[Some pathogenetic aspects of developing liver failure and preventing it in patients with liver cirrhosis after portosystemic shunting]. / Nekotorye patogeneticheskie aspekty razvitiia pechenochnoi nedostatochnosti i ee profilaktika u bol'nykh s tsirrozom pecheni posle portosistemnogo shuntirovaniia.

Patients with cirrhosis of the liver were found to have a considerable suppression of the system of biotransformation of the liver before operation which correlated with the data of the direct indices of monooxigenase system of hepatocytes--cytochrome P-450 and activity of N-demethylase of amidopyrine. Operative interventions on such patients independent of the type of portosystemic shunting result in considerably decreased content of metabolites of amidopyrine--4AAP and N-ac-4-APP in urine as compared with the preoperative level (p < 0.05). Hyperbaric oxygenation is the optimal stimulator of activity of the liver biotransformation system. Better indicators characterizing the increased metabolic activity of the liver were noted in patients with selective portosystemic anastomoses and hyperbaric oxygenation in the postoperative period.

A piezoelectric biomimetic sensor for aminopyrine with a molecularly imprinted polymer coating.

A molecularly imprinted polymer for aminopyrine was synthesized using methacrylic acid as functional monomer. The polymer was employed as the recognition element of a piezoelectric bulk acoustic wave biomimetic sensor for aminopyrine. Influencing factors were investigated in detail and optimized. This sensor exhibited high selectivity and sensitivity to aminopyrine. The response range of the sensor was between 5.0 x 10(-8) and 1.0 x 10(-4) M with a detection limit of 2.5 x 10(-8) M in the aqueous system. Scatchard analysis with UV spectrophotometry showed that the same class of binding sites was formed in the molecularly imprinted polymer in the studied concentration range, and the dissociation constant and the apparent maximum number of these binding sites were estimated to be 2.29 mM and 165.0 mumol g-1 dry polymer, respectively. Impedance analysis was employed to verify the imprinting effect and lack of variation in the viscoelasticity of the polymer coating during detection.

[Various mechanisms of the depriming effect of bacterial endotoxin on drug metabolism]. / Nekotorye mekhanizmy deprimiruiushchego vliianiia bakterial'nogo éndotoksina na metabolizm lekarstvennykh veshchestv.

The effect of an endotoxin from Sh. Boydii on the biotransformation of amidopyrine and acetanilide, the activity of microsomal monooxygenases, hemoxygenase, and xanthine oxidase, the lipid peroxidation (LPO) intensity, the phospholipid spectrum, and the solubilization of microsomal membrane components was studied by intraperitoneal injections (2.5 mg/kg) in rats. It was found that the endotoxin inhibits the reactions of C- and N-acetanilide hydroxylation, N-amidopyrine demethylation, acetanilide hydrolysis at the amide bond, conjugation of aminophenol metabolites with glucuronic acid and sulfate, and 4-aminoantipyrine binding to acetate. The endotoxin effect reached maximum 24 h after injection and was observed for 96 h. The inhibition of metabolism of the test preparations is related to a decrease in the content of cytochrome P-450 and in the activity of 1A2, its 2B, 2C, 3A, and 2E1 isoforms. This is obviously caused by activated LPO and enhanced nitric oxide synthesis, as evidenced by a tenfold increase in the content of NO metabolites (nitrites and nitrates) in the blood of test animals. In clinical practice, it is necessary to take into account the possibility of a significant biotransformation of drugs in the acute period of bacterial infection, which may lead to changes in the pharmacological effect and toxicity of some drugs.

Metabolism of aminopyrine and derivatives in man: in vivo study of monomorphic and polymorphic metabolic pathways.

1. The main metabolic pathways involved in the biodisposition of aminopyrine have been monitored in vivo in 60 healthy volunteers by measuring the amount of parent drug and metabolites recovered in the urine 24 h after oral administration of 250 mg aminopyrine. 2. The amount of metabolites in the 24-h urine was (mean +/- SD of 60 individuals): unchanged aminopyrine, 0.2 +/- 0.2 mg; methyl aminoantipyrine, 4.5 +/- 2.8 mg; formyl aminoantipyrine, 18.5 +/- 10.1 mg; aminoantipyrine, 9.2 +/- 6.6 mg; and acetyl aminoantipyrine, 31.8 +/- 21.1 mg. 3. Large interindividual differences (12-200-fold changes) are present in all the metabolic steps involved in aminopyrine biotransformation. These differences are not related to gender, intake of caffeine or alcohol, or known drug-metabolizing polymorphisms such as those involved in debrisoquine or mephenytoin metabolism. In contrast, smoking resulted in a decrease in the N(4)-demethylation ratio (p = 0.011). 4. The interindividual differences followed an apparently normal distribution in the N(4)- and N(2)-dimethylation and formylation pathways (p > 0.1). In contrast, acetylation follows a polymorphic distribution (p < 0.03), with an apparent antimode ratio close to 4. With the exception of the acetylation pathway, all of the metabolic ratios correlated between themselves (p < 0.001).

Determination of aminopyrine, dipyrone and its metabolites in urine by high-performance liquid chromatography.

A readily applicable and accurate isocratic high-performance liquid chromatography method for the detection of aminopyrine, dipyrone and its metabolites in urine is described. Parent drugs and four metabolites were chloroform-extracted from 1 ml of urine after addition of the internal standard isopropylaminoantipyrine and alkalinization. The organic phase was evaporated to dryness, and the residue was reconstituted in the mobile phase, which was injected onto a Spherisorb ODS 5 microns particle-size column (250 x 4.6 mm) using as mobile phase water, methanol, triethylamine, and acetic acid. The column eluent was monitored by ultraviolet absorption at 254 nm. Excellent linearity (r > 0.99) was obtained in the range 1-150 micrograms/ml urine, either for parent drugs and metabolites. This method offers a sensitive assay for aminopyrine, dipyrone (widely consumed in some countries) and its metabolites. After oral administration and collection of 24-h urine, this method allows the in vivo study of aminopyrine metabolism, which reflects liver function.

Determination of the "chromatographic pattern" for the identification of dipyrone urinary metabolites.

Sodium [N-(1,5-dimethyl-3-oxo-2-phenylpyrazolin-4-yl)-N-methylamino] methanesulfonate (dipyrone) cannot be detected as such in biological fluids since absorption is preceded by hydrolysis to 4-methylaminoantipyrine, which is actually absorbed and further metabolized. In the present work standardized TLC Rf values and gas chromatographic retention indices for the four main urinary metabolites of dipyrone were determined. Inclusion of these parameters in the principal component analysis "scores plot" allows dipyrone to be included as a possible candidate in the not oriented search for unknown drug assumption in cases of overdose intoxication or poisoning.

In vivo nitrosation of amidopyrine in humans: use of 'ethanol effect' for biological monitoring of N-nitrosodimethylamine in urine.

Under normal conditions a possible N-nitrosodimethylamine formation in vivo cannot directly be monitored in urine due to high metabolic conversion rate (greater than 99.9%). Own experiments showed an increased excretion rate (up to 2.4%) if ethanol was administered simultaneously. This model was used for monitoring experiments with respect to in vivo formation of N-nitrosodimethylamine. Amidopyrine, as a compound which is easily nitrosated, was administered (single oral dose of 500 mg) to volunteers. Under the influence of 20-30 g ethanol it was possible to detect N-nitrosodimethylamine in urine. From negative control experiments it must be concluded that this appearance of N-nitrosodimethylamine derives from in vivo nitrosation of the drug. The amount excreted in urine varied between 0.5 and 10 micrograms N-nitrosodimethylamine within 8 h and seemed to be influenced by salivary nitrite concentrations which ranged from 5 to 220 p.p.m. NO-2. In comparison with earlier excretion studies in humans it can be assumed that only 1-2% of the originally formed nitrosamine was found in urine. To our knowledge this is the first time that in vivo formation of N-nitrosodimethylamine was directly shown to occur in humans.

[Metamizol--acute overdose with suicidal intent]. / Metamizol--akute Uberdosierung in suizidaler Absicht.

An 18-year-old girl swallowed 98 tablets of Novalgin (corresponding to 49 g metamizole) with suicidal intent. After stomach lavage she received forced diuresis for 14 hours. Metamizole metabolites in serum and urine were measured by thin-layer chromatography. After 24 hours the serum concentration of metamizole metabolites was still clearly elevated. Renal elimination amounted to 11 g metamizole. The patient survived the severe overdosage without significant organ abnormalities. This favourable course differs from reports of lethal intoxication with other pyrazolone derivatives, especially those with metamizole combination drugs. The forced diuresis proved to be a satisfactory elimination procedure. Biotransformation and elimination of the metamizole metabolites still continued after 24 hours.

The determination of aminopyrin elimination for control of the metabolic capacity of the liver in man.

The kinetics of plasma and breath elimination of aminopyrine after 14C-aminopyrine given orally were studied using an open one-compartment model and first order rates of elimination. The study comprised eight healthy volunteers and two groups with histologically verified chronic liver diseases (cirrhosis, n = 12, and chronic aggressive hepatitis, n = 12). Elimination rates from plasma and breath were significantly reduced in the group with cirrhosis, but only so in chronic aggressive hepatitis when they were expressed relative to each other. Monomethylaminopyrine was eliminated more rapidly compared to aminopyrine, and the rate of formaldehyde formation was positively correlated to the excretion rate of CO2 (r = 0.53, P less than 0.002). No correlation was found with clinical or other laboratory data in the groups of liver diseases studied. The test is a quantitative indicator of the drug metabolizing mixed function oxidases of the endoplasmatic reticulum of the liver, and may reflect the degree of damage to this system in chronic liver disease.

Quantitative high-performance liquid chromatographic determinations of aminopyrine and its metabolites in man.

A quantitative high-performance liquid chromatographic method, using a polystyrene-divinyl benzene (Hitachi No. 3010 gel) column and aqueous methanol as the mobile phase, was employed for the determination of aminopyrine and its related compounds, 4-acetyl-aminoantipyrine, 4-aminoantipyrine and 4-monomethylaminoantipyrine. Baseline separation could be achieved within 25 min. The method was applied to the recovery of these materials from control urine and human urine. Before separation human urine was adjusted to pH 9 and extracted with ethyl acetate, chloroform and diethyl ether.

[Finding of analgesic components and their metabolites in doping control]. / Nálex soucástí analgetik a jejich metabolitu pri dopingové kontrole.

In doping controls it is important to exclude essential substances that are not in the list of forbidden drugs. Similarly it is important as well for these drugs to be proved in analgesic mixture abuse. An example being the proof of amidopyrine and its metabolites, further on p-phenetidine as a metabolie of phenacetin in alkaline urine extracts. Results are given in using thin-layer chromatography, gas chromatography and the identification by means of gas chromatography/mass spectrometry.