WO2001068069A2 - Pharmaceutical composition comprising paracetamol - Google Patents

Abstract

The present invention relates to the use of a paracetamol compound in combination with a glutathione enhancing compound as an analgesic or antipyretic. In particular, the present invention relates to the use of a paracetamol compound and a glutathione enhancing compound for simultaneous, separate or sequential use as an analgesic or antipyretic by a patient suffering from or susceptible to an allergic disease or an inflammatory lung desease. The present invention also relates to the use of a paracetamol compound and a glutathione enhancing compound for simultaneous, separate or sequential use as an analgesic or antipyretic by a pregnant woman to prevent the development of wheezing and/or asthma in the offspring.

Description

Pharmaceutical Composition

This invention relates to the control of asthma and other allergic diseases, and inflammatory conditions of the lung where such diseases are aggravated by the administration of certain analgesics or antipyretics.

Production of reactive oxygen species and nitric oxide by inflammatory cells is increased in asthmatic individuals. (Barnes PL, Free Rad. Biol. Med., 1990; 9:235-243) (Kanazawa H, et al, Chest, 1991, 100:1319-1322) (Kharitonov SA, Lancet 1994; 343:133-135). This endogenous oxidant burden, and inhaled oxidants such as nitrogen dioxide, ozone and cigarette smoke, may contribute to asthma pathogenesis by causing epithelial damage and increasing bronchial responsiveness. (Barnes PL, supra) The epithelial lining fluid of the airways contains antioxidants, such as ascorbic acid and α-tocopherol, (Slade R, Exp. Lung Res., 1993; 19:469-484) which may defend the lung against oxidative stress and thus limit the degree of airway inflammation in asthma. It has been proposed that a declining intake of dietary antioxidants has contributed to the rise in asthma in recent decades. (Seaton A, Thorax, 1994; 49:171-174)

Glutathione, an antioxidant in its reduced form (GSH), is present in very high concentrations in airway epithelial lining fluid (Cantin AM, J. Appl. Physiol., 1987; 63:152-157). The term glutathione as used herein refers to the reduced form of glutathione (GSH). Animal studies indicate that GSH plays an important role in preventing oxidative damage to the lung,

(Jenkinson SG, L Lab. Clin. Med., 1988; 112:345-351) (Smith LJ, Am. Rev. Respir. Dis.,

1990; 141:141-149) and in humans, levels of GSH in the airways are increased in individuals exposed to inhaled oxidants such as cigarette smoke (Cantin AM, J. Appl.

Physiol, 1987; 63:152-157) and nitrogen dioxide, (Kelly FJ, Am. L Respir. Crit. Care Med.,

1996; 154:1700-1705) suggesting a similar protective response. GSH may also be involved in defence against the oxidative stress of asthma inflammation, as levels of total (Smith LJ,

Am. Rev. Respir. Dis., 1993; 147:1461-1464) and oxidised (Kelly FJ, Lancet, 1999; 354:482-483) GSH were higher in the airways of adults with mild asthma, than in those of controls Furthermore, the ability of GSH to down-regulate the transcπption factor F-κB, (Rahman L Thorax 1998, 53 601-612) and the negative association between alveolar GSH levels and bronchial responsiveness seen m asthmatic adults, (Smith LJ, Am Rev Respir Dis . 1993, 147 1461 -1474) has also been disclosed However, there is no suggestion or in vno data m the pπor art indicating that depleting GSH will make asthma worse Furthermore, there is no suggestion in the art that supplementary asthmatics with GSH will reduce asthma symptoms

Aside from its function as a pulmonary antioxidant, GSH plays a key role in the hepatic detoxification of drug metabolites (Ketterer B, Environ Health Perspect , 1983, 49 59-69) and stores of GSH m the liver are depleted by the reactive metabolite of paracetamol

(acetaminophen) (Kourounakis AP, J Pharmacy Pharmacol . 199⁷, 49 938-942)

Paracetamol is also referred to in the art, especially m the USA as acetaminophen When glutathione stores become depleted, usually after an overdose of 15 g or more, liver or kidney failure can result Co-methiamol is a combined preparation of 500 mg paracetamol and 100 mg of the essential ammo acid DL-methionme, and is available over the counter in pharmacies This formulation was developed in order to prevent toxicity following overdose Methionme, an essential ammo acid, is a glutathione precursor, which is used as an oral antidote for paracetamol overdose Methionme given with paracetamol enables sufficient glutathione to be synthesised by the liver to prevent toxicity occurring m the event of an overdose It has no effect on the analgesic or antipyretic potency of paracetamol

In ammals administration of paracetamol also depletes the lung of GSH m a dose-dependent fashion (Chen TS, Drug Metab Disposition, 1990, 18 882-887 and Michel L. Environ Health Perspect , 1994, 102 Suppl, 9 63-64) However, there is no in vivo data showing such an effect m humans and there is great scepticism that such an effect is likely m humans with normal therapeutic doses of paracetamol, particularly as one of the cited animal studies used doses which, m human terms, would be huge and fatal

Inflammatory lung diseases in addition to asthma (also termed on allergic disease) are also associated with a decrease in levels of GSH In particular, patients with cryptogemc fibrosing alveolitis (CFA) or acute respiratory distress syndrome (ARDS) are known to have reduced levels of GSH in their lungs.

At the ERS Meeting held in Madrid during September 1999 a poster was presented suggesting a link between frequent paracetamol use and asthma. No data was presented demonstrating a direct causal link and the suggestion was received with considerable scepticism. The main reasons why the suggestion was considered sceptically is because most toxicologists do not believe the proposed GSH mechanism and because there are alternative interpretations ofthe epidemiological data presented in the poster.

There is a need for reducing the prevalence of allergic diseases, especially asthma in the population and for reducing the severity of the symptoms caused by the allergic diseases. There is also a need for reducing the prevalence of inflammatory lung disease in the population and for reducing the severity of the symptoms caused by inflammatory lung diseases.

The present invention provides the use of a paracetamol compound and a glutathione enhancing compound for simultaneous, separate or sequential use as an analgesic or antipyretic by a patient suffering from or susceptible to an allergic disease or an inflammatory lung disease.

The present invention also provides the use of a paracetamol compound and a glutathione enhancing compound in the manufacture of a medicament for simultaneous, separate or sequential use as an analgesic or antipyretic by a patient suffering from or susceptible to an allergic disease or an inflammatory lung disease.

The present invention further provides the use of a paracetamol compound and a glutathione enhancing compound in the manufacture of a medicament for simultaneous, separate or sequential use in the treatment or prophylaxis of pain or fever in a patient suffering from or susceptible to an allergic disease or an inflammatory lung disease. The present invention further provides a method of treatment comprising administering to a patient suffering from or susceptible to an allergic disease or an inflammatory lung disease and in need of an analgesic or antipyretic treatment an effective dose of a paracetamol compound and a glutathione enhancing compound simultaneously, separately or sequentially.

By delivering a paracetamol compound and a glutathione enhancing compound to a patient suffering from or susceptible to an allergic disease or inflammatory lung disease, a reduction in the severity of the disease symptoms is obtained and/or the development of the disease is prevented. Without being bound to any theory, it is suggested that the presence of paracetamol reduces the levels of GSH in the patient leading to greater inflammation, especially in the lungs. By delivering a glutathione enhancing compound to the patient, the reduction in GSH levels by paracetamol compounds is counteracted to ensure that there is no significant reduction in the levels of GSH.

The term "paracetamol compound" refers to paracetamol and to any derivative precursor or homolog of paracetamol, which on delivery to a patient has an analgesic or antipyretic effect and reduces the level of GSH in the patient's body. Preferably, the paracetamol compound is paracetamol.

The term "glutathione enhancing compound" refers to any compound which on delivery to a patient compensates at least partially, for any reduction in intracellular and/or extracellular levels of GSH caused by a paracetamol compound. Preferably glutathione enhancing compound fully compensates for any reduction in intracellular and/or extracellular levels of GSH caused by a paracetamol compound. It is further preferred that the glutathione enhancing compound increases the intracellular and/or extracellular levels of GSH above that normally in the patient's body. The glutathione enhancing compound may be methionine, glutathione, glutamine, whey protein, N-acetyl cysteine, oxothiazolidine carboxylate or dithilthione, or any derivative, precursor or homolog thereof which on delivery to a patient enhances the intracellular and/'or extracellular levels of glutathione in the patient's body. Preferably the glutathione compound is methionine. The methionine may be provided in any form, for example as a mixture ofthe D and L forms or as one ofthe D or L forms (preferably the L form). The methionine may also be provided as S-adenosyl methionine.

The term "allergic disease" refers to any atopic disease including asthma, rhinitis, hayfever and eczema. Preferably the allergic disease is asthma or rhinitis. Most preferably, the allergic disease is asthma.

The term "inflammatory lung disease" refers to any inflammatory lung disease such as non-atopic asthma, cystic fibrosis, bronchiectasis, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, cryptogenic fibrosing alveolitis, acute respiratory distress syndrome (ARDS), pneumonia, or bronchiolitis. Preferably, the inflammatory lung disease is cryptogenic fibrosing alveolitis.

A patient suffering from an allergic disease or an inflammatory lung disease displays symptoms of the disease and is diagnosed in accordance with the well established criteria known to those skilled in the art.

A patient susceptible to an allergic disease or an inflammatory lung disease is defined as an individual that is capable of developing an allergic disease or an inflammatory lung disease. Preferably, the individual is genetically and/or environmentally predisposed to the disease. For example, individuals who have a family history of the disease can be considered to be susceptible to the disease. Furthermore, individuals who work or live in an environment which is known to increase the risk of contracting the disease can be considered susceptible to the disease, e.g. smoking increases the risk of contracting chronic bronchitis and emphysema. Furthermore, individuals taking drugs which induce cytochrome P450, which leads to the production of toxic metabolites of paracetamol, will also be more susceptible to the diseases

Preferably the paracetamol compound is paracetamol and the GSH enhancing compound is methionine. Generally, an effective dose of paracetamol is 500 mg. In order to counteract the GSH reducing effect of the paracetamol methionine should be given to the patient simultaneously with, separately to or sequentially to the paracetamol. When the glutathione enhancing compound is methionme, it is preferred that methionme is present m a range of 40 mg to 260 mg per dose It is further preferred that methionme is present m a range of 40 mg to 100 mg per dose Preferably, the amount of methion e given per dose is about 100 mg The co-methiamol composition produced by Perm Pharmaceuticals compπses 500 mg paracetamol and 100 mg methionme As indicated above, the use of this composition was found to prevent the toxic effects of paracetamol on the liver

Preferably the ratio of paracetamol to methion e is between 12 5 to 1 and 1 9 to 1 (w/w)

When the GSH enhancing compound is not methionme, an effective dose for counteracting the effects of the paracetamol compound should be used Such an effective dose can be determined using routine procedures well known to those skilled m the art

Preferably, the present invention relates to the use of a paracetamol compound and a glutathione enhancing compound wherein the patient frequently takes paracetamol Frequent users of paracetamol are defined as those who take a paracetamol compound at least once a week, preferably at least 3 times a week, more preferably at least 5 times a week

By providing a paracetamol compound and a glutathione enhancing compound for simultaneous, separate or sequential use to a pregnant woman prevents the development of asthma or wheezing m the offspπng Accordingly, the present invention provides a paracetamol compound and a glutathione enhancing compound for simultaneous, separate or sequential use as an analgesic or antipyretic by a pregnant woman to prevent the development of asthma and/or wheezing m the offspring

The present invention further provides a paracetamol compound and a glutathione compound m the manufacture of a medicament for simultaneous, separate or sequential use as an analgesic or antipyretic by a pregnant woman to prevent the development of asthma and/or wheezing m the offspring The present invention further provides paracetamol compound and a glutathione enhancing compound in the manufacture of a medicament for simultaneous, separate or sequential use in the treatment or prophylaxis of pain or fever in a pregnant woman to prevent ■ the development of asthma and/or wheezing in the offspring.

The present invention further provides a method of treatment comprising administering to a pregnant woman in need of an analgesic or antipyretic treatment an effective dose of a paracetamol compound and a glutathione enhancing compound simultaneously, separately or sequentially to prevent the development of asthma and/or wheezing in the offspring.

The paracetamol compound and glutathione enhancing compound are as defined above. Furthermore, the preferred dose of the paracetamol compound and glutathione enhancing compound are also as defined above.

Preferably the paracetamol compound and the glutathione enhancing compound are taken throughout pregnancy (when required as an analgesic or antipyretic) in order to reduce the risks of the offspring developing wheezing and/or asthma. The wheezing may or may not be associated with asthma. Preferably the wheezing is associated with atopy that leads to asthma. It is particular preferred that the paracetamol compound is taken in combination with a glutathione enhancing compound during late pregnancy (20 to 32 weeks).

The combination of a paracetamol compound and a glutathione enhancing compound will be particularly beneficial for pregnant women who take paracetamol frequently. A frequent paracetamol user is as defined above.

The paracetamol compound and/or the methionine compound of the present invention may be in the form of pharmaceutically acceptable salts thereof and may be with any pharmaceutically acceptable carrier, adjuvant or vehicle. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

The paracetamol compound and/or the glutathione enhancing compound of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. Oral administration or administration by injection is preferred. The paracetamol compound and the glutathione enhancing compound of this invention may be admixed with any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal intrathecal, intralesional and intracranial injection or infusion techniques.

The paracetamol compound and/or the glutathione enhancing compound may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol Among the acceptable vehicles and solvents that may be employed are ma nitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as Ph. Helv or a similar alcohol. The paracetamol compound and/or the glutathione enhancing compound of this invention may be orally administered m any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch Lubricating agents, such as magnesium stearate. are also typically added For oral administration m a capsule form, useful diluents include lactose and dried corn starch When aqueous suspensions are administered orally, the active compounds are combined with emulsifying and suspending agents If desired, certain sweetening and/ or flavouring and/or colouπng agents may be added

The paracetamol compound and/or the glutathione enhancing compound of this invention may also be administered m the form of suppositoπes for rectal administration These compositions can be prepared by mixing a compound of this invention with a suitable non-irπtatmg excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt m the rectum to release the active components Such mateπals include, but are not limited to, cocoa butter, beeswax and polyethylene glycols

Topical administration of the paracetamol compound and/or the glutathione enhancing compound of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application For application topically, the paracetamol compound and/or the glutathione enhancing compound should be formulated with a suitable earner Carners for topical admimstration of the compounds of this invention include, but are not limited to mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxy- ethylene polyoxypropylene compound, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol emulsifying wax and water The paracetamol compound and/or the glutathione enhancing compound of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation

The paracetamol compound and or the glutathione enhancing compound of this invention may be administered by nasal aerosol or inhalation Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in salme, employing benzyl alcohol or other suitable preservatives. absorption promoters to enhance bioavailability, fluorocarbons, and/'or other solubilizing or dispersing agents known in the art.

Preferably, the paracetamol compound and the glutathione enhancing compound of the present invention are given as a combined preparation for oral administration. Preferably the paracetamol compound and the glutathione enhancing compound are given as co-methiamol.

The present invention is now illustrated in the appended examples with reference to the following figures.

Figure 1 shows scatter plot of 1994-1995 per capita paracetamol sales (gm/person/year) against 1994 per capita GDP ($/person/year). Data points are countries represented in both

ISAAC and ECRHS (squares), ISAAC only (circles), and ECRHS only (triangles).

Countries represented were Australia, Austria, Belgium, Eire, France, Germany, Greece,

Italy, New Zealand, Portugal, Spain, Sweden, UK and US (squares), Argentina, Brazil,

Canada, Chile, Finland, Hong Kong, Indonesia, Japan, Korea (South), Kuwait, Latvia, Malaysia, Mexico, Morocco, Pakistan, Peru, Phillipines, Poland, Singapore, South Africa,

Thailand and Uruguay (circles), and Denmark, Netherlands, Norway and Switzerland

(triangles).

Figure 2 shows 12-month prevalences of wheeze (A), disturbing sleep (B), atopic eczema (C), and allergic rhinoconjunctivitis (D) in 13 - 14 year olds against national per capita paracetamol sales. Data points are ISAAC centres in the "white English-speaking" countries (UK, Eire, USA, Canada, Australia and New Zealand) (crosses) and elsewhere (circles).

Figure 3 shows scatter plots of prevalences of wheeze (A), waking at night with shortness of breath (SOB) (B), diagnosed asthma (C) and rhinitis (D) in adults aged 20-44 against national per capita paracetamol sales. Data points are ECRHS centres in the "white English-speaking" countries (crosses) and elsewhere (circles).

Examples

Example 1 Comparing Asthma and Rhinitis with Paracetamol Use

Methods

As part of a population-based case-control study of asthma in young adults in South London, participants were asked to report how often they took paracetamol and aspirin. The study was based on 9709 individuals who responded to a survey of asthma morbidity, conducted during autumn 1996, in a random sample of adults aged 16-49 registered with 40 general practices in Greenwich, South London. (Premaratne UN, et al., BML, 1999, 318:1251-1255).

Individuals were defined as "asthmatic" if they responded positively to any of three screening questions (Have you been woken by an attack of shortness of breath in the last 12 months? Have you had an attack of asthma in the last 12 months? Are you currently taking any medicine for asthma?), which have been used previously to define asthma in adults of this age (Burney PG, Eur. Respir. L, 1994, 7:954-960) and have been shown to be predictive of bronchial hyperresponsiveness (Bumey PG, Int. J. Epidemiol, 1989, 18:165-173). Individuals who responded negatively to all three questions were defined as "non-asthmatic". The survey also asked whether participants had nasal allergies including hayfever. Those who responded positively to this question were designated as having "rhinitis".

Amongst asthmatic individuals, severity was measured in two ways: firstly, by the frequency of waking at night with asthma symptoms in the previous month (mild (not woken at all); moderately severe (woken twice a week or less); very severe (woken three times a week or more)); secondly, as a score, derived from Likert scale responses to 16 questions about the impact of asthma on activities and quality of life, which has been shown to be correlated with objective measures of asthma severity, (Marks GB, J. Clin. Epidemiol, 1992, 45:461-472) (Marks GB, J. Clin. Epidemiol, 1993, 46:1103-1111) and has been used previously in this population (Premaratne UN, BMJ., 1999, 318:1251-1255) (Marks GB, Eur. Respir. L, 1997, 10: 1224-1229) A higher score indicates a worse quality of life. Asthmatic individuals were also asked whether they had used a steroid inhaler on most days in the previous month.

Of the responders from the asthma survey we selected all 1,438 (15%) asthmatic individuals (cases) and a random sample of 2000 of the individuals without asthma (controls). These individuals were mailed a dietary and lifestyle questionnaire in September 1997. Non-responders were sent the questionnaires again on two further occasions at 3-4 week intervals. Of those who were sent a questionnaire, 720 (50.1%) cases and 980 (49.0%) controls replied. It was estimated from comparison of general practice lists in 1993 and 1996 that 10% of individuals moved per year; after allowing for this the overall response rate was 55%o. Based on information collected in the 1996 survey, response rates were lower in men, in younger persons and in current smokers.

The lifestyle questionnaire asked about potential risk factors for asthma, including smoking history (never/ex/current), exposure to passive smoke at home and at work, use of a gas cooker, ethnicity, total individuals living in the household and family history of atopic disease (asthma, eczema or allergic rhinitis in parents or siblings). It also enquired about socioeconomic information including employment status (coded as "not known" if no information given), housing tenure (owned/mortgaged or rented), use of a car, whether receiving benefits, whether a single parent, and current or last job. Current social class was classified in men and women according to the Registrar General's Classification of

Occupations (Standard Occupational Classification. 1991. HMSO) and was based on the subject's own occupation (or partner's occupation if the latter was classified higher); students were classified according to father's occupation; individuals with insufficient information on own occupation were assigned social class based on father's occupation at birth.

Participants were asked to specify how often they took aspirin and paracetamol (daily, weekly, monthly, never. If they reported taking one analgesic but did not provide information about the other, it was assumed that the latter was never taken. In January 1999 we mailed an additional questionnaire was mailed to individuals who, in the 1997 survey, had reported that they took either paracetamol or aspirin on a daily or weekly basis This asked about indications for frequent analgesic use and about asp inn avoidance

All analyses were done using the statistical package Stata Logistic regression \\ as used to examine the association between analgesic use and asthma (all cases and cases of diffenng se\ enty), after controlling for potential confounding factors Cases were also examined for the association with the quality of life score (square root transformed) using linear regression To examine the association between analgesic use and rhinitis, logistic regression was used with inverse probability weighting and robust standard errors This allows for the fact that asthmatic individuals had a higher probability of inclusion m the study than non-asthmatic individuals, and is necessary because of the strong association between asthma and rhinitis

Results

Of the 1700 responders m 1997, 1574 (664 cases and 910 controls) had complete information on analgesic use and potential confounding factors and were included m analyses Table 1 shows the distnbution of cases and controls according to nsk factors for asthma Compared to controls, cases were younger, of lower social class, and were more likely to be living m rented accommodation, unemployed, a single parent and exposed to passive smoking at home Participants' smoking habits were not related to asthma

Asthma and frequency of analgesic use

Of these individuals, 787 reported taking paracetamol only, 98 aspirin only, 536 were taking both analgesics and 153 did not report taking either Frequent (daily/weekly) paracetamol use was reported more commonly by women and by unemployed individuals, and frequent aspmn use by those who were single parents Aspmn use was similar among cases and controls However, increasing paracetamol use was strongly associated with asthma (Table 2) This association remained after controlling for factors listed m Table 1 and for aspmn use (P=0 0002) Compared with never-users, the odds ratios (95%. CI) m weekly and daily users were 1 79 (1 21 to 2 65) and 2 38 (1 22 to 4 64) respectively Further controlling for gas cooking, ethnicity, total number living in household, use of a car and receipt of benefits, in those 1497 participants with complete information, did not alter the findings.

When the effect of frequent (daily/weekly) paracetamol use with less frequent use (including never-users) in all individuals was compared, the odds ratio for asthma was 1.73 (95%o CI: 1.29 to 2.31), PO.001. On restricting this analysis to 634 individuals who were also taking aspirin, the odds ratio was 2.24 (1.30 to 3.89), P=0.004. The effect of paracetamol was stronger in men than in women (P interaction 0.09) but did not differ according to other factors in Table 1, or according to reported atopic disease among family members (P values for interaction all greater than 0.27).

Asthma severity and frequency of analgesic use

The number of cases with mild, moderately severe and very severe asthma (classified according to the reported frequency of waking at night with symptoms) was 327, 211 and 100 respectively (26 cases did not report frequency of waking). Table 3 shows associations between analgesic use and asthma when cases of differing severity were compared with controls. The strength of the association between asthma and frequent paracetamol use increased with increasing severity of disease. The association between aspirin use and asthma was inconsistent. There was some evidence that frequent use was less common in moderately severe cases than in controls, but more common in the most severe cases. However, there was no evidence that infrequent (monthly or less) use of aspirin was less common in cases, whatever the severity of disease.

Amongst cases the severity of asthma increased with increasing paracetamol use. The mean increase in square root quality of life score, per frequency of use group, was 0.09 (95%o CI 0.04 to 0.13, P=0.0002). This effect decreased a little when we controlled for regular use of steroid inhalers, to 0.08 ( 0.03 to 0.12, P=0.0006). Aspirin use was not associated with asthma severity (mean increase in score 0.02 (95% CI -0.03 to 0.07, P=0.49)). Rhinitis and frequency of analgesic use

The association between paracetamol use and rhinitis was analysed after controlling for aspirin use and potential confounding factors. Compared with never-users, the odds ratios (95% CI) for rhinitis in weekly and daily users were 1.80 (1.11,2.91) and 2.33 (1.09,4.96) respectively. The association with rhinitis was present in non-asthmatic but not in asthmatic individuals. Aspirin use was not associated with rhinitis.

Indications for frequent analgesic use

In the main study in 1997, frequent (daily or weekly) analgesic use was reported by 322 participants (172 asthma cases and 150 controls) of whom 220 used paracetamol only, 58 used aspirin only and 44 used both. A questionnaire was sent to these individuals in January

1999, asking about indications for use and aspirin avoidance, and 102 cases (59%) and 104 controls (69%) responded. Of the respondents, 83% of cases and 64%o of controls said that they were still taking analgesics daily or weekly. Table 4 shows indications for continuing frequent paracetamol and aspirin use. For both cases and controls, the most common indications were headache and general aches and pains. Of cases who used paracetamol frequently, 3 (4%) reported taking it for asthma. Of cases who used aspirin frequently, 4

(16%>) said they took it for asthma. Among frequent users of paracetamol, 40 (56%) cases and 21 (42%) controls said that they avoided taking aspirin.

Discussion

A strong positive association between frequent (daily or weekly) use of paracetamol and adult asthma in a population-based case-control study has been found. Frequent use of paracetamol was also associated with more severe asthma and, with rhinitis. In view of the small P values, it seems unlikely that our findings have arisen by chance.

Possible biases need to be considered. Cases and controls were selected from the same, clearly defined population of adults registered with 40 general practices. Selection bias seems unlikely as the study was community-based and participants were identified before exposure status was measured. Response rates, though not high, were similar in cases and controls. The case definition has been used previously in adults of this age, (Bumey PG, Eur Respir J , 1994, 7 954-960) is predic e of bronchial hyper-responsiveness, (Burney PG, Int J Epidemiol , 1989. 18 165-173) and does not depend exclusively on a doctor's diagnosis It is submitted that the findings cannot be attnbuted to increased recognition of asthma m frequent users of analgesics who may attend more frequently for health care Most importantly, there is no reason why selection, response or diagnostic biases would result in a strong association between asthma and paracetamol, but not aspmn Similarly, there is no reason why asthmatic individuals would

overestimated their use of paracetamol Although detailed information about dose of analgesic used, nor about additional use of paracetamol m compound preparations or m cough and cold remedies was not collected, such misclassification is likely to be random with respect to asthma, and would tend to lead to an underestimation of the strength of the association

A strong association between paracetamol and asthma remained after controlling for potential confounders One possible explanation to consider is that conditions req nng analgesics, and paracetamol m particular, are more common asthmatic than m non-asthmatic individuals A recent UK survey of adults found that the predominant reason for taking over-the-counter analgesics such as paracetamol was for non-migramous headache (Health Which June, 9-11 , 1999) Whilst β₂-agonιsts can cause headache, this is an uncommon side effect, and it was found that frequent use of paracetamol for headache was as common in cases who were not on asthma treatment as m those who were It has been suggested that migraine may be more common m asthmatic individuals, but evidence for a link is contradictory (Nelson HS, Ann Allergy , 1985, 55 441-447) and a large population-based study of young Bntish adults suggested that the association was not strong (Strachan DP, BMJ, 1996, 312 1195-1199) It is therefore unlikely that the more frequent use of paracetamol m cases is attnbutable to a higher prevalence of co-morbidity

An alternative explanation for the findings might be that cases were taking paracetamol to relieve symptoms associated with asthma However, m the re-survey only 4%o of cases, who were still taking frequent paracetamol, said that they took it frequently for asthma A sensitivity analysis suggested that this percentage does not approach that which would be needed to explain the magnitude of association observed with frequent paracetamol use (data not shown) Furthermore, amongst the 25 cases who reported frequent aspmn use, 4 said that they took it frequently for asthma, which may reflect the bronchodilator action of aspirin in some individuals. (Resta O, Respiration, 1984, 46:121-127)

Asthmatic individuals may take paracetamol in preference to aspirin and non-steroidal anti-inflammatory drugs (NSAID's) in order to avoid potential sensitivity reactions, and in the repeat survey of individuals who were still taking frequent paracetamol 14% more cases than controls said that they avoided aspirin. However, it is submitted that aspirin avoidance can explain only part of the association between frequent paracetamol use and asthma. First, aspirin use was not less common in cases as a whole, than in controls. Second, severe cases, who might be most likely to completely avoid aspirin, were just as likely as controls to report infrequent use of aspirin and were significantly more likely to report weekly use. Third, the strong association between frequent paracetamol use and asthma was not restricted to individuals taking paracetamol but not aspirin, but was also found in those taking both analgesics. Aspirin avoidance is even less likely to explain the association between frequent paracetamol use and rhinitis in individuals who did not have asthma.

Example 2

Paracetamol sales and atopic disease in children and adults: an ecological analysis

Outcome measures in children: ISAAC The International Study of Asthma and Allergies in Childhood (ISAAC) was conducted in

1994-1995. (Asher MI, Eur. Respir, J., 1995; 8:483-491) Symptom prevalences for asthma

(Anonymous, Eur Respir J 1998; 12:315-335), atopic eczema (Williams H, J. Allergy. Clin.

Immunol, 1999; 103:125-138) and allergic rhinoconjunctivitis (Strachan D, Pediatr.

Allergy. Immunol, 1997; 8: 161-176) were measured in up to 155 centres throughout the world, using standardized questionnaires, in children aged 13-14 years (self-assessed) and

6-7 years (parentally assessed). From these published data we extracted 12-month prevalences (%) of wheeze, wheeze disturbing sleep, atopic eczema, and allergic rhinoconjunctivitis (rhinitis and itchy eyes).

Outcome measures in adults: ECRHS The European Community Respiratory Health Survey (ECRHS) was conducted in Europe, the USA, Australia and New Zealand in 1991-1992 (Burney PG, Eur. Respir. J., 1994; 7:954-960). Phase 1 of the survey used a standardized questionnaire to study random samples of adults aged 20-44 years across 48 centres in 22 countries. Published data from Phase 1 (European Community Respiratory Health Survey, Eur. Respir. J., 1996; 9:687-695) on the age/sex-standardized prevalences of wheeze, waking at night with shortness of breath, rhinitis (hay fever or nasal allergies) and diagnosed asthma (asthma attacks or taking medication) in each centre was used. In Phase 2, random samples of Phase 1 respondents from some of the centres were assessed in greater detail. A smoking history was obtained, spirometry and bronchial challenge with methachohne (35 centres) were carried out (Chinn S, Eur. Respir. J., 1997; 10:2495-2501), and total and specific IgE (37 centres) were measured (Burney P, J. Allergy Clin. Immunol, 1997; 99:314-322). Bronchial responsiveness was measured as a methachohne dose-response "slope", expressed in ECRHS units (Chinn S, Eur. Respir. J., 1997; 10:2495-2501). (On this scale, zero represents the highest possible responsiveness, 10 represents no responsiveness, and scores over 10 are assigned to patients whose airways appear to relax (instead of constricting) in response to methachohne.) Atopy was defined as a specific IgE titre above 0.35kU/l to any of the four common allergens tested in each centre, namely Dermatophagoides pteronyssinus, timothy grass, cat, and Cladosporium herbarium (Burney P, J. Allergy Clin. Immunol, 1997; 99:314-322). For each centre, arithmetic mean "slope", geometric mean IgE, and prevalence of atopy was calculated, standardized by sex, age (<30 or 30+), and smoking (current smokers or non-smokers), to a hypothetical standard population. This standard population was assumed to be 50% male and 50% female, with 60% of each sex aged 30+ years, and 60% of each combination of sex and age group were assumed to be current non-smokers.

Paracetamol sales and GDP

Data on national paracetamol sales for 1994/1995 (the earliest year of availability) from IMS-Health (Global Services), London, UK, which collects sales data on drugs from pharmacies and hospitals in each country was obtained. In the case of pharmacies, IMS-Health receives sales records from a majority sample of wholesalers, and also from a stratified sample of retailers (typically several hundred in a country), to measure the smaller direct sales from manufacturers to retailers. In the case of hospitals, IMS-Health collects drug purchase data from a sample of hospitals in each country, the sampling fraction being at least 25%> in all countries and over 50%) in some countries. In both cases, appropriate projection factors and stratified sampling methods are used. These data, and 1994 gross domestic products (GDP) (United Nations, 1997.pp 159-76), were divided by 1994 populations (all ages) World Health Organisation, 1995.ppA3-A7), yielding per capita paracetamol sales (grams per person per year) and GDP (dollars per person per year) for each national market.

Statistical methods

The association of outcomes with per capita paracetamol sales and GDP using the Stata statistical package (Statacorp: Stata Corporation, 1999) to compute linear regression coefficients. Confidence limits were calculated using Huber variances, because of concern that residual variability might be unequal around different parts of the regression line. The increase (between countries) of per capita paracetamol sales with per capita GDP, were measured as well as the increase (between centres) in atopic outcomes (prevalences or means) for each gram increase in per capita paracetamol sales, with and without adjustment for a linear effect of per capita GDP.

Results

Paracetamol sales and GDP

Paracetamol sales data were available for 14 national markets represented both in ISAAC and in ECRHS, for 22 represented in ISAAC alone, and for 4 in ECRHS alone. Per capita sales varied from 1.07 grams/person/year in Uruguay to 43.61 grams/person/year in Denmark. Per capita GDP varied from $447 in Pakistan to 537,553 in Japan. Figure 1 shows the scatter plot of national per capita paracetamol sales and GDP for countries represented in either of the two studies. The poorest countries in ISAAC purchased very little paracetamol. On average, paracetamol sales increased by 0.54 gram (95% CI: 0.15 to 0.94 gram) per person per year for each SI 000 increase in per capita GDP. However, affluent countries showed great variation in sales. The highest rates (over 20 grams/person/year) were found in France, the Scandinavian countries (Sweden, Norway and Denmark), and the "white anglophone" countries (UK, Eire, US, Canada, Australia and New Zealand). In contrast, Japan, Germany, Austria and Switzerland (all with per capita GDP over $25,000) had paracetamol sales below 8 grams/person/year.

Atopic outcomes in children: ISAAC centres

Paracetamol sales were positively associated with all four atopic symptoms in 13-14 year olds. Table 5 shows the regression coefficients, before and after controlling for GDP. For example, the prevalences of wheeze and eczema increased by 0.52%o and 0.21%, respectively, for each gram increase in per capita paracetamol sales, adjusted for GDP.

Figure 2 shows the scatter plots of paracetamol sales and each symptom in 13-14 year olds.

In 6-7 year olds, significant associations were seen for all outcomes after controlling for GDP, although the regression coefficients for wheeze were smaller than in 13-14 year olds, and the confidence intervals were wider, reflecting smaller numbers of centres (Table 5).

Atopic outcomes in adults: ECRHS centres

GDP was negatively associated with the prevalence of waking at night with shortness of breath. After controlling for paracetamol sales, the prevalence of this symptom decreased by 0.19% (95% CI: 0.05 to 0.34%) for each $1000 increase in per capita GDP (P=0.011). However, GDP was not significantly associated with any of the other ECRHS outcomes (not shown).

Table 6 shows the regression coefficients of outcomes with respect to paracetamol sales, before and after controlling for GDP. Paracetamol sales were positively associated with the prevalences of wheeze, asthma and rhinitis, and negatively with mean "slope", indicating a positive association with bronchial responsiveness. For example, the prevalence of wheeze and rhinitis increased by 0.26%o and 0.35%, respectively, for every gram increase in per capita paracetamol sales. Paracetamol sales were not associated with the prevalence of waking at night with shortness of breath, or with mean total IgE, although there was some evidence for a positive association with atopy. Figure 3 shows the scatter plots of paracetamol sales and respiratory symptoms, asthma and rhinitis.

Post hoc analyses Viewing Figures 2 and 3, it was noticed that the prevalences of most outcomes were, broadly speaking, highest in centres in countries with sales over 20 gm/person/day of paracetamol and lowest in centres in countries with sales under 20gm/person/day. The former group of centres were mainly anglophone (the remainder being French and Scandinavian). It was therefore decided, post hoc, to carry out further regression analyses, controlling additionally for the "anglophone effect". As a result, the paracetamol effects for most outcomes were greatly attenuated or abolished and most became non-significant. An exception was the effect for atopic eczema in 13-14 year olds in ISAAC, which, though reduced, remained highly significant (0.13 (0.06 to 0.20); P<0.0005).

Discussion

It has been found that national paracetamol sales are positively associated with the prevalence of wheeze, asthma, rhinitis and atopic eczema in children across centres participating in ISAAC. The association with wheeze in 13-14 year olds was strong, the prevalence increasing by 0.5% for each gram increase in per capita paracetamol sales. Paracetamol sales were also positively associated with the prevalence of wheeze, asthma and rhinitis and with mean bronchial responsiveness in young adults across centres participating in the ECRHS, which supports the data given in Example 1 demonstrations that frequent use of paracetamol was positively associated with asthma and rhinitis in adults.

The substantial variation in the prevalence of asthma and other atopic diseases, and in rates of paracetamol sales, across countries in ISAAC and ECRHS, provided a good opportunity to confirm that paracetamol use is associated with allergic disease. A strength of the study is that the outcomes were measured in individuals in these large surveys, using a standardised methodology. It is believed that the paracetamol data used in our analyses, which comprise estimates of total over-the-counter and hospital sales, are the most comprehensive international data of their kind available. Furthermore, the uniform method of data collection and the large proportion of outlets sampled in each country make it less likely that the variation in paracetamol sales is artifactual.

This is in keeping with the results of Example 1, in which frequent paracetamol use was associated with asthma and rhinitis after controlling for age, sex, smoking, detailed socio-economic factors, and also dietary factors (data not shown).

These findings further demonstrate that, in countries with higher paracetamol sales, a high usage of paracetamol is strongly associated with a higher prevalence of atopic disease. Example 1 demonstrates that asthma was associated with an increased use of paracetamol in individuals and supports such a causal interpretation. This contrasts with an indirect link proposed by Varner et al, who suggested that substitution of paracetamol for aspirin over time may have contributed to the rise in childhood asthma, not because paracetamol had a detrimental effect, but because a protective effect of aspirin had been lost (Varner AE et al, Ann. Allergy Asthma Immunol, 1998; 81:347-351). The frequent use of paracetamol might influence asthma and rhinitis by depleting levels of reduced GSH in the nose and airways, thus shifting oxidant/antioxidant balance in favour of oxidative stress and increasing inflammation (see Example 1) . It is submitted that such a mechanism is plausible because, in hindsight, there are clues that GSH has a role in asthma (Kelly LJ, Lancet, 1999; 354:482-483) (Smith LJ, Am. Rev. Respir. Dis., 1993; 147:1461-1464). In adults, airway levels of total and oxidised GSH are increased in stable asthma and levels of reduced GSH are decreased in acute asthma (Comhair SAA, Lancet, 2000; 355:624-624), indicating a response to oxidative stress. Also, the ability of GSH to down-regulate NFκ-B, (Rahman I, Thorax, 1998; 53:601-612) and the inverse association between alveolar GSH and bronchial responsiveness (Smith LJ, Am. Rev. Respir. Dis. 1993; 147:1461-1464), suggests that GSH may modify asthma inflammation. Furthermore, studies in animals have found that paracetamol can deplete the lung of GSH (Chen TS, Drug Metab Disposition 1990; 18:882-887) (Micheli L, Environ. Health Persp., 1994; 102 Suppl 9:63-64). Recent in vitro work has shown that clinically relevant concentrations of paracetamol deplete GSH in alveolar macrophages and type 2 pneumocytes in rats (Dimova S, Biochem. Pharmacol, 2000; 59: 1467-75) and in human pulmonary macrophages (Nemery, personal communication). These effects in macrophages indicate that paracetamol might also influence atopic diseases more generally through another mechanism, namely the promotion of atopy, since depletion of GSH in antigen-presenting cells promotes Th2-type cytokine responses (Peterson JD, Proc. Natl. Acad. Sci. USA 1998; 95:3071-3076). This might explain why, in children, paracetamol sales were associated with atopic eczema as well as with asthma and rhinitis. The lesser contribution of atopy to wheeze in younger children might explain the weaker association observed between paracetamol sales and wheeze in 6-7 year olds compared with 13-14 year olds. Whilst the ECRHS analyses provide some evidence for an association between paracetamol and atopy, the relation was weak, suggesting that, in adults at least, depletion of antioxidant defences may be the predominant mechanism by which paracetamol influences asthma and rhinitis.

Example 3

Effects of Paracetamol in Pregnancy

In the Avon Longitudinal Study of Pregnancy and Childhood it was investigated whether the frequent use of paracetamol (most days/daily) by mothers in early pregnancy (before 18-20 weeks) and late pregnancy (20-32 weeks) was associated with an increased risk of wheezing and eczema in their children. The effect of frequent aspirin use in pregnancy was also studied. Information on wheezing obtained at 6 months and 42 months of age was used to define 12 month prevalence of wheeze at 30-42 months, and three wheezing phenotypes, namely, early transient (wheezed in first 6 months but not at 30-42 months), persistent (wheezed in both periods), and late-onset (wheezed at 30-42 months but not in first 6 months). Information at 30 months was used to define 12 month prevalence of eczema. Logistic regression, controlling for numerous potential confounding factors, was used in 9,400 children with complete data on wheezing and 10,216 children with complete data on eczema. There was no clear association between frequent use of paracetamol in early pregnancy and risk of wheezing at 30-42 months of age (Odds ratio (OR)), compared with no use, 1.19 (95% CI: 0.72 to 1.97); P=0.50). However, children whose mothers took paracetamol frequently in late pregnancy were more likely than those whose mothers never took it to wheeze at 30-42 months (OR 2.10 (1.30 to 3.41); P=0.003), and they were also more likely to have wheezed persistently since infancy (OR 2.34 (1.24 to 4.40); P=0.008). The risk of eczema was not increased in children whose mothers took paracetamol frequently in early pregnancy (OR, compared with no use, 0.85 (0.56 to 1.30); P=0.45) or late pregnancy (OR 1.04 (0.65 to 1.66); P=0.87). Frequent use of aspirin in pregnancy was not associated with wheezing at 30-42 months. However, an increased risk of early transient wheezing was observed in children whose mothers took aspirin frequently in early pregnancy (OR, compared with no use, 2.73 (1.57 to 4.76); PO.0005) and in late pregnancy (OR 2.54 (1.51 to 4.29); PO.0005).

The association with persistent wheezing indicates that frequent use of paracetamol in late pregnancy causes asthma in the offspring. The lack of an association with eczema suggests that prenatal paracetamol exposure does not influence atopy. The effect on wheeze may be mediated through depletion of glutathione in utero, through the promotion of the development of bronchial hyper-responsiveness. In contrast, frequent aspirin use in early and late pregnancy may cause transient wheezing in infancy by impairing prenatal airway growth.

Example 4

Relationship of Paracetamol Use with Serverity of Cryptogenic Fibrosing Alveolitis

(CFA)

An 87 year old patient who had recently developed CFA had been taking paracetamol regularly for some years for musculo-skeletal pains. The patient stopped taking paracetamol. Within 2 weeks the patient noticed that his cough had improved and had become less productive. The patient estimated that his cough had improved by about 50%. A marked reduction in pulmonary GSH is well known in CFA and thus in accordance with the non-binding theory given above, the frequent use of paracetamol would further reduce pulmonary GSH and result in more severe CFA symptoms.

This example clearly demonstrates that the use of paracetamol in an inflammatory lung disease exacerbates the symptoms.

Example 5

Comethiamol trial: pilot data A pilot study in 3 non-smoking adults with mild asthma (one man, two women; aged 33-49) who take paracetamol on a regular basis was performed. They were given comethiamol tablets (comprising 500 mg paracetamol and 100 mg methionme) to take as required in place of their usual paracetamol and were followed for a two-week period. Their consumption per week varied between 5 and 11 tablets. Spirometric lung function (pre-bronchodilator, forced expiratory volumes in one second (FEVi), forced vital capacity (FVC) and forced expiratory flow (FEF₂5-75)) at baseline and at the end of the two-week period was assessed as a measure of asthma severity, and the % change in these parameters analysed (follow-up minus baseline values).

Results

Outcome Mean % change (95% CI) Range of change (%)

FEV, 5.4 (-7.4 .0 +19.9) 2.2 to 11.9

FVC 4.4 (-4.1 to + 13.6) 1.7 to 8.5

FEF₂₅-75 7.3 (-8.8 to + 26.3) 1.7 to 15.5

These results show that asthma severity improved in these individuals after changing from ordinary paracetamol to comethiamol. Although the pilot study was not blinded and was uncontrolled, this is unlikely to have influenced the objective outcome measures of lung function. Example 6

Paracetamol versus co-methiamol in adults with asthma: randomised double blind cross-over trial

Methodology

Trial design

Randomised double-blind cross-over trial

Participants

Adults with asthma who are frequent users of paracetamol. Selection

Adults with asthma who responded to our previous surveys in Greenwich in 1996 and 1997, and who are identified as frequent users of paracetamol are recruited. (Many of the frequent users confirmed that they are still taking paracetamol frequently at a repeat survey in 1999).

These individuals were aged 16-50 years in 1997 and were registered with 40 general practices across the district. A short questionnaire is sent to 147 asthmatic individuals who previously reported taking paracetamol daily or weekly.

Eligibility

Up to 20 participants are recruited. All the participants satisfy the following conditions. - They still report asthma attacks or asthma treatment - They are taking paracetamol daily or on most days (at least 3 times per week)

Exclusion criteria prior to randomisation Inability to give informed consent Inability to swallow tablets Pregnancy/lactation

Randomisation

Treatment order is determined by simple randomisation. Codes are generated using computer-generated random numbers. The randomisation list is passed on to Perm Pharmaceuticals who make up tablet packs for each 2-week period of the study, distinguished only by study number and period for each participant. Labels on each package identify the study and give contact numbers of the trial investigators who are able to break the code if necessary by contacting Perm Pharmaceuticals.

Interventions Participants are to continue taking their usual asthma medication (if any) and to take our supplies of analgesia, as necessary and in the same way that they usually take their own paracetamol. At the start of the trial they are randomised to receive:

paracetamol (500 mg), or co-methiamol (paracetamol (500 mg) combined with methionine (100 mg)),

1-2 tablets 4-6 hourly, as required. (These are standard recommended doses).

The two tablet formulations, provided by Perm Pharmaceuticals, are film coated and blister-packed, and are identical in appearance and taste.

Treatment dispensing

Drug supplies are stored in Guy's pharmacy and the treatments are dispensed at 10 to 14 day intervals throughout the study in packs of 112 tablets (this is only a little over the maximum amount (100 tablets) that can currently be bought in pharmacies). This is equivalent to two week's supply of the maximum recommended dosage of paracetamol, i.e. up to 8 tablets per day, although many participants take lower doses. Every 10 to 14 days participants are visited at home by a doctor who collects unused tablets (returned to Guy's pharmacy for counting) and supplies a new treatment pack. Participants are given a warning card containing emergency contact numbers and a warning that they are currently taking paracetamol or co-methiamol. They are advised to carry this at all times.

Duration of treatments

The total duration of the trial is 16 weeks. This includes 6 weeks of the first treatment, followed by a 4 week period of "washout" (intended for those taking the combined preparation). During the washout period all participants are asked to continue with ordinary paracetamol (this is still supplied by the trial in order to maintain contact with participants). The participants then cross over to the alternative treatment for a further 6 weeks. Pharmacology and safety of co-methiamol

One of the metabolic pathways of paracetamol produces a reactive metabolite which requires adequate hepatic stores of the antioxidant glutathione for detoxification. When glutathione stores become depleted, usually after an overdose of 15 g or more, liver or kidney failure can result. Co-methiamol is a combined preparation of 500 mg paracetamol and 100 mg of the essential amino acid DL-methionine, and is available over the counter in pharmacies. This formulation was developed in order to prevent toxicity following overdose. Methionine, an essential amino acid, is a glutathione precursor, which is used as an oral antidote for paracetamol overdose. Methionine given with paracetamol enables sufficient glutathione to be synthesised by the liver to prevent toxicity occurring in the event of an overdose. It has no effect on the analgesic potency of paracetamol. The present invention demonstrates that it also prevents depletion of glutathione in the lungs by paracetamol, which is beneficial for asthma symptoms. Whilst co-methiamol is likely to increase glutathione levels in the lung rapidly (within hours/days), it may take at least 4 weeks before this effect translates into decreases in airway inflammation that can be detected by improvement in symptoms and airway lability, hence the length of the treatment and washout periods used.

Outcome measures

Primary:

Asthma quality of life score

This instrument has been used successfully in our previous Greenwich surveys and is assessed at the beginning and end of each treatment arm by questionnaire. The questions ask about the effect of asthma on quality of life in the previous 3 weeks.

Secondary:

1) Diurnal peak flow variability

Every three weeks for seven days participants are asked to record their peak flow (best of three blows every morning and evening before using bronchodilators. The "One Flow" instrument is used which is very compact and portable (battery powered). It stores the best blow each time and the time of measurement and allows serial data to be downloaded onto a laptop at home visits. The amplitude percentage mean ([maximum-minimum.mean]%), calculated each day and averaged over each week, is used as the measure of peak flow variability (Reddel H, et al, Diumal variability - time to change asthma guidelines. BMJ, 1999; 319:45-47).

2) FEV,

This is measured pre- and post-bronchodilator using a portable spirometer at home at the end of each seven day diary and peak flow recording period. Participants who normally take bronchodilators are asked not to take them for 4 hours before the visit. Following the pre-bronchodilator measurement salbutamol 200 mg is administered via a spacer device.

In addition information is collected on:

a) Symptom severity and use of medication: Every three weeks participants are asked to keep a seven-day diary. Nocturnal and daytime severity of respiratory (score 0-4) and nasal (score 0-3) symptoms are recorded the following morning and evening, respectively, allowing calculation of mean morning and evening scores. Use of paracetamol, other painkillers and any asthma medication is also documented daily in these diaries.

b) Exacerbations:

When the QoL questionnaire is completed participants are also asked about the following in the previous 3 weeks:

• increases in regular medication (eg courses of oral steriods) • emergency visits to the GP or hospital for asthma

They are also asked daily if they consider themselves to have a cold.

During a 1-week "run-in" period prior to the start of the trial, daily peak flow and symptom diaries allow calculation of mean peak flow variability and symptom score at baseline. It also allows the identification of episodes during the trial when mean morning peak flow falls by 30% or more from baseline on two or more consecutive days. (Peak flows and symptoms are similarly recorded during the last week of the washout period). Analyses

These are carried out following the "intention to treat" principle at the end of the trial, using Stata, version 6.0. Participants that drop out of the trial and outcomes cannot be measured they are excluded from the analyses. The primary outcome is square-root transformed quality of life score measured at the end of each treatment period. A linear regression model with observations corresponding to treatment periods (2 per patient), is used with Huber variance clustered by patient. The outcomes are regressed with respect to treatment (co-methiamol versus paracetamol), adjusting for quality of life at the beginning of the treatment period as possible linear confounder. The principle parameter estimated is therefore a between-treatment difference in quality of life at the end of the treatment period, adjusted for quality of life at the beginning of the treatment period. (The principle is a generalisation of a paired t-test, adjusted for the possibility that patients may be improving or deteriorating over time irrespective of treatment). Subsidiary analyses control for possible effects of order of treatment and for week of year.

Results

The preliminary results from the trial show that the use of co-methiamol reduces the severity of asthma. Accordingly, the use of co-methiamol instead of paracetamol as an analgesic results in improved asthma severity.

All references cited herein are hereby incorporated by reference.

Table 1. Association between asthma and risk factors included in analyses

Risk factor Number (%) of Number(%) of Crude OR cases (total 664) controls (total 910) (95% CI)

Sex

Female 412 (62) 538 (59) 1 Male 252 (38) 372(41) 0.88(0.72,1.09)

Age group

15-19 65(10) 55(6) 1 20-24 86(13) 72(8) 1.01 (0.63,1.63) 25-29 88(13) 104(11) 0.72(0.45,1.13) 30-34 98(15) 153(17) 0.54 (0.35,0.84) 35-39 107(16) 181 (20) 0.50(0.32,0.77) 40-44 100(15) 143 (16) 0.59(0.38,0.92) 45-51 120(18) 202 (22) 0.50(0.33,0.77)

Social class I 34(5) 92 (10) 0.44 (0.29,0.69) π 202 (30) 327 (36) 0.74 (0.57,0.96)

ΠLNM 201 (30) 241 (27) 1

ΠIM 117(18) 146(16) 0.96(0.71,1.31)

IV/V 110(17) 104(11) 1.27(0.91,1.76)

Type of accommodation Owned 377 (57) 635 (70) 1 Rented 287 (43) 275 (30) 1.76(1.43,2.17)

Unemployed No 465 (70) 715 (79) 1 Yes 179 (27) 174(19) 1.58(1.25,2.01) Not stated 20(3) 21(2) 1.46(0.79,2.73)

Single parent No 567 (85) 831 (91) 1 Yes 97(15) 79(9) 1.80(1.31,2.47)

Smoking

Never 306 (46) 445 (49) 1

Ex 124(19) 169(19) 1.07(0.81,1.40)

Current 234 (35) 296 (33) 1.15(0.92,1.44)

Passive smoking in household No 411 (62) 641 (70) 1 Yes 253 (38) 269 (30) 1.47(1.19,1.81) Table 2. Association between asthma and frequency of analgesic use

Cases Controls Crude OR OR

N (%) N (%) (95% CI) (95% CI)*

Aspirin

Never 403 (61) 537(59) 1 1

<Monthly 166 (25) 254 (28) 0.87(0.69,1.10) 1.04(0.81,1.35)

Monthly 49(7) 66(7) 0.99(0.67,1.46) 0.97(0.64,1.48)

Weekly 33(5) 39(4) 1.13(0.70,1.82) 1.01 (0.60,1.70)

Daily 13(2) 14(2) 1.24(0.58,2.66) 1.05(0.47,2.35)

P (trend) = 0.917

Paracetamol

Never 98(15) 153(17) 1 1

<Monthly 259 (39) 424 (47) 0.95(0.71,1.28) 1.06(0.77,1.45)

Monthly 172(26) 219 (24) 1.23(0.89,1.69) 1.22 (0.87,1.72)

Weekly 105 (16) 97(11) 1.69(1.16,2.46) 1.79(1.21,2.65)

Daily 30(5) 17(2) 2.76(1.44,5.26) 2.38 (1.22,4.64)

P (trend) = 0.0002

* controlling for other analgesic and factors listed in Table 1

Table 3 Association between asthma of diffeπng seventy and use of analgesics

327 cases with mild 21 1 cases with 100 cases with very asthma (no wakmg m moderately severe severe asthma (wakmg past month) asthma (wakmg twice more than twice a week) a week or less)

OR (95% CI)* OR (95% CI)* OR (95% CI)*

Aspmn

Never 1 1 1

<Monthly 1 10 (0 81,1 51) 1 02 (0 69,1 51) 0 91 (0 49,1 69)

Monthly 0 85 (0 50,1 46) 1 01 (0 56, 1 82) 1 21 (0 47,3 12)

Weekly 0 79 (0 40,1 56) 0 47 (0 19,1 21) 3 17 (1 37,7 32)

Daily 0 93 (0 32,2 73) 0 48 (0 10,2 32) 1 96 (0 58,6 70)

P (trend) = 0 600 P (trend) = 0 200 P (trend) = 0 021

Paracetamol

Never 1 1 1

<Monthly 0 92 (0 62,1 37) 0 96 (0 58,1 56) 1 38 (0 68,2 82)

Monthly 1 10 (0 72,1 68) 1 28 (0 77,2 14) 1 16 (0 53,2 55)

Weekly 1 56 (0 95,2 57) 1 73 (0 95,3 13) 2 50 (1 14,5 47)

Daily 1 35 (0 55,3 34) 2 25 (0 90,5 66) 8 15 (2 84,23 40)

P (trend) = 0 048 P (trend) = 0 0079 P (trend) = 0 0004

* controlling for other analgesic and factors listed m Table 1

Table 4. Indications for analgesic use among individuals who reported continuing frequent (daily/weekly) use when re-sun'eyed.

Paracetamol Aspirin

Indication Cases ln = 75) Controls (n=51 > Cases (n=25) Controls (n=28j

Headache 61 (81%) 40 (78%) 15 (60%) 15 (54%)

Migraine 14 (19%) 1 1 (22%) 1 (4%) 4 (14%)

Backache arthritis 22 (29%) 13 (26%) 5 (20%) 5 (18%)

General aches/ pams 26 (35%) 23 (45%) 8 (32%) 6 (21%)

Asthma/breathing problems 3 (4%) 0 (0%) 4 (16%) 0 (0%)

Hayfever/nasal allergv/blocked nose 10 (14%) 6 (12%) 3 (12%) 2 (7%)

Table 5. ISAAC centres: Regression coefficients of symptom prevalences with respect to national per capita paracetamol sales (% prevalence increase per gm/person/year of paracetamol), before and after adjusting lor per capita GDP

Unadjusted Adjusted for per capita GDP

Coefficient (95% CI) P Coefficient (95% CI) p

Ages 13-14'

Wheeze 0.49 (0.41, 0.58) O.0005 0.52 (0.44, 0.59) O.0005

Wheeze disturbing sleep 0.05 (0.03, 0.06) O.0005 0.06 (0.05, 0.07) O.0005

Atopic eczema 0.21 (0.18, 0.25) <0.0005 0.21 (0.16, 0.26) O.0005

Rhinoconjunctivitis 0.14 (0 09, 0.19) O.0005 0.12 (0.07, 0.17) O.0005

Ages 6-7^f

Wheeze 0.28 (0.11, 0.45) 0.002 0.31 (0.14, 0.48) 0.001

Wheeze disturbing sleep 0.03 (-0.02, 0.07) 0.251 0.04 (0.00, 0.08) 0.033

Atopic eczema 0.17 (0.10, 0.25) O.0005 0.18 (0.08, 0.29) 0.001

Rhinoconjunctivitis 0.11 (0.03, 0.18) 0.007 0.12 (0.04, 0.19) 0.002

"112 centres (110 for eczema) in 36 national markets ^f66 centres (65 for eczema) in 28 markets (27 for eczema)

Table 6. ECRHS centres: Regression coefficients of outcomes with respect toper capita paracetamol sales, before and after adjusting for per capita GDP

Unadjusted Adjusted for per capita GDP

Outcome (N of centres/markets) Coefficient (95% CI) P Coefficient (95% CI) P

Standardised prevalence (%) of

Wheeze (44/18) 0.23 (0 13, 0.34) <0.0005 0 26 (0 16, 0.37) O.0005

Waking with SOB^f (43/17) 0.00 (-0.05. 0.05) 0.935 0.02 (-0.03, 0 06) 0.706

Diagnosed asthma (43/18) 0 09 (0 05, 0 13) <0.0005 0.10 (0.06, 0 14) O.0005

Rhinitis (41/17) 0.36 (0.22. 0.51) <0.0005 0.35 (0 21 , 0 49) <0.0005

Standardised level of

BHR "slope"" (34/15) -0 02 (-0.03, -0.00) 0.009 -0.02 (-0.03, -0.00) 0.009

Total IgE" (34/14) -0 10 (-0.37, 0.18) 0.488 -0.09 (-0.36, 0.18) 0.496

Atopy¹ (34/14) 0.20 (-0.02, 0 42) 0 072 0 20 (-0.02, 0.41) 0.071

"By age group and sex ^tWakιng at night with shortness of breath 'By age group, sex and smoking mean (ECRHS units)

'Geometric mean (kU/1)

'Prevalence (%)

Claims

Claims

1 Use of a paracetamol compound and a glutathione enhancing compound for simultaneous, separate or sequential use as an analgesic or antipyretic by a patient suffenng from or susceptible to an allergic disease or an inflammatory lung disease

2 Use of a paracetamol compound and a glutathione enhancing compound m the manufacture of a medicament for simultaneous, separate or sequential use as an analgesic or antipyretic by a patient suffenng from or susceptible to an allergic disease or an inflammatory lung disease

3 Use of a paracetamol compound and a glutathione enhancing compound m the manufacture of a medicament for simultaneous, separate or sequential use m the treatment or prophylaxis of pam or fever m a patient suffenng from or susceptible to an allergic disease or an inflammatory lung disease

4 A method of treatment compnsmg admimstenng to a patient suffenng from or susceptible to an allergic disease or a inflammatory lung disease and m need of an analgesic or antipyretic treatment an effective dose of a paracetamol compound and a glutathione enhancing compound simultaneously, separately or sequentially

5 Use of a paracetamol compound and a glutathione enhancing compound for simultaneous, separate or sequential use as an analgesic or antipyretic by a pregnant woman to prevent the development of wheezing and/or asthma m the offspnng

6 Use of a paracetamol compound and a glutathione enhancing compound m the manufacture of a medicament for simultaneous, separate or sequential use as an analgesic or antipyretic by a pregnant woman to prevent the development of wheezing and/or asthma m the offspnng

7 Use of a paracetamol compound and a glutathione enhancing compound m the manufacture of a medicament for simultaneous, separate or sequential use m the treatment or prophylaxis of pain or fever in a pregnant woman to prevent the development of wheezing and/or asthma in the offspring.

8. A method of treatment comprising administering to a pregnant woman in need of an analgesic or antipyretic treatment an effective dose of a paracetamol compound and a glutathione enhancing compound simultaneously, separately or sequentially to prevent the development of wheezing and/or asthma in the offspring.

9. The use of any one of claims 1 to 3 or the method of claim 4, wherein the allergic disease is asthma, rhinitis, hayfever or eczema.

10. The use of any one of claims 1 to 3 or the method of claim 4, wherein the allergic disease is asthma.

11. The use of any one of claims 1 to 3 or the method of claim 4, wherein the inflammatory lung disease is cystic fibrosis, non-atopic asthma, bronchiectasis, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, cryptogenic fibrosing alveolitis, acute respiratory distress syndrome pneumonia, or bronchiolitis.

12. The use of any one of claims 1 to 3 or the method of claim 4, wherein the inflammatory lung disease is cryptogenic fibrosing alveolitis.

13. The use or method according to any one of the previous claims, wherein the paracetamol compound is paracetamol or any derivative, precursor or homolog of paracetamol which on delivery to a patient has an analgesic or antipyretic effect and reduces the level of glutathione in the patient's body.

14. The use or method of claim 13, wherein the paracetamol compound is paracetamol

15. The use or method according to any one of the previous claims, wherein the methionine compound is methionine, glutathione, glutamine, whey protein, N-acetyl cysteine, oxothiazolidine carboxylate or dithilthione, or any derivative, precursor or homolog thereof which on delivery to a patient enhances the intracellular and/or extracellular levels of glutathione in the patient's body.

16. The use or method according to claim 15, wherein the methionine compound is methionine.

17. The use or method according to any one of claims 1 to 12, wherein the paracetamol compound is paracetamol and the methionine compound is methionine.

18. The use or method according to claim 17, wherein about 500mg of paracetamol and about 40mg to about 260mg of methionine are present in each dose.

19. The use or method according to claim 17, wherein about 500mg of paracetamol and about lOOmg of methionine are present in each dose.

20. The use or method according to claim 17, wherein the ratio of paracetamol to methionine is between 12.5 to 1 .and 1.9 to 1 (w/w).

21. A pharamceutical preparation for the treatment of patients having an allergic disease or an inflammatory lung disease comprising a paracetamol compound and a glutathione enhancing compound.

22. A kit comprising a paracetamol compound, a glutathione enhancing compound and instructions to take the glutathione enhancing compound simultaneously with, separately from or sequential with the paracetamol compound for the prophylaxis or treatment of pain or fever by a patient suffering from or susceptible to an allergic disease or an inflammatory lung disease. Pharmaceutical Composition

The present invention relates to the use of a paracetamol compound in combination with a glutathione enhancing compound as an analgesic or antipyretic. In particular, the present invention relates to the use of a paracetamol compound and a glutathione enhancing compound for simultaneous, separate or sequential use as an analgesic or antipyretic by a patient suffering from or susceptible to an allergic disease or an inflammatory lung disease. The present invention also relates to the use of a paracetamol compound and a glutathione enhancing compound for simultaneous, separate or sequential use as an analgesic or antipyretic by a pregnant woman to prevent the development of wheezing and/or asthma in the offspring.