A randomized trial to determine the change in alanine aminotransferase during 10 days of paracetamol (acetaminophen) administration in subjects who consume moderate amounts of alcohol.

BACKGROUND: Previous studies have suggested that therapeutic doses of paracetamol (acetaminophen) are safe in alcoholic patients when administered for up to 3 days. However, 14 days of therapeutic doses of paracetamol has been associated with an increase in serum transaminases. AIM: To determine the effect of 10 days of the maximal therapeutic dose of paracetamol on serum alanine aminotransferase (ALT) activity in subjects who consume 1 to 3 alcoholic beverages per day. METHODS: This was a randomized, double blind, placebo-controlled trial. Subjects took 4 g of paracetamol (or placebo) daily for 10 days. Serum aspartate aminotransferase (AST), ALT, bilirubin and INR were measured at baseline, day 4 and day 11. Symptoms potentially related to liver injury were also recorded. RESULTS: Paracetamol and placebo groups had no change from baseline values at day 4, but the paracetamol group had an increase in mean ALT at day 11 of 8.7 IU/L. No subject developed symptoms of liver injury or met predefined criteria for hepatotoxicity or liver failure. CONCLUSION: Therapeutic dosing of paracetamol administered for 10 days appears to elevate serum ALT in moderate drinkers, but does not produce clinically evident liver injury.

The effect of acetaminophen (four grams a day for three consecutive days) on hepatic tests in alcoholic patients--a multicenter randomized study.

BACKGROUND: Hepatic failure has been associated with reported therapeutic use of acetaminophen by alcoholic patients. The highest risk period for alcoholic patients is immediately after discontinuation of alcohol intake. This period exhibits the largest increase in CYP2E1 induction and lowest glutathione levels. Our hypothesis was that common liver tests would be unaffected by administration of the maximum recommended daily dosage of acetaminophen for 3 consecutive days to newly-abstinent alcoholic subjects. METHODS: Adult alcoholic subjects entering two alcohol detoxification centers were enrolled in a prospective double-blind, randomized, placebo-controlled trial. Subjects were randomized to acetaminophen, 4 g/day, or placebo for 3 consecutive days. The study had 95% probability of detecting a 15 IU/L difference in serum ALT. RESULTS: A total of 443 subjects were enrolled: 308 (258 completed) received acetaminophen and 135 subjects (114 completed) received placebo. Study groups did not differ in demographics, alcohol consumption, nutritional status or baseline laboratory assessments. The peak mean ALT activity was 57 +/- 45 IU/L and 55 +/- 48 IU/L in the acetaminophen and placebo groups, respectively. Subgroup analyses for subjects presenting with an elevated ALT, subjects fulfilling a diagnosis of alcoholic hepatitis and subjects attaining a peak ALT greater than 200 IU/L showed no statistical difference between the acetaminophen and control groups. The one participant developing an increased international normalized ratio was in the placebo group. CONCLUSION: Alcoholic patients treated with the maximum recommended daily dose of acetaminophen for 3 consecutive days did not develop increases in serum transaminase or other measures of liver injury. Treatment of pain or fever for 3 days with acetaminophen appears safe in newly-abstinent alcoholic patients, such as those presenting for acute medical care.

Effect of maximal daily doses of acetaminophen on the liver of alcoholic patients: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Retrospective reports suggest that therapeutic doses of acetaminophen may be associated with fulminant hepatic failure and death in alcoholic patients. Millions of patients use acetaminophen; the prevalence of alcoholism in the United States is 5% to 10%. OBJECTIVE: To determine if hepatic injury was associated with maximal therapeutic dosing of acetaminophen to chronic alcohol abuse patients immediately following cessation of alcohol intake (the presumed time of maximal vulnerability). METHODS: Patients entering an alcohol detoxification center were enrolled in a randomized, double-blind, placebo-controlled trial. Exclusion criteria were baseline values of aspartate or alanine aminotransferase greater than 120 U/L, international normalized ratio greater than 1.5, serum acetaminophen level greater than 20 mg/L, or a history of ingesting more than 4 g/d of acetaminophen. Acetaminophen, 1000 mg, or placebo was administered orally 4 times daily for 2 consecutive days and liver test results were monitored for 2 more days. Acetaminophen was not administered until the alcohol had been eliminated. RESULTS: There were 102 patients in the acetaminophen-treated group and 99 patients in the placebo-treated (control) group. Demographic data, alcohol history, and baseline blood test results were similar in both groups. The mean (SD) aspartate aminotransferase level on day 4 was 38.0 +/- 26.7 U/L in the acetaminophen-treated group and 37.5 +/- 27.6 U/L in the placebo-treated group. There were 4 patients in the acetaminophen-treated group and 5 in the placebo-treated group who developed an increase in their serum aspartate aminotransferase level to greater than 120 U/L; it did not exceed 200 U/L in any patient. The mean (SD) international normalized ratio on day 4 was 0.96 +/- 0.09 in the acetaminophen-treated group and 0.98 +/- 0.11 in the placebo-treated group. CONCLUSION: Repeated administration of the maximum recommended daily doses of acetaminophen to long-term alcoholic patients was not associated with evidence of liver injury.

Attenuation of verapamil-induced myocardial toxicity in an ex-vivo rat model using a verapamil-specific ovine immunoglobin.

OBJECTIVE: To determine whether an ovine verapamil-specific immunoglobin G (V-IgG) attenuates verapamil toxicity in an ex-vivo rat left ventricular papillary muscle model. METHODS: The authors dissected left ventricular papillary muscle strips from male Sprague-Dawley rats (350-410 g) and suspended them in an oxygen-perfused Tyrode buffer bath at 37.5 degrees C. Muscle strips equilibrated for 90 minutes under electrical stimulation of 1 Hz. Resting and developed tension (mg) were monitored continuously. A concentration-response trial was performed with verapamil concentrations ranging from 31 to 1,020 nM; 510 nM produced consistent reduction in developed tension. A trial of V-IgG was then conducted by administering the following treatments to papillary muscle strips in a randomized manner: V-IgG + 510 nM verapamil, nonspecific ovine IgG (N-IgG) + 510 nM verapamil (protein control), and 510 nM verapamil alone. Immunoglobin G was administered in equimolar concentrations to verapamil. Attenuation was expressed as inhibition of the verapamil-induced reduction of developed tension. RESULTS: The V-IgG comparative trial indicated the V-IgG + verapamil treatment had a mean reduction in developed tension of 14.1% (SD +/- 12.2) compared with 36.2% (SD +/- 14.9) for N-IgG + verapamil and 34.9% (SD +/- 8.1) for verapamil alone (p < 0.05). There was no difference between the two control groups. CONCLUSION: Verapamil-specific IgG attenuated verapamil-induced reduction of developed tension in an ex-vivo rat model.

A randomized multicenter trial of crotalinae polyvalent immune Fab (ovine) antivenom for the treatment for crotaline snakebite in the United States.

BACKGROUND: Current therapy for crotaline snakebite includes antivenin (Crotalidae) polyvalent, an antivenom with numerous adverse effects. We compared the efficacy and safety of 2 dosing regimens with a new antivenom, Crotalinae polyvalent immune Fab (Fab AV). METHODS: A single dose of Fab AV alone (as-needed [PRN] group) was compared with an initial dose plus repeated treatments during 18 hours (scheduled group) in a multicenter randomized trial. The study included patients with minimal or moderate envenomation by a crotaline snake within the preceding 6 hours, aged 10 years or older, in whom worsening of the envenomation syndrome was observed before Fab AV treatment. After treatment with Fab AV to achieve initial control, patients were randomized to the scheduled or PRN treatment group. Scheduled group patients received additional doses of Fab AV every 6 hours for 3 doses. The PRN group received no planned additional doses of antivenom. RESULTS: The mean severity score of the 31 patients decreased from 4.35 to 2.39 points (P<.001); there was no difference between scheduled and PRN groups. No patient in the scheduled group received unplanned Fab AV doses, but 8 of 16 patients in the PRN group received unplanned doses (P =.002). Acute reactions occurred in 6 patients (19%), and serum sickness occurred in 6 (23%) of 26 patients who returned for follow-up. CONCLUSIONS: In the first randomized trial of antivenom in the United States, Fab AV effectively terminated venom effects. Since the unplanned use of Fab AV in the PRN group was common, the treatment regimen may require more than 1 initial dose.

Neutralization of Latrodectus mactans and L. hesperus venom by redback spider (L. hasseltii) antivenom.

OBJECTIVE: To test the effectiveness of L. hasseltii (redback spider) antivenom in neutralizing the lethal effects of L. hesperus and L. mactans (North American black widow) venoms. METHODS: LD50 values for the L. hesperus and L. mactans venom preparations were determined. A prospective, randomized, double-blind antivenom efficacy experiment was then performed for each venom using a mouse envenomation model. The following treatments were premixed and incubated at 25 degrees C for 1 hour prior to intraperitoneal injection: 1) saline control + protein control, 2) saline control + L. hasseltii antivenom, 3) L. hesperus or L. mactans venom + protein control, and 4) L. hesperus or L. mactans venom + L. hasseltii antivenom. The study endpoints were time elapsed until death and survival at 24 hours. RESULTS: The mouse LD50 values for L. hesperus and L. mactans venoms were 0.64 mg/kg and 0.26 mg/kg, respectively. In the efficacy trial, all mice in group 3 (L. hesperus or L. mactans venom and protein control) died. In both experiments, all mice in group 4 (L. hesperus or L. mactans venom + antivenom) survived (p < 0.0001). CONCLUSION: This is the first study to derive mouse LD50 values for L. hesperus and L. mactans venom obtained by electrical stimulation of live adult spiders. Redback spider antivenom is effective in neutralizing the lethal effects of L. hesperus and L. mactans venoms in a mouse envenomation model. While this study is limited by the optimized premixing of antigen with antibody, it generates the hypothesis that redback antivenom would be effective in the treatment of latrodectism in humans caused by the two clinically relevant species of North American widow spiders.

Time to reconstitution: purified Fab antivenom vs. unpurified IgG antivenom.

We conducted prospective, randomized analytical and observational trials to assess reconstitution times of two lyophilized crotaline snake antivenoms, Antivenin (Crotalidae) Polyvalent [Wyeth-Ayerst] (ACP) and affinity-purified, mixed monospecific crotalid antivenom ovine Fab (CroTAb) (Fab antivenom). The analytical experiment indicated Fab antivenom and ACP reached their maximum protein concentration at 25 and 45min, respectively. In the observational experiment, Fab antivenom (median 40min) had a shorter reconstitution time than ACP (>90min, p<0.008).

Recurrent coagulopathy after antivenom treatment of crotalid snakebite.

BACKGROUND: We studied whether recurrence of coagulopathy, defined as the return of a coagulation abnormality after initial normalization, occurred after the use of antivenin (Crotalidae) polyvalent. METHODS: A retrospective, blinded, descriptive analysis of 354 consecutive cases of North American crotalid snake envenomation was done. Inclusion criteria were documented clinical evidence of crotalid snakebite, presence of a coagulopathy (platelet count <150,000/mm3, prothrombin time above normal, or fibrinogen level <150 mg/dL), and treatment with antivenin (Crotalidae) polyvalent. RESULTS: Of 112 cases with a coagulopathy extending beyond 6 hours after envenomation, 31 had sufficient coagulopathy testing to detect recurrence. Fourteen of these patients (45%) had recurrence of coagulopathy, and two cases were severe (fibrinogen level 29 mg/dL; platelet count 36,000/mm3). CONCLUSION: Recurrence of coagulopathy after envenomation by North American crotalid snakes may occur after use of antivenin (Crotalidae) polyvalent and can result in severe coagulation abnormalities.

Heat and motion stability of polyvalent Crotalidae antivenin, ovine Fab.

This study was conducted to test the hypothesis that a Fab-based crotalid antivenin (FabAV) in commercially packaged vials will remain effective under more extreme heat and motion conditions than would be expected in field settings. Vials containing FabAV were subjected to heat or motion. The effect of heat or motion on the ED50 of FabAV was determined using a mouse model of crotalid snake envenomation. The ED50 for the heat stability groups (expressed as a ratio of mg antivenin to mg venom) were as follows: 4 degrees C x 60 days (control) = 26.5, 70 degrees C x 60 days = 66.3, 70 degrees C x 30 days = 52.4, 50 degrees C x 60 days = 25.8, 50 degrees C x 30 days = 34.0. The ED50 for the two motion stability groups were similar: 4 degrees C x 60 days = 40.3 and 70 degrees C x 60 days = 48.3. These results indicate that FabAV is heat stable at 50 degrees C for 60 days, but had less potency when heated to 70 degrees C for 30 days. FabAV appears less potent after agitation, but remains effective in the mouse model. We conclude that FabAV can be safely stored for at least 60 days without refrigeration under most field conditions where snake envenomation may occur.

Enzymatic methylation of arsenic compounds: assay, partial purification, and properties of arsenite methyltransferase and monomethylarsonic acid methyltransferase of rabbit liver.

A rapid, accurate, in vitro assay utilizing radioactive S-adenosylmethionine (SAM) has been developed for the methylation of arsenite and monomethylarsonate (MMA) by rabbit liver methyltransferases. The assay has been validated by separating, identifying, and measuring the products of the reaction using chloroform extraction, ion exchange chromatography, TLC, or HPLC. The enzymes involved in this pathway, arsenite methyltransferase and MMA methyltransferase, have been purified approximately 2000-fold from rabbit liver. After gel electrophoresis, a single band is obtained with both enzyme activities in it. The pH optima for purified arsenite methyltransferase and monomethylarsonic acid methyltransferase are 8.2 and 8.0, respectively. A thiol, S-adenosylmethionine, and arsenite are required for the partially purified arsenite methyltransferase that catalyzes the synthesis of monomethylarsonate. A different enzyme activity that catalyzes the methylation of monomethylarsonate to dimethylarsinate also requires SAM and a thiol. Even though arsenite methyltransferase and monomethylarsonate methyltransferase have different substrates, pH optima, and saturation concentrations for their substrates, whether the two activities are present on one protein molecule or different protein molecules is still uncertain. Both activities have a molecular mass of 60 kDa as determined by gel exclusion chromatography. There is no evidence at the present time for these enzyme activities being on different protein molecules. Neither arsenate, selenate, selenite, or selenide are methylated by the purified enzyme preparations. Results from the use of crude extracts, often called cytosol, to study the properties of these methyltransferases dealing with arsenic species should be viewed with caution since such crude extracts contain inhibiting and other interfering activities.

[Changes in the activity of the blood antioxidant enzymes during hemodialysis of patients with terminal kidney failure]. / Izmeneniia aktivnosti nekotorykh antiokislitel'nykh fermentov krovi v protsesse gemodializa u bol'nykh s terminal'noi pochechnoi nedostatochnosti'iu.

Paramagnetic centers of the blood were investigated in 75 patients with chronic uremia (Electron Spin Resonance, 77 K). The analysis of hemodialysis action on paramagnetic centers in the blood showed that this procedure provokes gradual depression of antioxidant defense.

Arsenic binding proteins of mammalian systems: I. Isolation of three arsenite-binding proteins of rabbit liver.

It is well known that arsenite/arsenate (As3+/As5+) administered to rabbits is bound initially to cellular proteins of the liver before methylated arsenic metabolites appear in urine. This protein binding may decrease the in situ toxicity of inorganic arsenic by decreasing its metabolic availability until it is methylated enzymatically. We have investigated the binding of As3+ and As5+ to the cytosolic proteins of rabbit liver. The results indicate that when cytosolic proteins are incubated with inorganic arsenic, the amount of As3+ bound is 13 times greater than that for As5+. Arsenite-specific binding sites on cytosolic proteins were determined to be 67% of the total (specific and non-specific) number of possible binding sites. Ammonium sulfate fractionation, non-denaturing PAGE and gel filtration chromatography indicate that three liver proteins with molecular weights of 100 kDa, 450 kDa and > 2000 kDa strongly bind arsenite. The radioactive profiles after gel filtration chromatography of liver cytosolic proteins are very similar whether As3+ binding occurs in vitro or in vivo. Thus, the in vitro model appears to be valid for further study of these arsenite-binding proteins.

N-(2,3-dimercaptopropyl)phthalamidic acid (DMPA) increases polonium-210 excretion.

Polonium-210 is one of the most hazardous radionuclides. As recently as 1988, there have been concerns regarding accidental exposures of humans to it. Yet, there have been no studies on the effectiveness of the newer dithiol chelating agents in increasing the excretion of this radioactive heavy metal. In order to accomplish this, a safe and effective method for determining the radioactivity of polonium-210, an alpha emitter, in the feces was developed. The excretion of polonium-210 was studied by giving male Sprague-Dawley rats 210Po (3.33 x 10(7) cpm/kg, intraperitoneal); 1 h later they were given either 5% sodium bicarbonate, N-(2,3-dimercaptopropyl)phthalamidic acid (DMPA) or meso-dimercaptosuccinic acid (DMSA) (0.20 mmol/kg, subcutaneous). Treatment was repeated daily for 12 days. DMPA and DMSA increased the urinary excretion of 210Po, as compared to control animals, 8-fold and 5-fold, respectively. DMPA increased the fecal excretion of 210Po compared to the other treatments and also decreased the level of 210Po in the spleen, a radiosensitive organ. DMPA (0.20 mmol/kg, intravenous) increased biliary levels of 210Po 5-fold compared to controls. The results indicate that DMPA has greater specificity in chelating and increasing the excretion of 210Po than DMSA.