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Objective: The pain-relieving effect and safety of compound aminopyrine phenacetin tablets, tramcontin (tramadol hydrochloride sustained-release tablets) and dolantin in the early stage of autologous tendon reconstruction of the anterior cruciate ligament (ACL) of the knee joint were compared., Methods: Retrospective analysis of postoperative pain and drug analgesia in 45 patients performed by the same group from November 2018 to February 2019. The random area group design was divided into two groups according to whether ACL rupture was combined with meniscal injury, group A was 24 patients with ACL reconstruction of knee joint and group B was 21 patients with ACL fracture combined with meniscus injury. The two groups were divided into three subgroups respectively according to the actual treatment of postoperative analgesic drugs received by the patients, including 4 cases of compound aminopyrine phenacetin tablets, 11 cases of oral tramcontin, 9 cases of intramuscular dolantin combined with phenergan in group A; 3 cases of compound aminopyrine phenacetin tablets, 10 cases of oral tramcontin, and 8 cases of intramuscular dolantin combined with phenergan in group B. When the early postoperative patients complain about pain and actively ask for analgesia. When the patients complained about pain after the operation and actively asked for analgesia, they were randomly given painkillers, tramcontin or dolantin combined with phenergan to relieve pain. Pain visual analogue scale (VAS) was used to evaluate pain relief and observe the occurrence of adverse reactions., Results: There were no significant dif-ferences in gender, age, body mass index, and time of hospital stay between the two groups of patients ( P > 0.05). In the patients who used tramcontin and dolantin combined with phenergan to relieve pain judging by VAS score before and 1 h after taking the drug, it was found that the pain situation of the patient was significantly relieved, and the difference before and after taking the drug had statistical significance ( P < 0.05). Pairwise comparisons of the three drugs applied in the two groups showed significantly greater pain relief in the dolantin combined with phenergan group than in the remaining two drugs. There was no significant difference ( P > 0.05). Dolantin was prone to nausea and vomiting, but the application of phenergan was also used to reduce side effects. In terms of adverse reactions, only 1 case of nausea occurred in the tramcontin group for simple ACL reconstruction, and none of the patients in the other groups showed serious complications and allergic reactions., Conclusion: Whether in cruciate ligament reconstruction alone or combined with meniscus molding or suture, compound aminopyrine phenacetin tablets, tramcontin, dolantin combined with phenergan can effectively relieve pain. Among the three drugs, dolantin caused the largest pain relief. At the same time, the combination of phenergan effectively reduced the adverse reactions, such as vomiting and nausea, and increased the drug safety.

Recently, a kind of 110‐kV transformer resistance decline defect was found during our routine preventive test of transformers in the Guangdong power grid. The number of defective transformers reached thirty. This phenomenon seriously threatened the safe and steady operation of the power grid. The analysis and treatment of this resistance decline defect were carried out. The key reason for this defect was confirmed. The insulating characteristics of insulating oil decreased. Aminopyrine is a kind of medicine used as an antipyretic analgesic. However, it was seldom investigated by the electric power industry. Aminopyrine as a potential contaminant was found to be present in insulating oils of transformers causing insulation resistance decline defect. Herein, the analysis process of defective insulating oils was introduced. The determination and quantitative detection of aminopyrine were performed using a gas chromatography‐mass spectrometer, in which the highest concentration of aminopyrine in insulating oil was determined to be nearly 100 mg/kg. The source of aminopyrine was surveyed. Moreover, the impact mechanism between aminopyrine and insulating property of transformer oil was discussed. Finally, we found adsorption was effective for this defect. To date, this method has been applied to solve this defect in the Guangdong power grid. © 2019 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc. [ABSTRACT FROM AUTHOR]

Objective To systematically evaluate the adverse drug reactions(ADR) and the Adverse drug events(ADE) of children using different aminopyrine in order to know the distribution of ADR and ADE, including the organ distribution, severity distribution, composition and influential factors of ADR and ADE. Methods Literature was retrieved in electronic databases covering CNKI, VIP, WANFANG data, CBM, Embase and PubMed, aminopyrine, analgin, medicine with the components of aminopyrine, and adverse drug reactions, adverse drug events, allergies etc. were taken as free words for comprehensive search. According to the criteria of inclusion and exclusion, the data were selected and collected. The total number and composition ratio of aminopyrine's ADR and ADE were calculated and the differences between the analgin, compound aminopyrine and the components of aminopyrine were analyzed according to different categories (age, drug allergy history, organ system involved, combination therapy, etc.). Results (1) A total of 484 Chinese literatures were included, including 555 cases，there were 205 cases of children;(2) A total of 70 English literatures were included, including 73 cases, there were 34 cases of children;(3) The ADR/ADE reported in Chinese and English literatures mainly involving the hematopoietic system, mucocutaneous system, urinary system, circulatory system which led to systemic reactions such as shock. The prognosis varies, with 174 cases recovered (72.80%), 30 cases death (12.55%)and 14 cases (5.86%) of the outcome were bone marrow transplantation, finger and toe amputation, subtotal gastrectomy and other serious adverse reactions. (4) most of the adverse reactions of the dose for the regular dose, but there were also over-dose medical staff caused by adverse events. Conclusion The use of aminopyrine might cause serious damage to children's hematopoietic system and urinary system, with serious adverse reactions and even deaths reported annually. It was suggested that aminopyrine as a potentially lethal drug should be withdrawal quickly. [ABSTRACT FROM AUTHOR]

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The incidence of non-alcoholic fatty liver disease (NAFLD) is rising across the globe, with the presence of steatohepatitis leading to a more aggressive clinical course. Currently, the diagnosis of non-alcoholic steatohepatitis (NASH) is based on histology, though with the high prevalence of NAFLD, a non-invasive method is needed. The 13C-aminopyrine breath test (ABT) evaluates the microsomal liver function and could be a potential candidate. We aimed to evaluate a potential change in liver function in NASH patients and to evaluate the diagnostic power of ABT to detect NASH. We performed a retrospective analysis on patients suspected of NAFLD who underwent a liver biopsy and ABT. 440 patients were included. ABT did not decrease in patients with isolated liver steatosis but decreased significantly in the presence of NASH without fibrosis and decreased even further with the presence of significant fibrosis. The predictive power of ABT as a single test for NASH was low but improved in combination with ALT and ultrasonographic steatosis. We conclude that microsomal liver function of patients with NASH is significantly decreased, even in the absence of fibrosis. The ABT is thus a valuable tool in assessing the presence of NASH; and could be used as a supplementary diagnostic tool in clinical practice.

Dipyrone is an analgesic and antipyretic drug that is sometimes encountered as an adulterant in illicit drug samples, particularly illicit fentanyl containing samples. It undergoes thermal decomposition to aminopyrine and 4-methylaminoantipyrine during analysis via gas chromatography (GC-FID) and gas chromatography-mass spectrometry (GC-MS). During analysis via high pressure liquid chromatography (HPLC) and high pressure liquid chromatography-mass spectrometry (HPLC-MS), it undergoes hydrolytic decomposition solely to 4-methylaminoantipyrine. Given that mass spectrometry is a widely used confirmatory analytical technique, these instabilities present challenges for the forensic chemist seeking to confirm the presence of dipyrone. Studies were conducted to determine rigorous confirmative protocols for the identification of dipyrone in multicomponent illicit drug samples. [ABSTRACT FROM AUTHOR]

• Rational hapten design strategy for aminopyrine was provided. • A specific antibody with IC 50 of 3.00 ng/mL was obtained for the first time. • Immunochromatographic assay for aminopyrine in herbal tea was proposed. Aminopyrine is a nonsteroidal anti-inflammatory drug only for medical purposes, however, it has been illegally added in traditional Chinese herbal teas for fraud activity recently. In this study, a specific antibody against aminopyrine with IC 50 of 3.00 ng/mL was obtained for the first time by a rational hapten design. Furthermore, an ultrasensitive gold nanoparticles immunochromatographic assay (AuNPs-ICA) for determination of aminopyrine based on a portable reader was firstly developed, with cut-off value of 100.00 ng/mL, limit of detection (LOD) of 4.80 ng/mL and limit of quantification (LOQ) of 5.71 ng/mL for herbal tea, respectively. The recovery rates ranged from 93.21 % to 105.61 %, with inter-assay coefficient of variation (CV) from 1.08 % to 3.82 %. Additionally, 24 blind samples were examined simultaneously by AuNPs-ICA and LC-MS/MS, demonstrating a good consistency for each other. The proposed AuNPs-ICA is an ultrasensitive and reliable tool for on-site surveillance screening of fraud additives in herbal tea. [ABSTRACT FROM AUTHOR]

One of the commonly used herbal medicines in Malaysia is Orthosiphon stamineus, Benth (family: Lamiaceae) or locally known as Misai Kucing. This experiment was undertaken to evaluate possible interaction of methanol extract of O. stamineus with aminopyrine, a model drug, in different age groups (young, adult and old) of Sprague-Dawley (SD) female rat hepatocytes. Hepatocytes were prepared by collagenase perfusion technique. Determination of aminopyrine N-demethylase activity was done by measuring formaldehyde formed. From these findings, only normal young female rat hepatocytes in the presence of 0.001 mg/ml of methanol extract of O. stamineus showed significant increase in aminopyrine N-demethylase activity. However, aminopyrine N-demethylase activity was not affected in hepatocytes of normal adult and old female SD rats. In conclusion, exposure of methanol extract of O. stamineus could affect phase I aminopyrine metabolism in normal young female SD rat hepatocytes but this effect was age-dependent.

This paper investigated the potential eco-toxicity changes of the drinking water containing aminopyrine (AMP) before and after chlorination. For the determination of the acute toxicity and genotoxicity, algal toxicity assay and SOS/ umu assay were adopted respectively. In these toxicity assays, the AMP exposure group was compared with the control group or the chlorination group to illustrate the changes. Results showed that the algal growth inhibition percentage increased with the increase of AMP concentration. After AMP chlorination, the inhibition percentage decreased at relatively low chlorine ratios (i.e., the AMP to chlorine molar ratio of 4:1 and 1:1) but increased at high chlorine ratios (i.e., the AMP to chlorine molar ratio of 1:2 and 1:5). The superoxide dismutase (SOD) activity was stimulated at AMP to chlorine molar ratios of 4:1 while inhibited at 1:5. The change of malondialdehyde (MDA) content was just opposite to the SOD activity. In SOS/ umu assay, when the molar ratios of AMP and chlorine were 1:1, 1:2 and 1:5, the values of induction ratio (IR) were over 1.5 and showed a positive genotoxicity signal in the absence/presence of S9 homogenate. Further, the Toxic Equivalent Quantity (TEQ) value, which was used to express the genotoxic potentials of those positive samples, gradually increased with the increase of chlorine ratio. In a word, the potential genotoxicity of chlorinated drinking water containing AMP should be of a concern. [ABSTRACT FROM AUTHOR]

The concentrations of residual aminopyrine and antipyrine in porcine muscle, milk, and egg samples were analyzed using liquid chromatography with tandem mass spectrometry after undergoing a series of sample pretreatment steps. Owing to an ion suppression effect, matrix-matched calibrations were used for analyte quantitation with determination coefficients (R²) > 0.9931. The recovery rates for aminopyrine and antipyrine in various matrices at two spiking levels (5 and 10 ng/g) fell in the range of 60.96-68.87 and 61.87-66.99%, respectively. Meanwhile, the intra- and inter-day precisions (expressed as relative standard deviation) were 1.02-12.95 and 1.71-5.50%, respectively. The method's detection limit (1 ng/g) was very low, thus enabling the detection of low residue levels. The applicability of the developed method was demonstrated with actual market samples and none of the tested analytes was detected in any of the samples. [ABSTRACT FROM AUTHOR]

Degradation efficiency, mechanism and intermediates’ toxicity of aminopyrine (an analgesic and antipyretic drug) upon ozonation were investigated under different oxidation approaches. Results showed that hydroxyl radical pattern (O 3 with H 2 O 2 addition) had the highest removal efficiency in aminopyrine, UV 254 and especially DOC. A total of 21 intermediates from aminopyrine oxidation were assessed by UPLC-Q-TOF-MS, which indicated that aminopyrine was degraded mainly from three pathways. The pyrazole ring break pathway consisted of pyrazole ring opening, demethylation, functional group loss, hydroxylation and substitution, demonstrating the major pathway for aminopyrine oxidation. The demethylation at 6 N position pathway was composed of demethylation at the 6 N position and further substitution at the 4 C position, principally occurred during the aminopyrine ozonation with H 2 O 2 addition. The dephenylization pathway was proved by only one intermediate (P21) during the aminopyrine ozonation without addition. Besides, lots of hydroxylated and di-hydroxylated intermediates were detected primarily during the oxidation without addition and with H 2 O 2 addition. The toxicity of these intermediates by EPA TEST showed that some of them were intended to be more toxic than aminopyrine. Further test from the toxicity of oxidized mixtures to the bioluminescent marine bacterium Vibrio fischeri demonstrated the samples could lead to the accumulation of toxic transformation products, especially for those by the oxidation with HCO 3 − addition. Finally, an O 3 -BAC system was applied to treat the raw water spiked with aminopyrine. Although three of the by-products could be detected during aminopyrine ozonation, they were expected to be easily removed by BAC adsorption. [ABSTRACT FROM AUTHOR]

With the popularity of herbal tea in China, many food fraudsters have added illegal drugs to herbal tea to enhance its functions, among which aminopyrine is widely abused as an antipyretic and analgesic. Presently, there is no immunoassays for aminopyrine, and it is difficult to achieve real-time detection in the field. Based on a polyclonal antibody of aminopyrine with high specificity and sensitivity, an optimal combination of coating antigen/antibody was obtained by screening different coating antigens. On this basis, a sensitive ic-ELISA method was established to detect aminopyrine in herbal tea. The detection limit of the ic-ELISA was 0.18 ng mL -1 , which was much lower than the 100 ng mL -1 required as a standard. The method had good consistency with LC-MS in the detection of actual samples and could be used as a reliable method for the detection of aminopyrine in herbal tea.

We report the development of a simple and accurate analytical method to detect aminopyrine in seized cocaine samples using a platinum electrode. The quantification of aminopyrine was performed using square wave voltammetry (SWV), where the peak current response was found to increase linearly with aminopyrine concentration over the range 100–1000 μmol L − 1 . The repeatability of the electrode response was determined to be 2.4% (n = 15), and the detection limit of the proposed method was estimated to be 22 μmol L − 1 (3σ/slope). The accuracy of the proposed method was evaluated comparing the measured aminopyrine concentration in seized cocaine sample to the value obtained by gas chromatography coupled to flame ionization detector (GC-FID). An addition and recovery protocol in seized cocaine samples was also performed. [ABSTRACT FROM AUTHOR]

1. It is inevitable that during some xenobiotic biotransformation studies, a certain metabolite or degradation product arises of which the identity is uncertain, the route of formation is ambiguous, or it is just a plain mystery. 2. The following communication draws attention to three drugs reported in the literature, chlorphentermine, phenothiazine and aminopyrine, where after many years of investigation there still exists uncertainty over some of their metabolites. Noticeably, these three examples probably involve (potential) interaction of a nitrogen centre within the drug molecule. 3. It is hoped that the resurrection and assemblage of these data will offer interesting reading and that these examples may prove sufficiently intriguing to motivate further exploration and some resolution of these lingering concerns. [ABSTRACT FROM AUTHOR]

Highlights: [•] Free chlorine can effectively remove PRP and AMP in the order: PRP>AMP. [•] Chlorine dosage was favorable to the removal of two pharmaceuticals by free chlorine. [•] Higher removal efficiencies of PRP and AMP were observed with neutral and slightly acidic pH, respectively. [•] PRP and AMP were not mineralized by free chlorine, but were transformed to other byproducts. [•] The substitution of Cl, dealkylation and ring-opening were the main transformation pathways. [Copyright &y& Elsevier]

As liver diseases are a major health problem and especially the incidence of metabolic liver diseases like non-alcoholic fatty liver disease ( NAFLD) is rising, the demand for non-invasive tests is growing to replace liver biopsy. Non-invasive tests such as carbon-labelled breath tests can provide a valuable contribution to the evaluation of metabolic liver function. This review aims to critically appraise the value of the 13C-labelled microsomal breath tests for the evaluation of metabolic liver function, and to discuss the role of cytochrome P450 enzymes in the metabolism of the different probe drugs, especially of aminopyrine. Although a number of different probe drugs have been used in breath tests, the perfect drug to assess the functional metabolic capacity of the liver has not been found. Data suggest that both the 13C2-aminopyrine and the 13C-methacetin breath test can play a role in assessing the capacity of the microsomal liver function and may be useful in the follow-up of patients with chronic liver diseases. Furthermore, CYP2C19 seems to be an important enzyme in the N-demethylation of aminopyrine, and polymorphisms in this gene may influence breath test values, which should be kept in mind when performing the 13C2-aminopyrine breath test in clinical practice. [ABSTRACT FROM AUTHOR]

BACKGROUND: Assessment of hepatic functional reserve in acute and chronic liver disease is a discriminating factor for prognostic and therapeutic reasons. For this reason dynamic liver function tests have been developed. AIM: To review the breath method with stable carbon isotopes in hepatological setting. MATERIALS AND METHODS: We conducted a literature review to analyze the experimental evidence about the diagnostic potential of breath tests of liver function. RESULTS: Liver breath tests are able to discriminate between healthy subjects and patients with liver cirrhosis. The use for the assessment of liver fibrosis seems to be still burdened with less capability to discriminate between intermediate stages. CONCLUSIONS: Liver breath test are a promising tool for the evaluation of hepatic functional reserve, but the use of such methods in clinical practice is limited to specialized or research centers. Most extensive studies are necessary to facilitate the spread of these methods in clinical practice. [ABSTRACT FROM AUTHOR]

Dimethyl sulfate is an important chemical raw material that is widely used in the synthesis of drugs, dyes, spices, and pesticides. The highly toxic and corrosive dimethyl sulfate residue in medicines is harmful to the human body, and hence, the residue level should be strictly controlled. Traditional detection methods use high-purity acetonitrile and anhydrous as the solvents, which limits the choice of detection solvents and degrades the versatility and accuracy of detection. Therefore, a simple and accurate method for the determination of dimethyl sulfate residues is urgently needed. Dimethyl sulfate is usually detected by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) with pyridine as the methylation substrate. In this study, a new method for the detection of dimethyl sulfate was established using tertiary amines such as aminophenazone, which has many advantages over pyridine, as the methylation substrate. For example, the hybrid orbital and electron cloud of the N atom are different, resulting in stronger nucleophilicity of aminophenazone. High temperatures that are detrimental to the stability of dimethyl sulfate are not required when using aminophenazone, and the aliphatic quaternary ammonium salt product is more stable, with good stability, low interference, good ionization properties, and high response. The separation was performed on a Waters Atlantis HILIC C18 column (100 mm×2.1 mm, 3.0 μm) using a mobile phase consisting of 10 mmol/L ammonium acetate solution-0.1% formic acid methanol solution (50∶50, v/v) at a flow rate of 0.3 mL/min. The column temperature was set at 40 ℃, and the sample size was 1 μL. Dimethyl sulfate was determined in the electrospray positive ionization (ESI + ) and multiple reaction monitoring (MRM) modes. Dimethyl sulfate showed good linear relationships within the range of 0.9935 to 7.9480 ng/mL ( r =0.9997). The limit of detection and limit of quantification for dimethyl sulfate were 0.50 ng/mL and 1.15 ng/mL, respectively. The recoveries ( n =3)of dimethyl sulfate were 94.9% to 106.4%. The relative standard deviations (RSDs) were 1.44% to 5.51%. The RSD of the methylated aminophenazone peak area was 4.32%, indicating good stability of the reaction product. Dimethyl sulfate genotoxic impurities were not detected in 9 batches of aminophenazone, caffeine, and tegafur samples, which indicated that the drug manufacturers paid attention to the control of these impurities. The proposed method is advantageous over the existing techniques in terms of the better ion peak shape and higher molecular weight, without interference from other fragments. The method is specific, sensitive, simple, rapid, and accurate, and it can be used for the determination of dimethyl sulfate genotoxic impurities in aminophenazone and other medicines.

Abstract: Background: In 2007, sorafenib was the first drug able to improve overall survival in patients with advanced hepatocellular carcinoma. Aim: In 2005 we designed a phase II study to assess safety and efficacy of sunitinib. Methods: This is a single arm, open-label, single-centre phase II trial. Eligibility criteria were advanced hepatocellular carcinoma; no prior chemotherapy, performance status 0–1; and Child≤B8. The treatment schedule was 50mg each day orally, 4 weeks on, 2 weeks off. Results: Between 10/2007 and 10/2010, 34 patients were enrolled. A significant worsening of liver functional reserve after sunitinib was observed. Grade 3/4 adverse effects occurred in 80% of patients and included fatigue (47%), nausea (15%), liver failure (15%), encephalopathy (12%) and upper gastrointestinal bleeding (12%). Six patients (18%) died within 60 days of enrolment. A partial response was observed in 4 patients (12%). Median time to tumour progression was 2.8 months and median overall survival was 5.8 months. Conclusion: A dose of 50mg/d induces a high rate of severe adverse events. Toxicity remains a key concern also at the dose of 37.5mg/d. However, sunitinib is able to induce a prolonged response in some patients. Positron Emission Tomography/Computed Tomography scans may select good responders. [Copyright &y& Elsevier]

Here, we describe 4-dimethylaminoantipyrine (4-DMAA)-mediated interfacing as a broad biochemical indicator to stabilize and promote the higher response of electrodes for immunological detection. We hypothesized that the improved biological interactions of 4-DMAA with electrodes and biological samples may be due to the interaction properties of the benzene and pyrazole chemical groups with graphite and proteins, respectively. In order to demonstrate that 4-DMAA could be used as a general indicator in electrochemical immunoassays, we used peptides as probes for the diagnosis of four neglected tropical infectious diseases Tegumentary leishmaniasis , Visceral leishmaniasis , Strongyloidiasis , and Leprosy on commercial graphite screen-printed electrodes. 4-DMAA oxidation was used to indicate specific biological recognition between the epitope-based peptide and serum immunoglobulin G (IgG) from infected patients. We demonstrated that 4-DMAA should be incorporated into the electrodes prior to serum application, which avoids interference with its sensitivity and specificity. In addition, 4-DMAA oxidizes at a low anodic potential, and the oxidation peak is useful for detecting proteins in biological fluids. In summary, we have successfully demonstrated the broad application of 4-DMAA as a general indicator for the specific diagnosis of four infectious diseases in electrochemical immunosensors. Such a strategy is quite advantageous for indirect detection of proteins that lack electrochemical activities or are spatially inaccessible on the electrode surface. This new indicator opens a new avenue for monitoring biological recognition, especially for immunosensors.

Background: The prediction of fibrosis is an essential part of the assessment and management of patients with chronic liver disease. Non-invasive tests (NITs) have a number of advantages over the traditional standard of fibrosis assessment by liver biopsy, including safety, cost-effectiveness, and widespread accessibility. Objectives: The aim of this study was to determine the accuracy of certain biomarkers and transient elastography (TE) alone or in combination to predict the stage of liver fibrosis in chronic hepatitis C (CHC). Also, we examined whether the combination of certain biomarkers and TE could increase the diagnostic accuracy of liver fibrosis assessment. Patients and Method: A total of 446 patients who were previously diagnosed with CHC were included in the study. In the study group, 6 blood-based scores (APRI, Forns, Fib-4, Hepascore, FibroTest, and Fibrometer) were calculated, and TE was performed to validate the stage of fibrosis, compared with liver biopsy (LB) as the standard. Results: Significant fibrosis (F . 2) was predicted with an AUROC of 0.727, 0.680, 0.714, 0.778, 0.688, 0.797, and 0.751 for the APRI, Forns, Fib-4, FibroTest, Hepascore, and Fibrometer scores and TE (Fibroscan), respectively. Severe fibrosis (F . 3) was predicted, with AUROCs ranging between 0.705 and 0.811 for Hepascore and Fibrometer, respectively. Of the biomarkers, Fibrometer had the highest AUROC value in predicting both significant and severe fibrosis. The combination of APRI or FIB-4 with Fibrometer increased the diagnostic accuracy for significant fibrosis (from 69.07 to 82.27 for APRI, P = 0.001 and from 57.74 to 81.33, P = 0.001 for Fib-4). Combining APRI or Fib-4 with TE also increased the diagnostic accuracy (from 69.07 to 80.70%, P = 0.001 for APRI and from 57.74 to 81.33%, P = 0.001 for Fib-4) for significant fibrosis. The association that included Fibrotest was also reliable for the improvement of diagnostic accuracy. These combinations were more accurate or the assessment of severe fibrosis. Conclusions: The synchronous association between a simple, inexpensive score and a complex but expensive score or TE increases the diagnostic accuracy of non-invasive methods for the assessment of liver fibrosis stage. [ABSTRACT FROM AUTHOR]

In this work, 3-aminopropyltriethoxysilane modified FeO nanoparticles (ATPS-FeO) were used to modify glassy carbon electrode for aminopyrine determination. ATPS-FeO showed obviously catalytic activity and adsorptivity towards aminopyrine oxidation proven by the increased oxidation peak current and the decreased oxidation peak potential. The best analytical response was obtained by immobilizing 8 μL 3 mg/mL APTS-FeO dispersion with an accumulation time of 200 s at −0.2 V in 0.1 M phosphate buffer solution (pH 9.0). The oxidation peak current of aminopyrine showed linear relationship with its concentration in the range from 0.5 to 100 and 100 to 1600 μM. The detection limit was 0.1 μM (S/N = 3). The proposed method showed satisfactory repeatability and anti-interference ability. The fabricated electrode was successfully applied to determine aminopyrine in pharmaceutical formulations. [ABSTRACT FROM AUTHOR]

Abstract: A microfluidic chip manufactured from glass substrate and indium tin oxide (ITO) coated glass use for contactless conductivity detection was developed. The detecting electrodes were fabricated by screen-printing and chemical etching methods using an ITO-coated glass wafer. Then, the glass substrate containing separation channels was bonded with the bare side of the processed ITO-coated glass, thus producing an electrophoresis chip integrated with contactless conductivity detector. The prepared microchip displayed considerable stability and reproducibility. Sensitive response was obtained at optimal conditions (including the gap between electrodes, excitation frequency, and excitation voltage). The feasibility of this microfluidic device was examined by detection of inorganic ions, and further demonstrated by the quantification of aminopyrine and caffeine in a compound pharmaceutical. The two ingredients can be completely separated within 1min. The detection limits were 8μgmL−1 and 3μgmL−1, respectively; with the correlation coefficient of 0.996–0.998 in the linear range from 10μgmL−1 to 800μgmL−1. The results have showed that the present method is sensitive, reliable and fast. [Copyright &y& Elsevier]

This review covers the kinetics of granulopoiesis, the functions and apoptosis of the granulocytes and the metabolism of the granulocyte series, along with a report of the various different drugs that cause alterations in the numbers of granulocytes. The mechanisms of drug induced idiosyncratic agranulocytosis are described, especially those activated after treatment with aminopyrine, amiodarone and clozapine. [ABSTRACT FROM AUTHOR]

A sensitive and selective LC–MS–MS method for the determination of aminopyrine in human plasma was developed and validated over the concentration range of 8–8,000 ng mL−1. After addition of carbamazepine as internal standard, a simplified protein precipitation with methanol was employed for the sample preparation. Chromatographic separation was performed on an Agilent Zorbax SB-C18 column with a mobile phase of methanol–water. The MS data acquisition was accomplished in multiple reactions monitoring mode with a positive electrospray ionization interface. The lower limit of quantification was 8 ng mL−1. For inter-day and intra-day tests, the precision (RSD) for the entire validation was less than 9%, and the accuracy was within the 97.8–106.3% range. The method is simple and fast, and suitable for application to the analysis of samples for clinical intoxication. [ABSTRACT FROM AUTHOR]

Morinda citrifolia Linn. (Rubiaceae), common name noni, has been used as a herbal medicine for over 2000 years. The consumption of noni, and especially the fruit, stresses the importance, urgency, and possibility of the examination of drug interaction when concomitantly administered with a drug. The objectives of this study were to determine the effects of noni juice (NJ) on aminopyrine N-demethylase (APND), uridine diphosphoglucuronosyl-transferase (UGT), and cytosolic glutathione S-transferase (GST) drug metabolizing enzymes and the molecular mechanism elucidation of NJ on APND using different inhibitors and stimulators. The in vitro results for APND showed that different concentrations of NJ significantly increased the activity in isolated hepatocytes at 1.0 ng/mL, 10 ng/mL, 10 μg/mL, 20 μg/mL, 50 μg/mL, and 100 μg/mL. The ex vivo results demonstrated that NJ (210 mg/kg) produced a statistically significant increase in APND activity following 1 day of NJ treatment. The results for UGT and GST showed a decrease in the activity of UGT at a dose of 21 mg/kg following 1 day of treatment, and at 2.1 and 21 mg/kg following 14 days of treatment. GST enzyme demonstrated an increase in activity by 100% for all doses following 1 day of treatment. Molecular mechanism elucidation of the ex vivo effect of NJ on phase I APND showed that KT5720 significantly reduced the activity as compared to control. A change in activity of APND, UGT, and GST following 1 day and 14 days of treatment suggests that all three metabolic pathways may play a role in herb–drug interaction by modulation of metabolic enzymes. [ABSTRACT FROM AUTHOR]

Reactive nitrogen species (RNS), namely nitric oxide (NO•) and peroxynitrite (ONOO-) are produced in the inflammatory sites and may contribute to the deleterious effects of inflammation. The aim of the present study was to evaluate the putative scavenging effect of a particular group of non-steroidal anti-inflammatory drugs (NSAIDs), the pyrazolone derivatives dipyrone, aminopyrine, isopropylantipyrine, and antipyrine against RNS, using in vitro non-cellular screening systems. The results obtained showed that dipyrone and aminopyrine were highly potent scavengers of NO• and ONOO- while antipyrine exerted little effect and isopropylantipyrine no effect whatsoever against these two RNS and that, in the presence of bicarbonate, the scavenging potencies of both dipyrone and aminopyrine were slightly decreased. It could thus be inferred that the observed scavenging effects may be of therapeutic benefit for patients under anti-inflammatory treatment with dipyrone and aminopyrine in the case of overproduction of RNS. On the other hand, the possible depletion of physiological NO• concentrations, namely at the gastrointestinal tract as well as the formation of reactive derivatives of aminopyrine and/or dipyrone, resulting from their reaction with RNS, may otherwise be harmful for these patients. [ABSTRACT FROM AUTHOR]

Abstract: Paracetamol is a widely used analgesic and antipyretic with weak anti-inflammatory properties. Experimental evidence suggests that inhibition of prostaglandin biosynthesis contributes to its pharmacological actions. Three cyclooxygenase (COX) isoenzymes are involved in prostaglandin biosynthesis, COX-1, COX-2 and a recently discovered splice-variant of COX-1, COX-3. Our aim was to identify the relative roles for these enzymes in the antinociceptive action of paracetamol in mice. We compared the antinociceptive action of paracetamol with the non-selective non-steroid anti-inflammatory drug, diclofenac and studied paracetamol antinociception in COX-1 and COX-2 knockout mice. Paracetamol (100–400 mg/kg) inhibited both acetic acid- and iloprost-induced writhing responses. In contrast, diclofenac (10–100 mg/kg) inhibited only acetic acid-induced writhing. Only diclofenac reduced peripheral prostaglandin biosynthesis whereas both drugs reduced central prostaglandin production. Prostaglandin E2 (PGE2) concentrations were reduced in different brain regions by administration of paracetamol. COX-1, COX-2 and COX-3 enzyme proteins were expressed in the same brain regions. The effects of paracetamol on writhing responses and on brain PGE2 levels were reduced in COX-1, but not COX-2, knockout mice. The selective COX-3 inhibitors, aminopyrine and antipyrine also reduced writhing responses and brain PGE2 biosynthesis. These results suggest that the antinociceptive action of paracetamol may be mediated by inhibition of COX-3. [Copyright &y& Elsevier]

The risk of agranulocytosis associated with the use of pyrazolone drugs at therapeutical doses and for short periods of time has been considered to be very low. However, little or no attention at all has been devoted to the possible hindrance of neutrophil burst and scavenging of neutrophil-generated reactive oxygen species (ROS) by these compounds. Such an effect could be beneficial in the case of overactivation of neutrophils but could also be highly detrimental if the number of circulating neutrophils is already decreased. Thus, the aim of the present study was to evaluate the putative inhibitory effect of the pyrazolones dipyrone, aminopyrine, isopropylantipyrine, and antipyrine against human neutrophil burst and their scavenging activity against O2•−, H2O2, HO•, ROO•, and HOCl. The obtained results showed that dipyrone and aminopyrine prevent phorbol-12-myristate-13-acetate-induced neutrophil burst with high efficiency, while isopropylantipyrine had little effect and antipyrine had no effect at all. Dipyrone and aminopyrine were highly potent scavengers of HO and HOCl, while, in accordance with the neutrophil burst results, isopropylantipyrine had little effect and antipyrine had no effect at all against these two ROS. None of the studied pyrazolones was capable of scavenging O2•− or H2O2, while dipyrone was shown to be the most reactive against ROO•. [Copyright &y& Elsevier]

The influence of pH on the permeability of p-toluidine (pKa, 5.3) and aminopyrine (pKa, 5.0) through shed snake skin as a model membrane was studied. The pH was adjusted to several values, and the solubility of the drugs in each donor was measured. Flux rates and permeability coefficients were calculated from the steady-state penetration portions. The flux rates of p-toluidine decreased as the pH value in the donor solution increased. On the other hand, the flux rates of aminopyrine were constant at any pH value. The permeability coefficients of each drug increased as the pH value in the donor solution increased. The partition coefficients (octanol/buffer) of each drug were dependent on the molecular fraction of un-ionized species. From these results, it is suggested that ionized species of p-toluidine transports through shed snake skin, but the ionized species of aminopyrine does not. [ABSTRACT FROM AUTHOR]

Peracetic acid (PAA) oxidation is an emerging technology in water disinfection and purification. This study evaluated the oxidation of three pyrazolone pharmaceuticals (i.e., Aminopyrine (AMP), Antipyrine (ANT), and Isopropylphenazone (PRP) by PAA. Experimental results showed that PAA exhibited structure selectivity to the above three pharmaceuticals and oxidized AMP with the highest reactivity. The degradation kinetics of AMP was investigated by calculating the apparent second-order rate constants (k app ) under different initial pH. Through kinetic simulation, the second-order rate constants of elementary reactions between AMP (i.e., neutral (AMP 0 ) and protonated (AMP + ) species) with PAA (i.e., neutral (PAA 0 ) and anionic (PAA - ) species) were obtained to be 0.34 ± 0.077 M -1  s -1 (k" AMP+, PAA0 ), 0.89 ± 0.091 M -1  s -1 (k" AMP0, PAA- ) and 5.94 ± 0.142 M -1  s -1 (k" AMP0, PAA0 ), respectively. The PAA could oxidize AMP via electrophilic attack, and the degradation site of AMP was confirmed to be the central nitrogen of -N(CH 3 ) 2 with the highest relative electrophilicity (s k - /s k + , 48.8614) by Density Functional Theory (DFT) calculation. The intermediates/products of AMP degradation were identified by high-performance liquid chromatography-mass spectrometry (LC-MS/MS), and the transformation pathways of AMP during PAA oxidation were inferred to be hydroxylation, demethylation, and CC cleavage. The genetic toxicity of AMP contaminated water could be reduced after PAA oxidation, which was evaluated by the micronucleus test of Vicia faba root tips., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Dietary habits are often considered as a pathogenic factor for fatty liver. The impact of dietary intake and steatosis on drug metabolism remains poorly investigated. Our aim was to assess the effect of dietary intake on in vivo cytochrome P450 (CYP) activities in eleven patients with abnormal liver function tests potentially due to fatty liver and associated with a high-sugar diet. Liver function tests, liver volume, aminopyrine breath test (ABT) and chlorzoxazone (CZ) pharmacokinetics (area under the curve, AUC) which are known to reflect CYP2E1 activity were evaluated before and after 2 months restriction of dietary sugar intake. Features at inclusion were an increased BMI (30·3 (sd 3·2) kg/m2), high hepatic volume (1·96 (sd 0·48) litres), hyperechogenic liver parenchyma, elevated liver enzyme activities (alanine aminotransferase (EC 2.6.1.2) 58·6 (sd 17·4) IU/l with alanine aminotransferase : aspartate aminotransferase (EC 2.6.1.1) ratio > 1), together with a normal ABT value (0·68 (sd 0·21) % specific activity of administered dose of [14C]aminopyrine in breath after 1 h) and a high CYP2E1 activity (CZ AUC 20·3 (sd 7·1) μg/ml per h). A dietary sugar restriction was prescribed. On the basis of repeated interviews by the same dietitian, unaware of any clinical and biochemical data, six patients remained compliant to the diet and exhibited reductions in BMI (P < 0·001), serum alanine aminotransferase (P = 0·008), liver volume (P = 0·002) and CYP2E1 activity (P = 0·007), a significant increase in ABT (P < 0·001) together with the disappearance of liver hyperechogenicity at ultrasound. In contrast, the five non-compliant patients did not show any significant change in any of these variables. In conclusion, CYP2E1 activity is induced in patients with perturbations of liver function tests potentially due to fatty liver. In these patients, effective dietary sugar restriction is associated with a reduction in liver volume, a reduction in CYP2E1 activity and an increased aminopyrine metabolism rate. [ABSTRACT FROM PUBLISHER]

The addition of antipyrine or aminopyrine to isolated hepatocytes derived from normal rats and incubated with ethanol caused a significant decrease in the oxidation of ethanol to acetate. This decrease was associated with a corresponding accumulation of acetaldehyde. The degree of inhibition with each drug was concentration-dependent, and there was a lag phase before inhibition of acetate formation and acetaldehyde accumulation became apparent. These effects were augmented in cells isolated from phenobarbital-treated rats, and the lag phase was reduced, implying that the effects of both drugs were dependent on their cytochrome P-450-mediated metabolism. The addition of the cytochrome P-450 inhibitor, cimetidine, significantly reduced the amount of acetaldehyde accumulating from ethanol when hepatocytes were incubated with either antipyrine or aminopyrine. Neither drug added directly to mitochondrial extracts inhibited the activity of aldehyde dehydrogenase. However, when neutralized extracts of hepatocytes that had undergone a 40-min incubation with ethanol and each drug were added to mitochondrial extracts, aldehyde dehydrogenase activity was substantially decreased. A greater inhibition was observed with neutralized extracts of hepatocytes from phenobarbital-treated rats. The results suggest that cytochrome P-450-generated metabolites of antipytine and aminopyrine cause an inhibition of the low Km mitochondrial aldehyde dehydrogenase and thus an accumulation of acetaldehyde from ethanol. [ABSTRACT FROM AUTHOR]

Breath tests (BT) using stable isotopically labelled substrates seem to fullfil all the demands and desires for a non-invasive investigation. There are no radiation hazards, substrates are given in tracer amounts perorally, breath and urine samples can be collected easily, and tests can be done repeatedly, thus easily allowing the monitoring of function with time. There are, however, some disadvantages. Any BT has the same assumption: after intake of the C tracer the substrate is metabolized to CO. An increase of CO above baseline levels is said to reflect the function investigated - in C sucrose studies, the amount of carbohydrate absorbed; in C aminopyrine BT, the liver function; in C glucose BT in a diabetic child, the impaired handling of glucose. However, as only the end product CO is measured, there is no information on all the pools and fluxes the labelled substrate and its metabolites have to pass. At least in inborn errors of metabolism, probably in any disease, one has to assume that these fluxes and pools are substantially changed. Therefore all calculations are weak and finally one has to resort to invasive methods, i.e. drawing blood to measure pools and fluxes to allow a correct interpretation of the BT data. Furthermore, changes in the basal exhalation of CO during the test will have an impact on the BT calculation. Another problem is that for an exact calculation, the basal metabolic rate (BMR) and the actual endogenous CO production in the patient is needed, which in most instances is unknown. It is not easy to maintain a stable endogenous CO production, particularly in younger children who will not rest or in neonates and toddlers who may fight against taking breath samples. Taking together these limitations are the reason why BT have not been able to reach the level of routine clinical methods, especially in the diagnostic work up of impaired liver function or inborn errors of metabolism. [ABSTRACT FROM AUTHOR]

We determined to what extent a change in the lipid composition of the smooth endoplasmic reticulum contributes to altered microsomal function in cirrhosis. Rats were rendered cirrhotic either by chronic exposure to phenobarbital/CCl (MCIR) or by bile duct ligation (BCIR). Microsomal function was tested in vivo by the aminopyrine breath test (ABT), then microsomes were prepared and their phospholipid and cholesterol composition analysed. ABT was reduced by 35 and 41% in BCIR and MCIR, respectively. Cholesterol in microsomes was increased in both cirrhotic groups. (BCIR +154%, MCIR +75%) while total phospholipid content was not affected. As shown in other membrane systems, the phospholipid/cholesterol (PL/XOL) ratio showed an excellent inverse correlation with fluorescence anisotropy determined by diphenylhexatriene fluorescence polarization (r=−0.896). The PL/XOL ratio was significantly correlated with aminopyrine N-demethylation in vivo (r=0.649). Alterations in the composition of phospholipid groups (an increase in sphingomyelin in both cirrhotic groups, and a decrease in phosphatidylcholine and an increase in phosphatidylethanolamine in BCIR) also contributed to increased membrane rigidity. We conclude that altered membrane fluidity contributes to diminished microsomal function but that other factors must also be involved since the PL/XOL ratio explained only 42% of the variance in aminopyrine N-demethylation. [ABSTRACT FROM AUTHOR]

A simple method for the quantitative estimation of the formation of N-nitrosodimethylamine (NDMA) in mice has been developed. Mice were frozen in liquid nitrogen and homogenized. NDMA was then extracted and analyzed by a gas chromatograph equipped with a thermal energy analyzer. In normal mice NDMA (100 nmole) administered orally was rapidly metabolized and recovery of NDMA was about 10% after 60 min. However, when pyrazole (300 mg/kg) was injected i.p. to mice 60 min before the administration of NDMA, more than 80% of the administered NDMA could be recovered within 60 min. This result suggested that in pyrazole pretreated mice the accurate amount of NDMA formed could be estimated. Therefore the NDMA formation was measured in the pyrazole pretreated mice. When 0.25 μmole of aminopyrine and from 0.25 to 2.0 umole of sodium nitrite were simultaneously administered orally, the amount of the NDMA formation in 20 min was found to be from 8.2 to 60.3 nmole. These values are equal to about from 30 to 200 μg/kg of body weight which are nearly daily doses expected to cause the carcinogenic effect on mice or rats. This method of measuring NDMA in pyrazole pretreated mice appears to be useful for investigating the in vivo formation of NDMA quantitatively. [ABSTRACT FROM AUTHOR]

Copyright of Archives of Toxicology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Archives of Toxicology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Nadolol, a non-cardioselective beta adrenoreceptor blocking agent, has been reported to decrease portal pressure without affecting liver function in cirrhotic patients treated for 1 month. There were no data about the long-term effects of nadolol on liver function. In 11 patients with cirrhosis and portal hypertension galactose eliminating capacity, aminopyrine metabolic capacity, ICG clearance and IGC intrinsic hepatic clearance according to the 'parallel tube' model were measured before and after 6 months of treatment with nadolol at a dose reducing resting heart rate by approximately 25%. No significant variation in any of these parameters was found. Thus 6 months of continuous oral administration of nadolol did not further impair liver function in cirrhotics. [ABSTRACT FROM AUTHOR]

The exhalation of CO derived from an i.v. tracer dose of [dimethylamine-C]aminopyrine has been investigated in normal controls and patients. They subsequently ingested 200 mg cyclobarbital calcium in the evening and the decline in the plasma drug level over the following 2 days was measured by thin-layer chromatography. The peak specific activity of exhaled CO occurred 0.5-2 h after C-aminopyrine injection in the absence of liver disease and in non-cirrhotic liver disorders. It was delayed in certain patients with cirrhosis. Compared to 8 medically healthy subjects, 10 patients with acute viral hepatitis, 8 with cirrhosis and 10 with fatty liver exhibited a significantly increased half-life of CO exhalation. Normal mean values were found in 12 patients with non-cirrhotic alcoholic liver disease and in 14 patients with non-hepatic diseases. The cyclobarbital (CB) half-life was prolonged and the clearance reduced in patients with viral hepatitis, cirrhosis, or alcoholic liver damage as compared to data from 17 control subjects. Due to a larger apparent volume of distribution, patients with fatty liver disease had an increased CB half-life, although its clearance was normal. A close negative correlation was detected between the clearance and the logarithm of the CB level measured 36 h after drug ingestion. The oral CB test evaluated from a single blood sample taken about 36 h after drug administration appears to be a useful indicator of human drug metabolising capacity. Discrimination between patients with and without disordered liver function was similar in the two drug elimination tests. [ABSTRACT FROM AUTHOR]

Four healthy subjects were investigated weekly for 14 weeks by the antipyrine one sample saliva test, the 48-h urinary excretion of major antipyrine metabolites and the 2-h aminopyrine breath test before, during and after stimulation and inhibition of drug metabolism with phenobarbital and cimetidine, respectively. The phenobarbital-induced enhancement of antipyrine clearance (1.33-2.03 times) and of the aminopyrine breath test (0.94-1.19 times) occurred one week after beginning drug administration and persisted for 10 days after its cessation. The cimetidine-related inhibition of antipyrine clearance (0.62-0.85 times) and of the aminopyrine breath test (0.52-0.93 times) was observed 24 h after beginning cimetidine administration and subsided within two days after the last dose. During enhancement and inhibition the clearance of antipyrine to 3-hydroxymethyl-, 4-hydroxy- and norantipyrine varied as the total antipyrine clearance. The intraindividual variation in antipyrine clearance was 6-8%, and the corresponding variation in urinary excretion of antipyrine metabolites was 10-20%. It is concluded that the influence of phenobarbital and cimetidine on hepatic microsomal enzyme activity can be monitored simply by measurement of the blood concentration of the drug. Whether this simple relationship applies to other microsomally mediated drug interactions requires further evaluation. [ABSTRACT FROM AUTHOR]

[Dimethylamine-C]-aminopyrine was given i.v. to 5 healthy volunteers and 5 medical patients in a dose of 1.67 mg/kg, containing 0.02 µCi/kg C. In 4 volunteers the experiment was repeated using oral administration of aminopyrine. Exhalation of CO was followed for 6-10 h and plasma levels of the drug and of its metabolites 4-methylamino-antipyrine, 4-amino-antipyrine, 4-acetylamino-antipyrine and 4-formylamino-antipyrine, were measured by thin-layer chromatography. The concentration-time profiles of the metabolites mostly failed to conform to a Bateman function. Areas under the curves from 1 to 6 h after dosing indicated distinct interindividual differences in metabolite patterns even in the absence of disturbed liver function, whereas the intraindividual data were closely reproducible. In most subjects, the area of 4-formylamino-antipyrine exceeded that of the acetyl analogue. The metabolite patterns did not exhibit a consistent relationship to the ratios between CO half-life in breath and aminopyrine half-life in plasma, which varied from 1.4 to 3.2. [ABSTRACT FROM AUTHOR]

The time-course of aminopyrine in plasma and ofCO in breath was determined for 6 hours after oral administration of (C-methyl) aminopyrine to healthy controls and to patients with hepatitis and hepatic fibrosis, cirrhosis and hepatic bilharziasis.CO in breath declined about 1.8 times more slowly than aminopyrine plasma levels, which suggests the occurrence of metabolite demethylation. This was confirmed by the slow elimination ofC from plasma, the formation ofCO after aminopyrine had disappeared and the presence of a considerable amount of monomethyl-aminopyrine in plasma. The meanCO concentration in breath was correlated with but was not proportional to aminopyrine clearance, which was attributed to individual differences in aminopyrine half-life. Both a correlation and proportionality were found whenCO extrapolated to zero time was used as a parameter ofCO production. Hepatic disease affected aminopyrine clearance to a variable extent. In the hepatitis and fibrosis group, aminopyrine clearance was affected in 2 out of five subjects. In all except one cirrhotic subject aminopyrine clearance was markedly decreased. Moreover, in three out of seven cases aminopyrine absorption was impaired, presumably due to decreased gastrointestinal blood-flow. This may produce an erroneously lowCO concentration in breath during the first two hours after aminopyrine administration. Hepatic bilharziasis was accompanied by very low aminopyrine clearance in all four cases. In two patients high apparent V values were observed, probably due to 'first-pass' metabolism. Patients with ascites had V values within normal limits. [ABSTRACT FROM AUTHOR]

The activity of the hepatic microsomal enzyme system, which may be of great importance for metabolic activation and deactivation of hepatotoxic agents and carcinogens, is changed by exposure to commonly used industrial chemicals. The antipyrine test is the most widely used method for assessing microsomal enzyme activity in man. The clearance of antipyrine can be accurately calculated from one sample of saliva obtained about 24 h after an oral dose of the drug. By measuring antipyrine metabolism during exposure to industrial chemicals and at the end of 3-4 weeks free from exposure, the impact of industrial chemicals on antipyrine metabolism can be estimated, provided the chemicals are eliminated within 3-4 weeks. This test can be performed by skilled and unskilled workers using written instructions. This has broadened the application of the test. Other noninvasive indices of microsomal enzyme activity include the aminopyrine and caffeine breath tests and the urinary excretion of 6- β-hydroxycortisol and d-glucaric acid. These tests probably reflect the activity of different but overlapping parts of the microsomal enzyme system and may be of value in research in occupational medicine. Previous studies indicate that chlorinated hydrocarbon insecticides, phenoxyacids, chlorophenols, polychlorinated biphenyles, some organic solvents and high concentrations of inhalation anaesthetics may stimulate microsomal enzyme activity, while styrene, toluene and inhalation anaesthetics in concentrations at about the allowed safety limit values have no effect. Lead, chemicals used by spray painters, and carbon disulphide probably inhibit the activity. While the short-term consequences of these changes include altered metabolism of hormones, vitamins, drugs, and other microsomally metabolized compounds, the possible impact on health on a long-term scale is unknown. It is now possible to study this with the use of the available noninvasive simple indices of microsomal enzyme activity. The potentially useful applications include biological monitoring of environmental carcinogenesis and hepatotoxicity. [ABSTRACT FROM AUTHOR]

Digital image processing of the pH-sensitive dye BCECF was used to examine the effects of high [K] media on cytoplasmic pH (pH) of individual cells within isolated rabbit gastric glands. When cells were acidified to pH 6.5 from the resting pH of 7.2-7.3 and then exposed to solution containing 77 m m K plus amiloride (to block Na/H exchange), recovery to pH 7.0 was observed. This K-induced alkalinization occurred in all cell types of the gland, including cells within antral glands that were devoid of parietal cells (PC). This process was independent of extracellular Na and Cl and was unaffected by: 5 m m Ba or 200 μ m bumetanide, or acute treatment with either 500 μ m ouabain or 100 μ m cimetidine, histamine or carbachol. SCH28080, which inhibits the PC H/K-ATPase when used in the low μ m range of concentrations, blocked the K effect on pH, at 100 μ m but was ineffective at 1 μ m. A similar pH recovery was also stimulated by Li, Cs (both 72 m m), and Tl (10 m m), in the order Li>K> Cs>Tl (all in the presence of amiloride), and these alkalinizations were also blocked by 100 μ m SCH28080. Parallel experiments were performed to test the effect of these ions on [C]-aminopyrine accumulation, an index of acid secretion by the H/K-ATPase at the lumenal membrane of the PC. There was no correlation between the rates of cation-induced pH recovery from an acid load and H secretion as measured by the accumulation of aminopyrine. We conclude that the K (and Cs-and Li-) dependent pH recovery is mediated by a novel cation/H exchange mechanism that is distinct from the PC H/K-ATPase. [ABSTRACT FROM AUTHOR]

The incidence of non-alcoholic fatty liver disease (NAFLD) is rising across the globe, with the presence of steatohepatitis leading to a more aggressive clinical course. Currently, the diagnosis of non-alcoholic steatohepatitis (NASH) is based on histology, though with the high prevalence of NAFLD, a non-invasive method is needed. The 13C-aminopyrine breath test (ABT) evaluates the microsomal liver function and could be a potential candidate. We aimed to evaluate a potential change in liver function in NASH patients and to evaluate the diagnostic power of ABT to detect NASH. We performed a retrospective analysis on patients suspected of NAFLD who underwent a liver biopsy and ABT. 440 patients were included. ABT did not decrease in patients with isolated liver steatosis but decreased significantly in the presence of NASH without fibrosis and decreased even further with the presence of significant fibrosis. The predictive power of ABT as a single test for NASH was low but improved in combination with ALT and ultrasonographic steatosis. We conclude that microsomal liver function of patients with NASH is significantly decreased, even in the absence of fibrosis. The ABT is thus a valuable tool in assessing the presence of NASH; and could be used as a supplementary diagnostic tool in clinical practice. [ABSTRACT FROM AUTHOR]

Aminopyrine is an inexpensive drug that is highly effective on analgesic and anti-inflammatory. However, it is found adulterated to traditional Chinese medicine by unscrupulous merchants though side effects, such as neutropenia, myelosuppression and formation of nitrosamine carcinogens, make it banned in many countries. In this work, terahertz time-domain spectroscopy has been proposed to perform characterization of aminopyrine in the range of 0.2∼2.4 THz. Characteristic absorption peaks of aminopyrine are found at 1.54 THz and 2.15 THz. To gain further insight, DFT studies have been carried out to simulate the THz spectrum and analyze molecular vibration mode of aminopyrine. The spectrum simulated is in good agreement with the experiments and the calcuated absorption peaks at 1.48 THz and 2.29 THz matches with the experimental result of 1.54 THz and 2.15 THz. The main vibrational modes of the characteristic peaks are the skeletal vibrations of the molecule, which is represented by the rotation and the swing of dimethylamino group, pyrazolone and benzene rings. This study shows that terahertz spectroscopy has potential application prospects for the detection of adulteration of aminopyrine in rheumatic Chinese patent medicines and the examination of counterfeit drugs. [ABSTRACT FROM AUTHOR]

Background: Chronic use of proton pump inhibitors (PPIs) in patients with impaired liver function may worsen cytochrome P450 (CYP450) activity, predisposing them to clinically relevant drug-drug interactions. The 13 C-aminopyrine breath test ( 13 C-ABT) is a non-invasive tool to study CYP450-dependent liver function., Aims: To assess 13 C-ABT modifications with different PPIs in patients with cirrhosis METHODS: Sixty consecutive patients with HCV-related cirrhosis and indication to start PPI therapy were randomised to receive omeprazole 20 mg/day, esomeprazole 20 mg/day, lansoprazole 15 mg/day, pantoprazole 40 mg/day or rabeprazole 20 mg/day. 13 C-ABT was performed at baseline and on the 15th day of PPI therapy., Results: At baseline, mean values of max 13 C% dose/h and 13 C% cum dose at 120 minutes did not differ significantly among groups. On the 15th day of therapy, max 13 C% dose/h and 13 C% cum dose at 120 minutes did not significantly differ with respect to baseline for pantoprazole (P = 0.184 and P = 0.309, respectively) or rabeprazole (P = 0.536 and P = 0.286, respectively), but were significantly decreased on omeprazole (P = 0.013 and P = 0.015, respectively), esomeprazole (P = 0.009 and P = 0.001, respectively), and lansoprazole (P = 0.033 and P = 0.035, respectively)., Conclusions: In patients with cirrhosis, omeprazole, esomeprazole and lansoprazole inhibit microsomal activity while pantoprazole and rabeprazole do not have a significant impact. Should our data be confirmed in larger cohort studies, pantoprazole and rabeprazole could be safely recommended for patients with cirrhosis., (© 2020 John Wiley & Sons Ltd.)