Water-soluble Prodrug Of Propofol Research Articles

The Innovator's Credo: Fail Early and Often

Editorial| June 2021 The Innovator's Credo: Fail Early and Often Steven L. Shafer, MD Steven L. Shafer, MD Search for other works by this author on: This Site PubMed Google Scholar ASA Monitor June 2021, Vol. 85, 5. https://doi.org/10.1097/01.ASM.0000754184.26241.a4 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Search Site Citation Steven L. Shafer; The Innovator's Credo: Fail Early and Often. ASA Monitor 2021; 85:5 doi: https://doi.org/10.1097/01.ASM.0000754184.26241.a4 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search nav search search input Search input auto suggest search filter All ContentAll PublicationsASA Monitor Search Advanced Search Topics: sharks, surgical procedures, operative, swimming, propofol, fospropofol, entrepreneurs, software, prodrugs I was in tears laughing as I read the investigator's brochure for fospropofol on a flight to Baltimore. Fospropofol was a water-soluble prodrug of propofol, rapidly metabolized into phosphate and propofol. Fospropofol was being developed, in part, to eliminate propofol pain on injection. Unfortunately, phosphate makes your genitals burn, as every anesthesiologist who has given a bolus of I.V. dexamethasone phosphate or codeine phosphate to an awake patient knows (no anesthesiologist ever does this twice). It struck me as an uneven trade. What, exactly, is one supposed to tell the patient before inducing with fospropofol? During the presentation I had been asked to give, I explained that the perceived benefits (slower onset and offset) were not benefits at all. I also shared my view that genital burning was a showstopper. To my amazement, and against both the available evidence and scientific first principles, the company leadership was convinced that fospropofol... You do not currently have access to this content.

Sedation in digestive endoscopy: innovations for an old technique.

Patient complexity, along with duration, number and invasiveness of procedures, increase every year in digestive endoscopy; so deep sedation, analgesia or general anesthesia requests are rising. The need for a safe, flexible, low cost and high-profile service play a central role in drugs, devices and monitoring development. The patient's degree of comfort and anxiety are also critical. On the other hand, the role of the anesthesiologist is still debated, and many European countries are promoting non-anesthesiologist administration of propofol (NAAP). For high risk patients, anesthesiologists play an important role in choosing sedative drugs, kind of anesthesia/analgesia and devices for airway control. New drugs with safe profile, low costs, and favorable pharmacokinetics are now available for digestive endoscopy. Among these, fospropofol, a water-soluble prodrug of Propofol, is a very promising compound. Moreover, new devices and different modalities of ventilation can help anesthesiologists in management of high-risk patients, like obese patients and others patients at risk of hypopnea/apnea. The main challenges for anesthesiologists in this setting are endoscopic retrograde cholangiopancreatography, management of obese patients and recovery time after procedure, since digestive endoscopies are frequently performed as outpatient procedures. Nevertheless, these short and at low risk procedures can induce cognitive impairment. Currently, only anesthesiologists seem to have the competences to maintain high levels of safety by an appropriate evaluation and sedatives' choice, and a detailed protocol should be present in each gastrointestinal endoscopy department. In conclusion, the role of the anesthetist should be to supervise endoscopy activities at every level.

An improved water-soluble prodrug of propofol with high molecular utilization and rapid onset of action

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 < 0.01) and the duration of anesthesia in the HX0921 group was also significantly shorter than that in the fospropofol group (22.35 ± 4.05 min vs. 29.15 ± 5.25 min, P < 0.01). These results suggest that the rapid onset and short action time of HX0921 was due to the rapid release and high molecular utilization of propofol carried by HX0921.

Synthesis and characterization of novel quick-release propofol prodrug via lactonization

The water-soluble derivatives of propofol have gained attention as a method to increase solubility of propofol. According to the principle of lactonization, the lead compound HX0969 was synthesized first and then the pharmacological features of HX0969 were evaluated in a comparison with those of propofol in the SD rats. Then, HX0969 disodium phosphate monoester (HX0969W) and glycine ester trifluoroacetic acid salt (HX101230) were synthesized, and their pharmacological features were compared with those of Lusedra®, which has been recognized and marketed as a water-soluble prodrug of propofol since 2008. The results showed that HX0969 could produce an anesthetic effect within a few seconds (3.6±3.0s) and its therapeutic index was 4.66 in the SD rat. The pharmacodynamic characteristics of HX0969W were similar to those of the Lusedra®. HX101230 could still produce an anesthetic effect within 60s in the rats though its therapeutic index was not so high (TI=2.96). Therefore, our study has indicated that HX0969 is a potentially useful lead compound of propofol derivative. Its rapid anesthetic effect is probably associated with lactonization.

Comparative canine Pharmacokinetics–Pharmacodynamics of Fospropofol Disodium Injection, Propofol Eemulsion, and Cyclodextrin-Enabled Propofol Solution Following Bolus Parenteral Administration

The pharmacokinetics and pharmacodynamics of fospropofol (FP) disodium injection, propofol emulsion (PE), and cyclodextrin-enabled propofol (CDP) solution following bolus parenteral administration in dogs was evaluated. Three healthy male beagle dogs were treated in a three-way cross-over study (14 day washout period) with 6 mg/kg propofol equivalents. Blood samples were collected predose and at 16 points postdose through 1440 min and analyzed for propofol and FP, when appropriate. From 5 min predose to 30 min postdose, brain electrical activity [electroencephalography (EEG)] was recorded and analyzed by power spectrum analysis techniques. Each formulation appeared to be well tolerated with transient discomfort observed in the PE and CDP animals and minor excitability in the FP animals prior to loss of consciousness. Blood propofol followed three-compartment pharmacokinetic behavior and derived parameters were not statistically different except for elimination half-life from the CDP formulation and onset, and duration of anesthesia from the FP formulation. The effect site concentrations at 50% the maximum EEG effect for the FP and CDP formulations were approximately one-half that of the PE formulation. Onset and duration of anesthesia are correlated with modeled effect site propofol concentrations. The implications of formulation on pain on injection and propofol activity are discussed.

Minimum infusion rates and recovery times from different durations of continuous infusion of fospropofol, a prodrug of propofol, in rabbits: a comparison with propofol emulsion

ObjectiveTo explore, in rabbits, the minimum infusion rates (MIR) required and recovery time from long duration (≤8 hours) continuous infusion of fospropofol disodium, a novel water-soluble prodrug of propofol, and compare it with propofol. Study designProspective, randomized, blinded experimental trial. AnimalsNinety-six adult laboratory rabbits, mean ± SD weight 2.20 ± 0.15 kg. MethodsStage 1. 16 rabbits were assigned to receive fospropofol disodium or propofol to measure MIR, using an up-and-down method with response to tail-clamping stimulus (TCS). Stage 2. Eighty rabbits were allocated to group F (fospropofol disodium) or group P (propofol), and further subdivided (n = 10 in each subgroup) according to infusion time (2, 4, 6 or 8 hours), to groups F2h, F4h, F6h, F8h and P2h, P4h, P6h, P8h. Fospropofol or propofol were infused, and tail clamping applied to maintain the same depth of anaesthesia until infusion was completed. Times to recover righting reflex (RR), to respond to TCS, and total recovery to different durations of continuous infusion of two anaesthetic drugs were noted. Respiratory and pulse rates and oxygen saturation were analyzed. The plasma concentrations of fospropofol disodium, the active metabolite propofol (propofolF) and propofol emulsion were measured with respect to loss and recovery of RR and TCS. ResultsMIR of fospropofol disodium was 2.0 mg kg−1 minute−1, and MIR of propofol was 0.9 mg kg−1 minute−1. Times in minutes to total recovery from anaesthesia in groups F and P were as follows, F2h 15 ± 3; F4h 26 ± 4; F6h 52 ± 6; F8h 84 ± 10; and P2h 10 ± 1; P4h 19 ± 7; P6h 36 ± 7; P8h 48 ± 5. Conclusions and clinical relevanceAfter continuous intravenous infusion in rabbits (≤8 hours), fospropofol disodium and propofol both show an extension of recovery time with increasing infusion time, fospropofol disodium showing a significantly greater prolongation compared to propofol emulsion when infusion time increases to 6 and 8 hours.

Propofol hemisuccinate suppresses cortical spreading depression

Propofol is a rapidly acting water-insoluble non-barbiturate anesthetic agent that is widely used as an intravenous sedative–hypnotic agent. Anecdotal evidence indicates that propofol may be effective at terminating intractable migraine headache. Cortical spreading depression (CSD) is believed to be the neural correlate of migraine aura and may be a trigger for migraine pain. Agents that block the induction or slow the spread of CSD may be of utility in treating migraine. Here we examined the ability of propofol hemisuccinate (PHS), a water-soluble prodrug of propofol, to affect CSD in mice. For comparison, we examinined dizocilpine, an NMDA receptor antagonist, that is well recognized to inhibit CSD. When administered 15min prior to activation of CSD by KCl application to the cortex, intraperitoneal PHS at doses of 120 and 200mg/kg decreased the number of CSD deflections without an effect on CSD amplitude, and at 200mg/kg caused a 77% reduction in CSD velocity. The minimally-effective dose of PHS (120mg/kg) did not cause sedation or motor impairment and while some animals receiving 200mg/kg did demonstrate motor impariment none exhibited loss-of-righting reflex (anesthesia). Dizocilpine produced comparable inhibition of CSD at doses of 0.5 and 2.5mg/kg. We conclude that acute PHS treatment inhibits CSD. Our results indicate that propofol, or its prodrug PHS, are worthy of further investigation as a treatment for migraine.

Fospropofol disodium and sedation

Background Fospropofol disodium (Fospropofol),a new type of medicine,demonstrates encouraging clinical application prospect in recent studies.Objective To summarize the pharmacology and clinical research progresses of fospropofol disodium.Content Fospropofol,a sedative/hypnotic drug,is a water-soluble prodrug of propofol,metabolized in vivo to produce liberated active propofol which performs sedative function.As its hydrolytic action in vivo,the pharmacokinetics and pharmacodynamics of fospropofol disodium are significantly different from lipid-emulsion-based propofol.Clinical trials proved that fospropofol disodium is safe and effective for the sedation in colonoscopy,flexible bronchoscopy and minor procedures.Trend Fospropofol can be used in combination with numerous kinds of anesthetics.Its adverse reactions are less than that of propofol.With further progress,fospropofol disodium will have a broader clinical application. Key words: Fospropofol disodium (Fospropofol); Sedation; Pharmacokinetics; Pharmacodynamics; Colonoscopy; Flexible bronchoscopy; Minor procedures

Fospropofol Disodium for Sedation in Elderly Patients Undergoing Flexible Bronchoscopy

BACKGROUND: Fospropofol disodium is a water-soluble prodrug of propofol. A subset analysis was undertaken of elderly patients (≥65 y) undergoing flexible bronchoscopy, who were part of a larger multicenter, randomized, double-blind study. METHODS: Patients received fentanyl citrate (50 mcg) followed by fospropofol at initial (4.88mg/kg) and supplemental (1.63mg/kg) doses. The primary end point was sedation success (3 consecutive Modified Observer's Assessment of Alertness/Sedation scores of ≤4 and procedure completion without alternative sedative or assisted ventilation). Treatment success, time to fully alert, patient and physician satisfaction, and safety/tolerability were also evaluated. RESULTS: In the elderly patients subset (n=61), sedation success was 92%, the mean time to fully alert was 8.0±10.9 min, and memory retention was 72% during recovery, and these were comparable with the younger patients subgroup (age, <65 y). Sedation-related adverse events occurred in 23% of the elderly and 18% of the younger patients (age, <65 y) group. Hypoxemia occurred in 26% of the elderly and 18% of the younger patients group, but no escalation of care was required. CONCLUSIONS: Fospropofol provided safe and effective sedation, rapid time to fully alert, and high satisfaction in this elderly subset undergoing flexible bronchoscopy, which was comparable with outcomes in younger patients.

AQUAVAN Injection, a Water-soluble Prodrug of Propofol, as a Bolus Injection: A Phase I Dose-escalation Comparison with DIPRIVAN (Part 2): Pharmacodynamics and Safety: Retraction

An analytical propofol assay inaccuracy was discovered after initial studies on the pharmacokinetics/pharmacodynamics and tolerability of fospropofol had been published. This assay inaccuracy makes the measured propofol plasma concentrations in the following previously published studies unreliable, and therefore these articles are retracted in their entirety:Reference Struys MM, Vanluchene AL, Gibiansky E, Gibiansky L, Vornov J, Mortier EP, Van Bortel L: AQUAVAN injection, a water-soluble prodrug of propofol, as a bolus injection: A phase I dose-escalation comparison with DIPRIVAN (part 2): Pharmacodynamics and safety. Anesthesiology 2005; 103:730–43

AQUAVAN Injection, a Water-soluble Prodrug of Propofol, as a Bolus Injection: A Phase I Dose-escalation Comparison with DIPRIVAN (Part 2): Pharmacodynamics and Safety: Retraction

An analytical propofol assay inaccuracy was discovered after initial studies on the pharmacokinetics/pharmacodynamics and tolerability of fospropofol had been published. This assay inaccuracy makes the measured propofol plasma concentrations in the following previously published studies unreliable, and therefore these articles are retracted in their entirety:Reference Struys MM, Vanluchene AL, Gibiansky E, Gibiansky L, Vornov J, Mortier EP, Van Bortel L: AQUAVAN injection, a water-soluble prodrug of propofol, as a bolus injection: A phase I dose-escalation comparison with DIPRIVAN (part 2): Pharmacodynamics and safety. Anesthesiology 2005; 103:730–43

Sedation with GPI 15715, a Water-Soluble Prodrug of Propofol, Using Target-Controlled Infusion in Volunteers

Sedation with GPI 15715, a Water-Soluble Prodrug of Propofol, Using Target-Controlled Infusion in Volunteers

AQUAVAN Injection, a Water-soluble Prodrug of Propofol, as a Bolus Injection: A Phase I Dose-escalation Comparison with DIPRIVAN (Part 1): Pharmacokinetics: Retraction

AQUAVAN Injection, a Water-soluble Prodrug of Propofol, as a Bolus Injection: A Phase I Dose-escalation Comparison with DIPRIVAN (Part 1): Pharmacokinetics: Retraction

AQUAVAN Injection, a Water-soluble Prodrug of Propofol, as a Bolus Injection: A Phase I Dose-escalation Comparison with DIPRIVAN (Part 1): Pharmacokinetics: Retraction

AQUAVAN Injection, a Water-soluble Prodrug of Propofol, as a Bolus Injection: A Phase I Dose-escalation Comparison with DIPRIVAN (Part 1): Pharmacokinetics: Retraction

Sedation with GPI 15715, a Water-Soluble Prodrug of Propofol, Using Target-Controlled Infusion in Volunteers

Sedation with GPI 15715, a Water-Soluble Prodrug of Propofol, Using Target-Controlled Infusion in Volunteers

Fospropofol

Fospropofol (fospropofol disodium), a sedative/hypnotic agent, is a water-soluble prodrug of propofol, metabolized in vivo to produce liberated propofol (producing the sedative effect), phosphate and formaldehyde. Intravenous fospropofol 6.5 mg/kg was significantly more effective than fospropofol 2.0 mg/kg (a placebo surrogate) as sedation in patients undergoing colonoscopy or flexible bronchoscopy, with regard to the primary endpoint of sedation success rate in randomized, double-blind, phase III trials. In patients undergoing colonoscopy, the sedation success rate was >3-fold higher among fospropofol 6.5 mg/kg (n = 158) than fospropofol 2.0 mg/kg recipients (n = 102). Similar results were observed in patients undergoing flexible bronchoscopy; the sedation success rate was >3-fold greater among fospropofol 6.5 mg/kg (n = 150) than among fospropofol 2.0 mg/kg recipients (n = 102). Fospropofol was generally well tolerated in clinical trials. Adverse events were mostly of mild to moderate severity, and were transient and self-limiting. Patients undergoing flexible bronchoscopy appeared to have a higher rate of sedation-related adverse events requiring airway assistance than did those undergoing colonoscopy or minor procedures.

Fospropofol Disodium for Procedural Sedation: Emerging Evidence of its Value?

Background Fospropofol is a phosphate-ester water soluble prodrug of propofol approved in the United States for the short-term sedation of adults undergoing diagnostic or therapeutic procedures with monitored anesthesia care. Fospropofol may be advantageous for procedural sedation because it is not a lipid formulation, it lacks pain on injection, it possesses a different pharmacokinetic profile due to in vivo conversion of fospropofol to propofol, and it offers rapid recovery from sedation. Objective To review published pharmacokinetic data, clinical trials, and the safety profile of fospropofol and provide comment on its use for sedation. Clinical trials Fospropofol has been studied for sedation in colonoscopy and bronchoscopy with fentanyl for analgesia. Results indicate that a 6.5 mg/kg bolus dose with repeated doses of 25% of the original bolus dose up to every 4 minutes produces an effective and safe level of sedation. Fospropofol comparisons to midazolam were not assessed. Patient satisfaction is high for those treated with the recommended dosage regimen. Most commonly reported adverse effects included pruritus and paresthesia. Sedation related side effects such as hypoxia and apnea were rarely reported and generally mild in scope. Conclusion Fospropofol represents an alternative sedative agent to midazolam and propofol for short-term sedation. However, the efficacy and safety of fospropofol compared to midazolam or propofol has not been assessed, therefore use will be based on practitioner preference. Restrictive package labelling requiring MAC poses medico-legal and cost-benefit issues thereby not conferring a benefit over propofol which caries similar labelling. Additional studies designed to compare fospropofol to propofol and/or midazolam for procedural sedation are needed.

Fospropofol: A New Sedative–Hypnotic Agent for Monitored Anesthesia Care

To summarize the published clinical data on fospropofol, critically review the safety and efficacy information, and provide pertinent information for formulary review. Data were collected from searches of MEDLINE (1966-June 30, 2009), EMBASE (1974-June 30, 2009), bibliographies of manuscripts, and www.fda.gov. Key search terms included fospropofol, Lusedra, Aquavan, sedative-hypnotic, and monitored anesthesia care. All Phase 1, Phase 2, and Phase 3 clinical trials studying the safety and efficacy of fospropofol were reviewed. Fospropofol is a water-soluble prodrug of propofol, a potent sedative-hypnotic agent. Propofol is highly lipophilic and is formulated in lipid-containing solvents, which have known disadvantages, including pain on injection, narrow therapeutic window with the potential to cause deep sedation, high lipid intake during long-term sedation, and risk of infection resulting from bacterial contamination. Due to its water solubility, fospropofol eliminates some of the known lipid emulsion-associated disadvantages of propofol and provides a more predictable peak onset of activity and more gradual recovery to a full state of consciousness. The pharmacokinetic and pharmacodynamic profiles of fospropofol make it an attractive agent for sedation for procedures of short duration. Unfortunately, the number of patients studied has been relatively small and the amount of safety data is limited. Of concern are reports of hypoxemia and hypotension; these reports are limited in number, but the episodes are serious and may require acute intervention. Although fospropofol holds promise for procedural sedation, due to limited safety data, the Food and Drug Administration has limited approval of fospropofol to monitored anesthesia care in patients undergoing diagnostic or therapeutic procedures. Fospropofol is a viable addition to the class of sedative-hypnotic agents due to the minimization of unwanted adverse effects of propofol and maintenance of a favorable pharmacokinetic profile facilitating sedation, anxiolysis, and rapid recovery. However, there are limited safety data to justify its use without the presence of dedicated anesthesia personnel.

A Phase 3, Randomized, Double-Blind Study To Assess the Efficacy and Safety of Fospropofol Disodium Injection for Moderate Sedation in Patients Undergoing Flexible Bronchoscopy

Fospropofol disodium is a water-soluble prodrug of propofol with unique pharmacokinetic/pharmacodynamic properties. This randomized, double-blind, multicenter study evaluated the use of fospropofol in patients undergoing flexible bronchoscopy. Patients >or= 18 years of age were randomized (2:3) to receive fospropofol, 2 mg/kg or 6.5 mg/kg, after pretreatment with fentanyl, 50 microg. Supplemental doses of each were given per protocol. The primary end point was sedation success, which was defined as follows: three consecutive Modified Observer's Assessment of Alertness/Sedation scores of <or= 4 plus procedure completion without alternative sedative medication and/or mechanical ventilation. Other end points included treatment success, patient/physician satisfaction, and safety. Of 252 patients, 150 were randomized to receive 6.5 mg/kg fospropofol; 102 were randomized to receive 2 mg/kg fospropofol. Sedation success rates were 88.7% and 27.5%, respectively (p < 0.0001). Treatment successes (91.3% vs 41.2%, respectively; p < 0.001), willingness to be treated again (94.6% vs 78.2%, respectively; p < 0.001), and absence of procedural recall (83.3% vs 55.4%, respectively; p < 0.001) were significantly better with the administration of 6.5 mg/kg fospropofol. The median time to full alertness was slightly longer for the 6.5 mg/kg dose (5.5 vs 3.0 min, respectively). The proportion of patients requiring supplemental therapy with analgesics (16.7% vs 37.3%, respectively) and the use of alternative sedative medications (8.0% vs 58.8%, respectively) were lower for patients in the 6.5 mg/kg dose group (all comparisons, p < 0.001). The most frequent adverse events (AEs) were transient and self-limited paresthesias and pruritus of mild-to-moderate severity. Hypoxemia (predominantly mild-to-moderate) was the most common sedation-related AE, and occurred in 15.4% and 12.6% of patients, respectively, in the 6.5 and 2 mg/kg fospropofol dose groups. Fospropofol provided safe and effective sedation for patients undergoing flexible bronchoscopy. Clinical Trials.gov Identifier: NCT00306722.

FOSPROPOFOL DISODIUM IS EFFECTIVE AND SAFE FOR SEDATION IN PATIENTS UNDERGOING FLEXIBLE BRONCHOSCOPY: RESULTS OF A PHASE 3, RANDOMIZED, DOUBLE-BLIND, DOSE-CONTROLLED TRIAL

PURPOSE: Fospropofol disodium (FP) is a water-soluble prodrug of propofol with unique pharmacokinetic and pharmacodynamic properties. This double-blind, multicenter study was designed to evaluate FP in patients undergoing flexible bronchoscopy.