Administration Of Dose Research Articles

Modulation of female reproductive hormones by Zingiber officinale and Allium sativum ethanol extracts administered singly and in combinations in female Wister rats

The reproductive system in females is responsible for producing gametes, sex hormones, and maintaining fertilized eggs as they develop. The female reproductive system is regulated by a balance of hormones. This study was aimed at analyzing the modulation of female reproductive hormones including FSH, LH and prolactin by Zingiber officinale and Allium sativum separately and in combination in female Wister rat models. A total of 40 mature female Wister rats were divided into 8 groups (n=5). Groups 1 were treated with distilled water and served as the normal control. Group 2 were treated with Zingiber officinale ethanol extract alone. Group 3 were treated with Allium sativum ethanol extract alone. Group 4-8 were treated with combined administration of Zingiber officinale and Allium sativum ethanol extracts in the ratios of ZO:AS = 2:8, 4:6, 5:5, 6:4, and 8:2 respectively.. Treatment were administered for 90 days. On the 91st day of treatment after administration of the 90th doses, blood samples were collected by ocular puncture from all the rats from each of groups 1-8 for serum hormone testing. Zingiber officinale monotherapy increased the serum levels of FSH and LH and decreased the level of prolactin. The reverse was the case with Allium sativum monotherapy. The combination of the two herbs increased FSH and LH; or decreased prolactin only when the proportions of Zingiber officinale were higher. In conclusion, only the monotherapy of Zingiber officinale enhanced the serum levels of FSH and LH and modulated prolactin level to a desired level.

Antiepileptic and antioxidant effects of aqueous extract of Lippia multiflora Moldenke (Verbenaceae) on pilocarpine-induced seizures in Mus musculus Swiss mice

Epilepsy is a chronic neurological disorder that affects the central nervous system. Approximately 3% of the population at some point in their lives would be affected by epileptic disorders in the world, that is to say nearly 70 million people and therefore about 85% live in developing countries. The objective of this study is to determine the anticonvulsant effects of Lippia multiflora on the animal model of epileptogenesis induced by pilocarpine injection in mice during the acute phase. Mice were treated with different doses of the aqueous extract of L. multiflora or sodium valproate. The anticonvulsant effects were evaluated 24 after the injection of pilocarpine by referring to the Racine scale. Then a daily treatment was done for one week corresponding to the acute stage of the disease. Oxidative stress parameters were measured from brain samples taken on the last day of treatment. The injection of pilocarpine induced the Status epilepticus, which is translated by the appearance of convulsive seizures while the administration of different doses of the aqueous extract of L. multiflora led to a significant decrease of the seizures induced by pilocarpine in mice. In addition, L. multiflora extract restored endogenous levels of oxidative stress markers (MDA and NO) and increased the activity of oxidative stress enzymes (SOD, CAT and GSH). L. multiflora possesses anticonvulsant properties mediated by the involvement of GABAA receptors and antioxidants.

Fecal microbiota transplantation in the treatment of hepatic encephalopathy: A perspective

Due to its complex pathogenesis, treatment of hepatic encephalopathy (HE) continues to be a therapeutic challenge. Of late, gut microbiome has garnered much attention for its role in the pathogenesis of various gastrointestinal and liver diseases and its potential therapeutic use. New evidence suggests that gut microbiota plays a significant role in cerebral homeostasis. Alteration in the gut microbiota has been documented in patients with HE in a number of clinical and experimental studies. Research on gut dysbiosis in patients with HE has opened newer therapeutic avenues in the form of probiotics, prebiotics and the latest fecal microbiota transplantation (FMT). Recent studies have shown that FMT is safe and could be effective in improving outcomes in advanced liver disease patients presenting with HE. However, questions over the appropriate dose, duration and route of administration for best treatment outcome remains unsettled.

Intra-procedural three-dimensional rotational angiography in cryoballoon ablation of atrial fibrillation - results from a randomised clinical trial

Abstract Introduction There are a variety of approaches for pre-procedural imaging to facilitate atrial fibrillation (AF) ablation. Intra-procedural three-dimensional rotational angiography (3DRA) is the least employed method and it can be advantageous regarding efficiency and procedural logistics (1). There is an open question whether LA imaging could improve safety and outcomes of cryoballoon (CB) ablation. Purpose The aim of this study is to evaluate possible benefits of 3DRA for procedural success, safety and long-term outcomes of CB ablation. Methods We designed a single-centre unblinded randomised clinical trial and recruited 134 patients (64.2% male, 59.0±11.6 years) with paroxysmal (93.3%) and early-persistent AF. Patients were randomised to no imaging or 3DRA which was performed intra-procedurally after trans-septal puncture. Angiographic images were segmented and overlaid to the fluoroscopy screen to guide the ablation procedure. Patients were scheduled for follow-up visits and twenty-four hour ECG recordings at 3, 6 and 12 months, and every 6 months thereafter. Results Of all the patients recruited, 66 (49.3%) were randomised to 3DRA and angiography was successfully performed in all but one patient (1.5%). Procedure time was significantly longer when 3DRA was performed (86.7±27.8 min compared to 67.2±22.1 in non-3DRA group, p<0.001). Total radiation dose (447.4±485.0 vs. 133.9±166.2 mGy, p<0.001) and contrast administration (131.8±28.3 vs. 40.8±26.5 ml, p<0.001) were significantly higher in the 3DRA group (Table 1). In patients who received no imaging one pulmonary vein (PV) couldn’t be isolated in 2 patients while this occurred in 3 patients in the 3DRA group (OR 1.57, 95% CI 0.25-9.72). Only minor complications were reported in both groups. Five patients developed large haematoma (4 in the 3DRA group vs. 1 in the control group). In each group there were 3 incidents of impending or transient phrenic nerve palsy. During 12 months of follow-up, 88.2% of patients in the control group and 81.8% in the 3DRA group were free of atrial fibrillation (OR 1.67, 95% CI 0.63-4.38). Two patients from the control group developed atrial flutter and were treated by ablation. In total, 10 patients underwent redo procedures (7 in the control and 3 in the 3DRA group respectively) and PV reconnections were detected in 9 cases. Conclusion 3DRA is a safe and efficient intra-procedural imaging method to guide CB ablation of AF. However, it significantly increases procedure duration, total radiation dose and contrast expenditure. In our trial it did not have any impact on the acute success rate of PV isolation or freedom from atrial fibrillation during 12-month follow-up.

#2823 High doses and levels of cholecalciferol for secondary hyperparathyroidism in hemodialysis patients

Abstract Background and Aims Vitamin D is crucial for musculoskeletal and general health. Low levels are associated with an increased risk of death and morbidity, including cancer, cardiovascular, autoimmune diseases and infections. In hemodialysis (HD) patients vitamin D deficiency plays additionally an important role in the pathogenesis of Chronic Kidney Disease–Mineral And Bone Disorder (CKD-MBD), including the development of secondary hyperparathyroidism (SHP). Determination of 25(OH)D levels in CKD patients and the administration of cholecalciferol according to the guidelines for the general population is recommended. The literature data show that therapy even with high doses of cholecalciferol appear to be safe and sufficient to increase 25(OH)D level > 30 ng/ml in HD patients. However, the prevailing opinion is that PTH lowering with cholecalciferol in CKD is unproven and clinically insignificant. The aim of the study was to evaluate the efficacy (including PTH concentration) and safety of increasing vitamin D levels from the recommended 30 ng/mL to >75 ng/mL in HD patients treated with high doses of cholecalciferol. Method 22 HD patients (16 M, 6 F)), with an average age of 72.5 ± 13.03 years and 25(OH)D concentration 30–50 ng/mL were administered cholecalciferol at a therapeutic dose of 70,000 IU/week (20,000 IU + 20,000 IU + 30,000 IU, immediately after each dialysis session) to reach the target serum 25(OH)D level > 75 ng/mL, but not longer than for 24 weeks. The baseline data on calcium, phosphate, 1,84 PTH, 25(OH)D and 1,25(OH)2D serum levels were compared with the data when 25(OH)D > 75 ng/mL was achieved or when the highest 25(OH)D levels were noted. Results A significant decrease in 1,84 PTH levels was observed during the study (542.36 ± 420.87 vs 230.99 ± 386.22 pg/mL; p < 0.005). No significant effect on calcium (8.91 ± 0.57 vs 9.03 ± 0.63 mg/dL; p = 0.23) and phosphate (4.6 ± 1.06 vs 4.81 ± 1.06 mg/dL; p = 0.93) concentrations was shown. There was also significant increase in 25(OH)D and 1,25(OH)2D levels (35.52 ± 8.26 vs 79.83 ± 21.38 ng/mL; p < 0.005, and 13.38 ± 7.26 vs 25.56 ± 12.80 pg/mL; p < 0.005, respectively). In the range of 25(OH)D levels 30-50 ng/mL 25(OH)D correlated positively with 1,25(OH)2D levels, r = 0.305. When 25(OH)D levels exceeded 50 ng/mL, there was negative correlation with 1,25(OH)2D levels (r = –0 .177 for 25(OH)D 50-75 ng/mL, and r = –0.262 for 25(OH)D >75 ng/mL). Conclusion Our study showed that the administration of high therapeutic doses of cholecalciferol to achieve 25(OH)D levels >75 ng/mL was safe, without the risk of hypercalcemia and hyperphosphatemia. Raising of 25(OH)D levels to the upper limit of the laboratory norm resulted in significant decrease in PTH levels. Cholecalciferol may be useful in the treatment of SHP in HD patients, but higher 25(OH)D levels seem to be crucial.

#1649 Obinutuzumab is effective for the treatment of rituximab-resistant membranous nephropathy

Abstract Background and Aims Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in nondiabetic adults. Rituximab has become the first-line therapy for patients with MN after the recognition of MN as an autoimmune disease. However, 40% of patients with MN do not respond to rituximab. Obinutuzumab is a humanized and glycoengineered type II anti-CD20 monoclonal antibody that has superior in vitro B-cell cytotoxicity compared with rituximab which might provide an attractive option for rituximab-resistant MN. We presented our single-center experience of treating MN with obinutuzumab. Method Fourteen patients with rituximab-resistant PLA2R-associated MN who received obinutuzumab at the First affiliated hospital of Xi'an Jiaotong university between January 2022 and June 2023 were included in this retrospective study. Resistance to rituximab was defined as the failure to achieve complete (urinary protein excretion <0.3 g/d along with normal serum albumin concentration and stable renal function) or partial (urinary protein excretion <3.5 g/d or with ≥50% reduction vs baseline, accompanied by improvement or normalization of serum albumin concentration and stable GFR) remission of NS in 3-6 months after 2 doses of rituximab administration. Clinical and laboratory parameters were evaluated at presentation, before and after obinutuzumab administration. Results Of all patients with an average age of 50.0 ± 13.6 years, 10 (71.4%) patients were men, 8 (57.1%) patients had hypertension and 4 (28.6%) patients had diabetes. The median disease duration was 1.3 (1.0, 4.8) years. At presentation, the proteinuria and albumin levels were 7.94 ± 4.23 g/d and 21.5 ± 3.6 g/L, respectively. The mean serum creatinine level was 70.5 ± 10.7 µmol/L and the patients had a median baseline anti-PLA2R level of 193.5 (104.5,299.2) RU/mL. Six patients had been previously exposed to steroids, alkylating agents, calcineurin inhibitors in different combinations in addition to rituximab. Both patients received 1 g of obinutuzumab on day 0 and day 15. At obinutuzumab administration, the proteinuria and albumin levels were 8.43 ± 3.36 g/d and 22.4 ± 4.0 g/L, respectively. The mean serum creatinine level was 85.1 ± 28.5 µmol/L and median anti-PLA2R level decreased to 32.7 (10.7,178.) RU/mL compared with that at presentation. After a median follow-up of 5.4 (4.0, 9.7) months after obinutuzumab therapy, complete remission was achieved in 4 (28.6%) and partial remission was achieved in 8 (57.1%) of patients. Of the remaining two patients who did not achieve complete or partial remission, 1 patient had a follow-up of 4 months and had a 33% decline in proteinuria accompanied by improvement in serum albumin. The other patient had an anti-PLA2R level higher than 1500 RU/mL (exceeding detection upper limit) at obinutuzumab administration and an inadequate follow-up of 3 months without proteinuria decline. Whereas, anti-PLA2R level decreased to 18.17 RU/ml accompanied by B-lymphocyte depletion (absolute CD19 count <5 cells/ml) at that time. Of the 12 patients who achieved complete or partial remission, the median time from treatment to remission was 4.7 ± 2.3 months. Two patients with longer follow-up maintained complete remission at 1 year. At first complete or partial remission, the proteinuria and albumin levels were 3.47 ± 1.99 g/d and 32.5 ± 3.3 g/L, respectively. The mean serum creatinine level was 74.8 ± 24.1 µmol/L and anti-PLA2R levels of 11 patients had a decline in the titer to <2 RU/ml (negative result for our immunology laboratory). B-lymphocyte depletion was achieved in all these patients. Conclusion Obinutuzumab may represent an attractive alternative therapy in patients with resistance to rituximab. Larger prospective studies are needed to validate these findings.

#1585 Ten years’ practice with calcimimetics and paricalcitol for the treatment of secondary hyperparathyroidism. Experience of one dialysis center

Abstract Background and Aims Secondary hyperparathyroidism (SHPT) remains one of the main problems in patients with chronic kidney disease (CKD), associated with deterioration in quality of life, progression of cardiovascular complications and mortality. Method Patients on HD (n = 2517) were treated from 2012 to 2023 years in our dialysis center with secondary SHPT were included in this study. All patients were divided into 2 groups: 1 gr. included −1536 (61%) patients whose PTH levels remained in the target range from 300 to 600 pg/ml, without therapy or with low doses of alfacalcidol (0.75-5 μg/week ); 2 gr. included - 981 (39%) patients with PTH levels >600 pg/ml were treated with calcimimetics (doses of cinacalcet used from 30 mg to 90 mg/day, doses of etelcalcetide used from 5 to 15 mg/week) as monotherapy or in combination with paricalcitol (5–15 μg/week). Phosphorus levels were controlled by an adequate dose of dialysis and administration of phosphate binders (sevelamer and sucrose iron oxyhydroxide). Results The average PTH level in 2 gr. of patients at the time of treatment initiation was 916.7 ± 879.9 pg/ml (601-2500 pg/ml). During the treatment the level of PTH decreased to target values and amounted 523.4 ± 216.7 pg/ml (63-594 pg/ml) in 73% of patients. Monotherapy with calcimimetics was effective in 41%; the remaining of patients (59%) were required the addition of paricalcitol to therapy to achieve target PTH values. Therapy of SHPT was also carried out in 15 (0.6%) patients with identified parathyroid adenomas (volume more than 1 cm3) and PTH levels >1000 pg/ml; the effect was achieved in 9 patients (60%), 6 patients underwent parathyroidectomy. During the previous years of observation, parathyroidectomy was required in all patients with SHPT with similar changes in the parathyroid glands. Conclusion In the overwhelming majority of patients with CKD5D and SHPT, the administration of calcimimetics as monotherapy or in combination with paricalcitol during the progression of SHPT allowed us to achieve target PTH values and maintain it for a long time (from 1 to 10 years), as well as reduce the number of surgical interventions for parathyroid glands, compared to the previous period.

Volenrelaxin (LY3540378) increases Renal Plasma Flow: A Randomized Phase 1 Trial.

Volenrelaxin, is a half-life-extended recombinant human relaxin protein developed for improving kidney perfusion and cardiorenal function. This study assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of volenrelaxin following single- and multiple-ascending doses (SAD and MAD) administration. In this Phase 1, 4-part, randomized, double-blinded, placebo-controlled SAD and MAD study in healthy participants, SAD participants (n=56) received an intravenous (IV) or subcutaneous (SC) dose of volenrelaxin or placebo in a dose-ascending manner. MAD participants (n=77) received volenrelaxin or placebo SC once weekly for 5 weeks. Effective renal plasma flow (ERPF) and measured glomerular filtration rate (mGFR) were determined by para-aminohippurate and iohexol clearance, respectively. Volenrelaxin demonstrated an extended half-life and increased acute and chronic placebo-adjusted ERPF change from baseline by 50% and 44%, respectively (p<0.0001). Measured GFR was unchanged, while filtration fraction and afferent/efferent renal arteriolar resistances were reduced. Systolic and diastolic blood pressures decreased, and pulse rate increased with increasing volenrelaxin exposures, demonstrating maximal model-derived placebo-adjusted changes (90% confidence interval) of -6.16 (-8.04, -4.28) mmHg, -6.10 (-7.61, -4.58) mmHg, and+4.39 (3.38, 5.39) bpm, respectively. Adverse events were mild, with no difference in orthostatic hypotension between volenrelaxin and placebo. Volenrelaxin was well-tolerated, safe and suitable for weekly SC dosing. Volenrelaxin showed a sustained improvement in kidney perfusion upon repeated dosing, supporting further clinical development in chronic kidney disease and chronic heart failure. Clinical trial registration: NCT04768855.

A Contribution to the Ethnobotany of Dhule and Thane Districts of Maharashtra State (India) - A Preliminary Report

Native medicinal uses of 11 plants common among Tadvi, Kokni &amp; Gavit tribes inhabiting Dhule district and Katkari, Varli &amp; Koli tribes of Thane district of Maharashtra State are reported. These plants have either not been reported by earlier workers or their uses mentioned here are unrecorded. Information is given on local name, locality, voucher number, native uses and mode of administration of doses.

Population pharmacokinetics of primaquine and its metabolites in African males

BackgroundPrimaquine (PQ) is the prototype 8-aminoquinoline drug, a class which targets gametocytes and hypnozoites. The World Health Organization (WHO) recommends adding a single low dose of primaquine to the standard artemisinin-based combination therapy (ACT) in order to block malaria transmission in regions with low malaria transmission. However, the haemolytic toxicity is a major adverse outcome of primaquine in glucose-6-phosphate dehydrogenase (G6PD)-deficient subjects. This study aimed to characterize the pharmacokinetic properties of primaquine and its major metabolites in G6PD-deficient subjects.MethodsA single low-dose of primaquine (0.4–0.5 mg/kg) was administered in twenty-eight African males. Venous and capillary plasma were sampled up to 24 h after the drug administration. Haemoglobin levels were observed up to 28 days after drug administration. Only PQ, carboxy-primaquine (CPQ), and primaquine carbamoyl-glucuronide (PQCG) were present in plasma samples and measured using liquid chromatography mass spectrometry. Drug and metabolites’ pharmacokinetic properties were investigated using nonlinear mixed-effects modelling.ResultsPopulation pharmacokinetic properties of PQ, CPQ, and PQCG can be described by one-compartment disposition kinetics with a transit-absorption model. Body weight was implemented as an allometric function on the clearance and volume parameters for all compounds. None of the covariates significantly affected the pharmacokinetic parameters. No significant correlations were detected between the exposures of the measured compounds and the change in haemoglobin or methaemoglobin levels. There was no significant haemoglobin drop in the G6PD-deficient patients after administration of a single low dose of PQ.ConclusionsA single low-dose of PQ was haematologically safe in this population of G6PD-normal and G6PD-deficient African males without malaria.Trial registration NCT02535767

Prediction of naloxone dose in opioids toxicity based on machine learning techniques (artificial intelligence).

Treatment management for opioid poisoning is critical and, at the same time, requires specialized knowledge and skills. This study was designed to develop and evaluate machine learning algorithms for predicting the maintenance dose and duration of hospital stay in opioid poisoning, in order to facilitate appropriate clinical decision-making. This study used artificial intelligence technology to predict the maintenance dose and duration of administration by selecting clinical and paraclinical features that were selected by Pearson correlation (filter method) (Stage 1) and then the (wrapper method) Recursive Feature Elimination Cross-Validated (RFECV) (Stage2). The duration of administration was divided into two categories: A (which includes a duration of less than or equal to 24 h of infusion) and B (more than 24 h of naloxone infusion). XGBoost algorithm model with an accuracy rate of 91.04%, a prediction rate of 91.34%, and a sensitivity rate of 91.04% and area under the Curve (AUC) 0.97 was best model for classification patients. Also, the best maintenance dose of naloxone was obtained with XGBoost algorithm with R2 = 0.678. Based on the selected algorithm, the most important features for classifying patients for the duration of treatment were bicarbonate, respiration rate, physical sign, The partial pressure of carbon dioxide (PCO2), diastolic blood pressure, pulse rate, naloxone bolus dose, Blood Creatinine(Cr), Body temperature (T). The most important characteristics for determining the maintenance dose of naloxone were physical signs, bolus dose of 4.5 mg/kg, Glasgow Coma Scale (GCS), Creatine Phosphokinase (CPK) and intensive care unit (ICU) add. A predictive model can significantly enhance the decision-making and clinical care provided by emergency physicians in hospitals and medical settings. XGBoost was found to be the superior model.

A Review on the Concept of Pottali

Introduction: Pottali word were found in classics in different contexts mainly meaning the word for bundling the various herbal drugs in a piece of cloth and to apply for sedation in various diseases. Pottali is a highly potent, concise form of medicament, which depicts maximum potency in low dosage form. The peculiarity of Pottali lies in its typical shape, form and preparatory methods. Thus, reviewing the concept of Pottali is the main objective of this article. Material and Methods: Available literature related to Pottali were searched from available printed form of various text books, journals, web-based search engines source were referred for updated research data. Results: The present article gives a review on concept of different preparatory procedures, types mentioned in various classical textbooks, dosage, and mode of administration and significance of Pottali Kalpana. Pottali Kalpana was invented with a vision for convenience in transportation, administration, dose fixation, preservation and enhancement of properties. Conclusion: More researches and documentation are required to be done for analytical and clinical evaluation of Pottali Kalpana.

EPIDEMIOLOGICAL FRAMEWORK OF MYOCARDITIS DURING SARS–COV–2 PANDEMIC AND VACCINATION CAMPAIGN

Abstract Rationale Myocarditis is an inflammatory condition of cardiomyocytes whose clinical course can be heterogeneous. Etiologies include infections (mostly viral), drugs or toxic exposures or auto–immunity, while few cases have been reported in association with vaccines (following, mainly, attenuated smallpox vaccine). Estimated prevalence is 2–22 cases/100000 people/year, with greater frequency in males aged 30–40. Since SARS–CoV–2 outbreak and vaccination campaigns there is growing interest in their association with myo–pericardial inflammatory conditions, with incidence reports of 1–5/100.000 and 1–5/1.000.000 respectively among vaccinated and unvaccinated subjects (as part of COVID–19) and relatively higher incidence in males after second (mRNA) vaccine administration. Study Design and Objective We designed this observational registry and included patients with CMR–confirmed myocarditis diagnosis admitted to Maggiore Hospital in Bologna from March 2017 to April 2023. Primary goal was to conduct an epidemiological analysis on myocarditis incidence in the era of SARS–CoV–2 and respective vaccination. Results We enrolled 48 patients, among which 37 were diagnosed during SARS–CoV–2 pandemic. 86% were male, and mean age at diagnosis was 31 years old; the vast majority did not show major modifiable CV risk factors (apart from cigarette smoking: 42%) or previous/comorbid CV conditions. Median LVEF (by CMR) at diagnosis was 56%, with 3 patients (6%) with LVEF &amp;lt; 47%. Median hsTnI and CRP peaks were respectively 7317 ng/L and 4,5 mg/dl. We reported 6 (12.5%) arrhythmic events during index hospitalization (1 patient had sustained VT and 5 had non–sustained VT). 8 out of 37 patients with myocarditis during SARS–CoV–2 outbreak reported previous COVID–19, with a median time of 130 days from infection, but only 1 had myocarditis as part of its clinical course. 16 patients had already received at least one SARS–CoV–2 vaccine dose (median: 2 doses) at diagnosis, with a median time of 117 days from dose administration (only two patients were diagnosed &amp;lt; 30 days from last administration). Conclusions Myocarditis epidemiology of our cohort seems to reflect available incidence data; furthermore, myocarditis as part of COVID–19 course or occurring shortly after vaccination appears to be an uncommon event. Our cohort consisted only of low or intermediate risk presentations. Data about diagnosis in the “COVID era” suggest a relative “underdiagnosis” in the previous period.

INVESTIGATION OF THE EFFICIENCY OF NON-STEROIDAL ANTI-INFLAMMATORY VETERINARY MEDICINAL PRODUCT IN THE COMPLEX TREATMENT OF DISEASES OF THE MUSCULOSKELETAL SYSTEM OF PIGS

The article presents the results of clinical trials of a non-steroidal anti-inflammatory veterinary drug when administered to fattening piglets with clinical signs of musculoskeletal diseases. For the treatment of the diseases, piglets of the experimental (I) and control (II) groups received an antimicrobial drug based on the tetracycline antibiotic. The animals of the experimental group were additionally administered orally with drinking water the test non-steroidal anti-inflammatory drug based on acetylsalicylic, ascorbic and citric acids, in the recommended dosage by the manufacturer. Blood for laboratory tests was selected from piglets before and after the use of drugs. Studies of hematological and biochemical parameters were conducted according to generally accepted methods. The therapeutic efficiecy of the drug and its effect on the morphofunctional state of the body was evaluated by comparing the statistically processed data obtained before and after treatment, as well as in comparison with the indicators of animals of the control group. The analysis of hematological parameters of piglets during the experiment showed a decrease in the number of leukocytes in the animal’s blood after the use of drugs. The normalization of the leukogram was also noted by reducing the relative number of rod-nuclear neutrophils. In particular, this indicator decreased by 17.4% in group I piglets, and by 12% in group II piglets. It is noted that the clinical response to therapy was faster and more pronounced in animals, which used a non-steroidal anti-inflammatory drug in combination with an antimicrobial drug than in piglets, which were treated only by antibiotic. According to the results of biochemical studies, it was found that the content of urea in the serum of animals of both groups before the use of drugs exceeded more than 3 times the upper limit of physiological values for a given age group of piglets. After therapy with the drugs a significant decrease in the urea content in the blood serum of groups 1 and 2 animals was noted by 3.42 and 2.98 times, respectively. It is established that the activity of marker enzymes of the liver physiological state (ALT, AST) in the serum of group I piglets after complex treatment with the studied drugs was slightly reduced and was within the physiological values. In the serum of group II animals, which were treated only with antimicrobial drug, ALT activity increased by 12,0 %, and AST – by 38,6 %, compared to the initial data, and exceeded the limit of physiological values. An increase in the content of iron by 37.4 % in the blood of group I piglets, compared to the period before drug administration, was noted. No adverse reactions and negative phenomena were detected during the use of the test drug, and the drug was well tolerated. According to the clinical condition of the experimental group animals and the results of laboratory tests it was established that the use of non-steroidal anti-inflammatory drugs based on acetylsalicylic, ascorbic and citric acids simultaneously with antimicrobial therapy led to a faster improvement in the state of the musculoskeletal system. Observation during the month of the piglet’s clinical conditions confirmed the safety of the drug in the recommended dosage and method of administration in the combined treatment of inflammatory processes of the musculoskeletal system.

How safe is gene therapy? : Second death after Duchenne therapy

Duchenne muscular dystrophy (DMD) is asevere monogenic hereditary disease with early manifestation and aprogressive course. Treatment options have so far been limited. Gene therapy opens up new options for DMD patients. Against the background of afurther death following DMD gene therapy, the side effects and risks of the gene therapeutics already approved or undergoing clinical trials will be evaluated and alternative gene therapeutics will be described. Based thereon, the future of DMD gene therapy will be discussed. For the first time, in June 2023, delandistrogene moxeparvovec (SRP-9001), agene replacement therapy based on an adeno-associated virus (AAV) vector, was approved in the USA for children aged 4-5years with DMD. Other promising gene therapies are in preclinical development or clinical trials, including CRISPR/Cas9-mediated strategies to restore dystrophin expression. Two deaths following DMD gene therapy with high-dose AAV vectors were attributed to AAV-mediated immune responses. The pre-existing disease underlying the therapy is most likely involved in the fatal AAV toxicity. Although gene therapy applications of AAV vectors are generally considered safe, the systemic administration of high vector doses can lead to severe side effects with apotentially fatal outcome in individual patients, especially after activation of the immune system. In the future, new methods for immunosuppression, reduction of AAV dose and alternative vectors will therefore increasingly come to the fore.

Knowledge, attitudes, and current practices toward lung cancer palliative care management in China: a national survey

ScopeThe present investigation seeks to illuminate the current state and disparities in the knowledge, attitudes, and practices (KAP) among healthcare professionals regarding the management of lung cancer palliative care (LCPC) in China, while simultaneously assessing the prevalence and context of patient-controlled analgesia (PCA) usage in the management of cancer-related pain.MethodsA total of 2093 healthcare practitioners from 706 hospitals across China completed a structured questionnaire that probed various facets of LCPC management. The questionnaire consisted of seven thematic sections, incorporating chi-square tests and Fisher’s exact probabilities to statistically assess the discrepancies in KAP among healthcare professionals across different hospital grades. Ordered data distributions among hospital grades were compared using non-parametric Kruskal-Wallis H and Mann-Whitney U tests. Multiple-choice items were subjected to multiple-response cross-tabulation analysis, while the Spearman rank-order correlation coefficient was employed to gauge potential associations among variables.ResultsAround 84.2% of the respondents perceived anti-tumor therapy to be of equal importance to palliative care. Statistically significant differences (χ² = 27.402, P = 0.002) in satisfaction levels were observed, with participants from Tertiary hospitals demonstrating higher satisfaction compared to those from Secondary and Primary hospitals. Pain emerged as the most prevalent symptom necessitating LCPC. Major impediments to LCPC adoption included patients’ and families’ concerns about the safety of long-term palliative care-related drug use. 31.1% of the respondents cited the most frequent rationale for PCA use as cases involving patients who required systemic administration of large opioid doses or exhibited intolerable adverse reactions to opioids. The principal deterrents against the use of PCA for cancer pain management were (1): apprehension about adverse drug reactions due to overdose (2), concern about the potential for opioid addiction, and (3) the anticipated increase in patients’ economic burdens. Over the preceding 24-month period, 33.9% of the surveyed healthcare practitioners reported no engagement in either online or offline LCPC-related training initiatives.ConclusionThis study emphasizes the pressing need for comprehensive training in LCPC among Chinese health personnels, particularly focusing on the effective management of cancer pain symptoms.

Effects of esketamine and fluoxetine on depression-like behaviors in chronic variable stress: a role of plasma inflammatory factors

Mounting evidence has identified the rapid and sustained antidepressive and anxiolytic-like effects of esketamine. However, the underlying mechanism of this no-monoamine target rapid-onset antidepressant is still underexplored. Immune-inflammatory pathways and cell-mediated immune activation, mainly including inflammatory cytokines in plasma, play a pivotal role in the pathogenesis of major depressive disorder and are also a potential therapeutic target for MDD. The current study was designed to clarify the role of esketamine on the expression of plasma cytokines in a depressive-like model introduced by chronic variable stress (CVS). In this study, a 21-day consecutive CVS protocol was applied to produce depressive- and anxiety-like behaviors. After the single dose or 7-day repeated administration of esketamine or fluoxetine, the depressive- and anxiety-like behaviors and the expression of inflammatory cytokines in plasma were examined. Both a single dose of esketamine and 7-days repeated fluoxetine administration elicited anti-depressive and anxiolytic effects in mice exposed to CVS. Additionally, CVS produced significant changes in the plasma inflammatory factors, notably increasing the expression of IL-1β, IL-6, IL-8, IL-17A, TNFα, IL-4, IL-9, IL-24, IL-37, IFN-β, and CXCL12, while reducing IL-10 and IL-33. With the administration of esketamine and fluoxetine, CVS-produced inflammatory disturbances were partially normalized. Together, our findings provide a novel insight that acute esketamine treatment could rescue CVS-produced depressive-like and anxiety-like behaviors in mice by normalizing the expression of inflammatory cytokines; this effect was similar to the repeated administration of fluoxetine. These results contributed to the understating of rapid anti-depressant effects elicited by esketamine.

The low and high doses administration of lutein improves memory and synaptic plasticity impairment through different mechanisms in a rat model of vascular dementia.

Vascular dementia (VD) is a common type of dementia. This study aimed to evaluate the effects of low and high doses of lutein administration in bilateral-carotid vessel occlusion (2VO) rats. The rats were divided into the following groups: the control, sham-, vehicle (2VO+V) groups, and two groups after 2VO were treated with lutein 0.5 (2VO+LUT-o.5) and 5mg/kg (2VO+LUT-5). The passive-avoidance and Morris water maze were performed to examine fear and spatial memory. The field-potential recording was used to investigate the properties of basal synaptic transmission (BST), paired-pulse ratio (PPR), as an index for measurement of neurotransmitter release, and long-term potentiation (LTP). The hippocampus was removed to evaluate hippocampal cells, volume, and MDA level. Treatment with low and high doses improves spatial memory and LTP impairment in VD rats, but only the high dose restores the fear memory, hippocampal cell loss, and volume and MDA level. Interestingly, low-dose, but not high-dose, increased PPR. However, BST recovered only in the high-dose treated group. Treatment with a low dose might affect neurotransmitter release probability, but a high dose affects postsynaptic processes. It seems likely that low and high doses improve memory and LTP through different mechanisms.

Intranasal vitamin B12 administration in elderly patients: A randomized controlled comparison of two dosage regimens.

Vitamin B12 deficiency is common in the elderly population. Standard treatment via intramuscular injections, however, has several disadvantages. Safer and more convenient dosage forms such as intranasal are therefore being explored. This study compares the effects of two intranasal vitamin B12 dosage regimens in elderly vitamin B12-deficient patients. Sixty patients ≥65 years were randomly assigned to either a loading dose (daily administration for 14 days followed by weekly administration) or a no loading dose (administration every 3 days) regimen for 90 days. Each dose contained 1000 μg cobalamin. Total vitamin B12, holotranscoblamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy) levels in serum were measured on days 0, 7, 14, 30, 60 and 90. Both dosage regimens resulted in a rapid increase of vitamin B12 and holoTC concentrations and normalization of initial high, MMA and tHcy concentrations. The loading dose regimen resulted in the fastest and greatest increase to a median vitamin B12 of 1090 pmol/L (reference 350-650 pmol/L) concentration after 14 days. Following weekly administration, B12 rapidly decreased to a median concentration of 530 pmol/L after 90 days. The no loading dose regimen resulted in a steady increase to a median vitamin B12 of 717 pmol/L after 90 days. Intranasal vitamin B12 administration is an effective and suitable way to replenish and sustain vitamin B12 levels in elderly patients.

Discovery of Potent, Selective, and Orally Available IRE1α Inhibitors Demonstrating Comparable PD Modulation to IRE1 Knockdown in a Multiple Myeloma Model.

The lack of selective and safe in vivo IRE1α tool molecules has limited the evaluation of IRE1α as a viable target to treat multiple myeloma. Focus on improving the physicochemical properties of a literature compound by decreasing lipophilicity, molecular weight, and basicity allowed the discovery of a novel series with a favorable in vitro safety profile and good oral exposure. These efforts culminated in the identification of a potent and selective in vivo tool compound, G-5758, that was well tolerated following multiday oral administration of doses up to 500 mg/kg. G-5758 demonstrated comparable pharmacodynamic effects to induced IRE1 knockdown as measured by XBP1s levels in a multiple myeloma model (KMS-11).