How to test for toxicity. Novel acetylcysteine regimens for treatment of paracetamol overdose

This article has been how to test for toxicity by other articles in PMC. Abstract Paracetamol acetaminophen overdose remains the leading cause of death or transplantation due to acute liver failure in many parts of the world. Acetylcysteine has long been recognized as an effective antidote, via oral or intravenous administration, minimizing the risk and severity of acute liver injury if administered sufficiently early after a paracetamol overdose.

Despite this, its mechanisms of action remain obscure, and there is uncertainty regarding the optimal dose and duration of treatment.

The intravenous infusion protocol was originally developed as a three-step loading regimen; it causes very high early peak plasma concentrations of acetylcysteine whereas the later maintenance infusion is associated with much lower concentrations.

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This pharmacokinetic profile is associated with two particular concerns: a high rate of occurrence of adverse effects that occur after the initial loading infusion, and the possibility that the maintenance phase of treatment might deliver too low a dose of acetylcysteine for optimum protection against liver injury.

Recently described novel administration regimens offer different rates of intravenous acetylcysteine administration in both the loading and maintenance phases.

EurLex-2 Studiile de toxicitate la animale şobolan, maimuţă, şoarece nu au evidenţiat nici o formă tipică de toxicitate, cu excepţia hepatomegaliei asociată cu hipertrofie hepatocelulară, care au apărut când s-au administrat doze mari de stiripentol, atât la rozătoare, cât şi la ne-rozătoare Preclinical safety data Toxicity studies in animals rat, monkey, mouse have not revealed any consistent pattern of toxicity apart from liver enlargement associated with hepatocellular hypertrophy, which occurred when high doses of stiripentol were administered to both rodents and nonrodents EMEA0. For a borderline positive response between an SI of 1,8 and 2,5, users may want to consider additional information such as dose-response relationship, evidence of systemic toxicity or excessive irritation, and where appropriate, statistical significance together with SI values to confirm that such results are positives EurLex-2 Rezultatele pozitive ale testelor corespunzătoare pe animale pot să includă datele obținute într-un test de toxicitate generală, care include date histopatologice din sistemul respirator.

These alternative regimens appear to be well tolerated in small patient groups, but too few clinical data are available to evaluate their comparative efficacy in preventing paracetamol-induced liver injury.

Keywords: acute liver toxicity, overdose, paracetamol Background Paracetamol acetaminophen overdose was first recognized as a cause of acute liver failure in the s [ Davidson and Eastham, ].

It has since become the leading cause of death or transplantation due to acute liver failure in the UK, the USA, and elsewhere, and the occurrence of paracetamol liver injury continues to rise [ Gow et al.

Acetylcysteine is highly effective in preventing severe liver injury if administered within 8—10 h after a significant paracetamol overdose [ Prescott et al. However, the standard regimen of intravenous acetylcysteine is associated with a high rate of occurrence of adverse effects, and treatment is normally reserved for patients who have absorbed substantial overdoses of paracetamol and who have a significant risk of acute liver injury [ Buckley and Eddleston, ; Heard, ].

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The precise pharmacological basis for the antidotal properties of acetylcysteine is somewhat uncertain, and several different mechanisms have been proposed [ Jones, ]. Moreover, there is uncertainty concerning the optimal dose and duration of acetylcysteine administration and important international differences exist concerning the precise indications for antidote therapy.

The basis for the prevailing acetylcysteine administration protocols is discussed, along with the pharmacological basis to support recently proposed novel administration regimens. Pathophysiology of aracetamol-induced liver injury Acute paracetamol administration is associated with significant depletion of glutathione GSHattributed to covalent binding of an intermediate paracetamol metabolite, N-acetyl-p-benzoquinone imine NAPQI to critical proteins and enzymes within hepatocytes.

Restoration of intrahepatic glutathione concentrations in animals minimized the extent of NAPQI covalent binding to hepatocytes, and how to test for toxicity the severity of the biochemical and histopathological changes observed after paracetamol-induced acute liver injury [ Jollow et al.

Therefore, NAPQI has been implicated as the toxic intermediate responsible of paracetamol-induced acute liver injury. Role of glutathione GSH is a tripeptide that consists of the amino acids cysteine, glycine, and glutamate. It possesses sulfhydryl donor groups and can act as a powerful intracellular reducing agent and antioxidant whilst being converted to its oxidized form, glutathione disulfide GSSG The contribution of oxidative stress to drug-induced organ toxicity and its detection in vitro and in vivo have recently been reviewed [ Pereira et al.

The initial metabolic step in the synthesis of GSH involves γ-glutamylcysteine synthetase. The rate and extent of GSH synthesis depends upon the local availability of cysteine, which is normally found in comparatively low concentrations in hepatocytes compared with other tissues [ Stipanuk et al. L-Cysteine normally does not greatly increase intrahepatic glutathione due to its rapid and extensive how to test for toxicity within the gut and circulation [ Frimpter, ].

Nonetheless, its direct intravenous administration protects against liver damage after paracetamol overdose in man [ Prescott, ].

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However, intravenous administration of large doses is technically difficult due to its poor solubility in aqueous media. Glutathione donors Early studies explored the efficacy of alternative sulfhydryl-containing agents. One example is cysteamine, which was shown to prevent paracetamol-induced liver injury in animals [ Mitchell et al.

Prescott and colleagues reported the successful treatment of paracetamol overdose patients with cysteamine, and it was more effective than either penicillamine or methionine [ Prescott et al.

However, cysteamine administration was frequently associated with very unpleasant adverse effects.

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Prescott and Matthew first suggested that N-acetylcysteine, which is converted into cysteine in vivo, might protect the liver against paracetamol toxicity [ Prescott and Matthew, ]. Acetylcysteine was subsequently shown to replenish hepatic GSH stores, and to be more effective than cysteamine and methionine in preventing paracetamol hepatotoxicity and death in animals [ Piperno and Berssenbruegge, ; Piperno et al.

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Acetylcysteine: pharmacodynamic properties Acetylcysteine prevents GSH depletion and minimizes hepatocyte injury caused by a number of different toxins [ Dawson et al. Animal studies of paracetamol-induced liver injury suggest that a primary mechanism of acetylcysteine is the provision of cysteine to stimulate replenishment of GSH to allow detoxification of NAPQI [ Viña et al. Perhaps more importantly, at a later stage it can also prevent toxicity by reversing the oxidation and arylation of critical hepatic proteins and enzymes [ Davies et al.

Aceste exemple pot conține termeni colocviali. În cazul în care testul de atriție conduce la formarea de substanțe respirabile, se efectuează un test de toxicitate prin inhalare. If an attrition test produces respirable substances, an inhalation toxicity test should be performed. Solicitantul poate opta pentru un test de toxicitate pe termen lung în locul celui pe termen scurt.

This action may contribute to the finding that acetylcysteine may improve liver function and lessen the severity of acute injury in patients with established paracetamol-induced liver failure, even when administered late after ingestion at a time when NAPQI concentrations would be expected to be negligible [ Keays et al.

These findings suggest that the therapeutic mechanism of acetylcysteine may be more complex than restoration of glutathione alone.

Novel acetylcysteine regimens for treatment of paracetamol overdose

The potent electron donor properties of acetylcysteine and the consequent ability to lessen oxidative stress might be another independent mechanism that protects against acute liver injury [ Acharya and Lau-Cam, ]. Intravenous acetylcysteine regimen The how to test for toxicity clinical trials of acetylcysteine in paracetamol-poisoned patients demonstrated virtually complete protection against severe liver damage if it was given within 10 h after the overdose [ Prescott et al.

The intravenous infusion regimen was developed with the objective of giving the highest tolerated dose as rapidly as possible in view of the short time window of therapeutic efficacy.

No pharmacokinetic data were available at that time. Despite these observations, the original infusion regimen developed in Edinburgh has persisted with virtually no alteration for more than 30 years.

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Following its original inception, a wealth of clinical experience has accrued to support the efficacy of this regimen, and it remains the standard treatment for paracetamol poisoning in the UK and elsewhere. Adverse effects of acetylcysteine The reported rate of occurrence of adverse effects varies according to whether data are collected prospectively or retrospectively.

Detailed evaluation of a subset of this patient population found that anaphylaxis is characterized clinically by symptoms of flushing, hypotension, and erythema [ Pakravan et al. Such reactions are around three times commoner in patients with asthma, although of similar severity, and wheeze and laryngeal oedema have been reported in severe cases [ Schmidt and Dalhoff, ].

The mechanism appears related to acetylcysteine concentration-dependent histamine release but, in contrast to true how to test for toxicity, it is independent of tryptase and immunoglobulin E [ Pakravan et al. Occurrence of anaphylaxis may require that acetylcysteine administration is temporarily withheld for a sufficient time to allow plasma concentrations to decline [ Kerr et al. In many cases, the reaction will resolve spontaneously, although antihistamine administration is effective and used in more severe cases.

These reactions do not have an allergic basis, so that acetylcysteine can normally be safely reintroduced. Other adverse effects include nausea, vomiting, generalized malaise, and abdominal pain, which appear dose dependent and consistent with the adverse effects observed after other sulphydryl-containing drugs. Gastrointestinal symptoms appear attributable to a direct local effect, and are particularly prominent after oral acetylcysteine administration, although localized histamine release may also be important.

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Gastrointestinal adverse effects do not normally require specific intervention, but in severe cases the infusion may need to be stopped temporarily and an antiemetic administered. It should be remembered that most patients with severe paracetamol poisoning will develop nausea and vomiting, at least in part due to coingestion of ethanol or opioids [ Waring et al.

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The rate of occurrence of adverse effects depends on the route and timing of acetylcysteine administration. For example, gastrointestinal symptoms were more common after oral than intravenous administration, 33 of Also, the rate of occurrence of anaphylactic reactions is highest in patients with low paracetamol concentrations, for example those that present late after ingestion [ Schmidt and Dalhoff, ; Waring et al.

Indications for acetylcysteine Acute overdose at a single time point After single time-point ingestion, the extent of paracetamol exposure is estimated from the serum paracetamol concentration at a known time after the overdose, and compared with a standard nomogram.

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Concentrations above the nomogram line are associated with a higher rate of occurrence of acute liver injury, and this is used as an indicator for acetylcysteine administration.

The nomogram was originally validated up to 15 h after paracetamol ingestion, but is widely extrapolated to 24 h in routine clinical practice. Discretion is normally applied to take account of patient reporting error, so that acetylcysteine is often administered when paracetamol concentrations lie close to the appropriate treatment line, particularly because the nomogram between 15 and 24 h represents paracetamol concentrations that are very close to the reported laboratory detection limits.

After more than 24 h, the decision to administer acetylcysteine is normally based upon clinical features, presence of risk factors, the reported dose, detectable paracetamol concentrations, and biochemical evidence of established liver injury. Specifically, it does not apply to patients who present after ingestion of multiple paracetamol doses at different time points or ingestion over more than 1 h, a so-called staggered overdose.

Acetylcysteine may be administered at a lower threshold in the presence of risk factors, or if there are clinical or laboratory indicators of established acute liver injury, hpv impfung dauer if the patient history how to test for toxicity reliably be ascertained.

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An international perspective In the UK, the decision to use the standard versus high-risk nomogram is based on a subjective evaluation of whether various risk factors are present, and there are no clinical data to support the validity of this approach.

Nonetheless, the general approach to risk assessment is broadly similar in many parts of the world insofar as the decision to administer acetylcysteine is based on the extent of paracetamol exposure. One notable exception is in Denmark, where acetylcysteine is routinely administered to all patients after paracetamol overdose irrespective of the extent of drug exposure [ Schmidt et al.

The Danish approach is not widely accepted due to the very low rate of liver injury after minor paracetamol overdose, offset against a higher rate of occurrence of anaphylactic reactions to acetylcysteine in patients with comparatively low paracetamol concentrations [ Waring et al.

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Issues with the existing infusion regimen Inadequate acetylcysteine delivery in late treatment phases In a pharmacokinetic study of 17 patients with severe paracetamol poisoning treated with the standard Prescott regimen the mean volume medicamente pentru tratamentul viermilor la adulți distribution of acetylcysteine was 0.

Confirmatory data using the same regimen in paracetamol overdose patients found that peak plasma acetylcysteine concentrations occur soon after the initial 15 m loading infusion and then progressively decline despite maintenance administration Figure 1.

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The pharmacokinetic profile is associated with progressively declining plasma concentrations despite the 16 h maintenance infusion part of the treatment regimen.

This raises a concern that acetylcysteine administration at 6.

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Whilst paracetamol concentrations are usually significantly diminished towards the end of the 20 h 15 min infusion, this does not necessarily indicate a lesser need for acetylcysteine at that time. NAPQI is highly reactive and is expected to disappear soon after paracetamol concentrations have fallen.

Nonetheless, paracetamol protein adducts are noted to be more persistent than paracetamol itself, and their clearance is enhanced by acetylcysteine administration [ James et al.

Somewhat paradoxically, in one study it was how to test for toxicity that very high acetylcysteine concentrations were associated with impaired recovery from paracetamol-induced acute liver injury, suggesting that a therapeutic range of desirable acetylcysteine concentrations might exist [ Yang et al.