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PubMed2005

Drug-induced hypersensitivity syndrome due to cyanamide associated with multiple reactivation of human herpesviruses.

Drug-induced hypersensitivity syndrome (DIHS), characterized by serious adverse systemic reactions in addition to skin rash, has unknown pathogenesis. Its association with human herpesvirus (HHV), mainly HHV-6, has been reported recently. A 46-year-old Japanese man is described in whom a generalized eruption developed about 1 month after taking cyanamide, a drug for alcoholism. This was associated with the following manifestations: high fever, lymphadenopathy, facial edema, marked leukocytosis with eosinophilia and atypical lymphocytes, lymphocytopenia, liver and renal dysfunction, and low IgG level. He was treated with 8 mg betamethasone daily and his condition improved, but he needed low-dose corticosteroid for almost 1 year because of several episodes of recurrence. HHV-6, HHV-7, herpes simplex virus (HSV), and cytomegalovirus (CMV) specific IgG titers showed more than a four-fold rise sequentially. Significant numbers of copies of HHV-6 and HHV-7 DNA were detected in the peripheral white blood cells by real-time polymerase chain reaction (PCR). HHV-6 and CMV DNA were detected in the serum by nested PCR. A patch test for cyanamide was positive. The diagnosis of DIHS due to cyanamide, which has never been reported as a causal drug of DIHS, accompanied by reactivation of not only HHV-6, but also HHV-7, CMV, and HSV, was made. Disturbance of the immune system was suggested by the persistent low level of IgG, and consecutive viral reactivation may have participated in the prolonged course in this case.

Agammaglobulinemia↗
PubMed1985

Endogenous acetaldehyde in rats. Effects of exogenous ethanol, pyrazole, cyanamide and disulfiram.

Male Long-Evans rats consumed the alcohol and aldehyde dehydrogenase inhibitors pyrazole, cyanamide or disulfiram, for 6 days. No endogenous blood acetaldehyde could be detected in controls and pyrazole treated rats, endogenous blood concentrations up to 2-5 nmoles/ml were, however, measured in the cyanamide and disulfiram-treated animals. Other rats received daily ethanol gastric intubations in addition to the consumption of the inhibitors. Little or no acetaldehyde was detected in the controls and pyrazole treated animals during acute ethanol intoxication or on the subsequent days. High blood levels (200-500 nmoles/ml) were observed in the rats consuming cyanamide and disulfiram, and concentrations up to 10-12 nmoles/ml were still found on the following day after all the ethanol had been eliminated. This acetaldehyde and the endogenous acetaldehyde could only be observed with the hemolyzation method in which blood hemolyzates were directly heated prior to headspace GC analysis; none was detected if blood proteins were first precipitated and removed with perchloric acid. It is suggested that aldehyde dehydrogenase inhibitors elevate endogenous concentrations of bound acetaldehyde and that exogenous ethanol increases this form of acetaldehyde.

Acetaldehyde↗
PubMed1994

Involvement of nitroxyl (HNO) in the cyanamide-induced vasorelaxation of rabbit aorta.

Relaxation of precontracted rabbit aortic rings in vitro by cyanamide, a clinically used alcohol deterrent drug, required catalase and H2O2, suggesting that a bioactivation mechanism was involved. Since the oxidation of cyanamide by catalase/H2O2 had been shown previously to lead to nitroxyl (HNO) generation via the intermediate N-hydroxycyanamide, and aortic ring relaxation was inhibited by the catalase inhibitor, 3-aminotriazole, HNO appears to be responsible for the vasorelaxation mediated by cyanamide. This was further supported by the observation that N,O-dibenzoyl-N-hydroxycyanamide (DBHC), a derivative of N-hydroxycyanamide that releases HNO in the absence of catalase/H2O2, was a potent vasorelaxant, with an EC50 of 4.2 +/- 1.3 x 10(-6) M.

Animals↗
PubMed1991

Liquid chromatographic method for the determination of calcium cyanamide using pre-column derivatization.

A specific and stability-indicating high-performance liquid chromatographic (HPLC) method has been developed for the analysis of calcium cyanamide in bulk material and dosage form. Calcium cyanamide in samples was converted into dansyl cyanamide. A muBondapak C18 column was employed for HPLC with 0.01 M sodium phosphate (pH 6.3)-acetonitrile (75:25, v/v) as the mobile phase. The proposed HPLC method was validated for linearity, specificity, accuracy and reproducibility.

Chromatography, High Pressure Liquid↗
PubMed1984

An evaluation of the mutagenic potential of cyanamide using the micronucleus test.

The bone-marrow micronucleus assay was used in mice to evaluate the mutagenic potential of cyanamide administered per os at doses of 10, 49 and 247 mg/kg. Bone-marrow smears were examined to find the incidence of micronucleated cells in 1000 polychromatic erythrocytes (PCE) and 1000 normochromatic erythrocytes ( NCE ). The ratio of NCE /PCE was also scored. No increase in the incidence of micronucleated polychromatic erythrocytes and no difference in the ratio NCE /PCE for the groups treated with cyanamide (10 and 49 mg/kg) were observed. The group treated with the highest dose of cyanamide (247 mg/kg) did, however, show an NCE /PCE ratio lower than the control group (p less than 0.05).

Animals↗
PubMed1979

Synthesis of protein, nucleosides and other organic compounds from cyanamide and potassium nitrite under possible primitive earth conditions.

The mixing of cyanamide and KNO2 produced changes from white solids to yellow liquid and then to orange solid. The gases cyanogen and ammonia were formed. No external energy was used. The reactions were carried out with a small amount of O2. The presence of proteins in the reaction product formed 13 months after the mixing was indicated by the positive reactions of the cyanamide-KNO2 reaction product with ninhydrin, microbiuret, and Folin reagent; the ultraviolet absorption at about 280 nm; the yield of 24% of 15 amino acids; and molecular weight measurements of more than 160,000. The presence of nucleosides, nucleic acid bases, hydrocarbons, and organic esters in the reaction product formed 2 months after the mixing was indicated by ultraviolet absorption at about 260 nm, and the results of ligand-exchange chromatography, paper chromatography, infrared analysis, mass spectral analysis, and NMR spectroscopy. Possible cyanamide-mediated dehydration reactions and mechanisms are discussed.

Amino Acids↗
PubMed1986

Inhibition of CO2 production from aminopyrine or methanol by cyanamide or crotonaldehyde and the role of mitochondrial aldehyde dehydrogenase in formaldehyde oxidation.

Previous results have shown that cyanamide or crotonaldehyde are effective inhibitors of the oxidation of formaldehyde by the low-Km mitochondrial aldehyde dehydrogenase, but do not affect the activity of the glutathione-dependent formaldehyde dehydrogenase. These compounds were used to evaluate the enzyme pathways responsible for the oxidation of formaldehyde generated during the metabolism of aminopyrine or methanol by isolated hepatocytes. Both cyanamide and crotonaldehyde inhibited the production of 14CO2 from 14C-labeled aminopyrine by 30-40%. These agents caused an accumulation of formaldehyde which was identical to the loss in CO2 production, indicating that the inhibition of CO2 production reflected an inhibition of formaldehyde oxidation. The oxidation of methanol was stimulated by the addition of glyoxylic acid, which increases the rate of H2O2 generation. Crotonaldehyde inhibited CO2 production from methanol, but caused a corresponding increase in formaldehyde accumulation. The partial sensitivity of CO2 production to inhibition by cyanamide or crotonaldehyde suggests that both the mitochondrial aldehyde dehydrogenase and formaldehyde dehydrogenase contribute towards the metabolism of formaldehyde which is generated from mixed-function oxidase activity or from methanol, just as both enzyme systems contribute towards the metabolism of exogenously added formaldehyde.

Aldehyde Dehydrogenase↗
PubMedDate not supplied

Use of cyanamide to determine localization of acetaldehyde metabolism in rat liver.

Various techniques have been employed previously to show that acetaldehyde is primarily oxidized in the mitochondrial matrix of rat liver. In this study, a new approach was tested. Mitochondrial low-Km aldehyde dehydrogenase (ALDH) was partially inactivated and the effect on acetaldehyde oxidation measured. Cyanamide was chosen as the ALDH inhibitor. An enzymatic activation of cyanamide, probably by catalase, was necessary for the drug to inhibit ALDH activity. The level of remaining ALDH activity after cyanamide treatment was correlated with the ability of either rat liver mitochondria or liver slices to oxidize acetaldehyde. Any inhibition of ALDH resulted in a decreased rate of acetaldehyde oxidation, indicating that there is no excess of ALDH in the cell above what is needed to oxidize acetaldehyde. Approximately 15% of the acetaldehyde disappearance at 200 microM was catalyzed by high-Km ALDH, and nearly 30% of the acetaldehyde was lost through binding to cytosolic proteins.

Acetaldehyde↗
PubMed2002

Role of catalase in the smooth muscle relaxant actions of sodium azide and cyanamide.

The aim of this study was to determine the role of catalase in the smooth muscle relaxant actions of sodium azide and cyanamide. The effects of 3-amino-1,2,4-triazole suggested a role for this enzyme in the relaxant actions of sodium azide on rat aorta and bovine retractor penis muscle and cyanamide on rat aorta. Moreover, results obtained using a difference spectrophotometric assay based upon the oxidation of haemoglobin were consistent with the catalase-dependent oxidation of sodium azide to nitric oxide (NO) and of cyanamide to nitroxyl anion. Surprisingly, however, no free nitric oxide or nitroxyl was detected in solution using a sensitive electrode. This anomaly might be explained if the stable complexes of catalase with nitric oxide or nitroxyl do not release their respective ligand except to sites of high affinity, such as the haemoglobin employed in the difference spectrophotometric assay, or indeed, the soluble guanylate cyclase within the smooth muscle.

Amitrole↗
PubMed2000

Hypothalamo-pituitary-adrenal axis activation by administration of cyanamide: a potent inhibitor of aldehyde dehydrogenase.

In this report, we investigated the effects of cyanamide (a potent inhibitor of aldehyde dehydrogenase (ALDH: EC 1.2.1.3)) on hypothalamo-pituitary adrenal (HPA)-axis using in situ hybridization histochemistry and radioimmunoassay. Cyanamide administration resulted in a dose-dependent increase in plasma corticosterone concentrations, significant increases in not only corticotrophin releasing factor (CRF) mRNA, but also arginine vasopressin (AVP) mRNA in the paraventricular nucleus (PVN) and proopiomelanocortin (POMC) mRNA in the anterior pituitary. These results suggest that cyanamide is able to activate the HPA axis at all levels of the axis.

Aldehyde Dehydrogenase↗
PubMed1998

Drinking patterns in genetic low-alcohol-drinking (LAD) rats after systemic cyanamide and cerebral injections of THP or 6-OHDA.

A key question related to the role of acetaldehyde and aldehyde adducts in alcoholism concerns their relationship to the genetic mechanisms underlying drinking. Experimentally, the low-alcohol-drinking (LAD) rat represents a standard rodent model having a strong aversion to alcohol. In these experiments, preferences for water vs. alcohol, offered in concentrations from 3% to 30%, were determined over 10 days in adult LAD rats (N = 6 per group). Then a saline vehicle or either 10 or 20 mg/kg of the aldehyde dehydrogenase (AIDH) inhibitor, cyanamide, was injected s.c. twice daily for 3 days. Secondly, either 0.5 or 1.0 microg of tetrahydropapaveroline (THP) was infused i.c.v. twice daily for 3 days in LAD rats (N = 8) and, as a genetic control, THP also was infused identically in Sprague-Dawley (SD) rats (N = 8). The results showed that the lower and higher doses of cyanamide augmented alcohol intakes in 33% and 50% of the LAD rats, respectively, with the patterns of drinking resembling that of genetic high-alcohol-drinking HAD or P rats. Although i.c.v. infusions of THP had little effect on alcohol preference of LAD rats, alcohol drinking was enhanced significantly in the SD rats. In a supplementary study, 200 microg of 6-hydroxydopamine (6-OHDA) also was infused i.c.v. in LAD rats (N = 7) on two consecutive days; no change occurred in the characteristic aversion to alcohol. These findings suggest that in certain individuals, a perturbation in the synthesis of AIDH can modify the genetically based aversion to alcohol, thus precipitating the liability for alcoholism. In that neither THP nor 6-OHDA lesioning exerted any effect on the genetic nondrinking LAD animal suggests that an unknown endogenous factor in the brain must underlie the cyanamide-induced shift to alcohol preference. We conclude that the genetic elements that normally prevent the progression to addictive drinking in most individuals appear to be invariant and irreversible.

Alcohol Drinking↗
PubMed1997

Novel prodrugs of cyanamide that inhibit aldehyde dehydrogenase in vivo.

S-Methylisothiourea (4), when administered to rats followed by a subsequent dose of ethanol, gave rise to a 119-fold increase in ethanol-derived blood acetaldehyde (AcH) levels-a consequence of the inhibition of hepatic aldehyde dehydrogenase (A1DH)-when compared to control animals not receiving 4. The corresponding O-methylisourea was totally inactive under the same conditions, suggesting that differential metabolism may be a factor in this dramatic difference between the pharmacological effects of O-methylisourea and 4 in vivo. The S-n-butyl- and S-isobutylisothioureas (8 and 9, respectively) at doses equimolar to that of 4 were nearly twice as effective in raising ethanol-derived blood AcH, while S-allylisothiourea (10) was slightly less active. However, blood ethanol levels of all experimental groups were indistinguishable from controls. Pretreatment of the animals with 1-benzylimidazole, a known inhibitor of the hepatic mixed function oxidases, followed sequentially by either 8, 9, or 10 plus ethanol, reduced blood AcH levels by 66-88%, suggesting that the latter compounds were being oxidatively metabolized to a common product that led to the inhibition of AcH metabolism. In support of this, when 8 was incubated in vitro with rat liver microsomes coupled to catalase and yeast A1DH, the requirement for microsomal activation for the inhibition of A1DH activity was clearly indicated. We suggest that S-oxidation is involved and that the S-oxides produced in vivo inhibited A1DH directly, or spontaneously released cyanamide, an inhibitor of A1DH. Indeed, incubation of 8 with rat liver microsomes and NADPH gave rise to cyanamide as metabolite, identified as its dansylated derivative. Cyanamide formation was minimal in the absence of coenzyme. Extending the side chain was detrimental, since S-benzylisothiourea (11) and S-n-hexadecylisothiourea (12) were toxic, the latter producing extensive necrosis of the liver and kidneys when administered to rats.

Acetaldehyde↗
PubMed1991

Isolation and properties of a nitrile hydratase from the soil fungus Myrothecium verrucaria that is highly specific for the fertilizer cyanamide and cloning of its gene.

A protein was purified from crude extracts of the soil fungus Myrothecium verrucaria by gel filtration and hydrophobic chromatography to homogeneity; this protein catalyzed the stoichiometric hydration of the fertilizer cyanamide to urea with high substrate specificity. This cyanamide hydratase (urea hydro-lyase; EC 4.2.1.69) contained zinc and consisted of six identical subunits with Mr = 27,700. It was partially sequenced. The protein was detectable only when the fungus was grown on cyanamide as the sole nitrogen source. Genomic DNA from the fungus was cloned, and the gene encoding the enzyme was mapped with an oligonucleotide probe derived from the amino acid sequence within a 25,800-base-pair DNA region. The subunit of the enzyme is encoded by a 795-base-pair DNA sequence containing a 63-base-pair intron. A cDNA clone containing the intronless gene with an open reading frame encoding a sequence of 244 amino acids expressed the enzyme in active form in Escherichia coli with excellent yield.

Amino Acid Sequence↗
PubMed1983

Cyanamide-induced liver injury. A predictable lesion.

Cyanamide, a drug frequently used for aversion therapy in chronic alcoholism, induces a liver-cell lesion consisting of cytoplasmic inclusion bodies, structurally similar to those of Lafora. In order to know how frequently the lesion is associated with the intake of this drug, a prospective study was carried out. A biopsy was performed in ten chronic alcoholic patients who had been treated with Cyanamide. Inclusion bodies were present in all patients (7 cases) whose biopsy was taken when they were on Cyanamide and in two other patients whose biopsies were taken 3 and 7 years after discontinuation of the treatment. Inclusion bodies were absent in one case who was treated for a short time and with a small dose and whose biopsy was performed 3 years after cessation of treatment. On the basis of these findings, the lesion may be considered to be predictable. The absence of inclusions in one patient may be explained by their disappearance after cessation of treatment.

Adult↗
PubMed1978

A comparative study on the effects of disulfiram, cyanamide and 1-aminocyclopropanol on the acetaldehyde metabolism in rats.

1-aminocyclopropanol (ACP) is a potent inhibitor of aldehyde dehydrogenase (ALDH) in vivo and in vitro. Like cyanamide it has a rapid onset of action in vivo with the highest inhibition occurring after 2--24 hrs. and a long duration of action like disulfiram with measurable inhibition after 144 hrs. All the three inhibitors decreased the activity of the mitochondrial low-Km ALDH strongly in vivo, however, in markedly different doses. Cyanamide inhibited the high-Km ALDH only in vivo, whereas in vitro, the hihgh-Km ALDH was unaffected by cyanamide but significantly inhibited by disulfiram and ACP. The inhibition produced by the inhibitors appeared to be irreversible. Acetaldehyde protected the low-Km enzyme at different extents depending on the inhibitor used. The inhibition of ALDH in intoxicated and control rats and its relation to acetaldehyde oxidation and the disulfiram-ethanol reaction are discussed.

Acetaldehyde↗
PubMed1985

Lack of hepatotoxicity after long-term administration of cyanamide in rats: a histological and biochemical study.

An experimental long-term hepatotoxicity study of cyanamide in Sprague-Dawley and Wistar rats has been carried out. After six months oral administration of cyanamide (2.7 and 25 mg/kg/day) no significant histological changes have been observed in the liver. Similarly, a one year intraperitoneal administration of 8 and 16 mg/kg/day has not induced any hepatic change. Specifically, no inclusion bodies in any cyanamide treated rat have been detected. Moreover, hepatic biochemical parameters have shown no significant impairment of hepatic function at doses used in human therapy (0.5-1 mg/kg).

Animals↗
PubMed1995

Changes in serotonin metabolism during treatment with the aldehyde dehydrogenase inhibitors disulfiram and cyanamide.

The effect of the aldehyde dehydrogenase inhibitors disulfiram (Antabuse) and cyanamide (calcium carbimide, Dipsan) on the metabolism of serotonin measured as relative amounts of the metabolites 5-hydroxyindole-3-acetic acid and 5-hydroxytryptophol in urine were studied in alcoholic patients. Sixteen out of 23 patients receiving drug therapy showed elevated excretion of 5-hydroxytryptophol. However, there was a marked, 15-fold, variability in 5-hydroxytryptophol excretion rate between patients. A high degree of variability was also seen in another group of patients studied before and after introduction of drug therapy. When patients were followed during the dose interval, a time-dependent response after each single dose could be observed. The disulfiram response lasted over the course of several days whereas the response to cyanamide lasted for less than 12 hr. It is concluded that treatment with disulfiram and cyanamide affects serotonin metabolism leading to increased production of 5-hydroxytryptophol, but there is a marked inter-individual variability in degree of response.

Adult↗
PubMed1987

Effect of the aldehyde dehydrogenase inhibitor, cyanamide, on the ex vivo sensitivity of murine multipotent and committed hematopoietic progenitor cells to mafosfamide (ASTA Z 7557).

The ex vivo sensitivity of murine multipotent (CFU-GEMM) and committed (CFU-Mk, CFU-GM, BFU-E and CFU-E) hematopoietic progenitor cells to mafosfamide was quantified with and without concurrent exposure to cyanamide, an inhibitor of aldehyde dehydrogenase activity. In the absence of cyanamide, CFU-GEMM, CFU-Mk and CFU-GM were approximately equisensitive to mafosfamide while the erythroid progenitors were more sensitive to the drug. Cyanamide potentiated the cytotoxicity of mafosfamide toward CFU-GEMM and CFU-Mk, but not toward CFU-GM, BFU-E and CFU-E. Cellular aldehyde dehydrogenases are known to catalyze the oxidation of 4-hydroxycyclophosphamide/aldophosphamide, the major intermediate in cyclophosphamide and mafosfamide activation, to the relatively nontoxic acid, carboxyphosphamide. Thus, our findings indicate that 1) murine CFU-GEMM contain the relevant aldehyde dehydrogenase activity, and 2) the relevant aldehyde dehydrogenase activity is retained upon differentiation to progenitors committed to the megakaryocytoid lineage, but lost upon differentiation to progenitors committed to the granulocytoid/monocytoid and erythroid lineages. The relative insensitivity of CFU-GM to mafosfamide is apparently due to a cellular determinant that influences their sensitivity to all cross-linking agents since CFU-GM were found to be relatively insensitive to non-oxazaphosphorine cross-linking agents as well.

Animals↗