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					                                                                                   Icarus Wan Wai Chan
                                                                                         PRN: 41227206


What adverse side effects should be anticipated (and why) when developing any
novel centrally acting anti-obesity agents.

Obesity has become a global epidemic, particularly in developed countries, where food is easily

accessible. Besides a cosmetic issue, obesity also significantly increases the rate of co-morbidity,
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such as cardiovascular disease (hypertension, pulmonary embolism, congestive cardiomyopathy,

coronary heart disease); neurological diseases (stroke, meralgia parethetica); respiratory disease

(obstructive sleep apnea, asthma) and diabetes. Anti- obesity agents in the past often come with

severe side effects (e.g.: Fen-phen, amphetamine). Therefore it is necessary to develop a novel

anti-obesity agent with reduced side effects and improved efficacy, so as to effectively control the

rapid spread of the epidemic.



The central nervous system (CNS) regulates food intake and energy expenditure by a well-
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balanced homeostatic feedback loop. The hypothalamus is a critical site for this function. This is

indicated in the 1940s and 1950s by degeneration studies. Hyperphagia was induced by

destruction of the hypothalamic ventromedial, paraventricular and dorsomedial nuclei. The

hypothalamus is therefore a target acting site for centrally acting anti-obesity agents. There are

many receptors in the hypothalamus which is responsible for energy homeostasis and food intake,

namely noradrenergic receptors, 5-HT2c serotonin receptor, dopamine receptors, and leptin

receptors. All of which are target sites for centrally acting anti-obesity agents. These receptors

can also be found in other tissue or organs beside the CNS. By activation the receptors elicit

different responses, and thus give rise to varieties of side effects. Current centrally anti-obesity

agents often reported with the following side effects, including tachycardia, hypertension,

insomnia, restlessness, palpitation, stroke, or even death. On the other head, there are subtypes

for these receptors. Activation of different receptor subtypes may give different responses.




1
  Current and investigational antio-besity agents and obesity therapeutic treatment targets,
  Harold E. Bays, Obesity Research Vol 12 No. 8 August 2004
2
  The hardship of obesity: a soft-wired hypothalamus,
  Tamas L Horvath, Nature neuroscience Vol 8 N0. 5 May 2005



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                                                                               Icarus Wan Wai Chan
                                                                                     PRN: 41227206


Some centrally acting anti-obesity agents reduce food intake by increasing satiety and suppress

appetite (appetite suppressants), and the others work by increase metabolism and energy

consumption (metabolism stimulants). Each of them has different working mechanisms. Side

effects and be anticipated in accordance of their working mechanism. In the following, some

examples of withdrawn centrally acting anti-obesity agents are given, and from the side effects

they gave we know what side effects we have to anticipate.



Fenfluramine and its stereoisomer, dexfenfluramine (together they are called Fen-phen), are

appetite suppressants categorised as serotonin and noradrenalin re-uptake inhibitors (SNRIs).

They enhance serotonin and noradrenalin level acting in synaptic cleft. It stimulates brain

serotonin release and block serotonin reuptakes. This effect results satiety and suppresses
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appetite. The drugs were withdrawn from the market at 1997 due to significant side effects.

Patients administered with Fen-phen were evaluated with echocardiograms to examine their

heart valves function. Finding indicates 30% of the patients show abnormal echocardiograms

even they show no symptoms. This suggests a potential risk of heart valve problems. 60 cases of

heart valve disease were reported, and 24 cases of rare valvular disease were reported in June

1997 from women who took Fen-phen. Thickening of leaflet and chordae tendinar are distinctive

valvular diseases seen amongst patients who took Fenfluramine. As mentioned above, receptor

consists of subtypes, and even same subtypes elicit different responses if they were located in
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different tissues. Roth 2007 suggests that fenfluramine and its active metabolite norfenfluramine

stimulate serotonin receptors, with norfenfluramine in particular a potent stimulant to 5-HT2B

(serotonin) receptors. Serotonin receptor in the CNS produces feel of satiety and supresses

appetite. The receptor is also abundant in heart valve and it regulates growth and cell division.

Roth suggests that the thickening of leaflet and chordae tendinar is due to inappropriate

stimulation of valve cell division. Roth argues that this phenomenon is also seen in other drugs

that act on 5-HT2B receptors. Fenfluramine is also claimed to cause pulmonary hypertension.

3
    http://www.fda.gov/cder/news/phen/fenphenpr81597.htm
4
    Drugs and Valvular Heart Disease,
    Bryan L. Roth, The New England Journal of Medicine Vol 356: 6-9 Jan 2007




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                                                                                  Icarus Wan Wai Chan
                                                                                        PRN: 41227206


5
    Electrocardiographic evidence shows that patients were developed with pulmonary hypertension

when taking fenfluramine, and it disappeared after withdrawal. Other side effects of fenfluramine
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includes nausea, vomiting, profound leathargy, diarrhoea, tiredness, dry mouth, and dreaming.

The other component of Fen-phen, dexfenfluramine, was claimed to induce primary pulmonary
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hypertension and neurotoxicity.           A study in 1996 showed the drug increases the risk of

developing primary pulmonary hypertension from 1-2 to 23 cases per million people per year.
7
    Reseachers from Johns Hopkins School of Medicine claim that dexfenflueramine may be

neurotoxic. They gave squirrel monkeys dexfenfluramine subcutaneously or orally, and they

found reduced serotonin concentrations in the frontal cortex. They suggest the result indicates

axonal neuropathology, and concern that this is also the case happens in human, that

dexfenfluramine has toxic potential toward brain serotonin neurons.



Therefore, when developing novel serotonergic appetite suppressants, we have to take

precaution on the drug’s binding specificity on serotonin receptors, the drug’s localisation that the

drug is confinded to a specific acting area and not activating receptors elsewhere besides its

target, and the effect of metabolite the drug produces, in order to reduce the drug’s side effect

and increase its efficacy. We also have to take precaution of neuroplasticity. Serotonergic

appetite supressant, like other neuronal drugs, may induce neurotoxicity and irriversibly change

the neuronal physiology and may leads to neuronal dysfunction.



With serotonergic appetite suppressant, it works by increase serontonin release and block its

reuptake to increase serotonin avaibility in the synaptic cleft. We may anticipate side effects

mentioned above.




5
  Pulmonary hypertension and fenfluramine
  J G Douglas, British Medical Journal Vol 283 october 1981
6
  Plasma fenfluramine levels, weight loss, and side effects
  J A Innes et al, British Medical Journal, 1977, 2, 1322- 1325
7
  Balancing the risks of anti-obesity pills
  Janet Fricker, The Lancet Vol 349 May 1997



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                                                                                      Icarus Wan Wai Chan
                                                                                            PRN: 41227206


Another class of centrally acting anit-obesity agent is cannabinoid receptor (CB1) antagonists.
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    Cannabinoid CB1 receptor is a G protein coupled receptor located in the CNS and in various

peripheral tissues. It is activated by endocannabinoids (ECBs). Agonism of CB1 receptor inhibits

neurotransmitter release in central neurons and trigger expression of hypothalamic anorexigenic

and orexigenic mediators, which gives signal of hungryness. Study found that over stimulation of

cannabinoid CB1 receptor is associated with nicotine dependence, fat accumulation and

excessive food intake. Rimonabant (Sanofi-Aventis) is a CB1 receptor antagonist. By reduces the

central ECB system and inhibit agonism of CB1 receptor, it diminishs the anorexigenic and
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orexigenic mediators, so as to prevent eating and weight gain. Rimonabant gives a variety of

side effects, such as upper respiratry tract infection, gastroenteritis, hot flush, nausea, diarrhoea,

vomiting, hyperhidrosis. Amongst them, psychiatric disorders and nervous system disorder is of

main concern. Commonly, patients experience depression, anxiety, memory loss and

hypoaesthesia. This is another example of side effect we have to anticipate when developing

novel centrally acting anti-obesity drugs. By administrating patients with anti-obesity agents, not

only weight loss we aim for, but also to induce patient a healthy diet habbit and life style. Centrally

acting anti-obesity agents work by altering neurotransmitters in the CNS, it may alter patient’s

psychology besides their appetite or metabolism rate. We do not want to induce any psychiatric

disorder to patients. Moreover, side effects such as depression may lead patient to compulsive

eating disorder, and that’s against the origin intention of taking anti-obesity drug. Again,

neuroplasitcity is another main concern, that body has an adaptation system. For example, by

blocking cannabinoid receptors, it may lead to increase number of postsynaptic receptor. If the

drug is withdrawn, and with the increased number of receptor, it increases the response.

Therefore patient would have greater feeling of hungryness and increase they food intake, which

may lead to weight regain. Patients regain weight may result depression or other eating disorder

such as bulimia. So, when developing centrally acting anti-obesity drug, we should prevent

possiblity of such negative cycle.


8
  The obesity pipeline: Current strategies in the development of anti-obesity drugs
  Dunstan Cooke, Nature reviews, Drug discovery, Vol 5, November 2006, 919
9
  http://www.sanofi-aventis.co.uk/products/Acomplia_SPC.pdf



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                                                                                  Icarus Wan Wai Chan
                                                                                        PRN: 41227206




Bupropion, an antidepressant as well as a centrally acting anti-obesity agent, which is

amphetamine like substance belongs to aminoketone class. Bupropion works by selectively

inhibit dopamine and noradrenalin reuptake to produce anoretic feeling. It was trade under the

name of Wellbutrin, and withdrawn from market due to clinical evidence shows it is 2 to 4 times

greater to induce seizure compared with other antidepressants, and seizure dissappeared after

termination of Wellbutrin. A modified version with reduced side effect was later introduced to the

market. Bupropion has common side effects include dry mouth, tremors, anxiety, agitation,

dizziness, headache, excessive sweating, seizure, aggressiveness, tinnitus, insomnia, dose

dependent hypertension, myocardio infarction, and activation of mania and psychosis. Bupropion

is metabolised in the liver, and there are possibility of hepatotoxicity. Studies in rats shows

chronic administeration of Bupropion increases incidence of hepatic hyperplastic nodules and

hepatocellular hypertrophy. Studies in dogs shows liver histologic changes, and laboratory tests

suggests there were mild hepatocellular injury. In patients who took bupropion, abnormal liver

function was noted. In German, there were five incidences of pancreatitis with elevations of

serum-amylase and lipase. All cases shows reversibility afer drag withdrawal. Since it is an

amphetamine like drug, it poses addiction potential. Study shows that people with experienced

use of amphetamine or cocaine, shows drug-seeking behaviour given with bupropion. In clinical

practice, they claim that there is no significant problem of addiciton in clinical dose, because the

dose required to induce addiciton would cause seizure in most people.



Amphetamine is a class of adrenergic appetite suppressant with sympathomimetic effects that

increases metabolism rate. It works by increases noradrenalin and dopamine release from

storage vesicles, and inhibits their reuptake, so as to enhance the neurotransmitter level acting

on synaptic cleft. It is very effective in terms of short term treatment, however, amphetamine is

notorious for its high addiction potential and risk of cardiovascular complications. Some other

examples of its side effects include anxiety, depersonalisation, dysphoria, dry mouth, euphoria,

palpitation, hyperventilation, mental depression, paranoia, restlessness, and insomnia. By




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                                                                                   Icarus Wan Wai Chan
                                                                                         PRN: 41227206


activation of the sympathetic nervous system it increase heart rate, alertness, breath rate,

responses similar to those in fight or flight in order to increase energy consumption by increasing

metabolism rate.



From the above examples, we can see that the side effects are related to the drug targeted

neuron. When developing drugs acting on the CNS we have to take precaution to the physiology

of our target site, and to physiological responses that they regulates. For centrally acting anti-

obesity agents, cardiovascular problem is often seen. This is because the neurotransmitter they

drug interfere has affect to the heart and vessels. Besides the above physiological problems we

have to consider of, we also have to consider about psychological side effects. First of all, drug

addiction. Amphetamine like agents have high addiction potentials. Withdrawal of drug usually

comes with weight regain, for those patients who have high expectation on the drug may develop

depression, or low self-esteem with weight regain. On the other head, there are unpredictable

side effects, individual differences lead to idiosyncratic reactions. This may due to genetic

variations. Allergic reaction is also occasional seen on some patients. After all, patients can’t rely

completely on anti-obesity drug. For effective weight loss and health improvement, diet and

exercise are essential, as well as a balance life style. Any kind of anti-obesity agents are only

used for aid, or for morbid obesity whose health is in severe risk.




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