Drug-drug interaction between cannabidiol and phenobarbital in healthy dogs

OBJECTIVE To assess drug-drug interactions between cannabidiol (CBD) and phenobarbital (PB) when simultaneously administered to healthy dogs. ANIMALS 9 healthy, purpose bred Beagles. PROCEDURES A 3-phase prospective, randomized pharmacokinetic (PK) interaction study of CBD and PB was performed as follows: phase 1, CBD PK determination and evaluation of CBD tolerability by 3 single-dose CBD (5 mg/kg, 10 mg/kg, and 20 mg/kg) protocols followed by 2-week CBD dosing; phase 2, a single-dose, 3-way, crossover PK study of CBD (10 mg/kg), PB (4 mg/kg), or CBD (10 mg/kg) administration plus PB (4 mg/kg); and phase 3, evaluation of chronic PB (4 mg/kg, q 30 d) administration followed by single-dose CBD (10 mg/kg) PK study. RESULTS Although there were variations in CBD PK variables in dogs receiving CBD alone or in conjunction with PB, significance differences in CBD PK variables were not found. No significant difference was observed in PB PK variables of dogs receiving PB alone or with CBD. During chronic CBD administration, mild gastrointestinal signs were observed in 5 dogs. At daily CBD doses of 10 to 20 mg/kg/d, hypoxia was observed in 5 dogs and increased serum alkaline phosphatase (ALP) activities (range, 301 to 978 U/L) was observed in 4 dogs. A significant increase in ALP activity was observed with chronic administration of CBD during phase 1 between day 0 and day 14. CONCLUSIONS AND CLINICAL RELEVANCE No significant PK interactions were found between CBD and PB. Dose escalation of CBD or adjustment of PB in dogs is not recommended on the basis of findings of this study.

A Feasible Solution for Rebalancing Large-Scale Bike Sharing Systems

City bikes and bike-sharing systems (BSSs) are one solution to the last mile problem. BSSs guarantee equity by presenting affordable alternative transportation means for low-income households. These systems feature a multitude of bike stations scattered around a city. Numerous stations mean users can borrow a bike from one location and return it there or to a different location. However, this may create an unbalanced system, where some stations have excess bikes and others have limited bikes. In this paper, we propose a solution to balance BSS stations to satisfy the expected demand. Moreover, this paper represents a direct extension of the deferred acceptance algorithm-based heuristic previously proposed by the authors. We develop an algorithm that provides a delivery truck with a near-optimal route (i.e., finding the shortest Hamiltonian cycle) as an NP-hard problem. Results provide good solution quality and computational time performance, making the algorithm a viable candidate for real-time use by BSS operators. Our suggested approach is best suited for low-Q problems. Moreover, the mean running times for the largest instance are 143.6, 130.32, and 51.85 s for Q = 30, 20, and 10, respectively, which makes the proposed algorithm a real-time rebalancing algorithm.

Enhanced oral bioavailability of Etodolac by liquisolid compact technique: optimisation, in-vitro and in-vivo evaluation

Background: Poor dissolution of Etodolac is one of the major challenges in achieving the desired therapeutic effect in oral therapy. Objective: This study aimed to assess the potential of liquisolid compact technique in increasing the rate of dissolution of Etodolac and thus its bioavailability. Methods: Liquisolid compacts were prepared using PEG 400, Avicel PH-200 and Aerosil 200 as non-volatile liquid, carrier and coating material respectively. Optimisation was carried out by applying a 32 full factorial design using Design expert software 11.0.3.0 to examine the effects of independent variables (load factor and carrier: coating ratio) on dependent variables (angle of repose and % cumulative drug release at 30 min [Q 30 min]).Assessment of bioavailability was based on pharmacokinetic study in rabbits and pharmacodynamics evaluation in rats respectively. Results: The formulation M3 was identified as the optimised formulation based on the better flow (lower angle of repose) and a higher rate of dissolution (Q 30 min >95%). The higher dissolution rate could be due to conversion of Etodolac into an amorphous molecularly dispersed state, availability of larger surface area, enhancement of aqueous solubility and enhanced wetting of drug particles. Studies with DSC, XRD, and SEM verified the transformation of Etodolac from crystalline to amorphous state, a key factor responsible for improving the dissolution rate. Pharmacokinetic profile of M3 was prominent, demonstrating higher absorption of Etodolac in comparison of oral suspension and immediate-release conventional tablets in rabbits. Liquisolid formulation exhibited 27% increment in paw thickness as compared to 57% and 46% increments for oral suspension and immediate-release conventional tablets respectively, after 7 hrs in carrageenan-induced paw model in rats. Conclusion: The results indicated liquisolid compact technique to be a promising strategy to enhance the bioavailability of Etodolac.

Q 30: 2‒5 in Near Eastern Context

This article aims to contextualize a short Qurʾānic passage – Q 30:2‒5 – with reference to Jewish and Christian materials that have not hitherto been deployed for this purpose. The article builds on the findings of recent scholarship, which reads this passage eschatologically rather than historically, and argues that there are, in fact, two texts that require contextualization: 1) The Qurʾānic verses themselves (which refer only to the fate of “the Romans”); and 2) The early exegetical traditions on these verses (which often add “the Persians” to the eschatological drama). Furthermore, it is argued that the Biblical book of Daniel, and its interpretation in late antiquity, contributed both to the verses themselves and to their exegesis.

Li-qawmin yatafakkarūn(Q. 30:21): Muhammad Asad's Qur'anic TranslatorialHabitus

Recent decades have seen a focus on the translator as a socialised individual as one approach favoured in Translation Studies. Scholars have employed sociological concepts such as habitus (socio-cultural conditioning) and field (environment) as methodological tools in empirical translation research, yielding new and interesting perspectives on the process of translation. In the field of Qur'an hermeneutics, however, such methodological tools have not been applied systematically. The present article constitutes an initial attempt to address this omission, by delineating Muhammad Asad's habitus against the backdrop of his socio-political, cultural, and intellectual background in order to explore the significance of its impact on his The Message of the Qur'an. It will contextualise Asad's rendition of the Qur'an into English through comparative critical intertextual and paratextual analysis, thereby introducing the ‘realm of sociology of translation’, a Translation Studies perspective, into Qur'anic studies.

“The Romans Will Win!” Q 30:2‒7 in Light of 7th c. Political Eschatology

This article addresses a prophecy found in vv. 2‒7 of the thirtieth Qurʾānic sūra, known as al-Rūm (“The Romans”). These verses report on the Romans’ (al-Rūm) involvement in a conflict against an unnamed enemy and predict its eventual outcome. The passage refers to the conflict between the Byzantines and Sasanians that lasted for about thirty years during the first three decades of the 7th c. (602‒628 CE). These verses are usually considered to be the only Qurʾānic allusion to a historical event that can be confirmed by sources external to the Islamic tradition. In this study I will argue that the prophecy on the Rūm has close parallels with other prophecies on the war that were circulating in the Middle East in the first half of the 7th c. The contextualization and comparison with other 7th c. prophecies will provide us with a better understanding of the Qurʾānic passage.

Validation of a testosterone-deficiency symptoms rating-scale in prostate cancer patients treated with androgen deprivation therapy and radiotherapy.

63 Background: Androgen deprivation therapy (ADT) plays an important role in the management of non-metastatic prostate cancer (NMPC). We prospectively assessed the performance of a symptom rating scale, the aging men’s symptoms score (AMS) in relation to other validated QOL tools. Methods: Following ethics approval, 145 patients with a diagnosis of NMPC receiving ADT as part of radical treatment were enrolled after informed consent. Data was collected using the EORTC QLQ-C30, the AMS and the International Index of Erectile Function score (IIEF-5) questionnaires at baseline, 3 months (post ADT) and after ADT was stopped. Results: Eighty six (58.1%) patients had ADT for <9 months, 7 (4.7%) had 9 -18 months and 55 (37.2%) had 27-36 months. A third (32.3%) of patients had moderate/severe symptoms of testosterone deficiency (TD) at baseline vs 62% and 44.4% at time points 2 & 3 (p<0.0001). Severe erectile dysfunction was common and worsened with ADT (45.3% & 74.1% respectively) and did not recover post ADT (p<0.0001). Few (1.6%) patients retained normal erectile function at the end of the study vs 15.6% at baseline. Self-reported QoL using EORTC QLQ C30 (Q.30) remained high at all time points (80.8%, 76.2%,75.8% respectively for a score of 5-7, 7 =very good, 1=very poor). Conclusions: TD due to ADT resulted in significant symptoms only in a subset of patients and not all symptoms resolved post ADT. However, self-reported QoL remained unaffected indicating that andropause symptoms may not affect QoL in radically treated prostate patients. This prospective data validates AMS scale and it could be used in routine clinical practice to assess TD symptoms in this group. [Table: see text]

199 Cardiac Safety and QTc Intervals With DM/Q Treatment for Pseudobulbar Affect: A Review of Clinical Trial Data

OBJECTIVEDextromethorphan hydrobromide and quinidine sulfate (DM/Q) 20mg/10mg is FDA approved to treat pseudobulbar affect (PBA), a neurological condition characterized by sudden, frequent, involuntary crying or laughing. Although the total dose of quinidine (20 mg) from twice daily DM/Q for PBA is well below the antiarrhythmic dose (600-1600 mg/day), clinicians may be reticent to use DM/Q due to concerns for cardiac safety.METHODDM/Q cardiac safety was evaluated in two thorough QTc (TQT) studies and by ECG monitoring in DM/Q phase 3 clinical trials. In the TQT studies, twice daily DM/Q 30mg/10mg (Study 08-AVR-126; N=50 enrolled) and supratherapeutic doses 30mg/30mg and 60mg/60mg (Study 05-AVR-119; N=36 enrolled) were studied in healthy volunteers. In phase 3 controlled clinical trials, the effects of DM/Q on Fridericia’s corrected QT intervals (QTcF) were assessed, as was the incidence of ECG outliers. Adverse events (AEs) were monitored in all clinical trials.RESULTSOverall, 47/50 participants completed TQT study 08-AVR-126 and 36/36 completed TQT study 05-AVR-119. Time-matched, placebo-corrected mean maximal changes in QTcF for DM/Q 30mg/10mg and 30mg/30mg occurred 3h post-dose (10.3 and 10.1ms, respectively) vs moxifloxacin (12.2 and 14.4ms at 1.5 and 1.0h). For the supratherapeutic DM/Q 60/60 mg dose, mean maximal QTcF change was 18.8ms. No participant had a QTcF >480 ms or QTc increase >60 ms. In PBA phase 3 controlled trials, mean changes in QTcF were similar for DM/Q containing Q 10 mg (0.4 to 3.5 ms; n=217) andplacebo (0.4 to 3.1 ms; n=183), but greater for DM/Q with Q 30 mg (2.9 to 7.6 ms; n=146). In an outlier analysis, a similar percentage of DM/Q-treated participants (3.9%) had a QTcF shift from <450 ms at baseline to ≥450 ms during treatment vs placebo (2.9%). No participant with PBA had a QTc change from baseline >60 ms or an absolute QTc interval >480 ms. No dose- or time-related trends in cardiac arrhythmias or other cardiac-related AEs were observed.Of 2552 DM/Q-treated patients and healthy participants across all controlled and open-label trials for any indication, 11 deaths due to any cardiovascular AE have been reported; none were attributable to DM/Q treatment and none occurred in placebo-controlled PBA clinical trials in any treatment group. Overall 16 patients had a QTcF that exceeded 500 ms at any ECG measurement.CONCLUSIONSThe TQT studies demonstrated that DM/Q has the potential to prolong the QT interval in a dose-dependent manner, but that the risk for QTc prolongation and arrhythmias with Q 10 mg formulations is low. In clinical trials with PBA patients, the cardiac safety profile of DM/Q 20mg/10mg or 30/10 mg was indistinguishable from placebo.Funding AcknowledgementsAvanir Pharmaceuticals, Inc.