Henry Matthew: the father of modern clinical toxicology.

Henry Matthew was appointed a consultant in the Royal Infirmary of Edinburgh in 1955, by which time he was a highly regarded general physician with an interest in cardiology. In 1964 he agreed, almost certainly reluctantly, to head the recently designated Regional Poisoning Treatment Centre, which he did until his retirement ten years later. Matthew quickly established himself as an authority in clinical toxicology, mainly from an unrivalled experience of treating poisoned patients, day-in and day-out, but also by publishing original research, letters and books. Such were his contributions that he is regarded as the father of clinical toxicology.

Paracetamol disposition in renal allograft recipients.

OBJECTIVE: To evaluate the disposition of paracetamol in renal allograft recipients. METHOD: Eight fasting renal allograft recipients were given 1 g soluble paracetamol orally. RESULTS: Paracetamol was absorbed rapidly, and the mean plasma half-life from 2 h to 8 h was 2.6 +/- 0.5 h. After that, disappearance of paracetamol from the plasma was slower. Both the glucuronide and sulphate conjugates of paracetamol had slow elimination half-lives of 15.1 +/- 8.8 h and 26.2 +/- 14.6 h, and there were residual amounts of both conjugates in the plasma at 24 h. The renal clearances of both conjugates were low (21 +/- 14.2 ml/min and 32.4 +/- 31.4 ml/min) and there was a significant negative correlation between total amount of paracetamol recovered in the urine in 24 h and serum creatinine (r = -0.89, P<0.01). CONCLUSION: Paracetamol disposition is abnormal in renal allograft recipients and seems to relate to abnormal renal function in these patients.

Paracetamol, alcohol and the liver.

It is claimed that chronic alcoholics are at increased risk of paracetamol (acetaminophen) hepatotoxicity not only following overdosage but also with its therapeutic use. Increased susceptibility is supposed to be due to induction of liver microsomal enzymes by ethanol with increased formation of the toxic metabolite of paracetamol. However, the clinical evidence in support of these claims is anecdotal and the same liver damage after overdosage occurs in patients who are not chronic alcoholics. Many alcoholic patients reported to have liver damage after taking paracetamol with 'therapeutic intent' had clearly taken substantial overdoses. No proper clinical studies have been carried out to investigate the alleged paracetamol-alcohol interaction and acute liver damage has never been produced by therapeutic doses of paracetamol given as a challenge to a chronic alcoholic. The paracetamol-alcohol interaction is complex; acute and chronic ethanol have opposite effects. In animals, chronic ethanol causes induction of hepatic microsomal enzymes and increases paracetamol hepatotoxicity as expected (ethanol primarily induces CYP2E1 and this isoform is important in the oxidative metabolism of paracetamol). However, in man, chronic alcohol ingestion causes only modest (about twofold) and short-lived induction of CYP2E1, and there is no corresponding increase (as claimed) in the toxic metabolic activation of paracetamol. The paracetamol-ethanol interaction is not specific for any one isoform of cytochrome P450, and it seems that isoenzymes other than CYP2E1 are primarily responsible for the oxidative metabolism of paracetamol in man. Acute ethanol inhibits the microsomal oxidation of paracetamol both in animals and man. This protects against liver damage in animals and there is evidence that it also does so in man. The protective effect disappears when ethanol is eliminated and the relative timing of ethanol and paracetamol intake is critical. In many of the reports where it is alleged that paracetamol hepatotoxicity was enhanced in chronic alcoholics, the reverse should have been the case because alcohol was actually taken at the same time as the paracetamol. Chronic alcoholics are likely to be most vulnerable to the toxic effects of paracetamol during the first few days of withdrawal but maximum therapeutic doses given at this time have no adverse effect on liver function tests. Although the possibility remains that chronic consumption of alcohol does increase the risk of paracetamol hepatotoxicity in man (perhaps by impairing glutathione synthesis), there is insufficient evidence to support the alleged major toxic interaction. It is astonishing that clinicians and others have unquestion-ingly accepted this supposed interaction in man for so long with such scant regard for scientific objectivity.

Therapeutic misadventure with paracetamol: fact or fiction?

As a consequence of its consistent safety profile and the low incidence of side effects, paracetamol is one of the most widely used analgesics, both in adults and children. However, paracetamol has the potential for hepatotoxicity, usually as a result of deliberate self-poisoning or, to a much lesser extent, accidental overdose. A variety of factors is thought to influence hepatotoxicity, including dose, concomitant use of microsome-inducing agents and other drugs, underlying disease, malnutrition, fasting, acute and chronic alcohol intake, ethnicity, and age. Unfortunately, none of these factors has been properly studied in humans. From a physiological standpoint, acute paracetamol hepatotoxicity at therapeutic doses is extremely unlikely despite reports of so-called therapeutic misadventure. It is clear that, in many of these cases, grossly excessive doses of paracetamol have been taken. Analyzing the various reports is difficult as the data are often incomplete. In summary, although hepatic toxicity is recognized in patients taking a major paracetamol overdose, the incidence of adverse events with its proper use is very low, particularly when considering with the enormous volume of drug use. Therapeutic misadventure is extremely uncommon and the facts are often misrepresented.

Paracetamol: past, present, and future.

Paracetamol (acetaminophen) is one of the most widely used of all drugs, with a wealth of experience clearly establishing it as the standard antipyretic and analgesic for mild to moderate pain states. First used clinically by von Mering in 1893, paracetamol did not appear commercially until 1950 in the United States and 1956 in Australia. During the 1960s and 1970s, increasing concern was raised about the toxicity of nonprescription analgesics, but in normal use paracetamol exhibited a consistent safety profile. Its exemplary safety record was marred by the discovery in 1966 that a major overdose could be complicated by severe and sometimes fatal liver damage. Fortunately, early treatment with N-acetylcysteine prevents liver toxicity. A turning point in the choice of pediatric analgesic came in the 1980s when aspirin was linked to Reye's syndrome. As a consequence, paracetamol became the mainstay analgesic and antipyretic for children with a subsequent reduction in the incidence of Reye's syndrome. Currently, paracetamol is a first-line choice for pain management and antipyresis in a variety of patients, including children, pregnant women, the elderly, those with osteoarthritis, simple headaches, and those with noninflammatory musculoskeletal conditions. With proper use, paracetamol seldom causes adverse events and reports of serious side effects are rare. It has a broad tolerability and is of particular value in the treatment of patients in whom nonsteroidal anti-inflammatory drugs are contraindicated such as aspirin-sensitive asthmatics and people at risk of gastrointestinal complications. In the future, a better insight into the mechanism of action of paracetamol may be gained from a fuller understanding of the cyclooxygenase enzymes. In the meantime, paracetamol may find applications in other therapeutic areas, such as the prevention of atherosclerosis via a potential antioxidant activity. In summary, although it is more than a century since the first clinical use of paracetamol, it continues to be a first-line therapy of choice in adults and children with fever and pain. In addition, current research suggests that paracetamol may have a much broader clinical utility in years to come.

Opioid-induced delay in gastric emptying: a peripheral mechanism in humans.

BACKGROUND: Opioids delay gastric emptying, which in turn may increase the risk of vomiting and pulmonary aspiration. Naloxone reverses this opiate action on gastric emptying, but it is not known whether this effect in humans is mediated by central or peripheral opiate antagonism. The importance of peripheral opioid receptor antagonism in modulating opioid-induced delay in gastric emptying was evaluated using methylnaltrexone, a quaternary derivative of the opiate antagonist naltrexone, which does not cross the blood-brain barrier. METHODS: In a randomized, double-blind, crossover placebo-controlled study, 11 healthy volunteers were given either placebo (saline), 0.09 mg/kg morphine, or 0.09 mg/kg morphine plus 0.3 mg/kg methylnaltrexone on three separate occasions before ingesting 500 ml deionized water. The rate of gastric emptying was measured by two methods: a noninvasive epigastric bioimpedance technique and the acetaminophen absorption test. RESULTS: The epigastric bioimpedance technique was sufficiently sensitive to detect opioid-induced changes in the rate of gastric emptying. The mean +/- SD time taken for the gastric volume to decrease to 50% (t0.5) after placebo was 5.5 +/- 2.1 min. Morphine prolonged gastric emptying to (t0.5) of 21 +/- 9.0 min (P < 0.03). Methylnaltrexone given concomitantly with morphine reversed the morphine-induced delay in gastric emptying to a t0.5 of 7.4 +/- 3.0 (P < 0.04). Maximum concentrations and area under the concentration curve from 0 to 90 min of serum acetaminophen concentrations after morphine were significantly different from placebo and morphine administered concomitantly with methylnaltrexone (P < 0.05). No difference in maximum concentration or area under the concentration curve from 0 to 90 min was noted between placebo and methylnaltrexone coadministered with morphine. CONCLUSIONS: The attenuation of morphine-induced delay in gastric emptying by methylnaltrexone suggests that the opioid effect is mediated outside the central nervous system. Methylnaltrexone may have the potential to decrease the side effects of opioid medications, which are mediated peripherally, while maintaining the central analgesia effect of the opioid.

Pharmacokinetics of N-acetylcysteine are altered in patients with chronic liver disease.

BACKGROUND: The threshold plasma paracetamol concentration at which N-acetylcysteine (NAC) treatment is recommended to treat paracetamol poisoning in a patient with induced liver enzymes (for example, with chronic liver disease or taking anticonvulsant drugs) is 50% lower than in a patient without induced liver enzymes. More patients with chronic liver disease might therefore be expected to be exposed to NAC treatment than previously. In addition, there is increasing use of NAC in patients with chronic liver disease for multiorgan failure or hepatorenal syndrome. Little is known of NAC's pharmacokinetic properties in patients with cirrhosis. AIM: The aim was to determine if the pharmacokinetics of NAC are altered by chronic liver disease. SUBJECTS AND METHODS: NAC was given intravenously in a dose of 600 mg over 3 min to nine patients with biopsy-proven cirrhosis (Child's grade; 1 A, 4 B, 4 C: aetiology: 7 alcohol-related, 1 primary biliary cirrhosis, 1 secondary biliary stenosis) and six healthy matched controls. Venous blood was taken at 20, 40, 60 and 90 min then at 2, 3, 4, 6, 8 and 10 h after NAC administration. Serum NAC was estimated by HPLC. The data were normalized to a standard body weight of 70 kg. RESULTS: The area under the serum concentration-time curve was increased (152.34 mg/L.h +/- 50.38 s.d.) in cirrhotics compared with normal controls (93.86 mg/L.h +/- 9.60 s.d.) (P < 0.05). The clearance of NAC was reduced in patients with chronic liver disease (4.52 L/h +/- 1.87 s.d.) compared with controls (6.47 L/h +/- 0.78: P < 0.01). CONCLUSIONS: Increased vigilance for untoward anaphylactoid reactions is necessary in cirrhotics as they may have higher plasma NAC concentrations. Further studies to determine the optimum dosage regimen in such patients are required.

A comparison of the effects of tramadol and morphine on gastric emptying in man.

In a previous study using an electrical bioimpedance technique and the paracetamol absorption test, we demonstrated that 0.09 mg.kg-1 of morphine delayed gastric emptying in healthy human volunteers. The aim of this study was to investigate whether analgesic doses of tramadol would cause a delay in gastric emptying similar to conventional opioids. Using the same volunteers and techniques as in our previous study, placebo or tramadol (1 mg.kg-1) was given in a randomised, double-blinded, cross-over placebo-controlled study. Gastric emptying was measured concurrently by a noninvasive epigastric bioimpedance technique and by the paracetamol absorption test. After the ingestion of 500 ml of deionised water plus paracetamol 1.5 g, the mean (SEM) time taken for gastric volume to decrease to 50% (t0.5) was recorded. No difference in gastric emptying rates (t0.5) between placebo, 7.7 (1 min), and tramadol, 9.5 (2 min), was noted. In our previous study, morphine prolonged t0.5 to 21 (3) min (p < 0.03). The maximum concentration and area under the curve of serum paracetamol concentrations following morphine were significantly different from placebo (p < 0.05) and tramadol (p < 0.05). We conclude that tramadol at a dose of 1 mg.kg-1 does not delay gastric emptying in humans.

Effect of food on the absorption of frusemide and bumetanide in man.

1. The influence of food on the absorption of frusemide and bumetanide was compared in two separate randomized crossover studies. 2. On three separate occasions frusemide 40 mg was administered to eight healthy male volunteers intravenously, orally in the fasting state and orally after a standard breakfast. Blood and urine were collected at intervals over 8 h and urine alone for a further 16 h. The study was then repeated in nine healthy volunteers using intravenous and oral bumetanide 2 mg. 3. Breakfast significantly reduced the peak plasma concentration of frusemide from 2.35 +/- 0.49 to 0.51 +/- 0.19 mg l-1 (95% confidence intervals (95% CI) = 1.39 to 2.28 mg l-1) and delayed the time to peak concentration from 0.69 +/- 0.21 to 1.91 +/- 0.93 h (95% CI = 0.41 to 2.03 h). The oral bioavailability of frusemide was significantly reduced by approximately 30% (75.6 +/- 10.6 to 43.2 +/- 16.8%; 95% CI = 13.5 to 51.4%). 4. With bumetanide, the meal also significantly reduced the peak concentration from 0.097 +/- 0.015 to 0.036 +/- 0.012 mg l-1 (95% CI = 0.048 to 0.073 mg l-1) and delayed the time to peak from 0.53 +/- 0.08 to 1.36 +/- 0.72 h (95% CI = 0.23 to 1.44 h). However, food had no statistically significant effect on the bioavailability and urinary recovery of bumetanide. 5. In this study, the absorption of bumetanide was affected less than frusemide by food.

Furosemide disposition in patients on CAPD.

Single doses of oral and intravenous furosemide were given to 8 healthy male volunteers (40 mg) and 11 patients with renal failure maintained on continuous ambulatory peritoneal dialysis (CAPD) (80 mg). In the volunteers, absorption was variable. Only one half of the intravenous dose and one third of the oral dose was available for renal pharmacological action as judged by the urinary recovery. In the patients, absorption was also variable and was markedly delayed (tmax 128 vs 90 min) but more complete (bioavailability 70.1 vs 53.6%). The differences between the two groups were not significant, however (95% C.I.: -90 to 30 and -40.4 to 7.5 respectively). The mean elimination half-life was significantly longer in the patients following both the oral (228 vs 65.1 min) and intravenous dose (195 vs 60.3 min). The total body clearance of furosemide in the volunteers was 138 ml x min(-1) and this was much lower in the CAPD patients (61.9 ml x min(-1)) in whom the renal clearance was negligible. Although there were trends indicating differences in absorption between the two groups, the significant differences in furosemide disposition observed in CAPD patients were due to renal failure.

The interaction of paracetamol with frusemide.

Following the administration of paracetamol (1 g 4 times per day) or placebo to 10 healthy female volunteers for 2 days, the pharmacological effects of intravenous frusemide (20 mg) were observed after a final dose of either paracetamol or placebo. Paracetamol pre-treatment had no effect on frusemide-induced diuresis or natriuresis. There was a significant reduction in the basal output of prostaglandin E2 (PGE2) with paracetamol pre-treatment (18.4 +/- 15.4 vs 7.6 +/- 5.0 ng h-1, P < 0.05; 95% confidence interval of the difference 0.2 to 21.8). Frusemide induced a transient increase in the urinary excretion rate of PGE2 and although this effect was reduced by paracetamol (46.6 +/- 50.9 vs 23.2 +/- 13.8) the differences in the change of excretion rate from baseline were not statistically significant (95% confidence interval of the difference -17.8 to 15.7). The basal level of 6-keto prostaglandin F1 alpha (PGF1 alpha) was less with paracetamol pre-treatment (61.7 +/- 41.1 vs 38.7 +/- 26.1 ng h-1, NS; 95% confidence interval of the difference -16.6 to 62.6) and the cumulative urinary output of PGF1 alpha in the 6 h after frusemide administration was significantly reduced (305.9 +/- 179.4 vs 181.8 +/- 100.2 ng h-1, P < 0.05; 95% confidence interval of the difference 32.2 to 216). The frusemide-induced rise in plasma renin activity was significantly less with paracetamol than placebo at 60 min (4.3 +/- 2.9 vs 2.7 +/- 1.9 ng ml-1 h-1, P < 0.01; 95% confidence interval of the difference 0.4 to 2.7).

Impaired absorption of paracetamol in vegetarians.

1. The absorption and disposition of paracetamol was investigated in 10 healthy male Thai vegetarians and 10 similar non-vegetarians following an oral dose of 20 mg kg-1. 2. The absorption rate of paracetamol was significantly impaired in the vegetarians compared with the non-vegetarians as shown by a lower mean Cmax (11.7 +/- 1.4 vs 15.6 +/- 1.6 mg l-1; 95% confidence interval of the difference 2.49 to 5.36), increased tmax (median 1.75, range 0.75 to 3 h compared with 0.75 and 0.25 to 2 h) and an increase in the time for input of 50% of the total amount absorbed (0.54 +/- 0.38 compared with 0.20 +/- 0.10 h; 95% confidence interval of the difference 0.063 to 0.61). 3. A significantly lower total 24 h urinary recovery of paracetamol and metabolites (72.1 +/- 5.4 vs 86.4 +/- 5.4% of the dose; 95% confidence interval of the difference 8.0 to 20.6) indicated a decrease in the extent of absorption in the vegetarians also, although the total AUC values did not differ significantly between the two groups. 4. The plasma paracetamol half-life, partial metabolic clearances and fractional urinary excretion of the glucuronide, sulphate, cysteine and mercapturic acid conjugates of paracetamol were similar in the vegetarians and non-vegetarians.