Nalmefene Hydrochloride Research Articles

Comparison of intranasal naloxone and intranasal nalmefene in a translational model assessing the impact of synthetic opioid overdose on respiratory depression and cardiac arrest.

Using a validated translational model that quantitatively predicts opioid-induced respiratory depression and cardiac arrest, we compared cardiac arrest events caused by synthetic opioids (fentanyl, carfentanil) following rescue by intranasal (IN) administration of the μ-opioid receptor antagonists naloxone and nalmefene. This translational model was originally developed by Mann et al. (Clin Pharmacol Ther 2022) to evaluate the effectiveness of intramuscular (IM) naloxone. We initially implemented this model using published codes, reproducing the effects reported by Mann et al. on the incidence of cardiac arrest events following intravenous doses of fentanyl and carfentanil as well as the reduction in cardiac arrest events following a standard 2 mg IM dose of naloxone. We then expanded the model in terms of pharmacokinetic and µ-opioid receptor binding parameters to simulate effects of 4 mg naloxone hydrochloride IN and 3 mg nalmefene hydrochloride IN, both FDA-approved for the treatment of opioid overdose. Model simulations were conducted to quantify the percentage of cardiac arrest in 2000 virtual patients in both the presence and absence of IN antagonist treatment. Following simulated overdoses with both fentanyl and carfentanil in chronic opioid users, IN nalmefene produced a substantially greater reduction in the incidence of cardiac arrest compared to IN naloxone. For example, following a dose of fentanyl (1.63 mg) producing cardiac arrest in 52.1% (95% confidence interval, 47.3-56.8) of simulated patients, IN nalmefene reduced this rate to 2.2% (1.0-3.8) compared to 19.2% (15.5-23.3) for IN naloxone. Nalmefene also produced large and clinically meaningful reductions in the incidence of cardiac arrests in opioid naïve subjects. Across dosing scenarios, simultaneous administration of four doses of IN naloxone were needed to reduce the percentage of cardiac arrest events to levels that approached those produced by a single dose of IN nalmefene. Simulations using this validated translational model of opioid overdose demonstrate that a single dose of IN nalmefene produces clinically meaningful reductions in the incidence of cardiac arrest compared to IN naloxone following a synthetic opioid overdose. These findings are especially impactful in an era when >90% of all opioid overdose deaths are linked to synthetic opioids such as fentanyl.

Post-ischemic treatment of nalmefene hydrochloride attenuated lung ischemia-reperfusion injury in rats via the Sirt1/Nrf2/HO-1 pathway with inhibition of ferroptosis

Objective: To study the effect and mechanism of post-ischemic treatment of nalmefene in alleviating the lung ischemia-reperfusion injury by inhibiting ferroptosis through activation of the Sirt 1/Nrf 2/HO-1 axis. Methods: A total of 60 rats were randomly divided into six groups equally (n=10): the sham group, the model group(I/R), the nalmefene group, the nalmefene+EX527 group, the nalmefene+ML385 group, the nalmefene+Fe-citrate group (nalmefene+Fe group). The sham group without drug treatment was not treated with ischemia-reperfusion. The pulmonary ischemia-reperfusion model was established by occlusion of the left pulmonary hilum in the model group without drug treatment. After ischemic treatment, the nalmefene group was injected with nalmefene (15 μg/kg) via the tail vein at 5 minutes before reperfusion. The nalmefene+EX527 group, the nalmefene+ML385 group, and the nalmefene+Fe group were injected intraperitoneally with EX527 (5 mg/kg), ML385 (30 mg/kg), Fe-citrate(15 mg/kg), respectively, 2 h before moulding and then injected with nalmefene (15 μg/kg) via the tail vein at 5 minutes before reperfusion. All rats were sacrificed three hours after reperfusion, and the specimens from the upper lobe of the left lung tissue were preserved. The degree of lung tissue injury and the wet/dry weight ratio were assessed in each group of rats. Fe 2+, MDA, TNF-α, and IL-6 content, GSH activity and the expression levels of Sirt1, Nrf2, HO-1, ACSL4 and GPX4 were determined. Results: Compared with the sham group, the wet/dry weight ratio, lung tissue injury score, ACSL 4 expression level, Fe 2+, TNF-α, IL-6 and MDA content, Sirt 1, Nrf 2, HO-1 messenger RNA and protein expression levels were significantly increased (P<0.01), while GPX 4 expression level and GSH activity were significantly decreased in the model group (P<0.01). Compared with the model group, wet/dry weight ratio, lung tissue injury score, ACSL 4 expression level, Fe 2+, TNF-α, IL-6, and MDA content decreased significantly (P<0.01), Nrf 2, HO-1 messenger RNA and protein, GPX 4 expression, and GSH activity were significantly increased in the nalmefene group and the nalmefene+EX527 group (P<0.01). Sirt 1 messenger RNA and protein expression increased significantly in the nalmefene (P<0.01) and the nalmefene+EX527 groups (P>0.05). In the nalmefene+ML385 group, the wet/dry weight ratio, lung tissue injury score, TNF-α and IL-6 content were decreased significantly (P<0.01), while Sirt 1 messenger RNA and protein expression levels were significantly increased (P<0.01), but there were no significant changes in Nrf 2, HO-1 messenger RNA and protein expression levels, ACSL 4 and GPX 4 expression levels, Fe 2+, MDA content, and GSH activity (P>0.05). In the nalmefene+Fe group, wet/dry weight ratio, lung-injury score, TNF-α, IL-6, MDA content were decreased significantly (P<0.01), messenger RNA and protein expression levels of Sirt 1, Nrf 2, HO-1, and GSH activity were increased significantly (P<0.01), but there were no significant changes in Fe 2+content, ACSL 4 and GPX 4 expression levels (P>0.05). Compared with the nalmefene group, in the nalmefene+EX527 group, the nalmefene+ML385 group and the nalmefene+Fe group, wet/dry weight ratio, lung tissue damage score, ACSL 4 expression level, TNF-α, IL-6 and MDA content were significantly increased (P<0.01), the expression level of GPX 4 and GSH activity were significantly decreased (P<0.01). The expression levels of Sirt 1, Nrf 2, HO-1 messenger RNA and protein were significantly decreased in the nalmefene+EX527 group (P<0.01). The expression levels of Nrf 2, HO-1 messenger RNA and protein decreased significantly in the namemefene+ML385 group (P<0.01), but there was no significant change in Sirt 1 messenger RNA and protein expression level (P>0.05). Sirt 1, Nrf 2, HO-1 messenger RNA-protein expression levels did not change significantly in the nalmefene+Fe group (P>0.05). Conclusion: Post-ischemic treatment with nalmefene hydrochloride may alleviate pulmonary ischemia-reperfusion injury by inhibiting ferroptosis through activation of the Sirt 1/Nrf 2/HO-1 axis.

Auto interpretable depth learning model to analyze the hemodynamic changes and pulmonary complications in laparoscopic gynecologic tumor surgery with nalmefene hydrochloride combined with general anesthesia.

In this work, based on intelligent computing, the biological signals of patients were analyzed to investigate the hemodynamic changes and pulmonary complications of Nalmefene Hcl combined with general anesthesia (GA) in laparoscopic gynecological tumor surgery (GTS). Eighty computer-aided GTS patients were randomly divided into a control group (n = 40) and an observation group (n = 40). Biomedical electrocardiogram (ECG) signals were detected by wavelet neural network in all patients undergoing laparoscopic gynecological tumor surgery and were computerized according to the android interface definition language model (AIDL). GA was used during surgery. The observation group was injected intravenously with 0.2 μg/kg naproxenacin hydrochloride after operation. The control group was given 1 mL 0.9% sodium chloride solution after operation. Mean arterial pressure (MAP), heart rate (HR), respiratory rate (RR), pulse oxygen saturation (SPO), coma score, and adverse reactions (AR) were compared between the two groups at 10, 20, and 30 minutes after wakefulness. The hemodynamic parameters between the two groups were compared. Serum urocholine (URO) and creatinine (Cre) levels were analyzed in patients without complications. ECG waveform based on wavelet neural network has a high recognition rate and strong generalization ability. 37 patients in the observation group recovered within 10 minutes after surgery, and the recovery rate at 30 minutes was 95%. 30 patients in the control group awoke 10 minutes after the operation, and the recovery rate at 30 minutes m-AR was 75%. The average abstract windows toolkit (AWT) of the observation group and control group was 11.87 ± 5.78 min and 16.46 ± 5.32 min, respectively, and the difference was significant (p < 0.05). There were significant differences in HR, systolic blood pressure (SBP), and diastolic blood pressure (DBP) between the observation group and the control group during the extubation (p < 0.05). Blood gas indexes PaO2, PvO2, PaCO2, and PvCO2 in the observation group were significantly different from those in the control group half an hour after the operation and half an hour after pneumoperitoneum (p > 0.05). Intelligent computational biological signal detection was beneficial to the development of surgery. Nalmefene Hcl combined with GA on the basis of the AIDL model has a significant effect on the awakening of GTS patients and can shorten sleep time. Patients with underlying cardiac disease were more likely to develop postoperative lung complications.

Med Check: No Accelerated Pathway for Donanemab and More

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: No Accelerated Pathway for Donanemab and MoreTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:24 Feb 2023https://doi.org/10.1176/appi.pn.2023.03.3.2FDA Declines Accelerated Approval for DonanemabThe U.S. Food and Drug Administration (FDA) has declined to accept Eli Lilly’s Alzheimer’s biologic donanemab into the accelerated approval pathway, the company announced in January. Donanemab is a monoclonal antibody that targets beta amyloid buildup in the brain, which is thought to contribute to Alzheimer’s disease.In its complete response letter to the accelerated approval application, the FDA specifically requested that Eli Lilly provide data from at least 100 patients who received a minimum of 12 months of continued treatment on donanemab.The FDA had previously granted Breakthrough Therapy designation for donanemab based on the results of a phase 2 clinical trial called TRAILBLAZER-ALZ that evaluated the safety and efficacy of donanemab in patients with Alzheimer’s disease. In the trial, 257 patients with early symptomatic Alzheimer’s disease received either donanemab or placebo intravenously every four weeks for up to 72 weeks. Compared with those who received placebo, those who received donanemab experienced less cognitive and functional decline over the course of the trial, as measured by the change from baseline on the Integrated Alzheimer’s Disease Rating Scale.Although the TRAILBLAZER-ALZ trial included more than 100 patients treated with donanemab, due to the speed of plaque reduction, many patients were able to stop dosing as early as six months of treatment, resulting in fewer than 100 patients receiving 12 months of donanemab. FDA Reviews Nasal Nalmefene for Treating Opioid OverdoseThe FDA has accepted for Priority Review a New Drug Application (NDA) for OPNT003 (nasal nalmefene) for the treatment of opioid overdose, Opiant Pharmaceuticals announced in January. Priority Review is granted to therapies that the FDA determines have the potential to provide a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious condition. OPNT003 was previously granted Breakthrough Therapy designation when a confirmatory pharmacokinetic study comparing a 3 mg spray of the drug with a 1 mg intramuscular nalmefene hydrochloride injection in 68 healthy patients revealed that OPNT003 achieved higher plasma concentrations compared with the intramuscular injection.The NDA also included data from a second study that found similar plasma concentrations of OPNT003 whether the treatment was administered as a single dose in each nostril or as two doses in a single nostril. A third study found the drug to be noninferior to intranasal naloxone and found that nasal nalmefene produced a greater reversal of remifentanil-induced respiratory depression that was nearly twice that produced by nasal naloxone at five minutes. Brexpiprazole Gets Priority Review for Treating Alzheimer’s Agitation In January Otsuka Pharmaceutical Co., Ltd. and H. Lundbeck A/S announced that the FDA has granted Priority Review for its supplemental NDA (sNDA) for brexpiprazole for the treatment of agitation associated with Alzheimer’s dementia.The sNDA submission includes data from two positive clinical phase 3 studies that investigated the treatment of brexpiprazole in patients with agitation related to Alzheimer’s dementia. In Study 331-12-283, 433 patients with agitation associated with Alzheimer’s took either 1 or 2 mg of brexpiprazole or placebo daily for 12 weeks. Those who took 2 mg of brexpiprazole had greater improvements in their Cohen-Mansfield Agitation Inventory (CMAI) Total Score from baseline to week 12 compared with placebo. In Study 331-14-213, which included 345 patients, patients were randomized to either 2 or 3 mg of brexpiprazole or placebo daily for 2 weeks. Those who took either dose of brexpiprazole had greater improvements in their CMAI Total Score from baseline to week 12 compared with placebo. ■ ISSUES NewArchived

Sufentanil combined with nalmefene reduce the adverse events in recovery period of patients undergoing uvulopalatopharyngoplasty – A randomized controlled trial

Background: The opioid receptors related to analgesia are mainly μ recipient, the μ receptor has a two-way mode of action: manifested by opioid analgesics and μ1 Receptor binding produces the desired analgesic effect, and μ2 Receptor binding may cause respiratory depression, nausea and vomiting and other adverse reactions. Nalmefene is an opioid receptor antagonist. Low dose Nalmefene has priority over μ2 Receptor binding makes opioid analgesics turn more to μ1 receptor binding, which is reversed μ2 Receptor mediated nausea, vomiting, respiratory depression and other adverse reactions, but does not reverse the analgesic effect. We assume that sufentanil combined with nalmefene could reduce respiratory adverse events in the patients who underwent uvulopalatopharyngoplasty during recovery.Methods: Patients with UPPP under general anesthesia were selected, and divided into control group (group C) and nalmefene group (group N) randomly. Patients in group N received sufentanil 0.1 μg/kg and nalmefene hydrochloride 0.25μg/kg at the end of the operation. Additionally, patients in group C received sufentanil 0.1 μg/kg at the end of the operation. The heart rate (HR) and mean arterial pressure (MAP) were observed and recorded before operation, immediately after extubation, and 5 min after extubation. The breathing recovery time, tracheal extubation time, consciousness score (Ramsay score、sedation-agitation scale (SAS)) and visual analog score (VAS) were carefully recorded at 5 min after extubation, and the various adverse reactions were monitored during the recovery period.Results: Ninety-six patients were finished our study finally. The breathing recovery and extubation time of group N was significantly shorter than those of group C (P < 0.05). The Ramsay score after extubation in group N was significantly lower as compared to that in group C (P < 0.05). The sedation-agitation scale of group N was observed to be significantly higher than that of group C (P < 0.05). Moreover, the incidences of respiratory depression, nausea and vomiting during the recovery period was significantly less than those in group C (P < 0.05).Conclusion: Nalmefene combined with sufentanil can significantly reduce adverse reactions in the cases of patients after UPPP, which may be beneficial to improve the quality and safety of emergence after general anesthesia.

Effect of Different Absorption Enhancers on the Nasal Absorption of Nalmefene Hydrochloride.

The purpose of this work is to explore the effects of novel absorption enhancers on the nasal absorption of nalmefene hydrochloride (NMF). First, the influence of absorption enhancers with different concentrations and types and drug concentrations on the nasal absorption of NMF was investigated in vivo in rats. The absorption enhancers studied include n-dodecyl-β-D-maltoside (DDM), hydroxypropyl-β-cyclodextrin (HP-β-CD), and polyethylene glycol (15)-hydroxy Stearate (Solutol®HS15). At the same time, the in situ toad palate model and rat nasal mucosa model were used to assess the cilia toxicity. The results showed that all the absorption enhancers investigated significantly promote the nasal absorption of NMF, but with different degrees and trends. Among them, the 0.5% (w/v) DDM had the strongest enhancement effect, followed by 0.5% (w/v) Solutol®HS15, 0.25% (w/v) DDM, 0.25% (w/v) Solutol®HS15, 0.1% (w/v) Solutol®HS15, 0.1% (w/v) DDM, and 0.25% (w/v) HP-β-CD, with absolute bioavailability of 76.49%, 72.14%, 71.00%, 69.46%, 60.41%, 59.42%, and 55.18%, respectively. All absorption enhancers exhibited good safety profiles in nasal ciliary toxicity tests. From the perspective of enhancing effect and safety, we considered DDM to be a promising nasal absorption enhancer. And in addition to DDM, Solutol®HS15 can also promote intranasal absorption of NMF, which will provide another option for the development of nalmefene hydrochloride nasal spray.

Effects of nalmefene hydrochloride on TLR4 signaling pathway in rats with lung ischemia-reperfusion injury.

To investigate the effect of nalmefene hydrochloride on TLR4 signaling pathway in rats with lung ischemia-reperfusion injury. Altogether 64 pure inbred male SD rats were divided into groups A, B, C, and D according to the principle of body weight similarity, with 24 rats in each group. Four groups of rats were respectively twisted on the left testis to establish unilateral testicular torsion rats. Group A was the control group, treated with normal saline, group B was the nalmefene hydrochloride high-dose group, treated with 20 μg/kg of nalmefene hydrochloride, group C was the nalmefene hydrochloride low-dose group, treated with 10 μg/kg of nalmefene hydrochloride, and group D was the sham operation group. Lung tissue was collected 60 h later. Western blotting was used to detect the expression levels of HMGB1, TLR4, CD14, and NF-κB protein, qPCR was used to detect the mRNA expression level, and enzyme-linked immunosorbent assay (ELISA) was used to detect the expression levels of inflammatory factors IL-17, IL-6, and ICAM-1. The expression levels of HMGB1, TLR4, CD14, NF-κB protein, mRNA, IL-17, IL-6, and ICAM-1 in group A were significantly higher than those in groups B, C, and D (p<0.05), while were significantly lower in group D than in groups B and C (p<0.05), and were significantly lower in group B than in group C (p<0.05). Nalmefene hydrochloride can effectively inhibit the signal pathway of TLR4, and can effectively reduce the injury caused by lung ischemia-reperfusion. The large dose is closely related to the good effect, which is worthy of promotion.

Determination of the Correction Factor for Dinalmefene Hydrochloride in Nalmefene Hydrochloride Injection

Objective: To calculate the detection correction factor for the impurity, that is, the dinalmefene hydrochloride in nalmefene hydrochloride injection. Methods: High performance liquid chromatography (HPLC) is used to analyze the impurities of nalmefene hydrochloride easily produced during storage, and the impurity is determined and correction factor is calculated for the known the dinalmefene hydrochloride. According to the standard curve method, the sample concentration is selected between the detection limit and the limit of quantification, and the standard curve is prepared. The correction factor is then calculated according to the slope of the standard curve. Results: finally, the correction factor for dinalmefene hydrochloride is 0.22. Conclusions: the correction factor calculated by the standard curve method is accurate and reliable, and can be used for impurity detection of nalmefene hydrochloride injection.

Nalmefene improves prognosis in patients with a large cerebral infarction: study protocol and preliminary results of a randomized, controlled, prospective trial

Background and objectives: Middle cerebral artery trunk occlusion can cause large infarctions. Clinically, thrombolytic therapy, defibrillation, vasodilation, and surgery are often used to treat these large infarctions. However, the therapeutic efficacy of these therapeutic interventions in promoting prognosis remains controversial. Nalmefene, an opioid receptor antagonist, exhibits a neuroprotective effect. Few clinical studies have reported on the therapeutic efficacy of nalmefene in the treatment of large cerebral infarctions. In this study, we investigated the therapeutic efficacy of nalmefene in restoring the neurologic function of patients with middle cerebral artery trunk infarction while using conventional treatment as a control. Design: A randomized, controlled, prospective trial. Methods: Two hundred and thirty-six patients with middle cerebral artery trunk infarction who will receive treatment at the First Hospital of Jilin University in China will be randomly divided into a control group (n = 116) and a nalmefene group (n = 120). Patients in the control group will receive conventional treatment. Patients in the nalmefene group will receive 10 successive days of intravenous nalmefene hydrochloride injection based on conventional treatment. Outcome measures and preliminary results: The primary outcome of this study is the efficacy rate at 20 days (i.e., 10 days after treatment). The secondary outcomes of this study include (1) the National Institutes of Health Stroke Scale (NIHSS) score at 20 days, which is used to evaluate neurologic function deficits; (2) Glasgow Coma Scale scores at 0 days (before treatment) and 10 days; (3) serum level of matrix metalloproteinase-9 at 0, 5, and 10 days (i.e., before treatment and 5 and 10 days of treatment); and (4) magnetic resonance imaging perfusion images of the head at 0 and 10 days. The results of a preliminary experiment involving participants receiving the same treatment as in the present study revealed that compared with the control group, the NIHSS score was significantly decreased, the efficacy rate was increased, Glasgow Coma Scale score was significantly increased, serum level of matrix metalloproteinase-9 was significantly decreased, cerebral blood flow and cerebral blood volume on the lesion side were significantly increased, and the mean transit time of contrast agent on the lesion side was significantly shortened in the nalmefene group. Discussion: Findings from this study will provide clinical evidence for use of nalmefene in combination with conventional treatment for large cerebral infarctions and data to support this combined therapy, which can improve the prognosis in patients with large cerebral infarctions. Ethics and dissemination: This study was designed in December 2011. Clinical ethics approval was received in November 2017. This trial was registered in December 2017. Patient recruitment will begin in January 2018 and end in January 2019. Data analysis will be completed in December 2019. Results will be disseminated for publication in a peer-reviewed journal. Trial registration: This trial was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR-IOR-17013871).

Optimization of the Preparation of Nalmefene Hydrochloride Injection

Optimization of the Preparation of Nalmefene Hydrochloride Injection

Development and Validation of a Method for Detecting Contaminants in Nalmefene Hydrochloride Injections

Development and Validation of a Method for Detecting Contaminants in Nalmefene Hydrochloride Injections

Impact of nalmefene hydrochloride on inflammatory reaction in rats with traumatic brain injury

Objective To observe the changes of TNF-α and NF-κB after different doses of nalmefene hydrochloride (NAL) therapy for traumatic brain injury (TBI) in an effort to identify the effect of NAL on TBI-induced inflammatory response and the possible mechanism.Methods A model of TBI in the rat was produced using the improved Feeney' s free-fall impact method.The animals were randomly divided into sham group,TBI group,TBI + large dose of NAL (ip,0.2 mg/kg) group (TBI + NAL1group),TBI + medial dose of NAL (ip,0.14 mg/kg) group (TBI + NAL2 group),TBI + small dose of NAL (ip,0.07 mg/kg) group (TBI + NAL3 group).Form of brain tissues in each group was observed and mRNA levels of TNF-α and NF-κB were measured by real-time quantitative PCR assay.Results HE staining revealed severe injury and inflammatory infiltration of brain parenchyma in TBI group ;on the contrary,the situation ameliorated in TBI + NAL1 group,TBI + NAL2 group and TBI + NAL3group,with especially obvious improvement in TBI + NAL2 group.In PCR assay,significant expression of NF-κB and TNF-α was observed at post-TBI days 1,3,5 and 7 (P ＜ 0.05),followed by great reverse after NAL therapy (P ＜ 0.05),particularly in TBI + NAL2 group.Conclusions NAL can reduce the inflammation response to TBI and promote post-injury recovery.Moreover,there exists a NAL concentration window. Key words: Brain injuries; Nalmefene hydrochloride; Tumor necrosis factor-alpha; Nuchear factor-κappa B

Supercritical AntiSolvent micronization of nalmefene HCl on laboratory and pilot scale

Supercritical AntiSolvent precipitation (SAS) has been used to produce micronized particles of nalmefene hydrochloride, a selective narcotic antagonist and a promising adjunctive for the treatment of several kinds of addiction. Experiments have been performed using a laboratory scale apparatus and a semi-industrial scale plant. Ethyl alcohol (EtOH) has been used as liquid solvent because of its acceptability in processing pharmaceutical compounds. The effects of SAS process parameters such as temperature, pressure, at a constant concentration of the solute in the liquid solution (1.9 wt.%) have been studied. We have related the different powder morphologies obtained to the position of the process operating point with respect to the vapor–liquid equilibria (VLEs) of the ternary system nalmefene HCl/EtOH/CO 2. Operating SAS well above the mixture critical point (MCP) of the mixture, nano-particles have been generated with a mean diameter ranging from 200 to 300 nm, near and below the MCP in the gas phase region, we have obtained submicro- and micro-particles with mean diameters ranging from 0.5 to 2 μm. Balloons larger than 10–20 μm in diameter and crystals have been also obtained. The results of interest obtained on the laboratory scale plant have been successfully reproduced on the semi-industrial scale plant. The micronized product has also been characterized using powder diffraction X-ray (XRD) and differential scanning calorimetry (DSC), to verify the influence of the micronization process on the final product properties. XRD analysis demonstrated that it is possible to obtain amorphous or crystalline precipitates, depending on the process conditions.

Application of a sensitive liquid chromatographic/tandem mass spectrometric method to pharmacokinetic study of nalmefene in humans

A sensitive, specific and rapid liquid chromatographic/tandem mass spectrometric (LC/MS/MS) method was developed and validated for quantification of nalmefene in human plasma. An aliquot of 200 μL plasma sample was simply precipitated by 400 μL methanol. Separation of nalmefene and the internal standard hydromorphone from the interferences was achieved on a C 18 column followed by MS/MS detection. The analytes were monitored in the positive ionization mode with a TurboIonspray source. The method had a total chromatographic run time of 4.5 min and linear calibration curves over the concentration range of 10–5000 pg/mL. The lower limit of quantification (LLOQ) was 10 pg/mL. The intra- and inter-day precision was less than 10.1% determined from QC samples at concentrations of 30, 300 and 4500 pg/mL, and the accuracy was within ±3.4%. As the method was more sensitive (10 times higher) than those reported previously, we investigated the pharmacokinetics of nalmefene in healthy volunteers after a single intravenous injection of low dose (30 μg) of nalmefene hydrochloride for the first time.

The Permeation of Nalmefene Hydrochloride across Different Regions of Ovine Nasal Mucosa

The permeability of nalmefene hydrochloride (NH) across different regions of ovine nasal mucosa was investigated in vitro. Five different regions of ovine nasal mucosa (superior turbinate mucosa, middle turbinate mucosa, inferior turbinate mucosa, posterior septum mucosa, and anterior septum mucosa) were studied. The results showed that the permeability coefficients of NH through different regions of nasal mucosa were different, and the suitable regions for the absorption of NH were the middle turbinate mucosa, the posterior septum mucosa and the superior turbinate. At the same time, the middle turbinate mucosa was the largest region among the five regions, thus it was the main absorption region for NH. The high uniformity of the middle turbinate mucosa also made it the most suitable model for the permeation of NH in vitro.

Nalmefene and the Urine Opiate Screen

1 Despite its structural similarity to opiates, the effect of therapeutic nalmefene hydrochloride use on subsequent urine toxicologic screening has not been reported. We undertook a prospective double-blinded trial to determine if a single intravenous dose of nalmefene would produce a falsely positive urine opiate screen. Nalmefene hydrochloride (Revex®, Baker Norton Pharmaceuticals) received FDA approval as an opiate reversal agent on April 17, 1995. Like naloxone, it has no opiate agonist properties and, therefore, no abuse potential (1)(2). Both medications work by antagonizing opiate receptors, although nalmefene has a slower clearance and a longer duration of action (1)(3)(4)(5)(6). Nalmefene, like naloxone, is structurally similar to opiates (Fig. 1⇓ ) (7). Concern has been raised over the potential for such medications to cross-react with enzymatic urine drug screens (8)(9). These common screens rely on a portion of a drug’s structure as an antigenic site to determine positivity. Because the use of urine drug screening is widespread both in and outside of clinical practice, faulty results may carry serious consequences. Nalmefene undergoes glucuronide conjugation in the liver and is primarily excreted in the urine. Less than 5% is excreted unchanged (3). It is also metabolized to trace amounts of an N-dealkylated metabolite. Nalmefene glucuronide is inactive, whereas the N-dealkylated metabolite has minimal pharmacological activity. Its terminal elimination half-life is 10.8 ± 5.2 h (3)(6)(10). Cross-reactivity of nalmefene metabolites in opiate immunoassays has not been reported. We used the urine enzyme-multiplied immunoassay technique II (Emit II; Behring Diagnostics) system for our opiate screening, a commonly used …

Stability of revex, nalmefene hydrochloride injection, in injectable solutions

The short-term stability of Revex, nalmefene hydrochloride injection, was determined in a number of diluents commonly employed for intravenous use. An HPLC method was used to follow the potency of the diluted solutions, and was fully validated for its intended concentration range prior to its use. Dilutions of Revex were prepared separately in 0.9% sodium chloride injection, 0.45% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.45% sodium chloride injection, lactated Ringer's injection, 5% dextrose and lactated Ringer's injection and 5% sodium hydrogencarbonate injection. Each admixture was stored at 4°C, room temperature (21°C) and 40°C, with samples being tested after storage at each temperature for 0, 24, 48 and 72 h. Defining stability as the retention of at least 95% of the initial drug concentration at the end of the storage period, it was concluded that the diluted solutions of Revex were uniformly stable for up to 72 h in all of the injectable solutions maintained at either 4, 21 or 40°C.

The effect of renal insufficiency and hemodialysis on the pharmacokinetics of nalmefene.

The disposition of nalmefene, an opioid antagonist intended for the reversal of opioid-induced respiratory depression, and its primary metabolite nalmefene glucuronide, were characterized in adult volunteers with normal renal function and in patients with end-stage renal disease (ESRD). The effect of hemodialysis on the elimination of nalmefene and nalmefene glucuronide also was assessed. Participants with normal renal function received a single intravenous dose of 2 mg, and patients with ESRD received two separate doses of 1 mg nalmefene hydrochloride. Terminal elimination half-life (t1/2) of both nalmefene and nalmefene glucuronide was prolonged in patients with ESRD compared with that in participants with normal renal function. The steady-state volume of distribution (Vdss) of nalmefene was significantly higher and total body clearance lower in patients with ESRD than in participants with normal renal function. Hemodialysis clearance of nalmefene was approximately 3.3% of total body clearance. Although the hemodialysis clearance of nalmefene glucuronide was 179.3 +/- 24.1 mL/min and its t1/2 was significantly reduced during dialysis to 5.2 +/- 2.3 hours, a dramatic rebound of nalmefene glucuronide concentrations of 75.7% was observed 7.7 +/- 5.4 hours after the end of hemodialysis. Thus, hemodialysis does not result in clinically significant alterations in the disposition of nalmefene or its primary metabolite, nalmefene glucuronide. These data suggest that there is no pharmacokinetic basis for modification of the initial dosage, but maintenance doses, if needed, should be administered less frequently due to the prolonged elimination of the active moiety, nalmefene.

Determination of nalmefene in plasma by high-performance liquid chromatography with electrochemical detection and its application in pharmacokinetic studies

A method for measuring human plasma levels of nalmefene after oral and intravenous administration is presented. The method consists of a solid-phase extraction procedure followed by HPLC analysis. A cyanopropyl column is used for the solid-phase extraction and 60% (v/v) acetonitrile in dilute sodium pentanesulfonic acid solution for elution. The concentrated and filtered eluate is injected into the HPLC system, which is equipped with an electrochemical dual-electrode detector. A phenyl column is used in this HPLC system with a mobile phase containing 30% (v/v) acetonitrile in dilute sodium pentanesulfonic acid solution. A signal-to-noise ratio of 4.5 is obtained when a 1 ng/ml spiked plasma sample is analyzed. To determine the applicability of this method for human pharmacokinetic studies, nalmefene levels in plasma were measured at time points up to 24 h following oral and intravenous administration of 30 mg of nalmefene hydrochloride to two subjects. These studies demonstrated that the proposed method is sufficiently sensitive to study the pharmacokinetic profile of nalmefene in man.

Human pharmacology and abuse potential of nalmefene

Nalmefene hydrochloride was administered to six male volunteers with histories of opiate abuse using a double-blind, randomized, Latin square design to determine if it produced typical morphine-like effects. A comparison of physiologic and subject- and observer-reported effects was made between morphine, 15 and 30 mg given intramuscularly; nalmefene, 25, 50, and 100 mg given orally; and placebo. Drowsiness or sleepiness was the most common drug effect reported after the administration of each treatment. Only morphine produced miosis and increased subject-reported euphoria and "drug liking." Neither drug increased Addiction Research Inventory subscale scores measuring dysphoria or sedation or produced changes on the Profile of Mood States questionnaire. Adverse effects reported only after the administration of nalmefene included agitation/irritability and muscle tension; these did not appear to be dose related. The data indicated that nalmefene did not produce typical morphine-like effects and has no apparent abuse potential.