesthesia in patients undergoing coronary artery bypass graft surgery. Further larger studies are needed to prove the safety of Fospropofol when given to provide general anesthesia for major cardiac surgical procedures.
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Requested retraction of six studies on the PK/PD and tolerability of Fospropofol.
Anesthesia and analgesia, 2010Co-Authors: Michel Struys, Jürgen Schüttler, Joerg Fechner, H. SchwildenAbstract:From the Department of Anesthesiology, University of Groningen, Groningen,The Netherlands and Professor, Department of Anesthesia, Ghent University,Gent (MMRFS), Belgium, Department of Anesthesiology, University Erlangen-Nuremberg, Erlangen (JF, JS), Germany and Section of ExperimentalAnesthesiology, University Erlangen-Nuremberg, Erlangen (HS), GermanyCorrespondence to Michel M.R.F. Struys, MD, PhD, Professor and Chair,Department of Anesthesiology, University of Groningen, Groningen, TheNetherlands and Professor, Department of Anesthesia, Ghent University, Gent,BelgiumTel: +31 0 50 361 55 19; fax: +31 0 50 361 3763;e-mail: m.m.r.f.struys@anest.umcg.nl
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Fospropofol disodium, a water-soluble prodrug of the intravenous anesthetic propofol (2,6-diisopropylphenol).
Expert opinion on investigational drugs, 2009Co-Authors: J. Fechner, Harald Ihmsen, Christian Jeleazcov, Jürgen SchüttlerAbstract:Background: Today, propofol or 2,6-diisopropylphenol is the anesthetic mainly used for monitored anesthetic care sedation and during intravenous anesthesia. The formulation, a lipid macroemulsion, shows several disadvantages. Therefore, during the past years considerable scientific effort has been undertaken to find either a better formulation or a prodrug of propofol. Fospropofol is the first propofol prodrug that has been intensively studied in man. It has been licensed in 2008 by the FDA for monitored anesthetic care sedation. Objectives and methods: This review describes first published study results of Fospropofol with regard to its pharmacokinetics/pharmacodynamics, drug safety, tolerability and drug side effects. Using a Medline search all published articles and abstracts containing the words Fospropofol or GPI 15715 were included. Results and conclusion: As the impact of an errorness drug assay for propofol liberated from Fospropofol is not exactly defined, no clear conclusions can be drawn from t...
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Pharmacokinetics and pharmacodynamics of GPI 15715 or Fospropofol (Aquavan injection) - a water-soluble propofol prodrug.
Handbook of experimental pharmacology, 2008Co-Authors: J. Fechner, H. Schwilden, Jürgen SchüttlerAbstract:Propofol (2,6-diisopropylphenol) is inadequably soluble in water and is therefore formulated as a lipid emulsion. This may have disadvantages when propofol is used to provide total intravenous anaesthesia or especially during long-term sedation. There has been considerable interest in the development of new propofol formulations or propofol prodrugs. GPI 15715 or Fospropofol (Aquavan injection; Guilford Pharmaceutical, Baltimore, MD) is the first water-soluble prodrug that has been thoroughly studied in human volunteers and patients. GPI 15751 or Fospropofol is cleaved by alkaline phosphatase to phosphate, formaldehyde and propofol. Formaldehyde is rapidly metabolised to formate. Although a formate accumulation is the principal pathomechanism responsible for the toxicity of methanol ingestion, so far there has been no report of toxicity due to the administration of Fospropofol or other phosphate ester prodrugs, such as fosphenytoin. Fosphenytoin has been successfully introduced into the market for the treatment of status epilepticus in 1996. The main side-effects were a feeling of paraesthesia after rapid i.v. administration of GPI 15715 or Fospropofol, which has also been described for fosphenytoin. The pharmacokinetics of GPI 15715 or Fospropofol could be described by a combined pharmacokinetic model with a submodel of two compartments for GPI 15715 and of three compartments for propofolG. The liberated propofolG compared to lipid-formulated propofol showed unexpected pharmacokinetic and pharmacodynamic differences. We found a significantly greater Vc, Vdss, significantly shorter α- and β-half-life and a longer MRT (mean residence time) for propofolG. The pharmacodynamic potency of propofolG appears to be higher than propofol when measured by EEG and clinical signs of hypnosis. In summary, GPI 15715 or Fospropofol was well suited to provide anaesthesia or conscious sedation.
Barbara S. Slusher - One of the best experts on this subject based on the ideXlab platform.
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Gastrointestinal delivery of propofol
2016Co-Authors: Krystyna M. Wozniak, James J. Vornov, Rana Rais, Bipin M Mistry, Barbara S. SlusherAbstract:from Fospropofol: its bioavailability and activity in rodents and human volunteer
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Gastrointestinal delivery of propofol from Fospropofol: its bioavailability and activity in rodents and human volunteers
Journal of translational medicine, 2015Co-Authors: Krystyna M. Wozniak, James J. Vornov, Bipin Mistry, Rana Rais, Barbara S. SlusherAbstract:Background Propofol is a safe and widely used intravenous anesthetic agent, for which additional clinical uses including treatment of migraine, nausea, pain and anxiety have been proposed (Vasileiou et al. Eur J Pharmacol 605:1–8, 2009). However, propofol suffers from several disadvantages as a therapeutic outside anesthesia including its limited aqueous solubility and negligible oral bioavailability. The purpose of the studies described here was to evaluate, in both animals and human volunteers, whether Fospropofol (a water soluble phosphate ester prodrug of propofol) would provide higher propofol bioavailability through non-intravenous routes.
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Gastrointestinal delivery of propofol from Fospropofol: its bioavailability and activity in rodents and human volunteers
Journal of Translational Medicine, 2015Co-Authors: Krystyna M. Wozniak, James J. Vornov, Rana Rais, Bipin M Mistry, Ying Wu, Barbara S. SlusherAbstract:Background Propofol is a safe and widely used intravenous anesthetic agent, for which additional clinical uses including treatment of migraine, nausea, pain and anxiety have been proposed (Vasileiou et al. Eur J Pharmacol 605:1–8, 2009). However, propofol suffers from several disadvantages as a therapeutic outside anesthesia including its limited aqueous solubility and negligible oral bioavailability. The purpose of the studies described here was to evaluate, in both animals and human volunteers, whether Fospropofol (a water soluble phosphate ester prodrug of propofol) would provide higher propofol bioavailability through non-intravenous routes. Methods Fospropofol was administered via intravenous, oral and intraduodenal routes to rats. Pharmacokinetic and pharmacodynamic parameters were then evaluated. Based on the promising animal data we subsequently conducted an oral and intraduodenal pharmacokinetic/pharmacodynamic study in human volunteers. Results In rats, bioavailability of propofol from Fospropofol delivered orally was found to be appreciable, in the order of around 20–70%, depending on dose. Availability was especially marked following Fospropofol administration via the intraduodenal route, where bioavailability approximated 100%. Fospropofol itself was not appreciably bioavailable when administered by any route except for intravenous. Pharmacologic effect following oral Fospropofol was confirmed by observation of sedation and alleviation of thermal hyperalgesia in the rat chronic constrictive injury model of neuropathic pain. The human data also showed systemic availability of propofol from Fospropofol administration via oral routes, a hereto novel finding. Assessment of sedation in human volunteers was correlated with pharmacokinetic measurements. Conclusions These data suggest potential utility of oral administration of Fospropofol for various therapeutic indications previously considered for propofol.
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gastrointestinal delivery of propofol from Fospropofol its bioavailability and activity in rodents and human volunteers
Journal of Translational Medicine, 2015Co-Authors: Krystyna M. Wozniak, James J. Vornov, Bipin Mistry, Rana Rais, Barbara S. SlusherAbstract:Propofol is a safe and widely used intravenous anesthetic agent, for which additional clinical uses including treatment of migraine, nausea, pain and anxiety have been proposed (Vasileiou et al. Eur J Pharmacol 605:1–8, 2009). However, propofol suffers from several disadvantages as a therapeutic outside anesthesia including its limited aqueous solubility and negligible oral bioavailability. The purpose of the studies described here was to evaluate, in both animals and human volunteers, whether Fospropofol (a water soluble phosphate ester prodrug of propofol) would provide higher propofol bioavailability through non-intravenous routes. Fospropofol was administered via intravenous, oral and intraduodenal routes to rats. Pharmacokinetic and pharmacodynamic parameters were then evaluated. Based on the promising animal data we subsequently conducted an oral and intraduodenal pharmacokinetic/pharmacodynamic study in human volunteers. In rats, bioavailability of propofol from Fospropofol delivered orally was found to be appreciable, in the order of around 20–70%, depending on dose. Availability was especially marked following Fospropofol administration via the intraduodenal route, where bioavailability approximated 100%. Fospropofol itself was not appreciably bioavailable when administered by any route except for intravenous. Pharmacologic effect following oral Fospropofol was confirmed by observation of sedation and alleviation of thermal hyperalgesia in the rat chronic constrictive injury model of neuropathic pain. The human data also showed systemic availability of propofol from Fospropofol administration via oral routes, a hereto novel finding. Assessment of sedation in human volunteers was correlated with pharmacokinetic measurements. These data suggest potential utility of oral administration of Fospropofol for various therapeutic indications previously considered for propofol.
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Additional file 2: Tables S1 and S2. of Gastrointestinal delivery of propofol from Fospropofol: its bioavailability and activity in rodents and human volunteers
2015Co-Authors: Krystyna M. Wozniak, James J. Vornov, Bipin Mistry, Rana Rais, Barbara S. SlusherAbstract:Absolute latency of ipsilateral paw in CCI rats before and after Fospropofol or vehicle treatment.
James J. Vornov - One of the best experts on this subject based on the ideXlab platform.
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Gastrointestinal delivery of propofol
2016Co-Authors: Krystyna M. Wozniak, James J. Vornov, Rana Rais, Bipin M Mistry, Barbara S. SlusherAbstract:from Fospropofol: its bioavailability and activity in rodents and human volunteer
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Gastrointestinal delivery of propofol from Fospropofol: its bioavailability and activity in rodents and human volunteers
Journal of translational medicine, 2015Co-Authors: Krystyna M. Wozniak, James J. Vornov, Bipin Mistry, Rana Rais, Barbara S. SlusherAbstract:Background Propofol is a safe and widely used intravenous anesthetic agent, for which additional clinical uses including treatment of migraine, nausea, pain and anxiety have been proposed (Vasileiou et al. Eur J Pharmacol 605:1–8, 2009). However, propofol suffers from several disadvantages as a therapeutic outside anesthesia including its limited aqueous solubility and negligible oral bioavailability. The purpose of the studies described here was to evaluate, in both animals and human volunteers, whether Fospropofol (a water soluble phosphate ester prodrug of propofol) would provide higher propofol bioavailability through non-intravenous routes.
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Gastrointestinal delivery of propofol from Fospropofol: its bioavailability and activity in rodents and human volunteers
Journal of Translational Medicine, 2015Co-Authors: Krystyna M. Wozniak, James J. Vornov, Rana Rais, Bipin M Mistry, Ying Wu, Barbara S. SlusherAbstract:Background Propofol is a safe and widely used intravenous anesthetic agent, for which additional clinical uses including treatment of migraine, nausea, pain and anxiety have been proposed (Vasileiou et al. Eur J Pharmacol 605:1–8, 2009). However, propofol suffers from several disadvantages as a therapeutic outside anesthesia including its limited aqueous solubility and negligible oral bioavailability. The purpose of the studies described here was to evaluate, in both animals and human volunteers, whether Fospropofol (a water soluble phosphate ester prodrug of propofol) would provide higher propofol bioavailability through non-intravenous routes. Methods Fospropofol was administered via intravenous, oral and intraduodenal routes to rats. Pharmacokinetic and pharmacodynamic parameters were then evaluated. Based on the promising animal data we subsequently conducted an oral and intraduodenal pharmacokinetic/pharmacodynamic study in human volunteers. Results In rats, bioavailability of propofol from Fospropofol delivered orally was found to be appreciable, in the order of around 20–70%, depending on dose. Availability was especially marked following Fospropofol administration via the intraduodenal route, where bioavailability approximated 100%. Fospropofol itself was not appreciably bioavailable when administered by any route except for intravenous. Pharmacologic effect following oral Fospropofol was confirmed by observation of sedation and alleviation of thermal hyperalgesia in the rat chronic constrictive injury model of neuropathic pain. The human data also showed systemic availability of propofol from Fospropofol administration via oral routes, a hereto novel finding. Assessment of sedation in human volunteers was correlated with pharmacokinetic measurements. Conclusions These data suggest potential utility of oral administration of Fospropofol for various therapeutic indications previously considered for propofol.
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gastrointestinal delivery of propofol from Fospropofol its bioavailability and activity in rodents and human volunteers
Journal of Translational Medicine, 2015Co-Authors: Krystyna M. Wozniak, James J. Vornov, Bipin Mistry, Rana Rais, Barbara S. SlusherAbstract:Propofol is a safe and widely used intravenous anesthetic agent, for which additional clinical uses including treatment of migraine, nausea, pain and anxiety have been proposed (Vasileiou et al. Eur J Pharmacol 605:1–8, 2009). However, propofol suffers from several disadvantages as a therapeutic outside anesthesia including its limited aqueous solubility and negligible oral bioavailability. The purpose of the studies described here was to evaluate, in both animals and human volunteers, whether Fospropofol (a water soluble phosphate ester prodrug of propofol) would provide higher propofol bioavailability through non-intravenous routes. Fospropofol was administered via intravenous, oral and intraduodenal routes to rats. Pharmacokinetic and pharmacodynamic parameters were then evaluated. Based on the promising animal data we subsequently conducted an oral and intraduodenal pharmacokinetic/pharmacodynamic study in human volunteers. In rats, bioavailability of propofol from Fospropofol delivered orally was found to be appreciable, in the order of around 20–70%, depending on dose. Availability was especially marked following Fospropofol administration via the intraduodenal route, where bioavailability approximated 100%. Fospropofol itself was not appreciably bioavailable when administered by any route except for intravenous. Pharmacologic effect following oral Fospropofol was confirmed by observation of sedation and alleviation of thermal hyperalgesia in the rat chronic constrictive injury model of neuropathic pain. The human data also showed systemic availability of propofol from Fospropofol administration via oral routes, a hereto novel finding. Assessment of sedation in human volunteers was correlated with pharmacokinetic measurements. These data suggest potential utility of oral administration of Fospropofol for various therapeutic indications previously considered for propofol.
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Additional file 2: Tables S1 and S2. of Gastrointestinal delivery of propofol from Fospropofol: its bioavailability and activity in rodents and human volunteers
2015Co-Authors: Krystyna M. Wozniak, James J. Vornov, Bipin Mistry, Rana Rais, Barbara S. SlusherAbstract:Absolute latency of ipsilateral paw in CCI rats before and after Fospropofol or vehicle treatment.
Tong J. Gan - One of the best experts on this subject based on the ideXlab platform.
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doi:10.1155/2011/458920 Review Article Perspectives on the Role of Fospropofol in the Monitored Anesthesia Care Setting
2016Co-Authors: Joseph V Pergolizzi, Stanford Plavin, Sumedha Labhsetwar, Tong J. Gan, Robert TaylorAbstract:License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Monitored anesthesia care (MAC) is a safe, effective, and appropriate form of anesthesia for many minor surgical procedures. The proliferation of outpatient procedures has heightened interest in MAC sedation agents. Among the most commonly used MAC sedation agents today are benzodiazepines, including midazolam, and propofol. Recently approved in the United States is Fospropofol, a prodrug of propofol which hydrolyzes in the body by alkaline phosphatase to liberate propofol. Propofol liberated from Fospropofol has unique pharmacological properties, but recently retracted pharmacokinetic (PK) and pharmacodynamic (PD) evaluations make it difficult to formulate clear conclusions with respect to Fospropofol’s PK/PD properties. In safety and efficacy clinical studies, Fospropofol demonstrated dose-dependent sedation with good rates of success at doses of 6.5 mg/kg along with good levels of patient and physician acceptance. Fospropofol has been associated with less pain at injection site than propofol. The most commonly reported side effects with Fospropofol are paresthesia and pruritus. Fospropofol is a promising new sedation agent that appears to be well suited for MAC sedation, but further studies are needed to better understand its PK/PD properties a
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a double blind randomized multicenter dose ranging study to evaluate the safety and efficacy of Fospropofol disodium as an intravenous sedative for colonoscopy in high risk populations
American Journal of Therapeutics, 2013Co-Authors: Sergio D. Bergese, Keith A Candiotti, Poorvi Dalal, Rashmi Vandse, Andrew Satlin, Zhengning Lin, Larry Cohen, Tong J. GanAbstract:Fospropofol is a sedative hypnotic with a slower onset and longer duration of action. Fospropofol has demonstrated successful dose-dependent sedation at 6.5 mg/kg. This study evaluated the efficacy and safety of a lower weight-adjusted dose compared with the approved dose (4.875 or 6.5 mg/kg depending on patient subgroup) in high-risk elderly patients undergoing colonoscopy. In this study, 153 subjects were classified into 3 subgroups based on the following: age, weight, and American Society of Anesthesiologist (ASA) physical status criteria. The patients were randomized to the approved dose or weight-adjusted dose of Fospropofol in a 1:1 ratio. Subgroup 1 (n = 50) consisted of patients weighing <60 kg, age 18-65 years, and ASA I or II; subgroup 2 (n = 50) consisted of patients weighing <60 kg; age 65 years and above, and ASA I-IV; and subgroup 3 (n = 53) consisted of patients weighing ≥60 kg, age 65 years and above, and ASA I-IV. Sedation, modified sedation and treatment success, and safety parameters were assessed. The approved dose had a significantly higher sedation success compared with the weight-adjusted dose: 96% versus 72% for subgroup 1; 84% versus 72% for subgroup 2; and 96% versus 67.9% for subgroup 3. There was a decreased need for alternative sedatives in subgroups 1 and 3 and fewer sedation- and treatment-emergent adverse events in all the subgroups for the approved dose. Additionally, sedation success data pooled across subgroups and examined based on age, weight, and ASA categories showed a significantly higher rate of sedation success in the approved dose arm across all the subgroups. The rate of sedation, modified sedation, and treatment success were higher in patients administered the approved dose for all the subgroups. No clinically significant advantage was demonstrated using a lower modified dose in this study population. The approved dose is recommended in the elderly, more obese, and high-risk patients when used for moderate sedation.
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A double-blind, randomized, multicenter, dose-ranging study to evaluate the safety and efficacy of Fospropofol disodium as an intravenous sedative for colonoscopy in high-risk populations.
American journal of therapeutics, 2013Co-Authors: Sergio D. Bergese, Keith A Candiotti, Poorvi Dalal, Rashmi Vandse, Andrew Satlin, Zhengning Lin, Larry Cohen, Tong J. GanAbstract:Fospropofol is a sedative hypnotic with a slower onset and longer duration of action. Fospropofol has demonstrated successful dose-dependent sedation at 6.5 mg/kg. This study evaluated the efficacy and safety of a lower weight-adjusted dose compared with the approved dose (4.875 or 6.5 mg/kg depending on patient subgroup) in high-risk elderly patients undergoing colonoscopy. In this study, 153 subjects were classified into 3 subgroups based on the following: age, weight, and American Society of Anesthesiologist (ASA) physical status criteria. The patients were randomized to the approved dose or weight-adjusted dose of Fospropofol in a 1:1 ratio. Subgroup 1 (n = 50) consisted of patients weighing
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A randomized, open-label study of the safety and tolerability of Fospropofol for patients requiring intubation and mechanical ventilation in the intensive care unit.
Anesthesia and analgesia, 2011Co-Authors: Keith A Candiotti, Tong J. Gan, Christopher C. Young, Alex Bekker, S. T. John Sum-ping, Richard L. Kahn, Philip Lebowitz, Jeffrey J. LittmanAbstract:Background Current drugs for induction and maintenance of sedation in mechanically ventilated patients in the intensive care unit have limitations. Fospropofol, a prodrug of propofol, has not been studied as a sedative in the ICU setting. Methods In this randomized, open-label pilot study, patients received 1 of 3 regimens with a goal of maintaining a Ramsay Sedation Score of 2 to 5: (1) Fospropofol IV infusion with a bolus and increased infusion rate for agitation events (infusion/bolus); (2) Fospropofol IV infusion with an increased infusion rate for agitation events (infusion only); or (3) propofol IV infusion with an increased infusion rate for agitation events. Results Sixty patients received study drug and were included in the safety and efficacy analyses. Because incidence rates for adverse events were similar between Fospropofol groups, and because the study was not powered to determine significant differences between treatment groups for safety variables, adverse events for both Fospropofol groups were combined. In the Fospropofol groups, 28 out of 38 patients (74%) experienced treatment-emergent adverse events in comparison with 14 out of 22 patients (64%) in the propofol group. The most common treatment-emergent adverse events with Fospropofol were procedural pain (21.1%) and nausea (13.2%). Two patients (1 each in the Fospropofol infusion/bolus and the propofol groups) experienced hypotension during the study as a potential sedation-related adverse event. Mean plasma formate levels were not significantly different among groups. Patients in all 3 treatment groups maintained Ramsay Sedation Scores of 2 to 5 for >90% of the time they were sedated. Conclusion This pilot study suggests that Fospropofol, administered in either an infusion/bolus or infusion-only regimen, is tolerable and effective for short-term induction and maintenance of sedation in mechanically ventilated intensive care unit patients.
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Safety evaluation of Fospropofol for sedation during minor surgical procedures.
Journal of clinical anesthesia, 2010Co-Authors: Tong J. Gan, Bradley D. Berry, Evan F. Ekman, Richard C. Muckerman, Neal Shore, Robert HardiAbstract:Abstract Study Objective To evaluate the safety of intravenous (IV) Fospropofol when used to provide minimal to moderate sedation in patients undergoing minor surgical procedures. Design Phase 3, open-label, single-arm study. Setting Multi-center. Patients 123 ASA physical status I, II, III, and IV patients, aged ≥18 years. Interventions Patients were pretreated with fentanyl 50 μg before receiving an initial dose of IV Fospropofol 6.5 mg/kg. Patients could receive up to 5 supplemental doses of Fospropofol 1.63 mg/kg to reach a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score ≤ 4 to allow the start of the procedure and to maintain adequate sedation levels during the procedure. Measurements Study endpoints included measures of sedation depth, requirement for supplemental sedative doses, use of alternative sedatives, and the frequency and nature of treatment-emergent and sedative-related adverse events. Main Results A mean of 2.4 supplemental doses of Fospropofol was administered, and in 60% of patients, two or fewer supplemental doses of Fospropofol were sufficient to initiate and complete the procedure. Alternative sedative medication was administered in 6 of 123 patients (4.9%). Mean (SD) MOAA/S score during the procedure was 3.8 (0.5). Sixty-one percent (61%) of patients had a MOAA/S score of 5 (fully alert) within two minutes after the end of the procedure. Few patients (7 of 123; 5.7%) had MOAA/S scores of 0 to 1 (deep sedation) during the procedure, and all 7 were either ASA physical status I (n = 1) or II (n = 6). The most common treatment-related adverse events (TRAEs) were self-limited: paresthesias (62.6%) and pruritus (27.6%). Five patients experienced sedation-related adverse events, including hypotension (n = 4), bradycardia (concurrently with hypotension and managed with atropine; n=1), or hypoxemia (less than one min and managed with chin lift and verbal stimulation; n=1). Twenty patients with previous or existing hepatic disease (ranging from minimal to severe) and 5 patients with severe renal impairment had adverse events similar to the overall population. No deaths were reported, and no patient discontinued the study due to adverse events. Conclusion An initial dose of IV Fospropofol 6.5 mg/kg with supplemental doses was safe and well-tolerated as moderate sedation for use in minor surgical procedures.