Party drugs: properties, prevalence, patterns, and problems

This review summarizes the latest literature on "party" or "club" drugs, defined as MDMA, GHB, ketamine, and Rohypnol, as published from 2002 to early 2005. Club drugs have been categorized as being used at raves and dance parties. The literature shows that each drug has different properties, users, and settings. Each drug has different adverse effects and requires different acute care protocols. Although these drugs were identified early, scientific information about them, including the toxicological tests to identify them, is still evolving. Increasing numbers of studies on the short- and long-term effects of these drugs on humans are being published, but because of limitations on research using human subjects, they may not always be as rigorous as desired and can be cited by drug users to discredit findings of harm. The lack of research-based information on these drugs has led to the emergence of web sites that may or may not provide accurate data. Evaluated chemical dependency treatment protocols using the latest research for each of these different drugs are needed.     

Party Drugs: Properties,Prevalence, Patterns,and Problems

This review summarizes the latest literature on “party” or “club” drugs, defined as MDMA, GHB, ketamine, and Rohypnol, as published from 2002 to early 2005. Club drugs have been categorized as being used at raves and dance parties. The literature shows that each drug has different properties, users, and settings. Each drug has different adverse effects and requires different acute care protocols. Although these drugs were identified early, scientific information about them, including the toxicological tests to identify them, is still evolving. Increasing numbers of studies on the short- and long-term effects of these drugs on humans are being published, but because of limitations on research using human subjects, they may not always be as rigorous as desired and can be cited by drug users to discredit findings of harm. The lack of research-based information on these drugs has led to the emergence of web sites that may or may not provide accurate data. Evaluated chemical dependency treatment protocols using the latest research for each of these different drugs are needed.     

Drug interactions in hypertensive patients. Pharmacokinetic, pharmacodynamic and genetic considerations

Antihypertensive treatment has proven benefits, and the number of patients being treated with these drugs is significant. Hypertensive patients may have other medical illnesses for which they receive medications, and interactions between antihypertensive agents and other drugs is likely. Some of these interactions may lead to undesirable effects or even loss of blood pressure control. However, drug interactions can also be beneficial when 2 antihypertensive drugs with different pharmacological actions are prescribed in combination and with a clear therapeutic objective in mind. Clinicians should be aware of the mechanisms and the consequences of the different types of interaction in hypertensive patients, so that a desired pharmacological response can be achieved with the fewest side effects in the patients.     

The differential effects of morphine,oxotremorine and antipsychotic drugs on DOPAC concentrations in rat brain

The effects of morphine and oxotremorine on concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in the rat striatum and tuberculum olfactorium (TO) have been compared with the effects of the antipsychotic drugs haloperidol, chlorpromazine and clozapine. All the drugs elevated DOPAC concentrations in both brain regions. While the dose-response curves for the antipsychotic drugs were parallel, had steep slopes and similar maxima, the curves for morphine and oxotremorine were irregularly shaped but the curve for morphine in the TO had some similarity to that of the antipsychotic drugs. From these findings, it is concluded that the dose-dependent increase in striatal DOPAC effected by antipsychotic drugs can be used to differentiate them from other drugs known to elevate dopamine metabolites.     

The differential effects of morphine, oxotremorine and antipsychotic drugs on DOPAC concentrations in rat brain

The effects of morphine and oxotremorine on concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in the rat striatum and tuberculum olfactorium (TO) have been compared with the effects of the antipsychotic drugs haloperidol, chlorpromazine and clozapine. All the drugs elevated DOPAC concentrations in both brain regions. While the dose-response curves for the antipsychotic drugs were parallel, had steep slopes and similar maxima, the curves for morphine and oxotremorine were irregularly shaped but the curve for morphine in the TO had some similarity to that of the antipsychotic drugs. From these findings, it is concluded that the dose-dependent increase in striatal DOPAC effected by antipsychotic drugs can be used to differentiate them from other drugs known to elevate dopamine metabolites.     

The discriminative stimulus properties and detection thresholds of intracranial self-stimulation: Effects of d-amphetamine,morphine, and haloperidol

A two-choice discrimination task was used to evaluate the effects of psychoactive drugs on the discriminative stimulus properties of brain self-stimulation in rats. In these experiments, brain stimulation served both as a discriminative stimulus and as a reinforcing stimulus, but the two effects were manipulated separately. Animals were trained to a criterion of 95% correct in choosing between two levers, and when this levels of accuracy was reached, the ability to choose correctly remained stable over an 8-month period. Increasing the current strength of the discriminative stimulus from zero to 100% of the training current produced a graded increase in the number of trials completed on the appropriate lever. The discriminative effects produced by brain stimulation were evaluated pharmacologically by using three prototypical psychoactive drugs in an attempt to change the detection threshold for the discriminative stimulus. Morphine, d-amphetamine, and haloperidol, drugs that reliably alter reinforcement thresholds for brain stimulation, failed to change detection thresholds. These results demonstrated that: (1) brain stimulation produces potent and reliable discriminative effects and (2) the effects of psychoactive drugs on detection thresholds can be dissociated from their effects on reinforcement thresholds for brain stimulation.     

Past, present, and future technologies for oral delivery of therapeutic proteins

Biological drugs are usually complex proteins and cannot be orally delivered due to problems related to degradation in the acidic and protease-rich environment of the gastrointestinal (GI) tract. The high molecular weight of these drugs often results in poor absorption into the periphery when administered orally. The most common route of administration for these therapeutic proteins is injection. Most of these proteins have short serum half-lives and need to be administered frequently or in high doses to be effective. So, difficulties in the administration of protein-based drugs provides the motivation for developing drug delivery systems (DDSs) capable of maintaining therapeutic drug levels without side effects as well as traversing the deleterious mucosal environment. Employing a polymer as an entrapment matrix is a common feature among the different types of systems currently being pursued for protein delivery. Protein release from these matrices can occur through various mechanisms, such as diffusion through or erosion of the polymer matrix, and sometimes a combination of both. Encapsulation of proteins in liposomes has also been a widely investigated technology for protein delivery. All of these systems have merit and our worthy of pursuit.     

Drug-related lupus. Incidence, mechanisms and clinical implications.

Adverse side effects to drugs and chemicals in which immune mechanisms may be responsible have been described in drug-related lupus (DRL). The spectrum of drugs that may elicit DRL includes such classes as the hydrazines, arylamines, and chemicals that can be metabolised to amines. The 2 major pathways of metabolism--acetylation and N-hydroxylation--are described in detail. The events leading to autoantibody production are not well understood; however, specific consideration of the genetic makeup of patients who are candidates for treatment with these drugs may help identify those at risk of developing DRL.     

Drug-drug interactions affected by the transporter protein, P-glycoprotein (ABCB1, MDR1) II. Clinical aspects

The simultaneous use of several drugs (polypharmacy) for the treatment of cancer, HIV, and other diseases and for multiple ailments of the elderly is a common practice in modern medicine. Co-administration of drugs may result in unwanted side effects. One reason for these side effects can be the altered function of transport proteins, especially of P-glycoprotein (Pgp), due to its simultaneous interaction with several drugs. We describe here some of the observed, unexpected side effects of polypharmacy in the clinic. We also describe intentional modulation of the function of Pgp that is introduced when facilitation of absorption of a drug through the intestines is needed and in cancer chemotherapy. In addition, we mention some methods of testing and ways by which doctors and patients can be alerted to potential side effects.     

Agonist efficacy, drug dependence, and medications development: preclinical evaluation of opioid, dopaminergic, and GABAA-ergic ligands

BACKGROUND: The general premise that receptor theory provides a useful framework for understanding the behavioral effects of psychoactive drugs has been a central tenet of behavioral pharmacology. OBJECTIVES: The purpose of this review is to reiterate this basic theme and, in particular, the proposition that current concepts of pharmacological efficacy can be effectively used to examine behavioral effects of drugs with abuse or dependence potential in a way that contributes to the discovery of drugs to treat drug dependence. EXPERIMENTAL DATA: The review begins by briefly introducing the concept of efficacy and follows with several illustrations of how our current understanding of efficacy can be used to address important research questions in drug discovery. In the first, the likelihood of developing novel opioid analgesics with reduced abuse potential is addressed by considering the different efficacy requirements for the discriminative-stimulus and antinociceptive effects of mu-opioids. From a pharmacologically different perspective within drug abuse research, the review continues with an exposition of efficacy-related differences in the behavioral effects of dopamine D1 agonists and how such differences might be exploited in different medications strategies for treating cocaine dependence. The principles of pharmacological efficacy also have come to guide the development of novel GABAA-related antianxiety medications, and this is illustrated in a discussion of the utility of low-efficacy agonists in the treatment of benzodiazepine dependence. The second half of the paper provides counterpoint to the several examples of how principles of efficacy can be applied in drug discovery. The counterpoint includes, first, a critical evaluation of how the concept of efficacy has been applied in the development of monoamine transport inhibitors as anti-cocaine medications and, in particular, the difficulties this may pose for data analysis. The review ends with a discussion of efficacy-based analysis in drug discrimination research and illustrates some of the obstacles that may be encountered in pharmacologically classifying drugs on this basis. CONCLUSIONS: Ample evidence indicates that many receptor systems can be activated in a graded manner and that principles of efficacy can be judiciously applied to understand and exploit the behavioral effects of drugs that result from such graded activation. However, as cautioned in the last sections, the misapplication of pharmacological concepts in behavioral studies of drugs may obscure their behavioral pharmacology and potentially confound drug discovery.     

Quinone methides and their prodrugs: a subtle equilibrium between cancer promotion, prevention, and cure

The importance of reactive drug metabolites in the pathogenesis of drug-induced toxicity has been investigated since the early 1950s, mainly to reveal the link between toxic metabolites and chemical carcinogenesis. This review mainly focuses on biologically active compounds, which generate reactive quinone methide (QM) intermediates either directly or after bioactivation. Several examples of anticancer drugs acting through the generation of QM electrophiles are given. The use of those drugs for chemotherapeutic purposes is also discussed. The key feature of those QM-generating drugs is their reactivity toward specific nucleophilic biological targets. Modulation of their reactivity represents a challenge for medicinal chemists because, depending on the reactivity of these QM intermediates, their interaction with critical proteins can alter the function of these key proteins and induce a wide variety of responses with functional consequences. Among the possible consequences, antiproliferative effects could be exploited for chemotherapeutic purposes. Information on how such QM-generating drugs can affect individual target proteins and their functional consequences are required to help the medicinal chemist in the design of more specific QM-generating molecules for chemotherapeutic use.     

Aggression,anxiety and vocalizations in animals: GABAA and 5-HT anxiolytics

A continuing challenge for preclinical research on anxiolytic drugs is to capture the affective dimension that characterizes anxiety and aggression, either in their adaptive forms or when they become of clinical concern. Experimental protocols for the preclinical study of anxiolytic drugs typically involve thesuppression of conditioned or unconditioned social and exploratory behavior (e.g., punished drinking or social interactions) and demonstrate the reversal of this behavioral suppression by drugs acting on the benzodiazepine-GABA_A complex. Less frequently, aversive events engenderincreases in conditioned or unconditioned behavior that are reversed by anxiolytic drugs (e.g., fear-potentiated startle). More recently, putative anxiolytics which target 5-HT receptor subtypes produced effects in these traditional protocols that often are not systematic and robust. We propose ethological studies of vocal expressions in rodents and primates during social confrontations, separation from social companions, or exposure to aversive environmental events as promising sources of information on the affective features of behavior. This approach focusses on vocal and other display behavior with clear functional validity and homology. Drugs with anxiolytic effects that act on the benzodiazepine-GABA_A receptor complex and on 5-HT_1A receptors systematically and potently alter specific vocalizations in rodents and primates in a pharmacologically reversible manner; the specificity of these effects on vocalizations is evident due to the effectiveness of low doses that do not compromise other physiological and behavioral processes. Antagonists at the benzodiazepine receptor reverse the effects of full agonists on vocalizations, particularly when these occur in threatening, startling and distressing contexts. With the development of antagonists at 5-HT receptor subtypes, it can be anticipated that similar receptor-specificity can be established for the effects of 5-HT anxiolytics.     

Effects of Surfactants on Lipase Structure,Activity, and Inhibition

Lipase inhibitors are the main anti-obesity drugs prescribed these days, but the complexity of their mechanism of action is making it difficult to develop new molecules for this purpose. The efficacy of these drugs is known to depend closely on the physico-chemistry of the lipid-water interfaces involved and on the unconventional behavior of the lipases which are their target enzymes. The lipolysis reaction which occurs at an oil-water interface involves complex equilibria between adsorption-desorption processes, conformational changes and catalytic mechanisms. In this context, surfactants can induce significant changes in the partitioning of the enzyme and the inhibitor between the water phase and lipid-water interfaces. Surfactants can be found at the oil-water interface where they compete with lipases for adsorption, but also in solution in the form of micellar aggregates and monomers that may interact with hydrophobic parts of lipases in solution. These various interactions, combined with the emulsification and dispersion of insoluble substrates and inhibitors, can either promote or decrease the activity and the inhibition of lipases. Here, we review some examples of the various effects of surfactants on lipase structure, activity and inhibition, which show how complex the various equilibria involved in the lipolysis reaction tend to be.     

Epigenetics, Drugs of Abuse, and the Retroviral Promoter

Drug abuse alone has been shown to cause epigenetic changes in brain tissue that have been shown to play roles in addictive behaviors. In conjunction with HIV-1 infection, it can cause epigenetic changes at the viral promoter that can result in altered gene expression, and exacerbate disease progression overall. This review entails an in-depth look at research conducted on the epigenetic effects of three of the most widely abused drugs (cannabinoids, opioids, and cocaine), with a particular focus on the mechanisms through which these drugs interact with HIV-1 infection at the viral promoter. Here we discuss the impact of this interplay on disease progression from the point of view of the nature of gene regulation at the level of chromatin accessibility, chromatin remodeling, and nucleosome repositioning. Given the importance of chromatin remodeling and DNA methylation in controlling the retroviral promoter, and the high susceptibility of the drug abusing population of individuals to HIV infection, it would be beneficial to understand the way in which the host genome is modified and regulated by drugs of abuse.     

Indirect dopaminergic effects of tofisopam, a 2,3-benzodiazepine, and their inhibition by lithium

Tofisopam, a 2,3-benzodiazepine, has been shown to have anxiolytic activity. However, in contrast to the widely used 1,4-benzodiazepines, it has no anticonvulsant, sedative or muscle relaxant effects. Tofisopam enhanced the behavioural actions of various dopaminergic drugs, both direct agonists, such as apomorphine (climbing behaviour in mice), and indirect agonists, such as (+)-amphetamine and amineptine (jumping behaviour in mice). Chronic treatment with lithium abolished the tofisopam-induced increase in the activity of these dopaminergic drugs. Thus tofisopam appears to induce acutely an increase in the sensitivity of central dopaminergic receptors which can be prevented by pretreatment with lithium.     

Identification, management, and prevention of adverse effects associated with highly active antiretroviral therapy.

PURPOSE: The adverse effects associated with highly active antiretroviral therapy (HAART), as well as potential options available for management of these complications, are summarized. SUMMARY: Effective treatment of human immunodeficiency virus (HIV) infection requires three or four drug regimens that are complicated and commonly associated with adverse effects. This makes compliance difficult and can result in treatment failures, development of resistance, and loss of future treatment options. In addition, some adverse effects may lead to an increase in morbidity and represent additional risk factors for future complications. Serious adverse events after the initiation of HAART are related to both patient and treatment characteristics. Most organ systems can be affected, depending on the drug or class of drugs being used; therefore, proper identification of adverse effects can be difficult. The most common adverse effects are gastrointestinal, neurologic, metabolic, and cardiovascular, although renal, dermatological, and hematologic events may also be encountered. Adverse-effect management has included treatment interruptions and therapeutic drug monitoring but most commonly involves switching to another drug or class of drugs. This requires a complete understanding of HAART regimens and their associated complications. HIV clinics that have employed clinical pharmacists have been able to successfully prevent or identify adverse effects through suggestions for effective treatment alternatives, medication counseling, and compliance education. CONCLUSION: The identification, management, and prevention of adverse events associated with HAART can be difficult but are integral components of effective treatment. Proper interventions are cost-effective and have resulted in improved quality of life for patients infected with HIV.     

Quinoids,quinoid radicals,and phenoxyl radicals formed from estrogens and antiestrogens

Estrogens have a variety of beneficial effects in vivo including protection against osteoporosis, coronary heart disease, Alzheimer's disease, and stroke. Similarly, antiestrogens have been shown to be effective both in treating breast cancer as well as preventing this disease. Despite the health benefits of these drugs adverse side effects have been reported including increased risk for developing certain hormone dependent cancers. Although an estrogenic mechanism likely contributes to mechanism of estrogen/antiestrogen carcinogenesis there is substantial evidence to suggest that metabolism to reactive intermediates is also involved. Both estrogens and antiestrogens can be metabolized to phenoxyl radicals, o-quinones, and semiquinone radicals, all of which could cause damage in cells either through alkylation or oxidation of cellular macromolecules including DNA. In contrast, there are several reports that estrogens and antiestrogens can act as antioxidants which could protect cells against free radical mediated damage and contribute to the beneficial effects of these compounds discussed above. The focus of this review is the role of quinoids, quinoid radicals, and phenoxyl radicals in the biological effects of estrogens and antiestrogens.     

Effects of indomethacin, cyclosporin, cyclophosphamide, and placebo on collagen-induced arthritis of mice

The long term effects of indomethacin, cyclosporin, cyclophosphamide, and placebo on collagen-induced arthritis in mice were tested under two different treatment protocols. A prophylactic experiment examined the effects of the daily drug administration for 180 days beginning one day before the first collagen injection. Under this dosage schedule, cyclophosphamide and cyclosporin decreased the severity of arthritis, while indomethacin did not. A therapeutic protocol examined the effects of these same drugs when daily administration was delayed until the animals had active disease at 78 days after the first collagen injection. Under this protocol, all three drugs reduced the progression of disease. In both protocols, the most significant suppression of arthritis was seen in animals receiving cyclophosphamide which was associated with a decrease in anti-collagen antibody levels. Collagen-induced arthritis in mice should be further investigated as a model to study the long term effects of "slow-acting" anti-rheumatic drugs.     

Psychoactive agents, seizure production, and sudden death in epilepsy

Major tranquilizers as well as antidepressant agents have been associated with clinical seizures in patients administered these agents. The incidence of such seizures is generally low when these drugs are administered in therapeutic doses. However, administration of large doses of these agents has been associated with many cases of convulsion production. The effects that these drugs have on animal models of epilepsy have been examined. It appears that the phenothiazines act as convulsant agents at lower doses, whereas, at higher doses, they act as anticonvulsant drugs. Antidepressants, on the other hand, appear to exert an anticonvulsant effect at low doses and convulsant effects at high doses. The mechanism by which these agents alter the seizure threshold is not yet known. Clinically, drugs of lower seizure production potential should be substituted for those drugs with greater potential in treating epileptic patients for psychiatric ailments. The problem of sudden death in epileptic patients is one that must be confronted. Sudden death has most frequently been attributed to autonomic dysfunction and cardiac arrhythmia in these patients. The contribution of stress in sudden death production also must be taken into account. In addition, some psychoactive agents have been associated with sudden death as well as cardiac arrhythmia and seizure production. Thus, in light of the possible additivity of the factors involved in the production of sudden death, the administration of a psychoactive agent to an epileptic patient should be approached with caution. Those agents that do not alter cardiac rhythm or seizure threshold should be administered if a psychoactive agent is deemed necessary for the management of psychiatric illness in the epileptic patient.