Adulterants in illicit drugs: a review of empirical evidence

Widespread public perception is that illicit drugs contain substances that are a serious risk to health, even though adulterants are often not considered in clinical or forensic toxicology. This review attempts to present an evidence-based overview of adulterants in illicit drugs, and their associated toxicity. Adulterants are deliberately added to increase bulk, enhance or mimic a pharmacological effect, or to facilitate drug delivery. Those present unintentionally are as a result of poor manufacturing techniques. From the reports gathered, adulterants are predominantly substances which are readily available, commonly being caffeine, procaine, paracetamol, and sugars. These are likely to have minimal impact on users' health at low dosages. Other adulterants, particularly in injectable drugs, have the potential to cause serious health issues, but the quantities reported, such as strychnine in heroin, are not life-threatening. The most commonly identified bacterial contaminants identified are Bacillus and Clostridium species. When death or serious illness due to adulteration occurs, circulation of information is particularly vital, such as in the USA regarding heroin and cocaine adulterated with fentanyl, and in Scotland recently regarding anthrax contaminated heroin. The complex interactions of supply, demand, and control of illicit drugs have a tangible impact on their adulteration. Continuing vigilance and the circulation of information is, therefore, desirable as a public health issue. As part of that strategy, analyses performed for adulterants needs to be encouraged, which are considerably limited in number and scope at the moment.     

Synthetic and natural coumarins as cytotoxic agents

Coumarins, an old class of compounds, are naturally occurring benzopyrene derivatives. A lot of coumarins have been identified from natural sources, especially green plants. The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution. Coumarins have attracted intense interest in recent years because of their diverse pharmacological properties. Among these properties, their cytotoxic effects were most extensively examined. In this review, their broad range of effects on the tumors as shown by various in vitro and in vivo experiments and clinical studies are discussed. Hence, these cytotoxic coumarins represent an exploitable source of new anticancer agents, which might also help addressing side-toxicity and resistance phenomena. These natural compounds have served as valuable leads for further design and synthesis of more active analogues. In this review, plant derived coumarins and their synthetic analogues were systematically evaluated based on their plant origin, structure-activity relationship and anticancer efficacy. Owing the their diverse effects and inconclusive results from different in vitro studies, the mechanism of their action is not yet fully understood and correlation of effects with chemical structures is not conclusive at the moment. It is the objective of this review to summarize experimental data for different coumarins, used as cytotoxic agents, because promising data have been reported for a series of these agents. Yet, the results from different coumarins with various tumor lines are contradictory in part. We therefore conclude that there is still a long way to go until we know which cytotoxic agent will clinically be suitable for what tumor entity for treatment. Their ability to bind metal ions represents an additional means of modulating their pharmacological responses.     

Detection of undeclared erectile dysfunction drugs and analogues in dietary supplements by ion mobility spectrometry

An ion mobility spectrometry (IMS) method was developed to screen for the presence of undeclared synthetic erectile dysfunction (ED) drugs or drug analogues in herbal dietary supplements claiming to enhance male sexual performance. Ion mobility spectra of authenticated reference materials including three FDA approved drugs (sildenafil citrate, tadalafil, vardenafil hydrochloride trihydrate) and five previously identified synthetic analogues (methisosildenafil, homosildenafil, piperidenafil, thiosildenafil, thiomethisosildenafil) were measured to determine their reduced ion mobilities (K₀). All eight compounds exhibited reduced mobilities between 0.8257 and 1.2876 cm²/(V s). Twenty-six herbal products were then screened for the presence of these compounds, and 15 of the 26 products tested positive for the presence of ED drug or drug analogue adulterants based on their reduced ion mobilities. IMS results were compared against the results obtained from an independent LC/MS reference method for the identical samples. Herbal dietary supplements containing adulterants were classified with 100% accuracy and most of the adulterants were correctly identified by a comparison of the K₀ of the adulterant to the K₀ of the authenticated reference material. The results demonstrate that IMS is a viable method for screening herbal dietary supplements for the presence of ED drug or drug analogue adulterants.     

New advances in anti-HSV chemotherapy

Treatment of human herpes simplex virus (HSV) diseases represents an important goal, as herpetic infections are not controlled by vaccination. Many therapeutic agents have been developed and used for HSV infections and several alternative natural compounds are under investigation. Most of the drugs clinically employed against HSV types 1 and 2 are represented by guanosine nucleoside analogues, such as aciclovir and aciclovir-like drugs. The emergence of aciclovir-resistant virus strains provided a stimulus for increased search of new effective agents. Alternative drugs are other nucleoside analogues, such as the vidarabine, brivudin, and cidofovir, or pyrophosphate analogues such as foscarnet, that showed efficacy for HSV infections refractory to aciclovir. However, the risk of adverse effects reported for available anti-herpetic compounds and the frequent development of drug-resistant strains of HSV following therapeutic treatment generate the need for new antiviral agents. In the last years, several studies have been carried out on the anti-HSV activity of different components of innate host defences such as cationic antimicrobial peptides. The antiviral activity of these peptides often appears to be related to the viral adsorption and entry process or is a result of a direct effect on the viral envelope. Other natural compounds, extracts from medicinal plants employed in ethnomedicine and displaying marked anti-herpetic activity, are at present under investigation to determine the scientific evidence and rationale for their clinical use. This review discusses the anti-HSV activity of compounds licensed for clinical use and promising natural molecules.     

Behavioural evaluation of peptides related to scotophobin

A synthetic pentadecapeptide, desacetylscotophobin analogue (DS 1-15), which differs from the natural product in terms of activity and in structure, has been tested in various behavioural tests. To determine the active core of DS 1–15, two other peptides corresponding to the residues 8–15 of the parent molecule (ZS 8–15 and HS 8–15) were tested in the same behavioural situations.

These three peptides given in a single subcutaneous injection of 5 μg delayed extinction of a pole jumping avoidance response in an equipotent manner for approximately 7 days. In a passive avoidance situation, in which latency to enter a dark box was measured after animals had experienced mild shock 24 hr previously, avoidance latency was increased for several days following a single subcutaneous injection of 5 μg DS 1–15 and HS 8–15, while ZS 8-15 was much less active. None of these peptides affected passive avoidance latency in rats which had no previous shock experience in the dark box.

Peptides were virtually inactive in a light-dark preference test and in an open field test.

It is suggested that discrepancies in data with scotophobin and analogues as reported in the literature could well be the result of differences in aversive stimulation to which animals might have been unintentionally exposed.     

Synthetic and natural coumarins as antioxidants

Coumarins, an old class of compounds, are naturally occurring benzopyrene derivatives. A lot of coumarins have been identified from natural sources, especially green plants. These natural compounds have served as valuable leads for further design and synthesis of more active analogs. The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution. Coumarins have attracted intense interest in recent years because of their diverse pharmacological properties. Among these properties, their antioxidant effects were extensively examined. In this review, plant derived coumarins and their synthetic analogs will be systematically evaluated based on their plant origin, structure-activity relationship and antioxidant efficacy. Owing their diverse effects and inconclusive results from different in vitro studies, the mechanism of their action has not yet been fully understood and the correlation of effects with chemical structure is not conclusive at the moment. It is the objective of this review will be to summarize experimental data for different coumarins used as antioxidant agents, because promising data have been reported for a series of these agents. In addition, their ability to bind metal ions represents an additional means of modulating their pharmacological responses.     

Synthetic and application perspectives of azapodophyllotoxins: alternative scaffolds of podophyllotoxin

Podophyllotoxin (1) has been known to possess anti-tumor activity and is still considered an important lead for research and development of antineoplastic agents. Derivatives of podophyllotoxin, namely etoposide (2), etopophos (3) and teniposide (4) have been developed and are currently used in clinic for the treatment of a variety of malignancies. These agents are also used in combination therapies with other drugs. Due to the drug resistance developed by cancer cells as well as side effects associated with the use of these agents in clinic, the search for new effective anticancer analogues of podophyllotoxin remains an intense area of research. The structural complexity of podophyllotoxin, arising from the presence of four stereogenic carbons in ring C has restricted most of the structural activity relationship (SAR) studied by derivatization of the parent natural product rather than by de novo multi-step chemical synthesis. These issues provide strong impetus to a search for analogues of 1 with simplified structures, which can be accessible via short synthetic sequences from simple starting materials. Even if such initial compounds might have diminished cytotoxic potencies compared with the parent cyclolignan, the ease of preparation of carefully designed libraries of analogues would lead to more informative SAR studies and expeditious structure optimization. In this regard, during the last two decades considerable efforts have been made to synthesize aza- analogs of podophyllotoxin, i. e. aza-podophyllotoxins, with hetero atoms at different positions of the podophyllotoxin skeleton, while keeping the basic podophyllotoxin structure. Recently, there have been significant efforts towards the convenient synthesis of aza-analogs of 1. The use of multicomponent reactions (MCRs) and the synergies of ultrasound and microwave irradiations have increased the synthetic speed and variety of azapodophyllotoxins which are and will be available to be tested against a diverse population of carcinomas and other diseases. It has been reported that several aza-podophyllotoxins retain a great fraction of the cytotoxicity associated with the parent lignan. This review focuses on the strategies towards synthesis of various aza-podophyllotoxin analogues and their biological activities.     

花椒及其混淆品的rDNA ITS区序列分析与鉴别

目的研究不同居群的花椒及其混淆品的rDNA ITS区碱基序列的特征及其差异，为花椒的鉴别提供可靠的分子标记。方法运用PCR产物直接测序和克隆测序法对甘肃、陕西、四川、河北等7个花椒居群及3个混淆种的rDNA ITS区(包括ITS1，5.8S，ITS2)碱基序列进行序列测定。结果首次报道花椒ITS区的碱基序列，序列总长度为619-620 bp，长度变异较少，与混淆种长度仅相差4 bp。花椒各居群中，rDNA ITS区碱基序列有15个变异位点、12个信息位点、3个特异性识别位点。与混淆品间的碱基差异则较为显著，多达71个变异位点，有4个花椒特异性识别位点。结论依据花椒ITS区的序列特征可准确鉴别各居群的花椒及其混淆品；亲缘关系密切的花椒居群在地理位置上也非常靠近；rDNA ITS序列特征可作为花椒种内和种间鉴别的有效分子标记。     

他克林衍生物及其类似物的研究进展

他克林是一个选择性较好但毒副作用明显的乙酷胆碱酯酶抑制剂。为了克服其不足，许多他克林衍生物和类似物都已被合成并进行了药理研究。从他克林的芳环、脂环和侧链氨基等3个方面对他克林衍生物及类似物的合成和药理研究进行综述。     

Levamisole in Illicit Trafficking Cocaine Seized: A One-Year Study

Cocaine use is increasing around the world and its purity is frequently altered through dilution, substitution, contamination, and adulteration. Sugars, talc, starch, and carbonates represent the principal diluents of cocaine, while phenacetin, levamisole, caffeine, and lidocaine are its major adulterants in Europe. Levamisole is used because it is an odorless powder, with physical properties similar to cocaine, and it has reasonable cost and availability, being widely used in veterinary medicine. For this study, we analyzed 88 cocaine samples. The seized cocaine analyzed showed an average purity of 55% and the most frequent adulterants identified were: levamisole (31.8%), caffeine (6.8%), lidocaine (2.3%), acetaminophen (2.3%), and phenacetin (1.1%). Our aim is the study of the presence of levamisole, over other adulterants in seized cocaine samples, due to its recognized human toxicity. The chronic use of levamisole-adulterated cocaine represents a serious public health issue because it may be responsible for side-effects such as dermal vasculopathy, leukoencephalopathy, leukopenia, agranulocytosis, pulmonary hemorrhage, multiple emboli, and several other effects. Moreover, aminorex can cause idiopathic pulmonary hypertension, presenting another harmful and mostly lethal side-effect from cocaine cut with levamisole. In conclusion, levamisole determination should be performed in routine toxicological analysis in deaths due to cocaine use.     

Old and new synthetic cannabinoids: lessons from animal models

Abstract

Synthetic cannabinoids have long been studied for their therapeutic potentials. However, during the last decade, new generations of synthetic cannabinoid agonists appeared on the drug market. These new psychoactive substances are currently sold as ‘marijuana-like’ products as they claim to mimic the effects of the psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC). Yet, their effects are more intense and potent than THC, typically last longer and are often associated to serious psychiatric consequences. Animal models of drug addiction are frequently used in preclinical research to assess the abuse potential of new compounds, evaluate drug positive reinforcing effects and analyze drug-induced behaviors. Some of these protocols have been used recently to study the newly synthesized cannabinoid agonists and have started elucidating their pharmacology and actions in the brain. The aim of this review is to summarize the major findings reported by animal studies that tested synthetic cannabinoids of first, second, and third generation by using self-administration and reinstatement models, drug discrimination and conditioned place preference procedures. Altogether, behavioral studies clearly indicate that synthetic cannabinoids possess abuse liability, are likely to activate the brain reward circuit and induce positive subjective and reinforcing effects.     

Direct C-glycosylation of guanine analogues: the synthesis and antiviral activity of certain 7- and 9-deazaguanine C-nucleosides

C-Glycosylation of two guanine analogues, 9-deaza- and 7-deazaguanine, has been achieved under Friedel-Crafts conditions, providing a direct synthetic route to 9-deazaguanosine (4; 2-amino-7-beta-D-ribofuranosyl-5H-pyrrolo[3,2-d]pyrimidin-4(3H)-one) and 8-beta-D-ribofuranosyl-7-deazaguanine (16), respectively. This electrophilic C-glycosylation was applied successfully to six guanine and substituted-guanine analogues resulting in yields of approximately 50%. This represents the first reported C-ribosylation of preformed nitrogen heterocycles isosteric with guanine. These C-nucleosides were evaluated for their ability to provide protection against a lethal Semliki Forest virus infection in mice, relative to 7-thia-8-oxoguanosine which was used as a positive control. Two of the C-nucleosides, 2-amino-6-chloro-5-methyl-7-beta-D-ribofuranosyl-5H-pyrrolo [3,2-d]pyrimidin-4(3H)-one (12) and the corresponding 6-bromo derivative (13), showed good prophylactic activity in this virus model system.     

Simple coumarins and analogues in medicinal chemistry: occurrence, synthesis and biological activity

Coumarins, also known as benzopyrones, are present in remarkable amounts in plants, although their presence has also been detected in microorganisms and animal sources. The structural diversity found in this family of compounds led to the division into different categories, from simple coumarins to many other kinds of policyclic coumarins, such as furocoumarins and pyranocoumarins. Simple coumarins and analogues are a large class of compounds that have attracted their interest for a long time due to their biological activities: they have shown to be useful as antitumoural, anti-HIV agents and as CNS-active compounds. Furthermore, they have been reported to have multiple biological activities (anticoagulant, anti-inflammatory), although all these properties have not been evaluated systematically. In addition, their enzyme inhibition properties, antimicrobial and antioxidant activities are other foremost topics of this field of research. The present work is to survey the information published or abstracted from 1990 till 2003, which is mainly related to the occurrence, synthesis and biological importance of simple coumarins and some analogues, such as biscoumarins and triscoumarins. Data are also highlighted, concerning the development of new synthetic strategies that could help in drug design and in the work on SAR or QSAR.     

Collision-induced dissociation pathways of H<Subscript>1</Subscript>-antihistamines by electrospray ionization quadrupole time-of-flight mass spectrometry

Over the past decades, mass spectrometry technologies have been developed to obtain mass accuracies of one ppm or less. Of the newly developed technologies, quadrupole time-of–flight mass spectrometry (Q-TOF–MS) has emerged as being well suited to routine and high-throughput analyses of pharmaceuticals. Dietary supplements and functional foods have frequently been found to be contaminated with pharmaceuticals. In our continuous efforts to develop methodologies to protect public health against adulterated dietary supplements, we have constructed a mass spectral database for 21 H₁-antihistamines encountered as adulterants by using liquid chromatography-electrospray ionization (LC-ESI)/Q-TOF–MS, and have proposed their possible collision-induced dissociation pathways. This database will be very useful for the rapid and accurate detection of H₁-antihistamines (known) and their analogues (unknown) illegally added to dietary supplements as well as in other sample matrices.     

Genotoxicity of hormonal steroids

Hormonal steroids have a widespread use in medicine and their side effects are continuously debated. The possible genotoxic activity of steroids has been the subject of many investigations. The natural estrogens estradiol, estrone and estriol are generally negative in the ICH core battery of tests, but several positive results have been obtained when using additional endpoints of genotoxicity. The genotoxic activity of the 4-hydroxy metabolites of estradiol and estrone is well established. The synthetic steroidal estrogens have a comparable profile of negative and positive test results. Cyproterone acetate and some of its analogues have a special position within the group of progestins. Their genotoxic potential has been established. Other progestins are generally negative in the routine tests. Anti-glucocorticoids, anti-progestins, corticosteroids, androgens, anabolics and anti-androgens appear to be devoid of genotoxic activities. The genotoxic potential of estradiol, estrone and cyproterone acetate with its analogues may play no role under normal physiological and therapeutic conditions. The metabolic conditions that are needed for the formation of DNA-reactive metabolites and oxygen radicals may not be present in humans. Epidemiological cancer data seem to support this view. The importance of thresholds in the dose-effect-relationship of genotoxicity data and their use in risk assessment is discussed.     

Synthesis of tacrine analogues and their structure-activity relationships

Three man synthetic routes to analogues of tacrine are described: reaction of anthranilonitriles with cyclohexanone and other ketones, reaction of various anilines with alpha-cyanoketones, and reactions involving anilines and cyclic beta-ketoesters. Although tacrine has a wide range of pharmacological effects, it is best known as an inhibitor of cholinesterase enzymes. Many of the analogues that have been made have not been tested against acetylcholinesterase or butyrylcholinesterase activity. Consequently, there is limited information from which a detailed understanding of structure-activity relationships can be derived. However, some halogenated derivatives are not only more potent acetylcholinesterase inhibitors than tacrine, they are also more selective for acetylcholinesterase than for butyrylcholinesterase.     

Challenge of studies on the development of new Zn complexes to treat diabetes mellitus

In recent years, people all over the world have suffered from various diseases such as cancer, myocardial infarction, osteoporosis, hypertension, and diabetes mellitus (DM). Especially, DM, well-known as one of lifestyle-related diseases, has been regarded as a serious problem, because it is difficult to fully recover. The number of patients suffering from DM in 2007 was reported to be approximately 200 million people worldwide. However, insulin preparations and synthetic therapeutics, which are clinically used treatment of DM, have been associated with problems such as physical and mental pain due to daily injections and certain severe side effects, respectively. Zn, which is an essential trace element in animals and humans and plays an important role in maintenance of their lives, has been indicated to exhibit insulin-like activity. Since the finding of insulin-like effects of Zn, several Zn complexes have been proposed as a new type of anti-diabetic therapeutics which is differ from existing medicines. In this symposium, we introduce the anti-diabetic effect, complication relieving effect, and action mechanism of bis(2-mercaptopyridine-N-oxidato)Zn complex with Zn(S(2)O(2)) coordination mode.