Protection of carbon tetrachloride hepatotoxicity by cinchona alkaloids

Elevated serum enzymes were observed due to all four cinchona alkaloids in male Sprague-Dawley rats after four day treatment. Only a slight effect on bile flow and excretion of phenolphthalein glucuronide in bile was noted. Animals treated with cinchona alkaloid for four days and then receiving CCl4 showed a partial protection against CCl4 induced hepatotoxicity. The levels of serum enzymes were lowered as compared to animals treated with CCl4 alone. Bile flow and excretion of phenolphthalein glucuronide in bile showed a trend of restoration towards control levels. All four cinchona alkaloids probably inhibit microsomal enzymes, thereby, inhibiting the bioactivation of CCl4 and hence reducing the toxicity.     

Selective protective effect of an extract from Fumaria parviflora on paracetamol-induced hepatotoxicity

1. The hepatoprotective activity of an aqueous-methanolic extract of Fumaria parviflora was investigated against paracetamol- and CCI4-induced hepatic damage. 2. Paracetamol (1 g/kg; orally) produced 100% mortality in mice; pretreatment of animals with the plant extract (500 mg/kg; orally) reduced the death rate to 50%. 3. Pretreatment of rats with plant extract (500 mg/kg, orally twice daily for 2 days) prevented (P < 0.001) the paracetamol (640 mg/kg)-induced rise in serum enzymes alkaline phosphatase (ALP) and transaminases (GOT and GPT), whereas the same dose of the extract was unable to prevent (P > 0.05) the CCI4-induced rise in serum enzyme levels. 4. Posttreatment with 3 successive doses of the extract (500 mg/kg, 6 hourly) also restricted the paracetamol-induced hepatic damage. 5. The plant extract (500 mg/kg; orally) caused significant prolongation in pentobarbital (75 mg/ kg)-induced sleep as well as increased strychnine-induced lethality in mice (P < 0.05), suggestive of an inhibitory effect on microsomal drug metabolizing enzymes (MDME). 6. It is conceivable therefore, that Fumaria parviflora extract exhibits a selective protective effect against paracetamol-induced hepatotoxicity, probably mediated through MDME inhibition.     

Effect of pretreatment of rats with an urinary preparation on liver injuries induced by carbon tetrachloride and alpha-naphthylisothiocyanate

The effect of oral administration of a preparation of human urine (PHU) on the progression of acute liver injury was examined in rats intoxicated with carbon tetrachloride (CCl4) and alpha-naphthylisothiocyanate (ANIT) PHU protected the liver from CCl4-induced injury as judged by morphological and biochemical observations. In contrast, PHU aggravated ANIT-induced injury as judged also by morphological and biochemical observation. PHU prevented the increase in hepatic glutathione (GSH) and lipid peroxidation induced by CCl4. But PHU enhanced the increase in hepatic GSH caused by ANIT. These results indicate that the effect of PHU on hepatic GSH concentrations is through an indirect pathway. Clinical application of PHU on hepatitis should be explored further.     

Colchicine antimitosis abolishes resiliency of postnatally developing rats to chlordecone-amplified carbon tetrachloride hepatotoxicity and lethality

We have previously reported that rats are resilient to the hepatotoxic and lethal combination of chlordecone (CD) and carbon tetrachloride (CCl4) during early postnatal development. The overall findings pointed to stimulated cell division and tissue repair mechanisms as the underlying cause of resistance. The objective of the current study was to investigate if the antimitotic effect of colchicine (CLC) abolishes this resiliency to CD + CCl4 by inhibiting ongoing and stimulated cell division. We used 45-day-old rats in this study because this age group exhibited partial sensitivity to CD + CCl4 in our previous studies. Male Sprague-Dawley rats were treated with a single low intraperitoneal dose of CCl4 (100 microl/kg) or corn oil after exposure to either 10 ppm CD in the diet or a normal diet (ND) for 15 days. CLC (1 mg/kg) was administered 6 or 30 hr after CCl4 to ND or CD rats, respectively. Administration of CLC resulted in increased CCl4-induced mortality from 25% to 85% in rats pretreated with CD, in contrast to 100% survival in ND rats. Liver injury was assessed by plasma alanine transaminase (ALT) and sorbitol dehydrogenase (SDH) elevations as well as by histopathology. Hepatocellular regeneration was assessed by 3H-thymidine (3H-T) incorporation into hepatonuclear DNA and proliferating cell nuclear antigen (PCNA) studies during 0-96 hr after CCl4. Administration of CLC to ND + CCl4 rats resulted in a slight delay in cell division and tissue repair, as indicated by 3H-T incorporation and PCNA, thereby leading to prolonged liver injury as revealed by elevations in plasma ALT, SDH, and histopathological lesions. In contrast, CLC administration to CD + CCl4-treated rats further delayed and diminished cell division by 80%, which led to unrestrained progression of CCl4-induced liver injury, resulting in 85% mortality. These findings underscore the importance of ongoing and toxicant-stimulated cell division and tissue repair mechanisms in hepatotoxicity, and the need for the inclusion of age factors in risk assessment of exposure to environmental and other chemicals.     

Studies on carbon tetrachloride toxicity

In a preliminary survey, 484 alumni of the Massachusetts Mental Health Residency Training Program from 1912 to 1967 were surveyed. Approximately 80% were found to have devoted half or more of their professional time to the nonprivate practice of psychiatry for at least one year. These data suggest that a training program with strong academic traditions might produce a preponderance of publicity of oriented psychiatrists. Since previous surveys have indicated a greater proportion of psychiatric time spent in private practice, we suggest that future surveys of psychiatric manpower need to consider the orientation of residency training programs in order to accurately assess the need for future psychiatric manpower.     

Comparison of paracetamol-induced hepatotoxicity in the rat in vivo with progression of cell injury in vitro in rat liver slices

The flux in rat hepatic ratio of adenosine triphosphate levels to adenosine diphosphate levels (ATP/ADP) during the onset and progression of paracetamol-induced cell injury both in vivo and in vitro were investigated and compared. Leakage of lactate dehydrogenase (LDH) and potassium (K+), and mg water/mg dry weight quantified cell injury. ATP and ADP levels were determined using the luciferin-luciferase bioluminescence assay. For in vitro studies, liver slices obtained from phenobarbitone-induced rats were exposed to 10 mM paracetamol for 120 min (T0-T120) and, then incubated without paracetamol up to a further 240 min (T120-T360). For in vivo studies, groups of four phenobarbitone-induced rats received i.p. injections of 800 mg/kg paracetamol. ATP/ADP ratios fall upon exposure to paracetamol both in vitro and in vivo. However, unlike the in vitro situation where the fall in ATP/ADP ratios precedes and accompanies the progression of cell injury, the in vivo fall in ATP/ADP ratios is shown to occur as cell injury measurements begin to recover to control levels. However, despite these differences classic paracetamol-induced centrilobular necrosis is observed to occur both in vitro and in vivo. This study demonstrates that the liver slice model is a simple and useful technique to investigate the underlying mechanisms of paracetamol-induced cell injury.     

Studies on the kinetics of carbon tetrachloride chlorination of tantalum pentoxide

Studies on the kinetics of chlorination of tantalum pentoxide powder by carbon tetrachloride vapor in dilution with nitrogen have been carried out by weight-loss measurements in two temperature ranges, i.e., 698 to 773 K and 793 to 853 K. The effect of time, temperature, and partial pressure of CCl₄ on the kinetics of chlorination of the powder Ta₂O₅, (−105+74 μm) has been investigated. In both the temperature ranges, the chlorination results have been found to fit the following relationship during the “initial periods:”

Late preventive effects of quinacrine on carbon tetrachloride induced liver necrosis

We have previously reported that treatments stimulating phospholipid (PL) synthesis or preventing PL degradation were late preventive agents against CCl4-induced liver necrosis. Later studies by others postulated that stimulation of phospholipase A2 (PLA2) plays a role in PL degradative processes responsible for CCl4 damage. Quinacrine (QUIN) is a well known inhibitor of PLA2. In this work we report that QUIN (150 mg/kg i.p.) partially prevents CCl4-induced liver necrosis at 24 h when given 30 min before or 6 or 10 h after CCl4 (2.5 ml/kg p.o.) QUIN administration does not modify at 1 or 3 h after poisoning CCl4 levels reaching the liver, covalent binding of CCl4 reactive metabolites to proteins or lipids, CCl4-induced lipid peroxidation process, CCl4-induced decreases in body temperature, or glutathione levels in liver. QUIN concentrations in liver at times from 1 to 24 h are well over those required to inhibit PLA2 activity. Results are compatible with the hypothesis that CCl4 activation of PLA2 at late stages of poisoning plays a role in CCl4-induced liver necrosis.     

Kinetics of chlorination of niobium pentoxide by carbon tetrachloride

Kinetics of the chlorination of Nb₂O₅ powder by CCl₄ vapor in mixture with N₂ in a static bed in the temperature range of 698 to 853 K were carried out at different partial pressures of CCl₄ (p _{CCl 4}), varying from 0.10 to 0.75 atm. The fraction of Nb₂O₅ chlorinated R at p _{CCl 4} of 0.6 atm in the temperature range of 698 to 773 K was found to be proportional to time t, and the activation energy E is calculated to be 112 kJ/mole. Results on the effect of p _{CCl 4} (0.4, 0.6, and 0.75 atm) at 723 K suggest that the rate v (R/min) is proportional to p _{CCl 4} ^1.5. However, at p _{CCl 4} of 0.2 atm, R is not linear with t, rather, R ^1/2 is linear with t. Based on these results, two mechanisms, one at low p _{CCl 4} (0.2 atm) and another at higher p _{CCl 4} values, in the temperature range of 698 to 773 K have been suggested. Similar studies in the higher temperature range (793 to 853 K), where p _{CCl 4} used to decompose to elemental chlorine and carbon, were also carried out. At all temperatures and p _{CCl 4} values, R is found to be directly proportional to t. At two higher p _{CCl 4} (0.4 and 0.6 atm), v is proportional to p _{CCl 4} ^1.5, whereas at two lower p _{CCl 4} (0.1 and 0.2 atm) it is proportional to p _{CCl 4} ^1.5. The E values obtained in the temperature range of 793 to 853 K at p _{CCl 4} of 0.6 and 0.2 atm are found to be 57 and 115 kJ/mole, respectively. In this higher temperature range, two different reaction mechanisms have been proposed.     

Recurrent liver failure with severe rhabdomyolysis after liver transplantation for carbon tetrachloride intoxication

Acute liver failure due to intoxication is a rare indication for liver transplantation which a usually has a good prognosis. We herein report the case of a young male, who underwent orthotopic liver transplantation for acute liver failure due to carbon tetrachloride intoxication. Apart from hepatic and renal failure, the patient also developed severe rhabdomyolysis, which has not thus far been described as a toxic effect of this chemical agent. Despite forced hyperventilation, which is known to be the most effective means of eliminating the specifically lipophylic agent, as well as excessive plasma exchange following intravenous administration of fat emulsions, liver failure recurred when blood carbon tetrachloride concentrations were already at non-toxic levels. Retransplantation of the liver together with a kidney was only temporarily successful, since the patient died due to aspergillus sepsis. Based on this experience, we would recommend that whenever possible in patients with carbon tetrachloride intoxication, liver transplant should be delayed until most of the toxic agent has been eliminated in order to prevent fatal graft damage.     

Phenobarbital in comparison with carbon tetrachloride and phenobarbital-induced cirrhosis in rat liver regeneration

PURPOSE: Status epilepticus (SE) is a major medical and a neurologic emergency associated with significant morbidity and mortality. The current definition of SE is continuous seizure activity or intermittent seizure activity without regaining consciousness, lasting > or =30 min. Epilepsy monitoring unit data indicate that many seizures self-terminate within minutes. Thus consideration was recently given to include seizure episodes lasting > or =10 min in the definition of SE. Because no large studies have been conducted on seizures lasting 10-29 min, this study was initiated to compare cases of SE and 10 to 29-min seizure episodes seen within the same period. METHODS: Patients seen at the Medical College of Virginia Hospitals of Virginia Commonwealth University over the same 2-year period were studied. Two hundred twenty-six prospective SE cases (91 children and 135 adults) and 81 retrospective 10- to 29-min seizure episodes (31 children and 50 adults) were compared. A standardized data-entry-form system was compiled on each patient and was used to evaluate the data collected. RESULTS: The 10- to 29-min seizure patients and the SE cases had similar demographic characteristics, such as sex, race, and age, and also had similar etiologies. The majority (93%) of SE cases required anticonvulsant (AED) treatment to control and stop seizure activity. In the 10- to 29-min group, 43% stopped seizing spontaneously, and the remainder (57%) required AED treatment to stop seizure activity. The mortality for the SE patients was 19% compared with 2.6% for 10- to 29-min group (p<0.001). In the 10- to 29-min group that stopped seizing spontaneously, the mortality was 0. In the 10- to 29-min patients that required AED treatment, the mortality was 4.4%. CONCLUSIONS: The results demonstrate that a significant number of patients experience seizure activity lasting from 10- to 29-min. Approximately half of these seizure events stopped spontaneously and did not require AED treatment. The other half of the patients responded quickly to medications and stopped seizing before the 30-min definition for SE. The overall mortality of this group was significantly lower than that of the patients with SE. The results demonstrate that further studies on the 10- to 29-min seizure group are needed to differentiate seizures that will stop spontaneously and those that will only stop with AED treatment. Because almost half of the prolonged seizures stopped spontaneously, further studies are needed before including prolonged seizure activity in the definition of SE.     

Studies on kinetics of low-temperature chlorination of ZrO2 by gaseous carbon tetrachloride

Studies on the kinetics of chlorination of ZrO₂. powder by carbon tetrachloride vapor in mixture with nitrogen in a low-temperature range of 650 to 825 K at different periods and partial pressures of carbon tetrachloride were carried out. The chlorination results at 650 and 675 K seem to follow a diffusion-controlled reaction model of Jander’s type: [1−(1−R)^1/3]² =k ₁t whereR is the fraction of ZrO₂ chlorinated in timet andk ₁ is the rate constant. The approximate activation energy of the process was calculated fromk ₁ values at the previously mentioned two temperatures and found to be 278 kJ/mole. For the chlorination in the temperature range of 700 to 750 K, the topochemical reaction model 1−(1−R) ^1/3 =k ₂t was followed. The rate constant,k ₂, was found to be proportional to the partial pressure of carbon tetrachloride. The activation energy of this reaction was calculated to be 154 kJ/mole. In the temperature range of 775 to 825 K, the rate of chlorination was found to be directly proportional to the time of chlorination following Langmuir’s Adsorption Isotherm. Because of the very high rate of chlorination and thermodynamic possibility of decomposition of CCl₄ above 773 K, the rate-controlling step has been suggested to be the decomposition of the adsorbed complex formed by ZrO₂ with carbon and chlorine atoms, obtained from the decomposition of CCl₄ vapor. The activation energy of the process was 54 kJ/mole. In view of nearly complete chlorination of ZrO₂ by CCl₄ in a very short period of about 15 minutes, at a temperature around 800 K and lesser possibility of formation of toxic product gases, the process is recommended for commercial application.     

Kinetics of chlorination and microstructural changes of xenotime by carbon tetrachloride

Among the rare earth minerals, fluorides, phosphates, and oxides have received attention from the rare earth industry. Traditional methods of decomposition of these minerals, usually alkaline or acid processes, involve several operations. Another possibility to obtain lanthanide chlorides or oxychlorides is reacting the mineral with chlorinating agents, such as gaseous chlorine, hydrogen chloride, thionyl chloride, and carbon tetrachloride, reducing the operation costs and making the process less complicated. In this context, we investigated the decomposition of xenotime using carbon tetrachloride at temperatures from 873 to 1173 K and kinetic and mechanistic studies have been performed. Powder X-ray diffraction, scanning electronic microscopy, energy dispersive X-ray spectrometry, ultra-violet/visible spectroscopy, and thermal analysis techniques were used in this study. The results showed that the reaction follows the shrinking-unreacted-core model with formation of a product layer (lanthanide oxychloride), confirmed by powder X-ray diffraction. Moreover, microstructural changes of xenotime grains during the chlorination reaction were verified.