Nicoboxil

Identification

Name
Nicoboxil
Accession Number
DB12911
Type
Small Molecule
Groups
Approved, Investigational
Description

Nicoboxil has been investigated for the treatment of Acute Low Back Pain, where it is typically considered an effective and safe therapeutic option. Nevertheless, it is predominantly found paired with nonivamide as a combination topical analgesic product where its proposed mechanism of action as a rubefacient is complementary and ultimately synergistic with nonivamide's capsaicin activity [5]. Such combination topical analgesics are only available for purchase and use (for humans) in some parts of Europe and Asia, like Germany and Australia [5, 7].

Despite topical nicoboxil/nonivamide topical analgesic medication being used since the 1950s, recent studies demonstrate continued interest in the medication(s) given its demonstrated efficacy, safety, and capability to be used as an alternative musculoskeletal pain therapy option with less systemic side effects when compared to the oral non-steroidal anti-inflammatory drugs and opioids that may be more typically prescribed [1, 2].

Structure
Thumb
Synonyms
  • beta-Butoxyethyl nicotinate
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Actinac PwrNicoboxil (24 mg) + Allantoin (24 mg) + Chloramphenicol (40 mg) + Hydrocortisone acetate (40 mg) + Octasulfur (320 mg)PowderTopicalRoussel Canada Inc.1978-12-311996-09-09Canada
Actinac PwsNicoboxil (24 mg) + Allantoin (24 mg) + Chloramphenicol (40 mg) + Hydrocortisone acetate (40 mg) + Octasulfur (320 mg)Powder, for solutionTopicalHoechst Roussel Canada Inc.1994-12-312001-07-20Canada
Categories
UNII
GSD5B9US0W
CAS number
13912-80-6
Weight
Average: 223.272
Monoisotopic: 223.120843411
Chemical Formula
C12H17NO3
InChI Key
IZJRISIINLJVBU-UHFFFAOYSA-N
InChI
InChI=1S/C12H17NO3/c1-2-3-7-15-8-9-16-12(14)11-5-4-6-13-10-11/h4-6,10H,2-3,7-9H2,1H3
IUPAC Name
2-butoxyethyl pyridine-3-carboxylate
SMILES
CCCCOCCOC(=O)C1=CN=CC=C1

Pharmacology

Indication

The primary therapeutic use for which nicoboxil is currently indicated for is as an active ingredient in combination with the capsaicinoid nonivamide compound as a topical analgesic for the temporary relief of the pain of rheumatism, arthritis, lumbago, muscular aches, sprains and strains, sporting injuries, and other conditions where local warmth is beneficial [5].

Nevertheless, most of the available studies regarding the use of nicoboxil and nonivamide topical analgesics focus specifically on their efficacy and safety in treating acute non-specific low back pain, typically finding the combination analgesic to be an effective, safe, and well-tolerated medication for such an indication [1, 2].

Pharmacodynamics

Topical applications consisting of the individual active ingredients of nicoboxil and nonivamide at doses considered to be therapeutic are generally not considered readily available commercially [1]. Subsequently, the pharmacodynamics of nicoboxil are considered useful in commercially available combination products largely because they combine with those of nonivamide to offer a synergistic effect from the unique complementary actions of these two agents [5].

Subsequently, nonivamide is a synthetic capsaicin analog with analgesic properties which are assumed to result from the depletion of Substance P in the peripheral nociceptive C-fibres and A-delta nerve fibers upon repetitive topical application [5]. Resultant stimulation of afferent nerve endings in the skin evidently causes a dilatory effect on the surrounding blood vessels accompanied by an intense, long-lasting sensation of warmth associated with the nonivamide use [5].

Given the proposed effect of nonivamide, it is believed that nicoboxil is a vitamin of the B complex [6] that possesses vasodilating properties facilitated by prostaglandin [5]. The observed hyperaemic increased blood flow effect of nicoboxil occurs earlier and is described as being more intense than the nonivamide hyperaemic effect [5]. Nicoboxil and nonivamide are consequently generally indicated as a combination product because the pharmacodynamics of nicoboxil are considered useful as a complement to those of nonivamide, and vice versa [5, 1]. In essence, both compounds induce vasodilation by different effects and therefore have complementary abilities inducing increased blood flow, thus hastening the hyperaemic skin reaction [7].

Mechanism of action

In particular, nicoboxil is considered a rubefacient [5, 1]. However, the specific mechanism of action by which rubefacients like nicoboxil elicit pharmacologic effects has not yet been formally elucidated [3, 4]. Nevertheless, it is generally proposed that rubefacients cause irritation of the skin when applied topically, and are believed to alleviate pain in muscles, joints, tendons, and other musculoskeletal pains in the extremities by counter-irritation [3]. This specific term, 'counter-irritant', derives from the fact that rubefacients can cause a reddening of the skin by causing the blood vessels of the skin to dilate, which gives a soothing feeling of warmth [3]. In essence, the term largely refers to the notion that irritation of the sensory nerve endings alters or offsets pain in the underlying muscle or joints that are innervated by the same nerves [3].

In fact, the vasodilation effect of rubefacients like nicoboxil has been considered the result of nerve conduction mechanisms as early as the late 1950s when certain studies demonstrated that the concomitant application of xylocaine could counteract or prevent the vasolidator response to rubefacients in 50% of such related experiments [4].

Absorption

Specific investigations on absorption of dermally applied nicoboxil in laboratory animals or target species were not available [6]. Published data for nicotinate esters related to nicoboxil indicated however, that members of this class of compounds are in principle able to penetrate skin [12].

Regardless, there is interest in the studies that demonstrate nicoboxil and nonivamide combination topical applications as effective and safe analgesic products precisely because such topical formulations are expected to have much lower systemic absorption - and thus less exposure to systemic side effects (ie. like gastrointestinal upset, drowsiness, etc.) - than the oral non-steroidal anti-inflammatory drugs, opioids, muscle relaxants, and steroids that may be more commonly prescribed over a rubefacient like nicoboxil [1, 2].

Nevertheless, despite the fact that topical nicoboxil and nonivamide products been available to use in some parts of Europe since the 1950s to treat discomfort of the muscuoskeletal system, the effects of nicoboxil and nonivamide have not been investigated in detail and a lack of detailed studies on nicoboxil pharmacodynamics and pharmacokinetics remains ongoing [1].

Volume of distribution

Despite the fact that topical nicoboxil and nonivamide products been available to use in some parts of Europe since the 1950s to treat discomfort of the muscuoskeletal system, the effects of nicoboxil and nonivamide have not been investigated in detail and a lack of detailed studies on nicoboxil pharmacodynamics and pharmacokinetics remains ongoing [1]. Readily accessible data regarding the volume of distribution of nicoboxil is subsequently not available.

Protein binding

Despite the fact that topical nicoboxil and nonivamide products been available to use in some parts of Europe since the 1950s to treat discomfort of the muscuoskeletal system, the effects of nicoboxil and nonivamide have not been investigated in detail and a lack of detailed studies on nicoboxil pharmacodynamics and pharmacokinetics remains ongoing [1]. Readily accessible data regarding the protein binding of nicoboxil is subsequently not available.

Metabolism

Any systemically absorbed nicoboxil is expected to be hydrolyzed to nicotinic acid and 2-butoxyethanol in blood plasma [6]. In vitro it is reported that such hydrolysis reactions are catalyzed by esterase-like activity of serum albumin and by plasma esterases [6]. The nicotinic acid metabolite is also capable of vascular dilatation [6]. In humans, the urinary elimination of 2-butoxyethanol's metabolite, 2-butoxyacetic acid was also reported [6].

The metabolism of nicoboxil is considered to be rapid [6].

Route of elimination

Following ester cleavage, the nicotinic acid metabolite is expected to enter the endogenous metabolic pool as a part of the vitamin B complex [6]. The 2-butoxyethanol metabolite is believed to be mainly excreted primarily in the urine and to a certain extent, in exhaled air [6]. In humans, the urinary elimination of 2-butoxyethanol's metabolite, 2-butoxyacetic acid was also reported [6].

Half life

The half-life of ester hydrolysis was found to be very short in the presence of human serum albumin - less than 15 minutes, 50uM [6].

Clearance

The elimination of nicoboxil is considered to be rapid [6].

Despite the fact that topical nicoboxil and nonivamide products been available to use in some parts of Europe since the 1950s to treat discomfort of the muscuoskeletal system, the effects of nicoboxil and nonivamide have not been investigated in detail and a lack of detailed studies on nicoboxil pharmacodynamics and pharmacokinetics remains ongoing [1]. Readily accessible data regarding the clearance of nicoboxil is subsequently not available.

Toxicity

Nicoboxil is of low acute toxicity [6]. No adverse side effects were reported in humans after therapeutic use of the combination of nicoboxil/nonivamide [6]. In a study using dermal application of nicoboxil/nonivamide in over 1000 patients, no allergic reactions were observed [6].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcetaminophenAcetaminophen may decrease the excretion rate of Nicoboxil which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Nicoboxil which could result in a higher serum level.
AlprazolamAlprazolam may decrease the excretion rate of Nicoboxil which could result in a higher serum level.
AmilorideAmiloride may increase the excretion rate of Nicoboxil which could result in a lower serum level and potentially a reduction in efficacy.
AmitriptylineNicoboxil may decrease the excretion rate of Amitriptyline which could result in a higher serum level.
AmlodipineAmlodipine may decrease the excretion rate of Nicoboxil which could result in a higher serum level.
AmoxicillinAmoxicillin may decrease the excretion rate of Nicoboxil which could result in a higher serum level.
AmphetamineAmphetamine may decrease the excretion rate of Nicoboxil which could result in a higher serum level.
AmpicillinAmpicillin may decrease the excretion rate of Nicoboxil which could result in a higher serum level.
AuranofinAuranofin may decrease the excretion rate of Nicoboxil which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Gaubitz M, Schiffer T, Holm C, Richter E, Pisternick-Ruf W, Weiser T: Efficacy and safety of nicoboxil/nonivamide ointment for the treatment of acute pain in the low back - A randomized, controlled trial. Eur J Pain. 2016 Feb;20(2):263-73. doi: 10.1002/ejp.719. Epub 2015 Apr 30. [PubMed:25929250]
  2. Blahova Z, Holm JC, Weiser T, Richter E, Trampisch M, Akarachkova E: Nicoboxil/nonivamide cream effectively and safely reduces acute nonspecific low back pain - a randomized, placebo-controlled trial. J Pain Res. 2016 Dec 14;9:1221-1230. doi: 10.2147/JPR.S118329. eCollection 2016. [PubMed:28008281]
  3. Matthews P, Derry S, Moore RA, McQuay HJ: Topical rubefacients for acute and chronic pain in adults. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD007403. doi: 10.1002/14651858.CD007403.pub2. [PubMed:19588430]
  4. FULTON GP, FARBER EM, MORECI AP: The mechanism of action of rubefacients. J Invest Dermatol. 1959 Dec;33:317-25. [PubMed:13825636]
  5. Finalgon Cream (nonivamide and butoxyethyl nicotinate) Label [File]
  6. European Agency for the Evaluation of Medicinal Products Veterinary Medicines Evaluation Unit: Committee for Veterinary Medicinal Products Nicoboxil Summary Report [File]
  7. Bundesinstitut fur Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report: Finalgon 4 mg/g + 25 mg/g Salbe Nonivamide, Nicoboxil [File]
External Links
KEGG Drug
D01677
KEGG Compound
C13138
PubChem Compound
14866
PubChem Substance
347829061
ChemSpider
14176
ChEBI
32322
ChEMBL
CHEMBL2105161
MSDS
Download (34.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAcute Low Back Pain1
3CompletedTreatmentLow Back Pain (LBP)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
PowderTopical
Powder, for solutionTopical
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility6.1 mg/mLALOGPS
logP1.99ALOGPS
logP2.04ChemAxon
logS-1.6ALOGPS
pKa (Strongest Basic)3.24ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area48.42 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity60.84 m3·mol-1ChemAxon
Polarizability25.03 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as pyridinecarboxylic acids. These are compounds containing a pyridine ring bearing a carboxylic acid group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridines and derivatives
Sub Class
Pyridinecarboxylic acids and derivatives
Direct Parent
Pyridinecarboxylic acids
Alternative Parents
Heteroaromatic compounds / Carboxylic acid esters / Monocarboxylic acids and derivatives / Dialkyl ethers / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
Pyridine carboxylic acid / Heteroaromatic compound / Carboxylic acid ester / Carboxylic acid derivative / Dialkyl ether / Ether / Monocarboxylic acid or derivatives / Azacycle / Organooxygen compound / Organonitrogen compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
pyridines, aromatic carboxylic acid (CHEBI:32322)

Drug created on October 20, 2016 19:12 / Updated on September 21, 2018 00:19