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Objective: The Z-drugs (zolpidem, zopiclone, zaleplon) are widely used to treat insomnia in patients receiving prescription opioids, and the risk of overdose resulting from this coprescription has not been explored. The authors compared the rates of overdose among patients using opioids plus Z-drugs and patients using opioids alone., Methods: All individuals 15 to 85 years of age receiving prescription opioids, regardless of underlying indication and without evidence of cancer, were identified in the IBM MarketScan database (2004-2017). Patients with concomitant exposure to Z-drugs were matched 1:1 to patients with exposure to prescription opioids alone based on opioid prescribed, morphine equivalents, number of days' supply, and hospitalization within the past 30 days. The primary outcome was any hospitalization or emergency department visit due to an overdose within 30 days, using an intention-to-treat approach. Fine stratification on the propensity score was used to control for confounding., Results: A total of 510,529 exposed patients and an equal number of matched reference patients were analyzed. There were 217 overdose events among the exposed patients (52.5 events per 10,000 person-years) and 57 events among the reference patients (14.4 events per 10,000 person-years), corresponding to an unadjusted hazard ratio of 3.67 (95% CI=2.75, 4.90). Using fine stratification on the propensity score (c-statistic: 0.66), the adjusted hazard ratio was 2.29 (95% CI=1.79, 2.91). Results were consistent across sensitivity analyses., Conclusions: Among patients receiving prescription opioids, after controlling for all confounding factors, concomitant treatment with Z-drugs was associated with a substantial relative increase in the risk of overdose. The potential implications are significant given the large number of opioid-treated patients receiving Z-drugs.

Aim: Design and synthesis of novel morpholinopyrimidine-5-carbonitriles as antitumor agents. Materials & methods: New series of morpholinopyrimidine-5-carbonitriles have been synthesized. 19 derivatives ( 3b, 4a, 5-6, 9-12, 13a-e , 14a-c and 15-17 ) were evaluated for their in vitro antitumor activity by the National Cancer Institute (NCI; MD, USA). Moreover, compound 13e was evaluated against PI3K (α, β and δ) and the mechanism of its cytotoxic activity on leukemia SR was studied. Results: Compound 13e possessed remarkable broad spectrum antitumor activity with GI 50 (median growth inhibition) and TGI (total growth inhibition) values of 6.15 and 28.66 μM, respectively, caused cell cycle arrest at G2-M phase and significant increase in the percentage of annexin V-FITC - positive apoptotic cells, also increased the level of active caspase-3. Moreover, 13e revealed good safety profile against transformed human liver epithelial-2 (THLE2).

The Z-drugs (zolpidem, zopiclone, and zaleplon), as the innovative hypnotics, have an improvement over the traditional benzodiazepines in the management of insomnia. Z-drugs have significant hypnotic effects by reducing sleep latency and improving sleep quality, though duration of sleep may not be significantly increased. As benzodiazepines, Z-drugs exert their effects through increasing the transmission of γ-aminobutyric acid. Z-drugs overdose are less likely to be fatal, more likely would result in poisoning. Z-drugs can be detected in blood, urine, saliva, and other postmortem specimens through liquid chromatography-mass spectrometry techniques. Zolpidem and zaleplon exhibit significant postmortem redistribution. Z-drugs have improved pharmacokinetic profiles, but incidence of neuropsychiatric sequelae, poisoning, and death may prove to be similar to the other hypnotics. This review focuses on the pharmacology and toxicology of Z-drugs with respect to their adverse effect profile and toxicity and toxicology data in the field of forensic medicine.

The Z-drugs zolpidem, zopiclone, and zaleplon were hailed as the innovative hypnotics of the new millennium, an improvement to traditional benzodiazepines in the management of insomnia. Increasing reports of adverse events including bizarre behavior and falls in the elderly have prompted calls for caution and regulation. Z-drugs have significant hypnotic effects by reducing sleep latency and improving sleep quality, though duration of sleep may not be significantly increased. Z-drugs exert their effects through increased γ-aminobutyric acid (GABA) transmission at the same GABA-type A receptor as benzodiazepines. Their pharmacokinetics approach those of the ideal hypnotic with rapid onset within 30 min and short half-life (1-7 h). Zopiclone with the longest duration of action has the greatest residual effect, similar to short-acting benzodiazepines. Neuropsychiatric adverse events have been reported with zolpidem including hallucinations, amnesia, and parasomnia. Poisoning with Z-drugs involves predominantly sedation and coma with supportive management being adequate in the majority. Flumazenil has been reported to reverse sedation from all three Z-drugs. Deaths from Z-drugs are rare and more likely to occur with polydrug overdose. Z-drugs can be detected in blood, urine, oral fluid, and postmortem specimens, predominantly with liquid chromatography-mass spectrometry techniques. Zolpidem and zaleplon exhibit significant postmortem redistribution. Zaleplon with its ultra-short half-life has been detected in few clinical or forensic cases possibly due to assay unavailability, low frequency of use, and short window of detection. Though Z-drugs have improved pharmacokinetic profiles, their adverse effects, neuropsychiatric sequelae, and incidence of poisoning and death may prove to be similar to older hypnotics.

Objective: To summarize the signalment, clinical signs observed, time to onset of clinical signs, duration of clinical signs, and the outcome in a large case series of nonbenzodiazepine sleep aid ingestions in dogs, including 2 sleep aids that have not been previously described in the veterinary literature., Design: Retrospective study conducted between 2004 and 2010., Setting: An animal poison control center based out of Bloomington, MN., Animals: During this time frame, 453 cases were identified involving 467 dogs. Of these cases, 150 cases were excluded due to incomplete medical records, multipet households, or the inability to calculate a dose exposure. A total of 317 dogs with presumed sleep aid medication toxicosis were included., Interventions: None., Measurements and Main Results: Records of dogs with sleep aid medication toxicosis identified by a review of an animal poison control center electronic database were evaluated. The most common sleep aid medications ingested were zolpidem (240/317 [75.7%]), eszopiclone (62/317 [19.5%]), and zaleplon (15/317 [4.7%]). Overall, clinical signs developed in 36% of patients (115/317), while 64% (202/317) remained asymptomatic. The most common organ systems affected and clinical signs seen involved the central nervous system (eg, agitation, sedation) and gastrointestinal tract (eg, anorexia, hypersalivation, vomiting)., Conclusions: Overall, the prognosis for dogs with sleep aid medication toxicosis was excellent, and no fatalities were reported in this clinical population. As significant clinical signs can still be seen with ingestion, appropriate decontamination is warranted in asymptomatic patients via emesis or gastric lavage, followed by activated charcoal administration. Symptomatic patients should be hospitalized for monitoring and supportive care for a minimum of 12 hours or until clinical signs resolve., (© Veterinary Emergency and Critical Care Society 2011.)

Paliperidone, or 9-hydroxy risperidone, is the newest atypical antipsychotic agent to be approved for use by the Food and Drug Administration. Despite being the primary active metabolite of risperidone, paliperidone differs in several ways from risperidone. The most notable difference is that paliperidone is formulated as an extended-release product. We present a case of a 14-year-old, 59-kg girl with a history of psychosis and major depressive disorder who developed toxicity after an ingestion of 180 mg (3.1 mg/kg) of paliperidone. This case is not only one of the first cases of paliperidone overdose described in the literature but also is unique in that it describes delayed onset of toxicity, as well as extended duration of symptoms., (Copyright © 2011 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.)

Introduction: Self-poisoning with herbicides is an important reason for hospital admission and death in Asia. Although some herbicides have a well-described toxicity profile in humans, many of the newer compounds rely on extrapolation from animal results as no published literature on clinical outcomes of human self-poisoning has been described. One example of these compounds is bispyribac, a selective herbicide used in rice and wheat cultivation that is marketed in two containers, one containing bispyribac 400 g/L with a solvent and the other the surfactant, polyethylene glycol. We present the first case series of acute human self-poisoning with an herbicide product containing bispyribac., Methods: Clinical data for all patients who presented with acute poisoning from a bispyribac-containing herbicide (Nominee) to two general hospitals in Sri Lanka from June 2002 to January 2009 were collected prospectively. Admission and serial blood samples were collected from consenting patients to confirm exposure and to study the toxicokinetics of bispyribac, respectively., Results: One hundred ten patients with a history of bispyribac ingestion presented after a median time of 4 h post-ingestion. There were three deaths at 15, 6, and 5 h post-ingestion because of asystolic cardiac arrest. All three patients had reduced Glasgow Coma Score (GCS) (3, 12, and 13, respectively) of whom the former two had co-ingested ethanol and developed tonic-clonic seizures. Admission blood sample was obtained from the former two of these patients but bispyribac was detected in only one of these patients. The other patient presented 2.5 h post-ingestion with a GCS of 12 but bispyribac was not detected. Excluding the patient with undetectable bispyribac, a conservative estimate of the case fatality ratio at 1.81% (95% confidence interval 0.32-5.8) can be made. The majority of the remaining patients had self-limiting upper gastrointestinal symptoms and eight patients had an abnormal GCS on presentation to hospital. The overall median hospital stay was 3 days. Bispyribac was not detectable on admission in 21 patients; in the remaining patients, the median plasma concentration was 50.55 microg/mL (interquartile range 1.28-116.5; n=32). The peak concentration was noted around 3 h post-ingestion and plasma bispyribac concentration did not predict the severity of poisoning., Conclusion: The majority of patients developed self-resolving symptoms and were successfully managed in rural general hospitals without transfer to larger tertiary hospitals. Patients who died developed significant poisoning within 6 h and plasma bispyribac concentrations did not appear to predict mortality. The lack of correlation between bispyribac outcomes and the available plasma concentrations may be because of exposure to nonbispyribac components or other undefined factors. Clinical outcomes from acute self-poisoning with bispyribac-containing herbicides appear to be relatively more favorable than other commonly used herbicides.

The present study deals with the genotoxicity assessment of vineyard pesticides in fish exposed in the field or in mesocosm conditions. Primary DNA damage was quantified as strand breaks using the single cell gel electrophoresis assay (Comet assay) applied to fish erythrocytes. In a first experiment, a significant genotoxic effect was observed following an upstream-downstream gradient in early life stages of brown trout (Salmo trutta fario) exposed in the Morcille River contaminated by a mixture of vineyard pesticides during three consecutive years. The pronounced response in terms of DNA damage reported in the present study could argue for a high sensitivity of fish early life stage and/or a high level of exposure to genotoxic compounds in the Morcille River. This stresses the interest in using trout larvae incubated in sediment bed to assess genotoxic compounds in the field. In a second experiment, adult European topminnow (Phoxinus phoxinus) were exposed in water running through artificial channels to a mixture of diuron and azoxystrobin, two of the main pesticides detected in the Morcille watershed. As compared with the unexposed channel, a 3-5-fold increase in the DNA damage was observed in fish exposed to chronic environmental pesticide concentrations (1-2 microg L(-1) for diuron and 0.5-1 microg L(-1) for axoxystrobin). A single 6h pulse of pesticide (14 microg L(-1) of diuron and 7 microg L(-1) of azoxystrobin) was applied to simulate transiently elevated chemical concentrations in the river following storm conditions. It did not increase genotoxicity. After a 1-month recovery period, DNA damage in exposed fish erythrocytes recovered to unexposed level, suggesting possible involvement of both repair mechanisms and cellular turnover in this transient response. This work highlights that vineyard treatment by pesticides and in particular diuron and azoxystrobin can represent a genotoxic threat to fish from contaminated watershed rivers.

Objective: Anticholinesterase compounds like organophosphorous and carbamates account for the majority of poisonings by the insecticides class agents. While the toxicokinetic depends on the extent of exposure and also on the chemical structure of the agent, the clinical symptoms range from the classic cholinergic syndrome to flaccid paralysis and intractable seizures. The carbamate ester pirimicarb (Pirimor), a toxic N-dimethylcarbamate pesticide, is used as insecticide. Our case presents the first poisoning associated with clinical and analytical findings., Patient: A 68-year-old male ingested an unknown amount of pirimicarb and developed cholinergic symptoms immediately, accompanied by seizures., Interventions: He was admitted in the Intensive Care Unit (ICU) and received intensive care including intubation for hypoxemia following seizures and drug therapy of hypertensive dysregulation. No Atropine but benzodiazepines were administered. The patient recovered in the ICU after 3 days and was discharged after a week., Measurements and Results: Pirimicarb stomach, blood, and urine levels were determined on admission and during hospitalisation. Using an one-compartment model the pesticide elimination was estimated and its terminal half-life in plasma, t1/2, was found to be 3.8 hours. The butyryl cholinesterase (BChE) activity was at the lower level of detection on the admission and recovered during the following 24 hours.

The development of discolored urine may have many possible causes. Here we present the case of a 76-year-old woman who was admitted after ingesting the inorganic herbicides, mefenacet and imazosulfuron. Her urine color changed to green almost immediately. Since the patient had no specific medication or medical history we considered that the most likely cause of the change in urine color was the ingestion of the herbicides. Spectrophotometric analysis of the urine was conducted and a peak was observed in the green area of the wavelength spectrum. These findings show that mefenacet and imazosulfuron should be considered in the differential diagnosis of green discolored urine.

Nine 3,9-diaryl- and 3,9-difuryl-bis-1,2,4-triazolo[4,3-a][4,3-c]pyrimidines (3a-i) have been synthesized by the oxidation of bis-2,4-pyrimidinylhydrazones of various araldehydes and furfural with 2equiv of iodobenzene diacetate (IBD) in dichloromethane and tested in vitro for their antibacterial activity. Three compounds, namely 3,9-di-(4'-fluorophenyl)-bis-1,2,4-triazolo[4,3-a][4,3-c]pyrimidine (3f), 3,9-di-(4'-nitrophenyl)-bis-1,2,4-triazolo[4,3-a][4,3-c]pyrimidine (3g) and 3,9-di-(5'-nitro-2'-furyl)-bis-1,2,4-triazolo[4,3-a][4,3-c]pyrimidine (3i), were associated with substantially higher antibacterial activity than some commercial antibiotics against Gram-positive bacteria namely Staphylococcus aureus, Staphylococcus epidermidis and Bacillus subtilis; two Gram-negative bacteria namely Salmonella typhi and Escherichia coli at MIC (minimum inhibitory concentration) 10microg/ml.

Unlabelled: There has been little data in the medical literature about intoxication with a new hypnotic agent zaleplon. The zaleplon, chemically N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamid, is a selective agonist of the benzodiazepine omega 1 receptor subtype. The case of a 15-year-old female who eat 60 mg of zaleplon (1.2 mg/kg) because of suicidal attempt was described. At the admission to the hospital the somnolence, blurred speech, slowdown, ataxia, tachycardia and hypokalaemia were observed. The child was treated symptomatically, and discharged from the hospital for further psychologic treatment after 36 hours., Conclusions: Acute intoxication with zaleplon had mild clinical course. The signs of intoxications were drowsiness, blurred speech, ataxia, tachycardia, dizziness, confusion and vomiting. The described case required only symptomatic treatment.

Zolpidem and zaleplon are used for the treatment of insomnia. The objective of this study was to compare the patterns of zolpidem and zaleplon exposures reported to Texas poison control centers during 1998-2004. There were 5842 total reported zolpidem exposures, of which 2918 (50%) were isolated exposures, and 467 total reported zaleplon exposures, of which 201 (43%) were isolated exposures. Zolpidem patients were 62% male and 67% adult. Zaleplon patients were 67% male and 34% adult. The exposure was intentional in 62% of zolpidem and 58% of zaleplon exposures. The exposure occurred at the patient's own residence in 94% of zolpidem and 97% of zaleplon exposures. Management occurred outside of a health care facility for 29% of zolpidem and 32% of zaleplon exposures. The medical outcome involved no symptoms due to exposure for 29% of zolpidem and 44% of zaleplon exposures, a statistically significant difference. Although many of the most frequently reported adverse clinical effects for the two drugs were similar (drowsiness, slurred speech, hallucinations, ataxia, tachycardia, dizziness, confusion, vomiting), the proportion of exposures with a given adverse clinical effect was generally lower for zaleplon. Thus, although zolpidem and zaleplon exposures were generally similar with respect to patient gender and age, exposure reason and site, and management site, zaleplon exposures were less likely to result in minor medical outcomes or manifest as adverse clinical effects.

Pyridoxine (vitamin B6) is a co-factor in many enzymatic pathways involved in amino acid metabolism: the main biologically active form is pyridoxal 5-phosphate. Pyridoxine has been used as an antidote in acute intoxications, including isoniazid overdose, Gyromitra mushroom or false morrel (monomethylhydrazine) poisoning and hydrazine exposure. It is also recommended as a co-factor to improve the conversion of glyoxylic acid into glycine in ethylene glycol poisoning. Other indications are recommended by some sources (for example crimidine poisoning, zipeprol and theophylline-induced seizures, adjunct to d-penicillamine chelation), without significant supporting data. The value of pyridoxine or its congener metadoxine as an agent for hastening ethanol metabolism or improving vigilance in acute alcohol intoxication is controversial. This paper reviews the various indications of pyridoxine in clinical toxicology and the supporting literature. The potential adverse effects of excessive pyridoxine dosage will also be summarized.

REBIN GT SC (glyphosate isopropylamine and butafenacil, hereinafter referred to as "REBIN") is a nonselective herbicide which was developed by Syngenta Japan K. K. and was registered in July 2001 as a herbicide. We report the first case of acute poisoning by REBIN. In this case (Age 67, male), high fever and general fatigue developed immediately after REBIN inhalation. Furthermore, urine sugar, urine protein, high LDH and high GPT were observed. But the patient showed a tendency of recovery after the lapse of 48 hours by the intravenous fluid replacement, hydrocortisone sodium succinate (Solu-Cortef), glycyrrhizin (Stronger Neo-Minophagen C) and glutathione (Tathion). He recovered satisfactorily. It is necessary to respect the instructions for the use of REBIN. In addition, in order to prevent inhalation of REBIN, the proper use of instruments and spray at about 30 cm under knee are essential.

We present a case of lethal ingestion of pyrimidifen, a new insecticide with an unclear mode of action. The primary manifestations were coma and circulatory shock, leading to irreversible multiorgan failure. Pyrimidifen was detected in the patient's blood, urine, brain tissue, and gastric content samples. Minimal structural homology exists between pyrimidifen and organochlorines. Currently, no antidote is available, and therapy is primarily supportive.

Zaleplon ("Sonata") is a pyrazolopyrimidine derivative approved for use in the United States for the treatment of insomnia. To date, there has been little data in the toxicological literature where zaleplon has been implicated as causing a fatal intoxication, either alone or in combination with other drugs. This report documents a case where zaleplon was identified in a suicide by multiple drug ingestion. The following zaleplon concentrations were found: heart blood 2.2mg/l; bile 8.6mg/l and urine 1.4mg/l. Zaleplon was also detected but not quantitated in the kidney and liver.

Fenarimol (Rubigan) is a pyrimidine ergosterol biosynthesis inhibitor used as a systemic fungicide. The authors present a fatal fenarimol intoxication case analysed in the Forensic Toxicology Service of the National Institute of Legal Medicine. The results were used to compare two different HPLC techniques, regarding selectivity and sensitivity: an HPLC system with a diode array detector (DAD) and an HPLC system with a DAD and a mass spectrometry detector (MSD) with an electrospray interface. All biological samples were submitted to a solid-phase extraction procedure. The detection and quantification limits of fenarimol, linearity, precision and accuracy were evaluated. The fenarimol concentration levels determined were of 89.0 mg/ml in gastric contents, 1.9 mg/g in liver and 0.4 mg/g in kidney. Blood was not available at autopsy. No published data related to fenarimol self-poisoning were found, so it was not possible to interpret the results obtained by comparison with toxic/lethal levels.

Crimidine (2 chloro, 4 methyl, 6 dimethyl amidopyrine) is a synthetic rodenticide which causes acute poisonings after oral ingestion in human. Major toxic effects are consciousness disorders, hypertonic coma and convulsions. Toxic level in human is about 5 mg/Kg. An intoxication case is reported. Five serums collected at different times were analyzed with HPLC/ES/MS. Crimidine was extracted with ethylacetate with recovery over 80%. Linearity was up to 800 micrograms/L. LOQ and LOD were 0.5 and 0.3 microgram/L respectively. The coefficients of variation were less than 10% for repeatability and reproductibility. Serum levels varied from 368 micrograms/L for H0 to 64 micrograms/L for H10 and elimination of crimidine was linear in time.

CTP synthetase (EC 6.3.4.2, UTP:ammonia ligase (ADP-forming)) activity in Saccharomyces cerevisiae is allosterically regulated by CTP product inhibition. Amino acid residue Glu161 in the URA7-encoded and URA8-encoded CTP synthetases was identified as being involved in the regulation of these enzymes by CTP product inhibition. The specific activities of the URA7-encoded and URA8-encoded enzymes with a Glu161 --> Lys (E161K) mutation were 2-fold greater when compared with the wild-type enzymes. The E161K mutant URA7-encoded and URA8-encoded CTP synthetases were less sensitive to CTP product inhibition with inhibitor constants for CTP of 8.4- and 5-fold greater, respectively, than those of their wild-type counterparts. Cells expressing the E161K mutant enzymes on a multicopy plasmid exhibited an increase in resistance to the pyrimidine poison and cancer therapeutic drug cyclopentenylcytosine and accumulated elevated (6-15-fold) levels of CTP when compared with cells expressing the wild-type enzymes. Cells expressing the E161K mutation in the URA7-encoded CTP synthetase exhibited an increase (1.5-fold) in the utilization of the Kennedy pathway for phosphatidylcholine synthesis when compared with control cells. Cells bearing the mutation also exhibited an increase in the synthesis of phosphatidylcholine (1.5-fold), phosphatidylethanolamine (1.3-fold), and phosphatidate (2-fold) and a decrease in the synthesis of phosphatidylserine (1.7-fold). These alterations were accompanied by an inositol excretion phenotype due to the misregulation of the INO1 gene. Moreover, cells bearing the E161K mutation exhibited an increase (1.6-fold) in the ratio of total neutral lipids to phospholipids, an increase in triacylglycerol (1.4-fold), free fatty acids (1.7-fold), and ergosterol ester (1.8-fold), and a decrease in diacylglycerol (1. 3-fold) when compared with control cells. These data indicated that the regulation of CTP synthetase activity by CTP plays an important role in the regulation of phospholipid synthesis.

Study was made of the effect of acute poisoning with primor or with an equitoxic mixture of primor/tiuram (oral dose amounting to 50% of LD50) on the dynamic equilibrium of catecholamines and serotonin in rat whole brain, anatomic parts of the brain, heart and suprarenal glands. Both primor and an equitoxic mixture of primor/tiuram were found to cause changes in the levels of the investigated neurotransmitters in the central and peripheral nervous system. The mixture, as compared with primor alone, displayed the same direction of action, but the changes proceeded with enhanced dynamics and lasted throughout the whole experimental period (12h). The action of primor alone usually manifested itself only during the first hour after poisoning. Both primor and an equitoxic mixture of primor/tiuram exhibited no selective affinity to any separate areas of the brain, and lowered the contents of dopamine and norepinephrine in all brain structures studied.

Not infrequently, the continuous use of pesticides leads to production of resistant species of agricultural pests which makes imperative to adopt the practice of intermittent, i. e. periodic application of the agricultural preparations. In this work the difference in degree of pathoanatomical damage upon chronic and periodic, weekly application of the new carbamide pesticide Pyrimor, extensively used in the Bulgarian farming economy, is discussed. The results of pathomorphological and histochemical study of the chief parenchymatous organs shows a clearcut difference in the group with continuous administration of the pesticide, as compared to the control and intermittently poisoned group. It is furthermore pointed out that the two-times higher dose, introduced at weekly intervals, leads to slighter lesions of parenchymatous organs in comparison with chronic, oral Pyrimor treatment. Season related, incessant use of pesticides results in occupational risk increase among the workers engaged in farming.

The diagnosis and treatment of a case of crimidine poisoning in a dog are described. Presenting signs were seizures and vomiting. The vomitus contained a purple coloured cereal grain. The signs and grain colour were suggestive for a rodenticide with convulsive effects. The diagnosis of crimidine poisoning was made by thin layer chromatography and was later confirmed by finding the source of the poison. Except for the administration of Vit B6, the specific antidote for crimidine, general treatment principles for poisoning were followed. The treatment of crimidine poisoning is time consuming and requires intensive care facilities.

The effect of fenarimol in blood cells and changes in liver and kidneys in rats were investigated. Fenarimol applied in doses 25 mg/ml intragastrically during 5 days, at 24h after the last doses caused functional and structural changes of blood cells and organs. The decreases of osmotic fragility of erythrocytes and phagocytic activity of neutrophils, and the increase of the percentage of lymphocytes without detectable lysosomes accompanied by the minor decrease of the number of blood cells was observed in the peripheral blood. The indistinctness of the structure of the hepatic lobules and of liver laminae and the vacuolized hepatic cells with pycnotic nuclei were visible in the liver. The abnormally enlarged cortical Malphighian++ glomeruli in kidney were found. The observed changes indicate the cytotoxic effect of fenarimol in strongly intoxicated rats. The impaired phagocytic activity of neutrophils may cause the growth of susceptibility to bacterial infection.