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Fenetylline: New results on pharmacology, metabolism and kinetics
Abstract
In the fenetylline molecule, theophylline is covalently linked with amphetamine via an alkyl chain. The inclusion of amphetamine and results from early metabolic studies have led to speculation that fenetylline may be merely a prodrug for amphetamine and/or theophylline. Although previous studies are not consistent with this hypothesis, additional studies were conducted to comparatively evaluate the profiles of activity exhibited by fenetylline and its two postulated primary metabolites, (+/-)-amphetamine and theophylline. Investigations were also initiated using newly developed high pressure liquid chromatography (HPLC) techniques to further characterize the metabolic pattern that fenetylline undergoes and to examine the relationship between plasma pharmacokinetics and the pharmacodynamic actions of the drug. Fenetylline inhibits activity associated with amphetamine in certain test systems, an effect similar to that previously observed with fenfluramine. Only small amounts of the amphetamine theoretically available in the fenetylline molecule are released. Pharmacodynamic activity associated with fenetylline administration is more closely tied to plasma levels of the parent compound than to any (+/-)-amphetamine produced.
... Captagon commercial use of a brand is the most common in Saudi Arabia, which are fake versions of legal drugs is still available so far despite being illegal for 20 years [4,5]. ...
... But they are squeezed and stamped to look like beads Captagon, and it's not original because some Captagon pills when analyzed does not contain Captagon [4] [5]. ...
... The way to know the person who is taking the Captagon is to analyze the urine from three to six days after the last dose was taken [4] [5]. ...
Introduction: The Captagon is the brand name of Fenethylline and it is a derivative of amphetamine. It was distributed as an
... Fenethylline (phenethylline or fenethylline) is amphetamine conjugated with theophylline via an alkyl chain [9,12,13] (fig. 1). ...
... Results from early metabolic studies had led to speculation that fenethylline could be a pro-drug for amphetamine and/or theophylline [9,12,13]. The 13.7% and 24.5% of an oral dose is apparently cleaved metabolically in human beings into theophylline (weak stimulant chemically and pharmacologically related to caffeine) and amphetamine (active stimulant), respectively [9,31,32]. ...
... The effects lasted approximately up to 180 min., although the respective duration of action in case of (AE)-amphetamine persisted for up to 240 min., as in case of theophylline. Thus, these results are not consistent to the hypothesis that fenethylline acts as a prodrug for amphetamine and suggest that it acts as a different entity [13]. In the same study, fenethylline exhibited a lower anorectic action than amphetamine and another stimulant used as anorectic agent, mazindol [13,36,37]. ...
Fenethylline is a theophylline derivative of amphetamine having stimulant effects similar to those of other amphetamine type derivatives. Fenethylline was used as medicament for hyperactivity disorders in children, narcolepsy and depression, but it has also been used as a drug of abuse under the common name of "captagon". Unlike other drugs of abuse, the clandestine synthesis of fenethylline is simple, using inexpensive laboratory instrumentation and raw materials legal to obtain. A review of all the existing knowledge of fenethylline is reported, concerning its chemistry, synthesis, pharmacology and toxicology, legislation, its prevalence and use as drug of abuse, as well as its analysis in biological or seized samples. Published or reported captagon-related cases and seizures are also presented. All the reviewed information was gathered through a detailed search of PubMed and the internet. The primary drug market for fenethylline (as captagon) has traditionally been countries located on the Arabian Peninsula but also North Africa since 2013. In Arab countries, millions of captagon tablets are seized every year which represents one-third of global amphetamines seizures within a year. Furthermore, three out of four patients treated for drug problems in Saudi Arabia are addicted to amphetamines, almost exclusively in the form of captagon. Significant information on fenethylline is provided for pharmacologists, toxicologists and forensic pathologists. Fenethylline, although old, has recently been introduced to the drug market, especially in Arab countries. Continuous community alertness is needed to tackle this current growing phenomenon. This article is protected by copyright. All rights reserved.
... Fenethylline is formed from two drugs amphetamine and theophylline. 2 Fenethylline is metabolized in the body to its major constituent's amphetamine (one quarter of oral does) and theophylline (14%). Fenethelline (Captagon) was marketed for use as a psychostimulant. ...
... It was originally developed in the 1960s and was used for ADHD symptomology and to an extent, narcolepsy and depression among some other therapeutic indications (23). Metabolic studies have shown that in vivo fenethylline metabolizes to form various metabolites, including amphetamine and theophylline with subsequent amphetamine-like activity (24,25). In recent years, concern has surrounded the abuse of fenethylline (clandestinely synthesized and marketed using its prior trade name "captagon") especially in West Asian and Arab countries (26). ...
The concept of a substance acting as a prodrug for an intended drug is not new and has been known and utilized with particular benefits within medicine for efficacy and patient safety. Prodrugs of psychoactive substances are also not particularly new but this has also extended to considerations of prodrugs of new psychoactive substances (NPS). The continuing evolution of NPS has been a constant forensic challenge. In some countries, this constant evolution has led to the introduction of various alternative methods of drug control. Whether for this reason or in the pursuit of user experimentation, prodrugs of NPS have been discussed, developed, and exploited, posing some distinct forensic challenges. This is especially the case within toxicological analysis of biological fluids and for some substances, also forensic chemical analysis, through inherent instability of the prodrug or metabolism in the body. Particular examples of NPS prodrugs include 1‐propanoyl‐LSD, 1‐butanoyl‐LSD, 1‐acetyl‐LSD, and 2C‐B‐AN. This is in addition to associated substances and medicines that may be used for an intended pharmacological effect. Various prodrugs for stimulant and hallucinogenic substances in particular have appeared in the literature and have been discussed within drug user forums and made available for purchase online. Presently, drug monitoring data from national and international systems indicate that prodrugs are not widely available or problematic. Nevertheless, it is important that there is sufficient awareness of the prodrug concept and potential impact and associated forensic implications, not just for chemical analysis but also for toxicological considerations when a substance has been used.
... Captagon is a central nervous system stimulant that was first introduced in the 1960s as a treatment for attention deficit hyperactivity disorder, depression and narcolepsy. [1][2][3] There is no current acceptable medical use for Captagon. 4,5 Since its first production in Germany in 1961, Captagon has never gained any approval for use by the United States Food and Drug Administration. ...
... Using our established knowledgebase and computational tools, we performed off-target prediction of Captagon with 5-HT receptors due to the lipophilicity of Captagon [72]. As shown in Fig. 13 (left), we mapped the prediction of these potential molecular targets of Captagon via the docking scores. ...
Serotonin (5-HT) receptors are proteins involved in various neurological and biological processes, such as aggression, anxiety, appetite, cognition, learning, memory, mood, sleep, and thermoregulation. They are commonly associated with drug abuse and addiction due to their importance as targets for various pharmaceutical and recreational drugs. However, due to a high sequence similarity/identity among 5-HT receptors and the unavailability of the 3D structure of the different 5-HT receptor, no report was available so far regarding the systematical comparison of the key and selective residues involved in the binding pocket, making it difficult to design subtype-selective serotonergic drugs. In this work, we first built and validated three-dimensional models for all 5-HT receptors based on the existing crystal structures of 5-HT1B, 5-HT2B, and 5-HT2C. Then, we performed molecular docking studies between 5-HT receptors agonists/inhibitors and our 3D models. The results from docking were consistent with the known binding affinities of each model. Sequentially, we compared the binding pose and selective residues among 5-HT receptors. Our results showed that the affinity variation could be potentially attributed to the selective residues located in the binding pockets. Moreover, we performed MD simulations for 12 5-HT receptors complexed with ligands; the results were consistent with our docking results and the reported data. Finally, we carried out off-target prediction and blood–brain barrier (BBB) prediction for Captagon using our established hallucinogen-related chemogenomics knowledgebase and in-house computational tools, with the hope to provide more information regarding the use of Captagon. We showed that 5-HT2C, 5-HT5A, and 5-HT7 were the most promising targets for Captagon before metabolism. Overall, our findings can provide insights into future drug discovery and design of medications with high specificity to the individual 5-HT receptor to decrease the risk of addiction and prevent drug abuse.
... Fenethylline is formed from two drugs amphetamine and theophylline. 2 Fenethylline is metabolized in the body to its major constituent's amphetamine (one quarter of oral does) and theophylline (14%). Fenethelline (Captagon) was marketed for use as a psychostimulant. ...
Drugs are implicated in wide range of kidney disease. Scheduled drugs are also known to cause injury. This report describes a young male who presented with an acute kidney injury after taking Captagon.Case report21‒year‒old male presented to the Emergency Room with abdominal pain, hematuria, lower limb swelling and oliguria. On admission, he was conscious and oriented. The patient’s past
(PDF) Acute nephrotoxicity an unusual side effect or adverse toxicity of Captagon. Available from: https://www.researchgate.net/publication/327420882_Acute_nephrotoxicity_an_unusual_side_effect_or_adverse_toxicity_of_Captagon [accessed Apr 22 2021].
... 3,4,[18][19][20] The ultimate source of fenethylline's psychoactive effects has historically been a debated subject, with some results supporting the position that the parent compound itself exhibits psychoactive effects distinct from those of other central stimulants, while others posit that it acts as merely an amphetamine prodrug. [6][7][8][9][10][11] Considering the additional effort required to synthesize fenethylline, its continued manufacture and use in resource-strained conflict areas provides support for the hypothesis that this drug exhibits exploitable psychostimulant effects that differ from amphetamine alone. ...
PARAGRAPH
Fenethylline, also known as Captagon, is a synthetic psychoactive stimulant that has recently been linked to substance use disorder and ‘pharmacoterrorism’ in the Middle East.1–4 Although fenethylline shares a common phenethylamine core with other amphetamine-type stimulants, it additionally incorporates a covalently-linked xanthine moiety into its parent structure.5,6 These independently-active pharmacophores are liberated during metabolism, resulting in a structurally-diverse chemical mixture being deployed to the central nervous system.7–9 Although fenethylline’s psychoactive properties have been reported to differ from other synthetic stimulants, the in vivo chemical complexity it manifests upon ingestion has impeded efforts to unambiguously identify the specific species responsible for these effects.10,11 Here we develop a ‘dissection through vaccination’ approach, called DISSECTIV, to mitigate fenethylline’s psychoactivity and show that its rapid-onset and distinct psychoactive properties are facilitated by functional synergy between theophylline and amphetamine. Our results demonstrate that incremental vaccination against single chemical species within a multi-component mixture can be used to uncover emergent properties arising from polypharmacologic activity. We anticipate that DISSECTIV will be employed to expose unidentified active chemical species and illuminate pharmacodynamic interactions within other chemically complex systems, such as those found in counterfeit or illegal drug preparations, post-metabolic tissue samples, and natural product extracts.
... The average amount of (-)-methamphetamine isomer excreted in the urine was found to be three times that of the (+)-isomer [80]. Fenethylline (Catpagon ® ), used in the treatment of attention deficit disorder, is metabolized to d,l-amphetamine [83]. Clobenzorex (Dinintel ® ), an anorectic, is metabolized to d-amphetamine, but use of the drug can be differentiated by measurement of the specific metabolite 4-hydroxyclobenzorex [7,107]. ...
Methamphetamine is a popular recreational drug that has also had some historical use as a therapeutic agent. Its effect profile is complex, with stimulant, alerting effects during acute low-dose administration, progressively more disorienting effects on cognition, reasoning, and psychomotor ability with increased dosing and duration of use, and a depressant-like profile during withdrawal, often compounded by delusions and psychotic episodes, especially after high-dose or chronic use. This manuscript reviews the synthetic, structural, and analytical chemistry of the drug; the pharmacology of its central and peripheral effects; its pharmacokinetics following various routes of administration and dosage regimens; and its pharmacodynamics in both acute and chronic administration and therapeutic and recreational doses, noting in particular its effects on judgment, decision making, risk-taking, cognition and psychomotor performance, and violence. Finally, the review considers the issue of how these various effects can impact driving ability and can contribute to impairment. From the material reviewed it is concluded that the use of methamphetamine in anything other than low-dose, therapeutic administration with medical oversight raises the likelihood of some impairment of performance in complex psychomotor tasks such as driving.
Copyright © 2002 Central Police University.
Captagon, known by its genetic name Fenethylline, is an addictive drug that complicates the War on Drugs. Captagon has a strong CNS stimulating effect than its primary metabolite, Amphetamine. However, multi-targets issues associated with the drug and metabolites as well as its underlying mechanisms have not been fully defined. In the present work, we applied our established drug-abuse chemogenomics-knowledgebase systems pharmacology approach to conduct targets/off-targets mapping (SP-Targets) investigation of Captagon and its metabolites for hallucination addiction, and also analyzed the cell signaling pathways for both Amphetamine and Theophylline with data mining of available literature. Of note, Amphetamine, an agonist for trace amine-associated receptor 1 (TAAR1) with enhancing dopamine signaling (increase of irritability, aggression, etc.), is the main cause of Captagon addiction; Theophylline, an antagonist that blocks adenosine receptors (e.g. A2aR) in the brain responsible for restlessness and painlessness, may attenuate the behavioral sensitization caused by Amphetamine. We uncovered that Theophylline’s metabolism and elimination could be retarded due to competition and/or blockage of the CYP2D6 enzyme by Amphetamine; We also found that the synergies between these two metabolites cause Captagon’s psychoactive effects to act faster and far more potently than those of Amphetamine alone. We carried out further molecular docking modeling and molecular dynamics simulation to explore the molecular interactions between Amphetamine and Theophylline and their important GPCRs targets, including TAAR1 and adenosine receptors. All of the systems pharmacology analyses and results will shed light insight into a better understanding of Captagon addiction and future drug abuse prevention.
Fenethylline, commonly known by the trademark name “captagon”, “biocapton” or “fitton”, is one of the most popular illegal drugs used by young communities in the Middle East. It is a theophylline derivate of amphetamine having stimulant effects similar to those of other amphetamine-type derivates. Fenethylline was used as medicament for hyperactivity disorders in children, narcolepsy and depression, but it is also used as a drug of abuse. Unlike other drugs of abuse, the clandestine synthesis of fenethylline is simple, using inexpensive laboratory instrumentation and raw materials legal to obtain. An innovative technique to detect and quantify captagon in waste water is showed, in order to help the police and the other army forces to find terrorists in a smaller district of city.
Corresponding author: Claire Twark, MD.
In diesen Tabellen sind die in Deutschland (D), Österreich (A) und der Schweiz (CH) im Handel erhältlichen Neuroleptika alphabetisch nach ihren gebräuchlichen Kurzbezeichnungen aufgeführt. Es wurden die in der Roten Liste 1997 verwandten internationalen Freinamen (INN), INNv (vorgeschlagene Freinamen) oder sonstigen Kurzbezeichnungen gewählt.
Captagon (fenethylline) has been banned in Saudi Arabia since 1986. Despite this, it remains popular with problem drug users and is in widespread illicit production. Of 667 batches of seized 'Captagon' tablets subjected to physical and chemical tests, 84% were found to be illicitly-produced fenethylline from a common source, and 16% were found to be fake tablets, consisting of a mixture of quinine and caffeine, also presumed to have a common origin. Fenethylline was synthesised by a modification of the German patented method.
This chapter discusses amphetamines. Amphetamines and methamphetamines are powerful central nervous system (CNS) stimulants that have been in use since the early 1900s. These drugs have a single asymmetric center and therefore exist as two enantiomers, each of which has different pharmacological activities. A group of related drugs, often referred to as “designer amphetamines,” comprises several methylenedioxy analogs that, although thought to have useful medicinal effects, are currently not recognized to have any legitimate medical use and are therefore included in Schedule I of controlled substances. They are often found on the illicit market as abused drugs. Nucleophilic (N)-substitution of amphetamine or methamphetamine has been used in the preparation of a number of drugs that have been developed for a variety of reasons. Many are the results of attempts to provide the anorexic effect of amphetamine and methamphetamine while decreasing the undesirable side effects and rapid tolerance seen with those drugs.
7-((RS)2-1-Methyl-2-phenylethylamino)propyl)-theophyllin 3 läßt sich vorteilhafter durch reduktive Aminierung von 7-Acetonyltheophyllin (4) mit (RS)-Amphetamin (2) (Diastereomerenverhältnis 1:1) als durch SN-Reaktion von Proxyphyllintosylat mit (RS)-2 darstellen (Diastereomerenverhältnis 9:1).
3 ist infolge sterischer Hinderung praktisch kein Prodrug mehr für die intermediäre Bildung von (RS)-2 (Ratte). Die Enantioselektivität des nach oraler Gabe im 24-h Harn in Mengen von ca. 1% der Dosis aus 3 gefundenen (RS)-2 wurde HPLC auf einer Cyclobond-Säule über seine Isoindolderivate, gebildet aus o-Phthalaldehyd, Thioglykolsäure und 2, zu 65.2% (Bereich 63–68%) S(+)- und 34.8% R(-)-Amphetamin (Bereich 32–37%) bestimmt.
Enantioselective Biotransformation of a New Theophylline Derivative
Reductive amination of 4 with (RS)-2 is an improved method to obtain 7-((RS)2-((RS)-1-Methyl-2-phenyl-ethylamino)propyl)-theophylline (3) (ratio of diastereomers 1:1) compared with SN-displacement of proxyphyllintosylate with (RS)-2 (ratio of diastereomers 9:1). Due to steric hindrance 3 is no noteworthy prodrug for the intermediate formation of (RS)-2 in rats. The enantioselectivity of 2 after a single oral dose of 3 is determined in 24-h urine by HPLC on a Cyclobond-column using the isoindole derivatives, formed from o-phthalaldehyde, thioglycolic acid, and 2. The R(-)-amphetamine isomer is formed to a lesser amount (34.8%, range 32–37%) than the S(+)-isomer (65.2%, range 63–68%).
Synthesis, Biotransformation, and Pharmacodynamics of a New Theophylline Derivative
7‐[( RS )2‐(( RS )‐1‐Methyl‐2‐phenyl‐ethylamino)propyl]‐theophylline (3) was not described until now. This fenetylline analogue is available by reaction of 7 with an excess of 2 at 150°C. If 2 reacts with 4, an E 2 ‐elimination overwhelms S N ‐nucleophilic displacement yielding compound 5. In vivo studies with male White‐Wistar rats, comparing biotransformation of 3 and 1, demonstrate, that the amount of 2 is decreased from 4.7% of ( RS )‐2 to 1%, probably due to steric hindrance of the attacking monooxygenases by the methyl group at C‐11 of 3. Pharmacodynamic studies of 3, tested with mice, gave similar results to those obtained with 1.
The substances under review are a heterogenous set of compounds from a pharmacological point of view, though many have a common phenylethylamine structure. Variations in structure lead to marked changes in potency and characteristic action.The introductory material presented here is meant to provide a set of chemical and pharmacological highlights of the 28 substances under consideration. The most commonly used names or INN names, Chemical Abstract (CA) names and numbers, and elemental formulae are provided in the accompanying figures. This provides both some basic information on the substances and a starting point for the more detailed information that follows in the individual papers by contributors to the symposium.
In sewer epidemiology, mass balances are used to back-extrapolate measurements of wastewater influent concentrations of appropriate drug residues to assess the parent illicit drug's level of use in upstream populations. This study focussed on developing and refining mass balances for the use of illicit methamphetamine, amphetamine and tetrahydrocannabinol. As a first step, a multi-criteria evaluation was used to select unchanged methamphetamine, unchanged amphetamine and 11-nor-9-carboxy-tetrahydrocannabinol as the most appropriate drug residues to track a selected population's use of illicit methamphetamine, amphetamine and tetrahydrocannabinol, respectively. For each of these selected drug residues, mass balances were developed by utilizing all disposition data available for their release from all their respective sources, incorporating route-of-administration considerations where relevant, and accounting for variations in the metabolic capacity of users of the various relevant licit and illicit sources. Further, since the selected drug residues for the use of methamphetamine and amphetamine cannot only result from their use but numerous other licit and illicit sources, comprehensive general source models were developed for their enantiomeric-specific release to sewers. The relative importance of the sources identified in the general source model was evaluated by performing national substance flow analyses for a number of countries. Results suggested that licit sources of methamphetamine are expected to be only of significance in populations where its illicit use is minor. Similarly, in populations where the use of illicitly produced amphetamine is currently of relevance, licit contributions to the sewer loads of amphetamine are likely to be of negligible importance. Lastly, the study of tetrahydrocannabinol back-extrapolation mass balances suggested that further research is required to assess the importance of fecal elimination of 11-nor-9-carboxy-tetrahydrocannabinol.
Infantile spasms are a severe epileptic encephalopathy with a variety of etiologies that occur in infancy and early childhood. Subjects with infantile spasms are at a higher risk for evolving into intractable epileptic spasms, tending to be refractory to conventional antiepileptic drugs. Genetic polymorphisms of the P-glycoprotein-encoding gene ABCB1 are suspected to be associated with pharmacoresistance phenotypes in epilepsy patients. Conflicting findings have been reported in different populations; few studies have explored whether this apparent association is affected by other host factors, such as specific epilepsy syndrome. We performed a case-control study to determine whether the risk of infantile spasms is influenced by common ABCB1 polymorphisms in a Han Chinese children's population consisting of 91 patients and 368 healthy individuals. DNA was isolated from whole blood, and three genetic polymorphisms (C1236T, G2677T/A, and C3435T) were assayed by PCR-RFLP. There were significant differences in the distributions of 3435TT [P = 0.001; odds ratio = 2.47; 95% confidence interval (CI) = 1.44-4.27] and 3435CT [P < 0.001; odds ratio = 0.28; 95% CI = 0.15-0.54] genotypes between infantile spasm cases and controls. No significant differences were observed in allelic and haplotypic frequencies of ABCB1 polymorphisms between the two groups. This study demonstrated that variations in the C3435T gene play an important role in the pathogenesis of infantile spasms in the Han Chinese population; 3435TT is associated with increased risk of having this epilepsy syndrome.
Reductive amination of 4 with (RS)-2 is an improved method to obtain 7-((RS)2-((RS)-1-Methyl-2-phenyl-ethylamino)propyl)-theophylline (3) (ratio of diastereomers 1:1) compared with SN-displacement of proxyphyllintosylate with (RS)-2 (ratio of diastereomers 9:1). Due to steric hindrance 3 is no noteworthy prodrug for the intermediate formation of (RS)-2 in rats. The enantioselectivity of 2 after a single oral dose of 3 is determined in 24-h urine by HPLC on a Cyclobond-column using the isoindole derivatives, formed from o-phthalaldehyde, thioglycolic acid, and 2. The R(-)-amphetamine isomer is formed to a lesser amount (34.8%, range 32-37%) than the S(+)-isomer (65.2%, range 63-68%).
Fenetylline (CAPTAGON) is included in a list of compounds to be considered by a World Health Organization (WHO) Expert Committee in April 1985 for possible international scheduling under the Convention on Psychotropic Substances, 1971. For over 23 years, this central stimulant has been used therapeutically in hyperkinetic children and other indications in place of amphetamines and other central stimulants with higher risk levels. In good correspondence with recent animal data fenetylline also shows significant qualitative and quantitative differences compared to amphetamine in man. It has few adverse side effects, a lower abuse potential and little actual abuse compared to amphetamine. Thus its benefit/risk assessment is substantially more favourable than that of other central stimulants. For proper therapeutic use of the substance, prescription status is or should be required by national authorities.
The interpretation of methamphetamine and amphetamine positive test results in biological samples is a challenge to clinical and forensic toxicology for several reasons. The effects of pH and dilution of urine samples and the knowledge about legitimate and illicit sources have to be taken into account. Besides a potentially legal prescription of amphetamines, many substances metabolize to methamphetamine or amphetamine in the body: amphetaminil, benzphetamine, clobenzorex, deprenyl, dimethylamphetamine, ethylamphetamine, famprofazone, fencamine, fenethylline, fenproporex, furfenorex, mefenorex, mesocarb, and prenylamine. Especially the knowledge of potential origins of methamphetamine and amphetamine turns out to be very important to prevent a misinterpretation of the surrounding circumstances and to prove illegal drug abuse. In this review, potential precursor compounds are described, including their medical use and major clinical effects and their metabolic profiles, as well as some clues which help to identify the sources.
Medical Review Officer interpretation of laboratory results is an important component of drug testing programs. The clinical evaluation of laboratory results to assess the possibility of appropriate medical use of a drug is a task with many different facets, depending on the drug class considered. This intercession prevents the reporting of positive results unless it is apparent that drugs were used illicitly. In addition to the commonly encountered prescribed drugs that yield positive drug testing results, other sources of positive results must be considered. This review describes a series of compounds referred to as "precursor" drugs that are metabolized by the body to amphetamine and/or methamphetamine. These compounds lead to positive results for amphetamines even though neither amphetamine nor methamphetamine were used, a possibility that must be considered in the review of laboratory results. Description of the drugs, their clinical indications, and results seen following administration are provided. This information allows for the informed evaluation of results with regard to the potential involvement of these drugs.
The purpose of the present investigation was to study effects of valtrate and acetoxyvaltrate hydrine on locomotor activity of mice. The method is characterized by the observation of single animals over two periods of activity. A differentiated effect curve caused by substances during 24 h was maintained and a therapeutic dose effect became evident. Locomotor activity was significantly inhibited by valtrate in a concentration of 0.1 mg/kg injected i.v. and 0.5 mg/kg if applied p.o. Higher concentrations did not result in an elongated effect. Acetoxyvaltrate hydrine, which is characterized by the absence of an epoxide structure, caused reduced locomotor activity in a concentration of 4 mg/kg.
Following oral administration of DL-[14C]prenylamine, about 40% of the dose administered was excreted in urine within 10 days. Less than 0.1% of the dose was excreted as unchanged prenylamine. The drug was extensively metabolized to at least 20 to 25 metabolites. The structure of 12 metabolites could be elucidated by means of g.c.m.s. Ring hydroxylation and further methylation of the phenolic metabolites are the main metabolic pathways involved. A substantial part of the drug and/or its metabolites is metabolized via cleavage of the CNC bond, giving rise to amphetamine and diphenylpropylamine which are further metabolized by aromatic and sidechain hydroxylation.
Amphetamine and secobarbital were compared with a placebo as to their effects on 57 college athletes. Performance was measured objectively. Subjective estimates of performance and mood were also obtained. Performance was significantly improved by 14 mg. of amphetamine sulfate, significantly impaired by 100 mg. of secobarbital, and not significantly influenced by 50 mg. of secobarbital. Subjects reported that amphetamine stimulated them, improved coordination and form, increased strength and endurance, and increased feelings of mental and physical activation, boldness, elation, and friendliness. The 100-mg. dose of secobarbital produced intoxication, elation, "deactivation," and distortion in judgment; the 50-mg. dose produced elation and activation.
Zentrale Wirkungen einiger Methylxanthine (Coffein, Theophyllin, Theobromin) und aromatisch substituierter Theophyllinderivate wurden untersucht und zu der Permeation dieser Substanzen in das ZNS, ihrer Gewebsbindung und ihrem Stoffwechsel in Beziehung gesetzt. 1. Die Wirkung der Xanthine auf die psychomotorische Aktivität und auf das reaktive Verhalten nach Dämpfung durch Chlorpromazin und Reserpin wurde an Mäusen, die Wirkung auf das EEG wurde an Kaninchen untersucht. Die Stimulation der Psychomotorik und die Wirksamkeit bei der Auslösung der EEG-Weckreaktion liefen etwa parallel; nur Coffein und Theophyllin waren die einzigen stärker wirksamen Substanzen. 2. Die Krampfwirksamkeit war am ausgeprägtesten bei aromatisch substituierten Theophyllinderivaten wie Amphetamino-Äthyltheophyllin (AAT) und Benzylamino-Äthyltheophyllin (BAT). Während die EEG-Weckreaktion durch Chlorpromazin gehemmt wurde, erfuhr die Krampfwirksamkeit der Xanthine durch Chlorpromazin eine Erhöhung. 3. In Versuchen an Katzen mit Durchschneidung im Mittelhirnbereich zeigten die Substanzen weitere Unterschiede. Die EEG-Weckreaktion nach Coffein und Theophyllin blieb auch nach Mittelhirndurchtrennung erhalten; durch AAT und BAT war nach der Durchtrennung keine Weckreaktion mehr auszulösen. Ihre Krampfwirksamkeit — rostral wie auch caudal der Durchtrennungsebene — blieb erhalten. 4. Bei intraventrikulärer Applikation an Katzen zeigten die Xanthine Wirkungen, die sich von denen nach Zuführung über den Blutweg stark unterschieden. 5. Bei den Methylxanthinen besteht kein Anlaß zu der Annahme, daß die Wirkungen nicht auf die injizierten Substanzen selbst zurückgeführt werden können. Bei AAT jedoch ist es sehr wahrscheinlich, daß die 2–3 Std nach Applikation beobachtete psychomotorische Erregung auf der Wirksamkeit eines AAT-Metaboliten beruht.
The metabolic fate of fenetylline, 7-[2-(α-methylphenethylamino)ethyl] theophylline hydrochloride was studied in four adult male volunteers after oral administration using two tritium-labeled forms, one labeled on the amphetamine and the other on the theophylline moiety. The comparative metabolism of 3H-d-amphetamine sulfate was also investigated. Within four hours after administration the rate of biotransformation of fenetylline (3H-amphetamine) to its metabolites, was similar to that obtained with 3H-d-amphetamine. Unchanged amphetamine, hippuric acid and p-hydroxylated amphetamine were identified and quantified for selected periods to 24 hr in the urine of the subjects receiving fenetylline (3H-amphetamine) and 3H-d-amphetamine. In subjects administered fenetylline (3H-theophylline) the metabolites were quantified and identified as 1,3-dimethyluric acid, 1,3-dimethylxanthine, 1-methyluric acid and 3-methylxanthine. Conclusions based on these metabolic data suggest that fenetylline pharmacologic action may be due primarily to its metabolic degradation to amphetamine and theophylline.
Amphetamine was administered to healthy subjects as the racemic mixture and as (+)- and (-)-isomers under conditions of urine acidification and alkalinization. Plasma and saliva concentration of each isomer was measured and the kinetics of the individual isomers were determined. (+)-amphetamine was eliminated more rapidly than the (-)-isomer. The difference in half-life between isomers was maximal under basic urinary pH conditions. Saliva amphetamine levels were higher than plasma levels and in the postabsorptive phase were predictably proportional to plasma drug levels.
A method using monkeys for the prediction of physical and psychic dependence was introduced by Dr. M. H. Seevers in 1936. Now it has become an indispensable method in many countries for the application of new analgesics, hypnotics, tranquillizers, etc.
Ten male volunteer subjects were administered single doses of one of the following compounds on five successive weekly occasions using a fully balanced design: 5 mg and 10 mg of amphetamine sulphate, 300 mg and 600 mg of caffeine citrate and lactose placebo. Two hours after ingestion subjective estimations of several mood attributes were made using graphic rating scales. The palmar skin conductance (sweat gland activity) and pulse rate were recorded during the presentation of twenty identical auditory stimuli consisting of one sec 1 kHz tones of 100 dB intensity, the interval between the tones varying randomly from 45 to 80 sec.The rate of diminution of the skin conductance responses to the repeated stimuli (habituation rate) was slowed by both drugs. The number of spontaneous fluctuations in the skin conductance tracing was increased by both drugs. Sloperatio bioassays were computed for both these variables which were then combined in a discriminant-function analysis to increase the precision of the assay. Pulse rate was elevated by amphetamine but not by caffeine.The subjective effects of the drugs were complicated because one subject demonstrated a paradoxical response to amphetamine being relaxed, drowsy and slow while under its influence.Some problems in comparisons of psychopharmacological agents in normal humans are discussed in the light of the results obtained.
Experiments with chickens, pidgeons, mice, rats, guinea-pigs, cats, dogs, squirrel-monkeys and chimpanzees show that stereotyped activity can be produced by amphetamine in doses of 1-20 mg/kg in all these species ranging from birds to primates. In man amphetamine in similar dose, i.e. higher than the therapeutic doses, can produce a psychosis, which so closely resembles schizophrenia, that misdiagnoses have been made. All the known symptoms of schizophrenia are reported, including stereotyped activity.
Pretreatment with fenfluramine considerably increased the concentration of amphetamine in the brain and delayed the disappearance of amphetamine from both brain and plasma.Fenfluramine prolonged the excitatory action of d-amphetamine by at least 4 hr.Pretreatment with fenfluramine counteracted the initial rise of body temperature to d-amphetamine alone. However, 3 hr later body temperature rose and after 4 hr it was 1.4° higher than in rats receiving fenfluramine alone.It is concluded that fenfluramine prolongs certain actions of d-amphetamine but antagonizes others. It is emphasized that metabolic interaction should be taken into account when studies of amphetamine in combination with other drugs are performed.
The toxicity of d-amphetamine in grouped mice is antagonized by theanorexic drug fenfluramine but not by its derivative S 992.The protection of the d-amphetamine toxicity in grouped mice correlates with a decrease in the hyperthermic effect of d-amphetamine.Fenfluramine does not antagonize the action of amphetamine in decreasing brain noradrenaline.
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.
BZT an aromatic amino alkyl theophylhnate, structurally related to amphetamine and theophylline, was injected intravenously into rabbits and an elcctroencephalographic analysis was made. It was found that small doses of 5--20 mg/kg produced transient EEG arousal patterns persisting for approximately 15 minutes while greater amounts of the drug, 20 mg/kg and above, could evoke EEG seizure patterns. Atropine irreversibly blocked the BZT induced EEG arousal. Chlorpromazine, however, proved to have reversible antagonistic EEG effects against BZT. The BZT alerting could be reversed to the chlorpromazine sleep pattern and this blocking effect was changed to an arousal following the administration of BZT. Brain stem transections anterior to the midbrain prevented the BZT alerting response. A different result was noted if the brain stem transection passed through the level of the inferior colliculus leaving the cephalad midbrain reticular formation intact. In this preparation the effects of BZT were the same of those seen in the intact animal as BZT continued to evoke an EEG arousal response. The effect of BZT on recruiting potentials elicited by stimulation of the anterior mediothalamic nuclei revealed a depression of response in only 2 of 6 experiments. Thus the BZT-evoked EEG activation does not appear to depend on depression of the sleep component originating in the mediothalamie nuclei. It is concluded that the effect evoked by BZT involves a mechanism of action that includes stimulation of the midbrain reticular formation. Amphetamine as well as xanthine and its derivatives are used extensively as central nervous system stimulants. However, their site of action in the brain has not been clarified. Theophylline (1,3 dimethyl * We wish to acknowledge the Johnson & Johnson Pharmaceutical Laboratories for liberally supplying us with BZT 7,2-(3 phenyl-2-propyl) aminoethyl theophylline HC1. ** G. F. AYALA on leave from Neurosurgical Clinic University of Milan, Milan, Italy.