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Diethylpropion (1-phenyl-2-diethylamine-1-propanone hydrochloride) is a stimulant drug with reinforcing properties that is used to treat obesity in humans. While the anorectic properties of diethylpropion are mediated by a noradrenergic mechanism, stimulant properties depend on its effects on the serotonergic (5-HT) and/or dopaminergic systems. In this study we investigated the role of the 5-HT1A-receptor in the acute behavioral effects of diethylpropion in marmosets (Callithrix penicillata). Animals were pretreated with the selective 5-HT1A-receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide trihydrochloride (WAY 100635; 0.2, 0.4, 0.8 mg/kg, i.p.) or saline (i.p.) and received a treatment with diethylpropion (10 mg/kg, i.p) or saline (i.p.). Diethylpropion induced an increase in locomotor activity in 60% of the monkeys, which were classified as diethylpropion sensitive, but did not affect locomotion in 40% of the monkeys (diethylpropion insensitive). Sensitivity analysis revealed two types of responders to diethylpropion. In the sensitive animals (type A) diethylpropion increased locomotor activity and anxiogenic-like behavior, but decreased bodycare activities. In the insensitive animals (type B) diethylpropion did not affect locomotor and bodycare activity after diethylpropion, but led to a strong increase in anxiogenic-like behavioral responses. Selective 5-HT1A-receptor antagonism modulated the acute diethylpropion effects responder type specifically. In the sensitive (type A) monkeys WAY 100635 blocked the diethylpropion-induced increase in locomotor activity, while not affecting anxiogenic-like behavioral responses or the suppression of bodycare activities. In the insensitive monkeys, WAY 100635 had no effect on locomotor activity after diethylpropion, but blocked diethylpropion effects on some anxiogenic-like behavioral responses. In conclusion, these results suggest an essential contribution of the 5-HT1A-receptor to the stimulant effects of diethylpropion, which is responder type specific. It also suggests the 5-HT1A-receptor to be a source of the interindividual variance in the acute behavioral response to the stimulant diethylpropion in monkeys.
Diethylpropion is a centrally acting appetite-suppressing drug thought to act primarily through catecholamine pathways in the brain. In the present study, four doses of diethylpropion (0, 10, 20, and 40 mg/kg, intraperitoneally) were administered to rats to examine the hypothesis that the drug has psychomotor stimulant properties such as the ability to induce conditioned behaviors and behavioural sensitization. The rats were administered drug and then vehicle on alternating days, and confined to a "drug" or vehicle-paired side of a two-compartment box for 16 pairings. Only the 10-mg/kg dose of diethylpropion increased spontaneous locomotor activity in comparison to vehicle; the 20- and 40-mg/kg doses significantly decreased spontaneous locomotion. All doses of diethylpropion decreased spontaneous rearing, and the 20-and 40-mg/kg doses produced significantly less rearing than the 10-mg/kg one. At the 10-mg/kg dose, conditioned place preferences, conditioned locomotion, and conditioned rearing were observed. The 40-mg/kg dose produced conditioned rearing and conditioned defecation. In response to a 5-mg/kg challenge injection of diethylpropion, behavioural sensitization in locomotion and rearing occurred in rats that had previously received any one of the three doses of diethylpropion. Over 36 days, decreased weight gain was observed only in the 20- and 40-mg/kg groups. The rats were killed 48 h after the last drug injection, and whole brain was analyzed for levels of the catecholamines, homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), 5-HT (not a catecholamine), and 5-hydroxyindoleacetic acid (5-HIAA) by HPLC with electrochemical detection.(ABSTRACT TRUNCATED AT 250 WORDS)
The anorectic activity of diethylpropion and d-amphetamine was studied in rats subjected to various treatments known to affect brain monoamines. The effect of diethylpropion, like that of d-amphetamine, was completely prevented by a lesion of the ventral noradrenergic bundle, which selectively decreases brain noradrenaline, but was not significantly modified in desipramine pretreated rats by an intraventricular injection of 6-hydroxydopamine, a condition decreasing only dopamine. Pretreatment with penfluridol significantly reduced the effect of d-amphetamine but not that of diethylpropion. A non-significant reduction of drug effect was found with alpha-methyl-p-tyrosine. Lesion of the nucleus medianus raphe, which destroys central serotonin neurons, or treatment with methergoline, a central serotonin antagonist, caused no changes in the effects of both compounds. The findings show that integrity of central noradrenergic neurons is an important condition for diethylpropion and d-amphetamine to exert their anorectic effect. Dopamine does not seem to play any role in the effect of diethylpropion but might contribute to that of d-amphetamine. The data are against any involvement of brain serotonin in diethylpropion anorexia.
Obese patients encountered in general practice were studied in order to determine whether a long-acting form of diethylpropion hydrochloride (Tenuate Dospan) was more effective than placebo for weight loss. One hundred and two patients completed this double blind, 16-week crossover study. During the first eight weeks, the patients treated with diethylpropion hydrochloride lost significantly (P smaller than 0.001) more weight than the patients treated with placebo (an average of 11-1 lb or 6-4% of their initial weight as compared with 6-2 lb or 3-6% of their initial weight). When the group taking diethylpropion hydrochloride crossed over to placebo for a second eight weeks, they lost an average of 1-5 lb (0-9% of their weight at the start of the second period), while the group who crossed from placebo over to diethylpropion hydrochloride lost an average of 6-7 lb (3-8%). The advantages of diethylpropion hydrochloride over placebo are statistically significant.
Amphetamine, diethylpropion and mazindol were administered to rats in both acute and chronic experiments to measure the changes in purine nucleotide (GDP) binding to the mitochondria from interscapular brown adipose tissue. There was a dose-dependent response to acute treatment with mazindol, but no such effect with diethylpropion. The effects of mazindol and amphetamine were present as early as 3 hours after treatment, and persisted for at least 48 hours, when compared to vehicle-injected rats when all rats were fasted from the time of injection until study. There was no effect when these drugs were added in vitro to mitochondria from brown adipose tissue. Diethylpropion had no effect on GDP binding either in vivo or in vitro at any of the times tested. Following 11 days of treatment with diethylpropion, amphetamine or mazindol, there was a significant increase in purine nucleotide (GDP) binding to mitochondria only in the amphetamine-treated animals. There was no difference in body weight or food intake with any of the three drugs after the third day of chronic treatment. The differences between the effects of these three drugs and those of fenfluramine are discussed in terms of their different central mechanisms of action.
Fifty cocaine-dependent patients completed a 2-week double-blind, double-dummy, parallel-group comparison of four dosage levels of diethylpropion and placebo. This clinical trial was designed to evaluate both diethylpropion's ability to attenuate cocaine cue-induced craving and its potential for development as a medication with cocaine-agonist properties. The results indicated that diethylpropion was not superior to placebo and confirmed earlier reports that craving for cocaine diminishes over the course of an inpatient hospitalization. Moreover, the results showed that the cocaine cue-induced craving paradigm employed is effective in stimulating craving for cocaine. Medications that are effective in attenuating this type of "conditioned" craving may have relevance to the breaking of the cycle of relapse and long-term treatment of cocaine dependence. Diethylpropion may not be an appropriate candidate for future medication development because of its lack of obvious therapeutic efficacy and the emergence of a significant number of side effects. However, a cocaine-agonist medication strategy may be appropriate for a subgroup of cocaine-dependent patients with coexisting attention deficit-hyperactivity disorder.
Fifty obese patients were entered into a 12-week parallel group study of mazindol with diethylpropion in a general practice group. Both drugs produced weight loss, but patients on mazindol lost 19.9 lbs in 12 weeks, while those on diethylpropion lost 11.6 lbs, a statistically significant difference (p less than 0.01). At each visit during the trial, patients had lost more weight with mazindol, but this was only significant statistically in the period 8-12 weeks (p less than 0.01). Patients developed tolerance to the effect of diethylpropion in the last period (8-12 weeks) but this was not evident in those patients taking mazindol. The number of side-effects was less in the mazindol group and mainly of an adrenergic, peripheral type, while those in the diethylpropion group are mainly of the central stimulant type.
Diethylpropion hydrochloride is an effective anorexiant at the recommended dose of 25 mg three times a day. Previous work in volunteers to evaluate the effects of much larger doses showed that 400 mg given orally was equipotent with 600 mg subcutaneously in terms of subjective and physiologic effects, i.e., the drug was more potent orally than subcutaneously. In one volunteer, blood level studies after a 600-mg subcutaneous dose showed concentrations of unchanged diethylpropion in the plasma about three times as high as those found after the equipotent 400 mg oral dose. In nine other volunteers, the plasma concentrations of unchanged diethylpropion found after a 75-mg oral dose was less than 1/100 of that observed after a 400-mg oral dose. These observations suggest a rapid but limited metabolic capacity for conversion of diethylpropion to its metabolites. The data indicate that the metabolites, rather than the parent drug, are responsible for the pharmacologic responses seen with doses much larger than those necessary for inducting anorexia.
The combination of diethylpropion hydrochloride with carboxymethylcellulose induces decomposition of the drug. The principal decomposition products obtained were 1-phenyl-1,2-propanedione, benzoic acid and diethylamine as hydrochloride and benzoate salts. These phenomena have been explained with reference to basic decomposition scheme of the diethylpropion. Additionally, the behaviour of diethylpropion in mixtures with other dietary fibres such as methylcellulose, wheat bran and wheat germ was examined. Diethylpropion in combination with methylcellulose is rather stable while in mixtures with wheat bran and wheat germ suffers degradation. An increase in the weight of the excipient, probably due to chemical binding of the drug and other degradation products by the excipient, was observed in all these cases. The decomposition reactions were studied by applying a sequence of selective solvent extractions and using high-performance liquid chromatography (HPLC).
A short term course (8-11 days) of diethylpropion 50 mg a day was administered to 12 obese children of both sexes fed a mixed low calorie diet containing about 1000 calories/day. A group of 10 obese children received the same diet and no medication. The sex-distribution was similar in both groups as well as the degree of overweight (appreciated by the Quettelet index). The urinary excretion of some noradrenergic derivative (adrenaline-A, noradrenaline-NA, vanillyl-mandelic acid VMA, metanephrines NM and methoxy hydroxyphenyl glycol-MHPG) and of homovanillic acid (HVA) was measured in both groups before and after drug therapy or diet, respectively. After the diethylpropion course, the urinary mean value of MHPG decreased (2.17 +/- 0.30, mean +/- SE vs 1.47 +/- 0.21) but the significance was borderline. The mean level excretion of NA, VMA, MN and HVA were significantly lower following diethylpropion. No significant change was observed in the diet-only group of patients as regards the same determinations. These observations are not entirely explained by the previous pharmacologic knowledge on diethylpropion and other sympathomimetic amines.
Three metabolites of diethylpropion (1), (+/-)-2-ethylamino-1-phenyl-propan-1-one (2), (1R,2S)-(-)-N,N-diethylnorephedrine (3a) and (1S,2R)-(-)-N,N-diethylnorephedrine (3b) were synthesized. Their uptake and release effects with biogenic amine transporters were evaluated. A major finding of this study is that the in vivo activity of diethylpropion on biogenic amine transporters is most likely due to metabolite 2 as diethylpropion (1) and the metabolites 3a and 3b showed little or no effect in the assays studied. These studies also revealed that 2 acted as a substrate at the norepinephrine (IC50 = 99 nM) and serotonin transporters (IC50 = 2118 nM) and an uptake inhibitor at the dopamine transporter (IC50 = 1014 nM). The potent action of 2 at the NE transporter supports the hypothesis that amphetamine-type subjective effects may be mediated in part by brain norepinephrine.
Dopamine agonists have been used with some success in treating cocaine addiction. However, both cocaine and psychostimulants have been reported to produce neurotoxic effects. We evaluated the effect of the stimulant diethylpropion on cognitive performance in a double-blind, placebo-controlled trial. Forty-six abstinent crack-cocaine users received either placebo, 25-mg, 50-mg, or 75-mg doses of diethylpropion. Patients were tested at baseline and again after 9-14 days of medication. There were no differences between placebo and medication groups on any test, indicating that, within the time frame studied, diethylpropion does not produce neurotoxic effects that can be detected with standardized neuropsychological tests.
The tolerance pattern to anorectic drugs was studied in starved rats by measuring two consecutive 2 h food intakes. 2 There was a reduction in the first 2 h food intake with development of complete tolerance after fenfluramine and phenmetrazine, and of partial tolerance after amphetamine, (+)-amphetamine and diethylpropion. 3 During the second 2 h intake, the anorectic effect was transient after fenfluramine and diethylpropion; while there was an absolute increase in the intake after amphetamine and (+)-amphetamine. 4 A pair-feeding experiment revealed that the increase in the second 2 h food intake was not a direct effect of the drug but a consequence of the deficit in food intake during the preceding 2 hours. 5 There was an overall correlation between the food and water intake. 6 A significant loss in body weight was observed after amphetamine, fenfluramine and phenmetrazine but not after (+)-amphetamine or diethylpropion. 7 The results indicate that so-called tolerance to the anorexigenic effect of drugs is apparent rather than real and that the duration of food access is a determining factor. The body weight changes may be brought about by the metabolic effects of these drugs rather than their effect on food and water intake.
A study was carried out in general practice to compare the effectiveness and tolerance of phentermine and diethylpropion in helping patients more than 20% above their desirable weight to lose weight. Patients were allocated at random to receive either one 30 mg capsule of phentermine (50 patients) or one 75 mg tablet of diethylpropion (49 patients) daily over a period of 12 weeks. They were also asked to restrict their calorie intake to 1500 calories per day. The results showed that there was a significantly greater weight loss in patients treated with phentermine which was particularly marked during the last 4 weeks of the study. There were significant reductions in blood pressure and heart rate in the phentermine group and of heart rate in the diethylpropion group. These were almost certainly related to weight loss rather than to a direct effect of drug treatment. Side-effects were generally minor in nature and the incidence and nature of them were comparable in the two groups.
In a double-blind, placebo-controlled evaluation in obese adults given comparable dietary and exercise recommendations, controlled-release diethylpropion hydrochloride promoted significantly more weight loss than matching placebo. The mean reduction in 12 weeks was 15.9 lb (average 1.32 lb/week) for 12 patients taking diethylpropion hydrochloride, 10.0 lb (0.84 lb/week) for 13 taking placebo, and 12.2 lb for 13 taking drug for two four-week periods separated by four weeks of placebo (1.38 lb/week on active drug and 0.30 lb/week on placebo). Amphetamine-like side effects were virtually absent. Diethylpropion hydrochloride is an effective adjunct to caloric restriction in therapy of obesity.
The case of a 36-year old woman who developed a paranoid psychosis while abusing diethylpropion is reported. It is suggested that the newer appetite-suppressing drugs have a bigger abuse potential than eas previously thought and may therefore be a hazard for a minority of susceptible subjects. The need to test separately for diethylpropion in cases of suspected drug-induced psychosis is emphasized.
The effects of perphenazine, cocaine, diethylpropion and d-amphetamine on responding maintained by both food delivery and electric shock avoidance were determined using a multiple schedule of reinforcement in rhesus monkeys. This schedule had three components, each separated by a timeout: a fixed-ratio schedule of food delivery, a schedule of spaced responding (differential reinforcement of low rates) maintained by food delivery and a fixed-ratio schedule of shock avoidance. Control rates of responding on both ratio schedules were similar and were high relative to the low rates generated by the schedule of spaced responding. Perphenazine decreased rates on all three schedules in a dose-dependent fashion. All three psychomotor stimulants decreased food-maintained ratio responding at doses which had little effect on or increased rates of shock avoidance. Except for diethylpropion and d-amphetamine in one animal in which rates were increased, low rates of spaced responding were also decreased.