High-intensity drinking and nonmedical use of prescription drugs: Results from a national survey of 12th grade students.

BACKGROUND: Nearly 10% of U.S. 12th graders report high-intensity drinking (10+ or 15+ drinks in a row), but the extent to which these drinkers also engage in nonmedical use of prescription drugs (NMUPD) is largely unknown. This study examined the associations between different thresholds of past two-week high-intensity drinking and past-month NMUPD among U.S. 12th graders. METHODS: The sample consisted of eleven nationally representative cross-sections of 12th graders in the Monitoring the Future study (2005-2015) who answered questions on past two-week drinking behaviors and past-month nonmedical use of prescription opioids, sedative, stimulants, and tranquilizers (N=26,502 respondents). RESULTS: High-intensity drinking during the past two-weeks was associated with an increased risk of past-month NMUPD. The odds of NMUPD were four times larger among 12th graders who indicated drinking 15 or more drinks on at least one occasion (AOR=4.43, 95% CI=3.18, 5.01) relative to those who had 0-4 drinks during the past two-weeks, after adjusting for relevant covariates. These associations were similar across different classes of prescription drugs and tended to be stronger among non-white respondents. A sub-analysis revealed simultaneous co-ingestion of alcohol and NMUPD was more prevalent among high-intensity drinkers. CONCLUSIONS: More than 1 in every 4 U.S 12th graders who engage in high-intensity drinking (15+ drinks in a row) also report NMUPD. Given the greater likelihood of simultaneous co-ingestion of alcohol and prescription drugs among high-intensity drinkers, adolescent substance use interventions need to address the risks associated with mixing alcohol and prescription drugs.

Histomorphological comparison of rat placentas by different timing of chlorpromazine-administration.

The effects of chlorpromazine-treatment timing on the development of the placenta in pregnant rats were examined. Chlorpromazine was administered intraperitoneally at 100mg/kg on gestation day (GD) 11 (GD11-treated group), GD 13 (GD13-treated group) or GD 15 (GD15-treated group) into pregnant rats. All treated dams exhibited decreased body weight, prone position, hypothermia, loss or decrease of locomotor activity, etc. The fetal mortality rates were increased up to 42.9% in the GD11- and GD13-treated groups and up to 16.7% in the GD15-treated group. The embryo/fetal weight was on a declining trend from GD 16 onward, and the intrauterine growth retardation (IUGR) rates on GD 21 were increased in all treated groups. The placental weight showed a declining trend from GD 15 onward in all treated groups. Histopathologically, apoptosis was detected 1 or 2 days after treatment, and led to hypoplasia in the labyrinth zone and metrial gland, and cystic degeneration in the basal zone on GD 21 in all treated groups. There was no difference in the histopathological lesions on GD 21 among the treated groups. Thus, it is considered that chlorpromazine-induced placental toxicity is characterized in that there is no obvious specific sensitive period from GD 11 to GD 15. Chlorpromazine induced a non-specific transient development retardation of the placenta by apoptosis independently of the cell proliferation period in each part/zone.

Depleción tisular de azaperona y su metabolito azaperol tras administración oral de azaperona en cerdo / Tissue depletion of azaperone and its metabolite azaperol after oral administration of azaperone in food-producing pigs

Azaperona es un tranquilizante de tipo butirofenona usado en ganado porcino. Los cerdos son particularmente sensibles al estrés durante el manejo y transporte al matadero. La azaperona es parcialmente metabolizada in vivo a azaperol, un metabolito con actividad farmacológica. Las concentraciones altas y persistentes de azaperona y azaperol en el lugar de inyección contraindican el uso de azaperona por vía intramuscular para el transporte de cerdos de producción de carne al matadero; el uso oral podría ser una alternativa para evitar residuos en el lugar de inyección. El presente estudio determinó la depleción en los tejidos de azaperona y su metabolito azaperol después de la administración oral de la formulación Stresnil®. Cerdos machos (30-45 kg de peso corporal) fueron tratados con Stresnil® (dosis oral única de 4 mg azaperona/kg de peso corporal) y se sacrificaron 6, 24 y 48 horas después de la administración. De cada animal se obtuvo músculo, piel + grasa, hígado y riñón. Azaperona y azaperol se analizaron por HPLC tras la extracción en fase sólida. Las concentraciones de azaperona más azaperol en todos los tejidos analizados no superaron el Límite Máximo de Residuos (LMR) establecidos por la Unión Europea (100 mg / kg en el músculo, el hígado, los riñones y la piel + grasa) en ningún momento del muestreo. Como consecuencia, según los resultados obtenidos en el presente estudio, los tejidos comestibles de los cerdos tratados por vía oral con 4 mg/kg de azaperona, 6 horas antes al sacrificio, podrían ser aceptables para garantizar la seguridad de los consumidores. Sin embargo, se estimó un tiempo de espera de cero horas por análisis de regresión lineal (AU)

Azaperone is a butyrophenone tranquilizer for swine. Food producing pigs are particularly sensitive to stress during handling and transport to the abattoir. In vivo, azaperone is partially metabolised to azaperol, a metabolite with pharmacological activity. The high and persistent concentrations of azaperone and azaperol in the injection site contra-indicates the use of azaperone using the intramuscular route for the transport of the food producing animals, pigs, to the slaughterhouse; the oral use could be an alternative to avoid residues at the injection site. The present study determined the tissue depletion of azaperone and its metabolite azaperol after oral administration of the formulation Stresnil®. Male pigs (30-45 kg of body weight) were treated with Stresnil® (single oral dose of 4 mg azaperone/kg body weight) and were sacrificed 6, 24 and 48 hours after the administration. Muscle, skin + fat, liver and kidney were collected from each animal. Azaperone and azaperol were assayed by HPLC after solid phase extraction. The concentrations of the azaperone plus azaperol in all analysed tissues did not exceed to the Maximum Residue Limit (MRL) established by the European Union (100 μg/kg in muscle, liver, kidney and skin plus fat) at any sampling time. As a consequence, from the results obtained in the present study, edible tissues of pigs treated orally with 4 mg/kg azaperone, 6 hours before to the sacrifice, might be acceptable to guarantee safety for the consumers. Nevertheless a withdrawal time of cero hours was estimated by linear regression analysis (AU)

In vitro inhibition of mitochondrial respiratory rate by antidepressants.

Mitochondria represent a possible drug target with unexplored therapeutic and toxicological potential. The possibility was suggested that antidepressants, mood stabilizers and other drugs may show some therapeutic and/or toxic effects through their action on mitochondrial functions. There are no sufficient data about the effect of these drugs on mitochondrial respiration in the brain. We investigated the in vitro effects of amitriptyline, fluoxetine, tianeptine, ketamine, lithium, valproate, olanzapine, chlorpromazine and propranolol on mitochondrial respiration in crude mitochondrial fractions of pig brains. Respiration was energized using substrates of complex I or complex II and dose dependent drug-induced changes in mitochondrial respiratory rate were measured by high-resolution respirometry. Antidepressants, but not mood stabilizers, ketamine and propranolol were found to inhibit mitochondrial respiratory rate. The effective dose of antidepressants reaching half the maximal respiratory rate was in the range of 0.07-0.46 mmol/L. Partial inhibition was found for all inhibitors. Differences between individual drugs with similar physicochemical properties indicate selectivity of drug-induced changes in mitochondrial respiratory rate. Our findings suggest that mood stabilizers do not interfere with brain mitochondrial respiration, whereas direct mitochondrial targeting is involved in mechanisms of action of pharmacologically different antidepressants.

Lithium induced toxicity in rats: blood serum chemistry, antioxidative enzymes in red blood cells and histopathological studies.

Lithium is commonly used in treating mental disorders and bipolar diseases. As physicians frequently keep the patients on long-term lithium therapy, awareness of the numerous side effects and pathogenesis of this lightest alkali metal is needed for such treatments. The present study was designed to evaluate the toxic effect of small doses of lithium chloride in male Wistar rats. The oral administration of lithium chloride (15, 30 mg/kg body wt) for 7 weeks through their drinking water elicited a significant alteration in their body weight and blood serum chemistry. The serum enzyme levels of alkaline phosphatase (ALP), high density lipoprotein (HDLP), and creatinine kinase (CK) were diminished, whereas the level of serum urea and glucose were elevated in the lithium treated animals, depicting the disturbed general physiological status. Furthermore, a marked inhibition in the levels of serum alanine and aspartate transaminases (ALT and AST) reflected a stimulating transamination reaction in hepatic and renal tissues. Lithium exposure also reduced the glutathione (GSH) level and stimulated the lipid peroxidation (LPO) level in the rat blood cells, indicating oxidative stress in the red blood cells due to lithium exposures. The histopathological observations of the liver and kidney tissues revealed many deformities and histological alterations due to lithium treatment. The results of present study suggest that small doses of lithium induce toxicity in rat blood as well as in liver and kidney tissues. However, the precise mechanism of lithium toxicity is still incompletely understood.

[A rare cause of cyanosis: Sulphaemoglobinaemia related to thiocolchicoside (Miorel)]. / Une cause rare de cyanose: sulfhémoglobinémie imputable au thiocolchicoside (Miorel).

INTRODUCTION: An acquired abnormality of haemoglobin is among the many causes of cyanosis, especially in patients with no identified cardiorespiratory cause. CASE REPORT: A 50-year-old woman, suffering from amyotrophic lateral sclerosis, was hospitalised for dyspnoea. Physical examination revealed cyanosis that persisted despite oxygen therapy. Discordance between the reduced arterial oxygen saturation and normal arterial oxygen tension led to a search for a dyshaemoglobinaemia as a possible cause. Use of co-oxymetry with spectrophotometry revealed sulphaemoglobinaemia. Sulphaemoglobinaemia is due to irreversible incorporation of a thiol radical into the porphyrin ring of a haem group. This decreases the affinity of haemoglobin for oxygen and thus reduces oxygen carrying capacity. A drug-induced cause is often identified. However, no previously described cause for sulphaemoglobinaemia was identified in our patient. The patient was currently being treated with thiocolchicoside (Miorel((R))). Thiocolchicoside was suspected as the cause because its chemical structure contains an easily hydrolysable thiol radical. Withdrawal of thiocolchicoside led to regression of the sulphaemoglobinaemia. CONCLUSIONS: This report underlines the importance of searching for an acquired abnormality of haemoglobin (methaemoglobinaemia or sulphaemoglobinaemia) in patients with cyanosis resistant to oxygen, in the absence of any cardiorespiratory abnormality. This case is the first to suspect thiocolchicoside as a possible cause of sulphaemoglobinaemia.

Movement disorder caused by abuse of veterinary anesthesia containing tiletamine.

Zoletil (Telazol) is a fixed-ratio combination of the tranquilizer zolazepam, with the dissociative anesthetic tiletamine, used for injection anesthesia in dogs, cats, wild, and zoo animals. We report a veterinarian who developed movement disorder after abuse of Zoletil for a 2-week period. Phencyclidine derivatives, that is, tiletamine can induce movement disorder in human. Tiletamine/zolazepam can be abused for recreational purpose, especially by those people with easy access to veterinary medications. Emergency physicians should have high alert to the diverse presentations of drug abuse. This case again highlights that the association between accessibility of scheduled drugs and health care professionals.

Vigilancia epidemiológica de la intoxicación aguda en el área sur de la Comunidad de Madrid: estudio Veia 2004 / Epidemiologic survey of acute poisoning in the south ara of the Community of Madrid. The Veia 2004 study

Objetivo: VEIA es un registro evolutivo de las intoxicaciones agudas (IA) atendidas en Urgencias del Hospital Doce de Octubre de Madrid en un año completo [1979 (2), 1985 (3), 1990 (4), 1994 (5), 1997 (6) y 2000 (7)] presentamos el estudio del año 2004 y comparamos los resultados con los de años anteriores (1-7). Métodos y resultados: el método es idéntico. De las 1.508 IA, 610 son intentos de suicidio (IBAIS) 319 etílicas (IAVE) y 219 drogas (IAVD). De los 2259 tóxicos implicados el 48% son medicamentos (50% diazepóxidos) alcohol 25% y drogas el 13%. Conclusiones: este año ha supuesto un importante aumento (34%) del número de casos y la incidencia supera a todas las publicadas en nuestro país (25,31,40) Aunque en el conjunto no hay diferencia significativa de género con el Censo de Área, la hay en IBAIS, IAVE y IAVD. Las IBAIS crecen un 35%; Se duplica el uso de benzodiacepinas y antidepresivos en los IS de mujeres y crecen también en hombres pero menos; El paracetamol se mantiene en el 23% AINES, adyuvantes y mío-relajantes aumentan en mujeres y también el uso de alcohol y otros no fármacos en los is de mujeres casi igualándose con los hombres. La cuarta parte de los hombres con IS eran adictos y aparecen 13 casos de trastornos alimentarios. En las IAVE crecen el grupo sin etilismo y baja el total. Las drogas se duplican con respecto al año anterior la cocaína supone los 2/3 también suben la MDMA (22 casos) y aparecen nuevas drogas, como el pegamento, sin duda efecto de la inmigración, y ketamina; incluso cuatro casos no pudieron ser etiquetados por la falta de medios diagnósticos en la urgencia

Objetive: VEIA study is an evolutional registry of acute poisonings (AP) attended in the Emergency Room of the Doce de Octubre Hospital in Madrid (Spain) in a whole year (1979,1985, 1990, 1994,1997 and 2000). We present the 2004 study and compare the results with the previous years. Methods and results: Methodology has been identical across VEIA STUDY. Of 1508 AP, 610 are suicide attempts (IAVIS), 319 ethylic, (IAVE), and 218 by illicit drugs (IAVD). Of the 2,259 toxics involved,48% are medications (50% benzodiacepines) alcohol 25% and illicit drugs 13%. Conclusions: There is an important increase (34%) of cases and the incidence surpasses all published in our country. There are no gender differences nor in the whole neither the Health Area Census, but there are differences in IAVIS, IAVE and IAVD. IAVIS increase in 35%. Benzodiacepines poisoning increases two-fold as well as antidepressive drugs do in women. In men also increase, but in a minor extent. Acetaminophenre mains the same in 23%. NSAID’s, adjuvants and myorelaxants increase in women as do also alcohol and other poisons that almost equal men’s. There are 13 cases of IAVIS in patients with alimentary disorders. Among men, a quarter are illicit drug abusers. In IAVE, the group without alcoholism grows and the total decreases. Illicit drugs duplicate the number of the former year. Cocaine supposes already 2/3 of the cases, MDMA ascends to 22 cases and they appear new substances as glue, without doubt as an effect of immigration and ketamine. Finally 205 house hold accidents and 57 industrial injuries complete the series

Lithium facilitates apoptotic signaling induced by activation of the Fas death domain-containing receptor.

BACKGROUND: Lithium, a mood stabilizer widely used to treat bipolar disorder, also is a neuroprotectant, providing neurons protection from apoptosis induced by a broad spectrum of toxic conditions. A portion of this neuroprotection is due to lithium's inhibition of glycogen synthase kinase-3. The present investigation examined if the neuroprotection provided by lithium included apoptosis induced by stimulation of the death domain-containing receptor Fas. RESULTS: Instead of providing protection, treatment with 20 mM lithium significantly increased apoptotic signaling induced by activation of Fas, and this occurred in both Jurkat cells and differentiated immortalized hippocampal neurons. Other inhibitors of glycogen synthase kinase-3, including 20 microM indirubin-3'-monoxime, 5 microM kenpaullone, and 5 microM rottlerin, also facilitated Fas-induced apoptotic signaling, indicating that the facilitation of apoptosis by lithium was due to inhibition of glycogen synthase kinase-3. CONCLUSIONS: These results demonstrate that lithium is not always a neuroprotectant, and it has the opposite effect of facilitating apoptosis mediated by stimulation of death domain-containing receptors.

Severe intoxication with the veterinary tranquilizer xylazine in humans.

Xylazine (Rompun, Proxylaz) is a veterinary tranquilizing agent. A case of self-injection of 1.5 g xylazine by a 27-year-old farmer is reported. He subsequently became comatose, hypotensive, bradycardic, and mildly glycemic. An intensive supportive therapy including intubation and ventilation was required. The patient made a full recovery over the next 30 h. The largest concentrations measured were 4.6 mg/L in plasma, 446 mg/L in gastric fluid, and 194 mg/L in urine. The calculated plasma half-life was 4.9 h. Kinetic data correlated with clinical symptoms. Qualitative and quantitative analyses of xylazine were done by thin-layer chromatography, gas chromatography-mass spectrometry, and high-performance liquid chromatography. These methods allow the detection of small amounts substance in stomach, plasma, and urine. Liquid-liquid extraction was used for the isolation of drug. The sensitvity is high, and with these methods, a rapid analysis is possible. Xylazine intoxications in humans are rare. We describe the management of acute poisoning and present a review of xylazine toxicity in humans.

[Genotoxic effects of metabolic derivatives of the new drug phosphabenzide]. / Genotoksicheskie éffekty metabolicheskikh proizvodnykh novogo lekarstvennogo preparata fosfabenzida.

Genotoxic action of four possible metabolites of the new tranquilizer phosphabenzide (acetylphosphabenzide, diphenylphosphinylacetic acid, phosphabenzide hydrazone with pyruvic acid, bis-1,2-(diphenylphosphinylacetyl)hydrazine) has been studied. These metabolites belong to slightly toxic phosphororganic compounds. The Ames Salmonella/microsomes tests performed on strains TA100 and TA98 showed that of these compounds only acetylphosphabenzide possessed mutagenic action. Metabolic activation of liver microsomes decreased the mutagenic effect. The mechanism of action of acetylphosphabenzide is likely to involve the formation of acetylhydrazine, capable of producing active electrophiles attacking DNA.

Lithium toxicity in yeast is due to the inhibition of RNA processing enzymes.

Hal2p is an enzyme that converts pAp (adenosine 3',5' bisphosphate), a product of sulfate assimilation, into 5' AMP and Pi. Overexpression of Hal2p confers lithium resistance in yeast, and its activity is inhibited by submillimolar amounts of Li+ in vitro. Here we report that pAp accumulation in HAL2 mutants inhibits the 5'-->3' exoribonucleases Xrn1p and Rat1p. Li+ treatment of a wild-type yeast strain also inhibits the exonucleases, as a result of pAp accumulation due to inhibition of Hal2p; 5' processing of the 5.8S rRNA and snoRNAs, degradation of pre-rRNA spacer fragments and mRNA turnover are inhibited. Lithium also inhibits the activity of RNase MRP by a mechanism which is not mediated by pAp. A mutation in the RNase MRP RNA confers Li+ hypersensitivity and is synthetically lethal with mutations in either HAL2 or XRN1. We propose that Li+ toxicity in yeast is due to synthetic lethality evoked between Xrn1p and RNase MRP. Similar mechanisms may contribute to the effects of Li+ on development and in human neurobiology.

Effects of psychotropic drugs on aldo-keto reductase activity in rat ovary and adrenal gland.

We investigated the effects of minor and major tranquilizers on ovarian and adrenal aldo-keto reductase activity towards five substrates in relation to ovulation in mature cycling rats. Nitrazepam (NZP) did not alter ovarian and adrenal weights or body weight, although ovulation was inhibited at 5 and 10 mg/kg. NZP decreased ovarian 13,14-dihydro-15-ketoprostaglandin F2 alpha (15KD-PGF2 alpha) and 4-benzoylpyridine (4BP) reducing activities. None of the doses of zopiclone (ZPC) influenced uterine and adrenal weights or body weight, but it increased ovarian weight at 10 mg/kg. No significant effects of ZPC on ovarian aldo-keto reductase activity were observed. NZP had inhibitory effects on adrenal aldo-keto reductase activity, whereas ZPC had a stimulatory effect. Chlorpromazine (CPZ) did not alter ovarian or adrenal weight, whereas the estrous cycles were abolished at 5 and 10 mg/kg. Reserpine (RSP) decreased ovarian weight and completely inhibited ovulation at 5 and 10 mg/kg, but it increased adrenal weight. Both CPZ and RSP decreased, dose dependently, ovarian aldo-keto reductase activity towards five substrates in agreement with the inhibition of ovulation. On the other hand, differences were found between the effects of CPZ and RSP on adrenal aldo-keto reductase activity. CPZ significantly increased 4BP reducing activity at 5 and 10 mg/kg, although no significant changes were observed in the other four reducing activities. RSP decreased 15KD-PGF2 alpha reducing activity in a dose-dependent manner, whereas the other four activities did not change.

Morphological and histochemical changes in the liver of albino Wistar rat given flupenthixol depot.

Histological findings and histoenzymatic reactions have shown that Flupenthixol Depot (FPX dep.) injected to rats in therapeutic doses induced morphologically observable degenerative lesions in the liver. No significant difference in the intensity of the lesions between the groups of male and female animals was found.

[Experimental and clinical study of the effectiveness of the combined use of anticonvulsants and tranquilizers in epilepsy]. / Eksperimental'noe i klinicheskoe izuchenie éffektivnosti kombinirovannogo primeneniia antikonvul'santov i trankvilizatorov pri épilepsii.

Using experimental and clinical methods, the authors studied the efficacy of combined use of anticonvulsants (phenobarbital, hexamidine, chloracon, trimetin, benzonal, diphenylhydantoin, carbamazepine) and tranquilizers (diazepam, chlordiazepoxide, meprotan, trioxazine, mebicar) in epilepsy treatment. The experimental findings showed that 13 combinations of the above drugs had a synergic effect. Five of these combinations (hexamidine-chlordiazepoxide, benzonal-chlordiazepoxide, phenobarbital-diazepam, phenobarbital-trioxazine, and phenobarbital-mebicar also proved clinically more effective than the use of anticonvulsants alone.

Bacterial mutagenicity of the tranquilizing constituents of Valerianaceae roots.

The valepotriates valtrate/isovaltrate and dihydrovaltrate are considered to be the main tranquilizing constituents of drugs derived from the roots of several Valerianaceae. The decomposition products of valtrate and isovaltrate include the metabolites baldrinal and homobaldrinal, respectively, whereas the decomposition products of dihydrovaltrate do not include baldrinal-like metabolites. Purified valtrate/isovaltrate, dihydrovaltrate, baldrinal and homobaldrinal were investigated for their genotoxic activity in the Salmonella/microsome test and the SOS-chromotest. The valepotriates developed mutagenic activity in these test systems only in the presence of S9 mix, whereas both baldrinals showed mutagenic effects in both tests with and without metabolic activation.

[Pain-alleviating action of gidifen and its combinations with analgesics]. / Izuchenie boleutoliaiushchego deistviia gidifena i ego sochetanii s anal'getikami.

The analgesic effect of gidifen, a new tranquilizer belonging to the group of organophosphorus compounds, manifests itself in relatively high doses (1/3 of the LD50). The quantitative characteristics of the analgesic action depends on the method for evaluating the analgesic action of the drug. On combined use of gidifen and analgesics applied in a definite dosage range the analgesic effect is potentiated. If the tranquilizer under study is combined with non-narcotic analgesics, the above potentiation is accompanied with an increase in the toxicity and myorelaxant activity of gidifen. On combination of the latter with morphine the parameters under consideration are unchanged. According to the pattern of interaction with analgesics gidifen does not differ in principle from benzodiazepine tranquilizers. However, the drug is not superior to benzodiazepines in this respect.