Calcium Carbimide Research Articles

Guideline No. 405: Screening and Counselling for Alcohol Consumption During Pregnancy.

To establish national standards of care for screening and counselling pregnant women and women of child-bearing age about alcohol consumption and possible alcohol use disorder based on current best evidence. Health care providers who care for pregnant women and women of child-bearing age. Pregnant women and women of child-bearing age and their families. Medline, EMBASE, and CENTRAL databases were searched for "alcohol use and pregnancy." The results were filtered for a publication date between 2010 and September 2018. The search terms were developed using Medical Subject Headings terms and keywords, including pre-pregnancy, pregnant, breastfeeding, lactation, female, women, preconception care, prenatal care, fetal alcohol spectrum disorder, prenatal alcohol exposure, drinking behavior, alcohol abstinence, alcohol drinking, binge drinking, alcohol-related disorders, alcoholism, alcohol consumption, alcohol abuse, benzodiazepines, disulfiram, naltrexane, acamprosate, ondansetron, topiramate, cyanamide, calcium carbimide, alcohol deterrents, disease management, detoxification, Alcoholics Anonymous, alcohol counselling, harm reduction, pre-pregnancy care, prenatal care, incidence, prevalence, epidemiological monitoring, and brief intervention. Evidence was included from clinical trials, observational studies, reviews, systematic reviews and meta-analyses, guidelines, and conference consensus. The content and recommendations in this guideline were drafted and agreed upon by the authors. The Board of Directors of the Society of Obstetricians and Gynaecologists of Canada approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology framework. Implementation of the recommendations in these guidelines using validated screening tools and brief intervention approaches may increase obstetrical care provider recognition of alcohol consumption and problematic alcohol use among women of child-bearing age and those who are pregnant. It is anticipated that health care providers will become confident and competent in managing and supporting these women so they can achieve optimal health and pregnancy outcomes. RECOMMENDATIONS (GRADE RATINGS IN PARENTHESES).

Alcoholism – the Worst Addiction

Introduction: The most common substance of abuse/dependence in patients presenting for treatment in western countries is alcohol. Ethyl or ethanol which is also called medicinal is used as an official drug compendium. It is also administered as an antidote in methanol poisoning. However, regular consumption of high amounts of alcoholic drinks induces dependence and addiction leading to alcoholism. Definition: Alcoholism is a broad term for advanced chronic ethanol abuse. It is, in fact, a compulsive and uncontrolled consumption of beverages usually to the detriment of the drinker's health, personal relationships, and social standing. World Health Organization expert committee discouraged the use of in medicine and recommended a preferred term of alcohol dependence syndrome. However, alcoholism is still used more frequently and the people suffering from alcoholism are called alcoholics. Clinical Manifestations and Complications: Women are more sensitive to ethanol than men. Long-term complications of dependence also develop more rapidly in women than in men with higher mortality. Genes play an important role in alcoholism and its complications. Brain, heart and liver are the main affected organs in alcoholism. Physical symptoms or diseases produced by addiction include cirrhosis of the liver, pancreatitis, epilepsy, polyneurpopathy, dementia, peptic ulcer, malabsorption, cardiovascular complications and even cancer. Death is mainly due to cardiovascular complications. Management: All factors which encourage an alcoholic to continue drinking must be considered to successfully prevent a relapse. Detoxification alone does not actually treat alcoholism. It is thus necessary to follow-up detoxification with an appropriate treatment program to reduce the risk of relapse. Medications (benzodiazepines, acamprosate, calcium carbimide, disulfiram and naltrexone) have been used for treatment of alcoholism without great success. Even various forms of psychotherapy, social supports with medications have had limited success. Conclusion: The most common and the worst substance of abuse is ethanol which leads to alcoholism with many social and health problems. Therefore, prevention of abuse is the most advisable.

Problem drinking in relation to treatment outcome among opiate addicts in methadone maintenance treatment

This study analyzed indicators of alcohol-related problems in opiate addicts before, during, and after leaving methadone maintenance treatment (MMT), in relation to illicit drug use and retention in treatment. The study was based on 204 patients, admitted to MMT for the first time between 1 January 1995 and 31 July 2000, and followed until 31 December 2000. Three measures were used to indicate alcohol use and alcohol-related problems; records of hospital care with an alcohol-related diagnosis, any treatment with alcohol-sensitizing drugs (disulfiram or calcium carbimide) during MMT, and results of the 5-hydroxytryptophol to 5-hydroxyindoleacetic acid ratio (5HTOL/5HIAA) in urine, a sensitive biomarker for recent drinking. Use of illicit drugs was determined by routine urine drug testing. About one third of the patients (n = 69) had a lifetime prevalence of hospital treatment for an alcohol-related diagnosis, 45 of whom had been hospitalized (mean 4.2 stays) prior to the start of MMT. There was a significant association (p<0.05) between the number of alcohol-related diagnoses prior to treatment and a positive 5HTOL/5HIAA test during MMT. The alcohol indicators first became positive on average 1.6 years after admission to treatment, compared with after about 4 months for illicit drugs. Use of cannabis or benzodiazepines was significantly associated with alcohol use. Female methadone patients with indications of alcohol-related problems relapsed more often into illicit drug use than did women without such indications (3.9 vs. 2.5 relapse periods/year; p<0.005), whereas no significant association was found for men. The results of the present study indicate that drinking problems among patients undergoing MMT is associated with an increased risk of relapse into illicit drug use and with discharge from treatment. Concurrent treatment of alcohol-related problems, including systematic monitoring of alcohol use, therefore should be recommended to reduce the risk for relapse into illicit drug use and improve overall treatment outcome in MMT.

Adverse hepatic reactions associated with calcium carbimide and disulfiram therapy: Is there still a role for these drugs

Disulfiram and calcium carbimide are two alcohol deterrants widely used in alcoholism treatment, however, there exist great concerns over their safety. Reports on hepatotoxicity, mainly related to disulfiram therapy, have been published. The hepatotoxic potential of calcium carbimide is less well characterized. Here, we describe four cases of liver damage related to this therapeutic group that were submitted to a Registry of hepatotoxicity and point out the limitations that we face when prescribing these compounds. A reassessment of the role of these compounds in the management of alcohol dependence is clearly needed.

Allergic Contact Dermatitis from Cyanamide

Cyanamide (carbimide or calcium carbimide) has been used to treat chronic alcoholism for more than 45 years. The skin reactions provoked by this medication are very rare and are generally associated with systemic reactions after ingestion of the product. However, allergic contact dermatitis has also been detected on persons who prepare cyanamide for administration to patients. We present a case of work-related allergic contact dermatitis from cyanamide that was confirmed by patch testing.

COMBINED CALCIUM CARBIMIDE AND ETHANOL TREATMENT INDUCES HIGH BLOOD ACETALDEHYDE LEVELS, MYOCARDIAL APOPTOSIS AND ALTERED EXPRESSION OF APOPTOSIS-REGULATING GENES IN RAT

The effects of ethanol and ethanol-derived acetaldehyde on rat myocardial apoptosis and expression of genes involved in the regulation of apoptosis and cell cycle arrest were studied. Combined ethanol and calcium carbimide treatment for 2, 5 or 8 days (E + CC) markedly increased blood acetaldehyde levels. Cytosolic DNA fragmentation was quantified in the 5-day treatment group. Increased amount of DNA-fragmentation, reflecting increased apoptosis, was evident in the E + CC group (23% increase compared to controls). mRNA levels of genes regulating apoptosis were measured by using quantitative PCR in the 2- and 8-day treatment groups. In the 2-day treatment group, p21 gene expression was increased by 25% and bax/bcl-2 mRNA ratio by 57% in E + CC, compared to the control, group. In the 8-day treatment group, p21 mRNA level was 24% lower, p53 mRNA level was 15% higher (P < 0.005), and bcl-2 mRNA level 36% higher in E + CC-treated, compared to the control, group. Interestingly, both ethanol and calcium carbimide treatments alone increased bax mRNA levels, as compared to the control group at 2 and 8 days. These results indicate that acetaldehyde might regulate the expression of apoptosis-linked genes and that apoptosis of myocardial cells may be involved in the development of alcoholic heart disease.

ROLE OF ACETALDEHYDE IN THE INDUCTION OF HEART LEFT VENTRICULAR ATRIAL NATRIURETIC PEPTIDE GENE EXPRESSION IN RATS

We studied the effects of ethanol and acetaldehyde on myocardial gene expression of atrial natriuretic peptide (ANP) and growth of rats. Combined ethanol and calcium carbimide treatment increased blood-acetaldehyde levels and ANP mRNA levels by 40-60% in 2-8 day experiments, compared to the controls. The results suggest a role for acetaldehyde in the development of alcoholic heart dysfunction.

Comparison of urinary 5-hydroxytryptophol, breath ethanol, and self-report for detection of recent alcohol use during outpatient treatment: a study on methadone patients

This study compared urinary 5-hydroxytryptophol (5HTOL) with breath-ethanol testing as objective ways to disclose recent drinking by outpatients attending a methadone maintenance treatment clinic. Information about quantity and frequency of alcohol use was obtained by confidential self-reports. Random screening was performed on Mondays–Fridays in connection with routine clinic visits for methadone dosing. An observed urine sample for monitoring of illicit drug use and determination of 5HTOL, expressed as a ratio to 5-hydroxyindole-3-acetic acid (5HIAA), was obtained from 202 patients (59 women and 143 men), 16 of whom refused to complete the self-report and/or do a breath-ethanol test. Patients taking disulfiram or calcium carbimide for alcohol detoxification were excluded. Among the 177 subjects remaining, 47 (26.6%) reported intake of any alcohol on the previous day (range, 10–230 g ethanol; median, 40). Only four of those could be identified by a positive breath-test, while 17 showed a urinary 5HTOL/5HIAA ratio above the cutoff limit. Their alcohol consumption (median, 60 g) was significantly higher compared with those showing ratios within the reference interval (median, 35 g). The sensitivity of 5HTOL/5HIAA testing for detecting self-reported drinking in excess of 50 g ethanol was 77%. An additional nine patients who claimed abstinence still showed abnormal 5HTOL/5HIAA ratios, and so did three of the patients who refused to do a breath-ethanol test and/or complete the self-report. Altogether, 59 of 190 methadone-maintained patients (31.1%) had been drinking any alcohol on the previous day (i.e. Sunday–Thursday) according to self-report and/or urinalysis data, 29 (49.2%) of whom were identified by the urinary 5HTOL/5HIAA ratio and only four (6.8%) by utilizing breathalyzer.

Urinary excretion of biomarkers for radical-induced damage in rats treated with NDMA or diquat and the effects of calcium carbimide co-administration

The urinary excretion of seven aldehydes, acetone, coproporphyrin III and 8-hydroxy-2′-deoxyguanosine (8-OH-dG) as non-invasive biomarkers of oxidative damage was measured in rats treated with diquat or N-nitrosodimethylamine (NDMA), two compounds causing hepatic damage by different mechanisms. Furthermore, the effect of co-administration of the aldehyde dehydrogenase inhibitor, calcium carbimide (CC) on the urinary excretion of the aldehydes was determined. Slight hepatotoxicity was found at the end of the experiment after treatment with NDMA (0.5, 4 and 8 mg/kg at t=0, 48 and 96 h, respectively) or diquat (6.8 and 13.6 mg/kg at t=0 and 48 h, respectively). In diquat treated rats slight nephrotoxicity was also found. Urinary excretion of aldehydes, acetone and coproporphyrin III remained largely unchanged in rats treated with NDMA. In the rats treated with diquat, the urinary excretion of several aldehydes was several-fold increased. An increase was also found in the urinary excretion of 8-OH-dG after the second dose of diquat. Treatment of rats with CC did not significantly influence the urinary excretion of aldehydes in control and NDMA rats. However, in rats treated with diquat, CC caused a potentiating effect on the excretion of acetaldehyde, hexanal and malondialdehyde (MDA), indicating that oxidation of aldehydes to carbonylic acids by aldehyde dehydrogenases (ALDHs) might be an important route of metabolism of aldehydes. In conclusion, increased urinary excretion of various aldehydes, acetone, coproporphyrin III and 8-OH-dG was observed after administration of diquat, probably reflecting oxidative damage induced by this compound. No such increases were found after NDMA administration, which is consistent with a different toxicity mechanism for NDMA. Therefore, excretion of aldehydes, acetone, coproporphyrin III and 8-OH-dG might be used as easily accessible urinary biomarkers of free radical damage.

Manipulation of Alcohol Drinking by Liver Transplantation

The procedure of liver transplantation in alcoholic liver disease raises the question whether it would be possible to regulate the recipient's future drinking by the choice of donor liver. To address this question, we conducted transplantations with rat lines selected for high (AA) and low (ANA) alcohol preference. AA recipients having alcohol experience before the operation remained heavy drinkers regardless of whether the graft came from an AA or ANA donor. However, in these AA recipients who started drinking only after the operation, differences emerged, with AA grafts creating heavy drinking and ANA donor livers resulting in very low drinking. An overall increase in the acetaldehyde levels was introduced by the ANA livers, thus reflecting the original line differences. Similarly, in subsequent experiments, it was observed that when the aldehyde dehydrogenase inhibitor calcium carbimide was introduced in different amounts to the diet, alcohol drinking was reduced more in animals not used to drinking. The magnitude of this effect, especially in situations with established heavy drinking, is of relevance in future contemplations about liver transplantations between humans with different aldehyde dehydrogenase genotypes.

HOW TO GET THE BEST OUT OF ANTABUSE

In the field of alcoholism treatment, disulfiram or calcium carbimide is one part of the treatment package and these deterrent drugs have to be combined with counselling and support to be effective. Besides adequate dosage and formulation of substance, the Antabuse tablet has to be taken under supervision by a therapist to strengthen compliance and motivate the patient to continue long-term treatment. Disulfiram metabolism is very complex and although new metabolites have been identified, clinically useful and practical determination of active substances for routine use has not been developed. In clinical situations, the disulfiram-ethanol reaction (DER) is still of major importance to demonstrate the effectiveness of the drug. This reaction was originally used to induce aversive conditioning. In the course of time, emphasis has focused more on sobriety and the DER has been used as a positive reinforcement during treatment. Antabuse therapy is remarkably free of serious side-effects. The latency time from start of treatment to the manifestation of adverse drug reactions differs according to organ. Hepatotoxicity has special interest in women with nickel dermatitis.

MEASURING AND REPORTING THE CONCENTRATION OF ACETALDEHYDE IN HUMAN BREATH

Most of the acetaldehyde generated during the metabolism of ethanol becomes tightly bound to endogenous molecules such as haemoglobin, amino acids and certain phospholipids. Free acetaldehyde passes the blood-brain barrier and traces of this toxic metabolite are excreted through the lungs and can be detected in the expired air. The blood/air partition coefficient of acetaldehyde at 34 degrees C, the average temperature of end-expired air, is about 190:1. Because of various problems associated with measuring acetaldehyde in blood samples, several research groups have instead investigated the analysis of acetaldehyde in breath which offers an indirect and alternative approach for clinical and research purposes. However, care is needed when interpreting the results of breath acetaldehyde measurements, because of the possibility of local formation from microflora inhabiting the upper airways and mouth. The concentration of acetaldehyde exhaled in breath after drinking alcohol demonstrates large inter-individual differences depending on various genetic (racial) and environmental factors. Moreover, acetaldehyde is an endogenous metabolite and even without drinking any alcohol the concentrations expelled in breath span from 0.2 to 0.6 nmol/l, with higher levels observed in smokers and abstinent alcoholics. Breath acetaldehyde concentration reached between 5 and 50 nmol/l in European subjects who drank a moderate dose of ethanol (0.4-0.8 g/kg), with the highest values seen in smokers. The concentration of breath acetaldehyde in Japanese subjects after drinking alcohol reached between 200 and 500 nmol/l at the peak. These much higher levels follow because a large proportion of Orientals (40-50%) inherit an inactive form of the low Km mitochondrial isoenzyme of aldehyde dehydrogenase (ALDH2). The highest concentration of breath acetaldehyde were seen in healthy Caucasians who drank a small dose of alcohol (0.25 g/kg) after taking the alcohol-sensitizing drug calcium carbimide, which blocks the action of ALDH isozymes. During the most intense acetaldehyde-flush reaction, breath acetaldehyde reached between 200 and 1300 nmol/l, but even these abnormally high concentrations did not interfere with the analysis of ethanol in breath by means of non-specific infrared analysers currently used in many countries for testing drinking drivers.

Decline in alcohol-related in-patient care and mortality in Stockholm County.

SummaryThere has been an impressive decline in in‐patient care for liver cirrhosis and pancreatitis for both sexes and in alcohol psychosis, alcoholism, alcohol intoxication (summed) for men since the end of the seventies in metropolitan Stockholm. The mortality in liver cirrhosis and pancreatitis has also dropped, while there has been a levelling‐off for alcohol psychosis, alcoholism and alcohol intoxication. The decrease of the 1978‐79 level to the 1983–84 level was between 20% and 40% for most parameters. This reduction is partly explained by a 20% fall in the sale of alcohol between 1976 and 1984. The decrease is also probably due to an increase in the sale and use of disulfiram and calcium carbimide (more than 70% since the end of the seventies). Alcohol policy, attitudes, in–patient care resources and social data are also discussed.

Effects of a small dose of ethanol and calcium carbimide-induced acetaldehyde intoxication on human platelet aggregation, associated thromboxane formation and urinary excretion of 2,3-dinor-6-keto prostaglandin F1 alpha.

We studied ADP-induced platelet aggregation, associated thromboxane B2 (TXB2) formation, urinary excretion of the prostacyclin metabolite 2,3-dinor-6-keto prostaglandin F1 alpha (2,3-dinor-6-keto PGF1 alpha) and formation of malondialdehyde in 10 healthy volunteers after ingestion of a small dose of ethanol (0.25 g per kg of body weight) and calcium carbimide (50 mg). Platelet aggregation in platelet-rich plasma (PRP) was suppressed (p less than 0.05) by ethanol, but no change occurred in platelet TXB2 formation. Ingestion of calcium carbimide caused significant elevations in blood acetaldehyde (p less than 0.001) and ethanol (p less than 0.05) levels, but acetaldehyde did not influence platelet aggregability or the aggregation-associated TXB2 formation. However, calcium carbimide per se significantly (p less than 0.05) elevated TXB2 formation. No effects were found on plasma malondialdehyde levels and urinary excretion of 2,3-dinor-6-keto PGF1 alpha. These observations indicate that a small dose of ethanol attenuates platelet aggregation without any significant effect on aggregation-associated TXB2 formation. By contrast, ingestion of calcium carbimide per se may enhance TXB2 formation.

Aldehyde dehydrogenase inhibitors as alcohol-sensitizing drugs: a pharmacological perspective

The aldehyde dehydrogenase inhibitors, disulfiram and calcium carbimide, have been available for at least three decades for adjunctive use in the treatment of alcoholism but have not received widespread acceptance. James F. Brien and Christopher W. Loomis discuss the role of alcohol-sensitizing drugs as pharmacological and psychological deterrents, in the treatment of alcoholism. They also examine the action of three new hepatic aldehyde dehydrogenase inhibitors, including methyltetrazolethiol, a selective inhibitor of hepatic low- K m aldehyde dehydrogenase with rapid onset, long duration of enzyme inhibition and high therapeutic index. They maintain that this type of inhibitor could represent a significant advance in the adjunctive pharmacotherapy of alcoholism.

A reinvestigation of the usefulness of breath analysis in the determination of blood acetaldehyde concentrations.

Human volunteers were given ethanol (0.4 g/kg) either intravenous or per os. They were also given ethanol (0.2 g/kg) intravenous 4 hr after receiving a dose of 50 mg citrated calcium carbimide, an aldehyde dehydrogenase inhibitor. During the first hour after starting the administration of ethanol, ethanol and acetaldehyde concentrations were determined in expired air, blood from the right atrium, arterial blood, and venous blood. In the absence of calcium carbimide treatment, the respective maximal blood acetaldehyde concentrations were (range): 6-30 microM (calculated from breath analysis using a blood:breath partition ratio of 190 for acetaldehyde); 0-3.5 microM (right atrium blood); and 0 microM (arterial and venous blood). After calcium carbimide treatment, the maximal blood acetaldehyde concentrations were 10-220 microM (calculated from concentrations in expired air), 38-280 microM (right atrium), 31-250 microM (arterial blood), and 7-186 microM (venous blood). With aldehyde dehydrogenase inhibition, a clear correlation existed between breath concentrations and blood concentrations. Without this inhibition, no such correlation was found. A clear arterio-venous difference was seen for acetaldehyde concentrations while they were artificially elevated by calcium carbimide. Our study suggests that factors other than the equilibration of acetaldehyde between alveolar air and pulmonary blood are of great importance in determining the concentration of acetaldehyde in expired air.

Effect of low-dose dopamine therapy on catecholamine values in cerebrospinal fluid in preterm neonates

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Decrease in calcium carbimide (calcium cyanamide)-induced inhibition of rat hepatic aldehyde dehydrogenases by multiple ethanol administration.

Ethanol (0.3 g/kg) was administered intravenously to adult, male rats at 3 h or at 1 and 3 h after gastric intubation of 7 mg/kg calcium carbimide (CC). For animals administered CC and two ethanol doses, blood ethanol concentration was similar for the two doses; however, blood acetaldehyde concentration was significantly less for the second ethanol dose compared with the first dose as determined by the area-under-curve data. Hepatic aldehyde dehydrogenase activity was determined over the 3.5- to 5-h interval after CC pretreatment. The inhibition of low Km and high Km aldehyde dehydrogenase activity in liver homogenate and in hepatic mitochondrial, cytosolic, and microsomal fractions was significantly less for rats administered CC followed by two ethanol doses compared with that for animals administered CC alone or CC followed by one ethanol dose. The data demonstrate that increased acetaldehyde concentration, produced during the CC - ethanol interaction, can augment the recovery of hepatic aldehyde dehydrogenase activity following CC pretreatment and indicate the existence of a displaceable enzyme inhibitor derived from CC.

Inhibition of hepatic aldehyde dehydrogenases in the rat by calcium carbimide (calcium cyanamide).

Oral administration of 7.0 mg/kg calcium carbimide (calcium cyanamide, CC) to the rat produced differential inhibition of hepatic aldehyde dehydrogenase (ALDH) isozymes, as indicated by the time-course profiles of enzyme activity. The low-Km mitochondrial ALDH was most susceptible to inhibition following CC administration, with complete inhibition occurring at 0.5 h and return to control activity at 96 h. The low-Km cytosolic and high-Km mitochondrial, cytosolic, and microsomal ALDH isozymes were inhibited to a lesser degree and (or) for a shorter duration compared with the mitochondrial low-Km enzyme. The time course of carbimide, the hydrolytic product of CC, was determined in plasma following oral administration of 7.0 mg/kg CC to the rat. The maximum plasma carbimide concentration (102 ng/mL) occurred at 1 h and the apparent elimination half-life in plasma was 1.5 h. Carbimide was not measurable in the liver during the 6.5 h time interval when carbimide was present in the plasma. There were negative, linear correlations between plasma carbimide concentration and hepatic low-Km mitochondrial, low-Km cytosolic, and high-Km microsomal ALDH activities. In vitro studies demonstrated that carbimide, at concentrations obtained in plasma following oral CC administration, produced only 19% inhibition of low-Km mitochondrial ALDH and no inhibition of low-Km cytosolic and high-Km microsomal ALDH isozymes. These data demonstrate that carbimide, itself, is not primarily responsible for hepatic ALDH inhibition in vivo following oral CC administration. It would appear that carbimide must undergo metabolic conversion in vivo to inhibit hepatic ALDH enzymes, which is supported by the observation of no measurable carbimide in the liver when ALDH was maximally inhibited following oral CC administration.

Gas-liquid chromatographic determination of salsolinol in the striatum of rat brain during the calcium carbimide--ethanol interaction.

An assay has been developed for the measurement of salsolinol in brain tissue that involves tissue homogenization in dilute hydrochloric acid, purification of the supernatant by cation-exchange chromatography, derivatization of the eluate with heptafluorobutyric anhydride, and analysis by gas-liquid chromatography with electron capture detection using p-tyramine as the internal standard. The lower limit of quantitative sensitivity, using aqueous standards, is 2.5 ng salsolinol per brain sample. This assay was used to study salsolinol formation in rat brain during the calcium carbimide-ethanol interaction. Rats were administered ethanol (1.0 g/kg) by oral intubation 3 h after intraperitoneal administration of calcium carbimide (7.0 mg/kg). Salsolinol was measured in the striatum over a 270-min period after ethanol administration. Salsolinol concentration appeared to be maximal (275 ng/g) at 90 min and then declined with an apparent elimination half-life of 39.8 min.