prn8099 - Number 17, April 1998

A latest study from the World Health Organisation’s International Agency for Research on Cancer (IARC) which is undergoing a review at the moment provides further evidence on the link between passive smoking and lung cancer. The study, conducted in 12 centres from seven European Countries included 650 cases of lung cancer and 1,542 controls is said to be the largest study carried out on European population to date. It is also the second largest of its kind in the world. The study (http://www.larc.ft/PRELEASES/izoe.htm) showed that an increase of 16% in the risk of lung cancer for non-smoking spouses of smokers, and a 17% increase for exposure to passive smoking at the workplace were observed. For other exposures, there was a dose-dependent relationship, i.e. greater extent of exposure was associated with a higher risk. Although no increased risk was found for lung cancer in adults who were exposed to passive smoking during childhood but other studies have shown that passive smoking by children worsens asthma and may cause several disease conditions including bronchitis and pneumonia.

In a response to these research findings, Malaysian Tobacco Company Bhd. (MTC) highlighted that the study reaffirmed the position of the tobacco industry that science did not show that being around smokers was a lung cancer risk. If added that the findings from the WHO research show that the risk of lung cancer from environmental tobacco smoke (ETS) to be either non-existent or too small to be measured at a meaningful level.

This new study when considered alone or as the latest of more than 40 studies of this type over the last 17 years proved that although some people find cigarette smoke at the workplace or in other enclosed areas and buildings more of a nuisance and an annoyance. The problem, it was suggested, can be worked out with effective ventilation systems. MTC also believed that smoking is an informed adult choice and that Malaysian adults should have access to a balanced view on any issue, such as ETS.

Based on this study too, MTC claimed that WHO has withheld from publication its own report that was aimed at but supposedly failed to prove that there is an association between passive smoking or ETS and a number of diseases, lung cancer in particular. This was denied by the WHO in its press release dated (see also accompanying statement on Page 2).

PRN’s Response

The WHO-IARC study in question has been submitted to a scientific journal for evaluation and at present is undergoing peer review before being accepted for publication. The study showed a relative risk of 1.16 for a non-smoker contracting lung cancer as a result of living with a smoking spouseor 1.17 relative risk from working in a smoking workplace. Taking into consideration these values, this study found that non-smokers are 16% more likely to get lung cancer if their spouse smokes than if they live with a non-smoking spouse. In practice this is a small risk as compared to an active smoker who has a risk of 20 times higher than a non-smoker. When applied to the millions of people under this situation however, there would be an additional 16-17% extra risk which would amount to an extra several hundred deaths per year due to ETS. A point to note in this case is that although the difference is not statistically significant, it could still be real. To illustrate this further, the data showed that there could have been a lesser incidence of lung cancer by as much as 16 percent in favour of non-exposure to ETS, which would certainly be important if it turned out to be the case.

The second issue raised was there is no association between passive smoking and lung cancer in the interpretation of the statistical test applied to these results. The opponents to the WHO-IARC claim that there was no statistically significant correlation between the risk numbers to indicate the association of lung cancer with living or working with a smoker. In the WHO-IARC study, the acceptance of the significant correlation for the above statement was taken from the application of the significance test to interpret any comparative result. The underlying test being used is a null hypothesis for which there is no difference in population parameters among the groups being compared. In other words, the null hypothesis is consistent with the notion that the observed difference is simply the result of random variation in the data. The principle involved in such testing usually involves a computing of the test statistic using a standard equation and comparing it with a critical value obtained from a set of statistical tables. When the test statistic exceeds the critical value, the null hypothesis is rejected and the difference is declared statistically significant. In any decision to accept or reject the null hypothesis, a significance level of testing is normally accepted where the risk of rejecting the null hypothesis is stated even though the hypothesis is correct. For example, if the significance level is at 5%, then there is a 5% chance of rejecting the null hypothesis when it is true. Although there is uncertainty at 5% level, the use of a lower test of statistical significance such as 20% level would certainly provide a statistically significant link between passive smoking and lung cancer in the WHO-IARC study. Thus, looking at the importance of this difference under a different context, it can be said that a policy decision by any government of no action towards passive smoking would be fiercely contested if it was 80% sure that it causes lung cancer.

Since the estimate of risk in the WHO-IARC study is based on a sample of 650 lung cancer cases, the above mentioned risk to the whole population could be not statistically different as the sample may not be exactly representative. The difference could be significant only if a bigger sample of lung cancer patients was used or the derived figures were compared with another larger study involving a bigger number of samples.

Based on this argument, a comparative study with another larger study of 4626 cases of lung cancer reported the October 1997 issue of BMJ, (315:980-988) showed that the derived ranges from WHO-IARC study overlap and therefore the results are consistent. The relative risk from the larger study showed that the significant exposure to environmental tobacco smoke was 1.44 or 44% more likely to develop lung cancer as compared to non-exposed population. As such, these two independent research indicate that there is a link between passive smoking and lung cancers.

In retrospect the opponents of WHO-IARC study have inverted this uncertainty to a rather limited view of accepting the study as evidence of ‘no effect’ or the risk is insignificant. Besides the epidemiology data, there are also sources of evidence that fully support the above argument. To conclude, an utmost important point to take note from the WHO-IARC study as well as other studies conducted elsewhere is PASSIVE SMOKING CAUSES LUNG CANCER IN NON-SMOKERS.

"Passive Smoking Does Cause Lung Cancer, DO NOT Let Them Fool You" - WHO

The World Health Organization (WHO) has been publicly accused of suppressing information. Its opponents say that WHO has withheld from publication its own report that was aimed at but supposedly failed to scientifically prove that there is an association between passive smoking, or environmental tobacco smoke (ETS), and a number of diseases, lung cancer in particular. Both statements are untrue.

The study in question is a case-control study on the effects of ETS on lung cancer risk in European populations, which has been carried out over the last seven years by 12 research centres in 7 European countries under the leadership of WHO’s cancer research branch — the International Agency for Research on Cancer (IARC).

The results of this study, which have been completely misrepresented in recent news reports, are very much in line with the results of similar studies both in Europe and elsewhere: passive smoking causes lung cancer in non-smokers.

The study found that there was an estimated 16% increased risk of lung cancer among non-smoking spouses of smokers. For workplace exposure the estimated increase in risk was 17%. However, due to small sample size, neither increased risk was statistically significant. Although, the study points towards a decreasing risk after cessation of exposure.

"It is extremely" important to note that the results of this study are consistent with the results of major scientific reviews of this question published during 1997 by the government of Australia, the US Environmental Protection Agency and the State of California", said Neil Collishaw, Acting Chief of WHO’s Tobacco or Health Unit in Geneva. "A major meta-analysis of passive smoking and lung cancer was also published in the British Medical Journal in 1997. From these and other previous reviews of the scientific evidence emerges a clear global scientific consensus - passive smoking does cause lung cancer and other diseases", he concluded.

"IARC is proud of the careful scientific work done by the European scientific team responsible for this study", commented Dr Paul Kleihues, the Agency’s director. "We are very concerned about the false and misleading statements recently published in the mass media.

Overview on
Poisoning Involving Selected First-Line Antiepileptic Drugs

by Abdul Fatah Haji Abdul Rahman PharmD

Epilepsy affects many individuals worldwide. In industrialised countries, the incidences vary from 28.9 to 53.1/100 000 person-years. The prevalence in these countries is about 3-9 per 1000 population. Higher preva-lences have been reported in Latin America and several African countries.

Epileptic patients are at risk of antiepi-leptic drug poisoning. Self-poisoning, either deliberate or accidental, in relatives of patients with epilepsy has also been reported.

This overview will discuss poisoning associated with some of the commonly used first-line antiepileptic drugs. This includes phenytoin, carbamazepine and valproic acid. Poisoning with phenobarbitone, another anticonvulsant will be reviewed separately under barbiturates.

What are the types of antiepileptics available in the country?

The types of antiepileptic drugs available in this country includes primidone, gabaarpentum and lamotrigine. Discussed below however are three important common types.

Phenytoin

Phenytoin formulations are available as suspension of 100mg/5ml containing phenytoin base, capsules of 30mg and 100mg containing phenytoin sodium salt and injection of 250mg/5ml containing phenytoin sodium salt in a mixture of propylene glycol and alcohol. Phenytoin injection is not used for maintenance therapy.

Carbamazepine

On the other hand, carbamazepine formulations are available as tablets 200mg, controlled-release tablets 200mg and 400mg, and syrup 100mg/5ml.

Valproic acid (sodium valproate)

As for sodium valproate the formulations are enteric-coated tablets 150mg, 200mg, and 300mg, syrup 200mg/5ml, slow-release tablet 500mg and injection 400mg per vial. Sodium valproate injection is not used for maintenance therapy.

How much is required to cause toxic effects?

Phenytoin

The usual dose range for phenytoin is 4 - 6mg/kg/day to achieve a drug concentration in the range of 10- 20mg/ml (generally accepted therapeutic range). Acute ingestion of more than 20mg/kg has been reported to result in signs and symptoms of toxicity. Based on plasma level toxic effects are rarely observed at plasma level of less than 15mg/ml, however, at plasma level of greater than 30mg/ml, toxicity may be demonstrated in50% of the cases. The mean lethal dose in adults is estimated to be 2 to 5g. However death is rare and survival has been reported in a 2 year old child who had ingested 300mg/kg of phenytoin and was treated with only conservative therapy.

Carbamazepine

The usual dose range for carbamazepine maintenance therapy in epilepsy is 10-20mg/kg/day. The generally accepted therapeutic range is 6-12mg/ml. The lethal dose of carba-mazepine in reported cases of overdosage ranged from 4 to 60g.

Valproic acid

The usual dose range for valproic acid maintenance therapy in epilepsy is 15-40mg/kg/day. The generally accepted therapeutic range is 50-100mg/ml. Tremor, irritability, confusion, and restlessness are observed above 100mg/ml.

What effects do they have in overdose situation?

Phenytoin

Acute toxicity usually produces central nervous system manifestations (see Table 2) such as nystagmus, slurred speech, ataxia, dizziness, drowsiness, diplopia, behavioral changes, and cognitive impairment. One or more of the clinical features may be absent because of individual variation. The presence of ataxia in an epileptic patient on phenytoin should always lead to the suspicion of phenytoin intoxication.

The presence of unusual clinical features in phenytoin intoxication has been reported. Involuntary movements (dyskinesias) involving the face, limbs and trunks may occur both in adults and children especially in those patients on more than one antiepileptic drugs. The duration of dyskinesias varies, lasting from hours to months. It may disappear spontaneously. Reducing the dose or discontinuing the drug may reverse the condition. Diazepam has also been used to reverse dyskinesias.

Exacerbation of epilepsy has been reported at high concentrations of phenytoin. It may even precipitate status epilepticus. In addition, coma and death have been reported.

Carbamazepine

Carbamazepine is structurally similar to some of the tricyclic antidepressants which accounts for many of its adverse effects (eg. anticholinergic effects, seizures, and cardiac conduction disturbances).

Anticholinergic effects of the drug reduce gut motility and late development of toxicity should be anticipated. There may also be gastrointestinal and anticholinergic symptoms. Common symptoms include nausea, drowsiness, vertigo, blurred vision, and slurred speech. More serious intoxication may result in respiratory depression. Impairment of consciousness progressing to a comatose state has been reported. Coma may develop at blood concentrations as low as 19mg/ml. Exacerbation of seizures has been reported in some patients with carbamazepine overdose.

Cardiac symptoms consist of sinus tachycardia, conduction disturbances, and hypotension. Bradycardia, first-degree and complete AV block have been reported, although QRS and QT widening are uncommon. Cardiac side effects are more likely to develop in older patients. Because of the risk of arrhythmias ECG monitoring for at least 24 hours may be required.

Valproic acid

Most acute overdosage results in no ill effects although several fatalities have been reported. The most common symptom is drowsiness. Other findings may include pinpoint pupils, hypotension, nausea, vomiting, and diarrhea. Ataxia, nystagmus, altered behaviour, confusion, hypernatremia, metabolic acidosis, hypocalcemia, and hyperthermia have been observed. Unconsciousness has been reported to occur with large ingestions (>200mg/kg). Gross movement disorders are rare.

How do you confirm/ensures a possible case of overdose following phenytoin, carbama-zepine for valproic acid?

Diagnosis is usually based on a history of ingestion or is suspected in an epileptic patient with the sign and symptoms that consistent with the respective anticonvulsant and accompanied with an elevated serum levels.

Serum levels are generallay available in most hospitals. In an overdose situation, the peak levels may be delayed. Under such circumstances, repeated or serial serum levels are recommended.

What approach should be taken in managing antiepileptic overdose?

There is no antidote available in cases of overdose. Thus, management are largely symptomatic and/or supportive in nature. In epileptic patients, the drug should be withdrawn. Gut evacuation and administration of activated charcoal may be instituted if overdose is recent and clinical status of the patient monitored frequently.

Phenytoin

The treatment of phenytoin toxicity or overdose is symptomatic. There is no antidote available for phenytoin. In cases of early presentation, gastric lavage with proper protection of the airway can be carried out. Multiple dose activated charcoal has been shown to increase phenytoin elimination and may play an important role in serious ingestions. The activated charcoal may be started with 30-100gm dose in adults and 15-30gm in children. In adults, the administration of activated charcoal repeated with a dosage range of 20-50gm every 6 hours. In children, the additional doses has not been established, but half the initial dose has been suggested. Repeated administration of the activated charcoal however is not recommended if patient had an ileus. Following the first dose of activated charcoal, magnesium sulfate 20-30gm may be given orally to enhance elimination of the charcoal. Diazepam (IV or PO) has been used to reverse dyskinesias. Dialysis and forced diuresis have not been found effective because of phenytoin extensive protein binding.

The decision to restart phenytoin in the same patient will depend on the resolution of toxic manifestations as well as the availability of drug concentration measurement. Because of the non-linear kinetics, adding the drug may push the existing therapeutic concentration back into the toxic range again. On the other hand, prolonged subtherapeutic concentration may put the patient at risk for seizure.

Table 3 may serves as a guide for appropriate blood sampling time and to estimate when the concentration will reach a suitable therapeutic concentration before restarting phenytoin.

Carbamazepine

The management of carbamazepine poisoning or overdose is largely supportive. There is no specific antidote. Acute overdose may cause delay in gut motility resulting in impaired carbamazepine absorption. Gastric lavage may be carried out up to 12 hour of ingestion. Multiple dose activated charcoal has been shown to reduce serum half-life by about 50%. Charcoal hemoperfusion accelerates the elimination of carba-mazepine and is highly effective. It is usually indicated for life-threatening intoxication such as those involving seizures and cardiac toxicity refractory to standard treatment. Forced diuresis, peritoneal dialysis, and hemodialysis are not recommended.

The decision to restart carbamazepine in the same patient will depend on the resolution of toxic manifestations as well as the availability of drug concentration measurement. Please refer to Table 3 for appropriate guide in blood sampling time and to estimate when the concentration will reach a suitable therapeutic concentration before restarting carbamazepine.

Valproic acid

Management of valproic acid intoxication consists of general supportive therapy. Because the drug is rapidly absorbed, gastric lavage may be of limited value (except for delayed-release tablet). Treatment should include multiple-dose activated charcoal. The role of hemodialysis or hemoperfusion is unclear but may be beneficial in life-threatening cases.

The decision to restart valproic acid in the same patient will depend on the resolution of toxic manifestations as well as the availability of drug concentration measurement. Table 3 serves as a guide for appropriate blood sampling time and to estimate when the concentration will reach a suitable therapeutic concentration before restarting valproic acid.

Conclusion

Poisoning with these types of antiepileptic drugs appears to carry a good prognosis. In the majority of cases, supportive measures are all that is required. Monitoring of the drug concentration in the blood will help confirm the diagnosis and the management of the poisoning cases. It should be noted however, that some patients may be taking more than one antiepileptic drug. Therefore knowing what drugs the patient is taking and monitoring these different drug concentrations will be very useful in assessing the efficacy of any method used to enhance elimination and in estimating a suitable time to reinstitute the antiepileptic therapy.

 Concern Over Further Increase in TOBACCO Production in MALAYSIA

At the first glance, the above news reports sound like another important development in Malaysia’s attempt to be a world leader in the production of tobacco and tobacco-related products. In fact, recently the National Tobacco Board (NTB) suggested initiatives to reduce the cost of tobacco production so that local tobacco would be as competitive as the ones from the Asean region. The industry as pointed by NTB would be opened to stiff competition once the Asean Free Trade Area’s Common Effective Preferential Tariff (CEPT) Scheme is implemented by January 2010. Under the new system the present mechanism of protecting local tobacco industry through tariffs and import duties would be removed and hence the actual production price of tobacco at RM11.40 per kg would definitely lose to the cheaper ones for example from Thailand, which is RM6.00 per kg.

Among the suggestions being considered by NTB in facing these competition is to increase tobacco production through the opening up of more farms, introducing integrated farming in small farms that have been restructured, replacing ineffective production systems with the individual farmer-curer system and the toll curer system as well as ensuring the distribution of quota size to be more flexible and relevant to the tobacco’s future plan preparation in facing CEPT challenges.

While these suggestions if implemented would give some economic benefits, they almost definitely increase the incidence of tobacco-related diseases and deaths in the country. The relationship between increased mortality and morbidity as well as increased health care cost due to tobacco use is something that is missing in the business plan to expand tobacco production in the country. This cannot be an oversight because very recently MTC categorically admitted in public that it "believes smoking to be a risk factor for diseases such as lung cancer" (The Sun, Feb. 6).

Views from the World Bank

In any case, the debate about tobacco and health have been publicised even by the World Bank. In the 9th World Conference on Tobacco and Health in 1994, a World Bank senior economist stated that "controlling the consumption of tobacco is not only good for people’s health but also an important policy for their countries’ economic prospects." Based on his estimation on the producer and consumer benefits from tobacco consumption in the US and comparing them to the economic costs, he estimated that one tonne of tobacco consumed causes an average of 0.65 deaths, with an average lag of 25 to 30 years. Through this, the calculated number of premature deaths and new cases of the four most prevalent tobacco-caused diseases (cancers, cardiovascular diseases, cerebrovascular diseases and chronic obstructive pulmonary diseases) over a thirty-year period for 1000 tonnes of added tobacco consumption were: 990 premature deaths and 650 new cases.

As a result, the direct medical costs for treatment of these diseases were (in 1990) US$5.6 million. While, the indirect costs according to the estimated value of life lost were US$11 million for premature death, and US$13.2 million for premature mortality.

Using the approach to the economic models of the estimated demand and supply responses of the market for tobacco, the benefits of consumption to producers and consumers (1990 prices) for 1000 added tonnes of tobacco consumption was calculated to be US$2.6 million. Thus, summing benefits and cost, he derived a global net loss of US$27 million for 1000 tonnes of tobacco. Looking at the global trend, he estimated that there were 7 million tonnes of tobacco produced in the worldin 1990 which would give a rough estimate of an annual global loss of US$200 billion, of which about 1/3 occurs in the low-income countries.

Thus based on this, the World Bank has come out with various policies.

WORLD BANK POLICY ON TOBACCO

• In the health sector, World Bank activities discourage the use of tobacco products.
• No direct loans, investment or guarantees for tobacco production, processing or marketing, except in the context of the few countries heavily dependent on tobacco as a source of income and foreign exchange. In those countries, the World Bank seeks to help them diversify away from tobacco.
• As much as practicable, the World Bank does not lend indirectly for tobacco production.
• Unmanufactured and manufactured tobacco, tobacco-processing machinery and equipment, and related services cannot be included under imports financed under loans.
• Tobacco and tobacco-related producer or consumer imports may be exempt from borrowers’ agreements with the Bank to liberalise trade and reduce tariff levels.

From the viewpoint of health care costs related to smoking, a recent study in a medical journal published last year has highlighted the health costs of smoking incurred by exposing infants and children to environmental tobacco smoke. It is already well-established that exposure to tobacco smoke increases risk of respiratory illness among children. To estimate the amount spent on children’s health care costs for respiratory illness attributable to exposure to environmental tobacco smoke, the authors examined data from the US concerning smoking, health care usage, health expenses for respiratory health care and socio-demographic features of the families of 2624 children under the age of 5 in 1987. Based on the results, the authors among others, noted that exposure to tobacco smoke causes more respiratory illness, and that the expenses incurred are higher than for non-exposed children with the same illness and that tobacco smoke increases both the period prevalence and the severity of the childhood respiratory conditions.

Further calculation on the healthcare cost showed that maternal smoking was estimated to increase direct health care costs per child of US$120 a year for children under 5, and US$175 a year for children under 2. Based on these figures, the US national level expenditures for respiratory illness due to maternal smoking were estimated to be US$460 million for children under 2 years old, US$201 million for children between 3 and 5 years old, or US$661 million for children under 6 years of age, about 19% of total expenditures for childhood respiratory conditions.

To conclude, it is hoped that the above information would work towards informing and helping our society and the government to recognise the consequences of the decision in supporting the tobacco industry, let alone expanding it even further.