Characterization and validation of a chronic retinal neovascularization rabbit model by evaluating the efficacy of anti-angiogenic and anti-inflammatory drugs

AIM: To establish a rabbit model with chronic condition of retinal neovascularization (RNV) induced by intravitreal (IVT) injection of DL-2-aminoadipic acid (DL-AAA), a retinal glial (Müller) cell toxin, extensive characterization of DL-AAA induced angiographic features and the suitability of the model to evaluate anti-angiogenic and anti-inflammatory therapies for ocular vascular diseases. METHODS: DL-AAA (80 mmol/L) was administered IVT into both eyes of Dutch Belted rabbit. Post DL-AAA delivery, clinical ophthalmic examinations were performed weekly following modified McDonald-Shadduck Scoring System. Color fundus photography, fluorescein angiography (FA), and optical coherence tomography (OCT) procedures were performed every 2 or 4wk until stable retinal vascular leakage was observed. Once stable retinal leakage (12wk post DL-AAA administration) was established, anti-vascular endothelial growth factor (VEGF) (bevacizumab, ranibizumab and aflibercept) and anti-inflammatory (triamcinolone, TAA) drugs were tested for their efficacy after IVT administration. Fluorescein angiograms were scored before and after treatment following a novel grading system, developed for the DL-AAA rabbit model. RESULTS: Post DL-AAA administration, eyes were presented with moderate to severe retinal/choroidal inflammation which was accompanied by intense vitreous flare and presence of inflammatory cells in the vitreous humor. Retinal hemorrhage was restricted to the tips of neo-retinal vessels. FA revealed maximum retinal vascular leakage at 2wk after DL-AAA injection and then persisted as evidenced by stable mean FA scores in weeks 8 and 12. Retinal vascular angiographic and tomographic features were stable and consistent up to 36mo among two different staggers induced for RNV at two different occasions. Day 7, mean FA scores showed that 1 µg/eye of bevacizumab, ranibizumab, aflibercept and 2 µg/eye of TAA suppress 65%, 90%, 100% and 50% retinal vascular leakage, respectively. Day 30, bevacizumab and TAA continued to show 66% and 44% suppression while ranibizumab effect was becoming less effective (68%). In contrast, aflibercept was still able to fully (100%) suppress vascular leakage on day 30. On day 60, bevacizumab, ranibizumab and TAA showed suppression of 7%, 12%, and 9% retinal vascular leakage, respectively, however, aflibercept continued to be more effective showing 50% suppression of vascular leakage. CONCLUSION: The DL-AAA rabbit model mimics RNV angiographic features like RNV and chronic retinal leakage. Based on these features the DL-AAA rabbit model provides an invaluable tool that could be used to test the therapeutic efficacy and duration of action of novel anti-angiogenic formulations, alone or in combination with anti-inflammatory compounds.

Variation and Variability in Drosophila Grooming Behavior

Behavioral differences can be observed between species or populations (variation) or between individuals in a genetically similar population (variability). Here, we investigate genetic differences as a possible source of variation and variability in Drosophila grooming. Grooming confers survival and social benefits. Grooming features of five Drosophila species exposed to a dust irritant were analyzed. Aspects of grooming behavior, such as anterior to posterior progression, were conserved between and within species. However, significant differences in activity levels, proportion of time spent in different cleaning movements, and grooming syntax were identified between species. All species tested showed individual variability in the order and duration of action sequences. Genetic diversity was not found to correlate with grooming variability within a species: melanogaster flies bred to increase or decrease genetic heterogeneity exhibited similar variability in grooming syntax. Individual flies observed on consecutive days also showed grooming sequence variability. Standardization of sensory input using optogenetics reduced but did not eliminate this variability. In aggregate, these data suggest that sequence variability may be a conserved feature of grooming behavior itself. These results also demonstrate that large genetic differences result in distinguishable grooming phenotypes (variation), but that genetic heterogeneity within a population does not necessarily correspond to an increase in the range of grooming behavior (variability).

Design of Oral Sustained-Release Pellets by Modeling and Simulation Approach to Improve Compliance for Repurposing Sobrerol

Sobrerol, an oral mucolytic agent, in a recent study showed promise for treating multiple sclerosis. A human equivalent dose of 486 mg of sobrerol administered thrice daily (i.e., 1459 mg of daily dose) demonstrated the highest therapeutic efficacy for repurposing use, which also points out the poor compliance of administration. In this study, oral sustained-release pellets of sobrerol were successfully developed with evaluated manufacturing conditions and drug release kinetics. For design of the target drug product, we used a modeling and simulation approach to establish a predictive model of oral pharmacokinetic profile, by exploring the characteristics and correlations corresponding to the pharmacokinetics and pharmacodynamics of sobrerol, such as absorption lag time (0.18 h), time-scaling in vitro–in vivo correlation (tin-vitro = 0.494 tin-vivo − 0.0904), gastrointestinal transit time (8 h), minimum effective concentration (1.61 μg/mL), and duration of action (12.8 h). Results showed that the frequency of administration and the daily dose remarkably reduced by 33.3% (i.e., from thrice to twice daily) and 22.8%, respectively, which indicates that this prototype approach can be adopted for rapidly developing a modified-release dosage form of sobrerol, with improvement of compliance of administration and therapeutic efficacy.

Insulin biosimilars in clinical practice

Diabetes mellitus (DM) is an important medical and social problem throughout the world due to its high prevalence. At the same time, the majority of patients have type 2 diabetes. The onset of the disease is gradual, with a prolonged asymptomatic preclinical stage. Therefore, it is necessary to conduct screening among patients at risk. Therapy for type 2 diabetes is carried out with oral hypoglycemic drugs. If it is impossible with their help to achieve adequate glycemic control, it is possible to add basal insulin to therapy, and if the own insulin secretion is depleted, an intensive insulin therapy regimen must be prescribed. Insulin preparations differ in the source of receipt, as well as in the duration of action: background, or basal (insulin of medium duration, long-term or ultra-long-acting) and prandial, or food (ultrashort and short insulin). Currently, along with original insulin preparations, their analogues, or biosimilars (biosimilars), appear on the pharmaceutical market. Biosimilar (biosimilar) is a biological product similar in quality, efficacy and safety parameters to a reference biological medicinal product in the same dosage form and having an identical route of administration. Biosimilars are used all over the world, and this applies not only to insulin preparations, but also to other biological preparations. Proof of bioequivalence is a long-term process that ensures comparability and the absence of clinically significant differences between the study and the reference drug, and includes preclinical and clinical studies. The task of studies of biosimilars of insulin is to confirm the comparability with a reference, previously well-studied biological product. The efficacy and safety of domestically produced biosimilars has been studied in a number of clinical studies, during which the bioequivalence of the drugs was shown. These drugs are of high quality and safe, and their pharmacological characteristics, immunogenicity and effectiveness do not differ from the original drugs.

Dexmedetomidine prolongs the duration of action of mepivacaine on anesthesia of the palmar digital nerves of horses

OBJECTIVE To determine whether palmar digital nerve (PDN) blockade in horses with a combination of dexmedetomidine and mepivacaine would block the response to mechanical force applied to the digit longer than would anesthetizing these nerves with mepivacaine alone or dexmedetomidine alone. ANIMALS 8 mares with no signs of lameness. PROCEDURES In a randomized, crossover, blinded, experimental study, both PDNs of the same forelimb of each horse were anesthetized by perineural injection with either 30 mg mepivacaine alone, 250 µg of dexmedetomidine alone, or 30 mg mepivacaine combined with 250 µg of dexmedetomidine. Each horse received each treatment, and treatments were administered ≥ 2 weeks apart. The mechanical nociceptive threshold was measured at a region between the heel bulbs with the use of a digital force gauge before (baseline) and at 15-minute intervals after treatment. RESULTS The mean duration of sensory blockade of the digit was 2-fold longer when a combination of mepivacaine and dexmedetomidine was administered (371 minutes), compared with when mepivacaine alone was administered (186 minutes). Treatment with dexmedetomidine alone did not change the mechanical nociceptive threshold substantially from baseline and resulted in no clinical signs of sedation. CLINICAL RELEVANCE Results indicated that relief from digital pain provided by perineural treatment with mepivacaine for PDN blockade can be extended by adding dexmedetomidine to the injectate.

Development of a Numerical Model to Analyze the Formation and Development Process of River Mouth Bars

An integrated sediment management approach that includes the recovery of the amount of declined sediment supply is effective as a fundamental solution to coastal erosion. During planning, it is essential to analyze the transfer mechanism of the sediments generated from estuaries (the junction between a river and sea) to assess the amount and rate of sediment discharge (from the river to sea) supplied back to the coast. Although numerical models that interpret the tidal sand bar flushing process during flooding have been studied, thus far, there has been no study focusing on the formation and development processes of tidal sand bars. Therefore, this study aims to construct wave deformation, flow regime calculation, and topographic change analysis models to assess the amount of recovered sediment discharge and reproduce the tidal sand bar formation process through numerical analysis for integrated littoral drift management. The tidal sand bar formation process was simulated, and the wave energy and duration of action concepts were implemented to predict the long-term littoral movement. The river flux and wave conditions during winter when tidal sand bars dominantly develop were considered as the external force conditions required for calculation. The initial condition of the topographic data directly after the Maeupcheon tidal sand bar flushing during flooding was set as the initial topography. Consequently, the tidal sand bar formation and development due to nearshore currents dependent on the incident wave direction were reproduced. Approximately 66 h after the initial topography, a sand bar formation was observed at the Maengbang estuary.

Advances in Reversal Strategies of Opioid-induced Respiratory Toxicity

Opioids may produce life-threatening respiratory depression and death from their actions at the opioid receptors within the brainstem respiratory neuronal network. Since there is an increasing number of conditions where the administration of the opioid receptor antagonist naloxone is inadequate or undesired, there is an increased interest in the development of novel reversal and prevention strategies aimed at providing efficacy close to that of the opioid receptor antagonist naloxone but with fewer of its drawbacks such as its short duration of action and lesser ability to reverse high-affinity opioids, such as carfentanil, or drug combinations. To give an overview of this highly relevant topic, the authors systematically discuss predominantly experimental pharmacotherapies, published in the last 5 yr, aimed at reversal of opioid-induced respiratory depression as alternatives to naloxone. The respiratory stimulants are discussed based on their characteristics and mechanism of action: nonopioid controlled substances (e.g., amphetamine, cannabinoids, ketamine), hormones (thyrotropin releasing hormone, oxytocin), nicotinic acetylcholine receptor agonists, ampakines, serotonin receptor agonists, antioxidants, miscellaneous peptides, potassium channel blockers acting at the carotid bodies (doxapram, ENA001), sequestration techniques (scrubber molecules, immunopharmacotherapy), and opioids (partial agonists/antagonists). The authors argue that none of these often still experimental therapies are sufficiently tested with respect to efficacy and safety, and many of the agents presented have a lesser efficacy at deeper levels of respiratory depression, i.e., inability to overcome apnea, or have ample side effects. The authors suggest development of reversal strategies that combine respiratory stimulants with naloxone. Furthermore, they encourage collaborations between research groups to expedite development of viable reversal strategies of potent synthetic opioid-induced respiratory depression.

Anabolic-androgenic steroid use among bodybuilders in Erbil city

Background and objective: Anabolic-androgenic steroids are synthetic testosterone derivatives with a longer duration of action than physiological androgens. They are abused by bodybuilders because of their potential to enhance muscle strength. Serious medical and psychological complications may be associated with their non-medical use. This study aimed to determine the prevalence of anabolic androgenic steroids among bodybuilders and their awareness of health-related risks. Methods: A cross-sectional study was carried out from the 1st of January 2019 to the end of July 2019 in 18 randomly selected gym centers in Erbil city, Iraq using stratified random sampling. A self-administered questionnaire was distributed to 400 bodybuilders to assess the prevalence and knowledge of using Anabolic-androgenic steroids. Results: The study showed a high prevalence of Anabolic-androgenic steroid consumption (26.3%) among gym users in Erbil city. Anabolic-androgenic steroid use was significantly higher among participants with a longer duration of bodybuilding practice ≥4 years (P = 0.001). Anabolic-androgenic steroid abuse was significantly associated with drinking alcohol, smoking cigarettes, and using growth hormones. Trainers were the commonest source of recommendation. Conclusion: The prevalence of anabolic androgenic steroids abuse is high among bodybuilders in Erbil city. Public health awareness is essential and may help avoid the propagation of the problem. Keywords: Anabolic steroids; Gym users; Bodybuilders; Knowledge, Erbil.

Time Synthesis in Organization of Sensorimotor Action

Time synthesis of sensorimotor action is reviewed as a process of a coherence setting action duration (expected duration), time sequence of required operations and significant changes in conditions. Aim: to experimentally set up the connection of time synthesis success and efficiency of realization sensorimotor action in changeable conditions. Hypothesis: successful time synthesis of the setting duration and the temporal sequence of operations in the mental organization of sensorimotor action in changing conditions is realized in accordance with the corresponding operational meaning and is allowed by anticipatory effects and an increase in the effectiveness of the action, materials and methods. An experimental study involved 152 male and female students. Participants of the investigation solved experimental tasks, implemented in a computer version, according to schemes of a simple visual-motor reaction and a choice reaction (separately and in combination), according to a scheme of sensorimotor action with a warning signal when the apperceptive scheme, setting duration and sequence of required operations were changed promptly. Results were reviewed in the aspect of disclosing the features of the subject's elimination of the uncertainty of the moment of achieving the goal in the future and the construction of a sequence of operations of sensorimotor actions in a connection with changes in external conditions, typical for the time deficit regime. The conditionality of the time synthesis of sensorimotor action by the actual operational meaning was established revealing that the successful temporal synthesis of sensorimotor action in changing conditions is associated with the fastest acceptance of an adequate apperceptive scheme, with effective anticipation of the moment of achieving the goal and the formation of a detailed setting duration of action, with the formation of a temporal sequence of required operations. Conclusions. The levels of success of the time synthesis of sensorimotor action in changing conditions are highlighted: “quite successful; moderately successful; unsuccessful.”

Three Studies Evaluating the Potential for Lidocaine, Bupivacaine or Procaine to Reduce Pain-Related Behaviors following Ring Castration and/or Tail Docking in Lambs

The use of local anesthesia at the time of ring castration and tail docking can improve lamb welfare. However, few local anesthetics are registered for sheep, and data on their duration of effect is limited. Three studies were conducted to evaluate the efficacy of procaine (P), lidocaine (L), and bupivacaine (B) in terms of observed alleviation of behavioral responses to castration and/or tail docking in 10-min blocks in the first 60 min post-treatment. In each study, comparisons were made between two groups of lambs castrated and/or tail docked with rubber rings and either receiving the agent using the NUMNUTS® instrument (N) or receiving no anesthetic agent (RR). Acute pain behavior was lower in NL (n = 28) than RRL (n = 15) males in the first 10 min post-procedure (p < 0.05); lower in NB (n = 16) than RRB (n = 16) males in periods 10–20 min (0.05 < p < 0.01), 20–30 min (p < 0.05) and 40–50 min (0.05 < p < 0.01); lower in NB (n = 16) than RRB (n = 16) females between 20 and 40 min post-procedure (0.05 < p < 0.01); lower in NP (n = 8) than RRP (n = 7) males in period 10–20 min (0.05 < p < 0.01), and lower in NP (n = 9) than RRP (n = 9) females in periods 0–10 min (0.05 < p < 0.01), and 10–40 min (p < 0.05). Benefits were modest, and the effects of procaine appear to last longer than lidocaine, while bupivacaine is slower to take effect than either procaine or lidocaine but may provide longer-lasting pain relief. The duration of action of local anesthetics is short in sheep, and detailed behavioral evaluations are required in the first hour post-procedure to establish efficacy.