Identification

Name
Calcium carbimide
Accession Number
DB09116
Type
Small Molecule
Groups
Approved, Withdrawn
Description

Calcium carbimide, sold as the citrate salt, is an alcohol-sensitizing agent. Its effects are similar to the drug disulfiram (Antabuse) in that it interferes with the normal metabolism of alcohol by preventing the breakdown of the metabolic product acetaldehyde. Calcium carbimide was conceived as an alternative for the treatment of alcoholism with a reduced side effect profile either when it is consumed accompanied by alcohol or without it.[1] This drug was developed by Lederle Cyanamid Canada Inc and approved for marketing in Canada in 1959. The current status of calcium carbimide is cancelled post marketing.[8]

Structure
Thumb
Synonyms
  • calcium cyanamide
  • carbimida calcica
  • carbimide calcique
  • Cyanamide calcique
  • Cyanamide, calcium salt (1:1)
  • Lime nitrogen
  • Lime-nitrogen
  • methanediimine, calcium salt (1:1)
  • Nitrogen lime
Product Ingredients
IngredientUNIICASInChI Key
Citrated calcium carbimide21ZCD2AA4H8013-88-5NEZBLMYXHFALIF-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Temposil Tab 50mgTablet50 mgOralLederle Cyanamid Canada Inc.1959-12-311999-04-12Canada
Categories
UNII
ZLR270912W
CAS number
156-62-7
Weight
Average: 80.103
Monoisotopic: 79.9687389
Chemical Formula
CCaN2
InChI Key
MYFXBBAEXORJNB-UHFFFAOYSA-N
InChI
InChI=1S/CN2.Ca/c2-1-3;/q-2;+2
IUPAC Name
calcium (azanidylenemethylidene)azanide
SMILES
[Ca++].[N-]=C=[N-]

Pharmacology

Indication

Calcium carbimide has not been approved by the FDA but the intended indication is for the treatment of alcoholism.[6] This medication was marketed in Canada, United Kingdom and Europe under the trade name of Temposil for the sole use of alcoholism treatment.[9]

Pharmacodynamics

Administration of calcium carbimide causes a syndrome characterized by intense flushing, rapid pulse, panting respiration and perception of acetaldehyde in the exhaled breath. This syndrome remains for a few hours after alcohol consumption and it stops completeley after 24 hours. This syndrome is caused by the accumulation of acetaldehyde and altered vascular reaction.[2] Therefore, the more the alcohol consumption the more the adverse effects caused by acetaldehyde accumulation.

Mechanism of action

Calcium carbimide is a potent inhibitor of the aldehyde dehydrogenase.[6] Ethanol is normally metabolized to acetaldehyde that is quickly metabolized because this molecule is toxic, thus it has to stay in very low quantities in the body. Carbimide performs its effect by being a competitive inhibitor of the hepatic aldehyde-NAD oxidoreductase dehydrogenase which is the enzyme responsible for the oxidation of acetaldehyde to water and acetate.[9]

TargetActionsOrganism
AAldehyde dehydrogenase family 3 member B2
antagonist
inhibitor
Human
Absorption

It presents a very rapid absorption which has caused the presence of side effects as nausea, headache and vomiting.[9] The oral bioavailability of calcium carbimide depends on the administered dose which can vary from 50-81% on a dose of 0.3-1.5 mg/kg respectively.[6] In preclinical trials, peak plasma concentration occurred at 60 minutes after administration.[9] The values of Cmax, AUC and T max of calcium carbimide of a dose of 1.5 mg/kg were 1.65 mcg/ml, 77.86 mcg/mg min and 12 minutes respectively.[5]

Volume of distribution

The apparent volume of distribution of ethanol in the presence of calcium carbimide is 0.64 l/kg compared to 0.68 l/kg when administered in the absence of any drug.[3] All the reports studying the pharmacokinetic profile of ethanol after administered with calcium carbimide agree with a reduced volume of distribution driven by the effect of calcium carbimide.

Protein binding

The metabolism and elimination of calcium carbimide is very rapid, which makes it unlikely to bind to plasma proteins.

Metabolism

The activity of calcium carbimide requires an initial metabolic transformation to the bioactive form. The transformation requires the activity of catalase and the presence of H2O2 for the formation of N-hydroxycyanamide. This bioactive compound will later spontaneosly decompose into cyanide and nitroxyl. The nitroxyl component will be the direct inhibitor of the aldehyde dehydrogenase.[7]

Route of elimination

The rate of elimination of ethanol when calcium carbimide is administered tends to be around 5% slower than the one presented in patients without any treatment. In the presence of calcium carbimide, the blood levels of acetaldehyde were increased from 1.7-6.5 microM to 40-242 microM.[4]

Half life

Calcium carbimide is metabolized and eliminated very rapidly so the apparent half-life is of 92.4 minutes.[9]

Clearance

After intravenous administration of calcium carbimide, there was a two compartment pharmacokinetic profile with a total plasma clearance rate ranging from 0.0123 to 0.0190 L/kg min.[5]

Toxicity

Calcium carbimide presents antithyroid activity which can be of clinical relevance in patients with preexisting hypothyroid disease. It can also present some other minor side effects as fatigue, skin rash, ear ringing, mild depression, increased urination and impotence.[9]

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

Interactions

Drug Interactions
DrugInteraction
CinnamaldehydeThe risk or severity of adverse effects can be increased when Calcium carbimide is combined with Cinnamaldehyde.
DisulfiramThe risk or severity of adverse effects can be increased when Calcium carbimide is combined with Disulfiram.
EthanolThe risk or severity of adverse effects can be increased when Calcium carbimide is combined with Ethanol.
MalonaldehydeThe risk or severity of adverse effects can be increased when Calcium carbimide is combined with Malonaldehyde.
P-HydroxybenzaldehydeThe risk or severity of adverse effects can be increased when Calcium carbimide is combined with P-Hydroxybenzaldehyde.
PhenylacetaldehydeThe risk or severity of adverse effects can be increased when Calcium carbimide is combined with Phenylacetaldehyde.
PhosphonoacetaldehydeThe risk or severity of adverse effects can be increased when Calcium carbimide is combined with Phosphonoacetaldehyde.
TucaresolThe risk or severity of adverse effects can be increased when Calcium carbimide is combined with Tucaresol.
Food Interactions
Not Available

References

General References
  1. ARMSTRONG JD, KERR HT: A new protective drug in the treatment of alcoholism; preliminary clinical trial of citrated calcium carbimide. Can Med Assoc J. 1956 May 15;74(10):795-7. [PubMed:13316670]
  2. Mukasa H, Arikawa K: A new double medication method for the treatment of alcoholism using the drug cyanamide. Kurume Med J. 1968;15(3):137-43. [PubMed:4888318]
  3. Jones AW, Neiman J, Hillbom M: Concentration-time profiles of ethanol and acetaldehyde in human volunteers treated with the alcohol-sensitizing drug, calcium carbimide. Br J Clin Pharmacol. 1988 Feb;25(2):213-21. [PubMed:3358883]
  4. Jones AW, Neiman J, Hillbom M: Elimination kinetics of ethanol and acetaldehyde in healthy men during the calcium carbimide-alcohol flush reaction. Alcohol Alcohol Suppl. 1987;1:213-7. [PubMed:3426682]
  5. Colom H, Prunonosa J, Peraire C, Domenech J, Azcona O, Torrent J, Obach R: Absolute bioavailability and absorption profile of cyanamide in man. J Pharmacokinet Biopharm. 1999 Aug;27(4):421-36. [PubMed:10826131]
  6. Barh D., Dhawan D. and Ganguly NK. (2013). Omics for personalized medicine. Springer.
  7. Vasiliou V. and Petersen D. (2010). Comprehensive toxicology (2nd ed., pp. 131-147). Elsevier.
  8. Health Canada [Link]
  9. Encyclopedia [Link]
External Links
KEGG Drug
D03288
KEGG Compound
C19113
PubChem Compound
56955933
PubChem Substance
310265033
ChemSpider
21106503
ChEBI
64301
ChEMBL
CHEMBL3301667
Wikipedia
Calcium_cyanamide
ATC Codes
N07BB02 — Calcium carbimide

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral50 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)1300ºCPerry D. Handbook of Inorganic compounds. Second edition. (2011)
boiling point (°C)Sublimes 1150-1200ºCPerry D. Handbook of Inorganic compounds. Second edition. (2011)
water solubilitySoluble Perry D. Handbook of Inorganic compounds. Second edition. (2011)
Predicted Properties
PropertyValueSource
Water Solubility8.71 mg/mLALOGPS
logP0.04ALOGPS
logP-0.25ChemAxon
logS-1.2ALOGPS
pKa (Strongest Basic)3.56ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area34.14 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity6.38 m3·mol-1ChemAxon
Polarizability2.91 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as carbodiimides. These are organic compounds containing a functional group consisting of the formula RN=C=NR.
Kingdom
Organic compounds
Super Class
Organic nitrogen compounds
Class
Organonitrogen compounds
Sub Class
Carbodiimides
Direct Parent
Carbodiimides
Alternative Parents
Organic calcium salts / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Organic calcium salt / Carbodiimide / Organopnictogen compound / Hydrocarbon derivative / Organic salt / Aliphatic acyclic compound
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
calcium salt (CHEBI:64301)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
Inhibitor
General Function
Aldehyde dehydrogenase [nad(p)+] activity
Specific Function
Not Available
Gene Name
ALDH3B2
Uniprot ID
P48448
Uniprot Name
Aldehyde dehydrogenase family 3 member B2
Molecular Weight
42634.6 Da
References
  1. Encyclopedia [Link]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Receptor binding
Specific Function
Occurs in almost all aerobically respiring organisms and serves to protect cells from the toxic effects of hydrogen peroxide. Promotes growth of cells including T-cells, B-cells, myeloid leukemia c...
Gene Name
CAT
Uniprot ID
P04040
Uniprot Name
Catalase
Molecular Weight
59755.82 Da
References
  1. Vasiliou V. and Petersen D. (2010). Comprehensive toxicology (2nd ed.). Elsevier.

Drug created on September 22, 2015 11:26 / Updated on November 02, 2018 08:58