A novel perspective on the preventive treatment of hydrazine compound-induced liver injury: Isoniazid liver injury as an example.

ETHNOPHARMACOLOGICAL RELEVANCE: Anethum graveolens L. (dill), which has been used as a medicine, spice and aromatic plant since ancient times, is not only a traditional Chinese medicines but also an important medicinal and functional food in Europe and Central and South Asia. In ethnomedicine, dill reportedly exerts a protective effect on the liver and has been widely used as a traditional medicine for the treatment of jaundice in the liver and spleen and inflammatory gout diseases in Saudi Arabia. Furthermore, studies have found that dill can regulate the NAT2 enzyme, and this plant was thus selected to study its alleviating effect on isoniazid liver injury. AIM OF THE STUDY: The purpose of this study was to explore the effect of dill on alleviating liver injury induced by hydrazine compounds represented by isoniazid through the use of network pharmacology combined with in vivo and in vitro experimental verifications. MATERIALS AND METHODS: First, we screened the key targets of dill in the treatment of liver injury through the use of network pharmacology; we then performed GO and KEGG pathway enrichment analyses using the DAVID database. We also verified the alleviative and anti-inflammatory effects of dill on isoniazid liver injury in rats by animal experiments. We further investigated the modulating effect of dill on the enzymatic activity of NAT2, a common metabolizing enzyme of hydrazine compounds. RESULTS: A total of 111 key targets were screened through network pharmacology. In vivo experiments showed that dill reduced the amount of inflammatory factors produced by isoniazid, such as IL-10, IL-1ß, TNF-α and IL-6, restored the levels of ALT, AST, r-GT, AKP and TBA in vivo, and attenuated isoniazid liver injury. Both in vivo and vitro results indicated that dill could regulate the expression of NAT2 enzymes. CONCLUSIONS: The results tentatively demonstrate that dill can alleviate isoniazid liver injury through multiple components, targets and pathways and exerts a regulatory effect on the NAT2 enzyme, and these findings thus provide new ideas for subsequent studies on hydrazide liver injury--reducing the risk of hydrazide-induced liver injury through anti-inflammation and regulation of NAT2 enzymes.

Path analysis and empirical test of medical service enhancement for common prosperity under government participation.

The level of medical services is the link between the two strategic goals of "healthy China" and "common prosperity," and government participation plays an important adjustment role in it, so it is of great theoretical and practical significance to study its inner logic. In this paper, we firstly analyze the mechanism of medical service level to promote the development of common prosperity and the role of government in it; secondly, we construct a panel dynamic regression model and a threshold regression model to verify the relationship between the three. It is found that the contribution of both equity and efficiency of health care services to the achievement of common wealth is non-linear, and the degree of government participation plays an important adjustment role, with single and double threshold effects between them and the level of common prosperity, respectively. In the process of participating in the medical service market, the government should clearly position itself, actively play the demand-led role of the market, encourage private capital to provide quality medical services, and purposefully optimize the financial expenditure structure according to the local actual situation. There are many ways in which the government can be involved in health care, and there will be differences between China and other countries around the world. These are all worthy of further discussion.

Fluorophosphorus derivative forms a beneficial film on both electrodes of high voltage lithium-ion batteries.

Layered lithium-rich oxides, as a series of highly promising cathode material for lithium-ion batteries, attract extensive attention due to their high specific capacity and high working potential (4.6 V vs Li/Li+). However, the poor interface stability of the cathode and electrolyte seriously restricts their practical application. In this article, theoretical calculations, linear sweep voltammetry and cyclic voltammetry results indicate that tris (pentafluorophenyl) phosphine (TPFPP) is a potential dual-functional electrolyte additive to solve interface problems. The TPFPP additive can decompose preferentially on the surface of both electrodes and form uniform and stable protective films, which effectively inhibit the continuous decomposition of the electrolyte and significantly alleviate the dissolution of transition metal ions during cycling. Owing to the above effects, the capacity retention and coulombic efficiency of Li1.17Ni0.25Mn0.58O2 (LLO)/graphite (Gr) cells are improved from 62.6% and 97.7% to 90.6% and 99.8% after 200 cycles at 0.3 C (1 C = 300 mA g-1), respectively. This study provides a wide prospect for the application of lithium-rich materials in the future.

[Evaluation of adsorption effect of activated charcoal on oral paraquat poisoning: an experimental study on large animal].

OBJECTIVE: To study the adsorption effect of activated charcoal suspension on paraquat (PQ) in gastrointestinal tract of beagles exposed to PQ. METHODS: Twenty healthy male beagles were randomly divided into experimental group and control group, with 6 beagles in each group. 20% PQ solution (a dose of 30 mg/kg) was prescribed through stomach for beagles in both groups. After exposure to PQ for 30 minutes, the beagles in experimental group were given activated charcoal suspension (1.0 g/kg of type I activated charcoal powder mixed with 100 mL of normal saline) by gavage, while the control group was only given equal volume of normal saline. After exposure to PQ for 10 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, and 48 hours, blood was collected from hepatic portal veins and peripheral veins to detect the PQ concentration change in the plasma. The toxicokinetics software DAS 2.1.1 was applied to analyze PQ concentration and compare the change in toxicokinetics parameters between the both groups. The change in vital signs including heart rate (HR), respiratory rate (RR) and pulse oxygen saturation (SpO2) was dynamically monitored 10 minutes before exposure, 4 hours and each day from the 1st to the 7th day after exposure. RESULTS: After exposure to PQ, the poison concentration in the plasma of hepatic portal veins and peripheral veins in the control group rose quickly and reached peak 4 hours later. It fell quickly at first, and fell slowly 8 hours later. But in the experimental group, the increase rate to the peak was significantly slow. Besides, PQ peak fell more obviously than that in the control group and it was about 50% of the control group (µg/L: 123.50±11.67 vs. 255.18±12.29 in blood from hepatic portal veins, 122.35±11.72 vs. 250.86±11.15 in blood from peripheral veins). After 8 hours it fell much more quickly than that of the control group. After exposure to PQ for 48 hours, PQ concentration in the plasma was still lower than that of the control group (µg/L: 0.53±0.18 vs. 15.98±5.58 in blood from hepatic portal veins, 0.31±0.01 vs. 15.03±4.82 in blood from peripheral veins, both P < 0.01). With the toxicokinetics analysis, compared with the control group, the maximum concentration (Cmax) and area under the curve (AUC) of PQ in the plasma of hepatic portal veins and peripheral veins in the experimental group were significantly decreased [Cmax (µg/L): 125.07±9.49 vs. 255.18±12.29 in blood from hepatic portal veins, 123.38±9.52 vs. 250.86±11.15 in blood from peripheral veins; AUC (mg×L-1×h-1): 1.6±0.2 vs. 3.3±0.4 in blood from hepatic portal veins, 1.5±0.2 vs. 3.2±0.3 in blood from peripheral veins], time to the peak (Tmax) of PQ was slowed (hours: 5.3±1.9 vs. 4.0±0.0 in blood from hepatic portal veins, 4.7±1.5 vs. 4.0±0.0 in blood from peripheral veins), and PQ plasma half-life (t1/2) and mean retention time (MRT) were significantly shortened [t1/2 (hours): 3.8±1.2 vs. 15.4±3.7 in blood from hepatic portal veins, 3.5±1.0 vs. 15.5±2.7 in blood from peripheral veins; MRT (hours): 8.0±1.5 vs. 13.4±1.2 in blood from hepatic portal veins, 7.6±1.3 vs. 13.3±1.2 in blood from peripheral veins; all P < 0.01]. After exposure to PQ, HR and RR in both the experimental group and the control group increased and reached to the peak about the 4th day and then the increase rate began to slow down gradually; SpO2 slowed down gradually and reached to the valley about the 4th day and then it began to recover, but the change range of vital signs in the experimental group was smaller than that of the control group, and the parameters were significantly better than those of control group [4-day HR (bpm): 134.50±3.04 vs. 142.00±6.43, 4-day RR (times/min): 31.00±0.58 vs. 34.33±0.94, 4-day SpO2: 0.900±0.006 vs. 0.873±0.005, all P < 0.05]. CONCLUSIONS: Activated charcoal administrated at 30 minutes after PQ poisoning can slow down the increase rate of PQ concentration in the plasma, decrease the peak concentration and has less influence on vital signs in beagles.

Hypertonic Saline Dextran Ameliorates Organ Damage in Beagle Hemorrhagic Shock.

OBJECTIVE: The goal of this study was to investigate the effect of hypertonic saline with 6% Dextran-70 (HSD) resuscitation on organ damage and the resuscitation efficiency of the combination of HSD and lactated ringers (LR) in a model of hemorrhage shock in dogs. METHODS: Beagles were bled to hold their mean arterial pressure (MAP) at 50 ± 5 mmHg for 1 h. After hemorrhage, beagles were divided into three groups (n = 7) to receive pre-hospital resuscitation for 1 h (R1): HSD (4 ml/kg), LR (40 ml/kg), and HSD+LR (a combination of 4 ml/kg HSD and 40 ml/kg LR). Next, LR was transfused into all groups as in-hospital resuscitation (R2). After two hours of observation (R3), autologous blood was transfused. Hemodynamic responses and systemic oxygenation were measured at predetermined phases. Three days after resuscitation, the animals were sacrificed and tissues including kidney, lung, liver and intestinal were obtained for pathological analysis. RESULTS: Although the initial resuscitation with HSD was shown to be faster than LR with regard to an ascending MAP, the HSD group showed a similar hemodynamic performance compared to the LR group throughout the experiment. Compared with the LR group, the systemic oxygenation performance in the HSD group was similar but showed a lower venous-to-arterial CO2 gradient (Pv-aCO2) at R3 (p < 0.05). Additionally, the histology score of the kidneys, lungs and liver were significantly lower in the HSD group than in the LR group (p < 0.05). The HSD+LR group showed a superior hemodynamic response but higher extravascular lung water (EVLW) and lower arterial oxygen tension (PaO2) than the other groups (p < 0.05). The HSD+LR group showed a marginally improved systemic oxygenation performance and lower histology score than other groups. CONCLUSIONS: Resuscitation after hemorrhagic shock with a bolus of HSD showed a similar hemodynamic response compared with LR at ten times the volume of HSD, but HSD showed superior efficacy in organ protection. Our findings suggest that resuscitation with the combination of HSD and LR in the pre-hospital setting is an effective treatment.

Paraquat-induced convulsion and death: a report of five cases.

Paraquat (PQ) is a potent toxicant for humans, and poisoning with PQ is associated with high mortality. Patients with severe PQ-induced poisoning may die of multiple organ failure involving the circulatory and respiratory systems. Death resulting from epilepsy-like convulsions, which are infrequently noted reported with PQ poisoning, is observed clinically with this condition. This study presents the clinical data of five patients with severe PQ-induced poisoning who died of epilepsy-like convulsions, and related publications were reviewed in order to investigate the pathogenesis, clinical manifestations, and prognosis of these convulsions. Our results may help prevent this event and improve the success of treatment.

[Detoxification effects of two drugs in thallium -poisoned mice].

OBJECTIVE: To observe the thallium eliminating effect of prussian blue, pentetate zinc trisodium (Zn-DTPA), and their combined use in the treatment of acute thallium poisoning in mice. METHODS: Thallium poisoned mice were reproduced by oral administration of 0.2 ml thallous nitrate (3 mg/ml). They were assigned randomly to four groups according to the random number table method, namely, model group, prussian blue group, Zn-DTPA group and the combination therapy group, with 10 mice in each group. Prussian blue was administered orally [4.52 g×kg(-1)×d(-1), total four times], and Zn-DTPA was injected intraperitoneally [500 mg×kg(-1)×d(-1), one time]4 hours after giving thallium. The dosage of both drugs in combination treatment was as the same as described above. After treatment for 5 days, all the animals were sacrificed. Brain, intestine, kidney and liver of 1 mouse from each group were collected for pathological examination to observe the necrosis. Thallium contents of blood, brain, urine and feces from the other mice were determined. RESULTS: Pathological examination showed that the damage to intestine, kidney and liver was less obvious in treatment group compared with those of the model group. The effect was most obvious in the combination treatment group. However, brain damage was slightly improved. Thallium content in blood (mg/ml) of prussian blue group and the combination treatment group decreased obviously compared with the model group, and the decrease was more obvious in the combination treatment group (0.05 ± 0.01 vs. 0.18 ± 0.02). Thallium content in urine (mg/ml) and feces (mg/kg) was significantly increased after treatment, and the thallium elimination was most significant in the combined treatment group (urine: 11.34 ± 0.81 vs. 0.02 ± 0.01, feces: 13.11 ± 1.84 vs. 0.21 ± 0.07, both P < 0.01). Thallium content in brain was similar among all the groups. CONCLUSIONS: The single and combined use of prussian blue and Zn-DTPA could reduce the damage in intestine, kidney and liver. Combined use of prussian blue and Zn-DTPA for acute thallium poisoning mice is more efficacious than single use of either drug.

Prognostic significance of arterial blood gas analysis in the early evaluation of paraquat poisoning patients.

OBJECTIVE: To examine the utility of arterial blood gas analysis (ABG) in early evaluation of prognosis in paraquat poisoning. METHODS: Our aim was to summarize the case data of 138 patients poisoned with oral paraquat treated in the Emergency Department of 307 Hospital of the Chinese People's Liberation Army from June 2009 to Sept. 2010, and analyze the correlations between various indices of arterial blood gas analysis (including pH, PO(2), PCO(2), base excess [BE], HCO(3)(-)) to prognosis and blood PQ concentration of patients presenting within 24 h after taking paraquat. RESULTS: PCO(2), HCO(3)(-) and BE values in deceased patients were significantly lower than those in surviving patients, p values 0.0003, <0.0001, <0.0001; PCO(2), HCO(3)(-) and BE values in patients who died in < 3 d were significantly lower than those in those who died in 3-7 d and 7 d after taking paraquat (p < 0.0001). The results of Cox Regression Analysis showed that there was correlation between paraquat amount, blood paraquat concentration and BE values and patients' survival time; the larger the absolute BE value was, the higher the death rate. Nevertheless, there were no correlations between early pH or PO(2) and prognosis in these patients. CONCLUSION: BE values may be a reliable index in early evaluation of prognosis in paraquat poisoning.

[Studying the therapeutic effects of hemoperfusion with continuous venovenous hemofiltration on the patients with acute paraquat poisoning].

OBJECTIVE: To explore the therapeutic effects of hemoperfusion (HP) with continuous venovenous hemofiltration (CVVH) on the patients with acute paraquat poisoning. METHODS: Ninety-one patients with acute paraquat poisoning were randomly divided into HP group (49 cases) and HP-CVVH group (42 cases). The mortality, survival duration and the death causes between the two groups were compared and analyzed. RESULTS: There were no significant differences in mortality (59.2% versus 61.9%) between the two groups. The mean time between poisoning and death in HP-CVVH group was (4.9 +/- 3.1) days, which was significantly longer than that (3.5 +/- 2.0) days in HP group (P < 0.05). The death proportion on 4th day after poisoning in HP group was 62.1% (18/29), which was significantly higher than that (30.8%, 8/26) in HP-CVVH group (P < 0.05). The hypoxia appeared in 4.3 +/- 2.5 days after poisoning in HP-CVVH group, which was significantly longer than that (3.2 +/- 1.9) days in HP group (P < 0.05). The mortality due to respiratory failure in HP group was 20.4% (10/49), which was significantly lower than that (40.5%, 17/42) in HP-CVVH group (P < 0.05). The incidence of acute renal failure in HP group was 63.3% (31/49), which was significantly higher than that (40.5%, 17/42) in HP-CVVH group (P < 0.05). CONCLUSION: The combined therapy of HP and CVVH can prevent the patients with acute paraquat poisoning from early death and prolong the survival duration, but can not reduce mortality for the patients with acute paraquat poisoning.

[Study on the prognosis of patients with acute paraquat intoxication].

OBJECTIVE: To study the correlation factors of acute paraquat intoxication prognosis. METHODS: The early paraquat concentration in plasma and urine, leukocyte count, hepatic and renal function, amylase, electrolyte and the parameters of arterial blood gas were analyzed retrospectively in 111 patients with acute paraquat intoxication. RESULTS: 43 cases (38.7%) of all the 111 patients survived and the other 68 cases (61.3%) died. The patient, whose paraquat concentration was not more than 8.0 µg/ml in plasma and 276.0 µg/ml in urine, could survive. But some patients could die, only if there was no paraquat found in plasma. The paraquat levels in plasma and urine were significantly lower in survivors [(0.82 ± 1.70), (28.12 ± 51.17) µg/ml] than in nonsurvivors [(9.32 ± 12.04), (384.53 ± 597.93) µg/ml, respectively] (P < 0.01). The levels of leukocyte count, serum creatinine, aspartate aminotransferase (AST), and amylase were significantly higher in nonsurvivors than in survivors (P < 0.05, P < 0.01). In addition, metabolic acidosis was easier to appear in nonsurvivors. The multiple logistic regression analysis indicated that the paraquat concentration in plasma and urine, leukocyte count, creatinine and base excess were all related to survival. CONCLUSION: The higher paraquat concentration in plasma and urine, leucocytosis, renal dysfunction and metabolic acidosis are all important factors for the prognosis of paraquat intoxication.

Pharmacokinetics and safety of a new bioengineered thrombolytic agent, human tissue urokinase type plasminogen activator in Chinese healthy volunteers.

The aim of our study was to investigate the pharmacokinetics and safety of human tissue urokinase type plasminogen activator (HTUPA) in healthy Chinese subjects after intravenous administration. Thirty-two subjects were given intravenous injection doses of 5-35 mg of HTUPA for safety evaluation. Twenty-four subjects were given 10, 20 or 30 mg HTUPA for pharmacokinetic assessment. Safety and tolerance were evaluated by monitoring adverse events, laboratory parameters, electrocardiography and vital signs. HTUPA concentration in human serum samples was determined by an enzyme-linked immunosorbent assay (ELISA) method. The main pharmacokinetic parameters were calculated by DAS software. HTUPA was generally well tolerated and in the whole study course no serious adverse events occurred. The main pharmacokinetic parameters were as follows: geometric mean [95% confidence interval, CI] for t1/2 were 1.5 (1.4, 1.6), 1.3 (1.2, 1.4), and 1.2 (1.2, 1.3) h, AUC0-t were 1.0 (0.7, 1.3), 2.1 (1.5, 2.7), and 5.6 (4.7, 6.6) mg h L(-1), AUC0-∞ were 1.1 (0.8, 1.3), 2.1 (1.5, 2.7), and 5.8 (4.7, 6.7) mg h L(-1) for 10, 20, and 30 mg group, respectively. The main pharmacokinetic parameters were not significantly different between males and females (P>0.05). No serious adverse events were reported by the subjects or revealed by clinical or laboratory examinations, suggesting the given doses were safe and well tolerated.

[The diagnostic value of butyrylcholinesterase in acute organophosphorus pesticide poisoning].

OBJECTIVE: To assess the value of butyrylcholinesterase (BuChE) in the diagnosis of acute organophosphorus pesticide poisoning (AOPP), and to investigate the relationship between the activity of whole blood acetylcholinesterase (AChE) and plasma BuChE in patients of AOPP in order to re-evaluate the diagnostic value of BuChE. METHODS: An improved Ellman method was employed to determine the activity of AChE and BuChE in 21 AOPP inpatients due to different kinds of pesticides (from April to September in 2009) during the course of the illness, with 26 healthy volunteers as normal control. The relationship between BuChE activity and other clinical indicators of 113 inpatients (from January 2008 to April 2009) was also retrospectively analyzed. RESULTS: The normal value of AChE and BuChE were (105 + or - 33) U/Hb and (15 807 + or - 3 495) U/L . The inhibition levels of these two enzymes were different. When the AChE activity was lower than 50%, 30% or 20%, the activity of BuChE was lower than 20%, 10% or 5% correspondingly. The tendency of changes in the two enzymes was similar and coincided well with the clinical symptoms after poisoning. The results of sequential detection showed that a significant decrease or persistent inhibition of BuChE activity by less than 5% indicated a high level of organophosphorus pesticide in the body. However, an elevation of BuChE indicated a favorable outcome. CONCLUSION: BuChE is one of the ideal diagnostic and classification criteria for AOPP. When the inhibition level of BuChE reaches 20%, AOPP is of moderate degree, when it reaches 10%, severe AOPP can be diagnosed, with different kinds of organophosphorus pesticides taken into consideration.

Suppression of perfluoroisobutylene induced acute lung injury by pretreatment with pyrrolidine dithiocarbamate.

Perfluoroisobutylene (PFIB) is produced as a main by-product in large quantities by the fluoropolymer industry. As a highly toxic compound, even the case of brief inhalation of PFIB can result in acute lung injury (ALI), pulmonary edema and even death. To test for any preventive or therapeutic effects of pyrrolidine dithiocarbamate (PDTC), a NF-kappaB activation inhibitor, against PFIB inhalation-induced ALI, mice were exposed in a flow-past exposure system to PFIB and the prophylactic and therapeutic effects of PDTC were studied. The inhibitory effects of PDTC on ALI, the activation of NF-kappaB, as well as the expression of cytokines (IL-1beta and IL-8) after PFIB exposure were evaluated. The results demonstrated that pretreatment with PDTC (120 mg/kg, 30 min before PFIB exposure) could significantly lower the lung coefficient (wet lung-to-body weight ratio, dry lung-to-body weight ratio, water content in the lung, and lung wet-to-dry weight ratio) and protein content in bronchoalveolar lavage fluid (BALF), but no effects of PDTC were found when PDTC was treated after PFIB inhalation, suggesting a preventative effect rather than a therapeutic effect of PDTC. Furthermore, the above preventative effects of PDTC (when given at 30 min before PFIB exposure) on PFIB-induced lung injury were achieved in a dose-dependent manner. In support of these preventive effects of PDTC, our toxicological studies demonstrated that PFIB-inhalation induced a quick activation of NF-kappaB (0.5 h post PFIB exposure) and expression of IL-1beta and IL-8 (0.5 h and 1 h post PFIB exposure, respectively). Pretreatment with PDTC (120 mg/kg, 30 min before PFIB exposure) resulted in a significant inhibitive effect on the activation of NF-kappaB (0.5 h post PFIB exposure) and expression of IL-1beta and IL-8 (1 h post PFIB exposure). The mortality, the extent of lung injury of the mice indexed by lung coefficients, the content of total protein and albumin in BALF, as well as the lung histopathologic changes, were dramatically alleviated in PFIB exposure after pretreatment with PDTC, clearly suggesting that PDTC has a prophylactic role against PFIB inhalation-induced ALI, and that NF-kappaB activation might play a central role in initiating an acute inflammatory response and in causing injury to the lungs after PFIB inhalation.

The prophylactic and therapeutic effects of cholinolytics on perfluoroisobutylene inhalation induced acute lung injury.

Perfluoroisobutylene (PFIB) is a kind of fluoro-olefin that is ten times more toxic than phosgene. The mechanisms of the acute lung injury (ALI) induced by PFIB inhalation remain unclear. To find possible pharmacological interventions, mice and rats were exposed to PFIB, and the prophylactic or therapeutic effects of 3-quinuclidinyl benzilate (QNB) and anisodamine were studied and confirmed. It was observed that the wet lung/body weight and the dry lung/body weight ratios at 24 h after PFIB exposure (130 mg/m(3) for 5 min) were significantly decreased when a single dose of QNB (5 mg/kg) was administered intraperitoneally either 30 min before exposure or 10 h after exposure. Anisodamine was without any prophylactic or therapeutic effects at single doses below 30 mg/kg. The effects of QNB against PFIB inhalation induced ALI were well evidenced by the significantly decreased mice mortality at 72 h, the total protein concentration in bronchoalveolar lavage fluid at 24 h after the PFIB exposure, as well as the ultrastructural observations. The analysis of the time courses of lung sulfhydryl concentration, myeloperoxidase (MPO) activity and hemorheology assay showed that the toxicity of PFIB may be due to consumption of lung protein sulfhydryl, influx of polymorphonuclear leukocytes (PMNs) into the lung, and increased peripheral blood viscosity at a low shear rate, all of which were partially blocked by QNB intervention except for PMN influx. The results suggest that cholinolytics might have prophylactic and therapeutic roles in PFIB inhalation induced ALI.