Reduced variability in tacrolimus pharmacokinetics following intramuscular injection compared to oral administration in cynomolgus monkeys: Investigating optimal dosing regimens

Tacrolimus is one of the most commonly used immunosuppressive agents in animal models of transplantation. However, in these models, oral administration is often problematic due to the lowered compliance associated with highly invasive surgery and due to malabsorption in the intestinal tract. Therefore, we carried out a study to determine the pharmacokinetics of tacrolimus after intramuscular (IM) injection and to determine the optimal IM dosing regimens in primate models. Six male cynomolgus monkeys (Macaca fascicularis) were used in the study. Doses of 0.1 mg/kg and 5 mg were administered via IM injection and oral administration, respectively, once to determine single-dose pharmacokinetics and once daily for 5 days to determine multiple-dose pharmacokinetics. According to pharmacokinetic model estimates, the inter- and intra-individual variabilities in bioavailability following IM injection were remarkably reduced compared with those following oral administration. Monte Carlo simulations revealed that C_peak, C_trough and AUC would also have less variability following IM injection compared with oral administration. In this study, we found that the pharmacokinetic characteristics of tacrolimus were more constant following IM injection compared with oral administration. These results suggest that IM injection can be an alternative route of administration fin non-human primate model studies.     

Biomechanics of milk extraction during breast-feeding

How do infants extract milk during breast-feeding? We have resolved a century-long scientific controversy, whether it is sucking of the milk by subatmospheric pressure or mouthing of the nipple–areola complex to induce a peristaltic-like extraction mechanism. Breast-feeding is a dynamic process, which requires coupling between periodic motions of the infant’s jaws, undulation of the tongue, and the breast milk ejection reflex. The physical mechanisms executed by the infant have been intriguing topics. We used an objective and dynamic analysis of ultrasound (US) movie clips acquired during breast-feeding to explore the tongue dynamic characteristics. Then, we developed a new 3D biophysical model of the breast and lactiferous tubes that enables the mimicking of dynamic characteristics observed in US imaging during breast-feeding, and thereby, exploration of the biomechanical aspects of breast-feeding. We have shown, for the first time to our knowledge, that latch-on to draw the nipple–areola complex into the infant mouth, as well as milk extraction during breast-feeding, require development of time-varying subatmospheric pressures within the infant’s oral cavity. Analysis of the US movies clearly demonstrated that tongue motility during breast-feeding was fairly periodic. The anterior tongue, which is wedged between the nipple–areola complex and the lower lips, moves as a rigid body with the cycling motion of the mandible, while the posterior section of the tongue undulates in a pattern similar to a propagating peristaltic wave, which is essential for swallowing.Breast-feeding is strongly publicized and encouraged by many societies and communities. It is well accepted that breast milk provides the infant both nutrients and immunities required for growth and development during the first months after birth. It is less known that breast-fed infants exercise and prepare their orofacial muscles for future tasks of speaking and chewing (1), and also have higher oxygen saturation than bottle-fed infants (2). Breast-feeding is the outcome of a dynamic synchronization between oscillation of the infant’s mandible, rhythmic motility of the tongue, and the breast milk ejection reflex that drives maternal milk toward the nipple outlet. First, the infant latches onto the breast and nipple so that the nipple, areola, and underlying mammary tissue and lactiferous ducts are drawn into the infant’s mouth with the nipple tip extended as far as the hard–soft palate junction (HSPJ). Then, the infant moves its mandible up and down, compressing the areola and the underlying lactiferous ducts with its gums in a suckling process that extracts the milk into its mouth (3, 4). Simultaneous with compression, spontaneous undulating motions of the infant tongue channel the milk posteriorly and trigger the swallowing reflex (5). During breast-feeding, suckling, swallowing, and breathing are coordinated by the central nervous system in a way that allows for the infant’s continuous feeding without breathing interruptions (2, 6, 7).The physical mechanisms that enable the infant to extract milk from the breast have intrigued scientists for more than a century (8). The two proposed mechanisms that have been a subject of scientific controversy to this day are (i) sucking—emptying of the nipple–breast contents by development of subatmospheric pressures within the infant oral cavity (9–12) and (ii) mouthing—squeezing out of the nipple–areola contents by compression between the jaws or other mouth parts (3). With the appearance of cine–X-ray and ultrasound (US) imaging modalities, a significant role was also attributed to tongue undulation which was naturally referred to as “tongue peristalsis” while chewing the nipple (13, 14). However, advanced computational modeling has not yet been used along with imaging data to perform hypothesis testing on the underlying explanations of the suckling behavior during breast-feeding.We have explored the physical aspects of infant feeding via noninvasive visualizations of the moving components in the oral cavity and a biophysical model. An objective dynamic analysis of submental US imaging of the midsagittal cross-section of the oral cavity during infant feeding was used to study the dynamic characteristics of tongue motion with respect to the rigid upper palate. A 3D fluid–structure interaction (FSI) biophysical model was developed to simulate milk extraction during breast-feeding.     

Quantitative Prediction of Oral Bioavailability of a Lipophilic Antineoplastic Drug Bexarotene Administered in Lipidic Formulation Using a Combined In Vitro Lipolysis/Microsomal Metabolism Approach

For performance assessment of the lipid-based drug delivery systems (LBDDSs), in vitro lipolysis is commonly applied because traditional dissolution tests do not reflect the complicated in vivo micellar formation and solubilization processes. Much of previous research on in vitro lipolysis has mostly focused on rank-ordering formulations for their predicted performances. In this study, we have incorporated in vitro lipolysis with microsomal stability to quantitatively predict the oral bioavailability of a lipophilic antineoplastic drug bexarotene (BEX) administered in LBDDS. Two types of LBDDS were applied: lipid solution and lipid suspension. The predicted oral bioavailability values of BEX from linking in vitro lipolysis with microsomal stability for lipid solution and lipid suspension were 34.2 ± 1.6% and 36.2 ± 2.6%, respectively, whereas the in vivo oral bioavailability of BEX was tested as 31.5 ± 13.4% and 31.4 ± 5.2%, respectively. The predicted oral bioavailability corresponded well with the oral bioavailability for both formulations, demonstrating that the combination of in vitro lipolysis and microsomal stability can quantitatively predict oral bioavailability of BEX. In vivo intestinal lymphatic uptake was also assessed for the formulations and resulted in <1% of the dose, which confirmed that liver microsomal stability was necessary for correct prediction of the bioavailability.     

Prognostic Significance of Somatostatin Receptor Heterogeneity in Progressive Neuroendocrine Tumor Treated with Lu-177 DOTATOC or Lu-177 DOTATATE

European Journal of Nuclear Medicine and Molecular Imaging - One of the primary prerequisites for peptide receptor radionuclide therapy (PRRT) in patients with neuroendocrine tumors (NET) is the...     

Different forms of locomotion in the spinal lamprey

Forward locomotion has been extensively studied in different vertebrate animals, and the principal role of spinal mechanisms in the generation of this form of locomotion has been demonstrated. Vertebrate animals, however, are capable of other forms of locomotion, such as backward walking and swimming, sideward walking, and crawling. Do the spinal mechanisms play a principal role in the generation of these forms of locomotion? We addressed this question in lampreys, which are capable of five different forms of locomotion – fast forward swimming, slow forward swimming, backward swimming, forward crawling, and backward crawling. To induce locomotion in lampreys spinalised at the second gill level, we used either electrical stimulation of the spinal cord at different rostrocaudal levels, or tactile stimulation of specific cutaneous receptive fields from which a given form of locomotion could be evoked in intact lampreys. We found that any of the five forms of locomotion could be evoked in the spinal lamprey by electrical stimulation of the spinal cord, and some of them by tactile stimulation. These results suggest that spinal mechanisms in the lamprey, in the absence of phasic supraspinal commands, are capable of generating the basic pattern for all five forms of locomotion observed in intact lampreys. In spinal lampreys, the direction of swimming did not depend on the site of spinal cord stimulation, but on the stimulation strength. The direction of crawling strongly depended on the body configuration. The spinal structures presumably activated by spinal cord stimulation and causing different forms of locomotion are discussed.     

Engineered retroviral virus-like particles for receptor targeting

Retroviral gag proteins, as well as fragments minimally containing the capsid (CA) and nucleocapsid (NC) subunits of Gag, are able to spontaneously assemble into virus-like particles (VLPs). This occurs in mammalian and bacterial cells as well as in in vitro systems. In every circumstance, nucleic acids are incorporated into the forming particles. Here, we took advantage of an in vitro system for the generation of non-enveloped Mason-Pfizer monkey virus (M-PMV) VLPs derived from a self-assembling CA-NC subunit of Gag. These VLPs were modified through N-terminal extension of CA-NC with short oligopeptides that, after the assembly process, were exposed on the surface of VLPs. The employed N-terminal modifications allowed specific interaction with target cells expressing prostate-specific membrane antigen. Using this system, we were able to incorporate selected siRNA into forming VLPs and deliver it into the cytosol of target cells. In comparison with other viral vectors designed for targeted transgene delivery, this M-PMV VLP system represents the lowest risk of generating virus-associated pathology, as the VLPs do not contain any viral coding sequences and are formed in a cell-free system.     

Analyses of Vibration Signals Generated in W. Nr. 1.0038 Steel during Abrasive Water Jet Cutting Aimed to Process Control

The presented research was aimed at finding a suitable tool and procedure for monitoring undercuts or other problems such as cutting without abrasive or inappropriate parameters of the jet during the abrasive water jet (AWJ) cutting of hard-machined materials. Plates of structural steel RSt 37-2 of different thickness were cut through by AWJ with such traverse speeds that cuts of various qualities were obtained. Vibrations of the workpiece were monitored by three accelerometers mounted on the workpiece by a special block that was designed for this purpose. After detecting and recording vibration signals through the National Instruments (NI) program Signal Express, we processed this data by means of the LabVIEW Sound and Vibration Toolkit. Statistical evaluation of data was performed, and RMS was identified as the parameter most suitable for online vibration monitoring. We focus on the analysis of the relationship between the RMS and traverse speed.     

Three-Dimensional Endoscopy-Assisted Excision and Reconstruction for Metastatic Disease of the Dorsal and Lumbar Spine: Early Results

BackgroundThe aim of this study was to explore the role of three-dimensional (3D) endoscopy in surgical management of metastatic disease of the dorsal and lumbar spine.MethodsThis is a prospective study on 33 patients (15 men and 18 women, mean age of 61.6 ± 8.9 years) with biopsy-proven metastatic disease of the spine managed by sequential/staged posterior decompression-stabilization, followed by 3D endoscopy-assisted anterior corpectomy and stabilization with a mesh cage. All patients had significant extradural compression or spinal instability or both. Sixteen patients had neurological deficits. Visual analog scale (VAS), Frenkel grade (neurological deficits), Karnofsky performance status scale, and the 36-item short-form health survey (SF-36) were used for assessment preoperatively and at 3, 6, and 12 months from surgery.ResultsAt a mean follow-up of 1.7 ± 0.7 years from surgery, 18 patients were alive. VAS showed significant improvement at the latest follow-up compared to preoperative levels (4.39 vs. 6.61, p = 0.001). Karnofsky status did not show any significant improvement. Frenkel grade improved in 5 patients, deteriorated in 4 patients, and remained unchanged in 24 patients. Regarding SF-36 parameters, general health showed deterioration, but role functioning—physical, role functioning—emotional, social functioning, and body pain showed statistically significant improvement. There was no change in physical health, viability, and mental health. Subjectively the surgeons felt better depth perception and smoother surgical experience with the 3D optics technology. The only complication was delayed wound healing in three patients who had a previous history of radiotherapy to the surgical site.Conclusions3D endoscopy is a valuable tool in the management of metastatic spinal disease requiring excision and reconstruction using the combined posterior and anterior approaches. These early results warrant confirmation with more data and longer follow-ups.