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At least 19 recordsLinked to original sources
PubMed1986

Induction of neoplastic lesions in the livers of C57BL x C3HF1 mice by chloral hydrate.

Chloral hydrate is a compound of environmental significance. The current investigation was undertaken to evaluate the carcinogenic effect of chloral hydrate, because it is present in drinking water and it is also used as a sedative. Fifteen-day-old C57BL x C3HF1 male mice were given a single dose of chloral hydrate in distilled water at two dose levels: group 1, 5 micrograms/g BW; group 2, 10 mu/g BW (20-25 mice per group). Thirty-five mice given distilled water only served as controls. Animals were sacrificed at 24 hr and thereafter at various intervals up to 92 weeks. The entire liver was fixed and examined histologically. Mice sacrificed between 48 and 92 weeks showed hepatic lesions ranging from hyperplastic to trabecular carcinomas. The tumor incidence in mice given 10 micrograms/g chloral hydrate (six of eight) was significantly higher (P less than 0.05) than the incidence in the controls (two of 19). These findings indicate that chloral hydrate should be more thoroughly studied for potential carcinogenicity.

Animals↗
PubMed1998

Studies on the mutagenic and carcinogenic potential of chloral hydrate.

Chloral hydrate (CAS 302-17-0), a widely used hypnotic and sedative agent, is reassessed on its mutagenic and carcinogenic potential on the evidence of recently unpublished and already published data. The compound was administered to rats in a carcinogenicity study in the drinking water for 124 (males) or 128 (females) weeks at dosages of 15, 45 and 135 mg/kg b.w./day. The administration of chloral hydrate produced no effects on survival, appearance and behaviour. At necropsy, there was no evidence of treatment-related changes, histopathology revealed an increased incidence of hepatocellular hypertrophy at the high dose level. There was no indication for a carcinogenic potential of chloral hydrate examined as life-time carcinogenicity study in rats. Further, in several in vitro and in vivo test systems no indication for a mutagenic potential was detected. Still unresolved is the end-point 'aneuploidy'. However, no validated in vivo test systems are available at the moment to confirm the positive results observed in vitro under certain experimental conditions and to assess the relevance of the in vitro findings for man, above all, since chloral hydrate is quickly metabolised to trichloroethanol in man. Based on the extensive range of data available, it can be concluded, that chloral hydrate has to be considered as a safe and effective substance.

Animals↗
PubMed2004

The assessment of genotoxic effects in lymphocyte cultures of infants treated with chloral hydrate.

Chloral hydrate is a sedative commonly used in pediatric medicine. It was evaluated for genotoxicity in cultured peripheral blood lymphocytes of infants who were given chloral hydrate for sedation. Sister chromatid exchange and micronucleus frequencies were determined before and after chloral hydrate administration. After treatment, the frequencies of sister chromatid exchange and micronuclei were significantly increased, suggesting that chloral hydrate has moderate genotoxic potential in infants.

Bromodeoxyuridine↗
PubMed1998

[The plasma level of the neurotoxin 1-trichloromethyl-1,2,4,5-tetrahydro-beta-carboline (TaClo) in man after oral administration of chloral hydrate].

Chloral hydrate (CAS 302-17-0) is a widely used hypnotic and sedative agent. It was recently reported in the literature that a neurotoxin, TaClo (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline), may be formed in vitro from tryptamine (Ta) and chloral (Clo). Intraperitoneal administration of TaClo led to parkinson-like symptoms in the rat. Hence, the plasma levels of TaClo were determined at various time-points in 18 healthy volunteers in two periods each during a bioavailability study of several chloral hydrate preparations. The limit of quantitation for TaClo was 5 ng/ml. No TaClo could be determined in the plasma of the various volunteers following administration of human therapeutic doses of chloral hydrate. Hence, it is unlikely that TaClo will be formed in man after application of therapeutic doses of chloral hydrate to patients.

Adult↗
PubMed1990

Efficacy of sedation of children with chloral hydrate.

Chloral hydrate has been used extensively to sedate children, but at Brooke Army Medical Center, other drug combinations were becoming increasingly popular due to a perception that chloral hydrate had a high rate of failure, especially with younger or neurologically impaired children. Therefore, 50 children were given the drug before a diagnostic study, and patient data and a sedation score were recorded on a worksheet. Of 50 children, 43 (86%) were "successfully sedated" on the first attempt with no side effects. Children with neurologic disorders had a much greater (27% vs 4%) failure rate than "normal" children. The sedation rate did not significantly differ by age, sex, or initial drug dosage. The study suggest that chloral hydrate is a safe and effective oral sedative but that children with neurologic disorders may need alternative drugs for sedation.

Administration, Oral↗
PubMed1992

Early clinical neurochemistry of CNS-active drugs. Chloral hydrate.

Chloral hydrate was introduced into therapeutics more than 120 years ago, and soon became popular as a somnifacient. It is the first synthetic CNS depressant. Its metabolite, urochloralic acid, was detected early. Studies of the biochemical pharmacology of chloral hydrate have engaged the attention of many investigators in succeeding years. Its mode of action in producing sleep was initially attributed to the possibility that it gives rise to chloroform in vivo. Although this hypothesis did not stand up to scientific scrutiny, it led to efforts to establish how chloral hydrate brings about its action. This seems to be through its reduced metabolite, trichloroethanol. The precise mode of action on the nervous system remains to be worked out.

Animals↗
PubMed1982

Humoral and cell-mediated immune status in mice exposed to chloral hydrate.

Chloral hydrate has been found in our drinking water supplies at levels up to 5 micrograms/1. The purpose of this study was to evaluate the functional status of the immune system in random-bred CD-1 mice exposed to chloral hydrate for 14 and 90 days. Male mice, following 14 or 90 days of exposure to 1/10 and 1/100 the actual oral LD50, exhibited no alterations in either humoral or cell-mediated immunity. However, female mice exposed for 90 days to chloral hydrate in the drinking water demonstrated a significant depression in humoral immune function. This depression was observed when spleen cells from exposed mice were evaluated for their ability to produce antibody against sheep erythrocytes. These females did not demonstrate any changes in cell-mediated immune status.

Animals↗
PubMed2003

Lipid peroxidation and cell death mechanisms in rats and human cells induced by chloral hydrate.

Chloral hydrate (CH) is widely used as a sedative and hypnotic in pediatric medicine. It is also a by-product of water chlorination and a metabolite of trichloroethylene. We examined the toxicological effects and cell death mechanisms of CH in rats and human Chang liver cells and lymphocytes. Monitoring of urinary 8-epi-PGF2alpha and serum levels of TNF-alpha served as index of lipid peroxidation and cytokine stimulation. The results indicated that a single intraperitoneal injection of 100 mg/kg CH in rats led to a nearly five-fold increase in urinary 8-epi-PGF2alpha on day 1, and a mild decrease on day 2 and day 3. The same treatment also induced significantly higher amounts of serum TNF-alpha on day 2 (about seven-fold). When the rats were treated with CH and vitamin E simultaneously, the amount of urinary 8-epi-PGF2alpha and serum TNF- were significantly lower than that in the rats treated with CH alone. CH caused a greater cytotoxic effect in human Chang liver cells than in comparison with lymphocytes. After treatment with CH, apoptosis features were observed in human lymphocytes, but not Chang liver cells. CH-induced cell damage in lymphocytes may offer signals for the induction of caspases activation. Further studies are needed to evaluate the relationship between caspases activation and the cleavage of other death substrates during postmitotic apoptosis in human lymphocytes.

Animals↗
PubMedDate not supplied

Conscious sedation of pediatric dental patients: an investigation of chloral hydrate, hydroxyzine pamoate, and meperidine vs. chloral hydrate and hydroxyzine pamoate.

This study evaluated two oral sedative regimens for the conscious sedation of pediatric dental patients (mean age 37.0 months) unmanageable by traditional behavior management techniques. Regimen A included chloral hydrate (Noctec--E.R. Squibb and Sons, Princeton, NJ) at 50 mg/kg with 25 mg hydroxyzine pamoate (Vistaril--Pfizer Laboratories, New York, NY), plus meperidine (Demerol--Winthrop-Breon, New York, NY) at 1.5 mg/kg. Regimen B included chloral hydrate at 50 mg/kg with 25 mg hydroxyzine pamoate. In a crossover research design, 10 patients were assigned randomly to receive one regimen, to be followed by the alternative regimen during the second appointment. The primary purpose of this study was to determine if meperidine would improve patient behavior, and increase the prevalence of respiratory compromise. A secondary purpose of the study was to develop an objective method to assess behavior during the conscious sedation of pediatric dental patients. Results revealed that the addition of oral meperidine to chloral hydrate and hydroxyzine pamoate resulted in improved behavior (P less than 0.01) during local anesthetic injection, rubber dam delivery, and the operative dental procedure. There was no increase in the prevalence of respiratory compromise with the addition of meperidine.

Anesthesia, Dental↗
PubMed1993

Sensitivity of aldehyde dehydrogenases in murine tumor and hematopoietic progenitor cells to inhibition by chloral hydrate as determined by the ability of chloral hydrate to potentiate the cytotoxic action of mafosfamide.

Several murine aldehyde dehydrogenases, most notably AHD-2, are known to catalyze the detoxification of cyclophosphamide, mafosfamide, and other oxazaphosphorines. Thus, cellular sensitivity to these agents decreases as the relevant aldehyde dehydrogenase activity increases, and vice versa. Chloral hydrate is a sedative/hypnotic agent that is sometimes administered to patients being treated with cyclophosphamide. It is known to inhibit some, but not all, aldehyde dehydrogenases. Murine (CFU-S, CFU-GEMM and CFU-Mk) and human (CFU-Mix, CFU-GM, BFU-E and CFU-Mk) hematopoietic progenitor cells, as well as murine oxazaphosphorine-resistant (L1210/OAP and P388/CLA) tumor cells, are known to contain the relevant aldehyde dehydrogenase activity but the identity of the specific enzyme present in the normal cells is unknown and may be different than that, namely AHD-2, present in neoplastic cells. In that event, the potential exists to inhibit the detoxification of the oxazaphosphorines in tumor cells without inhibiting this event in normal cells; the net effect of such a selective inhibition would be to increase the margin of safety of the oxazaphosphorines. In ex vivo experiments, chloral hydrate markedly potentiated the antitumor activity of mafosfamide against oxazaphosphorine-resistant L1210/OAP and P388/CLA cells. It did not potentiate the cytotoxic action of mafosfamide against any of the murine or human hematopoietic cells tested, even at concentrations which fully restored the sensitivity of the resistant tumor cell lines to this agent. One explanation for these observations is that hematopoietic progenitor, and the resistant tumor, cells express different relevant aldehyde dehydrogenases and that these aldehyde dehydrogenases differ in their sensitivity to inhibition by chloral hydrate. Consistent with this notion were the observations that AHD-2 was exquisitely sensitive to inhibition by chloral hydrate, whereas two other aldehyde dehydrogenases that also catalyze the detoxification of aldophosphamide, namely AHD-12a, b and AHD-13, were relatively unaffected.

Aldehyde Dehydrogenase↗
PubMed1983

Inhibition of alcohol dehydrogenase by chloral hydrate and trichloroethanol: possible role in the chloral hydrate-ethanol interaction.

Both chloral hydrate and trichloroethanol inhibited mouse liver alcohol dehydrogenase (LADH) in vitro. The inhibition of LADH by chloral hydrate appears to be non-competitive in nature with an inhibition constant (Ki) of about 2.7 X 10(-4) M. The inhibition of LADH by trichloroethanol was competitive and the (Ki) was about 2.7 X 10(-5) M. The elimination of ethanol from the blood and brain was significantly reduced in chloral hydrate- or trichloroethanol-pretreated mice. Since reduced elimination of ethanol could result in the prolongation of its central depressant activity, we suggest that this should be considered as a factor in the enhanced pharmacological effects of ethanol-chloral hydrate mixtures.

Alcohol Dehydrogenase↗
PubMed1995

Potential carcinogenicity of chloral hydrate--a review.

Chloral hydrate is commonly used to sedate children for diagnostic or therapeutic procedures. The drug has been extensively used for many years, but there are remarkably few data on its long-term health effects. Concern in this regard is raised by recent studies showing chloral hydrate to be genotoxic, causing chromosome changes and other effects in vivo and in vitro. In addition, chloral hydrate is a reactive metabolite of trichloroethylene, a known carcinogen, and is structurally similar to other carcinogenic intermediates. Two carcinogenicity studies performed using the oral route of administration in mice indicate that the drug is potentially carcinogenic--in one case after a single dose lower than the typical dose used for sedation. Practitioners should be aware of chloral hydrate's genotoxicity and potential carcinogenicity. Discretion in its use seems appropriate until further studies clarify its long term health consequences.

Animals↗
PubMed1993

A review of laboratory animal anesthesia with chloral hydrate and chloralose.

Chloral hydrate (CH) and alpha-chloralose (CS) are often used to anesthetize laboratory animals although, to our knowledge, there have been no controlled studies of their anesthetic or analgesic effects. Induction of and recovery from anesthesia can be stressful, and anesthesia and analgesic quality have been questioned. Intraperitoneal (i.p.) administration of CH has resulted in adynamic ileus and peritonitis in rats, gastric ulcers in rats, and peritonitis in swine. Light anesthesia is induced in rats. In dogs, CH induces sedation to deep anesthesia when given intravenously. Gastric irritation in dogs can occur when CH is given orally. Chloral hydrate is considered a good sedative-hypnotic for farm animals. Intravenously administered CS anesthetizes dogs and cats for 5 to 10 hours, but the animals may require respiratory support. Chloralose appears to be a satisfactory anesthetic for dogs when stage III thiobarbiturate anesthesia is first induced. It is difficult to gauge the depth of anesthesia and analgesia with CS. In our clinical experience with swine and calves, CH given i.p. leads to adynamic ileus. We have found that CS given i.p. causes an inflammatory response in guinea pigs, rats, and calves. We observed that CS analgesia varies with the type of surgical procedure performed. Based on a literature review and our clinical experience, we suggest that CH or CS anesthesia should be preceded by administration of barbiturates, opioids, alpha-2 agonists, or phenothiazine tranquilizers. Chloral hydrate should only be used as a sedative or hypnotic for dogs; CS should not be used as a sole anesthetic agent. Neither drug should be used i.p. for survival surgery.

Anesthesia↗
PubMedDate not supplied

Carcinogenicity of chloral hydrate administered in drinking water to the male F344/N rat and male B6C3F1 mouse.

Male B6C3F1 mice and male F344/N rats were exposed to chloral hydrate (chloral) in the drinking water for 2 years. Rats: Measured chloral hydrate drinking water concentrations for the study were 0.12 g/L, 0.58 g/L, and 2.51 g/L chloral hydrate that yielded time-weighted mean daily doses (MDDs) of 7.4, 37.4, and 162.6 mg/kg per day. Water consumptions, survival, body weights, and organ weights were not altered in any of the chloral hydrate treatments. Life-time exposures to chloral hydrate failed to increase the prevalence (percentage of animals with a tumor) or the multiplicity (tumors/animal) of hepatocellular neoplasia. Chloral hydrate did not increase the prevalence of neoplasia at any other organ site. Mice: Measured chloral hydrate drinking water concentrations for the study were 0.12 g/L, 0.58 g/L, and 1.28 g/L that gave MDDs of 13.5, 65.0, and 146.6 mg/kg per day. Water consumptions, survival, body and organ weights, were not altered from the control values by any of the chloral hydrate treatments. Enhanced neoplasia was observed only in the liver. Prevalence and multiplicity of hepatocellular carcinoma (HC) were increased only for the high-dose group (84.4%; 0.72 HC/animal; p < or = 0.05). Values of 54.3%; 0.72 HC/animal and 59%; 1.03 HC/animal were observed for the 13.5- and 65.0-mg/kg per day treatment groups. Prevalence and multiplicity for the control group were 54.8%; 0.74 HC/animal. Hepatoadenoma (HA) prevalence and multiplicity were significantly increased (p < or = 0.05) at all chloral hydrate concentrations: 43.5%; 0.65 HA/animal, 51.3%; 0.95 HA/animal and 50%; 0.72 HA/animal at 13.5, 65.0, and 146.6 mg/kg per day chloral hydrate compared to 21.4%; 0.21 HA/animal in the untreated group. Altered foci of cells were evident in all doses tested in the mouse, but no significant differences were observed over the control values. Hepatocellular necrosis was minimal and did not exceed that seen in untreated rats and mice. Chloral hydrate exposure did not alter serum chemistry and hepatocyte proliferation in rats and mice or increase hepatic palmitoyl CoA oxidase in mice at any of the time periods monitored. It was concluded that chloral hydrate was carcinogenic (hepatocellular neoplasia) in the male mouse, but not in the rat, following a lifetime exposure in the drinking water. Based upon the increased HA and combined tumors at all chloral hydrate doses tested, a no observed adverse effect level was not determined.

Adenoma↗
PubMed2006

Severe esophageal burn following chloral hydrate overdose in an infant.

Chloral hydrate is generally considered to be a safe hypnotic drug, and is commonly used for short-term sedation before diagnostic procedures. Its irritant actions to the mucous membranes are usually limited. We report a rare complication of chloral hydrate overdose in an infant. An 8-month-old male infant became unconscious and required ventilation support after an overdose of chloral hydrate was administered to provide sedation for an ophthalmologic examination. White plaques and sloughing of the oropharyngeal mucosa were observed on the next day. Esophagogastroscopy revealed severe corrosive lesions on the whole esophagus. The child recovered after supportive treatment and his oral intake remained well without dysphagia after 1 year. This report illustrates the potential corrosive effect of chloral hydrate. Strict attention should be paid to the dosing and administration protocol of chloral hydrate in infants. The condition of the oropharyngeal mucosa should be carefully monitored after chloral hydrate administration.

Burns, Chemical↗