Naloxone (2.0 mg/kg, continuous infusion of 1.7 mg/kg/h) dramatically improved neurobehavioral outcomes in rats, with this effect lasting up to 4 weeks. Naloxone therapy leads in a moderate, nonsignificant elevation in mean arterial blood pressure (MAP) [1]. Naloxone (0.4 mg/kg) can improve memory and inhibit the amnestic effects of ACTH and epinephrine in rats [2]. Naloxone administration lowers the intensity of first tetanus in cats in a dose-related manner. Naloxone (5 or 10 mg/kg, intravenously) generates decreased PTP inhibition with subsequent doses of morphine but has no effect on maximal twitch inhibition [3].

Absorption, Distribution and Excretion
The bioavailability of naloxone administered intranasally is 42-47%. After intranasal administration of 8 mg naloxone, the peak plasma concentration (Cmax) was 12.3-12.8 ng/mL, the time to peak concentration (Tmax) was 0.25 h, and the area under the curve (AUC) was 16.7-19.0 hng/mL. After intramuscular injection of 0.4 mg naloxone, the peak plasma concentration (Cmax) was 0.876-0.910 ng/mL, the time to peak concentration (Tmax) was 0.25 h, and the AUC was 1.94-1.95 hng/mL. After intravenous injection of 2 mg naloxone, the peak plasma concentration (Cmax) was 26.2 ng/mL, and the AUC was 12.8 hng/mL. Following oral or intravenous administration, 25-40% of naloxone is excreted in the urine within 6 hours, 50% within 24 hours, and 60-70% within 72 hours. Metabolites naloxone-3-glucuronide, norhydroxymorphone, and naloxol are all detectable in urine. The volume of distribution of naloxone is 200 liters. Naloxone rapidly distributes to tissues and crosses the placenta and blood-brain barrier. The clearance of naloxone is 2500 liters/day. Naloxone distributes rapidly throughout the body, with higher concentrations in the brain, kidneys, spleen, skeletal muscle, lungs, and heart. The drug also readily crosses the placenta. Oral absorption of naloxone is minimal because it is rapidly destroyed in the gastrointestinal tract. Higher doses are required to achieve any pharmacological effect using this route of administration. Intravenous naloxone has a very rapid onset of action (usually 1-2 minutes). Intramuscular naloxone usually has an onset of action within 5 minutes of administration. The duration of action is typically 45-90 minutes, but can be as long as 3 hours. Naloxone is rapidly inactivated after oral administration. Although effective orally, a much larger dose is required to completely antagonize the effects of heroin than parenteral administration. In one study, a single oral dose of 3 grams of naloxone hydrochloride effectively antagonized the effects of 50 mg of heroin, with an effect lasting 24 hours. Naloxone takes effect within 1-2 minutes after intravenous injection and within 2-5 minutes after subcutaneous or intramuscular injection. The duration of action depends on the dose and route of administration, with intramuscular injection having a longer duration than intravenous injection. In one study, after neonates received 35 or 70 micrograms of naloxone hydrochloride via umbilical vein injection, peak plasma naloxone concentrations reached 4-5.4 ng/mL and 9.2-20.2 ng/mL, respectively, within 40 minutes. In the same study, after neonates received 0.2 mg of naloxone intramuscularly, peak plasma naloxone concentrations reached 11.3-34.7 ng/mL within 0.5-2 hours. For more complete data on the absorption, distribution, and excretion of naloxone (14 items in total), please visit the HSDB record page.

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Metabolism/Metabolites
Naloxone is primarily metabolized by glucuronidation to naloxone-3-glucuronide. Naloxone can also undergo N-dealkylation to norhydroxymorphone, or 6-ketoreduction to naloxol. Naloxone is rapidly metabolized in the liver, primarily through conjugation with glucuronic acid. The main metabolite is naloxone-3-glucuronide. Naloxone also undergoes N-dealkylation and 6-ketoreduction, followed by a conjugation reaction. In the human body, N-allyl-7,8-dihydro-14-hydroxynormorphine and 7,8-dihydro-14-hydroxynormorphone are produced; Weinstein, SH, Pfeffer, M, Schor, JM, Indindoli, L, & Mintz, M, J Pharm Sci, 60, 1567 (1971). In the human body, naloxone-3-β-D-glucuronide is produced; Fujimoto, JM, J Pharmac Exp Ther, 168, 180 (1969). /Excerpt from Table/
...Oxidative deallylation, 6-keto reduction, and glucuronidation occur in the human body.
...Naloxone-3-glucuronide (major), 3-sulfate (minor), naloxol and its conjugates (minor), and 7,8-dihydro-14-hydroxynormorphine and its conjugates have been identified as metabolites of naloxone. Furthermore, preliminary evidence suggests the presence of two polar hydroxylated metabolites (the hydroxylation site may be located at position 2 of the 17-side chain or aromatic ring). 7,8-dihydro-14-hydroxynormorphone and two polar metabolites were also observed in brain tissue. ...

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Biological Half-Life
The mean half-life of naloxone hydrochloride is 1.8–2.7 hours after intranasal administration, 1.4 hours after intramuscular administration, and 1.2 hours after intravenous administration. In neonates, the mean half-life of naloxone is 3.1 ± 0.5 hours.
After intramuscular or subcutaneous injection of naloxone hydrochloride using an auto-injector, the mean plasma half-life of naloxone is 1.28 hours; while after intramuscular or subcutaneous injection using a standard syringe, the plasma half-life is 1.36 hours.
Naloxone has been reported to have a half-life of 30–81 minutes in adults and approximately 3 hours in neonates.
Plasma naloxone levels in three groups of newborns within 6–36 hours were determined using radioimmunoassay (RIA): (1) 35 μg naloxone hydrochloride administered intravenously within 1 minute of birth (n = 6); (2) 70 μg naloxone hydrochloride administered intravenously (n = 6); (3) 200 μg naloxone hydrochloride administered intramuscularly within 1 minute of birth (n = 17). After intravenous administration of 35 μg and 70 μg naloxone, peak levels of 4–15 ng/mL and 9–20 ng/mL were reached within 5–40 minutes, respectively, with a mean plasma half-life of 3.1 ± 0.5 hours for both doses.

Toxicity Summary
Identification and Uses: Naloxone is a crystalline substance. Naloxone hydrochloride is used to completely or partially reverse opioid depression caused by natural and synthetic opioids, including respiratory depression (for human and veterinary use). It is also used as an adjunct in the treatment of septic shock to raise blood pressure. A higher concentration formulation (Trexonil) is used to reverse sedation in wild animals. Human Exposure and Symptoms: Adverse reactions associated with naloxone use include seizures, severe hypertension, hypotension, and/or bradycardia. In non-addicted individuals, intravenous administration of 0.2, 0.4, and 0.6 mg at 11, 22, and 33 minutes, respectively, for a total dose of 1.2 mg, resulted in miosis, decreased core body temperature, and decreased systolic blood pressure. Naloxone-induced acute pulmonary edema is an extremely rare but fatal complication. Endogenous opioids appear to modulate blood pressure in some hypertensive patients, therefore, the use of opioid antagonists such as naloxone in these patients must be approached with caution. Children taking naloxone may experience a moderate increase in respiratory rate, heart rate, and blood pressure, but more serious complications are rare. Naloxone is weakly positive in the in vitro human lymphocyte chromosomal aberration assay. Naloxone may affect some functions of the human immune system, but its effects are transient. Animal studies: Injection of naloxone into the medial septal nucleus of rats significantly increased the release of hippocampal acetylcholine in a dose-dependent manner. Studies also found that rats injected with naloxone exhibited enhanced motor activity and occasionally behavioral seizures. Subcutaneous injection of 100 mg/kg/day in rats for 3 weeks caused only transient salivation and partial ptosis after injection. Injection of naloxone into rats starting from day 17 of gestation significantly increased neonatal mortality. Naloxone administration slightly inhibited weight gain. Naloxone was weakly positive in the Ames mutagenicity assay and negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in vivo rat bone marrow chromosomal aberration studies.

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Interactions
Because buprenorphine binds and dissociates slowly from opioid receptors, its effects are prolonged, requiring high doses of naloxone to antagonize it. Buprenorphine antagonism is characterized by a gradual reversal effect and a shortened duration of the usually prolonged respiratory depression. The barbiturate metoclopramide appears to block naloxone-induced acute withdrawal symptoms in opioid addicts.
Concomitant administration of flunitrazepam and naloxone to volunteers increased respiratory rate and minute ventilation, but did not alter end-tidal carbon dioxide partial pressure, inhaled volume, or alveolar ventilation compared to naloxone alone.

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Non-human toxicity values
Mouse intravenous LD50: 90 mg/kg / Naloxone hydrochloride/
Rat intravenous LD50: 107 mg/kg / Naloxone hydrochloride/
Rat intraperitoneal LD50: 239 mg/kg / Naloxone hydrochloride/
Rat subcutaneous LD50: 500 mg/kg / Naloxone hydrochloride/
Mouse subcutaneous LD50: 286 mg/kg / Naloxone hydrochloride/

[1]. Beneficial effect of the nonselective opiate antagonist naloxone hydrochloride and the thyrotropin-releasing hormone (TRH) analog YM-14673 on long-term neurobehavioral outcome following experimental brain injury in the rat. J Neurotrau.

[2]. Endocannabinoid activation of CB1 receptors contributes to long-lasting reversal of neuropathic pain by repetitive spinal cord stimulation. Eur J Pain. 2017 May;21(5):804-814.

[3]. Effect of ACTH, epinephrine, beta-endorphin, naloxone, and of the combination of naloxone or beta-endorphinwith ACTH or epinephrine on memory consolidation. Psychoneuroendocrinology. 1983;8(1):81-7.

[4]. Neuromuscular effects of morphine and naloxone. J Pharmacol Exp Ther. 1973 Jan;184(1):136-42.

Therapeutic Uses
Anesthetic Antagonists Clinical Trials/ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes summary information about the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for providing patient health information) and PubMed (for providing citations and abstracts of academic articles in the medical field). Naloxone is listed in the database. Naloxone hydrochloride injection (USP) is indicated for the complete or partial reversal of opioid depression, including respiratory depression, caused by natural and synthetic opioids, including propoxyphene, methadone, and certain mixed agonist-antagonist analgesics: nalbuphine, pentazocine, butorphanol, and cyclozoxin. Naloxone hydrochloride injection (USP) is also indicated for the diagnosis of suspected or known acute opioid overdose. /Included on the US product label/ Naloxone hydrochloride injection (USP) may be used as an adjunct therapy for the treatment of septic shock to raise blood pressure. /Included on the US product label/ For more complete data on the therapeutic uses of naloxone (14 in total), please visit the HSDB record page.

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Drug Warning
Rare reports of nausea and vomiting have been reported in postoperative patients receiving parenteral doses of naloxone hydrochloride higher than the usual recommended dose; however, a causal relationship has not been established. Some patients who received naloxone for opioid overdose experienced tremors and hyperventilation, accompanied by sudden recovery of consciousness. While a causal relationship with the drug has not been established, there have been reports of severe cardiopulmonary adverse reactions (e.g., hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, cardiac arrest) in patients receiving naloxone hydrochloride post-surgery, leading to death, coma, and encephalopathy. Adverse cardiopulmonary reactions most commonly occur in post-operative patients with a pre-existing cardiovascular condition or those taking other medications that can produce similar cardiovascular adverse reactions. Seizures are rare following naloxone hydrochloride administration; however, a causal relationship between this and the drug has not been established. When high-dose oral naloxone is used to treat opioid addiction, some patients experience adverse reactions such as depression, apathy, poor concentration, somnolence, irritability, anorexia, nausea, and vomiting. These adverse reactions usually appear in the first few days of treatment and subside rapidly with continued treatment or dose reduction. One case of erythema multiforme resolved rapidly after discontinuation of naloxone. For more complete data on naloxone (23 total), please visit the HSDB record page. Pharmacodynamics: Naloxone is an opioid receptor antagonist used to reverse opioid overdose. Naloxone has a shorter duration of action than opioids and may require multiple doses. Naloxone has a wide therapeutic window and is ineffective if the patient is not taking opioids. Patients receiving naloxone may experience opioid withdrawal symptoms; administrators should be aware that reversing opioid overdose may not eliminate all symptoms if the patient is taking other medications concurrently.

C19H21NO4

327.37

327.147

465-65-6

Naloxone hydrochloride;357-08-4;Naloxone-d5;1261079-38-2

5284596

Crystals from ethyl acetate

1.43 g/cm3

532.8ºC at 760 mmHg

184ºC

276.1ºC

1.239

2

5

2

24

594

4

C=CCN1CC[C@@]23C4=C5C=CC(=C4O[C@H]3C(=O)CC[C@]2([C@H]1C5)O)O

UZHSEJADLWPNLE-GRGSLBFTSA-N

InChI=1S/C19H21NO4/c1-2-8-20-9-7-18-15-11-3-4-12(21)16(15)24-17(18)13(22)5-6-19(18,23)14(20)10-11/h2-4,14,17,21,23H,1,5-10H2/t14-,17+,18+,19-/m1/s1

(4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-prop-2-enyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)