Current Drug Therapy - Volume 8, Issue 2, 2013

Objective: To assess the efficacy of inhaled, repeat doses (28 days) of the glucocorticoid agonist GW870086. Methods: This was a randomised, placebo-controlled, parallel group study in subjects with persistent asthma (n=135) who received GW870086 (2, 3, or 4 mg, once-daily) or placebo. Results: Improvements in forced expiratory volume in one second (FEV1) were seen following all three doses of GW870086 relative to placebo. Mean improvements (95% confidence interval) of: 0.172 L (0.015, 0.329), 0.105 L (-0.053, 0.263) and 0.159 L (0.001, 0.316) were observed for 2 mg, 3 mg and 4 mg, respectively, at Day 28. Peak expiratory flow rate results were consistent with FEV1 and rescue medication was administered more frequently in the placebo group than all three GW870086 treatment arms. Conclusion: This study provided a positive outcome with all doses of GW870086 demonstrating improvements in lung function compared with placebo.

Aim and Methods: We conducted two studies in healthy male subjects to assess the effect on serum cortisol levels of the novel inhaled corticosteroid GW870086, dosed at 6 mg, 12 mg and 15 mg/day (dry powder inhaler; NCT00549497) for 3 days and 5 mg and 8.75 mg/day (nebules; NCT01160003) for 14 days. Results: In the 3-Day Study, the greatest suppression of serum cortisol weighted mean (0-24 hour) of GW870086, compared with placebo, was observed on Day 1 (29% suppression at the 15 mg dose). In the 14-Day Study, the greatest suppression was 15% for GW870086 5 mg. None of these values was considered clinically significant. After 3 days’ dosing, GW870086 was absorbed slowly (tmax: 0.8-3.5 hours) and eliminated with a t1/2 of 22.7 hours; the highest systemic exposure (AUC) was 26.7 ng.hour/mL. After 14 days, GW870086 tmax was 0.3-0.4 hours and t1/2 25.0-29.6 hours; the highest AUC was 16.7 ng.hour/mL. No safety issues were identified in these studies. Conclusion: At estimated therapeutic and supratherapeutic doses, which achieved high exposure (AUC) in both studies, GW870086 did not exhibit the usual level of hypothalamic-pituitary-adrenal axis suppression that would be expected with traditional inhaled corticosteroids.

Tuberculosis is a neglected disease caused by Mycobacterium tuberculosis. Some evidence suggests its existence since thousands of years and today it still represents a public health problem. Current treatment presents serious problems such as adverse effects, high cost, long term, besides the emergence of resistant strains. Therefore the search for new antimicrobials is still in need. In this work we reviewed tuberculosis treatment as well as the synthesis of the current drugs and new synthetic derivatives that have been developed against M. tuberculosis. In this context we explored the medicinal chemistry and molecular modeling strategies as important tools to guide the rational design and synthesis of novel chemotherapeutic agents for use in tuberculosis.

Inflammatory bowel disease (IBD), commonly known as Crohn’s disease and ulcerative colitis, is a frequently occurring disease in Gastroenterology, which is characterized by a chronic intestinal inflammatory ailment. The therapy of IBD is dominated by the administration of anti-inflammatory and immune-modulating drugs, which suppress the intestinal inflammation and thus improve disease-related symptoms. The enhanced insight and more detailed knowledge about the pathophysiological mechanisms of IBD accelerate the research and development of innovative drugs and new treatment strategies. In the last decades, many evolutionary as well as revolutionary innovations were developed and investigated in clinical trials. This review is believed to give an overview about established and future-orientated treatment approaches, including antisense gene therapy, non-embryonic stem cell therapy, leucocytapheresis and faecal biotherapy. Additionally, this review illuminates other smaller clinical trials, which follow interesting and maverick approaches, like lecithinmediated mucosal healing, Trichuris suis ova-supported treatment or several herbal treatment strategies. The main focus is pointed in the conceivable explanation of the respective molecular target mechanisms as well as potential to modulate the inflammatory and immunological process. Additionally, this review gives a brief insight in the therapeutical benefits and mediates about the risks of the respective treatment approaches.

Delivery of hydrophobic drugs via buccal route is a challenging approach. Isradipine (IDP) is a highly hydrophobic drug and is practically insoluble in water. Though the log p value of Isradipine permits the drug to pass through buccal membrane, the amount of drug delivered is low. The aim of present investigation is to develop buccal tablets containing Isradipine complexed with a β-cyclodextrin. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies were used to examine the physicochemical properties of the inclusion complexes. Based on the solubility experiments, the 1:2 molar ratio (Isradipine:β-Cyclodextrin) has given good results. From the photostability studies it was concluded that Isradipine in the inclusion complex was more stable than pure Isradipine. Addition of βCD to the matrix increased the flux by increasing the solubility of drug, thus improving the diffusible form of the drug species at the tablet membrane interface. The flux (FS5) was found to be increased by 1.833 folds with a permeability coefficient of 0.022 cm h-1. Moreover Isradipine undergoes extensive hepatic metabolism. Thus formulating a buccal delivery system of Isradipine with βCD may improve the bioavailability and photostability of the drug along with patient compliance.

We summarize the alterations of classical neurotransmitters and neuropeptides, including their specific subreceptors, involved in schizophrenia. The essential susceptibility genes in schizophrenia and their coherence to neurotransmitter alterations are highlighted. In this sense, dopamine and serotonin hyperactivity in the mesolimbic system and the hippocampus is due to a reduced presynaptic inhibition carried out by GABA and glutamate, which is due to the susceptibility genes. A neuronal network in the brain regions involved in schizophrenia is developed in order to derive novel therapeutic approaches. A survey of the mechanisms of action of conventional and newer antipsychotic drug is given. We suggest the appropriate antipsychotic drugs considering the symptoms of schizophrenic and their possible side effects. It is important to examine the susceptibility genes in a cohort of patients in order to find out which patients profit more from antipsychotic drugs: those that exert a stronger D2 antagonistic effect or those that exert a stronger 5HT2A antagonistic effect. One question to be answered is whether refractory symptoms such as persistent acoustic hallucinations could be improved with novel antipsychotic drugs.