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Literature and experimental data relevant for the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing levetiracetam are reviewed. Data on solubility and permeability suggest that levetiracetam belongs to class I of the biopharmaceutical classification system (BCS). Levetiracetam's therapeutic use, its wide therapeutic index, and its favorable pharmacokinetic properties make levetiracetam a valid candidate for the BCS-based biowaiver approach. Further, no BE studies with levetiracetam IR formulations in which the test formulation failed to show BE with the comparator have been reported in the open literature. On the basis of the overall evidence, it appears unlikely that a BCS-based biowaiver approach for levetiracetam IR solid oral dosage forms formulated with established excipients would expose patients to undue risks. Thus, the BCS-based biowaiver approach procedure is recommended for IR solid oral dosage form containing levetiracetam, provided the excipients in the formulation are also present in products that have been approved in countries belonging to or associated with the International Committee on Harmonization and are used in their usual quantities, and provided the dissolution profiles of the test and reference product comply with the current requirements for BCS-based biowaivers., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Purpose: Visual sensations in patients with blindness and retinal degenerations may be restored by electrical stimulation of retinal neurons with implantable microelectrode arrays. A prospective trial was initiated to evaluate the safety and efficacy of a wireless intraocular retinal implant (EPIRET3) in six volunteers with blindness and RP., Methods: The implant is a remotely controlled, fully intraocular wireless device consisting of a receiver and a stimulator module. The stimulator is placed on the retinal surface. Data and energy are transmitted via an inductive link from outside the eye to the implant. Surgery included removal of the lens, vitrectomy, and implantation of the EPIRET3 device through a corneal incision. The clinical outcome after implantation and explantation of the device was determined. The implant was removed after 4 weeks, according to the study protocol., Results: Implantation was successful in all six patients. While the anterior part was fixed with transscleral sutures, the stimulating foil was placed onto the posterior pole and fixed with retinal tacks. The implant was well tolerated, causing temporary moderate postoperative inflammation, whereas the position of the implant remained stable until surgical removal. In all cases explantation of the device was performed successfully. Adverse events were a sterile hypopyon effectively treated with steroids and antibiotics in one case and a retinal break in a second case during explantation requiring silicone oil surgery., Conclusions: The EPIRET3 system can be successfully implanted and explanted in patients with blindness and RP. The surgical steps are feasible, and the postoperative follow-up disclosed an acceptable range of adverse events.

Visual sensations in blind patients suffering from retinal degenerations may be restored by electrical stimulation of retinal neurons using implantable microelectrode arrays. The EPI-RET-3 project was initiated to evaluate a wireless intraocular retinal implant system for human use in terms of safety and efficiency. The implant is a remotely controlled fully intraocular prosthesis consisting of a receiver and a stimulator module. The stimulator is placed onto the retina's surface. Data and energy are transmitted via an inductive link from outside the eye to the implant. The EPI-RET-3 device was implanted into six legally blind patients with Retinitis Pigmentosa (RP) for a period of four weeks. The surgery was performed without complications. The implants were activated on days 7, 14 and 27 after implantation. All patients reported visual sensations such as dots, arcs, or lines of different colours and intensities. The required stimulation thresholds were found to be very low. Implantation of the wireless EPI-RET-3 device is safe and the system is suitable to elicit visual sensations in blind RP patients. Major problems in the design and fabrication of a prosthesis for artificial vision could be solved in this approach.

Various dopaminergic drugs have been studied for their efficacy in the treatment of cocaine addiction. Pretreatment with either selective dopamine D1 receptor agonists or selective dopamine D2 receptor antagonists prevents reinstatement of cocaine-seeking in animal models of drug craving and relapse. We tested a novel ergoline derivative with combined D1 agonistic and D2 antagonistic effects, 9,10-didehydro- N-methyl- N-(2-propynyl)-6-methyl-8beta-aminomethylergoline bimaleate (LEK-8829), for its effects on cocaine-seeking in the intravenous cocaine self-administration model in rats. Pretreatment with systemic injections of LEK-8829 attenuated reinstatement of cocaine-seeking induced by cocaine priming injections and diminished cocaine intake in cocaine self-administration sessions. LEK-8829 itself did not induce reinstatement of cocaine-seeking and did not maintain intravenous self-administration. The results of our study indicate that LEK-8829 is a candidate medication for the treatment of cocaine craving in cocaine addiction.

The contribution describes an "intraocular vision aid (IOVA)" system for patients suffering from corneal opacification. In order to gain patients' acceptance the system has to be miniaturized to a magnitude that image acquisition, image processing, and power supply can be integrated into a portable unit. A CMOS camera whose dynamic range covers more than 100 dB takes pictures of the scenery. Its image sensor has a resolution of 380 x 300 pixel. In order to reduce fixed pattern noise correlated double sampling is implemented on-chip. In addition, this sensor stands out for low power consumption, random pixel access, and local brightness adaptation. An analog-digital-converter allows direct coupling to an external signal processor or a monolithically integrated unit for image processing to compress data.

Wireless power and data transmission system developed for an intraocular vision aid for blind patients will be described. This system is applicable for patients suffering from bilateral corneal opacification but with intact posterior ocular. The system consists of an external unit as well as an implant. The external unit is required for image acquisition, channel coding, IR data transmission, and RF power transmission to the implant. The implantable unit contains a CMOS receiver, a receiver antenna coil, and the microdisplay based on a LED array. The CMOS receiver serves for reception and decoding of image data as well as driving circuits for the miniaturized LED array. In this case, mechanical wiring between the external unit and the implant is neither useful nor comfortable. An optimal technical solution needs a wireless data transfer. If the power is transferred to the implant wireless, too, the solution grows ideal. The system described in this communication employs wireless power and data transmission using an 13.56 MHz RF link for power transmission and an near IR (NIR) optical link for data transmission from an external CMOS camera and telemetry unit to the implantable micro display.

Background: The contraction/relaxation response of thoracic aortal rings clamped with two clamping pressures to KCl, noradrenaline and carbachol was studied., Methods: Clamp A had the tip pressure PA = 0.60 N/mm2 and clamp B PB = 5.16 N/mm2. In fifteen Wistar albino rats, weighing 328 +/- 19 g (mean +/- SD) the thoracic aorta was occluded for 15 minutes and then three vascular rings (2 mm wide) were excised. The proximal unclamped ring served as a control. From distal rings the diameter of the aorta was calculated from their circumference 1.61 +/- 0.01 mm (n = 15, dmin = 1.51 mm, dmax = 1.70 mm). The rings were challenged with cumulative additions of KCl (10-80 mmol/l) to measure the contraction. Then cumulative relaxation to carbachol (0.01-100 mumol/l) as a response to noradrenaline precontraction (0.1 mumol/l) was determined., Results: A significant loss (p < 0.05) of vascular relaxation in all clamped rings (clamped with PA and PB clamping pressures) was seen. No significant differences (p > 0.05) were observed for contraction between clamped and control rings clamped with clamp A, however the rings clamped with clamp B showed a significant reduction in contraction (p < 0.05). No significant differences were seen from control rings between groups A and B (p > 0.05), or from clamped rings between groups A and B (p > 0.05) for both the contraction and relaxation part of experiments., Conclusions: Endothelial vascular layers are much more susceptible to pressure injuries than was previously believed.

In a structure-activity study, carried out in rabbit isolated aorta, the effect of different structural modifications in the ergoline nucleus upon the activity at 5-HT2 receptors and alpha-adrenoceptors was determined. 9,10-didehydro-N-methyl-N-(2-propynyl)-6-methylergoline-8 beta-carboxamide (LEK 8842) was chosen as the basic backbone of this study. The parent compound LEK 8842 showed strong alpha-adrenoceptor agonistic activity and partial 5-HT2 receptor agonistic activity, and its potency (pD2 = 6.41) was comparable with that of 5-hydroxytryptamine (5-HT, pD2 = 6.84) and noradrenaline (pD2 = 6.82). Hydrogenation of the double bond in the position 9,10 (LEK 8822) attenuated the potency (pD2 = 5.35) as well as the intrinsic activity on alpha-adrenoceptors and eliminated 5-HT2 receptor agonistic activity. LEK 8822 acted on the alpha-adrenoceptors not only as a partial agonist but also as a competitive antagonist of responses elicited by noradrenaline. When tested against 5-HT, LEK 8822 acted as an antagonist. Bromination in position 2 yielded the derivative LEK 8841 with no agonistic activity at concentrations up to 3 mumol/l, yet the affinity for 5-HT2 receptors and alpha-adrenoceptors was preserved. LEK 8841 was the only one that acted as pure simple competitive antagonist of responses elicited by 5-HT (pA2 = 7.93) and noradrenaline (pA2 = 6.45). Its activity was qualitatively similar to that observed with the 5-HT2/alpha-adrenoceptor antagonist ketanserin which was tested for comparison. Concerning selectivity for 5-HT2 receptors versus alpha-adrenoceptors, LEK 8841 proved to be more selective for 5-HT2 receptors than ketanserin. pA2 values for ketanserin antagonistic activity to 5-HT and to noradrenaline were 8.22 and 7.48, respectively. Finally, quaternization in the N(6) position (LEK 8827) almost completely eliminated affinity for 5-HT2 receptors and for alpha-adrenoceptors. This study has shown that relatively small modifications in the structure of the ergoline system led to pronounced changes in the affinity as well as intrinsic activity at both receptors studied.

The popliteal entrapment syndrome is an entity increasingly reported over the past few years. Anatomical variations should be considered if a localized stenosis or occlusion of the popliteal artery is diagnosed in a young, otherwise healthy individual. This case report documents a complicated course of the disease in a young man in whom diagnosis was made only after futile attempts of intraarterial lysis and dilatation at the time of a second operation. A complex crural reconstruction was necessary in order to revascularize the treatment limb.