Terms of abuse as expression and reinforcement of cultures

In this study terms of abuse are investigated in 11 different cultures. Spontaneous verbal aggression is to a certain extent reminiscent of the values of a certain culture. Almost 3000 subjects from Spain, Germany, France, Italy, Croatia, Poland, Great Britain, USA, Norway, Greece, and The Netherlands were asked to write down terms of abuse that they would use given a certain stimulus situation, and in addition, to give their rating of the offensive character of those terms. A total set of 12,000 expressions was collected. The frequencies of the expressions were established, and the total list of expressions was reduced to 16 categories. Results point to some etic taboos, like sexuality and lack of intelligence. On the other hand clear differences across cultures were found, which cannot easily be explained by existing classifications of national cultures. Explanations are provided in terms of dimensions on which the 11 cultures differ.

Gamma-hydroxybutyrate does not maintain self-administration but induces conditioned place preference when injected in the ventral tegmental area

Gamma-hydroxybutyric acid (GHB) is an endogenous brain substance that has diverse neuropharmacological actions, including rewarding properties in different animal species and in humans. As other drugs of abuse, GHB affects the firing of ventral tegmental neurons (VTA) in anaesthetized animals and hyperpolarizes dopaminergic neurons in VTA slices. However, no direct behavioural data on the effects of GHB applied in the VTA or in the target regions of its dopaminergic neurons, e.g. the nucleus accumbens (NAc), are available. Here, we investigated the effects of various doses of intravenous GHB in maintaining self-administration (from 0.001 to 10 mg/kg per infusion), and its ability to induce conditioned place preference (CPP) in rats when given orally (175-350 mg/kg) or injected directly either in the VTA or NAc (from 10 to 300 microg/0.5 microl per side). Our results indicate that while only 0.01 mg/kg per infusion GHB maintained self-administration, although not on every test day, 350 mg/kg GHB given orally induced CPP. CPP was also observed when GHB was injected in the VTA (30-100 microg/0.5 microl per side) but not in the NAc. Together with recent in-vitro findings, these results suggest that the rewarding properties of GHB mainly occur via disinhibition of VTA dopaminergic neurons.

Polymer-phospholipid complexes for the solubilisation and delivery of drugs to the eye

Aim: Topical application of ophthalmic drugs is very inefficient; contact lenses used as drug delivery devices could minimize the drug loss and side effects. Styrene-maleic acid copolymers (PSMA) can form polymer-phospholipid complexes with dipalmitoyl phosphatidylcholine (DMPC) in the form of nanometric vesicles, which can easily solubilise hydrophobic drugs. They can be dispersed on very thin contact lens coatings to immobilize the drug on their surface. Methods: Two types of complexes stable at different pH values (5 and 7 respectively) where synthesized and loaded with drugs of different hydrophilicities during their formation process. The drug release was studied in vitro and compared to the free drug. Results: The mean sizes of the complexes obtained by light scattering were 50 nm and 450 nm respectively with low polydispersities. However, they were affected by the drugs load and release. An increase was observed in the duration of the release in the case of hydrophobic drugs, from days to weeks, avoiding initial “burst” and with a lesser amount of total drug released due to the interaction of the drug with the phospholipid core. The size and charge of the different drugs and the complexes nature also affected the release profile. Conclusions: Polymer-phospholipid complexes in the form of nanoparticles can be used to solubilise and release hydrophobic drugs in a controlled way. The drug load and release can be optimised to reach therapeutic values in the eye.

Strategic development and physicochemical analysis of oral preparations for unstable drugs

Oral liquid formulations are ideal dosage forms for paediatric, geriatric and patient with dysphagia. Dysphagia is prominent among patients suffering from stroke, motor neurone disease, advanced Alzheimer’s and Parkinson’s disease. However oral liquid preparations are particularly difficult to formulate for hydrophobic and unstable drugs. Therefore current methods employed in solving this issue include the use of ‘specials’ or extemporaneous preparations. In order to challenge this, the government has encouraged research into the field of oral liquid formulations, with the EMEA and MHRA publishing list of drugs of interest. The current work investigates strategic formulation development and characterisation of select API’s (captopril, gliclazide, melatonin, L-arginine and lansoprazole), each with unique obstacles to overcome during solubilisation, stabilisation and when developing a palatable dosage from. By preparing a validated calibration protocol for each of the drug candidates, the oral liquid formulations were assessed for stability, according to the ICH guidelines along with thorough physiochemical characterisation. The results showed that pH and polarity of the solvent had the greatest influence on the extent of drug solubilisation, with inclusion of antioxidants and molecular steric hindrance influencing the extent of drug stability. Captopril, a hydrophilic ACE inhibitor (160 mg.mL-1), undergoes dimerisation with another captopril molecule. It was found that with the addition of EDTA and HP-β-CD, the drug molecule was stabilised and prevented from initiating a thiol induced first order free radical oxidation. The cyclodextrin provided further steric hindrance (1:1 molar ratio) resulting in complete reduction of the intensity of sulphur like smell associated with captopril. Palatability is a crucial factor in patient compliance, particularly when developing a dosage form targeted towards paediatrics. L-arginine is extremely bitter in solution (148.7 g.L-1). The addition of tartaric acid into the 100 mg.mL-1 formulation was sufficient to mask the bitterness associated with its guanidium ions. The hydrophobicity of gliclazide (55 mg.L-1) was strategically challenged using a binary system of a co-solvent and surfactant to reduce the polarity of the medium and ultimately increase the solubility of the drug. A second simpler method was developed using pH modification with L-arginine. Melatonin has two major obstacles in formulation: solubility (100 μg.mL-1) and photosensitivity, which were both overcome by lowering the dielectric constant of the medium and by reversibly binding the drug within the cyclodextrin cup (1:1 ratio). The cyclodextrin acts by preventing UV rays from reaching the drug molecule and initiated the degradation pathway. Lansoprazole is an acid labile drug that could only be delivered orally via a delivery vehicle. In oral liquid preparations this involved nanoparticulate vesicles. The extent of drug loading was found to be influenced by the type of polymer, concentration of polymer, and the molecular weight. All of the formulations achieved relatively long shelf-lives with good preservative efficacy.

Childhood abuse is associated with structural impairment in the ventrolateral prefrontal cortex and aggressiveness in patients with borderline personality disorder

Volume reduction and functional impairment in areas of the prefrontal cortex (PFC) have been found in borderline personality disorder (BPD), particularly in patients with a history of childhood abuse. These abnormalities may contribute to the expression of emotion dysregulation and aggressiveness. In this study we investigated whether the volume of the PFC is reduced in BPD patients and whether a history of childhood abuse would be associated with greater PFC structural changes. Structural MRI data were obtained from 18 BPD patients and 19 healthy individuals matched for age, sex, handedness, and education and were analyzed using voxel based morphometry. The Child Abuse Scale was used to elicit a past history of abuse; aggression was evaluated using the Buss-Durkee Hostility Inventory (BDHI). The volume of the right ventrolateral PFC (VLPFC) was significantly reduced in BPD subjects with a history of childhood abuse compared to those without this risk factor. Additionally, right VLPFC gray matter volume significantly correlated with the BDHI total score and with BDHI irritability and negativism subscale scores in patients with a history of childhood abuse. Our results suggest that a history of childhood abuse may lead to increased aggression mediated by an impairment of the right VLPFC. © 2013 Elsevier Ireland Ltd.

Zonisamide as a treatment for partial epileptic seizures:A systematic review

Although the majority of people with epilepsy have a good prognosis and their seizures can be well controlled with pharmacotherapy, up to one-third of patients can develop drug-resistant epilepsy, especially those patients with partial seizures. This unmet need has driven considerable efforts over the last few decades aimed at developing and testing newer antiepileptic agents to improve seizure control. One of the most promising antiepileptic drugs of the new generation is zonisamide, a benzisoxazole derivative chemically unrelated to other anticonvulsant agents. In this article, the authors present the results of a systematic literature review summarizing the current evidence on the efficacy and tolerability of zonisamide for the treatment of partial seizures. Of particular interest within this updated review are the recent data on the use of zonisamide as monotherapy, as they might open new therapeutic avenues. © 2014 Springer Healthcare.

The immune system as drug target

The immune system is perhaps the largest yet most diffuse and distributed somatic system in vertebrates. It plays vital roles in fighting infection and in the homeostatic control of chronic disease. As such, the immune system in both pathological and healthy states is a prime target for therapeutic interventions by drugs-both small-molecule and biologic. Comprising both the innate and adaptive immune systems, human immunity is awash with potential unexploited molecular targets. Key examples include the pattern recognition receptors of the innate immune system and the major histocompatibility complex of the adaptive immune system. Moreover, the immune system is also the source of many current and, hopefully, future drugs, of which the prime example is the monoclonal antibody, the most exciting and profitable type of present-day drug moiety. This brief review explores the identity and synergies of the hierarchy of drug targets represented by the human immune system, with particular emphasis on the emerging paradigm of systems pharmacology. © the authors, publisher and licensee Libertas Academica Limited.