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Table 7 In vitro monoamine-releasing effects of simple amphetamines

NE release, EC50 (nmolL 1) DA release, EC50 (nmolL 1) 5-HT release, EC50 (nmolL 1)

Table 7 In vitro monoamine-releasing effects of simple amphetamines

NE release, EC50 (nmolL 1) DA release, EC50 (nmolL 1) 5-HT release, EC50 (nmolL 1)

( + )Amphetamine

7.07 + 0.95

24.8 + 3.5

1765+94

( + )Methamphetamine

12.3 + 0.7

24.5 + 2.1

736+ 45

( + fenfluramine

302 + 20

> 10 000

51.7+ 6.1

(-)Fenfluramine

>10 000

> 10 000

147+19

( + )Norfenfluramine

72.7 + 5.4

924 + 112

59.3 + 2.4

(-)Norfenfluramine

474 + 40

> 10 000

287+14

Phentermine

39.4 + 6.6

262 + 21

3511 + 253

Diethylpropion

>10 000

> 10 000

> 10 000

N-dealkylated diethylpropion

99.3 + 6.6

> 1000

2118+ 98

Phendimetrazine

> 10 000

> 10 000

>100 000

( + )Phenmetrazine

37.5 + 4.3

87.4 + 7.8

3246 + 263

(-)Phenmetrazine

62.9 + 9.5

415 + 45

> 10 000

Data taken from 6Ä

6.18.6.2.8.2 Ephedrine and ephedrine/caffeine combinations

Another pharmacologic approach to inducing weight loss has been through the use of the sympathomimetic ephedrine alone or in combination with caffeine. This was done primarily through the use of dietary supplements, i.e., the use of plant materials that naturally contain ephedrine (and related compounds), so that the product could be marketed without the need of a prescription. This was a very popular over-the-counter medication, and the plant-derived ephedrine/caffeine combination was often referred to as herbal phen-fen. While much has been written about the effects of ephedrine and the ephedrine/caffeine combinations on obesity, it is difficult to dissect the mechanisms of the effects from the lore surrounding the use of these agents.

Ephedrine and related compounds are natural constituents of a number of different plant species, especially of the family Ephedraceae (e.g., Ephedra sinica, E. equisetina, and E. gerardiana). The plants of this group are often collectively referred to as ephedra or ma huang (mahuang). Ephedrine can also be made synthetically. Since it contains two chiral centers, four stereoisomers are possible (Figure 5). The literature has described ephedrine as both a direct-acting (i.e., directly interacting with adrenoceptor) and an indirect-acting (i.e., NE-releasing) sympathomimetic. However, a comprehensive evaluation of ephedrine and its enantiomers suggests that there is little, if any, direct effect on adrenergic receptors and that the most likely mechanism of action is through promoting the release of NE.16

A number of small studies looking at the effects of ephedrine/caffeine combinations or herbal combinations containing ephedrine and caffeine have concluded that they are efficacious in reducing weight.13 However, it is not clear that the magnitude of this effect is different than that described for the other anorectic agents that act by releasing NE.

A milestone in the use of ephedrine to promote weight loss was the final ruling of the FDA in 2004 prohibiting the sale of dietary supplements containing ephedrine alkaloids (ephedra). In issuing this ruling the FDA concluded that ''dietary supplements containing ephedrine alkaloids pose a risk of serious adverse events, including heart attack, stroke, and death, and that these risks are unreasonable in light of any benefits that may result from the use of these products.''34

While the sale of dietary supplements containing ephedrine alkaloids was banned, ephedrine itself is still approved as a prescription medication for certain indications. Approved indications include use as a vasopressor in shock, as a bronchodilator to treat asthma/bronchospasm, and as a decongestant for the relief of nasal congestion due to cold, hayfever, rhinitis, or sinusitis. It should be noted that ephedrine is not approved for the treatment of obesity.

Caffeine (Figure 6) is a plant-derived material, and it is generally categorized as a CNS stimulant. A broad segment of society is exposed to caffeine via its natural occurrence in tea and coffee and through its addition to many other beverages. Caffeine appears to produce its effects primarily by acting as an antagonist at both adenosine A1 and A2A receptors. By itself, caffeine seems to have little effect on body weight. It is claimed that caffeine facilitates the weight-reducing effects of ephedrine; however, the rigor with which this has been demonstrated can be questioned.

Ephedrine, either alone or in combination with caffeine, has often been described as thermogenic, i.e., having the ability to increase energy expenditure, and this has often been used to explain the weight-reducing effects of ephedrine/caffeine. While it is clear that this combination can produce small increases in energy expenditure, it is not clear that this is significantly different from other sympathomimetic compounds or that this contributes significantly to the overall effects of these compounds on weight reduction.

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