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EXHIBIT 25

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Late evening dose doesn't interfere with sleep.

Since Tenuate is practically free of CNS stimulation, it can be given in mid-evening, when TV snacks run up a high calorie count. Doses given to control evening snacks will not interfere with sleep." Tenuate cuts the urge to eat. So well, in fact, that weight loss on Tenuate averages over 1.5 lbs. a week. (see chart)

Record of safety-Tenuate can be used even in overweight cardiacs or hypertensives.

EKG studies substantiate Tenuate's lack of appreciable CNS stimulation. No effect on heart rate.

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[From J.A.M.A., July 9, 1960, Vol. 173, No. 10]

COUNCIL ON DRUGS

REPORT TO THE COUNCIL

The Council has authorized publication of the following report,
H. D. Kautz, M.D., Secretary

STATUS AND PROSPECT OF DRUGS FOR OVEREATING

Walter Modell,' M.D., New York

A unified statement on the pharmacotherapy of obesity is difficult to make, largely because, even as a symptom-to say nothing of it as a syndrome, obesity implies neither a specific disturbance in physiological function nor a specific physical abnormality; rather, it is a consequence of a variety of nonrelated etiological factors. There is only one feature common to most instances of obesity, that of caloric intake in excess of normal energy requirements. Since this discrepancy provides both a clear and a tangible point of attack, it is the usual target. Hence, rather than to consider the effect of drugs in obesity, it is more realistic as well as more practical to consider the drugs at hand for controlling overeating.

Although studies in the laboratory and observations of animals in their natural environment have not elucidated the appetite mechanism, they seem to indicate adequate natural homeostatic arrangements to relate appetite to physiological needs for food. The eating patterns of most modern human adults, however, are so distorted that appetite drive and specific food selection appear to have little to do with energy and metabolic requirements. Customs of diverse subcultures enter into the motivation for eating patterns; the physical configuration one cultural group considers pleasing another considers ugly; what one set feels has porcine or boorish implications another considers representative of virility or opulence. In our own subculture, social protocol also complicates matters. The business luncheon with cocktail, the before-meal highball or two or three, the with-highball canapés, all are part of the mores which consider the slim figure desirable but provide eating customs which make it hard to achieve.

Psychological factors are also concerned in the kind, amount, and frequency of eating. Many people eat more when they are bored than when they are busy. Some persons eat more when they are anxious than when they are at ease, and, conversely, some persons lose appetite when under tension; others cannot sleep shortly after eating, but many find the bedtime snack has a "sedative" action and cannot fall asleep without it; still others raid the refrigerator whenever sleep is disturbed. When the latter condition is well developed, it is given status by a psychiatric designation, the "night-eating syndrome," but compulsive eating also commonly occurs during the day. None of this eating can be presumed to be in response to normal stimulation of an appetite-control mechanism.

Although hereditary predisposition appears to be important in some persons, this is often difficult to distinguish from culturally based obesity. Genetic, glandular, and oher physical and physiological causes play a statistically small role in obesity, probably in less than 10% of all cases.

It may also be a fact that most persons who regularly overeat do not attempt to achieve satisfaction of the appetite per se but eat compulsively much as the alcoholic person drinks compulsively. Just as the latter does not stop his drinking when he has attained what others might consider a pleasant state of inebriation but continues on to stupor so the compulsive overeater often continues stuffing himself beyond satiation, and sometimes he does so until it becomes physically unpleasant to eat more food. If more were known about the normal appetite mechanism, perhaps something more rational and lasting could be done about it pharmacologically. However, although we have many hypotheses, neither the central site nor the precise mechanisms of normal appetite control are yet definitely established.

1 Director, Clinical Pharmacology, Cornell University Medical College.

APPROACH TO THERAPY

Today it is more common to treat the patient's obesity on the basis of intake rather than output.

Thus, the popular therapeutic approach is to contrive to have the obese patient eat less, whereas it is far less common to increase his metabolic rate or to depress his ability to assimilate the food he ingests. It is generally conceded that the first procedure is the safest as well as the most practical method.

The problem of judging the effects of drugs and regimens in the treatment of obesity is seriously complicated by the psychological issues involved in abnormal eating patterns. In the beginning of therapy, almost any regimen applied with sufficient suggestion will have some effect. Thus, Aldersberg and Mayer showed in a long-term study that excellent results were obtained during the early stages of almost all types of treatment, reflecting, in a large part, both the early willingness of subjects to cooperate with a new physician and the psychological impact of a new therapy.

The findings of Stunkard bear heavily on the ultimate value of the pharmacological approach. In a large number of obese patients, Stunkard found that only 12 percent followed treatment long enough to experience significant weight losses. Furthermore, half of these had regained their weight at the end of one year, and, at the end of the second year, only 2 percent of the original group had maintained their weight losses. He found that about half of the persons on the weight-losing regimens had suffered some psychic reactions to it, and half of these reactions were severe emotional disturbances. It seems clear from these results that. along with the weight-losing regimen, an adequate substitute must be provided for the psychological satisfaction which the obese person derives from overeating. Since psychogenic factors are so important, there are many physicians who are inclined to believe that the best hope for sustained results from therapy lies in the psychological approach to overeating. They point to the fact that the best long-term results (about 50 percent sustained improvement) have been reported from this form of treatment. Group therapy for obesity has already been successfully instituted. Self-help groups are also in operation.

PHARMACOLOGICAL AGENTS FOR HYPERPHAGIA

The agents used for hyperphagia may be divided into (1) central appetite depressants, (2) central-stimulating appetite distractors, (3) metabolic stimulants, (4) sedatives and tranquilizers, (5) bulk producers, (6) purgatives and diuretics, and (7) miscellaneous devices.

Central Depression of Appetite.-True depression, i.e., direct central depression of appetite, occurs regularly in disease, as in hepatitis, and as the undesirable consequence of other therapies, for example, digitalis overdosage. Although this type of depression appetite is common cause of weight loss, even if it were safe as a therapeutic aproach, it is not likely to be pursued because it is associated with distress. Whether true central depression of appetite can be dissociated from nausea or a "sick" sensation remains to be demonstrated. If such a drug effect were deliberately induced, after the depressive effect on the appetite was lifted lost weight would be regained as the patient responded to his rejuvenated appetite drive. Such an effect of a drug on appetite is not now consciously used in the treatment of obesity.

Central-Stimulating Appetite Distractors.-The mainstay of current pharmacotherapy of obesity is the so-called anorexigenic (anorexiant, anorectic, or anorexic) drug. The terminology is unsatisfactory, however, because it is probable that none of the drugs in common use to which the words are now applied are true central appetite depressants; therefore, they are not really anorexigenic, and none of the terms is a proper portmanteau word for the drugs on hand. However, the effect of the central stimulants which decrease hyperhagia is acceptable to the patient, and he is likely to continue taking the drug. This is largely because, in the use of this group of drugs, the patient's abnormal drive for food is distracted by a sense of well-being or "lift."

Amphetamines.-When given in sufficiently large doses, the sympathomimetic amine-type of central stimulant will depress eating in normal man and laboratory animals; in the usual clinical doses, these agents do not uniformly depress the appetite in ali who overeat. Therefore, they may have little or no effect at all on the normal appetite, although central stimulation resulting in anxiety, increased mental and physical activity, and insomnia are regular consequences of these agents. The indications are that the desire to eat is eased because of the central stimulation. Many patients clearly experience and distinguish a pleasant effect or "lift," and the distraction from hyperphagia is thought to be secondary to it. On the other hand, in bulimia after frontal lobotomy these drugs do not depress appetite. Central stimulation, not a specific central depressant effect on appetite, is then the common mechanism through which these drugs act; it is clear, therefore, why undesirable central stimulant effects, which have constituted their chief clinical limitation, have thus far appeared to be indivisible from anorexigenic action.

A loss of acuity or olfactory and gustatory sensibility has also been described which may conceivably contribute to appetite depression. Although denied by some physicans, it has been suggested that the increased physical activity also helps, not only through its modest calorigenic effect but also because activity per se sometimes seems to alleviate the drive to overeat. The degree of depressant effect on gastrointestinal activity is not considered significant.

In any event, if seems clear that the combined effects do not produce appetite suppression in obese persons sufficiently to make them lose weight without simultaneous dietary control. Gelvin and others state that, "the role of the anorexigenic agents is that of a 'crutch'; their use should be eliminated as early in the therapeutic program as possible."

It has long been known that anorexia follows the use of ephedrine. However, since the drug has been used mainly for other purposes, the loss of appetite, along with anxiety and insomnia, has been considered an untoward effect of this drug. It is of interest here because it emphasizes the invariable association of diminution of eating with central stimulation in the entire series of drugs. With the introduction of amphetamine (Benzedrine) sulfate, however, the development of a potent cephalotropic action made its use in the treatment of obesity feasible. The sulfate and phosphate of levo-amphetamine (and more recently levo-amphetamine alginate [Levonor]), amphetamine resin complex (Biphetamine Resin), dextro-amphetamine (Dexedrine), methamphetamine (Amphedroxyn, Desoxyephedrine, Desoxyn, Desyphed, Dexoval, Doxyfed, Drinalfa, Efroxine, Methamphetamine, Norodin, Semoxydrine, Syndrox) hydrochloride, phenylpropanolamine (Propadrine), phenmetrazine (Preludin), phenyltert-butylamine resin (Ionamin), and diethylpropion (Tenuate, Tepanil) hydrochloride also belong to the series. However (as if amphetamine were somehow loathsome), manufacturers of the newer amphetamine congeners tend to avoid and even to disclaim in promotional literature that there is any connection between their compound and amphetamine. The lack of similarity among the so-called generic names designated for these newer amphetamine congeners is worthy of note. Yet it is a simple matter to demonstrate their close chemical and pharmacological relationship. As can be seen in the structural formulas of these agents in the figure, they differ very little from one another, and, as indicated by the heavy lines and lettering, there is a configuration common to them which apparently confers the cephalotropic action. Thus, they are all amphetamine congeners, and, since amphetamine is so well understood and well established, it seems appropriate to use it as a reference standard.

Whereas it is probable that the structural differences between members of the amphetamine series makes one or the other a more or less potent cephalotropic drug than is amphetamine, it is also probable (no evidence to the contrary)

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