Current Medicinal Chemistry - Volume 19, Issue 33, 2012

Cocaine abuse represents a significant health issue worldwide. Besides cardiovascular complications, psychiatric and neurologic symptoms are the most common manifestations of cocaine toxicity. In cocaine abusers brain abnormalities have been shown with computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), or single photon emission computed tomography (SPECT). The spectrum of neuropathologic alterations seen in cocaine abusers is broad. The major findings consist of vascular complications such as stroke, subarachnoid and intracerebral hemorrhages and cerebral ischemia. Persons with underlying arteriovenous malformation or aneurysm are especially prone for such events. Except for a few incidents of vasculitis, the etiology of cocaine- related cerebrovascular events is still unclear. Cocaine-induced vasospasm, impaired hemostasis and platelet function, as well as decreased cerebral blood flow, have been proposed as possible mechanisms. On the molecular level, alterations in the expression of transcription factors and changes of brain neurotransmitter systems have been reported.

Cocaine is a potent psychoactive illicit substance and its abuse represents a major health burden worldwide. The pharmacodynamics and toxicity of cocaine have been extensively documented, and are generally associated to its affinity towards neurotransmitters transporters and several receptors. However, drug-related formation of reactive compounds, as is the case of pro-oxidant reactive species, and interaction at molecular level is still an understudied matter. The involvement of oxidative stress (OS) in cocaine-induced toxicity has been reported in both human and animal models, in several organs and systems, including heart, liver, kidney, and central nervous system (CNS). Cytochrome P450 (CYP450)-mediated cocaine metabolism yields the reactive pro-oxidant compound norcocaine (NCOC) and further oxidative metabolites. Special emphasis should be given to the stable radical norcocaine nitroxide (NCOC-NO·), which plays a key role in cocaine-induced hepatotoxicity, either by entering a futile redox cycle with an N-oxidative metabolite, or by being further oxidized to a highly reactive ion. In fact, cocaine-induced generation of reactive oxygen species (ROS) and consequent OS has been postulated based on the reactivity of cocaine N-oxidative metabolites. Depletion of cellular antioxidant defenses and impairment of mitochondrial respiration have also been considered important causes of ROS production, and subsequent cell death mediated by cocaine. The present review provides a thorough description of the current knowledge on cocaine oxidative metabolism and its role on drug-induced liver and kidney damage.

Medicinal agents, beside occupational and environmental agents, remain one of the most common causes for interstitial lung diseases (ILD). A major problem with ILD is the recognition of the causative agent. In some cases more or less characteristic features of presentation are described. Often, the connection between drug-use and the development of related inflammatory damage or idiosyncratic toxicities is hard to recognize and objectify. Cocaine, a xenobiotic and the most commonly used illicit drug, causes serious medical and social problems. An increasing incidence of lung toxicity related to cocaine or crack-use is being reported worldwide. However, the mechanism of the resulting lung injury is not fully understood. This review summarizes possible molecular mechanisms explaining intraindividual variability in cocaine response and lung toxicity. The importance of including pharmacogenomics in the work-up of patients with suspected drug-induced lung toxicity is highlighted.

Cocaine remains the second most commonly used and trafficked illicit drug in the world after cannabis. This psychostimulant drug has become an essential part of the world drug scene with a different use among countries. Prevalence of cocaine use (lifetime, last year, last month use) is particulary high among males aged between 15 and 34 years. Five per cent of cocaine users will develop a substance- dependence during the first year of use, and 20% of these will become long-term cocaine-dependent patients. The number of patients entering drug treatment for primary cocaine use has been increasing in Europe for several years. Cocaine addiction is a worldwide public health problem, which has somatic, psychological, psychiatric, socio-economic and judicial complications. This article aims to provide the clinician with a detailed description of the clinical aspects, the adverse effects and the complications of cocaine addiction. Literature searches were conducted for the period from January 1985 to February 2012 using PubMed, EMBASE, PsycInfo, and Google Scholar.

Cocaine-induced cardiovascular disorders such as hypertension, thrombosis, myocardial dysfunction, cardiac dysrhythmias and endocarditis have received widespread attention in the context of cocaine abuse. The number of sudden deaths from cardiac causes, including myocardial infarction, ventricular tachyarrhythmia or aortic dissection, is also increasing. This manuscript will highlight the recent employment of study about cocaine cardiotoxicity and oxidative stress. Evidence has revealed that cardiac oxidative stress is a prominent early event of cocaine administration, which severely compromises the cardiac antioxidant cellular system and causes cardiac antioxidant cellular system injuries. Oxidative damage such as peroxidation of membrane phospholipids and depletion of nonenzymatic antioxidants such as glutathione have been found in the myocardium of chronic cocaine-treated animals and in patients. The data indicate that cocaine administration compromised the heart's antioxidant defense system. About the mechanisms involved in the cellular damage, the evidence that cocaine causes apoptosis in the heart comes from in vivo study. In animals model after short-term and long term-cocaine administration, the investigators demonstrates the role of Reactive Oxygen Species as a trigger of cardiac injury induced by cocaine. Cocaine also increased infiltration of inflammatory cells in the heart, and apoptotic cells were predominantly found near inflammatory cells. The role of oxidative stress in cocaine-induced apoptosis in the heart is wide studied and documented.

Cocaine is a powerful stimulant of the sympathetic nervous system by inhibiting catecholamine reuptake, stimulating central sympathetic outflow, and increasing the sensitivity of adrenergic nerve endings to norepinephrine (NE). It is known, from numerous studies, that cocaine causes irreversible structural changes on the brain, heart, lung and other organs such as liver and kidney and there are many mechanisms involved in the genesis of these damages. Some effects are determined by the overstimulation of the adrenergic system. Most of the direct toxic effects are mediated by oxidative stress and by mitochondrial dysfunction produced during the metabolism of noradrenaline or during the metabolism of norcocaina, as in cocaine-induced hepathotoxicity. Cocaine is responsible for the coronary arteries vasoconstriction, atherosclerotic phenomena and thrombus formation. In this way, cocaine favors the myocardial infarction. While the arrhythmogenic effect of cocaine is mediated by the action on potassium channel (blocking), calcium channels (enhances the function) and inhibiting the flow of sodium during depolarization. Moreover chronic cocaine use is associated with myocarditis, ventricular hypertrophy, dilated cardiomyopathy and heart failure. A variety of respiratory problems temporally associated with crack inhalation have been reported. Cocaine may cause changes in the respiratory tract as a result of its pharmacologic effects exerted either locally or systemically, its method of administration (smoking, sniffing, injecting), or its alteration of central nervous system neuroregulation of pulmonary function. Renal failure resulting from cocaine abuse has been also well documented. A lot of studies demonstrated a high incidence of congenital cardiovascular and brain malformations in offspring born to mothers with a history of cocaine abuse.

Drug use is seen more as an individualistic behaviour and is therefore not readily conceived of from a population perspective. There is general recognition of several phases and degrees of drug abuse, from initiation and early-use patterns to long-term chronic use. Cocaine and its derivative "crack" cocaine provide an example of both the globalization of substance use and the cyclical nature of drug epidemics. Cocaine is a powerful CNS (Central Nervous System) stimulant but exerts its action in a several types of adverse health effects, including acute toxic effects (i.e. overdose, accidental injury and violence), dependence, cardiovascular disease, cirrhosis, bloodborne bacterial and viral infections, and mental disorders. Of interest, many people who use Cocaine will use also other drugs; therefore, ascribing adverse health effect to a certain drug might be difficult. Any mucous membrane can act as a port of entry for cocaine and the systemic effect is greatly influenced by the route and speed of administration. The effects of Cocaine mainly depend on the user’s addiction, the dose received and the mode of assumption. Laws restricting the availability of cocaine saw a decrease in consumption in these countries until the 1960s. The number of cocaine users worldwide ranged from 14 million to 21 million (0·3–0·5% of the population aged 15–64 years). The largest market was North America, then western and central Europe and South America.

Cocaine is one of the most used psychomotor stimulants all over the world. On this basis, the interest for the pharmacological activity and the pharmacodynamic and pharmacokinetic aspects of this drug is very prominent in both clinical and forensic toxicological environments. The review presents and discusses 65 scientific publications covering all the aspects of cocaine toxicokinetic, including absorption, distribution, metabolism and elimination of the drug. Particular attention has been dedicated to the studies on the disposition of the drug in alternative biological matrices, such as oral fluid, hair, fetus fluids and tissues, and sweat. In fact, in the last years the use of these matrices has been proposed in clinical and forensic drug analysis in order to obtain additional information to that which can be obtained by analyzing the traditional biological matrices, such as blood and urine.

Cocaine is a widely abused drug responsible for the majority of deaths ascribed to drug overdose. Many mechanisms have been proposed in order to explain the various cocaine associated cardiovascular complications. Conventionally, cocaine cardiotoxicity has been thought to be mediated indirectly through its sympathomimetic effect, i.e., by inhibiting the reuptake and thus increasing the levels of neuronal catecholamines at work on adrenoceptors. Increased oxidative stress, reactive oxygen species, and cocaine-induced apoptosis in the heart muscle have suggested a new way to understand the cardiotoxic effects of cocaine. More recent studies have led the attention to the interaction of cocaine and some metabolites with cardiac sodium, calcium and potassium channels. The current paper is aimed to investigate the molecular mechanisms of cocaine cardiotoxicity which have a specific clinical and forensic interest. From a clinical point of view the full knowledge of the exact mechanisms by which cocaine exerts cardio – vascular damage is essential to identify potential therapeutic targets and improve novel strategies for cocaine related cardiovascular diseases. From a forensic point of view, it is to be underlined that cocaine use is often associated to sudden death in young, otherwise healthy individuals. While such events are widely reported, the relationship between cardiac morphological alterations and molecular/cellular mechanisms is still controversial. In conclusion, the study of cocaine cardiovascular toxicity needs a strict collaboration between clinicians and pathologists which may be very effective in further dissecting the mechanisms underlying cocaine cardiotoxicity and understanding the cardiac cocaine connection.

Cocaine belongs to the group of psychostimulants and together with amphetamines has been recognized as one of the most significant examples of drug abuse. Cocaine abuse is due to intense feelings of euphoria, friendliness, empathy, and hyperactivity, which result from its potent inhibitory effects on presynaptic dopamine and noradrenaline re-uptake. Misuse of cocaine can induce severe toxic effects, including neurotoxicity, cardiotoxicity, hepatotoxicity. There are a number of data, both experimental and clinical, regarding its hepatotoxic effects, associated with lipid peroxidation-induced oxidative damage. The oxidative metabolism of cocaine to reactive oxygen species (ROS) like nitrogen peroxide and superoxide anion radicals are thought to be responsible for the cocaine associated liver injury. This review summarizes the present information on cocaine hepatic biotransformation and the possible role of its oxidative metabolism in cocaine-induced hepatic injury.

Metabolic fate plays an important role in the elimination of drugs and other foreign compounds from the body. Metabolism through various enzyme systems, makes the parent compound more hydrophilic, thus, it can be readily excreted from the body. Some active metabolites of drugs are produced following N-, O-, and S-desalkylation. These metabolites are either more or less potent, or as potent as their parent drugs. The removal of alkyl groups from tertiary aliphatic and acyclic amines is carried out by hepatic cytochrome P450 mixed-function oxidase enzymes. Several drugs undergo this process, which yields free hydroxyl-, or amino-groups, in addition to aldehyde from the splitted alkyl group. Metabolism of drugs into clinically active compounds indicates an extra target of therapeutic drug monitoring. Numerical data of logP values show how lipophilicity changes through metabolism to facilitate excretion. The example of phenacetin – paracetamol opened up a way for improving pharmacological effect by the use of a metabolite. This review gives a detailed description of these drugs, their active and major metabolites found in humans or animals, metabolizing cytochrome P450s, and the most recent analytical methods for their determination.

The mdm2 oncogene has recently been suggested to be a valuable target for cancer therapy and prevention. Overexpression of mdm2 is often seen in various human cancers and correlates with high-grade, late-stage, and more treatment-resistant tumors. The MDM2-p53 auto-regulatory loop has been extensively investigated and is an attractive cancer target, which indeed has been the main focus of anti-MDM2 drug discovery. Much effort has been expended in the development of small molecule MDM2 antagonists targeting the MDM2-p53 interaction, and a few of these have advanced into clinical trials. However, MDM2 exerts its oncogenic activity through both p53-dependent and -independent mechanisms. Recently, there is an increasing interest in identifying natural MDM2 inhibitors; some of them have been shown to decrease MDM2 expression and activity in vitro and in vivo. These identified natural MDM2 inhibitors include a plethora of diverse chemical frameworks, ranging from flavonoids, steroids, and sesquiterpenes to alkaloids. In addition to a brief review of synthetic MDM2 inhibitors, this review focuses on natural product MDM2 inhibitors, summarizing their biological activities in vitro and in vivo and the underlying molecular mechanisms of action, targeting MDM2 itself, regulators of MDM2, and/or the MDM2-p53 interaction. These MDM2 inhibitors can be used alone or in combination with conventional treatments, improving the prospects for cancer therapy and prevention. Their complex and unique molecular architectures may provide a stimulus for developing synthetic analogs in the future.

Plague is an infectious disease with a high mortality rate that has repeatedly impacted human society. It remains a threat in many parts of the world today. Plague is caused by the bacterium, Yersinia pestis (Y. pestis), which has as one of its required virulence factors, the protein-tyrosine phosphatase, YopH. Therefore, YopH represents a potential target for the treatment of Y. pestis infection. Recent recognition of Y. pestis as a possible bioterrorism agent and the fact that it is still the cause of endemic disease around the world make it an important object of study and heighten the need for new anti-plague agents. The current review covers aspects of plague and its historical occurrence and summarizes approaches to developing YopH inhibitors.

While prognostic factors can help to classify the standard risk of subpopulations of patients with the same tumor entity, it is still not possible to predict the response of individual patients to specific therapies. The reason for such wide variation in cancer therapy responses remains largely unknown. The field of chemotherapy is currently undergoing a paradigm shift from classical cytotoxic chemotherapy to targeted therapy in order to kill tumor cells more efficiently with fewer side effects on normal tissue. In the present review, we focus on colorectal carcinoma, which is one of the most frequent tumor types worldwide and represents a leading cause of cancer-related deaths. The signaling pathways downstream of epidermal growth factor receptor (EGFR) are central to the biology of colorectal cancer. A considerable achievement during the past years was the development of targeted therapies against EGFR using monoclonal antibodies and small molecule inhibitors. Two major pathways mediate signal transduction through EGFR: the RAS/RAF/MAPK/ERK and the PI3K/AKT/ PTEN/mTOR pathways. Sometimes, predictive biomarkers can provide information on the expected response of tumors to standard chemotherapy. Such molecular markers for EGFR-targeted treatment have been described. However, disease progression and resistance towards EGFR-directed drugs frequently develop due to mutations in genes downstream of EGFR. In this review, we describe the mechanisms by which colorectal cancers gain resistance against EGFR-targeted therapies as well as strategies to bypass mutationinduced resistance in these two signaling pathways.

Following the demonstration that addition of a 2-cyano group to aziridines prevented DNA alkylation and thus reduced toxicity, many novel 2-cyanoaziridines were synthesized and evaluated as immunomodulating and antitumor agents. They typically reacted with thiols such as cysteine, depleting them and allowing the accumulation of reactive oxygen species. Two of these compounds, azimexon and ciamexon, showed activity against tumors in clinical trials. Imexon was produced by cyclization of 2-cyanoaziridine-1- carboxamide in the presence of hydroxide ions. The two enantiomers were prepared by a process involving chiral chromatography. They were equipotent against cultured tumor cells. Imexon also reacts with thiols and it is especially potent against multiple myeloma in cell cultures. An efficient chemical synthesis and a lyophilization formulation of imexon as a water soluble, injectible drug, were developed. In Phase I and I/II clinical trials imexon showed hints of activity against a variety of tumors, but a randomized double-blind Phase II trial of imexon plus gemcitabine versus gemcitabine alone in pancreatic cancer showed no enhancement of activity above that of gemcitabine alone. This result was disappointing because in cell culture and mice the two compounds were synergistic. Based on a complete response in a Phase I trial, a new Phase II clinical trial of imexon is underway in non-Hodgkins lymphoma.

Liposomes loaded with lactosyl-norcantharidin phospholipid complex (LPC) were prepared, in which soybean phosphatidylcholine was used to improve the liposolubility of lactosyl-norcantharidin (Lac-NCTD). The pH-sensitive LPC liposomes (pH-LPC-lips) were obtained by electrostatic adsorption of the carboxymethyl chitosan onto the surface of the liposomes. The in vitro drug release of pH-LPC-lips and LPC-lips was investigated in dissolution media with pH ranging from 1.0 to 8.0. The in vitro antitumor activity and cellular uptake of Lac-NCTD and its liposomes to HepG2 cells were studied. The pH-LPC-lips demonstrated strong cytotoxicity against the cells and easily permeated the cell membrane. The in vivo antitumor activities of Lac-NCTD and its liposomes were evaluated in mice bearing H22 liver tumors. The pH-LPC-lips displayed the best tumor inhibitory effect. The optical imaging results indicated that Cy7- labeled pH-LPC-lips showed excellent hepatocyte specificity in H22 tumor-bearing mice. Therefore, pH-LPC-lips can be regarded as liver-targeting agents that combine targeting and active releasing.