Abuse Potential and Pharmacodynamic Characteristics of Oral and Intranasal Eluxadoline, a Mixed µ- and κ-Opioid Receptor Agonist and δ-Opioid Receptor Antagonist.

Drugs with µ-opioid receptor (OR) activity can be associated with abuse and misuse. The peripherally acting mixed µ-OR and κ-OR agonist and δ-OR antagonist eluxadoline is approved in the United States for the treatment of irritable bowel syndrome with diarrhea. In two separate crossover studies, we evaluated the oral and intranasal abuse potential of eluxadoline versus placebo and the active control oxycodone. Healthy recreational opioid users received eluxadoline 100, 300, and 1000 mg, oxycodone 30 and 60 mg, and placebo (oral study), or eluxadoline 100 and 200 mg, oxycodone 15 and 30 mg, and placebos matched to eluxadoline and oxycodone (intranasal study). In the oral study, Drug Liking Visual Analog Scale (VAS) peak (maximum) effect (Emax) score (primary endpoint) was significantly greater with eluxadoline 300 and 1000 mg versus placebo, but scores were significantly lower versus oxycodone. Following intranasal insufflation of eluxadoline, Drug Liking VAS Emax scores were not statistically different versus placebo, and were significantly lower versus oxycodone. Across other subjective measures, eluxadoline was generally similar to or disliked versus placebo. Pupillometry indicated no or minimal central effects with oral and intranasal eluxadoline, respectively. Adverse events of euphoric mood were reported with oral and intranasal eluxadoline but at a far lower frequency versus oxycodone. These data demonstrate that eluxadoline has less abuse potential than oxycodone in recreational opioid users.

Can behavioural differences in Platypus cylindrus (Coleoptera: Platypodinae) from Portugal and Tunisia be explained by genetic and morphological traits?

Platypus cylindrus is an important wood borer of cork oak trees (Quercus suber) in the Mediterranean region, namely Portugal, Morocco and Algeria where its presence has drastically increased in the past few decades. On the contrary, the insect is not a relevant pest in Tunisia. The aim of this work is to analyze morphological and genetic differences among Tunisian and Portuguese populations in order to understand their role in the diverse population dynamics (e.g., aggressiveness) of the insect. The information could be used as a novel tool to implement protective measures. Insects were collected from cork oak stands in Tunisia (Ain Beya, Babouch and Mzara) and Portugal (Chamusca and Crato). Morphological traits of female and male mycangial pits were determined, using scanning electron microscopy but no significant differences were found. Genetic differences were analyzed using nuclear (internal simple sequence repeat polymerase chain reaction) and mitochondrial (cytochrome oxidase I (COI)) molecular markers. The results showed a very low level of intraspecific polymorphism and genetic diversity. The alignment of COI sequences showed high percentage of identical sites (99%) indicating a very low variation in nucleotide composition. Other variables related with the ecology of the insect and its associated fungi must be studied for a better understanding of the differences in the insect population's dynamic in Mediterranean countries.

(Na+-K+)-ATPase interaction with L-ascorbic acid. Effect on p-nitrohenylphosphatase partial reaction.

L-ascorbic acid preincubation with rabbit kidney (Na+-K+)-ATPase inhibits the activity of p-nitrophenylphosphatase partial reaction with a pseudo-first order decay. The presence of the pseudosubstrate, p-nitrophenylphosphate, counteracts the inhibiting effect. During the reaction course, the kinetic rate is enhanced at ascorbic acid concentrations below 0.7 mmol/1, but is inhibited above that amount. The intrinsic fluorescence of the enzyme in E1 and E2 conformations is modified suggesting the occurrence of ascorbate-induced intermediate forms, distinct from those provoked by the addition of cations, magnesium and phosphate. These destabilized forms appear easier to be converted into catalytically active or increasingly inhibited states.

Construct Failure in an Atypical Femoral Fracture treated with Intramedullary Nailing: A Case Report.

ABSTRACT: The aim of this paper is to document a rare case of construct failure in a 68-year old Filipina who sustained an atypical femoral fracture (AFF) in her left subtrochanteric area. The patient previously had a 40-month history of alendronate 70mg + vitamin D 5600u therapy for osteoporosis and underwent closed intramedullary nailing for the AFF. Six months postoperatively, she began to experience progressive pain in her operated thigh. Radiographs revealed a broken nail at the proximal screw hole and non-union of the AFF. The patient was treated with exposure of the fracture site, removal of the broken device, exchange intramedullary nailing, and iliac bone grafting. She had radiographic and clinical union and was full weight bearing after three months.

Outcome of surgery for unstable intertrochanteric fractures in octogenarians.

ABSTRACT: This study aims to determine pre-morbid parameters as possible predictors of outcome of hip fracture in octogenarians with unstable intertrochanteric fracture treated operatively. Presence of co-morbidities, pre-injury level of ambulation, type of surgery, and period of delay in surgery were considered, and their effect on the post-operative outcome was evaluated using the Harris Hip Score. The computed probability of survival of octogenarians who had surgery was approximately 11 months. In patients with two or more co-morbidities, there is a significant effect on Harris Hip Score in terms of pain and deformity. Delay in surgery of more than two weeks significantly decreased the distance travelled at one year. The overall recovery is correlated to preinjury level of ambulation and delay in surgery. Patients with intertochanteric fracture in this age group, who have less co-morbidities and with more independent ambulation, are good candidates for timely operative treatment.

Revisiting the outcome of displaced two-part fractures of the humeral neck in elderly patients after conservative treatment.

ABSTRACT: The aim of this study was to evaluate our experience with regard to the outcome of displaced two-part fractures of the humeral neck in elderly patients that were treated conservatively. Between July 2008 and June 2010, 53 consecutive patients (42 females and 11 males; mean age = 74; range = 60-92) with an acute, displaced, two-part fracture of the humeral neck were treated conservatively using a sling and swathe for two weeks, followed by a standard rehabilitation protocol. The inclusion criteria were a displacement of the shaft >50% of its width and/or angulation of the shaft >45 degrees on standard radiographs. The exclusion criteria were patients younger than 60 years of age and those with cognitive or systemic impairment that would preclude the recommended physiotherapy. Patients were followed-up for one year, and were assessed at 3, 6, and 12 months using the Constant- Murley Score (CMS) and the Disabilities of the Arm, Shoulder, and Hand Questionnaire (DASH). Patients were divided into two groups, those below 70 years of age and those above 70-. Two-way repeated measures analysis of variance (ANOVA) was used to determine if there were significant differences between the results at 3, 6 and 12 months for both groups, and if the results were significantly different between the two groups. Forty-eight out of 53 patients (91%) were able to complete the follow-up schedule, while five patients died. The mean CMS improved progressively at three (51.3), six (60.4), and 12 (61.3) months. The mean DASH also improved progressively at three (38.8), six (34.8), and 12 (32.6) months. For both groups, the CSS and DASH improved significantly from three to six months and from three to 12 months. However, the improvements were not significant from just six to 12 months. Between the two groups, the results at three, six, and 12 months were not significantly different from each other. On final follow-up, 42 out of 48 patients (88%) were satisfied with their outcome and reported that they would choose to undergo the same treatment if they had to do everything all over again. Conservative management of displaced two-part fractures of the humeral neck in elderly patients is a safe, efficacious, and acceptable treatment.