-
Regulatory Toxicology and Pharmacology... Aug 2020In the pharmaceutical industry, cleaning criteria are required for multipurpose manufacturing facilities. These Health Based Exposure Limits (HBELs), also called...
In the pharmaceutical industry, cleaning criteria are required for multipurpose manufacturing facilities. These Health Based Exposure Limits (HBELs), also called permitted daily exposures (PDEs) values, are derived from toxicological and pharmacological evaluation of the active pharmaceutical ingredients (APIs). The purpose of this publication is to show an example of how authors from different companies evaluate a generic drug, paracetamol, and discuss different approaches and relevance of the nonclinical studies for deriving PDEs. PDE limits of 25 mg/day for the oral route, and 20 mg/day for the intravenous (i.v.) and inhalation (inhal.) routes, respectively, were established herein. However, it has been already recognised that there are acceptable differences in the PDE calculations, which may be based on data accessibility, company-specific science-policy decisions or expert judgments. These differences can cause up to a 3-fold lower or higher values. If unnecessarily high factors are applied, this would result in a very conservative PDE value and unneeded additional cleaning and higher manufacturing costs. The PDE values presented are considered to be protective against adverse and pharmacological effects observed in clinical trials and in this case, a very long postmarketing period of paracetamol.
Topics: Acetaminophen; Analgesics; Animals; Drug Industry; Humans; Occupational Exposure; Occupational Health
PubMed: 32522580
DOI: 10.1016/j.yrtph.2020.104692 -
Expert Opinion on Pharmacotherapy Jan 2003Paracetamol (acetaminophen) is one of the over-the-counter analgesics that is used frequently for the self-management of some of the common disorders. There seems to be... (Review)
Review
Paracetamol (acetaminophen) is one of the over-the-counter analgesics that is used frequently for the self-management of some of the common disorders. There seems to be two types of relations between paracetamol and asthma - paracetamol intolerance leading to bronchospasm in analgesic-induced asthmatics; and the relation between asthma and the amount and frequency of consumption of paracetamol. Paracetamol is generally recommended as one of the safer analgesics in both analgesic tolerant and intolerant asthmatics, without the fear of severe bronchospasm that aspirin and other non-steroidal anti-inflammatory drugs can induce in these patients. However, Paracetamol is reported to cross-react with aspirin at a rate of approximately 20-30% in a dose-dependent way. Therefore, it should not be recommended to analgesic intolerant asthmatics, without performing oral provocation tests to prove its safety. The possible association between the amount and frequency of paracetamol consumption and the prevalence and degree of asthma as suggested by some of the recent surveys, needs to be investigated further.
Topics: Acetaminophen; Asthma; Drug Interactions; Humans
PubMed: 12517240
DOI: 10.1517/14656566.4.1.13 -
Hepatology (Baltimore, Md.) Sep 1995Hepatic injury in alcoholics due to intake of acetaminophen (APAP or acetylparaaminophenol) with therapeutic intent has been reported, but the extent of the phenomenon...
Hepatic injury in alcoholics due to intake of acetaminophen (APAP or acetylparaaminophenol) with therapeutic intent has been reported, but the extent of the phenomenon is not clear, pertinent details of the association remain insufficiently clarified, and the importance of the phenomenon is not widely appreciated. The present report describes 67 patients who developed hepatic injury after ingestion of APAP with therapeutic intent. All were regular users of alcohol. Sixty-four percent of the patients were considered to be "alcoholic" or reported intakes greater than 80 g/d, 35% took 60 g/d or less, and the remainder were vague in their reporting. Doses of APAP were in the "nontoxic" range ( < 6 g/d) in 60% of the group, within the recommended range ( < 4 g/d) in 40%, and at 4.1 to 6 g/d in 20%. Characteristic feature was the towering level reached by aspartate transaminase (AST) with figures ranging from 3,000 to 48,000 IU in more than 90% of cases. Almost 20% of the patients died. The data on these patients were similar to 94 cases of injury from APAP taken with therapeutic intent reported in the literature. This study provides further evidence of hepatic injury in regular uses of alcohol, especially chronic alcoholics, who take APAP with therapeutic intent. Susceptibility is presumably caused by induction of cytochrome P-4502EI by ethanol and by depletion of glutathione (GSH) because of the effects of alcohol, the malnutrition often associated with alcoholism, and the depletion associated with chronic use of APAP and impaired glucuronidation caused by fasting perhaps as well. The syndrome of liver injury is distinctive, marked by uniquely elevated levels of AST, and poses a significant threat.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Acetaminophen; Adult; Alcoholism; Aspartate Aminotransferases; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Liver; Male; Middle Aged
PubMed: 7657281
DOI: No ID Found -
Nordisk Medicin 1995Administration of paracetamol (acetaminophen) has analgetic and antipyretic effect. After trauma paracetamol has an anti-inflammatory activity. It was presumed that... (Review)
Review
Administration of paracetamol (acetaminophen) has analgetic and antipyretic effect. After trauma paracetamol has an anti-inflammatory activity. It was presumed that paracetamol in therapeutic doses had fewer and more acceptable side-effects than other analgetic drugs such as acetylsalicylic acid and NSAID-drugs. However, in toxic concentrations, paracetamol is more life-threatening. The toxic effects of paracetamol most often occur in the liver and kidneys. Phosphate and lactate turn-over can also be impaired. Paracetamol poisoning can induce temporary liver disfunction or even irreversible liver failure with liver transplantation as the only therapeutic possibility. Chronic alcoholics are especially at risk, as liver damage may occur following paracetamol even in recommended doses. When intoxication with paracetamol is presumed, administration of N-acetylcysteine is vital. N-acetylcysteine therapy should be initiated not later than 15 hours after paracetamol intake. Moreover, the antitoxic effect has been observed even when N-acetylcysteine therapy is initiated 24-36 hours after presumed paracetamol intake. Measures of preventing further absorption of paracetamol from the gastrointestinal tract should be taken. Activated charcoal should be given if less than two hours have passed since paracetamol intake. Between two and four hours following paracetamol intake gastric lavage should be performed. During the last 10 years the incidence of paracetamol self-poisoning has increased, but death following paracetamol poisoning is relatively constant at around nine per year in Denmark. It is suggested that the incidence of serious cases of paracetamol poisoning could be reduced by simple measures. Special attention should be paid to the risk-group of chronic alcoholics.
Topics: Acetaminophen; Acetylcysteine; Alcoholism; Charcoal; Denmark; Intestinal Absorption; Kidney; Liver; Poisoning; Risk Factors
PubMed: 7753607
DOI: No ID Found -
Orvosi Hetilap May 1998
Topics: Acetaminophen; Humans; Infant, Newborn
PubMed: 9613169
DOI: No ID Found -
Tidsskrift For Den Norske Laegeforening... Apr 1994
Topics: Acetaminophen; Drug Interactions; Humans; Risk Factors
PubMed: 8209311
DOI: No ID Found -
Krankenpflege Journal Apr 1989
Topics: Acetaminophen; Fever; Humans; Pain
PubMed: 2724904
DOI: No ID Found -
Canadian Journal of Anaesthesia =... Mar 1988Acetaminophen is frequently administered orally to children for its analgesic properties, although its potency has never been clearly evaluated in this population. In... (Clinical Trial)
Clinical Trial Comparative Study
Acetaminophen is frequently administered orally to children for its analgesic properties, although its potency has never been clearly evaluated in this population. In certain situations (patients vomiting or unconscious), acetaminophen has to be given rectally. However, the rectal absorption of suppositories is frequently erratic. We undertook this study first, to measure the absorption of an aqueous solution of acetaminophen administered rectally. Secondly, we evaluated acetaminophen's postoperative analgesic effects in children aged 1 to 8 years old undergoing adenoidectomy and/or tonsillectomy and compared its efficacy to meperidine. Twenty children received 20 mg.kg-1 of acetaminophen at the time of induction of anaesthesia while 20 others received 1 mg.kg-1 of meperidine intramuscularly. Thirty-two patients required meperidine in the Recovery Room. There was no statistical difference between the patients who received acetaminophen (18), and those who received meperidine (14). The absorption of acetaminophen was incomplete (peak serum concentration: 70.8 mumol.L-1) and delayed. We conclude that the rectal administration of acetaminophen at the induction of anesthesia results in incomplete and delayed absorption and does not prevent the occurrence of immediate postoperative pain in children undergoing adeno-tonsillectomy.
Topics: Acetaminophen; Adenoidectomy; Administration, Rectal; Child; Child, Preschool; Double-Blind Method; Female; Humans; Infant; Male; Meperidine; Pain, Postoperative; Tonsillectomy
PubMed: 3356051
DOI: 10.1007/BF03010655 -
Journal of Chromatography. A Apr 2022Acetaminophen (paracetamol, APAP) is one of the most widely used drugs worldwide. Unfortunately, its overdose, which is caused by predominant oxidation of APAP, can lead...
Optimization of gradient reversed phase high performance liquid chromatography analysis of acetaminophen oxidation metabolites using linear and non-linear retention model.
Acetaminophen (paracetamol, APAP) is one of the most widely used drugs worldwide. Unfortunately, its overdose, which is caused by predominant oxidation of APAP, can lead to acute liver injury. In liver, oxidized APAP is conjugated with glutathione, leading to APAP-glutathione conjugate, which is metabolized to APAP-cysteine and APAP-N-acetylcysteine conjugates. Thus, all of those compounds could be used to monitor APAP metabolism in the overdosed patients. To date, only a limited number of rapid and accurate methods have been reported for the assessment of APAP oxidation metabolites using simple instrumentation, and thus this work was aimed at developing a fast and convenient gradient HPLC-UV/MS method. For this purpose, APAP conjugates with glutathione, cysteine, and N-acetylcysteine were synthesized, purified by preparative liquid chromatography, and characterized by NMR and high-resolution mass spectrometry. The gradient elution conditions were optimized using the window diagram approach and the effects of mobile phase composition and additives on separation and detection sensitivity were evaluated using two, i.e., linear and non-linear isocratic retention models. Quantitative parameters of the developed method were evaluated and the effectiveness, sensitivity, and specificity of the method were demonstrated on the analysis of human kidney HK-2 cell lysates, confirming the suitability of the method for routine use in studies on APAP toxicity.
Topics: Acetaminophen; Acetylcysteine; Chromatography, High Pressure Liquid; Chromatography, Liquid; Chromatography, Reverse-Phase; Humans
PubMed: 35306469
DOI: 10.1016/j.chroma.2022.462956 -
Anaesthesia Jan 2009This article is a review of the peri-operative use of paracetamol. It reviews the pharmacology of paracetamol, highlighting new information about the mechanism of... (Review)
Review
This article is a review of the peri-operative use of paracetamol. It reviews the pharmacology of paracetamol, highlighting new information about the mechanism of action, and examines its therapeutic use in the peri-operative period, focusing on efficacy, route of administration, and the use of a loading dose to improve early postoperative analgesia.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Drug Administration Routes; Drug Administration Schedule; Humans; Pain, Postoperative; Postoperative Care
PubMed: 19087009
DOI: 10.1111/j.1365-2044.2008.05674.x