Pharmaceuticals, Volume 3, Issue 7 (July 2010) – 20 articles , Pages 1988-2361

Prevalence of psychostimulant use is high, and raising in several countries. Nicotine is the legal stimulant causing the most important public health impact. Cocaine ranks among the most used illicit substances after cannabis. Stimulant medications are frequently misused. Psychostimulants can lead to addiction, have physical, psychological and social health consequences and can induce a great disease burden. The aim of the present article is to provide a literature review on the health effects of stimulants as potential drugs of abuse. It will cover essentially cocaine, amphetamines and its derivatives (including methamphetamines and 3-4-methylenedioxymethamphetamine, ecstasy), nicotine, caffeine and khat, and touch upon the issues of prescribed substances (anti-depressants, weight control medications, attention-deficit hyperactivity disorder medications, hypersomniac disorder). Their pharmacology, addictive potential, health consequences and treatment will be discussed. We used Medline for the literature review from 1990 to the date of this review, and mention the findings of human and animal studies (the latter only if they are of clinical relevance). Full article

This review summarizes progress in treating severe and complicated malaria, which are global problems, claiming at least one million lives annually, and have been accompanied by advances in our understanding of the pathogenesis of severe malaria complications. New drugs such as intravenous artesunate (AS) and intramuscular artemether (AM) are improving outcomes and decreasing malaria deaths. Trials comparing AM to the traditional parenteral drug, quinine, have not demonstrated however convincing evidence of a mortality advantage for AM. The South East Asian Quinine Artesunate Malaria Trials (SEAQUAMAT), a multicenter, randomized, open-label study comparing AS with quinine showed that parenteral AS was shown to be associated with a 35% reduction in the risk of mortality compare to quinine, and is now the recommended treatment by the WHO for severe and complicated malaria in low-transmission areas and in the second and third trimesters of pregnancy, with almost all the benefit reported in those with high parasite counts. Artesunate is a semisynthetic derivative of artemisinin whose water solubility facilitates absorption and provides an advantage over other artemisinins because it can be formulated as oral, rectal, intramuscular, and intravenous preparations. Artesunate is rapidly hydrolyzed to dihydroartemisinin, which is the most active schizonticidal metabolite. Injectable AS results in a more rapid systemic availability of AS compared with intramuscular AM. This pharmacokinetic advantage may provide a clinical advantage in the treatments of severe and complicated malaria. Full article

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the isoenzymes COX-1 and COX-2 of cyclooxygenase (COX). Renal side effects (e.g., kidney function, fluid and urinary electrolyte excretion) vary with the extent of COX-2-COX-1 selectivity and the administered dose of these compounds. While young healthy subjects will rarely experience adverse renal effects with the use of NSAIDs, elderly patients and those with co-morbibity (e.g., congestive heart failure, liver cirrhosis or chronic kidney disease) and drug combinations (e.g., renin-angiotensin blockers, diuretics plus NSAIDs) may develop acute renal failure. This review summarizes our present knowledge how traditional NSAIDs and selective COX-2 inhibitors may affect the kidney under various experimental and clinical conditions, and how these drugs may influence renal inflammation, water transport, sodium and potassium balance and how renal dysfunction or hypertension
may result. Full article

Mycobacterium tuberculosis is an extraordinarily successful human pathogen, infecting one-third of the world’s population and causing nearly two million deaths each year. In this article, current trends in worldwide tuberculosis (TB) incidence, prevalence, and mortality are discussed along with standard TB treatment regimens, characteristics of first-line and second-line anti-tuberculosis drugs, and mechanisms of antibiotic resistance. The global TB emergency has been further exacerbated by extensively drug-resistant (XDR) TB strains that are resistant to our best antibiotics and very difficult to treat. This review also focuses on the emergence of XDR-TB strains, the global health impact, and existing treatment options and outcomes for XDR-TB disease. Finally, this review briefly describes new anti-tuberculosis drugs currently in Phase II clinical evaluations and the impetus for discovering new antibacterial compounds to target drug-resistant M. tuberculosis and improve tuberculosis therapy. Full article

The expression of multiple ion channels and receptors is essential for nociceptors to detect noxious stimuli of a thermal, mechanical or chemical nature. The peripheral sensory transduction systems of the urinary bladder include sensory nerve endings, urothelial cells and others whose location is suitable for transducing mechanical and chemical stimuli. There is an increasing body of evidence implicating the Deg/ENaC and TRP channel families in the control of bladder afferent excitability under physiological and pathological conditions. Pharmacological interventions targeting these ion channels may provide a new strategy for the treatment of pathological bladder sensation and pain. Full article

The incidence of prostate cancer increases with age and because of its high prevalence this disease has become a major public health concern. Despite advances in our understanding of the biological mechanisms responsible for the development of this cancer, the transition to the hormone refractory stage (HRPC) and metastatic progression pose real problems of clinical management. Currently, docetaxel chemotherapy has been shown to have a slight but significant impact on survival, though the gain in median survival is still less than three months. Research is therefore continuing to improve treatment outcomes. The progression of prostate cancer is accompanied by the overexpression of EGFR (epidermal growth factor receptor) in a very large majority of cases, suggesting that this may play a mechanistic role. Unfortunately, although preclinical findings seem to be promising for therapies targeting the EGFR in HRPC, current clinical results are disappointing. These results should however encourage us to look for different ways of using anti-EGFR agents or combining them with other targeted therapies. Full article

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely prescribed medications in the World. A frequent complication of NSAID use is gastroduodenal bleeding. Risk factors for gastroduodenal bleeding while on NSAID therapy are age, prior peptic ulcer and co-medication with anti-platelet agents, anticoagulants, glucocorticosteroids and selective serotonin-reuptake inhibitors (SSRI). Prevention strategies for at-risk patients include the use of the lowest effective dose of NSAIDs, co-therapy with proton-pump inhibitors and/or the use of a COX-2 selective agent. Treatment of Helicobacter pylori infection is beneficial for primary prophylaxis of NSAID-induced gastroduodenal bleeding in NSAID-naive patients. For patients with cardiovascular risk factors requiring NSAIDs, naproxen should be selected. In very high risk patients for both gastrointestinal and cardiovascular complications NSAID therapy should be avoided altogether. Full article

Cystic Fibrosis (CF) is the most common lethal genetic disorder in North America and Europe. Most patients succumb to progressive lung disease characterized by an exaggerated neutrophilic inflammation. In animal models of chronic infection, high-dose ibuprofen was demonstrated to reduce inflammation without hindering bacterial clearance. This led to two clinical trials, which demonstrated a benefit in slowing the progression of lung disease in CF. However, concerns about potential adverse effects have limited the use of high-dose ibuprofen in CF patients. There are a variety of potential mechanisms to account for the observed clinical benefit. A better understanding of these mechanisms could potentially lead to more targeted and better-tolerated anti-inflammatory therapies. Full article

Cannabis contains the psychoactive component delta⁹-tetrahydrocannabinol (delta⁹-THC), and the non-psychoactive components cannabidiol (CBD), cannabinol, and cannabigerol. It is well-known that delta⁹-THC and other cannabinoid CB₁ receptor agonists are neuroprotective during global and focal ischemic injury. Additionally, delta⁹-THC also mediates psychological effects through the activation of the CB₁ receptor in the central nervous system. In addition to the CB₁ receptor agonists, cannabis also contains therapeutically active components which are CB₁ receptor independent. Of the CB₁ receptor-independent cannabis, the most important is CBD. In the past five years, an increasing number of publications have focused on the discovery of the anti-inflammatory, anti-oxidant, and neuroprotective effects of CBD. In particular, CBD exerts positive pharmacological effects in ischemic stroke and other chronic diseases, including Parkinson’s disease, Alzheimer’s disease, and rheumatoid arthritis. The cerebroprotective action of CBD is CB₁ receptor-independent, long-lasting, and has potent anti-oxidant activity. Importantly, CBD use does not lead to tolerance. In this review, we will discuss the therapeutic possibility of CBD as a cerebroprotective agent, highlighting recent pharmacological advances, novel mechanisms, and therapeutic time window of CBD in ischemic stroke. Full article

For over 160 years, general anesthetics have been given for the relief of pain and suffering. While many theories of anesthetic action have been purported, it has become increasingly apparent that a significant molecular focus of anesthetic action lies within the family of ligand-gated ion channels (LGIC’s). These protein channels have a transmembrane region that is composed of a pentamer of four helix bundles, symmetrically arranged around a central pore for ion passage. While initial and some current models suggest a possible cavity for binding within this four helix bundle, newer calculations postulate that the actual cavity for anesthetic binding may exist between four helix bundles. In either scenario, these cavities have a transmembrane mode of access and may be partially bordered by lipid moieties. Their physicochemical nature is amphiphilic. Anesthetic binding may alter the overall motion of a ligand-gated ion channel by a “foot-in-door” motif, resulting in the higher likelihood of and greater time spent in a specific channel state. The overall gating motion of these channels is consistent with that shown in normal mode analyses carried out both in vacuo as well as in explicitly hydrated lipid bilayer models. Molecular docking and large scale molecular dynamics calculations may now begin to show a more exact mode by which anesthetic molecules actually localize themselves and bind to specific protein sites within LGIC’s, making the design of future improvements to anesthetic ligands a more realizable possibility. Full article

Cannabinoids are used clinically on a subacute basis as prophylactic agonist antiemetics for the prevention of nausea and vomiting caused by chemotherapeutics. Cannabinoids prevent vomiting by inhibition of release of emetic neurotransmitters via stimulation of presynaptic cannabinoid CB₁ receptors. Cannabis-induced hyperemesis is a recently recognized syndrome associated with chronic cannabis use. It is characterized by repeated cyclical vomiting and learned compulsive hot water bathing behavior. Although considered rare, recent international publications of numerous case reports suggest the contrary. The syndrome appears to be a paradox and the pathophysiological mechanism(s) underlying the induced vomiting remains unknown. Although some traditional hypotheses have already been proposed, the present review critically explores the basic science of these explanations in the clinical setting and provides more current mechanisms for the induced hyperemesis. These encompass: (1) pharmacokinetic factors such as long half-life, chronic exposure, lipid solubility, individual variation in metabolism/excretion leading to accumulation of emetogenic cannabinoid metabolites, and/or cannabinoid withdrawal; and (2) pharmacodynamic factors including switching of the efficacy of Δ⁹-THC from partial agonist to antagonist, differential interaction of Δ⁹-THC with Gs and Gi signal transduction proteins, CB₁ receptor desensitization or downregulation, alterations in tissue concentrations of endocannabinoid agonists/inverse agonists, Δ⁹-THC-induced mobilization of emetogenic metabolites of the arachidonic acid cascade, brainstem versus enteric actions of Δ⁹-THC, and/or hypothermic versus hyperthermic actions of Δ⁹-THC. In addition, human and animal findings suggest that chronic exposure to cannabis may not be a prerequisite for the induction of vomiting but is required for the intensity of emesis. Full article

While aspirin may offer protection, other non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) can cause serious cardiovascular side effects and complications. This has led to a general "black box" warning for cardiovascular adverse events for NSAIDs. This review explores the different mechanisms underlying the protective effects of aspirin, the NSAID associated renovascular effects causing hypertension, edema and heart failure, the cardiovascular effects causing myocardial infarction and stroke, and the possible deleterious interaction between NSAIDs and aspirin. Full article

Protein kinases are intimately integrated in different signal transduction pathways for the regulation of cardiac function in both health and disease. Protein kinase A (PKA), Ca²⁺-calmodulin-dependent protein kinase (CaMK), protein kinase C (PKC), phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) are not only involved in the control of subcellular activities for maintaining cardiac function, but also participate in the development of cardiac dysfunction in cardiac hypertrophy, diabetic cardiomyopathy, myocardial infarction, and heart failure. Although all these kinases serve as signal transducing proteins by phosphorylating different sites in cardiomyocytes, some of their effects are cardioprotective whereas others are detrimental. Such opposing effects of each signal transduction pathway seem to depend upon the duration and intensity of stimulus as well as the type of kinase isoform for each kinase. In view of the fact that most of these kinases are activated in heart disease and their inhibition has been shown to improve cardiac function, it is suggested that these kinases form excellent targets for drug development for therapy of heart disease. Full article

Epilepsy is a serious neurological disorder that affects around 50 million people worldwide. Almost 30% of epileptic patients suffer from pharmacoresistance, which is associated with social isolation, dependent behaviour, low marriage rates, unemployment, psychological issues and reduced quality of life. Currently available antiepileptic drugs have a limited efficacy, and their negative properties limit their use and cause difficulties in patient management. Antiepileptic drugs can provide only symptomatic relief as these drugs suppress seizures but do not have ability to cure epileptogenesis. The long term use of antiepileptic drugs is limited due to their adverse effects, withdrawal symptoms, deleterious interactions with other drugs and economic burden, especially in developing countries. Furthermore, some of the available antiepileptic drugs may even potentiate certain type of seizures. Several in vivo and in vitro animal models have been proposed and many new antiepileptic drugs have been marketed recently, but large numbers of patients are still pharmacoresistant. This review will highlight the difficulties in treatment and management of epilepsy and the limitations of available antiepileptic drugs and animal seizure models. Full article

This review summarizes the current use of non-steroidal anti-inflammatory drugs (NSAIDs) in obstetrics, gynecology and infertility. These medications are commonly used in different fields of reproductive medicine, for pain management after operative procedures and to relieve dysmenorrhea. In addition to their analgesic effect, NSAIDs are helpful in the management of menorrhagia by decreasing menstrual blood loss. NSAIDs alleviate pain associated with medical abortion, assist in undertaking natural cycle in-vitro fertilization by preventing follicular rupture and reducing premature ovulation, and serve as tocolytics in preterm labor. New NSAIDs may have a growing role in management of women's health. Full article

The detailed kinetic model of Prostaglandin H Synthase-1 (PGHS-1) was applied to in silico screening of dose-dependencies for the different types of nonsteroidal anti-inflammatory drugs (NSAIDs), such as: reversible/irreversible, nonselective/selective to PGHS-1/PGHS-2 and time dependent/independent inhibitors (aspirin, ibuprofen, celecoxib, etc.) The computational screening has shown a significant variability in the IC50s of the same drug, depending on different in vitro and in vivo experimental conditions. To study this high heterogeneity in the inhibitory effects of NSAIDs, we have developed an in silico approach to evaluate NSAID action on targets under different PGHS-1 microenvironmental conditions, such as arachidonic acid, reducing cofactor, and peroxide concentrations. The designed technique permits translating the drug IC₅₀, obtained in one experimental setting to another, and predicts in vivo inhibitory effects based on the relevant in vitro data. For the aspirin case, we elucidated the mechanism underlying the enhancement and reduction (aspirin resistance) of its efficacy, depending on PGHS-1 microenvironment in in vitro/in vivo experimental settings. We also present the results of the in silico screening of the combined action of sets of two NSAIDs (aspirin with ibuprofen, aspirin with celecoxib), and study the mechanism of the experimentally observed effect of the suppression of aspirin-mediated PGHS-1 inhibition by selective and nonselective NSAIDs. Furthermore, we discuss the applications of the obtained results to the problems of standardization of NSAID test assay, dependence of the NSAID efficacy on cellular environment of PGHS-1, drug resistance, and NSAID combination therapy. Full article

Phospholipase D2 (PLD2) generates phosphatidic acid through hydrolysis of phosphatidylcholine. PLD2 has been shown to play a role in enhancing tumorigenesis. The epidermal growth factor receptor (EGFR) can both activate and interact with PLD2. Murine lymphoma EL4 cells lacking endogenous PLD2 present a unique model to elucidate the role of PLD2 in signal transduction. In the current study, we investigated effects of PLD2 on EGF response. Western blotting and RT-PCR were used to establish that both parental cells and PLD2 transfectants express endogenous EGFR. Levels of EGFR protein are increased in cells expressing active PLD2, as compared to parental cells or cells expressing inactive PLD2. EGF stimulates proliferation of EL4 cells transfected with active PLD2, but not parental cells or cells transfected with inactive PLD2. EGF-mediated proliferation in cells expressing active PLD2 is dependent on the activities of both the EGFR and the PI3K/Akt pathway, as demonstrated by studies using protein kinase inhibitors. EGF-induced invasion through a synthetic extracellular matrix is enhanced in cells expressing active PLD2, as compared to parental cells or cells expressing inactive PLD2. Taken together, the data suggest that PLD2 acts in concert with EGFR to enhance mitogenesis and invasion in lymphoma cells. Full article

Gene silencing resulting from aberrant DNA methylation can lead to tumorigenesis. Therefore, drugs that inhibit or interfere with DNA methylation have been used to reactivate and induce silenced gene re-expression in malignancies. Two demethylating agents, azacitidine and decitabine, are approved for the treatment of myelodysplastic syndromes (MDS) by the U.S. Food and Drug Administration (FDA), and are now considered the standard of care in MDS. In this review, we discuss clinical data, including clinical benefits and toxicities, which led to the approval of azacitidine and decitabine. We also summarize findings from clinical trials that used these two demethylating agents in the treatment of solid tumors. Lastly, we discuss some limitations in the use of azacitidine and decitabine in cancer therapy. Full article

Colon cancer is common worldwide and accounts for significant morbidity and mortality in patients. Fortunately, epidemiological studies have demonstrated that continuous therapy with NSAIDs offers real promise of chemoprevention and adjunct therapy for colon cancer patients. Tumour growth is the result of complex regulation that determines the balance between cell proliferation and cell death. How NSAIDs affect this balance is important for understanding and improving treatment strategies and drug effectiveness. NSAIDs inhibit proliferation and impair the growth of colon cancer cell lines when tested in culture in vitro and many NSAIDs also prevent tumorigenesis and reduce tumour growth in animal models and in patients, but the relationship to inhibition of tumour cell proliferation is less convincing, principally due to gaps in the available data. High concentrations of NSAIDs are required in vitro to achieve cancer cell inhibition and growth retardation at varying time-points following treatment. However, the results from studies with colon cancer cell xenografts are promising and, together with better comparative data on anti-proliferative NSAID concentrations and doses (for in vitro and in vivo administration), could provide more information to improve our understanding of the relationships between these agents, dose and dosing regimen, and cellular environment. Full article

Linezolid, the first oxazolidinone to be used clinically, is effective in the treatment of infections caused by various Gram-positive pathogens, including multidrug resistant enterococci and methicillin-resistant Staphylococus aureus. It has been used successfully for the treatment of patients with endocarditis and bacteraemia, osteomyelitis, joint infections and tuberculosis and it is often used for treatment of complicated infections when other therapies have failed. Linezolid resistance in Gram-positive cocci has been encountered clinically as well as in vitro, but it is still a rare phenomenon. The resistance to this antibiotic has been, until now, entirely associated with distinct nucleotide substitutions in domain V of the 23S rRNA genes. The number of mutated rRNA genes depends on the dose and duration of linezolid exposure and has been shown to influence the level of linezolid resistance. Mutations in associated ribosomal proteins also affect linezolid activity. A new phenicol and clindamycin resistance phenotype has recently been found to be caused by an RNA methyltransferase designated Cfr. This gene confers resistance to lincosamides, oxazolidinones, streptogramin A, phenicols and pleuromutilins, decrease the susceptibility of S. aureus to tylosin, to josamycin and spiramycin and thus differs from erm rRNA methylase genes. Research into new oxazolidinones with improved characteristics is ongoing. Data reported in patent applications demonstrated that some oxazolidinone derivatives, also with improved characteristics with respect to linezolid, are presently under study: at least three of them are in an advanced phase of development. Full article