Faster Onset Research Articles

Characterization of six clinical drugs and dietary intervention in the non-obese CDAA-HFD mouse model of MASH and progressive fibrosis.

The choline-deficient L-amino acid defined-high fat diet (CDAA-HFD) mouse model is widely used in preclinical metabolic dysfunction-associated steatohepatitis (MASH) research. To validate the CDAA-HFD mouse, we evaluated disease progression and responsiveness to dietary and pharmacological interventions with semaglutide, lanifibranor, elafibranor, obeticholic acid (OCA), firsocostat and resmetirom.Disease phenotyping was performed in C57BL/6J mice fed CDAA-HFD for 3-20 weeks and ranked using the MASLD Human Proximity Score (MHPS). Semaglutide, lanifibranor, elafibranor, OCA, firsocostat or resmetirom were profiled as treatment intervention for 8 weeks, starting after 6 weeks of CDAA-HFD feeding. Semaglutide and lanifibranor were further evaluated as early (preventive) therapy for 9 weeks, starting 3 weeks after CDAA-HFD diet feeding. Additionally, benefits of dietary intervention (chow reversal) for 8 weeks were characterized following 6 weeks of CDAA-HFD feeding. CDAA-HFD mice demonstrated a non-obese phenotype with fast onset and progression of MASH and fibrosis, high similarity to human MASH-fibrosis, and tumor development after 20 weeks of diet-induction. Semaglutide and lanifibranor partially reversed fibrosis when administered as prevention, but not as treatment intervention. Elafibranor was the only interventional drug to improve fibrosis. In comparison, chow-reversal resulted in complete steatosis regression with improved liver inflammation and fibrosis in CDAA-HFD mice. CDAA-HFD mice recapitulate histological hallmarks of advanced MASH with progressive severe fibrosis, however, in the absence of a clinical translational obese dysmetabolic phenotype. CDAA-HFD mice are suitable for profiling drug candidates directly targeting hepatic lipid metabolism, inflammation, and fibrosis. The timing of pharmacological intervention is critical for determining antifibrotic drug efficacy in the model.

Pharmacokinetics and Safety of a Novel Extended-Release Microsphere Formulation of Risperidone in Patients with Schizophrenia or Schizoaffective Disorder.

Risperidone extended-release injectable suspension (R-ERIS; marketed as RYKINDO) is a novel immediate-release version of risperidone formulated as extended-release microspheres for biweekly intramuscular injection to treat schizophrenia in adults. The pharmacokinetics (PK) and safety of R-ERIS were evaluated in a multicenter, randomized, open-label, multiple-dose study in patients with stable schizophrenia or schizoaffective disorder. Eligible patients (N = 108) 18 to 65 years old were randomized (1:1) to receive IM injections of R-ERIS 25 mg or the comparator, a biweekly risperidone long-acting injectable (BW-RLAI; marketed as RISPERDAL CONSTA) 25 mg for a total of 5 injections. The primary objective was to evaluate the relative bioavailability of active moiety (risperidone plus 9-hydroxyrisperidone) at steady state. Blood samples were analyzed for risperidone and 9-hydroxyrisperidone using a validated, specific, and sensitive liquid chromatography with tandem mass spectrometry method. Plasma concentration-time data were analyzed using non-compartmental methods. Pharmacokinetic parameters were calculated based on individual patient PK profiles. Safety was assessed using standard measures. At steady state, mean plasma concentrations of the active moiety were similar for R-ERIS and BW-RLAI. R-ERIS rapidly released risperidone after the injection without apparent lag time. Plasma active moiety levels reached steady state after the second injection of R-ERIS. The elimination of the drug was completed approximately 2weeks earlier for R-ERIS as compared to that for BW-RLAI. R-ERIS was safe and well tolerated. Overall, R-ERIS exhibited a faster onset and offset than BW-RLAI and statistical analysis of exposure parameters demonstrated bioequivalence at steady state.

7277 Diabetic Ketoacidosis As The First Manifestation Of Ectopic Cushing’s Syndrome

Abstract Disclosure: R.S. Medeiros: None. Introduction: Ectopic Cushing’s Syndrome (ECS) represents 10-20% of all ACTH-dependent CS, and the majority of cases arise from lung carcinoids. These indolent lesions usually evolve clinically over 6-24 months, whereas carcinomas are associated with faster onset of ECS. Diabetic Ketoacidosis (DKA) as a presenting manifestation of Cushing’s Syndrome (CS) is very rare, with the few cases published to date related to Cushing’s disease. Clinical Case: A 42-year-old woman was admitted in the emergency room with DKA and COVID-19. During stabilization, florid CS was clinically suspected. She reported a 6-month history of secondary amenorrhea, lack of concentration and memory, easy bruising, proximal myopathy with frequent falls evolving to daily life dependency from relatives. She also reported a 2-month diagnosis of dyslipidemia, Diabetes and hypertension, and a diagnosis of atypical pneumonia 6 months ago. Physical exam showed typical cushingoid appearance, especially for marked limb sarcopenia and proximal myopathy. An overnight dexamethasone suppression test (morning cortisol: 25.7 ug/dL), 24h urinary free cortisol (UFC; 1072.5 ug/dL; reference: <176) and serum cortisol at 23h00 (25.5 ug/dL) confirmed CS. ACTH-dependent CS was diagnosed. She had non-suppressible serum cortisol in high dose dexamethasone suppression test, and CRH stimulation test was suggestive of Cushing’s disease only by a 20% rise of cortisol at 30 minutes. Pituitary MRI was normal. Inferior Petrosal Sinus sampling was postponed for several months due to healthcare strikes. The patient started 750 mg of metyrapone in three divided doses but rapidly decreased the dose and stopped it due to clinical resolution of CS, a dramatic improvement of all glucocorticoid-related comorbidities leading to discontinuation of statin, insulin, main oral anti-hyperglycemic and antihypertensive medications, and normal midnight salivary cortisol and 24h UFC. She remained in this eucortisolemic state for 12 months. Thoracic CT scan revealed thymic hyperplasia and a 25x15 mm well-defined nodule in the lingula. A 68Ga-DOTANOC PET/CT showed a single uptake in the same lung region. The patient underwent lingulectomy plus excisional biopsy of interlobar lymph nodes, and pathology revealed a low-grade neuroendocrine tumor (Ki67<2%, <2 mitosis) without involved lymph nodes. The patient is weaning off from physiologic doses of hydrocortisone. Conclusion: DKA can rarely be the presenting manifestation of severe CS, including ECS. Clinicians should suspect on this etiology of DKA based on clinical signs and cumulative morbidity not typical of a young patient. This hint would lead to the expedite implementation of targeted therapies for initial stabilization of the CS patient, and the timely institution of a proper diagnostic approach and definitive treatment of this challenging patients. Presentation: 6/2/2024

Alkylsulfones: novel chemical scaffolds targeting the vesicular acetylcholine transporter usher in a new generation of insecticides.

Insecticides targeting the nervous system have been the most widely used to control arthropod pests due to their fast onset of action leading to efficient crop protection. With their continued use, resistance has and will become an inevitable challenge that demands continued efforts in identifying and developing new insecticidal chemistries acting on novel targets. In a recent publication, the results of a comprehensive study investigating the mode of action of novel chemical scaffolds based on the 2-(3-ethylsulfonyl-2-pyridyl)-heterocycles, alkylsulfones, was presented, concluding that their primary target is the vesicular acetylcholine transporter. © 2024 Society of Chemical Industry.

Role of SIRT1-mediated synaptic plasticity and neurogenesis: Sex-differences in antidepressant-like efficacy of catalpol

BackgroundCatalpol, an important compound found in Rehmannia glutinosa (a plant with high nutritional and antidepressant medicinal value), exhibits various biological activities and has the ability to penetrate the blood-brain barrier. Our recent studies revealed a gender difference in the antidepressant activity of Rehmannia glutinosa with females showing better responses than males. Catalpol is likely the key compound responsible for this gender-specific difference, which caters to current clinical observations that the severity and impact of depression are approximately two to three times higher in females than in males. However, the sex-specific mechanism of catalpol's antidepressant effects remains unclear. Purpose and MethodsOur recent molecular network predictions suggest that the gender-specific antidepressant properties of catalpol primarily involve the regulation of SIRT1-mediated synaptic plasticity and neurogenesis. Building on this, the present study used a well-established chronic unpredictable mild stress model of depression in mice to confirm the sex-specific antidepressant characteristics of catalpol over time and intensity. Furthermore, using SIRT1 inhibitors and activators, behavioral tests, hematoxylin & eosin, Nissl, and Golgi staining, western blotting, immunofluorescence, and real-time PCR, we evaluated the key indicators of depressive behavior, synaptic plasticity, and neurogenesis before and after SIRT1 intervention to comprehensively assess whether the sex-specific antidepressant mechanism of catalpol indeed involves SIRT1-mediated synaptic plasticity and neurogenesis. ResultsThe gender-dependent antidepressant effects of catalpol are characterized by a faster onset and stronger effects in females compared to males, with females showing stronger regulation of SIRT1-mediated synaptic plasticity and neurogenesis. Activation of SIRT1 preserved the gender differences in catalpol's effects on depressive behavior, hippocampal synaptic plasticity (including neuronal consolidation, neuronal density, dendritic spines, and PSD95 and SYP gene and protein expression), and neurogenesis (including enhancement of GAP43 and MAP2 expression, activation of c-myc, cyclinD1, Ngn2, and NeuroD1 mRNA levels, and upregulation of the Wnt3a/β-catenin/GSK-3β pathway), while inhibition of SIRT1 abolished these gender differences in the effects of catalpol. ConclusionsCatalpol exhibits higher antidepressant activity in female mice compared to male mice, and the mechanism underlying this gender difference in antidepressant effects may depend on catalpol's higher sensitivity in improving hippocampal SIRT1-mediated synaptic plasticity and neurogenesis in females. The novelty of this study lies in its first-time revelation of the gender-specific phenotypes, targets, and molecular mechanisms of the antidepressant effects of catalpol.

Comparative Study between Dexmedetomidine and Fentanyl as Adjuvants to Bupivacaine for Prevention of Post Spinal Shivering in Caesarean Sections

Abstract Background Shivering is a common complication in regional anesthesia during cesarean sections. It can impair monitoring and increase oxygen demand, CO2 production, and wound pain, healing, and discharge. Spinal anesthesia can increase vulnerability to hypothermia, leading to shivering. Dexmedetomidine and fentanyl have been shown to prevent post-spinal shivering. Aim of the Work This study aimed to compare the efficacy and safety of fentanyl and dexmedetomidine in preventing perioperative shivering and their effects on block intensity, hemodynamics, sedation, postoperative pain, and analgesic requirement. Patients and Methods 150 obstetric patients were included and randomized into three equal groups: control, fentanyl, and dexmedetomidine group. Each group received 12.5 mg hyperbaric bupivacaine 0.5% intrathecally with different adjuvants. Results Both fentanyl and dexmedetomidine groups showed a decreased incidence and intensity of shivering compared to the control group. There was no statistically significant difference between the two groups in this regard (p-value >0.05). The onset and duration of sensory and motor block were faster and prolonged in both fentanyl and dexmedetomidine groups compared to the control group, but dexmedetomidine showed faster onset and more prolonged duration than fentanyl. Dexmedetomidine also showed a statistically significant difference regarding hypotension (p-value <0.05) but non-significant regarding bradycardia (p-value >0.05) compared to other groups. There were no statistically significant differences in sedation intensity between the groups (p-value >0.05). Fentanyl showed a higher incidence of nausea, vomiting, and pruritis compared to other study groups. Conclusion Both fentanyl and dexmedetomidine are safe to use with bupivacaine for prevention of perioperative shivering in cesarean sections. Both drugs decreased the incidence and intensity of shivering, and dexmedetomidine was more effective in terms of prolongation of sensory and motor block duration and reducing opioid requirements. Dexmedetomidine showed fewer side effects during the intra and postoperative period compared to fentanyl.

Comparison of the Effects of Intravenous Fentanyl and Intravenous Dexmedetomidine on Characteristics of Spinal Anesthesia.

Introduction and aim Spinal anesthesia is a widely used technique for lower abdominal and lower limb surgeries, offering effective pain control and muscle relaxation. Various adjuvants have been explored to enhance the quality and duration of spinal anesthesia, with opioids and α-2 agonists being popular choices. Fentanyl, a potent opioid, and dexmedetomidine, a highly selective α-2 agonist, have both shown promising results when used as adjuvants. This study aimed to compare the effects of intravenous fentanyl versus intravenous dexmedetomidine on the characteristics of spinal anesthesia, including onset and duration of sensory block, hemodynamic stability, postoperative analgesia, and side effects. Methods This is a prospective, randomized, double-blind, comparative study involving sixty patients aged 18 to 65 years. The patients were classified as American Society of Anesthesiologists physical status I and II and were scheduled for elective infraumbilical surgery under subarachnoid block. The patients were randomly divided into two groups as follows: group D and group F. Patients of group D received IV dexmedetomidine 0.5 µg/kgand group F received IV fentanyl 1 µg/kgas premedication 5 minutes before spinal anesthesia over10 minutes. Vital parameters, the onset of sensory and motor block, the highest level of sensory blockade achieved, regression time of spinal anesthesia by two segments, Ramsay sedation score, postoperative numerical rating scale, and time of requirement of first dose of postoperative rescue analgesic were recorded and analyzed. Results Both group D and group F were comparable in terms of age, gender distribution, BMI, American Society of Anesthesiologists (ASA) grading, and type of surgery. The time to achieve T10 sensory blockade was significantly faster in group F (5.5±1.27 minutes) compared to group D (6.5±1.6 minutes, p=0.01). However, the difference between the highest level of sensory blockade achieved and the time to achieve motor blockade was not statistically significant. Group D showed a significantly longer time to two-segment regression of spinal level (141.8±23.5 minutes vs. 94.33±13.6 minutes, p<0.001). Hemodynamic parameters were comparable between groups. Group D demonstrated higher Ramsay sedation scores from 10 minutes to 45 minutes postanesthesia with maximum difference at 15 minutes (p<0.001) and lower pain scores at 4 and 6 hours postsurgery (p=0.02 and p=0.008, respectively). The time to rescue analgesia was significantly longer in group D (6.9±1.5 hours vs. 5.5±0.63 hours, p<0.001). Side effects were minimal and comparable between the two groups. Conclusion While both fentanyl and dexmedetomidine are valuable intravenous adjuncts to spinal anesthesia, dexmedetomidine offers advantages in terms of prolonged sensory block, better postoperative analgesia, and longer time to rescue analgesia. Fentanyl, on the other hand, provides a faster onset of sensory block. Dexmedetomidine produced a slightly higher level of sedation, particularly in the early postanesthesia period. The choice between these two drugs should be tailored to the specific requirements of the surgical procedure and individual patient factors.

Comparison study between Sevoflurane/Remifentanil with Isoflurane/Remifentanil to induce hypotension in Rhinoplasty Operations

Background: Answering the question of “which modality and combination is having the upper handy?” in bleeding control during rhinoplasty surgery through controlled hypotension achieved by administering anesthesia with two different inhalation agents: sevoflurane or isoflurane, both in combination with remifentanil. Numerous studies and articles are published annually, yet the wider question regarding the efficacy of each formula has remained unaddressed. Methods: This prospective observational study utilized convenient sampling with a total of 100 patients undergoing rhinoplasty. Participants were divided into two groups: one receiving remifentanil combined with sevoflurane and the other receiving remifentanil combined with isoflurane. Controlled hypotension was achieved and monitored throughout the procedure. Results: Both anesthesia combinations effectively achieved controlled hypotension and created a dry operative field. Notably, the sevoflurane/remifentanil combination resulted in a faster onset of decreased heart rate and mean arterial blood pressure (MAP) within the first 40 minutes of the procedure compared to the isoflurane/remifentanil combination. Conclusion: The study demonstrated that both sevoflurane/remifentanil and isoflurane/remifentanil combinations are effective in controlling bleeding during rhinoplasty. Sevoflurane/remifentanil showed a quicker initial effect on cardiovascular parameters, but both protocols successfully met the primary goal of minimizing bleeding and enhancing surgical visibility.

Formulation, Development and Optimization of Silymarin Loaded Nanoparticle Orodispersible Tablets for its Anti-inflammatory Activity

The objective of this work was to enhance the anti-inflammatory properties of silymarin by developing and refining an orodispersible tablet formulation loaded with nanoparticles. Formulation development and optimization of silymarin-loaded nanoparticle orodispersible tablet for its anti-inflammatory activity is the focus of this research paper. Nanoparticle drug delivery systems can help to overcome these limitations by enhancing solubility and absorption. Disintegration and dissolution of Orodispersible tablets take place in the mouth rapidly without water, providing a faster onset of action. These nanoparticles were then incorporated into orodispersible tablets containing superdisintegrants and sweeteners using direct compression. A Box-Behnken design was utilized to systematically optimize the tablet formulation based on responses including disintegration time, wetting time, hardness and friability. After 15 minutes, SL-NP Formulation -3, which contains 5% crospovidone as a superdisintegrant, demonstrated maximal drug release, or 98.5%. Rats with paw edema caused by carrageenan were used to test the anti-inflammatory potential. Following three hours, the 400 mg/kg dose showed a strong 48% inhibition; the impact grew to 52% after three hours. Overall, the development of silymarin nanoparticle orodispersible tablets shows promise for improving the anti-inflammatory effects of silymarin through a synergistic combination of nanoencapsulation and rapid disintegrating tablet technologies.

Preparation of Mouth Dissolving Sublingual Film of Fixed Dose Combination of Hydrochlorothiazide and Losartan Potassium and Statistical Optimization of Film.

Fast-dissolving films (FDFs) are innovative dosage forms offering advantages such as improved patient compliance, rapid onset of action, precise dosing, and favorable taste. Particularly beneficial for patients unable to swallow or require immediate drug absorption, FDFs dissolve rapidly in the mouth, releasing medication directly into the oral cavity. The sublingual application enhances drug delivery due to the high permeability of the sublingual mucosa, bypassing hepatic first-pass metabolism. This route is advantageous for drugs like losartan potassium (LP) and hydrochlorothiazide (HCZ), which benefit from enhanced bioavailability and faster onset of action. Preformulation studies included UV spectroscopy for λmax determination (LP: 282 nm, HCZ: 250 nm), DSC for thermal analysis (LP: 289.11°C, HCZ: 104.76°C), and solubility studies confirming LP’s solubility in acidic pH and HCZ’s increased solubility in pH 6.7 buffer. Compatibility studies using FTIR and DSC validated stability with excipients. Formulation optimization with HPMC E15 resulted in films with characteristics like film weight (145.66–167.0 mg), thickness (0.246–0.326 mm), folding endurance (898.0–1274.0), pH (6.0–6.70), disintegration time (77.66–174.6 s), tensile strength (77.04–141.90 g/cm²), and drug release profiles (LP: 68.78–96.22%, HCZ: 59.49–95.43% at 21 minutes). In summary, this study successfully developed LP and HCZ FDFs with optimized characteristics, demonstrating their potential in hypertension management and improving therapeutic outcomes.

Design and in vitro Evaluation of Cocoa Butter-based Amlodipine Besylate Fast Melt Tablets

Background: Oral fast-melting tablets (FMTs) have been gaining popularity due to their advantages in resolving swallowing issues of conventional oral tablets. Cocoa butter is an excipient of choice to develop FMT with an acceptable taste and faster onset of action of the drug. Purpose: The present study aimed to prepare and characterize the amlodipine besylate-loaded cocoa butter FMTs. objective: To prepare and characterise the formulation of cocoa butter tablet as fast melt buccal delivery system of amlodipine besylate. Method: Amlodipine besylate FMTs were prepared using a simple freezing (refrigeration) method. Cocoa butter (Form V) was used as the base to achieve a final tablet weight of 500 mg with drug and other functional excipients. The designed prototype tablet formulations were subjected to disintegration tests to determine the robust selected batch. The formulation F4, containing 7% high-molecular-weight chitosan, exhibited the quickest disintegration time of 1.45 ± 0.10 min. Afterwards, the selected formulation, F4, was subjected to quality evaluation parameters. Results: Fourier transform infrared spectroscopy (FTIR) studies revealed that there was no incompatibility between amlodipine besylate, cocoa butter, and other excipients. The average hardness of the F4 formulation tablet batch was found to be 2.69 ± 0.21 kg/cm2 and a friability of less than 1%. The drug content in F4 tablets was found to be 102.38 ± 5.29% and showed an in-vitro drug release of 94.30 ± 2.63% within 30 min. Over a six-month stability testing period, the chosen F4 formulation did not significantly change in terms of tablet average weight, disintegration time, drug content, and in-vitro dissolution rate. Conclusions: Selected formulation F4 with 7% of high molecular weight chitosan exhibited good physical properties, indicating the suitability of cocoa butter as a base to produce FMTs with the aid of a natural super-disintegrant.

Abstract A075: Racial and ethnic inequities in receipt of degarelix among patients diagnosed with advanced prostate cancer in United States

Abstract Background: Prostate cancer (CaP) is the most commonly diagnosed non-cutaneous cancer among men in the United States (US). Limited data currently exists regarding inequities in access to androgen deprivation therapy (ADT) which is the backbone of systemic treatment in management of advanced CaP. Gonadotropin-releasing hormone (GnRH) antagonists, first approved in 2008, represent a novel class of ADT drugs with faster onset of action and without initial testosterone surge or symptom flare when compared to GnRH agonists. There is also some evidence that GnRH antagonists, compared to GnRH agonists, may be associated with lower cardiovascular complications. Thus, in this study, we assessed inequities in access to GnRH antagonist (degarelix) by examining the associations of race and ethnicity with initiation of this drug among patients diagnosed with distant CaP. Methods: Using the Surveillance, Epidemiology and End Results (SEER) data linked to Medicare fee-for-service (Parts A, B, and D), we identified a cohort of patients, at least 66 years of age, who were diagnosed with distant CaP between 2008 and 2019 with follow-up through 2020. We defined treatment initiation with a GnRH antagonist (degarelix) or GnRH agonists (leuprolide, goserelin, histrelin, or triptorelin) as starting treatment with the study drug within one year after diagnosis. Poisson regression models were used to estimate adjusted rate ratios (aRR) and 95% confidence intervals (CI) for the association between race and ethnicity and degarelix treatment initiation (vs GnRH agonists, no treatment). All models were adjusted for age and Gleason score and compared Non-Hispanic Black (NHB), Hispanic, Non-Hispanic Asian American and Pacific Islander (NHAAPI), and Non-Hispanic American Indian and Alaska Native (NHAIAN) with Non-Hispanic White (NHW) patients. Results: There were 25,277 patients diagnosed with CaP in our analytic cohort, 3,033 (12.0%) initiated degarelix, and 14,045 (55.6%) initiated GnRH agonists over the study period. Mean (SD) age in the study population was 77.8 (7.8). Among all patients, 19,231 (76.1%) were NHW, 3,013 (11.9%) were NHB, 2,075 (8.2%) were Hispanic, 770 (3.0%) were NHAAPI, and 119 (0.5%) were NHAIAN. In the primary analysis, NHB (aRR: 0.58, 95% CI: 0.51-0.66), Hispanic (aRR: 0.59, 95% CI: 0.51-0.69), NHAIAN (aRR: 0.85, 95% CI: 0.49-1.47), and NHAAPI (aRR: 0.75, 95% CI: 0.59-0.94) were less likely to initiate degarelix compared with NHW patients. Discussion: In this US population-based study of patients diagnosed with distant CaP, we observed lower rates of treatment initiation with degarelix among patients of all other racial and ethnic groups compared to NHW patients, which may suggest lower access to these new class of ADT in these groups. Additional research is needed to elucidate health systems, provider, and patient access barriers that contribute to these inequities. Citation Format: Farzin Khosrow-Khavar, Mingchao He, Elizabeth Handorf, Tina Mayer, Thomas Jang, Saum Ghodoussipour, David Golombos, Biren Saraiya, Elisa V. Bandera, Hari S. Iyer. Racial and ethnic inequities in receipt of degarelix among patients diagnosed with advanced prostate cancer in United States [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A075.

Antibacterial effect of Cu2O/TiO2 visible-light photocatalytic composite on Xanthomonas campestris.

In this study, a Cu2O/TiO2 (CuTi) visible-light photocatalytic composite was employed for the treatment of Xanthomonas campestris and X. campestris-infected Brassica napus seedlings. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values against X. campestris were determined to be 8 and 32 μg ml-1, respectively. Transmission electron microscopy analysis demonstrated a direct correlation between the extent of bacterial cell damage and the concentration of CuTi. Noteworthily, a bactericidal rate of 100% was achieved at a concentration of 150 μg ml-1 over a treatment duration of 120 min. Moreover, alterations in active oxidants and antioxidants, including reactive oxygen species, glutathione reductase, superoxide dismutase, peroxidase, and catalase within the bacterial cells, were examined to elucidate the underlying mechanism of inhibition by the CuTi. The B. napus infected by X. campestris was treated with CuTi, and the efficacy was validated through determination of plant resistance indexes. The combined data confirmed that the CuTi is characterized by a low dose, fast onset, good effect, and higher safety for killing X. campestris, and it is expected to be developed as an antimicrobial agent for vegetables.

Comparison of Duration of Action in Spinal Anesthesia of 0.5% Bupivacaine and 0.5% Bupivacaine with Dexmedetomidine

Background: Spinal anesthesia is a common technique for surgeries below the navel, utilizing bupivacaine, a local anesthetic. Adding adjuncts like dexmedetomidine may enhance the efficacy and duration of the block.Objective: To compare the duration of action of 0.5% bupivacaine versus 0.5% bupivacaine with dexmedetomidine in spinal anesthesia.Methods: This quasi-experimental trial included 60 patients aged 20-60 years, ASA grade 1 or 2, undergoing general, plastic, orthopedic, or urological surgery at CMH Karachi. Patients were non-randomly assigned to Group B (0.5% bupivacaine, n=30) or Group BD (0.5% bupivacaine plus 5 mcg dexmedetomidine, n=30). Onset and duration of sensory and motor blocks, duration of analgesia, and adverse effects were recorded. Data were analyzed using SPSS version 25, with a p-value ≤ 0.05 considered significant.Results: Group BD showed faster onset of sensory block (7.08 ± 0.54 mins vs. 13.48 ± 0.73 mins, p &lt; 0.001) and motor block (10.32 ± 0.91 mins vs. 17.55 ± 0.69 mins, p &lt; 0.001). Duration of motor block was longer in Group BD (284.06 ± 5.64 mins vs. 133.93 ± 5.72 mins, p &lt; 0.001), as was duration of analgesia (218.07 ± 4.86 mins vs. 125.36 ± 5.42 mins, p &lt; 0.001).Conclusion: The addition of dexmedetomidine to 0.5% bupivacaine significantly enhances the onset and duration of spinal anesthesia with a comparable safety profile.

Comparative effectiveness of combined biologic agents versus standard therapies in the treatment of plaque psoriasis: a retrospective analysis.

Plaque psoriasis is a persistent skin disorder that necessitates efficient management. This study investigates the therapeutic effectiveness and timeline for skin lesion resolution in plaque psoriasis patients treated with combined biologic agents compared to standard therapies. Conducted retrospectively between March 2020 and March 2023, the study included 162 patients with moderate to severe plaque psoriasis. Participants were divided into two groups: the Control Group, which received standard treatments, and the Combined Biologic Agent Group, which received additional biologic therapy with secukinumab. Participants in the Control Group received standard treatments, while those in the Combined Biologic Agent Group received standard treatments plus secukinumab. The results showed that the Combined Biologic Agent Group experienced a significantly faster onset of therapeutic effects, with an average time of 3.04 ± 2.25 days compared to 6.12 ± 2.06 days in the Control Group. Additionally, skin lesion resolution occurred more rapidly in the biologic agent group (7.04 ± 2.13 days) than in the control group (14.56 ± 4.73 days). By week 24, the Psoriasis Area and Severity Index (PASI) scores demonstrated a more substantial reduction in the biologic agent group, decreasing from 26.98 ± 11.28 to 2.48 ± 3.01, whereas the control group showed a reduction from 25.82 ± 10.47 to 10.40 ± 7.63. The overall effectiveness rate was higher in the biologic agent group, with no cases of ineffectiveness, compared to a 20.99% ineffectiveness rate in the control group. Furthermore, there was no recurrence of the disease in the biologic agent group, while the control group experienced an 11.11% recurrence rate. Both groups had a similar incidence of adverse reactions, indicating that the addition of biologic agents does not significantly increase the risk of adverse events. These findings suggest that combined biologic agent therapy offers a more effective and faster treatment option for plaque psoriasis without compromising safety. However, larger-scale clinical trials are necessary to validate these results and establish the long-term benefits and safety of this treatment approach in diverse patient populations.

BUILDING AND CONSTRUCTION RECONSTRUCTION DESIGN

In order to create the necessary conditions for life and development of society, the production of various products are organized. The nomenclature and consumer qualities of the produced products are determined by the level of scientific and technical development, economic and social living conditions. For the production of products, houses and buildings are erected, which are equipped with certain means of production. The term of functioning of means of production is due to physical and moral wear and tear of machines and mechanisms. Buildings and structures in, which means production are located and function also age physically and morally, although this aging occurs slower than the means of production.Scientific and technical progress is currently characterized by a faster onset of wear and tear of the nomenclature of manufactured products. In addition, in connection with the changes taking place in society, the nomenclature of manufactured products replaced. The problem of retooling the functioning industry (replacing morally or physically outdated means of production, the emergence of need to produce new types of products) arose before humanity a long time ago.Under reconstruction - the production of works, which carried out according to single project:- with a change in volume-planning decisions;- replacement or strengthening of existing structures;- demolition of existing and construction of new structures related to the operation of technological equipment;- with the replacement of obsolete or physically worn equipment;- with mechanization, production automation, etc. When carrying out the reconstruction of the main production facility, as a rule, significant volumes of work are always performed on auxiliary and service facilities.Reconstruction also includes the construction of new workshops and facilities instead of those, which being liquidated, the further operation of which is deemed impractical due to technical and economic conditions. They can be erected both on free territories and on areas vacated as a result of the liquidation (demolition) of the object.Technical re-equipment is clear as the implementation of a set of measures in accordance with the technical development plan of the enterprise according to projects and estimates for individual objects and types of work (without expanding existing production areas) to raise the technical level of individual areas of production, aggregates, and installations to modern requirements by introducing new equipment and technology, mechanization and automation of production processes, modernization and replacement of obsolete or physically worn equipment with new, more productive ones.Sometimes technical rearmament considered as a type of reconstruction with a relatively small amount of construction and installation work. As it is not difficult to see from the given definitions, new construction and expansion are in fact new construction, while the difference between them is only in the conditions of execution of works. Expansion of construction is carried out in difficult (compressed) conditions. Technical rearmament, as it was emphasized, mainly involves the organization of the dismantling of the old and the installation of new equipment on the existing foundations.In the future, the main attention will be paid to the issues of actual reconstruction, namely:- organization of works related to the strengthening of existing building structures, their replacement with temporary transfer of loads;- replacement of beams and trusses in areas of the covering located in areas difficult to reach for installation cranes;- by increasing the pitch of the columns without disassembly.

Long-term Safety Monitoring and Efficacy Status of Infliximab and its Biosimilars in Psoriasis Management

Abstract: Infliximab (INF), a murine human monoclonal antibody, is a substantially more successful biologic than topical drugs for treating mild to severe psoriasis because it clears the skin rapidly due to its fast onset of action. Loss of responsiveness over time and some adverse effects, especially the experience of infusion reactions, are the major causes of non-compliance with INF medication. Therefore, evaluation of the long-term reliability of anti-tumor necrosis factor (TNF) medications is necessary for the assessment of the risks associated with long-term anti-TNF therapy. For psoriasis, there are registered safety statistics; however, these individuals might not receive the same level of care as those in a randomized study. Few assessments of the safety of anti- TNF medications across indications, including their biosimilars, are present, but it’s still unknown how anti-infliximab antibodies arise and produce harmful effects. INF biosimilars, when subjected to human studies to reduce cost and improve access, provide therapeutic benefits with associated adverse events, showing variations in incidence depending upon varying patient populations and no new safety indications. During therapy, certain individuals develop antibodies against INF, which are believed to be linked to a loss of response (LOR). Additional research aimed at identifying individuals who are susceptible to treatment resistance is likely to assist doctors in accurately selecting the appropriate candidates for anti-TNF-α therapy and enhancing the long-term effectiveness of the treatment. From clinical studies, we expect to learn about how to utilize INF or its biosimilars more effectively in the management of psoriasis. Therefore, the paper focuses on the efficacy and safety monitoring of INF and developed biological therapies.

Buprenorphine with Bupivacaine 0.5% Heavy Versus Clonidine with Bupivacaine 0.5% Heavy Versus Bupivacaine 0.5% Heavy Alone in Patients Undergoing Total Abdominal Hysterectomy: A Comparative Study

Background and Aims: This research aimed to determine which of three spinal anaesthetic medication combinations—clonidine–bupivacaine, buprenorphine–bupivacaine and bupivacaine alone—is the most effective for total abdominal hysterectomy. Material and Methods: In this prospective study, approved by the Institutional Ethical Committee, 120 patients aged 35–60 years scheduled for elective total abdominal hysterectomy under spinal anaesthesia were included, following informed consent. Comprehensive pre-anaesthetic assessments, including detailed medical histories, clinical examinations and routine surgical investigations, were conducted. The study, spanning 24 months, utilised purposive sampling and a cross-sectional design. The inclusion criteria encompassed ASA I and II patients aged 35–60 years, undergoing elective total abdominal hysterectomy with a weight exceeding 45 kg, height over 150 cm, and valid informed consent. Exclusion criteria involved ASA Class III or higher, patient unwillingness for spinal anaesthesia, gross spinal deformities, bleeding diathesis, known allergy to the test drug, history of cardiac, respiratory, or central nervous system disease, hepatic or renal dysfunction and elevated intracranial pressure. Results: The onset time of sensory blockade was faster in the Bupivacaine + Buprenorphine group than in the Clonidine + Bupivacaine group, with the Bupivacaine group exhibiting the slowest onset. The Bupivacaine + Buprenorphine group had a significantly faster onset of motor block than the Clonidine + Bupivacaine and Bupivacaine groups. The total duration of motor block was shorter in both the Bupivacaine + Buprenorphine and Bupivacaine groups than in the Clonidine + Bupivacaine group. The Clonidine + Bupivacaine group showed higher incidences of bradycardia and hypotension than the other groups. The Bupivacaine + Buprenorphine group reported more side effects, including chest pain, cough, nausea and vomiting, than the other groups. Conclusion: This study found that spinal clonidine, in comparison to bupivacaine alone, gives better post-operative analgesia and sensory and motor blockage over a longer period of time.

Ultrasound-Guided Lumbar Plexus-Sciatic Nerve Blocks Versus Epidurals for Orthopaedic Surgeries: A Study to Compare the Competency of Novice Anaesthesiology Residents in a High-Volume Level 1 Trauma Centre.

The relative merits of peripheral nerve blocks (PNB) over central neuraxial anaesthesia and the advantages of the above two techniques over general anaesthesia for surgical interventions of the lower limb are well established. The competency of anaesthetic trainees in a high-volume level 1 trauma centre in administering dual ultrasound and nerve stimulator-guided lumbar plexus-sciatic nerve block(DUNLuPS) vs. epidural anaesthesia (EA) was compared by reporting the adequacy of anaesthesia with the two techniques, time taken for the performance of block, time of onset of sensoryblock (TOSB), and time of onset of motor block (TOMB). This prospective, randomized, study enrolled 92 patients aged 18-80 years with lower limb fractures admitted in trauma triage and scheduled for surgery. Thepatients were randomly allocated equally into the EA group and the DUNLuPS group. A total of 20 anaesthesia trainees in the third year of residencywith clinical experience of more than 15 independent lumbar plexus-sciatic nerve blocks were included in the study.A volume of 20 ml of 0.5% ropivacaine was administered in the lumbar plexus (Shamrock technique) but the volume used for sciatic nerve (subgluteal approach) was varied so that the cumulative dose did not exceed 3 mg/kg. For each block, the onset of nerve blockade was assessed every five minutes, and the assessments continued for an additional 30 minutes after the nerve blocks were finished. Clinical characteristics and adequacy of anaesthesia were comparable, i.e., 95.65% and93.47% success in the EA (n = 46) and DUNLuPS (n = 46) groups, respectively. Performance time was significantly more in the DUNLuPS group but followed by significantly less TOSB and TOMB. The time for the first analgesic request was 351.63 ± 148.70 minutes in the DUNLuPS group and 147.60 ± 52.65 minutes in the EAgroup (p < 0.0001). Both EA and DUNLuPS provide effective and comparable intra-operative anaesthesia for orthopaedic lower limb surgeries (OLLS) when administered by residents with more than two years of experience (third year of residency)in ultrasound-guided regional nerve blocks in a high-volume level 1 trauma centre. Statistically significant differences in the block performance characteristicshad no clinical advantage as it was compensated by the faster onset time in the DUNLuPS group. Post-operative pain management was better in the DUNLuPS group, sothe practice and conduct of anaesthesia for trauma patients should focus on the establishment of "block rooms" and timely training of residents in the former so that the advantages can be extended to the patient population.

Comparison of the Analgesic Duration Using Ultrasound-guided Popliteal Sciatic Nerve Block between Diabetics with Neuropathy and Nondiabetics without Neuropathy.

In India, the prevalence of diabetes mellitus neuropathy was reported to be as high as 30%. Eight percentage of the diabetic population suffer from foot ulceration and 1.8% have amputations. Popliteal nerve block can be potentially used for foot and ankle surgery with several advantages. To compare analgesic duration of an ultrasound (US)-guided popliteal sciatic nerve block between diabetics with neuropathy and nondiabetics without neuropathy. Participants were allocated into two groups for popliteal sciatic nerve blocks under US guidance. The primary outcome was the duration to onset of sensory and motor blockade. The secondary outcome was the duration to rescue analgesic and the visual analog scale scoring within 24 h. Hemodynamic outcomes were also monitored along with the above variables. It was observed that the onset of sensory blockade was faster in participants with diabetes mellitus with peripheral neuropathy as compared to the nondiabetic participants and the duration for onset of motor blockade in dorsiflexion was faster in diabetic patients as compared to the nondiabetic patients (17.48 ± 3.21 min). However, there was no significant changes when comparing the onset of duration to loss of plantar flexion, in diabetics (17.86 ± 2.29 min) versus in nondiabetics (18.51 ± 3.32 min). The duration for rescue analgesics was found to be longer in diabetic participants (13.19 ± 2.14 h) as compared to the nondiabetic participants (11.44 ± 1.86 h). No differences were observed in the hemodynamic changes and the complications associated with local anesthetics in either group. Diabetic patients with neuropathy have faster onset of blockade when compared to nondiabetic patients without neuropathy which may be due to the degenerative condition of the peripheral nerves in them. The hemodynamic parameters do not play a role in defining the outcome of the block.