prn8099 - Number 15, October 1997

 

PRN wishes you a HAPPY DEEPAVALI

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PRN wishes you a HAPPY DEEPAVALI

Our rights to ‘clean’ and ‘salubrious’ air

Dzulkifli Abdul Razak

Now with some initial signs that the haze is gradually abating, it is time for all of us to take a very deep breath, before it worsens again. For the last couple of months, we have been forced to hold our breath for fear that our fragile lungs will soon be filled with assortments of toxic pollutants. Although now many are still holding their breath, this time it is because of the anxiety of not knowing whether the relevant authorities will finally change their hazy ways in managing the environment. Appropriately enough as we celebrate the Quality month of October, ‘Quality Air’ must top the agenda this time and all the time! After all air quality is fundamental to a healthy natural and human environment. Air pollution in any significant amount like during the time of haze can make life not only unpleasant but also dangerous to human health.

At this juncture, it is worthwhile to recall that barely four months ago, on 23-27 June 1997, the 19th United Nations General Assembly Special Session (UNGASS) to Review the Implementation of Agenda 21 concurred that the state of the global environment has continued to deteriorate and the trends are be coming worse. This is despite some successes in a number of countries in curbing pollution and decelerating the rate of resource degradation. Increasing levels of pollution threaten to exceed the capacity of global environment to absorb them. Indeed progress has been slow, with increased obstacles to the implementation of commitments made during the United Nation Conference on Environment and Development at Rio de Janeiro, in Brazil some 5 years ago. In fact, the goal of spending 0.7 per cent of GNP to improve the environment - agreed upon at the 1992 Earth Summit - was far from being attained in many countries.

At about the same time, the World Health Organization (WHO) issued a warning that 25 per cent of preventable illnesses are caused directly by environmental degradation. This was unveiled in a special report that was prepared for UNGASS. The report claimed that one billion people were exposed to severe air pollution, and one million died each year because of it. The report blamed an unhealthy environment for 60 per cent of severe respiratory illnesses and 90 per cent of diarrhoeal diseases. The environment too was allegedly

responsible for some 10 per cent of mental illnesses, in particular those brought on by housing conditions and lead poisoning, according to Wilfried Kreisel, the executive director of WHO for the environment. [For the further analysis of the impact of lead poisoning, please refer: Dzulkifli Abdul Razak, ‘Heeding the ‘smog’ signal about lead poisoning,’ PRN8099 (No. 12), April 1997]

At that time, to most Malaysians the link between health and the environment was the least of our concern in this country. Who would have thought that cases of simple ailments of the respiratory functions could increase by leaps and bounds over such a short period of time as the environment degenerates. Forest fires that in the past were just child’s play have now razed many millions of hectares in the areas of Kalimantan and Sumatera, and play havoc with our everyday life.

Even then there are those who accused the UN agency of exaggerating the problems. But rightly or wrongly for us the suffocating incident of the past months convinced us that health consequences arising from environmental degradation can be no exaggeration. It is no exaggeration that we are rudely awakened by an environmental nightmare - unthinkable just months ago. It is no exaggeration that the number of people falling ill shot up dramatically due to the haze. It is also no exaggeration that we have let down our guard for too long, making it much easier for the country to be overwhelmed by smoke, particles, haze and other obnoxious fumes.

In 1994, Malaysia had an inkling of the dangers of haze due to forest fires in Kalimantan. But we did little and now have little defense against the ever-deteriorating environment. We could have learnt from the tragedy of the 1952 London smog, namely the action taken to promulgate and enforce the Clean Air Act of 1956. The action has been "so successful that smoke and sulphur dioxide concentrations in our [British] cities fell progressively through the following three decades" claimed a medical authority in a recent issue of the Journal of the Royal Society of Medicine. Such able decisions seem to be much more a question of political will rather than anything else.

As remarked by Wilfried Kreisel, "The primary factor in my view is really political will to change the situation. We do have the knowledge, we do have the means, but we don’t have the political will." Ironically today, the haze is costing the government unnecessary financial burden, maybe in the billions. Now with the concurrent ‘economic haze,’ it will cost us that much more put things back to where it was, let alone ensure us of clean and salubrious air.

Time to mend our ‘hazy’ ways

While for some the worst perhaps may be over, the full implications of the haze on health until today is still largely uncertain. Despite the fact that the numerical interpretations of Air Pollutant Index (API) are often in health terms, the general impression it gives is more about ‘impediment to visibility’ mainly as a result of suspended dusts, debris and particles accumulating in the thickening air, and little beyond that. The index, being a composite value, unfortunately do not make direct references to the more devastating components like sulphur oxides, atmospheric oxidants (ozone, nitrogen dioxide), carbon monoxide and heavy metals like lead, even though the API allegedly takes into account most of these toxic substances.

As such, to date we do not yet know the exact toll the haze is costing us in terms of health. Although the number of people suffering from pollution-induced ailments has reportedly increased, we are still to account for those who would be suffering from long-term chronic eventualities, unless the exact chemical composition of the haze is precisely spelt out.

For example, long term exposure to ozone leads to scarring of lung tissue and lowered lung efficiency. In fact ozone has been implicated as the second most common cause of lung diseases affecting terminal bronchioles and alveolar ducts. A similar health effect has also been reported for the other gases like sulphur dioxide and nitrogen dioxide. Unfortunately, as this commentary is written, such information is still not forthcoming even on days considered "unhealthy’ or even "hazardous" as in the case of Kuching with API in the 800s.

What this could mean is that some of us may have our lungs filled with deposits of toxic particulate which eventually will cost us our health. Let us not forget that in many disasters involving air pollution around the world, lives have been lost. The London smog of December 1952, for instance, was associated with some 4,000 excess deaths in just one-week. Although the circumstances may be quite different, but carry on the way we are, the message will be the same: air pollution can kill especially when it contained hazardous chemicals.

It is therefore appalling to note that during near emergency situations (or even when ‘Emergency’ was declared in the case of Sarawak) such detailed vital pieces of information are still being withheld from the public. A report carrying the headline: No need to make API details public: Official (Sun, Sept.18) was at the very least shocking. It is even more surprising to read that even the Health Ministry was denied such details of the index and "will only be released to government agencies on request."

One would have expected in a situation such as the haze, where there are no clear immediate solution in sight, the public should have been informed to the fullest as to nature of the dangers that are or could be plaguing them. This is to allow them to make informed decisions pertaining to their own health and that of their immediate family. Relevant authorities have the obligation to ensure that this is done in a systematic way, purveying the information in clearly digestible form so that it will not incite unnecessary panic and overt aggression. The public has the right to know and be aware because their health is ultimately their own responsibility, and to deny them of the vital information is to deny them of their rights.

In this regard, PRN issued a statement that was carried by the same newspaper on the same day and page to express its concern. In fact, as late as last year, through its official bulletin, PRN8099 (No. 10), October 1996, the Centre emphasised the following point:

"Noxious fumes, gases and other pollutants spewed into the air are known to affect health in a multitude of ways, especially those suffering from asthma and other respiratory illnesses, as well as causing undue irritations to the skin and eyes. This time, unfortunately, the damage could extend beyond the workplace, affecting the population at large. Water and land pollution further adds to the already deteriorating situations notwithstanding the efforts and measures put in place by the various government agencies. [Ed: It is obvious that air pollution is yet another dimension that ought not to be missed in this discussion.

In view of this, we further suggested,

"…that there are information that could be shared by all parties….. The out-moded attitude that "information is power" can only serve as a stumbling block and must be dispensed away in the interest of health. It is important to reiterate that in matters of health care to derive "power" by wholesale embargo (read "sulit"), or hoarding pertinent bits and pieces of information that could in essence improve and better health outcomes is at least unprofessional if not outright unethical."

The commentary too, noted that: "While ‘secrecy’ has its place in protecting the rights of the individuals, it must not be allowed to overshadow the common good that could be derived in making such data or information available." Only then can we claim to have the health interest of the people at heart.

The ‘poverty’ and ‘greed’ factors

In any case, at the very critical moments during the haze, it is indeed very heartening to hear the assurance given by the Deputy Prime Minister that the health of the people must come first. It clears the air as which direction we are heading, especially in difficult moments where little else seems important. Such expressed concern has a direct bearing on the less fortunate group of the population given the fact that they are invariably forced to stay in the "unhealthy" environment; either due to the call of duty, or even more so because of the need to supplement their meager income, what now with the falling ringgit. They are the first to feel, not only the immediate impact of economic loss due to the haze, but also the ill consequences due the loss of good health. The news report that more policemen in the Federal Territory fell sick at the end of September underscored the many dilemmas faced by one such group during the current period of environmental degradation. In short, while ensuring that the environmental standards are maintained, and hence the health of the people, it is also important to consider their economic needs.

Moreover, the WHO was quoted as saying that more than 90 per cent of people living in "absolute poverty" were in developing countries, where those with the least opportunities were concentrated in environmentally poor areas. This implies that, poverty too has a major role in environmental degradation. In some cases, it could lead to deforestation as noted recently - especially when they are hired to slash-and-burn. A number of minor incidences could also be associated with the state of poverty of the people where they are more prone to resort to any means of survival regardless of the environmental consequences.

The other dimension in the equation is of course the question of "absolute greed" - involving people who never know enough irrespective of the end results. How significant are they in contributing towards environmental degradation needs no elaboration. This time around the evidence is fairly clear. The forest fires in Indonesia involve no longer just the small-time shifting cultivators but also a number of giant plantation owners some of whom have roots in this country.

In this regards, the news report quoting the Minister of Science, Technology and Environment to have asked the Chief Justice to impose maximum penalty on people bent on causing pollution could not have come at a better time, provided it is carried out without fear or favour. Indeed, "heavier penalties and speedy hearings will serve as a deterrent" and undoubtedly is a necessary step in a rapidly industrialising country like ours. This is especially so in shaping a more transparent and socially responsible generation of business community as often voiced out by the Deputy Prime Minister himself.

In fact, there are those who argued that the irresponsible acts of environmental pollution leading to a national disaster as it is today, is no less than an act of a heinous crime. The reason is simple enough. The current assault on the environment has a number of parallels to the sarin-poison attack that took place at the Tokyo subway in March 1995. These two seemingly unrelated incidences have very much in common in terms of health consequences and the way that people are put in a life-threatening situation.

Much like those who are trapped in the Japanese subway and having to inhale the unknown gas after being released clandestinely, Malaysians in general are equally ‘trapped’ in the haze forcing them to inhale the unhealthy fumes together the mysterious concoction contained in them. So much so, as admitted by the Prime Minister when declaring that Sarawak is in the state of emergency, we virtually have nowhere to go even though as the situation threatens life much as in the sarin-gas attack. In other words, the whole country could be placed on ransom arising from an environmentally criminal act.

In view of this a maximum fine of about RM 100,000 is not sufficiently high enough to match the ‘environmental crime’, committed by big-time polluters. Remember the company that dumped 4l drums of super-toxic cyanides in Pangkor Island a couple of years ago? How much has the company got to pay eventually? No more than a token sum and a day stay in jail. This is a case that could involve 7 million death should the incident turned into a national disaster. As such RM100,000 to many of those who are bent on testing the limits of the law is just that - a token sum. So we are back to square one.

Cleaning up our act in cleaning the air

To make it worst, more often than not, we do not put our money where our mouth is. Clearly, self-discipline and voluntary regulations do not work in the attempt to secure a safe environment. And we have really a long way to go in demonstrating how serious we are. Sadly, we still need to exercise punitive measures before there can be any long lasting impact on our carefree attitude, including that of some Ministers.

The solution plainly lies in putting our words into action. As the axiom goes - action speaks louder than words! It does not matter who says what, and in what capacity; but if he does not "walk the talk" then the signals send to those polluters, and other criminals for that matter, are pretty clear: we are not too serious in whatever we do, especially if top-ranking governmental officials are involved. We are good in only providing lip services and assigning blames. It works wonders in pacifying irate Malaysians who would soon forgive and forget! Then all of us can go back to our old habits even though that tantamount to killing ourselves. We are proven as a nation of kind-hearted people, fond of giving in (read: endless ‘grace’ periods) until a perfectly manageable situation yields tragic results.

As noted by the World Bank president recently, it is not the question of money in attempting to solve the situation that he described as "terrible" and "tragic." It is more the question of attitude. It looks like we Malaysians have always to learn the hard way and then forget it as soon as things seem normal again. This is apparent across the board beginning with the common man on the streets to law enforcers and decision-makers as well as policy planners.

Many examples could be cited. The most recent perhaps is the Clean Air Action Plan, which despite being proposed by an authoritative governmental agency – DOE, was shelved for some reason. Hence, if we see fit to compromise on guaranteeing our citizens "clean air" - a vital commodity which is rapidly dissipating, then we seem to have deserved what we got. Now assuming that the Action Plan hurriedly got implemented, we have just polluted the little we have left. In other words, more resources (perhaps in the millions) will be required and invariably the little savings that we made are already up in smoke.

Thus we must immediately change our hazy ways and clear the air as soon as possible. The statement of the Minister of Science, Technology and Environment must be really seen to make a difference this time. Lest it will be just another good old lip service once again. Over the years the ministry has been on record issuing various directives to strictly enforce anti pollution measures each time the haze strikes – but each time the situation gets worse. We have suffered enough as a nation and we cannot be holding our breath forever. It is time to clean up our act in ensuring our rights to a clean and healthy environment


PRN CONSULT Recently, FDA requested the withdrawal of fenfluramine, dexfenfluramin and "fen-phen" drugs in the use for treatment of obesity.

 Review on ADVERSE EFFECTS OF ANTI-OBESITY Drugs

Mohd Isa Abd Majid, Ph.D

Many serious disorders are associated with severe obesity. These serious disorders have led to a reduction in longevity among the moderate to severe obese individuals as compared to non-obese persons. A number of diseases associated with obesity are shown in Table 1. Obesity also complicates the condition of the disease faced by an individual. As an example, massive obesity during pregnancy was found to be associated with a sevenfold increase in toxemia, a tenfold increase in diabetes, and a twofold risk of maternal mortality. In addition, substantial excess weight is also associated with altered pharmacokinetics of certain drugs.

Table 1: Diseases associated with obesity

  • Cerebrovascular disease
  • Congestive heart failure
  • Diabetes
  • Gall bladder disease
  • Flat feet
  • Hiatus hernia
  • Hyperlipidemia
  • Hypertension
  • Intertriginous dermatitis
  • Obstetric complications
  • Osteoarthritis
  • Respiratory distress syndrome (Pickwickian)
  • Varicose veins

What are Anti-Obesity drugs?

Ideally, an anti-obesity drug (ASD) should be safe and acceptable for long-term administration. It should also produce a dose-related reduction in body fat, and spare the body from protein loss and the loss of other tissues. A drug is considered effective in treating obesity based on several criteria which includes a weight loss of at least 5% of the initial body weight and maintenance of that loss; a reduced body weight through a reduction of body fat with a sparing of body protein; improvement of other associated diseases such as hyperglycemia, hypertension, dyslipidemias and a minimum of tolerable side effects and low abuse potential.

Appetite suppressant drugs are normally prescribed as a last resort and only to patients who are clinically obese and respond to them. The appropriate choice for the use of such drugs as defined by an expert group in United Kingdom is patients with a body mass index greater than 30 kg/m2 who fail to reduce their weight by 10% after three months of determined effort through diet, exercise and behaviour change. These slimming pills are usually prescribed for three months and with a continuation of these drugs for patients who have achieved a 10% reduction during that time and did not regain more than 3 kg of body weight. However, a report also mentioned that by continuing the medication for more than 12 weeks, only one in nine patients is likely to benefit from longer term prescription.

Amphetamines-like drugs

Amphetamine was first used clinically in the mid-1930’s to treat narcolepsy, a rare disorder resulting in an uncontrollable desire for sleep. After the introduction of the amphetamines into medical practice, the number of conditions for which they were prescribed multiplied as did the quantities made available. In the United States, they were sold initially without prescription as inhalers and other over-the-counter preparations. As the abuse of the inhalers became popular among teenagers, restrictive measures were introduced to limit its usage. Besides this, the empiric reduction for the central nervous system (CNS) properties of the amphetamines have led to chemical alterations of the original molecule in the hope of creating a drug with appetite-suppressant activity without the potential for abuse. Thus alterations of the side chain and ring structure of amphetamine have produced drugs with appetite-suppressing effects (e.g., benzphetamine, phendimetrazine, diethylpropion, phentermine) but markedly lower risks for CNS stimulation and abuse.

As at present, the medical use of amphetamines is limited to narcolepsy, hyperkinetic behavioral disorders in children, and certain cases of obesity-as a short-term adjunct to a restricted diet for patients refractory to other forms of therapy.

Anorectic drugs

A number of drugs have been manufactured and marketed to replace amphetamines as appetite suppressants. Examples of anorectic drugs are benzphetamine, chlorphentermine, clortermine, diethylpropion, fenfluramine, mazindol, phendimetrazine, phentermine. They produce many of the effects of the amphetamines but are generally less potent. Abuse patterns of some of them have not yet been established, but all are controlled because of the similarity of their effects to those of the amphetamines. Fenfluramine differs somewhat from the others in that at low doses it produces sedation. These chemical derivatives of amphetamine can be largely divided into two groups namely the noradrenergic and the serotonergic drugs. See Table 2 for overview of these drugs.

Noradrenergic drugs

Initially, no clinical need exists for noradrenergic drugs in the treatment of obesity due to the abuse of their chemical analogues, the amphetamines. The non-amphetamine anorexiants are indirect-acting sympathomimetic amines. Except for mazindol, phenmetrazine and phendimetrazine, all drugs under this category are phenethylamine (amphetamine-like) analogues. They suppress appetite by direct stimulation of the satiety center in the hypothalamic and limbic regions of the brain. Diethylpropion and phentermine act primarily on adrenergic pathways, whereas mazindol acts on both adrenergic and dopaminergic pathways. Besides the main pharmacological action, these drugs also produce CNS stimulation and blood pressure elevation.

The more common adverse effects of these anorexiants include a false sense of well being, irritability, nervousness or restlessness, and insomnia. After these stimulant effects have worn off, unusual fatigue or weakness, drowsiness, trembling, or mental depression may occur. Less common adverse effects of the anorexiants include blurred vision, impotence, heart palpitations, and dizziness or light-headedness.

Serotonergic drugs

Serotonergic drugs offer a different approach for the treatment of obesity. These drugs act by partially inhibiting the reuptake of serotonin and releasing serotonin from nerve endings. The process of satiation is believed to begin with the ingestion of dietary starch from foodstuffs that are converted to sugar. Sugar in turn stimulates the pancreas to secrete insulin, and, subsequently, insulin raises the levels of the amino acid tryptophan in the brain. Tryptophan is a precursor of serotonin, and serotonin regulates mood, producing a sense of well being. The increase of serotonin in the neuronal cleft is thought to be responsible for satiation, thereby reducing food intake. Examples of drugs acting on the serotonergic system include fluoxetine, fenfluramine and dexfenfluramine.

Fluoxetine

The link between serotonin and eating disorders was observed during clinical trials of the serotonin reuptake inhibitor fluoxetine when patients who took it demonstrated weight loss. In addition, high-carbohydrate snacks are known to improve mood, and premenstrual women and smokers trying to quit also tend to eat more carbohydrates, which seems to increase mood.

Studies have demonstrated that serotonergic drugs help overeaters reduce the tendency of taking snacks and can induce weight loss in a short period of time. Weight loss gradually becomes slower after the first few months of therapy that then minimised after 6 to 10 months. Following this, the body weight would be maintained only as long as the patient remains on the drug. Weight gain usually occurs when the drug is discontinued which highlight the need for an integrated program of behavioral modification through diet and exercise. The recommended daily dose of fluoxetine for obesity is 60mg which is triple the recommended dose for depression. Such a high dose shows the possibility for toxicity to occur under its use for weight control that could cause anxiety, nervousness, diarrhea and drowsiness.

Fenfluramine and Dexfenfluramine

The dose for fenfluramine is usually 60-120 mg/day although a higher dose of 2mg/kg per day have been recommended. After oral ingestion, about half the dose is absorbed in 1 hour; plasma half-life is slow at 24 hours. Fenfluramine is converted in the liver to norfenfluramine whose plasma half-life is twice as long. It is excreted in the urine mostly as 3-trifluoromethylhippuric acid. In man, plasma concentrations of about 200ng/ml (1m mol/l) correlate with the best rate of weight loss. Fenfluramine is taken up by the adipose tissue and this may be the basis for the long washout periods that occur after the drug is stopped in patients with obesity. Weight loss occurs over about 20 weeks but reaches a steady state at about that time; the amount lost is no more than can be achieved from equivalent food restriction, so the drug does not increase energy consumption. Fenfluramine enhances glucose uptake by peripheral tissues and may reduce hepatic glucogenesis without increasing insulin release.

Fenfluramine is a racemic mixture of D- and L-steroisomers. Dexfenfluramine is the D-isomers of fenfluramine which is primarily anorectic based on animal studies, in which dose for dose weight loss with pure dexfenfluramine may be twice that with fenfluramine. The L enantiomer has a longer half-life and produces some of the untoward side effects of the racemate. The appropriate dose of dexfenfluramine is 15-30 mg twice daily-i.e. half that of D,L-fenfluramine. Like that of fenfluramine, dexfenfluramine’s mechanism of action appears to be influencing serotonin pathways that effect serotonin release and slow its depletion. As a consequence, carbohydrate craving is reduced and patients feel satiated.

In contrast to the CNS stimulation by the noradrenergic agents, fenfluramine and dexfenfluramine used as a single agent produce CNS depression. Doses of fenfluramine within 80 to 400 mg have been associated with euphoria, derealization, and perceptual changes. The most common adverse effects associated with fenfluramine and dexfenfluramine are diarrhea, drowsiness, and dry mouth. It is thought that dexfenfluramine might be used in "fen-phen" therapy because of its milder adverse effects. However, this combination was still cautioned because data in humans are limited. Also, dexfenfluramine has been shown to cause a rare adverse effect through primary pulmonary hypertension. The incidence of this serious condition in the general population is estimated at 1 to 2 cases per million adults per year if the drug is used for longer than three months. The symptoms of this complication include vague chest discomfort or shortness of breath.

Another precaution noted in the use of dexfenfluramine is the risk of brain damage. In primates and rodents, dexfenfluramine has been demonstrated to exhibit this neurologic toxicity by causing a massive release of serotonin from neuron to the extent that when the compound is reabsorbed back into the neuron and metabolized at once, neurotoxic oxidation intermediates are produced. These intermediates then destroy the neuron. Thus from this experience, a racemic mixture of fenfluramine was recommended as it gives credence to its safety.

UPDATE: Withdrawal of Fenfluramine & Dexfenfluramine

Based on the latest development, the Food and Drug Administration has issued an instruction on 15th September 1997 to manufacturers of fenfluramine and dexfenfluramine to voluntarily withdraw both treatments for obesity from the market. The action was taken based on new findings from doctors who have evaluated patients taking these two drugs with echocardiograms, a special procedure that can test the functioning of heart valves. These findings indicate that approximately 30 percent of patients who were evaluated had abnormal echocardiograms, even though they had no symptoms. This is a much higher than expected percentage of abnormal test results. However, FDA yet is not requesting the withdrawal of phentermine, the third widely used medication for obesity.

"Fen-Phen"

This pharmacologic approach was developed in the early 1990s to treat obese patients using lowers doses of the serotonergic drug, fenfluramine (60 mg) and the noradrenergic drug, phentermine resin (15 mg) rather than usual doses when given alone (i.e., fenfluramine 120 mg or phentermine 30 mg). The fenfluramine stimulates the release of serotonin and inhibits its reuptake by afferent neurons, reducing the feelings of agitation and deprivation often associated with hunger. The phentermine enhances levels of dopamine and norepinephrine, which affect blood flow, heartbeat, movement, and reaction to stress.

The use of this drug combination for obesity therapy was originally described by Weintraub et al (1992). The study initially enrolled 121 men and women between the ages of 18 and 60 who were 30% to 80% above their ideal body weights. None of the subjects had hypertension, diabetes mellitus, other long-term conditions, or were taking chronic medications. Participants were randomly assigned to two groups-one group used the combination fenfluramine/phentermine; the other group used a placebo. All subjects began an exercise program, diet, and behavior modification before starting the medication. After 34 weeks, the group taking the combination therapy lost an average of 14.5 kg (about 16% of their body weight), while the placebo group lost an average of 4 kg (about 4.6% of their body weight). Those subjects who lost weight in the study did so in the first 24 weeks of treatment.

The adverse effect of "fen-phen" was noted to be dry mouth, which some patients experienced for four months of therapy. The severity of this effect and the number of complaints diminished over time. Gastrointesitnal symptoms (e.g., abdominal pain, nausea, metallic taste, diarrhea, and constipation) were also common during treatment. However, after four weeks of "fen-phen" therapy, complaints of diarrhoea diminished. Fatigue was also reported in the first two weeks, but then diminished to low levels. Other CNS complaints (e.g., drowsiness, dizziness, nervousness, sadness, increased dreaming) persisted up to six weeks before decreasing. The use of ‘fen-phen" in obesity is an "off-label" indication.

UPDATE: Fen-Phen Withdrawal

The recent withdrawal of this combination from the market by the US Food and Drug Administration is based on the significant incidence of valvular heart disease among fen-phen users. The agency has received reports of abnormalities of mitral, aortic and tricuspid valves in women aged 30 to 72 years who took the drugs for 12 months on average. The valve damage seen in these users is characterised by a glistening white macroscopic appearance and the damage was thought to be related to high circulating serotonin concentrations. At the microscopic level, endothelial fibrosis is seen which causes the valve to malfunction. According to the evaluation done on these patients, no previous cardiac diseases were noted from them and the damage seen was similar to that of malignant carcinoid or ergotamine toxicity.

Others

Phenylpropanolamine

As a sympathomimetic, phenylethylamine derivative, phenylpropanolamine (PPA) is a direct agonist of postsynaptic alpha- and beta-adrenoreceptors and acts indirectly by increasing noradrenaline concentrations from sympathetic nerve endings. It is well absorbed from the gastro-intestinal tract and has an elimination half-life that ranges between three and four hours. Although 80% of an oral dose is excreted unchanged in urine, a portion of the drug is hepatically coverted to noradrenaline.

The exact mechanism by which PPA exerts its anorexic effect is unknown. One theory is that it may activate post-synaptic alpha-1 adrenergic receptors within the medial hypothalamic paraventricular nucleus. Stimulation of this nucleus may activate the human satiety mechanism. Other research has noted that PPA can increase energy by accelerating the breakdown of fat tissue, an effect similar to that of ephedrine, which may account for its efficacy in weight loss.

Serious reported adverse effects of PPA include cerebral infarction, intracerebral hemorrhage, seizures, acute interstitial nephritis, and cardiac arrhythmias. In the US, FDA permits a PPA dose of up to 37.5 mg in immediate-release products and up to 75 mg in sustained-release products with a maximum daily dose of 75 mg.

Benzocaine

In many obese persons, constant snacking is characteristic of the "oral syndrome". The rationale for using benzocaine for weight loss lies in its ability to decrease taste sensations by numbing the oral cavity and the gastric mucosa. The drug has been claimed to decrease the sensitivity to sweetness, discouraging snacking and decreasing caloric consumption. Benzocaine is delivered in the form of gum, wafers, or hard candy to be used between meals. This keeps the patient orally active. Generally, a dose of 3 to 15 mg in gum, lozenges, or candy just prior to a meal was generally appropriate. A daily dosage of greater than 45 mg is discouraged for fear that topical anesthesia may impair swallowing, increasing the danger of aspiration. Also, numbness of the tongue or buccal mucosa may increase the risk of biting trauma.

CONCLUSION

Successful approaches to the management of obesity are often difficult and pose a significant challenge to individuals interested in reducing their weight. There is no standard treatment that is effective in most or even a large fraction of obese patients, and weight reduction programmes must be designed to fit the personality, life-style, and health status of each patient. Success depends on the individuals motivation, on behavioral modification, and on the establishment of reasonable goals and expectations. Crash programmes and demands for extreme alterations from established life-styles are uniformly unsuccessful in the long run and potentially dangerous.

A comprehensive weight reduction program incorporates components of caloric restriction, exercise, behavioral modification and possibly pharmacologic and invasive approaches. The critical factor is that caloric expenditures must exceed caloric demands, and that permanent change in caloric intake must be achieved to maintain desired weight.

TABLE 2: DRUGS USED IN TREATMENT OF OBESITY

DRUGS

(Trade Name)

SIDE-EFFECTS

CNS

Others

Abuse* Potential

Comments

Typical daily dosage

Noradrenergic Agents

Source: MIMS/DIMS, Malaysia, 1st issue, 1997

Phenylpropanolamine

Moderate

Increased blood pressure (doses > 75mg per day); typical noradrenergic side-effects

Low

No trials over three months duration; weight loss not enhanced by combining with benzocaine.

25mg three times daily.

Extended release: 75mg once daily

Diethylpropion

Moderate

Typical noradrenergic side-effects

Moderate

Side effects may be less frequent than with other noadrenergic agents

25mg three times daily

Extended release: 75mg once daily

Mazindol

(Teronac)

High

Typical noradrenergic side-effects; dry mouth, sweating

Moderate

Enhanced insulin secretion; may have hypolipidemic effects independent of weight loss

1mg three times daily

2mg once daily

Phentermine (Duromin, Adipex Retard, Ionamin, Panbesy)

Moderate

Typical noradrenergic side-effects

High

No apparent dose-response relationship; alternate-month therapy as effective as continuous therapy

15 to 37.5mg once daily

Benzphetamine

High

Typical noradrenergic side-effects

High

-

50mg one to three times daily

Phendimetrazine

High

Increased free fatty acids and/or glycerol; typical noradrenergic side-effects

High

-

35mg two or three times daily

Extended release: 105mg daily

Serotonin Agents

Abuse potentials are relative; all anorectics have a low potential for abuse when used under medical supervision

Fenfluramine

(Dietoff, Ponderax)

May cause depression if stopped abruptly; mildly sedating (drowsiness, lethargy); gastrointestinal symptoms

None

Low

Increased risk of primary pulmonary hypertension; decrease blood glucose by non-insulin-dependent mechanisms; avoid if history of depression; may be preferred if history of anxiety

20 to 40mg three times daily

Fluoxetine

(Prozac)

Drowsiness, gastrointestinal symptoms, nervousness, insomnia, headache

None

None

Not FDA-approved for weight loss; some patients regain weight after 16-20 weeks; produces weight loss in normal as well as obese patients; produces weight loss in depressed patients

10 to 20mg daily

Dexfenfluramine (Adifax, Siran)

Diarrhoea, dry mouth, drowsiness; upon discontinuation: asthenia, headache, depression

None

Low

Increased risk of primary pulmonary hypertension, especially with use longer than three months (rare, but serious); should not be used concomitantly with MAO inhibitors or serotonergic agents

15mg twice daily

 


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