The influence of neuroleptic drugs on urinary excretion of non-protein nitrogen (author's transl)]

During treatment with thioxanthenes or phenothiazines of schizophrenic patients non-protein nitrogen in urine was measured. The values were calculated in relation to the excretion of creatinine. a) Flupentixol or fluphenazine applied in optimal dosage, increased the excretion of urea and the amino acids asp, glu + gln, and gly. b) Moreover, if the drug induced a parkinsonoid (thioridazine) the excretion of ser and thr was increased, too. The usual desalting procedure by ion-exchanging resins before chromatography increases the contents of several amino acids, e.g. asp, asn, ala, gly, cys, ser, thr, indicating a breakdown of some instable products.     

Effects of methyl methacrylate on non-protein thiols and drug metabolizing enzymes in rat liver and kidneys

Male Wistar rats received methyl methacrylate monomer (MMA) i.p. in olive oil 1.0 g/kg body weight on 3 successive days. The weight of the livers and kidneys, and the body weights did not differ from their controls. On the fifth day after treatment, hepatic NADPH-cytochrome c reductase, 7-ethoxycoumarin 0-deethylase and the 2,5-diphenyloxazole hydroxylase exhibited maximal decreases in activity (25%, 58%, 36%, respectively) without any coincident effect on the total amount of cytochrome P-450 hemoprotein itself. One week later these activities had returned to control levels. The enzymatic changes in the kidneys were smaller in magnitude, and they were also reversed sooner. A single i.p. dose of MMA (2 g/kg body weight) caused elevation of serum alanine aminotransferase activity. A tenfold increase of the excretion rate of urinary thioethers was also discovered. The hepatic reduced glutathione (GSH) was depleted in 3 h to 20% and the GSSG to half of the value in controls. In kidneys, the GSH was decreased to 48% in 3 h before an apparent phase of overrecovery. At the end of the 24 h observation period, cytochrome P-450 concentrations were somewhat decreased in the liver. The GSH contents showed dose and time-dependent reversible decreases in isolated hepatocytes when incubated for 2 h in a medium containing MMA at the nominal concentrations of 0, 2, 5, or 10 mM. None of the treatments affected either the content of cytochrome P-450 or the viability of the liver cells.     

Intoxication by cholinesterase inhibitors versus opioid intoxication

A 47 y-old male shopkeeper from a rural area ingested an unknown substance while under the effects of ethylic alcohol. He was admitted at the University Hospital of the Andes in generally poor condition with a cholinergic syndrome. An erroneous diagnosis of acute pulmonary edema and opioid intoxication was reached. The value of a patient's history (background) and careful evaluation of the physical examination findings without underestimating critical clinical signs are very important when handling a clinical intoxication.     

L-Arginine-dependent production of nitrogen oxides by rat pulmonary macrophages

Rat alveolar and pleural macrophages incubated with lipopolysaccharide, opsonized zymosan or recombinant interferon-γ, but not with recombinant tumor necrosis factor-, produced nitrite dose and time depcndently. This production depends on the presence and amount of L-arginine in the culture medium. The precursor of the nitrite was demonstrated as being nitric oxide, by bleaching of ferredoxin at 410 nm when added to the culture medium. Addition of N^G-monomethyl-L-arginine, an inhibitor of nitric oxide synthesis, and cycloheximide, a protein synthesis inhibitor, to the medium resulted in a decrease of nitrite production. Glucocorticoids were able to block the induction of nitrite production in alveolar macrophages. These data indicate that pulmonary macrophages are capable of secreting L-arginine-derived nitrogen oxides.     

Intoxication of goats by Plumbago scandens in Northeastern Brazil

In the State of Paraiba, Northeastern Brazil, goat mortality occurred with the ingestion of Plumbago scandens. The fresh plant was then given experimentally to 4 goats at 5, 10, 17.5 or 25 g/kg bw. Depression, anorexia, salivation with foamy saliva, bellowing, bruxism, humpbacked posture, bloat, ruminal atony, continuous lateral head movements, tachycardia, dyspnea and dark brown to black urine were observed in the goats given 17.5 or 25 g/kg bw. The goats receiving 5 or 10 g/kg bw had less severe signs. The goat dosed with 25 g/kg bw died after 18-20 h. All others recovered in 3-9 d. At necropsy of the high dose goat, the main lesions were dark violet to black discoloration of the mucosa of the tongue, esophagus, reticulum and ventral sac of the rumen, and gelatinous edema in the visceral ruminal peritoneum. Histologically the reticulum and ventral rumen sac had diffuse epithelial necrosis and severe edema and neutrophilic infiltration of the submucosa. Separation of the ruminal epithelium from the submucosa was observed. Epithelial degeneration and necrosis was also seen in the omasum, esophagus and tongue. Reproduction of the disease with clinical signs similar to those observed by the farmer in the spontaneously affected goats suggests that the clinical mortality was caused by ingestion of Plumbago scandens.     

Discriminative response control by d-amphetamine and related compounds in the rat

Rats were trained to discriminate between two levers utilizing drug-induced physiological states as discriminative stimuli. Drug injections were associated with reinforcement of response on one lever and saline was associated with reinforcement on the other lever. At equimolar doses, d- and l-amphetamine but not para-hydroxyamphetamine, functioned effectively as cues. Following training, stimulus generalization between these drugs was evaluated. Transfer of response control was observed between the d- and l-isomers, and between para-hydroxyamphetamine and saline in rats trained to utilize d- or l-amphetamine versus saline as cues. These findings suggest the importance of central pharmacological activity in this type of response control.This research was supported by National Institute of Mental Health Grant MH-19651.     

In vitro hemolysis of rat erythrocytes by selenium compounds

Rat erythrocytes were incubated in vitro with various selenium compounds at 37°. Hemolysis occurred with some selenium compounds but not with corresponding sulfur analogues. Selenite induced more rapid loss of intracellular glutathione (GSH) than did selenocystine but was less hemolytic. Cystine caused neither loss of intracellular GSH nor hemolysis. Addition of GSH to the incubation medium enhanced hemolysis by selenite and selenium dioxide but inhibited hemolysis by selenocystine. Inclusion of glucose in the incubation medium also inhibited selenocystine-induced lysis of erythrocytes from both selenium-supplemented rats and selenium-deficient rats. The results suggest a relationship between the oxidation of intracellular GSH and the hemolysis by selenocystine, selenite and selenium dioxide,     

Comparative metabolism and elimination of acetanilide compounds by rat

1. ¹⁴C-labelled propachlor, alachlor, butachlor, metolachlor, methoxypropachlor and some of their mercapturic acid pathway metabolites (MAP) were given to rat either by gavage or by perfusion into a renal artery. MAP metabolites were isolated from bile and urine.

2. Rat gavaged with propachlor and methoxypropachlor eliminated ¹⁴C mostly in urine, whereas rat gavaged with alachlor, butachlor and metolachlor eliminated ¹⁴C about equally divided between urine and faeces. When bile ducts were cannulated, the gavaged rat eliminated most of the ¹⁴C in bile for all compounds. The amount of ¹⁴C in bile from the propachlor-gavaged rat was less than that for the other acetanilides, with the difference being in the urine.

3. The mercapturic acid metabolites 2-methylsulphinyl-N-(1-methylhydroxyethyl)-N-phenylacetamide and 2-methylsulphinyl-N-(1-methylmethoxyethyl)-N-phenylacetamide were isolated from the urine and bile of the methoxypropachlor-gavaged rat.

4. Bile was the major route for ¹⁴C elimination when MAP metabolites of alachlor, butachlor and metolachlor were perfused into a renal artery. Urine was the major route for ¹⁴C elimination when MAP metabolites of propachlor and methoxypropachlor were perfused. Mercapturic acid conjugates were major metabolites in bile and urine when MAP metabolites were perfused.

5. We conclude that alkyl groups on the phenyl portion of the acetanilide causes biliary elimination to be favoured over urinary elimination.     

非蛋白巯基对顺铂在HEK293细胞内累积量的影响

谷胱甘肽(GSH)和N-乙酰-半胱氨酸(NAC)等非蛋白巯基(NPSH)化合物因含巯基(-SH)而具有亲核和还原特性，有参与解毒或保护上皮细胞免受氧化剂和其他活性亲电物的损伤。肝脏是血浆GSH的主要来源，肾小管上皮细胞主要从血浆摄取现成的GSH，也可通过摄取半胱氨酸或NAC自行合成GSH。肾毒物被摄取进入细胞内或在细胞外(即血浆)均可与NPSH相遇，或被解毒，或形成加合物而影响肾毒物的吸收。     

Intoxication by Non-Protein Nitrogen Compounds In Rat Feed

ABSTRACT

Last year our white rats (Wistar origin) showed acute behavioral and physiological changes followed by death in 70% of the animals. We detected that the malfunctions could be attributed to the new batch of laboratory rat pellets provided two weeks before. High levels of urea (260 mg/kg) and ammonia (540 mg/kg) were found in the feed while usual values in other similar feed were 48 mg/kg and 82 mg/kg respectively. Suspecting an ammonia intoxication, concentrations of ammonia and urea were determined in blood, brain and liver. Brain neurotransmitters and blood tryptophan and serotonine (5-HT) were also determined. Blood ammonia in rats fed the contaminated feed was about 100% higher than those fed the normal feed while liver and brain ammonia were three and four fold high respectively. Liver and brain urea were four to five fold and about 100% higher in the exposed group than in the group fed the control diet respectively. Blood 5-HT increased 62.33% in females and 99% in males whereas brain 5-HT increased 83.13% in females and 70.47% in males. But, we detected a 59.8% decrease in brain dopamine levels in females and a 38.65% decrease in males. Liver histology showed small droplets of fat stores mainly in centrolobular hepatocyte. No differences in blood or liver cholesterol concentrations were observed whereas liver triacylglycerides were significantly higher in intoxicated females. This study illustrates a problem of food borne intoxication that justifies the need for exhaustive analyses of even not usual compounds in every feed batch; moreover, it is demonstrated that rat behavior appears to be the earliest biomarker of ammonia exposure.     

Investigation of lipid peroxidation induced by hydrazine compounds in vivo in the rat

Phenylhydrazine caused lipid peroxidation in rats in vivo as detected by expiration of ethane but this was not due to lipid peroxidation in liver, as there was no associated MDA production in this tissue. Hydrazine did not cause either ethane expiration or MDA formation. Both hydrazine and phenylhydrazine caused a significant increase in propane expiration. Phenylhydrazine significantly decreased packed cell volume and haemoglobin levels but hydrazine had no effect on these parameters. These data indicate that the early toxicity of hydrazine does not involve peroxidation of lipids whereas phenylhydrazine causes lipid peroxidation possibly within the erythrocyte, perhaps by interaction with red cell haemoglobin.     

Dose-dependent effects of vinyltoluene inhalation on non-protein thiols and drug biotransformation in liver and kidneys of the rat

1. Male Wistar rats were exposed to atmospheres of 50, 100 or 300 p.p.m. vinyltoluene 6h/day, 5 days/week, for one or two weeks.

2. Hepatic non-protein sulphydryl content decreased in a dose-dependent manner when measured 0·5?h after the last exposure, both after one and two weeks.

3. The content of hepatic non-protein sulphydryl groups progressively increased 20?h after stopping the vinyltoluene exposure.

4. The activity of 7-ethoxycoumarin O-deethylase showed a dose-dependent increase both in liver and kidneys. The activity of UDP-glucuronosyltransferase also increased in a dose-related manner in both organs studied.     

Analysis of procainamide hydrochloride and acecainide hydrochloride in rat feed

An extraction and GLC assay procedure was developed for quantitation of procainamide hydrochloride and acecainide hydrochloride in rat feed. 4-Amino-N-[2-(dipropylamino)ethyl]benzamide hydrochloride was synthesized and utilized as an internal standard. The assay has good precision and accuracy and was used to establish the stability of acecainide hydrochloride and procainamide hydrochloride in rat feed.