Long Duration Of Action Research Articles

The role of tadalafil in treated hypertensive patients with erectile dysfunction.

In this issue, Kloner and colleagues showed in a pooled safety analysis that tadalafil—a phosphodiesterase type 5 (PDE-5) inhibitor—is safe in treated hypertensive patients and is not associated with increased hypotension-related treatment adverse events and major cardiovascular (CV) events.1 The safety data were extracted from 72 Phase II–IV clinical studies of tadalafil used for erectile dysfunction (ED) or benign prostate hypertrophy. PDE-5 inhibitors are vasodilating drugs that work by blocking the degradation of cyclic GMP by PDE-5 in the smooth muscle cells lining the blood vessels supplying various tissues. The increase of the intracellular cyclic GMP prolongs its duration of action resulting in increase in nitric oxide bioavailability, smooth muscle relaxation, vasodilation and increased blood flow in the corpora cavernosa, and penile erection. The main PDE-5 inhibitors are sildenafil, vardenafil, avanafil, and tadalafil. They differ in their pharmacodynamic and pharmacokinetic properties allowing targeting the treatment to the patients' needs. Avanafil has the fastest onset of action and tadalafil has the longest duration of action (half-life of 17.5 h and duration of action up to 36 h).2 ED impairs the quality of life of affected individuals and may be a prognostic marker for the development of CV disease.3 The prevalence of ED in the general population is around 15–20% and it is significantly higher in patients with hypertension,2, 4 probably due to vascular changes. Hypertension is a major modifiable risk factor for CV disease and lowering blood pressure is beneficial. Lowering blood pressure may cause or aggravate ED and it is not clear whether it is a side effect of the antihypertensive treatment or a result of the blood pressure decrease. The development of ED is one of the major reasons to withdraw antihypertensive treatment leading to inadequate blood pressure control. PDE-5 inhibitors improve ED and improve adherence to antihypertensive therapy, improve blood pressure control, and thereby may reduce CV risk in hypertensive patients with ED. The effect of PDE-5 inhibitors is not limited to the corpora cavernosa and they also vasodilate other vascular beds thereby reducing blood pressure. There was a concern that blood pressure decrease may cause CV side effects particularly in patients with CV risk factors. Kloner and colleagues in this issue showed that in subjects not receiving antihypertensive medications the incidence of hypotension related treatment emergent adverse events was low, but it was significantly higher in the tadalafil group than in the placebo group.1 Most subjects (>90%) not receiving antihypertensive medications were normotensives, and in this group, lowering blood pressure by tadalafil may increase the incidence of hypotension-related events. However, in hypertensive patients on antihypertensive medications tadalafil does not increase the hypotension related events. The co-administration of tadalafil with doxazosin, a blood pressure lowering alpha blocker is associated with a remarkable blood pressure decrease that maybe deleterious.5 However, with other antihypertensive agents tadalafil is not associated with hypotensive related side effects. The co-administration of PDE-5 inhibitors with various antihypertensive drugs, except alpha blockers, is safe. This was observed even in those who used several antihypertensive agents.1 It has been shown that all PDE-5 inhibitors are safe in treated hypertensive patients.2 The hypotensive effect of PDE-5 inhibitors should be exploit to treat resistant hypertension, particularly in those with ED. Since tadalafil has the longest duration of action it will probably be the best PDE-5 inhibitor to use for lowering blood pressure. Low dose tadalafil (5 mg daily) can improve blood pressure control and erectile function. The fact that PDE-5 inhibitors can lower blood pressure and improve erectile function suggests that lowering blood pressure by itself does not cause ED and it is probably related to the antihypertensive medications. The safety profile of tadalafil presented by Kloner in this issue may justify wider use of the drug in hypertensive patients. Wide use of tadalafil in hypertensive patients may improve erectile function and blood pressure control leading to a decrease in CV events. Further long term studies should be done to prove this concept. The author has no competing interests.

Acute Pain Management for a Tibial Plateau Fracture Shortly After a Buprenorphine XR Depot Injection: A Case Report

Acute pain management of patients on buprenorphine for opioid use disorder remains a challenge. The buprenorphine extended-release depot injection which lasts for 1 month and has a higher plasma concentration of buprenorphine compared to the sublingual formulation is increasingly being used in patients. Acute pain management of patients on buprenorphine depot remains a challenge because waiting for the washout of the medication is not feasible and discontinuation is challenging because it requires surgical excision. We describe here the pharmacokinetics of the buprenorphine depot formulation and the clinical implications of its long duration of action. A 39-year-old woman with a history of alcohol and opioid use disorder, on buprenorphine depot, was admitted to the hospital with a left tibial plateau fracture. Acute pain service managed her pain by utilizing a multimodal analgesia plan including femoral and popliteal nerve catheters, intravenous patient-controlled analgesia and oral opioid and nonopioid medications. The patient had a prolonged length of stay of 11 days but was successfully weaned off nerve catheters and intravenous medications and converted to an oral medication regiment such that she could be discharged from the acute care hospital.

Construction and safety aspects for the arrangement of mobile explosive deposits

The execution of the blasting works involves the management of the problem of storage of explosive materials. This aspect is easier to solve in the case of mines activities with long exploitation time and where storage capacities are arranged, according to the legislation that provides constructive and safety criteria depending on the type and quantity of explosive materials stored. In the case of isolated blasting works, those for road construction, building demolition, underwater or forestry, etc., storage facilities must be arranged for shorter periods of time and smaller capacity, but which must comply with security, environmental and risk requirements, such as high-capacity deposits with long duration of activity. Considering that for the execution of such blasting works, the national legislation provides the possibility of arranging temporary explosive depots, of small capacity, but without specifying the constructive details and the necessary safety requirements to be observed, mentioning only that they must be executed on the basis of a specialized project. This paper presents a series of tests conducted by INSEMEX, in order to establish recommendations regarding the constructive and safety requirements that must be observed when designing and building mobile explosive depots.

Donepezil-loaded PLGA-b-PEG Nanoparticles Enhance the Learning and Memory Function of Beta-Amyloid Rat Model of Alzheimer’s Disease

Our aim is to reduce the side effects and increase the efficiency of donepezil by formulating donepezil-loaded poly(lactic-co-glycolic acid)-block-poly(ethylene glycol) nanoparticles (NPs) directly targeting amyloid beta (Aβ) fibrils in the brain and evaluate behavioral changes in this fibril model of AD. AD model was developed by intracerebroventricular injection of pre-aggregated β25-35 fibrils. Rats were intravenously administered either solvent, donepezil-loaded NPs (15µg/kg) or free donepezil (1mg/kg) 3 times for a week except for naïve controls. The effect of treatments on anxiety, motor functions, and cognitive functions was tested by elevated plus maze, locomotor activity, novel object recognition, and Morris's water maze tests, respectively. Accumulation of Aβ25-35 fibrils in brain sections was confirmed. Anxiety-like behavior was observed in the Aβ Alzheimer and free donepezil treatment groups while donepezil-loaded NP treatment showed hypo-anxiety-like behavior. Donepezil-loaded NPs were successful in treatment of short-term memory deficit better than free donepezil injection. In Morris's water maze, both donepezil-loaded NPs and free donepezil groups found the platform in shorter time compared to Aβ Alzheimer group. In locomotor activity test, both donepezil treated groups moved less than the Aβ Alzheimer group and naïve controls. After the pharmacological experiments, acetylcholinesterase activity was determined and showed an increase in Aβ Alzheimer group compared to controls. Donepezil-loaded NPs inhibited the acetylcholinesterase activity more efficiently than the free donepezil group. Targeting with donepezil-loaded PLGA-b-PEG-NPs increases efficiency, helps to inhibit acetylcholinesterase activity more substantially, improves cognitive decline due to its longer duration of action and destabilizing effect on amyloid fibrils.

Effectiveness of 0.125% Bupivacaine versus 0.125% Ropivacaine in Epidural Labour AnalgesiaA Randomised Clinical Study

Introduction: Epidurally administered local anesthetics provide most effective analgesia during labour process. Among the available local anesthetics Bupivacaine and ropivacaine are the most commonly used drugs in concentrations ranging from 0.0625% to 0.125% and 0.08% to 0.125%, respectively. Both these drugs are weak bases, highly protein bound, highly lipid soluble, and have a pKa of 8.1, low unionised fraction, thus having a slightly longer time for onset of action but with a longer duration of action and have less transfer across the placenta. Hence, they are ideal drugs for use in labour analgesia. Aim: To compare the effectiveness of programmed intermittent bolus of 0.125% bupivacaine and 0.125% ropivacaine in low volumes in full term primigravidas for epidural labour analgesia. Materials and Methods: This randomised clinical study was conducetd at PES Institute of Medical Sciences and Research, Kuppam, Andhra Pradesh, India, between June 2020 and December 2021 among 80 full term primi parturients requiring normal vaginal delivery. They were randomly divided into two groups of 40 each. Group B received 10 mL of 0.125% bupivacaine and group R received 10 mL of 0.125% ropivacaine as initial bolus dose. Repeat doses of 5 mL was given every 60 minutes or when the patient had Visual Analogue Score (VAS) score >4 with a maximum dose of 10 mL/hr with a 20 minute interval between two doses. Parameters assessed were onset, duration, level and quality of analgesia, motor blockade, number of epidural top ups, total volume of drug consumed, mode of delivery, duration of labour, APGAR score, haemodynamics, patient satisfaction and complications. Data was entered in Microsoft Excel 2010 version and analysed using Statistical Package for Social Sciences (SPSS) version 20.0. Results: Both drugs were equally effective in terms of analgesia, maternal and foetal outcomes. Bupivacaine had a faster onset of action (7.075±0.916 min) compared to ropivacaine (8.225±0.891 min) (p-value=0.001). Ropivacaine had a shorter duration of action (43.1±2.30 min vs. 47.9±4.16 min in group B) (p-value=0.0001), requiring more top-up doses (5.2±0.46 versus 4.77±0.61 in group B) (p-value=0.0007), and more total volume of drug (38.5±3.08 mL versus 35.5±4 mL in group B) (p-value=0.002). It also caused lesser motor blockade (Bromage score of 1 in 1 parturient vs. 8 parturients in group B) (p-value=0.0129) and better overall maternal satisfaction score (excellent) in 30 parturients versus 25 parturients in group B. APGAR scores at 1 minute and 5 minutes were comparable between the two groups. Mean heart rates, mean blood pressures were also comparable between the two groups. There were no significant adverse effects in either groups. Conclusion: By providing minimal motor blockade and adequate analgesia 0.125% ropivacaine allows parturients to go through the labour process with excellent maternal satisfaction and minimal adverse effects compared to 0.125% bupivacaine

Buffered articaine infiltration for primary maxillary molar extractions: a randomized controlled study.

BackgroundDental pain management is an important aspect of patient management in pediatric dentistry. Articaine is considered the most successful anesthetic agent for infiltration anesthesia. Buffered articaine has been observed to have faster onset and longer duration of action with less pain on injection. The aim of this study was to evaluate and compare pain on injection, onset of action, and pain during extraction using buffered (using Sodium bicarbonate (NaHCO3)) and non-buffered 4% articaine (with 1:100000 adrenaline) infiltrations for primary maxillary molar extractions in 4–10-year-old children.MethodsSeventy children who required extraction of maxillary primary molars were enrolled in this triple-blind randomized study. Children undergoing extraction were randomly divided into two groups, with 35 in each group. The study group was the buffered articaine group; the control group was the non-buffered articaine group. Buccal and palatal infiltrations were administered with either buffered or non-buffered articaine. Subjective evaluation was done for pain on injection, pain during extraction using Wong–Baker Faces Pain Rating Scale (WBFPR) and onset of anesthesia in seconds. Pain on injection, pain during extraction were objectively evaluated using Sound Eye Motor (SEM) scale and onset of anesthesia was also evaluated objectively by pricking with sharp dental probe.ResultsThe outcome was, significantly less pain on injection and significantly faster onset of anesthesia with significantly less pain during extraction for both subjective and objective evaluations in the buffered articaine group. Subgroup analysis was also performed and it showed variable results, with only significant difference for WBFPR scores in age subgroup 4–7 years for palatal infiltration.ConclusionLess pain on injection, faster onset of anesthesia, and less pain during extraction were observed when buffered articaine was used for maxillary primary molar extraction.

Nanotechnology strategies for hepatocellular carcinoma diagnosis and treatment.

Hepatocellular carcinoma (HCC) is a common malignancy threatening human health, and existing diagnostic and therapeutic techniques are facing great challenges. In the last decade or so, nanotechnology has been developed and improved for tumor diagnosis and treatment. For example, nano-intravenous injections have been approved for malignant perivascular epithelioid cell tumors. This article provides a comprehensive review of the applications of nanotechnology in HCC in recent years: (I) in radiological imaging, magnetic resonance imaging (MRI), fluorescence imaging (FMI) and multimodality imaging. (II) For diagnostic applications in HCC serum markers. (III) As embolic agents in transarterial chemoembolization (TACE) or directly as therapeutic drugs. (IV) For application in photothermal therapy and photodynamic therapy. (V) As carriers of chemotherapeutic drugs, targeted drugs, and natural plant drugs. (VI) For application in gene and immunotherapy. Compared with the traditional methods for diagnosis and treatment of HCC, nanoparticles have high sensitivity, reduce drug toxicity and have a long duration of action, and can also be combined with photothermal and photodynamic multimodal combination therapy. These summaries provide insights for the further development of nanotechnology applications in HCC.

Efficacy of Different Doses of Cisatracurium for Intubation for Surgeries under General Anaesthesia- A Randomised Clinical Study

Introduction: Cisatracurium is a new non depolarising, Neuromuscular Blocking Drug (NMBD) with fast onset and short duration of action. It is a stereoisomer of atracurium with a potency of approximately 3 to 4 times greater than that of atracurium. As it is devoid of histamine release, it reduces the chances of adverse effects during operative procedures. However, the optimum intubating dosage needs to be established in patients. This warrants the need for studies focusing on the efficacy of different doses of cisatracurium and their outcomes. Aim: To study the efficacy of three different doses of cisatracurium {2x Effective dose (ED) 95, 4x ED95, and 6x ED95} for the time of onset of action, duration and haemodynamic stability offered for intubation. Materials and Methods: A double-blind, randomised clinical study was conducted from December 2017 to July 2019 at a tertiary care hospital and research center, Kolhapur, Maharashtra, India. Total 90 patients, undergoing surgeries under general anaesthesia were allocated into three groups, group A received 0.1 mg/kg, group B received 0.2 mg/kg and group C received 0.3 mg/kg of cisatracurium. Time taken for Train Of Four (TOF) to reach 0 was taken as the onset of action, and appearance of TOF 2/3 or patient’s attempt to breathe was taken as duration of action. Haemodynamic changes were also assessed preoperatively and postintubation immediately after confirmation of placement of ETT. Results: Mean age 33.23±6.26 years in group A, 37.70±10.80 years in group B, 38.23±8.764 years in group C (p-value=0.06). Least time was required for the TOF to become zero by group C (5.10±1.01 minutes) as compared to groups A and B (9.91±1.39 and 7.48±1.45 minutes) which was statistically significant (p-value <0.001). The duration of action was also more in group C (49.83±5.33) compared to group A (27.23±6.97) and group B (36.17±7.62) (p-value=0.00001). Group C had better haemodynamic stability as the heart rate remained more stable than group A and group B. Conclusion: Higher dose of cisatracurium provides faster onset, longer duration of action with better cardiovascular stability. This predictable recovery from non depolarising muscle relaxation makes it a good choice of muscle relaxant agent for intubation.

Perindopril Arginine, Indapamide, and Amlodipine Fixed Dose Combination Induced Gingival Overgrowth: Two Cases with Specific Clinical Presentation

Drug induced gingival overgrowth (DIGO) is a frequent adverse effect of systemic medications. Amlodipine, although accepted as a safe antihypertensive drug due to its longer duration of action with lower dose and fewer adverse reactions compared to other antihypertensive agents, is among the causative drugs. As the aetiology of hypertension is multifactorial, a fixed dose combination containing amlodipine and other antihypertensive agents is currently preferred by physicians as a new treatment approach. The aim of this article is to report two cases of perindopril arginine, indapamide, and amlodipine fixed dose combination induced gingival overgrowth with an emphasis on the specific clinical presentation. Intraoral examination revealed poor oral hygiene, excessive dental plaque accumulation, and erythematous, oedematous, lobulated, enlarged marginal and interdental gingivae prone to bleeding. It was noteworthy that a red band appearance was present on the enlarged labial marginal gingivae in the patients. One month after the drug substitution, proper oral hygiene education and plaque control, and non-surgical periodontal treatment, a marked regression in DIGO and accompanying inflammatory symptoms were observed. Medical and dental practitioners should be aware that antihypertensive drugs used alone or in combination with other agents have the potential to cause gingival overgrowth.

Inhaled mosliciguat (BAY 1237592): targeting pulmonary vasculature via activating apo-sGC

BackgroundOxidative stress associated with severe cardiopulmonary diseases leads to impairment in the nitric oxide/soluble guanylate cyclase signaling pathway, shifting native soluble guanylate cyclase toward heme-free apo-soluble guanylate cyclase. Here we describe a new inhaled soluble guanylate cyclase activator to target apo-soluble guanylate cyclase and outline its therapeutic potential.MethodsWe aimed to generate a novel soluble guanylate cyclase activator, specifically designed for local inhaled application in the lung. We report the discovery and in vitro and in vivo characterization of the soluble guanylate cyclase activator mosliciguat (BAY 1237592).ResultsMosliciguat specifically activates apo-soluble guanylate cyclase leading to improved cardiopulmonary circulation. Lung-selective effects, e.g., reduced pulmonary artery pressure without reduced systemic artery pressure, were seen after inhaled but not after intravenous administration in a thromboxane-induced pulmonary hypertension minipig model. These effects were observed over a broad dose range with a long duration of action and were further enhanced under experimental oxidative stress conditions. In a unilateral broncho-occlusion minipig model, inhaled mosliciguat decreased pulmonary arterial pressure without ventilation/perfusion mismatch. With respect to airway resistance, mosliciguat showed additional beneficial bronchodilatory effects in an acetylcholine-induced rat model.ConclusionInhaled mosliciguat may overcome treatment limitations in patients with pulmonary hypertension by improving pulmonary circulation and airway resistance without systemic exposure or ventilation/perfusion mismatch. Mosliciguat has the potential to become a new therapeutic paradigm, exhibiting a unique mode of action and route of application, and is currently under clinical development in phase Ib for pulmonary hypertension.

Patient and retina specialists' preferences in neovascular age-related macular degeneration treatment. A discrete choice experiment.

Neovascular age-related macular degeneration (nAMD) leads to severe and permanent visual impairment, significantly impacting patients' quality of life and functional independence. Although treatment with anti- vascular endothelial growth factor (VEGF) prevents and, in some cases, reverses visual damage, the need for frequent monitoring visits and intravitreal injections represents a significant burden on patients, caregivers and retina specialists. To elicit preferences for nAMD treatment characteristics from the perspectives of patients and retina specialists. A discrete choice experiment was conducted. Participants (patients > 50 years with nAMD receiving anti-VEGF drugs for at least 2 years and without previous experience with anti-VEGF and retina specialists working in the Spanish National Healthcare System) were asked to select one of two hypothetical treatments resulting from the combination of five attributes (effects on visual function, effects on retinal fluid, treatment regimen, monitoring frequency, and cost); their levels were identified by reviewing the literature and two focus groups. The relative importance (RI) given to each attribute was estimated using a mixed logit model. The marginal rates of substitution (MRS) were calculated taking cost as the risk attribute. A total of 110 patients (P) [aged 79.0 (SD:7.4) years; 57.3% women; 2.3 (SD:0.7) years with nAMD; 2.1 years (SD:0.1) in treatment] and 66 retina specialists (RS) participated in the study. Participants gave greater RI to improvements in their visual function [60.0% (P); 52.7% (RS)], lower monitoring frequency [20.2% (P); 27.1% (RS)] and reduction in retinal fluid [9.8% (P); 13.0%(RS)]. Patients and retina specialists would agree to an increase in cost by 65.0% and 56.5%, respectively, in exchange for improvements of visual function; and 25.5% and 43.3% on delaying monitoring frequency by one month. Efficacy of treatment, in terms of visual function improvements, is the main driver for treatment election for both patients and retina specialists. Treatment monitoring requirements are also considered, mainly from the retina specialist's perspective. These results suggest that the use of more efficacious anti-VEGF agents with a longer duration of action may contribute to aligning treatment characteristics with patients/specialists' preferences. A better alignment would facilitate better disease management, fulfilling the unmet needs of patients and retina specialists.

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.

Inhibition of Sema-3A Promotes Cell Migration, Axonal Growth, and Retinal Ganglion Cell Survival.

PurposeSemaphorin 3A (Sema-3A) is a secreted protein that deflects axons from inappropriate regions and induces neuronal cell death. Intravitreal application of polyclonal antibodies against Sema-3A prevents loss of retinal ganglion cells ensuing from axotomy of optic nerves. This suggested a therapeutic approach for neuroprotection via inhibition of the Sema-3A pathway.MethodsTo develop potent and specific Sema-3A antagonists, we isolated monoclonal anti-Sema-3A antibodies from a human antibody phage display library and optimized low-molecular weight Sema-3A signaling inhibitors. The best inhibitors were identified using in vitro scratch assays and semiquantitative repulsion assays.ResultsA therapeutic approach for neuroprotection must have a long duration of action. Therefore, antibodies and low-molecular weight inhibitors were formulated in extruded implants to allow controlled and prolonged release. Following release from the implants, Sema-3A inhibitors antagonized Sema-3A effects in scratch and repulsion assays and protected retinal ganglion cells in animal models of optic nerve injury, retinal ischemia, and glaucoma.Conclusions and Translational RelevanceCollectively, our findings indicate that the identified Sema-3A inhibitors should be further evaluated as therapeutic candidates for the treatment of Sema-3A-driven central nervous system degenerative processes.

Rapid-Onset Anti-Stress Effects of a Kappa-Opioid Receptor Antagonist, LY2795050, Against Immobility in an Open Space Swim Paradigm in Male and Female Mice.

The kappa-opioid receptor (KOR) / dynorphin system is implicated with behavioral and neurobiological effects of stress exposure (including heavy exposure to drugs of abuse) in translational animal models. Thus some KOR-antagonists can decrease the aversive, depressant-like and anxiety-like effects caused by stress exposure. The first generation of selective KOR-antagonists have slow onsets (hours) and extremely long durations of action (days-weeks), in vivo. A new generation of KOR antagonists with rapid onset and shorter duration of action can potentially decrease the effects of stress exposure in translational models, and may be of interest for medication development. This study examined the rapid onset anti-stress effects of one of the shorter acting novel KOR-antagonists (LY2795050, (3-chloro-4-(4-(((2S)-2-pyridin-3-ylpyrrolidin-1-yl)methyl) phenoxy)benzamide)) in a single-session open space swim (OSS) stress paradigm (15 min duration), in adult male and female C57BL/6 J mice. LY2795050 (0.32 mg/kg, i.p.) had rapid onset (within 15 min) and short duration (<3 h) of KOR-antagonist effects, based on its blockade of the locomotor depressant effects of the KOR-agonist U50,488 (10 mg/kg). LY2795050 (0.32 mg/kg), when administered only 1 min prior to the OSS stress paradigm, decreased immobility in males, but not females. With a slightly longer pretreatment time (15 min), this dose of LY2795050 decreased immobility in both males and females. A 10-fold smaller dose of LY2795050 (0.032 mg/kg) was inactive in the OSS, showing dose-dependence of this anti-stress effect. Overall, these studies show that a novel KOR-antagonist can produce very rapid onset anti-immobility effects in this model of acute stress exposure.

M5. Effect of Macitentan on pulmonary vascular resistance index in patients with congenital heart disease-pulmonary arterial hypertension: a meta-analysis

Abstract Background and Aims Macitentan is a novel dual endothelin receptor antagonist which proven effective as treatment in adults with pulmonary arterial hypertension. Methods and Results We performed a systematic search from inception until May 31, 2021, according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines comparing PVRi baseline and after Macitentan 10mg and selected studies according to our pre-defined inclusion and exclusion criteria. Two reviewers extracted data into the predefined tables in the Microsoft Excel (Microsoft Corp., New Mexico, US) sheet. We used RevMan software to perform a meta-analysis and draw Forest plots. We used a random effects model to estimate risk ratios. A two-sided p-value of ≤ 0.05 was considered statistically significant. A total of three randomized control trials (RCTs) with 325 patients were included in our analysis. Macitentan 10mg a day showed moderately associated with lower PVRi compare with baseline value (SMD: -0.72) and statistically significant (p = 0.002; 95% CI=-1.18-(-0.25)). Conclusion Macitentan was developed by modifying the structure of Bosentan in order to increase the efficacy and safety. Macitentan has slower receptor dissociation kinetics and longer duration of action which allows once-daily dosing. The safety profile of Macitentan appears to be superior with respect to hepatic safety and edema than other therapy such as Bosentan and Ambrisentan, respectively. Macitentan is a promising drug to treat pulmonary hypertension which is well tolerated and associated with improvements.

Mechanism-Based and Computational-Driven Covalent Drug Design.

Covalent drugs offer higher efficacy and longer duration of action than their noncovalent counterparts. Significant advances in computational methods for modeling covalent drugs are poised to shift the paradigm of small molecule therapeutics within the next decade. This viewpoint discusses the advantages of a two-state model for ranking reversible and irreversible covalent ligands and of more complex models for dissecting reaction mechanisms. The relation between these models highlights the complexity and diversity of covalent drug binding and provides opportunities for mechanism-based rational design.

P051 QLS-215 IS A LONG-ACTING MONOCLONAL ANTIBODY PLASMA KALLIKREIN INHIBITOR FOR THE POTENTIAL TREATMENT OF HAE

Plasma kallikrein is a validated target for prevention of HAE attacks. High potency and long duration of action are key drivers of prophylactic efficacy of plasma kallikrein inhibitors. We sought to generate a monoclonal antibody (mAb) plasma kallikrein inhibitor with high potency and potential for long duration of action.

8-Hydroxyquinolin-2(1H)-one analogues as potential β2-agonists: Design, synthesis and activity study.

β2-Agonists that bind to plasmalemmal β2-adrenoceptors causing cAMP accumulation are widely used as bronchodilators in chronic respiratory diseases. Here, we designed and synthesized a group of 8-hydroxyquinolin-2(1H)-one analogues and studied their β2-agonistic activities with a cellular cAMP assay. Compounds B05 and C08 were identified as potent (EC50<20 pM) and selective β2-agonists among the compounds tested. They behaved as partial β2-agonists in non-overexpressed HEK293cells, and possessed rapid smooth muscle relaxant actions and long duration of action in isolated guinea pig tracheal strip preparations. In summary, B05 and C08 are β2-agonists with potential applicability in chronic respiratory diseases.

Pharmacokinetic, pharmacodynamic, and behavioural studies of deschloroketamine in Wistar rats.

Deschloroketamine (DCK), a structural analogue of ketamine, has recently emerged on the illicit drug market as a recreational drug with a modestly long duration of action. Despite it being widely used by recreational users, no systematic research on its effects has been performed to date. Pharmacokinetics, acute effects, and addictive potential in a series of behavioural tests in Wistar rats were performed following subcutaneous (s.c.) administration of DCK (5, 10, and 30 mg·kg-1 ) and its enantiomers S-DCK (10 mg·kg-1 ) and R-DCK (10 mg·kg-1 ). Additionally, activity at human N-methyl-d-aspartate (NMDA) receptors was also evaluated. DCK rapidly crossed the blood brain barrier, with maximum brain levels achieved at 30 min and remaining high at 2 h after administration. Its antagonist activity at NMDA receptors is comparable to that of ketamine with S-DCK being more potent. DCK had stimulatory effects on locomotion, induced place preference, and robustly disrupted PPI. Locomotor stimulant effects tended to disappear more quickly than disruptive effects on PPI. S-DCK had more pronounced stimulatory properties than its R-enantiomer. However, the potency in disrupting PPI was comparable in both enantiomers. DCK showed similar behavioural and addictive profiles and pharmacodynamics to ketamine, with S-DCK being in general more active. It has a slightly slower pharmacokinetic profile than ketamine, which is consistent with its reported longer duration of action. These findings have implications and significance for understanding the risks associated with illicit use of DCK.

Future Perspectives for Antiangiogenic Therapy in Retinal Diseases

The World Health Organization considers eye disorders as the serious problem of our time [1]. According to world statistics, the number of people with visual impairment is 1.3 billion, most of this number are people over 50 years old [2]. Over the past 20 years, developments in the treatment of AMD and fundus diseases have advanced and include drugs such as vascular endothelial growth factor inhibitors. The molecular structures of drugs intended for intravitreal use range from RNA aptamers (pegaptanib) to full-length monoclonal antibodies (mAb: bevacizumab) to Fab fragments (ranibizumab) and an antibody conjugate (aflibercept). In addition, single-chain variable fragment (scFv: brolucizumab), bispecific monoclonal antibody (faricimab) and DARPin (abigar pegol) show promising results in clinical trials.[6],[7] Brolucizumab (RTH258) was developed by ESBATech (ES-BATech AG — Schlieren ZH, Switzerland) originally under the name ESBA1008, an inhibitor of the humanized single chain antibody fragment (scFv) of all isoforms of vascular endothelial growth factor-A (VEGF-A). [6],[7],[11]. The Faricimab (ROCHE, Switzerland) molecule is characterized by the presence of a bispecific antibody that simultaneously binds to both VEGF-A and Ang-2; the drug consists of an anti-Ang-2 antigen-binding fragment (Fab), an anti-VEGF-A Fab and a crystallizing modified fragment (Fc region) with a total size of 150 kDa. This “crossover” effect provided high affinity for both targets while also maintaining a good stability profile compared to natural antibodies [8]. Abicipar Pegol (Abicipar, Allergan. Dublin, Ireland) is a DARPin aimed at binding all VEGF-A isoforms, like ranibizumab. It has a higher affinity and a longer half-life from the eye than ranibizumab (&gt;13 days versus 7.2 days), making it a potential drug with a longer duration of action and the need for less frequent injections [15]. In this article, we tried to summarize the literature data on new anti-VEGF drugs being developed and ready for release. We hope that the appearance of these drugs on the market will make it possible to reduce the injection load on the patient and optimize their material costs.