Does the Heart Want What It Wants? A Case for Self-Adapting, Mechano-Sensitive Therapies After Infarction

There is a critical need for interventions to control the development and remodeling of scar tissue after myocardial infarction. A significant hurdle to fibrosis-related therapy is presented by the complex spatial needs of the infarcted ventricle, namely that collagenous buildup is beneficial in the ischemic zone but detrimental in the border and remote zones. As a new, alternative approach, we present a case to develop self-adapting, mechano-sensitive drug targets in order to leverage local, microenvironmental mechanics to modulate a therapy's pharmacologic effect. Such approaches could provide self-tuning control to either promote fibrosis or reduce fibrosis only when and where it is beneficial to do so.

501 Clinical PK of XW10172 for Once Nightly Therapy in Patients with Narcolepsy or Sleep Disorders in Neurodegenerative Diseases

Introduction Patients with narcolepsy and patients with sleep disorders secondary to neurodegenerative diseases have been shown to respond to oxybate. To overcome the limitations of current oxybate therapies, we designed XW10172, a new chemical entity and GABA-B agonist with no sodium or other cation content and for once nightly dosing. The objectives of two clinical studies were to assess the XW10172 pharmacokinetics (PK), pharmacodynamics (PD) and safety/tolerability in normal study participants. Methods Two XW10172 studies in healthy participants assessed ascending single and multiple doses, comparison to sodium oxybate in immediate release (IR) and extended release (ER) formulations. PK parameters were calculated from concentration vs. time data. Safety and tolerability were assessed by monitoring adverse events, laboratory tests, and vital signs. Results To date, 84 study participants received XW10172 and the PK from single and multiple dose administration showed doses of 0.1 to 7.25 g had a mean oxybate half-life range of 0.5 to 1.3 hours. Oxybate levels from the drug were about 6-fold higher than XW10172 levels. Oxybate PK from XW10172 (IR) was the same as from equal molar doses of sodium oxybate. XW10172 (ER) formulations showed delayed Tmax with extended oxybate exposure compatible with single nightly dose therapy. PK-PD assessment of somnolence, the desired pharmacologic effect, showed a concentration-effect relationship (Cmax p=0.0004, AUC p<0.0001). XW10172 was generally well tolerated and adverse events were those known to be associated with oxybate. Conclusion These data support progression of XW10172 (ER) in further clinical development studies to assess this once nightly GABA-B agonist therapy for the treatment of patients with various sleep disorders. Support (if any) XWPharma

Short-term choroidal vascular changes after aflibercept therapy for neovascular age-related macular degeneration

Introduction The purpose of this study was to evaluate choroidal vascular changes in patients with neovascular age-related macular degeneration (nAMD) treated with aflibercept injection over a 3-month period. Methods Enhanced depth imaging optical coherence tomography scans of 60 eyes with treatment-naïve nAMD and 60 unaffected fellow eyes were retrospectively analyzed. Data was collected at baseline and after 3 monthly intravitreal injections of aflibercept. The ImageJ software was used to binarize OCT scans and measure total choroid area (TCA), luminal area (LA), and stromal area (SA). Choroidal vascularity index (CVI) was defined as the ratio of LA to TCA. Results After treatment, subfoveal choroidal thickness (CT) in nAMD eyes significantly decreased from 210. 6 ± 61.6 to 194.6 ± 58.7 μm (P < 0.001), TCA from 1.620 ± 0.502 to 1.500 ± 0.451 mm2 (P < 0.001), LA from 1.075 ± 0.335 to 0.985 ± 0.307 mm2 (P < 0.001), SA from 0.545 ± 0.176 to 0.516 ± 0.153 mm2 (P = 0.005), and CVI from 66.36 ± 2.89 to 65.46 ± 2.87% (P = 0.009). The decrease of CVI after treatment was significantly correlated with baseline CVI (Rs = 0.466, P < 0.001), but not with the change in BCVA and presence of dry macula after treatment (always P > 0.05). Conclusion Choroidal thickness and vascularity significantly decreased after treatment with aflibercept in nAMD eyes. Besides the pharmacologic effect on the neovascular lesion, aflibercept may induce vascular changes also on the underlying choroid.

Benzodiazepine Receptors in the Periphery

The benzodiazepines are almost universally thought to produce one and only one pharmacologic effect: positive allosteric modulation of GABAA receptors located in the brain. This results in an increased Cl−ion influx, greater negative transmembrane potential difference, and neurons that are less likely to fire in response to anxiety-producing stimulation. Unfortunately, the simplicity and success of this mono-target belief has distracted researchers and clinicians from studying and appreciating their other pharmacology. A glaring example is the general lack of awareness of the peripheral benzodiazepine receptor. The peripheral benzodiazepine receptor alters mitochondrial function (energy supply), cholesterol transport, and immune function. A patient who is on long-term benzodiazepine therapy (or withdrawing from them) will have these sites affected, just as are the sites located in the brain. One can easily imagine that the adverse effects associated with the peripheral sites would be fundamental, varied, and potentially profound—involving lack of energy, altered cholesterol metabolism, and aberrant immune function.

Pilot Study: Assessment of Drug-Food and Drug-Drug Interactions in the Outpatient Settings

Background: A drug-drug interaction arises when the pharmacologic effect of a medication is changed by the action of other medication causing unexpected clinical effects. Drug-drug interactions are widely known but the identification of the consequences of food and drug interactions has been growing slowly. Aim: The present study aims to describe the occurrence of drug –food and drug-drug interactions in the outpatient settings in Riyadh city. Methodology: A retrospective study was piloted in Riyadh city. The prescriptions were reviewed to identify potential drug - food and drug–drug interactions using Drug Interactions Checker. Results: About 16.16% of the prescriptions included a drug - drug interaction. The most frequent interaction was the interaction between ciprofloxacin and metronidazole (25.00%) that is a minor interaction. Regarding drug – food interactions there were 40 interactions, the majority of these interactions were moderate. The most common drug - food interactions were metronidazole with food (20.00%) that is a major interaction. Conclusion: Drug interactions with other drugs or with foods are common. These interactions could have a beneficial or a harmful effect. Physicians and pharmacists should use programs that detects the drug interactions.

VEGF-A polymorphisms affect the pharmacologic effect of bevacizumab on VEGF-A levels in patients with metastatic colorectal cancer.

e15505 Background: Bevacizumab treatment presents large interpatient variability in efficacy. Mutations in VEGF-A rs699947 are associated with longer overall survival and progression free survival in bevacizumab-treated metastatic colorectal cancer (mCRC) patients. The aim of the present study was to investigate correlations between VEGF-A polymorphisms and VEGF-A levels in patients receiving bevacizumab for mCRC. Methods: 46 patients were studied. Blood samples were collected for VEGF-A (rs2010963, 1570360, rs699947) genotyping, and measurement of bevacizumab and VEGF-A levels. The Spearman's rank correlation coefficient was used to study the correlation between VEGF-A and bevacizumab levels. For the multiple analysis, we used linear regression with residual analysis and considering multicollinearity while the effects are reported with 95% confidence intervals. Results: In total 171 samples for VEGF-A and 157 for bevacizumab levels were analyzed. A very strong negative correlation between bevacizumab and VEGF-A levels (coef. = -0.625, p < 0.000001) was noted. Interestingly, VEGF-A rs699947 plays an important role in the model (p = 0.0002, 95% CI 32.5-58.1) and as VEGF-A levels were found to be significantly lower in patients with mutant rs699947 (p < 0.0001, 95% CI 25.2 - 53.8). Conclusions: In conclusion, genetic factors significantly affected the effect of bevacizumab on VEGF-A levels. Significantly lower VEGF levels were measured in carriers of mutant rs699947. These results may explain the favorable clinical outcomes reported in this sub-group of patients. These findings might enable clinicians to distinguish patients, who may benefit more and in a long-term. Finally, can be used to design individualized dosing schemes for bevacizumab.

Clinical Analysis of Late Age Somatoform Algic Disorder Case Following with Pain in Maxillofacial Area: Example of Dental Treatment Groundlessness

Case of somatoform algic disorder with pain in maxillofacial region is described on a 58 years old patient. The patient have been observed by different specialists and underwent numerous medical examinations which led as a result to groundless medical manipulations such as several teeth extirpation, removal of previously mounted metalloceramic constructions.Latest observations show that there is a link between age and pain localization rate at mouth area as well as changes in hypochondriac experience to the increase of supervaluable generations. Thus condition described becomes a disorder which is hard to diagnose and a social problem concerning early diagnostics and treatment. With time and increase of life expectancy as well as increase of assortment and affordability of dental procedures problem of somatoform algic disorder diagnostics in late age becomes more urgent. Clinical case illustrates accumulated practical experience of late age somatoform disorders treatment by combinations of antidepressants and small doses of antipsychotics. Ethiopathogenesis of this condition assessed as nociceptive, neuropathologic and then as psychogenic pain is still to be investigated. Late diagnostics in this case points to a necessity of multidisciplinary approach to such patients’ treatment in order to develop criteria to apply in practice for diagnostic mechanisms optimization and pharmacologic effect on early disorder stages.