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
An intranasal dose of naloxone is 42-47% bioavailable. An 8 mg dose of nasal naloxone reaches a Cmax of 12.3-12.8 ng/mL, with a Tmax of 0.25 hours, and an AUC of 16.7-19.0 h\*ng/mL. A 0.4 mg intramuscular dose reaches a Cmax of 0.876-0.910 ng/mL, with a Tmax of 0.25 hours, and an AUC of 1.94-1.95 h\*ng/mL. A 2 mg intravenous dose reaches a Cmax of 26.2 ng/mL with an AUC of 12.8 h\*ng/mL.
After oral or intravenous administration, naloxone is 25-40% eliminated in the urine within 6 hours, 50% in 24 hours, and 60-70% in 72 hours. The metabolites naloxone-3-glucuronide, noroxymorphone, and naloxol are all detected in the urine.
The volume of distribution of naloxone is 200 L. Naloxone distributes into tissues rapidly. It can also cross the placenta and blood-brain barrier.
The clearance of naloxone is 2500 L/day.
Naloxone is distributed rapidly throughout the body with high levels found in the brain, kidneys, spleen, skeletal muscle, lung, and heart. The drug also readily crosses the placenta.
Naloxone is only minimally absorbed when given orally as it is rapidly destroyed in the GI tract. Much higher doses are required if using this route of administration for any pharmacologic effect. When given IV, naloxone has a very rapid onset of action (usually 1-2 minutes). If given IM, the drug generally has an onset of action with 5 minutes of administration. The duration of action usually persists from 45-90 minutes, but may act for up to 3 hours.
Naloxone is rapidly inactivated following oral administration. Although the drug is effective orally, doses much larger than those required for parenteral administration are required for complete antagonism. In one study, a single 3-g oral dose of naloxone hydrochloride was required to effectively antagonize the effects of 50 mg of heroin for 24 hours. Naloxone has an onset of action within 1-2 minutes following iv administration and within 2-5 minutes following subcutaneous or im administration. The duration of action depends on the dose and route of administration and is more prolonged following im administration than after iv administration.
Following administration of 35 or 70 ug of naloxone hydrochloride into the umbilical vein in neonates in one study, peak plasma naloxone concentrations occurred within 40 minutes and were 4-5.4 ng/mL and 9.2-20.2 ng/mL, respectively. After im administration of 0.2 mg to neonates in the same study, peak plasma naloxone concentrations of 11.3-34.7 ng/mL occurred within 0.5-2 hours.
For more Absorption, Distribution and Excretion (Complete) data for NALOXONE (14 total), please visit the HSDB record page.

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Metabolism / Metabolites
Naloxone primarily undergoes glucuronidation to form naloxone-3-glucuronide. Naloxone is also N-dealkylated to noroxymorphone or undergoes 6-keto reduction to naloxol.
Naloxone is rapidly metabolized in the liver, principally by conjugation with glucuronic acid. The major metabolite is naloxone-3-glucuronide. Naloxone also undergoes N-dealkylation and reduction of the 6-keto group followed by conjugation.
Yields N-allyl-7,8-dihydro-14-hydroxynormorphine, 7,8-dihydro-14-hydroxynormorphinone in man; Weinstein, SH, Pfeffer, M, Schor, JM, Indindoli, L, & Mintz, M, J Pharm Sci, 60, 1567 (1971). Yields naloxone-3-beta-d-glucuronide in man; Fujimoto, JM, J Pharmac Exp Ther, 168, 180(1969). /From table/
... Oxidative N-deallylation, redn of 6-keto-group, and glucuronidation occur in man.
... Naloxone-3-glucuronide (major), 3-sulfate (minor), naloxol and conjugated naloxol (minor), 7,8-dihydro-14-hydroxynormorphine, 7,8-dihydro-14-hydroxynormorphine and their conjugates were shown to be the metabolites of naloxone. In addition, tentative evidence was obtained for two polar hydroxylated metabolites (with hydroxylation presumably in the 17-side chain or in position 2 of the aromatic nucleus). 7,8-Dihydro-14-hydroxynormorphinone and 2-polar metabolites were also observed in brain. ...

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Biological Half-Life
The mean half life of naloxone hydrochloride is 1.8-2.7 hours intranasally, 1.4 hours intramuscularly, and 1.2 hours intravenously. In neonates, the mean half life is 3.1 ± 0.5 hours.
The mean plasma half-life of naloxone was 1.28 hours following IM or subcutaneous injection of naloxone hydrochloride using an auto-injector, compared with 1.36 hours following IM or subcutaneous injection using a standard syringe.
The half-life of naloxone has been reported to be 30-81 minutes in adults and about 3 hours in neonates.
Plasma naloxone levels were determined by RIA over a period of 6--36 hr in three groups of neonates, (1) those given 35 microgram iv (n = 6), (2) those given 70 microgram iv (n = 6) and (3) those given 200 microgram im (n = 17) naloxone HCl within 1 min of birth. After intravenous administration of 35 and 70 microgram of naloxone peak levels of 4--15 ng/mL and 9--20 ng/mL respectively were reached in 5--40 min and the mean plasma half-life after both doses was 3.1 +/- 0.5 hr.

Toxicity Summary
IDENTIFICATION AND USE: Naloxone is composed of crystals. Naloxone hydrochloride is used for the complete or partial reversal of opioid depression, including respiratory depression, induced by natural and synthetic opioids (both human and veterinary cases). It may also be useful as an adjunctive agent to increase blood pressure in the management of septic shock. A formulation for wildlife use (Trexonil) is more concentrated and used to reverse tranquilization in wild animals. HUMAN EXPOSURE AND SYMPTOMS: Adverse effects associated with naloxone use have included seizures, severe hypertension, and hypotension and/or bradycardia. A total of 1.2 mg administered intravenously as 0.2, 0.4, and 0.6 mg at 11, 22, and 33 minutes respectively to nonaddicts caused miosis, decreased core temperature, and systolic blood pressure. Naloxone-induced acute pulmonary edema is an extremely rare but lethal complication. Endogenous opioids appear to regulate blood pressure in some hypertensive patients and opiate antagonists such as naloxone must be administered with caution to these individuals. Moderate increases in respiratory rate, heart rate, and blood pressure occur after naloxone administration to children, but development of more serious complications is rare. Naloxone was weakly positive in the in vitro human lymphocyte chromosome aberration test. Naloxone may affect some functions of the immune system in humans, but its action is transient. ANIMAL STUDIES: The injection of naloxone into the medial septal nucleus of rats produced a marked increase in hippocampal ACh release in a dose-dependent manner. It was also found that rats given an injection of naloxone showed an increase in motor activity and occasionally exhibited behavioral seizures. Subcutaneous injection of 100 mg/kg/day in rats for 3 weeks produced only transient salivation and partial ptosis following injection. Administration of naloxone to rats from day 17 of pregnancy significantly increased neonatal death. Body weight increase was slightly retarded by administration of naloxone. Naloxone was weakly positive in the Ames mutagenicity test and was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and the in vivo rat bone marrow chromosome aberration study.

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Interactions
Large doses of naloxone are required to antagonize buprenorphine since the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. The barbiturate methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts.
The combined admin of flunitrazepam and naloxone to volunteers incr resp frequency and resp min vol but did not alter endexpired pCO2 pressure, resp inhalation vol, or alveolar ventilation when compared with naloxone treatment alone.

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Non-Human Toxicity Values
LD50 Mouse iv 90 mg/kg /Naloxone hydrochloride/
LD50 Rat iv 107 mg/kg /Naloxone hydrochloride/
LD50 Rat ip 239 mg/kg /Naloxone hydrochloride/
LD50 Rat sc 500 mg/kg /Naloxone hydrochloride/
LD50 Mouse sc 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
Narcotic Antagonists
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Naloxone is included in the database.
Naloxone Hydrochloride Injection, USP is indicated for the complete or partial reversal of opioid depression, including respiratory depression, induced by natural and synthetic opioids, including propoxyphene, methadone, and certain mixed agonist-antagonist analgesics: nalbuphine, pentazocine, butorphanol, and cyclazocine. Naloxone Hydrochloride Injection, USP is also indicated for diagnosis of suspected or known acute opioid overdosage. /Included in US product label/
Naloxone Hydrochloride Injection, USP may be useful as an adjunctive agent to increase blood pressure in the management of septic shock. /Included in US product label/
For more Therapeutic Uses (Complete) data for NALOXONE (14 total), please visit the HSDB record page.

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Drug Warnings
Nausea and vomiting have been reported rarely in postoperative patients who were receiving a parenteral dose of naloxone hydrochloride greater than that usually recommended; however, a causal relationship has not been established. Tremor and hyperventilation associated with an abrupt return to consciousness has occurred in some patients receiving naloxone for opiate overdosage.
Although a causal relationship to the drug has not been established, severe cardiopulmonary effects (eg, hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, cardiac arrest) resulting in death, coma, and encephalopathy have been reported in patients following postoperative administration of naloxone hydrochloride. Adverse cardiopulmonary effects have occurred most frequently in postoperative patients with preexisting cardiovascular disease or in those receiving other drugs that produce similar adverse cardiovascular effects.
Seizures have occurred rarely following administration of naloxone hydrochloride; however, a causal relationship to the drug has not been established.
When high oral doses of naloxone have been used in the treatment of opiate addiction, some patients have experienced mental depression, apathy, inability to concentrate, sleepiness, irritability, anorexia, nausea, and vomiting. These adverse effects usually occurred in the first few days of treatment and abated rapidly with continued therapy or dosage reduction. One case of erythema multiforme cleared promptly after naloxone was discontinued.
For more Drug Warnings (Complete) data for NALOXONE (23 total), please visit the HSDB record page.

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Pharmacodynamics
Naloxone is an opioid receptor antagonist indicated in the reversal of opioid overdoses. Naloxone has a shorter duration of action than opioids and multiple doses may be required. The therapeutic window of naloxone is wide, as it has no effect if a patient has not taken opioids. Patients treated with naloxone may experience opioid withdrawal and a person administering naloxone should be aware that reversal of opioid overdoses may not resolve all the symptoms a patient is experiencing if other drugs are involved.

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.)