Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor gamma

Ajulemic acid (AJA) is a synthetic analog of THC-11-oic acid, a metabolite of tetrahydrocannabinol (THC), the major active ingredient of the recreational drug marijuana derived from the plant Cannabis sativa. AJA has potent analgesic and anti-inflammatory activity in vivo, but without the psychotropic action of THC. However, its precise mechanism of action remains unknown. Biochemical studies indicate that AJA binds directly and selectively to the isotype gamma of the peroxisome proliferator-activated receptor (PPARgamma) suggesting that this may be a pharmacologically relevant receptor for this compound and a potential target for drug development in the treatment of pain and inflammation. Here, we report the crystal structure of the ligand binding domain of the gamma isotype of human PPAR in complex with ajulemic acid, determined at 2.8-A resolution. Our results show a binding mode that is compatible with other known partial agonists of PPAR, explaining their moderate activation of the receptor, as well as the structural basis for isotype selectivity, as observed previously in vitro. The structure also provides clues to the understanding of partial agonism itself, suggesting a rational approach to the design of molecules capable of activating the receptor at levels that avoid undesirable side effects.     

Targeting Astrocytomas and Invading Immune Cells with Cannabinoids: A Promising Therapeutic Avenue

The last quarter century has borne witness to great advances in both the detection and treatment of numerous cancers. Even so, malignancies of the central nervous system, especially high-grade astrocytomas, continue to thwart our best efforts toward effective chemotherapeutic strategies. With prognosis remaining bleak, the time for serious consideration of alternative therapies has arrived. Various preparations of the marijuana plant, Cannabis sativa, and related synthetic and endogenous compounds, may constitute just such an alternative. Cannabinoids, although much maligned historically for their psychotropic effects and clear abuse potential, have long been used medicinally and are now staging an impressive comeback, as recent studies have begun to explore their powerful anti-tumoral properties. In this study, we review in vitro and in vivo evidence supporting the use of cannabinoids for treatment of brain tumors. We further propose the continued intense investigation of cannabinoid efficacies as novel anti-cancer agents, especially in models recapitulating such properties within the unique environment of the brain.     

Effects of short-term exposure to lithium on antiapoptotic Bcl-xL protein expression in cortex and hippocampus of rats after acute stress

The antiapoptotic protein Bcl-xL is involved in development of neurobiological resilience to stress; hence, the possibility of use of psychotropic drugs to increase its expression in brain in response to stress is of considerable interest. Lithium is a neurotropic drug widely used in psychiatry. In work, we studied effects of lithium administration (for 2 or 7 days) on the expression of Bcl-xL mRNA and protein in the hippocampi and cortices of rats subjected to stress that induced depression-like behavior in the animals. In contrast to the brain-derived neurotrophic factor (BDNF), whose expression decreased in the hippocampus in response to acute stress, stress increased the level of Bcl-xL mRNA in the hippocampus, but decreased it in the frontal cortex. Treatment of stressed animals with lithium for 2 or 7 days increased Bcl-xL protein levels 1.5-fold in the hippocampus, but it decreased them in the cortex. Therefore, Bcl-xL expression in the brain can be modulated by both stress and psychotropic drugs, and the effects of these factors are brain region-specific: both stress exposure and lithium administration activated Bcl-xL expression in the hippocampus and suppressed it in the frontal cortex. The activation of Bcl-xL expression in the hippocampus by lithium, demonstrated for the first time in this study, suggests an important role of this protein in the therapeutic effects of lithium in the treatment of stress-induced psychoemotional disorders.     

Endocannabinoids and the regulation of their levels in health and disease

PURPOSE OF REVIEW: Endocannabinoids are defined as endogenous agonists of cannabinoid receptors, that is, of the two G-protein-coupled receptors for the Cannabis psychoactive principle Delta-tetra-hydrocannabinol. Two such endogenous mediators have been most thoroughly studied so far: anandamide and 2-arachidonoylglycerol. Here we review the mechanisms for the regulation of their levels under physiological and pathological conditions, and recent findings on their role in disease. RECENT FINDINGS: It is becoming increasingly clear that, although both anandamide and 2-arachidonoyl-glycerol are produced and degraded 'on demand', the levels of these two compounds appear to be regulated in different, and sometimes even opposing, ways, often using redundant molecular mechanisms. Alterations of endocannabinoid levels have been found in both animal models of pain, neurological and neurodegenerative states, gastrointestinal disorders and inflammatory conditions, and in blood, cerebrospinal fluid and bioptic samples from patients with various diseases. SUMMARY: Endocannabinoid levels appear to be transiently elevated as an adaptive reaction to re-establish normal homeostasis when this is acutely and pathologically perturbed. In some chronic conditions, however, this system also contributes to the progress or symptoms of the disorder. As a consequence, new therapeutic drugs are being designed from both stimulants and blockers of endocannabinoid action.     

Focus: Addiction: Marijuana for Glaucoma: A Recipe for Disaster or Treatment?

Marijuana has been shown to lower intraocular pressure (IOP) but with limited duration of action and numerous adverse effects. Use of marijuana to lower IOP as a means of glaucoma treatment would require frequent use throughout the day, leading to significant adverse effects, possible progression toward Cannabis Use Disorder (CUD), and/or withdrawal symptoms. The treatment of glaucoma based on the cannabis plant or drugs based on the cannabinoid molecule should be considered carefully before being prescribed. Considerations should include the adverse physical and psychological adverse effects, including substance abuse. Currently, the deleterious effects of marijuana outweigh the benefits of its IOP-lowering capacity in most glaucoma patients. Under extremely rare circumstances, a few categories of glaucoma patients may be potential candidates for treatment with medical marijuana. Further studies on alternate routes and more focused means of cannabinoid molecule delivery to the eye for glaucoma treatment are needed.     

PPAR-gamma: a nuclear receptor with affinity for cannabinoids

An increasing number of cannabinoid actions are being reported that do not appear to be mediated by either CB1 or CB2, the known cannabinoid receptors. One such example is the synthetic analog ajulemic acid (AJA), which shows potent analgesic and anti-inflammatory effects in rodents and humans. AJA binds weakly to CB1 only at concentrations many fold higher than its therapeutic range, and is, therefore, completely free of psychotropic effects in both normal subjects and pain patients suggesting the involvement of a target site other than CB1. AJA as well as several other cannabinoids appear to have profound effects on cellular lipid metabolism as evidenced by their ability to transform fibroblasts into adipocytes where the accumulation of lipid droplets can be readily observed. Such transformations can be mediated by the activation of the nuclear receptor PPAR-gamma. A variety of small molecule ligands including AJA have been shown to induce the activation of PPAR-gamma and, in some cases this has led to the introduction of clinically useful agents. It is suggested that PPAR-gamma may serve a receptor function for certain actions of some cannabinoids.     

The toxicology of cannabis and cannabis prohibition

The acute side effects caused by cannabis use are mainly related to psyche and cognition, and to circulation. Euphoria, anxiety, changes in sensory perception, impairment of memory and psychomotor performance are common effects after a dose is taken that exceeds an individually variable threshold. Cannabis consumption may increase heart rate and change blood pressure, which may have serious consequences in people with heart disease. Effects of chronic use may be induction of psychosis and development of dependency to the drug. Effects on cognitive abilities seem to be reversible after abstinence, except possibly in very heavy users. Cannabis exposure in utero may have negative consequences on brain development with subtle impairment of cognitive abilities in later life. Consequences of cannabis smoking may be similar to those of tobacco smoking and should be avoided. Use by young people has more detrimental effects than use by adults. There appear to be promising therapeutic uses of cannabis for a range of indications. Use of moderate doses in a therapeutic context is usually not associated with severe side effects. Current prohibition on cannabis use may also have harmful side effects for the individual and the society, while having little influence on prevalence of use. Harm is greatest for seriously ill people who may benefit from a treatment with cannabis. This makes it difficult to justify criminal penalties against patients.     

Long-term health status of Danish women with silicone breast implants

Long-term safety data are important in the evaluation of possible adverse health outcomes related to silicone breast implants. The authors evaluated long-term symptoms and conditions and medication use among 190 Danish women with cosmetic silicone breast implants compared with 186 women who had undergone breast reduction surgery and with 149 women from the general population. Breast implant and reduction surgeries were performed from 1973 to 1988 at one public hospital and one private plastic surgery clinic. Among women with breast implants, the average implantation time was 19 years, 60 percent (n = 114) had only one implantation, and 10 percent (n = 19) had undergone explantation before the time of study (1997 to 1998). The authors found no material differences in self-reported diseases or symptoms among study groups, except for breast pain, which was reported nearly three times as often by women with implants than by women with breast reduction (odds ratio, 2.8; 95 percent confidence interval, 1.4 to 5.3). Approximately 80 percent of women in each study group reported at least one symptom. No consistent differences were observed in the seroprevalences of antinuclear antibodies or other autoantibodies. Self-reported use of psychotropic drugs was higher among women with breast implants than among either control group. The authors conclude that long-term cosmetic breast implantation may cause capsular contracture and breast pain but does not appear to be associated with other symptoms, diseases, or autoimmune reactivity. The authors' finding of excess use of drugs for treatment of depression and anxiety among women with breast implants may warrant further investigation.     

Medicating children: the case of Ritalin

In response to recent concerns about the overmedication of children, this paper considers ethical and conceptual issues that arise in the issue of when children who are diagnosed with attention deficit hyperactivity disorder should be given stimulants such as the psychotropic drug Ritalin as part of their treatment. There is considerable resistance and worry about the possibility of overmedication. This is linked to the worry that the diagnosis of ADHD is overused, and the paper considers some reasons to worry about the overuse of the diagnosis itself. The paper then focuses on the resistance to the use of drugs, which is particularly strong for children in the gray area of diagnosis, where it is dubious whether the children really meet the strict diagnostic criteria. The reasons behind such resistance are often not well articulated, so part of the task of the paper is spell out what they might be. The reasons are given the following labels: side effects, unnaturalness, profit motives, thought control, competitiveness, and doctors' power. The paper ends in taking the polemical position that while there is some legitimate concern about possible short and long term side effects of children taking psychotropic drugs, the other reasons for resistance are not well-founded.     

Medicating Children: The Case of Ritalin

In response to recent concerns about the overmedication of children, this paper considers ethical and conceptual issues that arise in the issue of when children who are diagnosed with attention deficit hyperactivity disorder should be given stimulants such as the psychotropic drug Ritalin as part of their treatment. There is considerable resistance and worry about the possibility of overmedication. This is linked to the worry that the diagnosis of ADHD is overused, and the paper considers some reasons to worry about the overuse of the diagnosis itself. The paper then focuses on the resistance to the use of drugs, which is particularly strong for children in the gray area of diagnosis, where it is dubious whether the children really meet the strict diagnostic criteria. The reasons behind such resistance are often not well articulated, so part of the task of the paper is spell out what they might be. The reasons are given the following labels: side effects, unnaturalness, profit motives, thought control, competitiveness, and doctors' power. The paper ends in taking the polemical position that while there is some legitimate concern about possible short and long term side effects of children taking psychotropic drugs, the other reasons for resistance are not well-founded.     

Ontwikkeling van algoritmes voor oordeelkundig gebruik van psychofarmaca bij ouderen met verhoogd valrisico

Psychotropic drugs (hypno-sedatives, antidepressants and antipsychotics) are commonly used in the older population. On the long term, psychotropic drug use in older persons is associated with several negative functional outcomes such as an increased risk of falls. Gradual withdrawal of psychotropic drugs in older persons is feasible and leads to a significant reduction of falls. Both withdrawal of psychotropic drugs as well as the initiation of appropriate treatment with psychotropic drugs requires knowledge, consultation and cooperation between disciplines and a mentality change among healthcare professionals. In order to inform and support healthcare professionals, the Centre of Expertise for Fall and Fracture Prevention Flanders developed three clinical practice algorithms for the appropriate use of psychotropic drugs in older persons with high risk of falls and a fact sheet with background information.     

New Applications for Cryotherapy

Cryotherapy, or more commonly known as cold therapy, is the use of low temperatures in medical treatment. The most prominent use of cryotherapy is for cryosurgery where application of very low temperatures is used to ablate diseased tissue (e.g., most commonly in dermatology). Recent research, however, shows that low temperature may modulate collagen fibers beyond the already known effects of extreme cooling on joint pain relieve and inflammation. The goal of this brief review is to outline the known effects of extreme cooling on molecular, fiber and cell physiology and to leverage these properties in various potential medical applications. Specially, we will discuss potential cryotherapies for treatment of osteoarthritis and destruction of fat cells (i.e., cryolipolysis) for treatment of diabetes. Osteoarthritis (OA) is a degenerative disease, where joint pain and stiffness worsen over time. One of the most effective ways to relief joint pain is cooling the joint. Indeed, when evaluating different strategies to externally cool affected joints, it was found that reducing the internal joint temperature by ~ 10°C has beneficial effects in terms of pain reduction and regression in local inflammation. Moreover, collagen, whose deterioration is a major part of OA pathophysiology, regains elasticity after several freeze-thaw cycle. Finally, cartilage cells response to cold by increasing collagen formation and reducing matrix enzyme production, and adipose tissue within the joint that promote OA by supporting inflammation is susceptible to cold temperatures. Obesity is also a devastating disease that contributes to OA. Reduction of the temperature within the joint results in reduced inflammation, renewed collagen synthesis and reduced pain. Similarly, induction of extreme low temperatures in adipose tissue results in adipocytes loss without damage to surrounding tissues. Hence, cryotherapy has applications to modulation of collagen and fat cells for various therapies.     

The safety of psychotropic drug use during pregnancy: a review

A substantial number of women of childbearing age are prescribed psychotropic drugs, and because nearly 50% of pregnancies are unplanned, many women are still taking them upon becoming pregnant. This article reviews the various classes of psychotropic drugs that are commonly used to treat psychiatric disorders--antidepressants, benzodiazepines, antipsychotics, antiepileptics, lithium and monoamine oxidase (MAO) inhibitors--in terms of their safety during pregnancy. Evidence-based information from epidemiologic studies indicates that most psychotropic drugs are relatively safe for use during pregnancy. There is also an increasingly large body of evidence-based information in the literature indicating that it may be more harmful to both the mother and her baby if she is not treated appropriately when suffering from a severe psychiatric disorder. Therefore, it is important for women with psychiatric disorders and their healthcare providers to have access to evidenced-based information about the safety of these drugs when taken during pregnancy to ensure that women make an informed decision as to whether they should continue with the pharmacotherapy they have been using to treat their condition.     

Le nouveau paysage du cannabis II. Données récentes sur la psychotoxicité du cannabis

After delta-9-tetrahydrocannabinol (Δ9-THC) has supported the anandamidergic tone, thereby increasing its anxiolytic and antidepressant effects, it loses its efficacy in this respect. Anxious and/or depressive troubles which could have prompted the abuse of cannabis then reappear more intensely. They peak when consumption is completely stopped. Cannabis consumption may contribute to polydrug abuse. Its association with tobacco makes it more difficult to give up both substances of abuse. Cannabis use encourages the consumption of alcohol and this association is especially deleterious as regards car accidents. Δ9-THC sensitises cannabis abusers to perceive the appetitive effects of heroin in a more acute manner. Cannabis consumption also makes withdrawal symptoms associated with heroin abuse more severe. Cannabis appears to be able to reveal schizophrenia in patients bearing a neurobiological vulnerability substratum to this disease. It seems especially appreciated by people suffering of negative symptoms of schizophrenia, which could prompt them to abuse cannabis, and then triggering the positive symptoms of the disease. These positive symptoms are particularly resistant to treatment with antipsychotic medication when cannabis abuse is continued. All this recent data necessitates extreme care with this drug of abuse, whose dangerous effects are becoming more and more known.     

Relevance of Higher-Order Epistasis in Drug Resistance

We studied five chemically distinct but related 1,3,5-triazine antifolates with regard to their effects on growth of a set of mutants in dihydrofolate reductase. The mutants comprise a combinatorially complete data set of all 16 possible combinations of four amino acid replacements associated with resistance to pyrimethamine in the malaria parasite Plasmodium falciparum. Pyrimethamine was a mainstay medication for malaria for many years, and it is still in use in intermittent treatment during pregnancy or as a partner drug in artemisinin combination therapy. Our goal was to investigate the extent to which the alleles yield similar adaptive topographies and patterns of epistasis across chemically related drugs. We find that the adaptive topographies are indeed similar with the same or closely related alleles being fixed in computer simulations of stepwise evolution. For all but one of the drugs the topography features at least one suboptimal fitness peak. Our data are consistent with earlier results indicating that third order and higher epistatic interactions appear to contribute only modestly to the overall adaptive topography, and they are largely conserved. In regard to drug development, our data suggest that higher-order interactions are likely to be of little value as an advisory tool in the choice of lead compounds.     

Worden psychofarmaca in het verpleeghuis te vaak voorgeschreven?

Are psychotropic drugs too frequently prescribed in Dutch nursing homes? In 1993 Ribbe en Hertogh published a paper in which they expressed their concern about the high prevalence of psychotropic drug use in Dutch nursing homes. Since then, this situation does not seem to have been changed significantly. Recent figures from psychotropic drug use in patients with dementia show prevalence rates of over 60%. The Dutch government decided to choose the prevalence of psychotropic drug use as an indicator of the quality of care and invested in a specific improvement project that aims to reduce psychotropic drug use among nursing home patients. There is a small body of evidence from international research that antipsychotics safely can be reduced without a rise in problem behaviours. In combination with the limited effectiveness and the risk of stroke and increased mortality, the question raises whether these agents should be prescribed at all at least for patients with dementia. A recent study from the UK however, found a significant decrease of antipsychotic drug use by heavily investing in all kinds of person-centered care skills of the nursing staff. These findings underscore the necessity of investing in the caregivers of nursing homes to be able to cope with the complex problems they are faced with. Tijdschr Gerontol Geriatr 2007; 38: 270-273     

On the pharmacological properties of Delta9-tetrahydrocannabinol (THC)

Cannabis is one of the first plants used as medicine, and the notion that it has potentially valuable therapeutic properties is a matter of current debate. The isolation of its main constituent, Delta9-tetrahydrocannabinol (THC), and the discovery of the endocannabinoid system (cannabinoid receptors CB1 and CB2 and their endogenous ligands) made possible studies concerning the pharmacological activity of cannabinoids. This paper reviews some of the most-important findings in the field of THC pharmacology. Clinical trials, anecdotal reports, and experiments employing animal models strongly support the idea that THC and its derivatives exhibit a wide variety of therapeutic applications. However, the psychotropic effects observed in laboratory animals and the adverse reactions reported during human trials, as well as the risk of tolerance development and potential dependence, limit the application of THC in therapy. Nowadays, researchers focus on other therapeutic strategies by which the endocannabinoid system might be modulated to clinical advantage (inhibitor or activator of endocannabinoid biosynthesis, cellular uptake, or metabolism). However, emerging evidence highlights the beneficial effects of the whole cannabis extract over those observed with single components, indicating cannabis-based medicines as new perspective to revisit the pharmacology of this plant.     

The molecular mechanisms that underpin the biological benefits of full-spectrum cannabis extract in the treatment of neuropathic pain and inflammation

Cannabis has been shown to be beneficial in the treatment of pain and inflammatory diseases. The biological effect of cannabis is mainly attributed to two major cannabinoids, tetrahydrocannabinol and cannabidiol. In the majority of studies to-date, a purified tetrahydrocannabinol and cannabidiol alone or in combination have been extensively examined in many studies for the treatment of numerous disorders including pain and inflammation. However, few studies have investigated the biological benefits of full-spectrum cannabis plant extract. Given that cannabis is known to generate a large number of cannabinoids along with numerous other biologically relevant products including terpenes, studies involving purified tetrahydrocannabinol and/or cannabidiol do not consider the potential biological benefits of the full-spectrum cannabis extracts. This may be especially true in the case of cannabis as a potential treatment of pain and inflammation. Herein, we review the pre-clinical physiological and molecular mechanisms in biological systems that are affected by cannabis.     

Antiarrhythmic drug therapy: new drugs and changing concepts

The effective treatment of life-threatening ventricular arrhythmias (VA) leading to sudden cardiac death remains a major health problem. Cellular electrophysiological techniques that have provided insight into the underlying mechanisms of these arrhythmias have also provided a convenient classification of antiarrhythmic drugs based on their dominant electrophysiological action. Traditional pharmacological approaches to the management of VA have involved primarily class I agents. Newer drugs in this class are potent conduction depressants (class IC agents), which, however, have been limited in their clinical impact on VA because of unwanted cardiac and extracardiac side effects. Other recent approaches include the introduction of class III agents, which are thought to interrupt primarily reentrant impulses by specific prolongation of action potential duration and refractoriness without compromising normal cardiac conduction. Newer approaches may also include drugs with greater specificity of action, agents with combinations of electrophysiological effects (class I/III, I/II), drugs exemplifying novel mechanisms of action such as anion antagonism (class V), and agents controlling sympathetic neural outflow. The growing awareness of the potential proarrhythmic effects of antiarrhythmic drugs has also become important in drug development and assessment, as emphasized by the search for improved methods of drug selection (e.g., programmed electrical stimulation). Finally, the desired characteristics of a new antiarrhythmic agent are presented as a goal for future drug development.     

Role of drugs in traffic accidents.

Serum samples from 201 drivers who presented at emergency departments within six hours after being injured in a road accident and 325 control drivers selected randomly at petrol stations were screened for drugs by combined thin-layer and gas chromatography. Blood alcohol concentrations were also measured, and a questionnaire on the subjects'' state of health and use of drugs administered. At interview 30 patients (15%) and 44 controls (13%) said that they had taken drugs in the previous 24 hours. Four patients (2%) and six controls (2%) said that they had taken psychotropic drugs, but serum analysis detected psychotropic drugs in 10 patients (5%) and eight controls (2.5%). Diazepam was found in 16 of the 18 subjects in whom psychotropic drugs were detected. Alcohol was detected in 30 patients (15%) and three controls (1%). Drug use appeared to be somewhat lower in Finland than in other Western countries, and illness to be a more important traffic hazard than drugs in general. Interview was not a reliable method of establishing whether drivers had taken psychotropic drugs. Taking diazepam may increase the risk of being involved in a traffic accident, but alcohol was the most powerful risk factor.