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PubMed2002

Interaction of the anorectic medication, phendimetrazine, and its metabolites with monoamine transporters in rat brain.

Phendimetrazine is an effective and widely prescribed appetite suppressant. Preclinical findings show that phendimetrazine displays stimulant properties similar to amphetamine, but few studies have examined the neurochemical mechanism of the drug. In the present work, we characterize the activity of phendimetrazine and its putative metabolites [phenmetrazine, pseudophenmetrazine, and associated stereoisomers] at biogenic amine transporters. All drugs were tested in vitro using assays to measure uptake and release of [3H]dopamine, [3H]norepinephrine, and [3H]serotonin ([3H]5-HT) in rat brain synaptosomes. Selected drugs were tested in vivo using microdialysis to measure extracellular dopamine and serotonin (5-HT) in rat nucleus accumbens. Phendimetrazine itself had no effect on uptake or release of any transmitter. In contrast, the trans-configured N-demethylated metabolite, phenmetrazine, was a potent releaser of [3H]norepinephrine (EC(50)=50 nM) and [3H]dopamine (EC(50)=131 nM). The cis N-demethylated metabolite, pseudophenmetrazine, displayed modest potency at releasing [3H]norepinephrine (EC(50)=514 nM) and blocking [3H]dopamine re-uptake (IC(50)=2630 nM). All drugs tested were inactive or weak in the [3H]5-HT assays. When injected intravenously, phendimetrazine had minimal effects on extracellular transmitter levels, whereas phenmetrazine produced dose-related elevations in extracellular dopamine. The collective findings suggest that phendimetrazine is a "prodrug" that is converted to the active metabolite phenmetrazine, a potent substrate for norepinephrine and dopamine transporters.

Animals↗
PubMed1987

Reinforcing and subjective effects of several anorectics in normal human volunteers.

A discrete-trial choice procedure was used to examine the reinforcing and subjective effects of four anorectic drugs (mazindol, benzphetamine, phenylpropanolamine and phenmetrazine) in groups of normal healthy adults. For each experiment, subjects first sampled placebo and a dose of one of the drugs (mazindol: 0.5, 1.0 and 2.0 mg; benzphetamine: 25 and 50 mg; phenylpropanolamine: 12.5, 25 and 50 mg; phenmetrazine: 25 and 50 mg; all p.o.). Subjects were then allowed to choose between drug and placebo on five separate occasions. The relative frequency with which active drug was chosen over placebo was used as an index of the drug's reinforcing efficacy. Subjective effects were measured with an experimental version of the Profile of Mood States, a short form of the Addiction Research Center Inventory and a series of visual analog scales. The rank order for reinforcing efficacy was benzphetamine approximately phenmetrazine greater than placebo greater than phenylpropanolamine much greater than mazindol. Ratings of drug liking were positively correlated with number of drug choices for each drug. Benzphetamine and phenmetrazine produced subjective effects characteristic of amphetamine-like drugs and increased ratings of drug liking. Mazindol produced only dysphoric subjective effects and decreased ratings of drug liking. Phenylpropanolamine had no significant effects on subjective measures or drug-liking ratings. These findings are consistent with the presumed dependence potential of these compounds, and demonstrate the validity of this experimental paradigm for assessing the reinforcing effects of anorectics in normal human volunteers.

Adult↗
PubMed1976

[Investigations of the decomposition and detection of morazone by thin-layer- and gas-liquid-chromatography].

Three decomposition products of Morazone (ingredient of the pharmaceutical preparation Rosimon-Neu) were observed following heat treatment in acid medium (hydrochloric or tartaric acid). These products were isolated by TLC and identified as bis-antipyryl-methane, phenmetrazine and 4-hydroxymethyl-antipyrine by mass spectrometry and IR-spectroscopy and 1H-nuclear magnetic resonance. Morazone and the metabolite phenmetrazine may be extracted from alkaline urine using chloroform, however acid hydrolysis (pH 1) of the urine before alkaline extraction will improve the sensitivity of detection of morazone by producing the metabolite phenmetrazine in addition to bis-antipyrylmethane. The metabolite 4-hydroxymethyl-antipyrine is barely detectable by TLC from alkaline extraction of urine.

Antipyrine↗
PubMed1975

Self-administration of CNS stimulants by dog.

Drug-naive dogs were trained to respond for intravenous infusions of either d-amphetamine, phenmetrazine, or methylphenidate until a stable response rate per 4-hr daily session was achieved. The magnitude of reinforcement (i.e., mg/kg/infusion) was then varied systematically across a wide range for each drug. An inverse relationship between unit dose and number of self-administered infusions per session was seen. Thus, total drug intake per session remained relatively constant and was independent of unit dose. Using a parallel line bioassay design, the relative potencies of d-amphetamine, phenmetrazine, and methylphenidate to maintain self-administration were estimated. By comparing the unit doses of d-amphetamine which yielded the same rate of self-administration it was found that 1 mg of phenmetrazine is equivalent to 0.1 mg of d-amphetamine. It was also determined that 1 mg of methylphenidate is equivalent to 0.75 mg of d-amphetamine. These data indicate the dog can be used to assess the reinforcing properties of psychomotor stimulants.

Animals↗
PubMed1986

An in vivo voltammetric comparison of the effects of three psychomotor stimulants on electrically evoked neostriatal dopamine release.

The effects of three psychomotor stimulants (mazindol, beta-phenylethylamine and D-phenmetrazine) on electrically evoked neostriatal dopamine release were studied by in vivo voltammetry. Mazindol (10 mg/kg) enhanced release and this effect persisted after dopamine synthesis inhibition by alpha-methyl-p-tyrosine. beta-Phenylethylamine (100 mg/kg) caused a large decrease in stimulated dopamine release and exerted no effect after dopamine synthesis inhibition. D-Phenmetrazine (45 mg/kg) enhanced dopamine release on the first post-drug stimulation and also restored release after dopamine synthesis inhibition. Disruption of vesicular dopamine storage by Ro 4-1284 abolished electrically stimulated dopamine release. Only D-phenmetrazine was able to cause dopamine release following Ro 4-1284. These results imply different biochemical modes of action of these three stimulants.

Amphetamine↗
PubMedDate not supplied

Self-administration of amphetamine analogues in rats.

In rats self-injecting amphetamine (0.25 mg/kg/injection) at a stable level during daily 3 hr sessions, three different amphetamine analogues )phenmetrazine, diethylpropion and fenfluramine) were substituted for amphetamine, one at a time on different experimental days. Phenmetrazine (1.0 mg/kg/injection) and diethylpropion (2.0 mg/kg/injection) were self-administered but not fenfluramine (in doses of 0.1, 0.5 and 2.0 mg/kg/injection). It is concluded that amphetamine, phenmetrazine and diethylpropion have reinforcing properties, whereas fenfluramine has not.

Amphetamine↗
PubMed1988

Substitution and cross-tolerance profiles of anorectic drugs in rats trained to detect the discriminative stimulus properties of cocaine.

Rats were trained to discriminate cocaine, 10.0 mg/kg, using a two-lever operant procedure. Dose-effect data were determined for the substitution of cocaine, diethylpropion, methylphenidate, phenmetrazine, phentermine, and fenfluramine for the cocaine stimulus. All of these drugs, except fenfluramine, substituted fully for the cocaine stimulus. Subsequently, training was halted and cocaine, 20 mg/kg/8 h, was administered for 9 days, and dose-effect data were redetermined for all of these drugs on days 7-9 of chronic administration. Chronic administration of cocaine produced tolerance to the stimulus properties of cocaine, and cross-tolerance to the stimulus properties of methylphenidate, phenmetrazine, and phentermine, such that doses approximately two-fold higher than those used acutely were necessary to reproduce the original effect; the potency for the substitution of diethylpropion for the cocaine stimulus was decreased greater than four-fold; and fenfluramine still failed to substitute for the cocaine stimulus. These data suggest that 1) a common mechanism may mediate tolerance to the discriminative stimulus properties of cocaine, methylphenidate, phenmetrazine, and phentermine, and 2) tolerance in the drug discrimination procedure may have potential for establishing a comprehensive evaluation of dependence liability of CNS stimulants.

Animals↗
PubMed1987

Anorectics: effects on food intake and self-administration in rhesus monkeys.

The effects of the anorectics benzphetamine, chlorphentermine, clortermine, mazindol, phendimetrazine, and phenmetrazine on food intake were compared to the effects of d-amphetamine in rhesus monkeys given daily access to food pellets. The ability of these compounds to maintain intravenous self-administration under a fixed-ratio 10 schedule was also determined in rhesus monkeys. All drugs reduced food intake in a dose-related manner. d-Amphetamine was the most potent. Mazindol, chlorphentermine, phenmetrazine, and phendimetrazine were approximately 1/5 to 1/9 as potent as d-amphetamine while benzphetamine and clortermine were 1/14 and 1/20 as potent, respectively. Benzphetamine, mazindol, and phenmetrazine were self-administered above saline levels and were approximately equipotent. Chlorphentermine and clortermine were not self-administered and phendimetrazine was self-administered by only one of four monkeys at one dose. Thus, although all of the compounds were effective anorectics, chlorphentermine, clortermine, and phendimetrazine did not function as positive reinforcers. Since the ability of a drug to function as a positive reinforcer is related to its dependence potential, these three compounds might be less subject to abuse when used therapeutically. Within the group of 3 compounds that was self-administered, benzphetamine was relatively more potent as a positive reinforcer than as an anorectic. Therefore, this drug might be a less desirable compound for therapeutic use.

Animals↗
PubMed1996

[Treatment of excessive daytime sleepiness].

Excessive day-time sleepiness (EDS) is in more than 80% of the subjects caused by the sleep apnoe syndrome (SAS), narcolepsy and idiopathic hypersomnia. SAS is treated by continuous positive airway pressure or by uvulopalatopharyngoplasty. Narcolepsy is manifested by imperative sleepiness which may be preceded by a period of non-imperative EDS. In the treatment of narcolepsy "preventive" day-time naps and administration of stimulants are used. EDS cannot be completely eliminated in some narcoleptics. EDS in idiopathic hypersomnia can be usually influenced only by stimulants. The author gives an account of the medication used in 57 patients with narcolepsy (mean age 51.7 years, range 16-75) and experience with this therapy. Ephedrine was used by 45.6% patients (usually combined with phenmetrazine) amphetamines in 26.3%, phenmetrazine in 82.5% and mazindol in 19.3%. Significant phenmetrazine dependence was developed by one patient from a group of more than 200 narcoleptics. Other causes of EDS are illnesses and circumstances which interfere with nocturnal sleep. There it is important to influence at the first place the quality of the nocturnal sleep. Diseases of circadian rhythmicity elicit EDS teo and can be treated using special therapeutical approaches. EDS may be the manifestation of psychiatric diseases.

Adolescent↗
PubMed1996

A convenient derivatization method for the determination of amphetamine and related drugs in urine.

The most commonly abused CNS stimulant in Sweden is amphetamine followed by phenmetrazine. Methamphetamine and phentermine are rarely seen but still of interest. This paper describes a rapid and sensitive method for the analysis of amphetamine, methamphetamine, phentermine, and phenmetrazine in urine using gas chromatography with nitrogen sensitive detection (GC-NPD). The method also qualitatively determines ephedrine and norephedrine. The derivatization was carried out at room temperature with methyl chloroformate to form the corresponding carbamates. Other chloroformate analogues were also tested. Because methyl chloroformate is relatively stable in the presence of water the extraction and derivatization were combined in one step. A concentration step was not necessary to achieve sufficient sensitivity. The recovery was more than 83% for all analytes. The LOQ was 0.05, 0.03, 0.07 and 0.01 (microgram/mL urine) for amphetamine, methamphetamine, phentermine and phenmetrazine respectively. The cut-off was set at 0.2 microgram/mL. The within-day and between-day relative standard deviation (RSD) for amphetamine were 2.2% (n = 9) and 4.7% (n = 5) respectively. There was a good quantitative correlation (r2 = 0.995) between GC-NPD using chloroformate derivatives and gas chromatography-mass spectrometry (GC-MS) using trifluoroacetic anhydride (TFA) as derivatizing agent for the determination of amphetamine in authentic samples.

Amphetamines↗
PubMed1979

The effects of psychomotor stimulants on single-spatial alternation behavior in dogs.

Dogs were trained to pedal press for drinking water in a noncued, single-spatial alternation task. After the dogs were exhibiting stable performance at or above predetermined criteria levels, they were given three doses of four different drugs (methylphenidate, 0.2, 0.4, and 0.8 mg/kg; d-amphetamine, 0.15, 0.3 and 0.6 mg/kg; cocaine, 0.5, 1, and 2 mg/kg; and phenmetrazine, 0.6, 1.2 and 2.4 mg/kg). In general, all four drugs produced similar changes in performance. The number of correct responses was an especially sensitive indicator of drug effects. All four drugs also produced significant increases in both the average response latency and total session duration, but there were few significant changes in either the total number of responses or number of intertrial interval responses. Relative to d-amphetamine, the potencies of cocaine and phenmetrazine, but not methylphenidate, were generally higher for the measures of single-spatial alternation than for self-administration.

Animals↗
PubMed1980

Influence of intravenous self-administered psychomotor stimulants on performance of rhesus monkeys in a multiple schedule paradigm.

Rhesus monkeys were trained to complete three multiple schedules. The schedules consisted of three components: a fixed interval (component 1), a variable interval (component 2), and a fixed ratio (component 3). During components 1 and 2, pressing lever 1 was always reinforced by food delivery. During component 3, pressing lever 2 resulted in either food delivery or intravenous infusions of saline solution, solutions of cocaine, of d-amphetamine, of phenmetrazine, or fenetylline. In schedule I, animals were presented with all three components independent of key-pressing behavior during components 1 and 2. In schedule II the availability of component 2 was dependent on completion of component 1. Component 3 was made available only on completion of component 2. Noncompletion of components 1 or 2 resulted in time-out of 15 and 10 min, respectively. Schedule III was identical with schedule II, except that in schedule III the completion of components was indicated only by a change in the lever lights. The influence of self-administered drugs on behavior in all three components was evaluated. Self-administration of psychomotor stimulants impaired the performance of animals and delayed completion of components 1 and 2 of schedules I, II, and III. The effects on behavior were similar with low drug intake in schedule III, moderate intake in schedule II, and high drug intake in schedule I. These effects were strong with self-administration of phenmetrazine, moderate with self-administration of cocaine and d-amphetamine, and weak with self-administration of fenetylline.

Amphetamines↗
PubMed1977

Open-field behavior after intravenous amphetamine analogues in rats.

A variety of behaviors were studied in an open-field setting after i.v. amphetamine (0.5, 2.0, 8.0 mg/kg), phenmetrazine (1.0, 4.0, 16.0 mg/kg), or fenfluramine (1.0, 4.0, 16.0 mg/kg). Amphetamine and phenmetrazine increased ambulation initially and rearing during the whole experiment, and decreased grooming. At 30 and 60 min, with the three higher doses of amphetamine, stereotyped behaviors interfered with and decreased both ambulation and groomin. Fenfluramine decreased ambulation, rearing, and grooming, and was the only drug to induce backing. The technique seems to be a simple and rapid method to establish dependence liability in amphetamine analogues. Interrater and test-retest reliability was established through ITV recordings.

Animals↗
PubMed1980

Effects of diet, exercise and anorexigenic drugs on serum thyroid hormones.

The serum levels of T4, T3 and rT3 were estimated in moderately obese women treated with diet (900-1000 kcal) and 4 h of exercise, supplemented with placebo or anorexigenic drugs (phenmetrazine, phentermine and mazindol). After 12 days of treatment, no change in serum T4 occurred in the placebo group (-4%), while in the groups with anorexigenic drugs a significant rise of T4 was observed (phenmetrazine +33%, phentermine +14% and mazindol +20%). Serum T3 decreased significantly in the placebo and the anorexigenic groups to a similar extent (from -21% to -27%) with the exception of mazindol. We did not notice any decrease of T3 in this group (-3%). A rising trend of serum rT3 was observed in all 4 groups, with a statistical significance for mazindol only. It is suggested that 1) a combined energy deficit produced by diet and exercise leads to a pattern of serum thyroid hormones similar to that observed in resting patients on a total fast; 2) the rise of serum T4 after the administration of anorexigenic drugs is due to their sympathomimetic effects; 3) the largest weight decrease observed in the mazindol group (6.7 kg) may be due to the unchanged serum T3 level, while in the other groups a decrease of serum T3 was observed. The lowest weight loss was observed in the placebo group (4.9 kg) with a pronounced decrease of T3 (-24%).

Appetite Depressants↗
PubMed1982

Drug treatment and obesity.

(1) The initial treatment of obesity must include an attempt to modify previous eating pattern and may involve group therapy or behavioral modification. Drug treatment is not indicated unless this dietary approach is shown to be ineffective. (2) Since anti-obesity drugs do not help to establish a new and permanent eating habit, they should never be prescribed except as part of an overall management plan. (3) The potential for abuse with amphetamine and phenmetrazine is such that their use cannot be justified as anorectic agents. (4) Phenmetrazine, diethylpropion, mazindol and fenfluramine will all produce an additional mean weight loss of approximately 0.2 kg per week. They are contraindicated if there is a history of drug misuse, drug dependence or psychiatric illness. They should always be prescribed with caution. With the exception of fenfluramine, they are best given intermittently on the grounds of efficacy, safety and cost benefit. (5) The individual response to drug therapy is extremely variable and may reflect differences in drug pharmacokinetics, metabolic adaptation or, less frequently, drug tolerance. (6) Following drug withdrawal, weight regain is the rule. It follows that therapy can most easily be justified if there is a short term need for weight loss, e.g. prior to elective surgery. (7) The safety and efficacy of long term drug therapy has yet to be established. It may prove justifiable in patients most at risk from obesity or from obesity associated disorders such as diabetes and hypertension. However, at present the only established indication for prolonged administration of the currently available drugs is the use of metformin in insulin independent diabetics. (8) The indications for the pharmacological treatment of obesity remain poorly defined. A number of new approaches are being evaluated, and the future may lie in the development of drugs which enhance thermogenesis or primarily act upon the gastrointestinal tract.

Appetite Depressants↗
PubMed1976

Anorectic drugs: use in general practice.

The treatment of obesity is one of the major measures available today in the field of preventive medicine. In particular, the coronary epidemic of Western civilisation would be halted, and most cases of maturity-onset diabetes prevented, if obesity were to be treated effectively. Anorectic drugs act mainly on the satiety centre in the hypothalamus to produce anorexia. They also have various metabolic effects involving fat and carbohydrate metabolism, but many of these may be secondary to loss of weight. Most of the drugs are related directly or indirectly to amphetamine and in addition act by increasing general physical activity. Anorectic drugs tend to lose their effect after some months, and part of this reduction in effect may be due to chemical alterations produced by the drugs in the brain. All the drugs, with the exception of fenfluramine, have a stimulant effect on the central nervous system in some individuals, resulting in restlessness and nervousness, irritability and insomnia. Fenfluramine commonly produces drowsiness in normal doses, but has stimulant effects with overdosage. Dexamphetamine, phenmetrazine and benzphetamine all tend to cause euphoria and the risk of addiction is therefore considerable. Euphoria occasionally occurs with diethylpropion, phentermine and chlorphentermine, but to a much lesser extent. Side-effects also occur due to sympathetic stimulation and gastro-intestinal irritation. These side-effects may cause some individuals to stop taking the drug, but are never serious or dangerous. Drug interactions may occur with monoamine oxidase inhibitors and to a clinically unimportant extent, with antihypertensive drugs. The anorectic drugs have a very definite part to play in the treatment of obesity, mainly for those individuals who have altered their eating habits but have come to a plateau of weight which they find difficult to get below. The drugs are best given in a long-acting form and can safely be continued as long as weight loss persists, provided that the clinician exercises careful supervision. Dexamphetamine, phenmetrazine and benzphetamine should rarely be used because of the danger of addiction, and chlorphentermine is potentially hazardous for long-term use. Diethylpropion emerges as the drug of first choice, as fenfluramine has a tendency to cause depression and has a higher incidence of side-effects. Fenfluramine is mainly useful for people who are especially tense and for obese maturity-onset diabetics who have been unable to lose weight with the biguanides. Mazindol and phentermine appear to be useful as alternative drugs.

Adipose Tissue↗
PubMed1989

Effects of anorectic drugs on the topography of feeding behavior in baboons.

Food intake of six adult male baboons (Papio c. anubis) was monitored during daily experimental sessions lasting 22 hr. Food was available under a chain schedule with two-components. After completion of the first "procurement component" response requirement, access to food, i.e., a meal, became available under the second "consumption component" during which each response produced a 1-g food pellet. After 10 min in which no response occurred, the consumption component was terminated. When given p.o. 45 to 60 min before the start of the daily session, anorectic drugs, with the exception of (+/-)-phenylpropanolamine, produced dose-dependent decreases in food intake, with the following order of potency: phentermine greater than mazindol greater than diethylpropion greater than phendimetrazine = chlortermine = phenmetrazine = chlorphentermine. Feeding topography was differentially affected by drug administration. The latency to the first meal was increased by all of the drugs except chlorphentermine. Only diethylpropion, phendimetrazine and mazindol decreased the number of daily meals, whereas only diethylpropion, phendimetrazine, phenmetrazine and clortermine decreased the size of the first meal. Mazindol was the only anorectic drug tested that did not decrease intake during the first 8 hr of the session. (+/-)-phenylpropanolamine did not decrease food intake in the tested dose range. Phencyclidine, by decreasing intake during the first 8 hr, but not the entire 22-hr session, affected feeding topography differently than the anorectic drugs. In contrast to anorectic drug administration, decreases in food intake after phencyclidine administration were followed by caloric compensation for this initial decrease.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1975

Lethal intoxications with centrally stimulating amines in Sweden 1966-1973.

Fatal intoxications with centrally stimulating amines (CSA) have become increasingly common in Sweden. Toxicological data and pathological findings of 32 cases of amphetamine and phenmetrazine intoxications which occurred from 1966-1973 in Sweden are described. Furthermore, 13 cases where these drugs were not the cause of death, but found in urine and organs, are reported.

Accidents↗