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.

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.

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.

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.

Formation of nitroso compounds and mutagens from tranquilizers by drug/nitrite interaction.

The formation of nitroso compounds and mutagens by drug/nitrite interaction was screened for 14 tranquilizers. The drug (0.05 M) was reacted with nitrite (0.5 M) at pH 3-3.5. After 4 h at 37 degrees C, nitroso compound formation was observed for flupentixol, chlordiazepoxide, spiperone, thiothixene, and chlorprothixene in more than 40% yield. Mutagenicity was found in the reaction products of opipramol, chlordiazepoxide, bromazepam, thiothixene, and carpipramine by the Ames assay using Salmonella typhimurium TA98 and TA100 as tester strains.

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.

Efficacy and toxicity of drug combinations in treatment of physostigmine toxicosis.

Atropine, in combination with 1 of 6 other drugs, was tested in mice for the ability to prevent death by an otherwise lethal dose of the cholinesterase inhibitor, physostigmine. The atropine dose (4 mg/kg, i.p.) was kept constant, while the dose of the other drug in the pair was tested in 5 geometrically spaced doses, ranging down to 1/16 of the maximum dose (which caused no gross behavioral signs). Atropine alone saved 20% of the mice. The combination of atropine and benactyzine saved 100% of the mice at all 5 doses of benactyzine; similar complete protection was afforded by the combination of atropine and the largest dose of an oxime, TMB4 (15 mg/kg). Over 80% survivals were achieved with the larger doses of atropine combinations involving hexamethonium, mecamylamine, and diazepam. No enhanced protection occurred with atropine combinations with the oxime, 2-PAM. The toxicity of the effective combinations, when used in high doses without physostigmine challenge, revealed that deaths occurred over a narrow range of doses of all combinations except atropine/diazepam. An additive toxic effect of atropine was suggested with its combinations with TMB4, mecamylamine, and diazepam, whereas no additive toxicity occurred with combinations involving hexamethonium or benactyzine (i.e., the LD50 of the combinations was about the same as for hexamethonium or benzactyzine alone). The combinations with the best therapeutic safety ratio were with diazepam (no deaths at a dose 10 times that which saved 100% of mice) and benactyzine (no deaths at a more than 50-fold dose).

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.

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.

[In vitro effect of psychopharmacologic drugs on the embryonic brain tissue of the fetuses of schizophrenic mothers]. / Osobennosti vliianiia in vitro psikhofarmakologicheskikh sredstv na émbrional'nuiu tkan' mozga plodov bol'nykh shizofrenie materei.

The author studied the influence on the adaptation of the nervous tissue explantations from 25 fetuses of schizophrenic mothers and a similar amount of fetuses from normal women (embryonal development--7-12 weeks) during the initial period of explantation in vitro (5-6 days) with 10 psychopharmacological preparations (aminasine, majeptile, stelasine, triphtasine, tesercin, theralen, haloperidol, eglonyl, mellipramin, seduxen). Their final concentration in a nourishing medium was approximately the same as in the blood of schizophrenic patients, treated by phenothiasine preparations. The adaptation of the fetus pervous tissue from schizophrenic mothers differed from the corresponding reaction of fetus brain explantation from normal women. There was a tendency to a higher stability of experimental cultures. However, there were differences depending upon the character of introduced drugs.

[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.

[Use of Allium fistulosum L. seeds as a preliminary test for studying mutagenic factors in the environment (drugs)]. / Ispol'zovnaie smeian Allium fistulosum L. v kachestve predvaritel'nogo testa pri izuchenii mutagennykh faktorov okruzhaiushchei sredy (lekarstvennykh sredstv).

The mutagenic activity was studied for the following 14 psychotropic drugs: aminazinum, fluphenazinum-decanoate, thioproperazinum, reserpinum, chlordiazepoxidum, diazepam, oxazepam, trioxazin, tavor, dipheninum, hexamidinum, benzonalum, carbamazepinum, ethosuximidium. It is shown that carbamazepinum, benzonalum, chlordiazepoxidum considerably increase the frequency of chromosome aberrations in the Allium fistulosum L. cells. These drugs were selected for studying their mutagenic activity on the laboratory animals.

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.

[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.