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1. An array of therapeutically used analgetic and antirheumatic
drugs cause severe liver damage, The present study investigates
the hepatoprotective effects of inhibitors of NAD-dependent adenoribosylation
reactions and of antioxidants in analgesic-induced hepatic injury.
2. Male NMRI mice were treated PO with 500 mg/kg of acetaminophen,
and the activities of both glutamate-oxaloacetate transaminase
(GOT) and glutamate-pyruvate transaminase (GPT) were determined
in serum.
3. The acetaminophen-induced release of both GOT and GPT from
injured liver cells could be inhibited in a dose-dependent manner,
when mice were injected additionally either with increasing amounts
(from (25 mg/kg to 100 mg/kg TP) of the PARP-inhibitor nicotinamide,
with increasing amounts (from 25 mg/kg to 100 mg/kg IF) of the
antioxidant N-acetylcysteine, or with increasing amounts (from
50 mg/kg to 300 mg/kg IF) of the amino acid L-methionine.
4. A combination of both nicotinamide and N-acetylcysteine (at
the low dose of 12.5 mg/kg IP each) results in a complete protection
from acetaminophen induced release of GOT and GPT from injured
liver cells.
5. A combination of both L-methionine and N-acetylcysteine or
nicotinamide (at the low dose of 12.5 mg/kg IP each) resulted
also in complete protection from acetaminophen-induced release
of GOT and GPT. Copyright (C) 1997 Elsevier Science Inc.
Author: KROGER H, DEUTSCH RHEUMAFORSCHUNGSZENTRUM BERLIN, MONBIJOUSTR 2, D-10117 BERLIN, GERMANY Source: GENERAL PHARMACOLOGY 1997 FEB;28(2):257-263
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Dr. Alistair J. Makin and associates at King's College Hospital
in London say they identified 560 patients with acetaminophen-induced
liver failure over the seven-year period ending December, 1993.
The number of hospital admissions for severe acetaminophen-induced
hepatotoxicity increased from 58 in 1987, to 123 in 1993. Fortunately,
survival improved during the corresponding period, rising from
less than 50% in 1987 to 78% in 1993.
Dr. Makin credits improved survival to prompt initiation of N-acetylcysteine
therapy and greater availability and success of liver transplantation.
The primary causes of acetaminophen hepatotoxicity: the amount
of drug taken (12 g was the lowest dose that produced liver failure)
and acetominophen ingestion with alcohol and other drugs.
Gastroenterology 1995;109:1907-1916.
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Hepatitis secondary
to current non-steroidal anti-inflammatory agents
The authors report 83 cases of acute hepatitis secondary to non
steroid anti-inflammatory drugs (NSAID), published in the literature.
The NSAID in question are: niflumic acid, tolfenamic acid, diclofenac,
fenoprofen, ibuprofen, indomethacin, naproxen, piroxicam, pirprofen
and sulindac. Six deaths are directly ascribed to NSAID: although
rare, these forms of hepatitis deserve therefore to be reported.
They are usually mixed immuno-allergic forms of hepatitis (cytolytic
as well as cholestatic). They often affect elderly women taking
multiple medications. Monitoring of the liver function tests is
necessary, during prolonged treatment with NSAID, especially during
the first six months.
Author: Hannequin JR, Doffoel M, Schmutz G, Service de Rhumatologie, CHU de Strasbourg. Source: Rev Rhum Mal Osteoartic 55: 983-988 (1988)
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Morbid Prognostic
Features in Patients With Chronic Liver Failure Undergoing Nonhepatic
Surgery
Henry E. Rice, MD; Grant E. O'Keefe, MD; W. Scott Helton, MD;
Kaj Johansen, MD, PhD
Background: Although the risk of portal decompression surgery
is accurately predicted by objective scoring systems (Child classification
and Pugh score), few useful prognostic criteria exist regarding
nonhepatic surgery in patients with chronic liver failure.
Objective: To evaluate the clinical findings associated with perioperative
mortality in patients with chronic liver failure undergoing nonhepatic
surgery.
Design: A retrospective cohort study.
Setting: University teaching hospitals.
Patients: Forty consecutive patients with an International Classification
of Diseases, Ninth Revision (ICD-9), diagnosis of chronic liver
failure and one or more of the following: jaundice, cirrhosis,
chronic hepatitis, or alcoholism.
Interventions: Forty operations, including 28 abdominal procedures,
2 coronary artery bypass grafts, 5 orthopedic procedures, and
5 miscellaneous procedures.
Main Outcome Measures: Thirty-day mortality as related to 19 preoperative
clinical and laboratory variables.
Results: Eleven (28%) of the patients died within 30 days of surgery.
By univariate analysis, the following variables were significantly
(P<.05, Pearson chi2 test for categorical data or Mann-Whitney
U test for continuous data) associated with nonsurvival: encephalopathy,
congestive heart failure, the need for emergent surgery, infection,
hyperbilirubinemia, international normalized ratio greater than
1.6, hypoalbuminemia, and an elevated creatinine level. By multiple
logistic regression analysis, an international normalized ratio
greater than 1.6 and encephalopathy were associated with a greater
than 10- and 35-fold increased mortality risk, respectively. Child
classification and Pugh score failed to predict 30-day mortality.
Conclusions: We identified 8 clinical and laboratory variables
associated with death within 30 days in patients with chronic
liver failure undergoing nonhepatic surgery. Two factors-international
normalized ratio greater than 1.6 and encephalopathy-independently
predicted mortality by multivariate analysis. Neither Child classification
nor Pugh score was prognostically helpful. Nonhepatic surgery
confers a substantial mortality risk in patients with chronic
liver failure.
Arch Surg. 1997;132:880-885
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Drugs That May Cause
Liver Dysfunction or Damage
The liver is the principal organ that is capable of converting drugs into
forms that can be readily eliminated from the body. Given the diversity in
use today and the complex burden they impose upon the liver, it is not
surprising that a broad spectrum of adverse drugs effects on liver functions
and structures has been documented. The reactions range from mild and
transient changes in the results of liver function tests to complete liver
failure with death of the host. Many drugs may affect the liver adversely in
more than one way, as cited below in several listings. The use of the
following drugs requires careful monitoring of their effects on the liver
during the entire course of treatment.
Drugs that may cause ACUTE DOSE-DEPENDENT LIVER DAMAGE
(resembling acute viral hepatitis)
acetaminophen salicylates (doses over 2 grams daily)
Drugs that may cause ACUTE DOSE-INDEPENDENT LIVER DAMAGE
(resembling acute viral hepatitis)
acebutolol indomethacin phenylbutazone
allopurinol isoniazid phenytoin
atenolol ketoconazole piroxicam
carbamazepine labetalol probenecid
cimetidine maprotiline pyrazinamide
dantrolene metoprolol quinidine
diclofenac mianserin quinine
diltiazem naproxen ranitidine
enflurane para-aminosalicylic acid sulfonamides
ethambutol penicillins sulindac
ethionamide phenelzine tricyclic antidepressants
halothane phenindione valproic acid
ibuprofen phenobarbital verapamil
Drugs that may cause ACUTE FATTY INFILTRATION OF THE LIVER
adrenocortical steroids phenothiazines sulfonamides
antithyroid drugs phenytoin tetracyclines
isoniazid salicylates valproic acid
methotrexate
Drugs that may cause CHOLESTATIC JAUNDICE
actinomycin D chlorpropamide erythromycin
amoxicillin/clavulanate cloxacillin flecainide
azathioprine cyclophosphamide flurazepam
captopril cyclosporine flutamide
carbamazepine danazol glyburide
carbimazole diazepam gold
cephalosporins disopyramide griseofulvin
chlordiazepoxide enalapril haloperidol
ketoconazole norethandrolone sulfonamides
mercaptopurine oral contraceptives tamoxifen
methyltestosterone oxacillin thiabendazole
nifedipine penicillamine tolbutamide
nitrofurantoin phenothiazines tricyclic antidepressants
nonsteroidal phenytoin troleandomycin
anti-inflammatory drugs propoxyphene verapamil
Drugs that may cause LIVER GRANULOMAS (chronic inflammatory
nodules)
allopurinol gold phenytoin
aspirin hydralazine procainamide
carbamazepine isoniazid quinidine
chlorpromazine nitrofurantoin sulfonamides
diltiazem penicillin tolbutamide
disopyramide phenylbutazone
Drugs that may cause CHRONIC
LIVER DISEASE
Drugs that may cause active chronic hepatitis
acetaminophen (chronic use, large doses)
dantrolene methyldopa isoniazid
nitrofurantoin
Drugs that may cause liver cirrhosis or fibrosis (scarring)
methotrexate nicotinic acid
Drugs that may cause chronic cholestasis (resembling
primary biliary cirrhosis)
chlorpromazine/valproic imipramine thiabendazole
acid (combination) phenothiazines tolbutamide
chlorpropamide/erythro- phenytoin
mycin (combination)
Drugs that may cause LIVER TUMORS (benign and malignant)
anabolic steroids oral contraceptives thorotrast
danazol testosterone
Drugs that may cause DAMAGE TO LIVER BLOOD VESSELS
adriamycin dacarbazine thioquanine
anabolic steroids mercaptopurine vincristine
azathioprine methotrexate vitamin A (excessive doses)
carmustine mitomycin
cyclophosphamide/cyclosporine (combination) oral contraceptives
SOURCE: The Essential Guide to Prescription Drugs, 1994 Edition, by James W.
Long and James J. Rybacki. ISBN 0-06-273211-0
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