Daily Dose Of Drug Research Articles

Prescription trends in Japanese advanced Parkinson's disease patients with non-motor symptoms: J-FIRST.

Non-motor symptoms (NMS) are important factors when selecting treatments for patients with advanced Parkinson's disease (PD). We sought to elucidate the prescribing practices for advanced PD patients with NMS in Japanese clinical practice. We examined the prescription rates and doses of anti-PD drugs, and the use of non-steroidal anti-inflammatory drugs (NSAIDs) in post hoc analyses of a 52-week observational study of 996 PD patients with wearing-off on levodopa-containing therapy and ≥1 NMS. Dopamine agonists were the most frequently prescribed drugs combined with levodopa-containing drugs, followed by entacapone, zonisamide, istradefylline, selegiline, and amantadine. The daily dose of levodopa-containing drugs, rotigotine, entacapone, istradefylline, and droxidopa, and the levodopa-equivalent dose increased during the observation period. In a subgroup analysis of patients stratified by NMS status (improved/unchanged/deteriorated), the deteriorated group had higher prescription rates of entacapone and istradefylline, whereas the improved group had higher prescription rates of NSAIDs and zonisamide at Week 52. Prescriptions varied by geographical region for anti-PD drugs and by NMS status for NSAIDs. There were significant changes in the prescriptions and dosing of selected anti-PD drugs, especially newer drugs. Anti-PD drug and NSAID prescriptions also varied by changes in NMS status and geographic region.

40 The gut microbiota modifies host-parasite interactions

Abstract It is well documented that parasitic infections induce a profound change in the structure and function of host gut microbiota, likely due to infection-associated perturbations in the gut microenvironment. However, the mechanisms remain largely unknown. Here we aim to understand how the gut microbiota is modified by host-parasite relationships or vice versa using an integrated multi-omics analysis in a swine-Ascaris infection model. Female pigs (n = 30; 6 to 8 mo of age) were randomly divided into three groups (n = 10 per group). One group served as normal uninfected controls (NU); the remaining 20 pigs were inoculated per os with ~10,000 infective A. suum eggs; and the infection was allowed to progress for 35 d post-inoculation (dpi). At 21 dpi, one of the infected groups (IP) was treated with a single daily dose of an anthelmintic drug, Panacur, for three consecutive days while the other infected pigs remained untreated (IU). At necropsy, intestine tissue, serum and fecal samples were collected for untargeted metabolome analysis using UPLC-MS/MS and the fecal microbiota was characterized using full-length 16S rRNA gene-based sequencing with DADA2. Fecal and serum metabolites were categorized for their origin using MetOrigin. An integrated multi-omics analysis was performed using DIABLO algorithms and NetCoMi networking tools. Our results showed that A. suum worms were well developed in pigs from the IU group, which harbored a significantly reduced microbiota alpha diversity (Simpson, P < 0.005) compared with NU. The infection altered the abundance of at least 17 bacterial species/strains, including multiple butyrate-producing Clostridium spp., such as C. butyricum. The infection also dysregulated 51 fecal metabolites, including microbiota-derived metabolites such as glutaric acid and p-Cresol sulfate, and succinate of mixed origin. Moreover, the anthelmintic treatment was efficacious and eliminated all worms from the gut. Nevertheless, 11 pathways of both host and microbiota origin were significantly enriched in the gut of pigs from the IP group, including peptidoglycan biosynthesis, histidine metabolism (in both feces and serum), and primary bile acid biosynthesis, suggesting the infection-induced alterations may not be transient. In conclusion, the host microbiota modified swine-Ascaris interactions via three different mechanisms. First, microbiota-derived metabolites directly regulate host gene expression, which in turn affects host physiology and immune responses. Second, plasticity of the gut microbiota allows the exploitation of the niche differentiated upon infection, resulting in blossom of certain strains in the gut of post-treated animals. Lastly, the host microbiota is likely one of the key determinants of parasite gut microbiota, indirectly exerting its effect on parasite physiology and nutrition. Further studies aiming to understand reciprocal yet complex relations between the gut microbiota, the host, and parasites (including parasite gut microbiota) will be conducive to the design of next-generation functional anthelmintics.

Targeting maternal gut microbiome to improve mental health outcomes-a pilot feasibility trial.

Perinatal depression and anxiety (PDA) is prevalent in new and expectant mothers, affecting millions of women worldwide. Those with a history of mood and anxiety disorders are at the greatest risk of experiencing PDA in a subsequent pregnancy. Current safety concerns with pharmacological treatments have led to a greater need for adjunctive treatment options for PDA. Changes in the composition of the microbiome have been associated with various diseases during pregnancy, and these changes are thought to play some role in perinatal mood disorders. While the relationship between PDA and the microbiome has not been explored, evidence suggests that nutritional interventions with fiber, fish oils, and probiotics may play a favorable role in neuropsychiatric outcomes during and after pregnancy. The primary objective of the present study is to assess the feasibility and acceptability of a combination of nonpharmacological interventions to maintain stability in pregnant women who have a history of depression and/or anxiety. This study will also aim to understand ease of recruitment and protocol adherence in this cohort. This is a single-centered, partially randomized, placebo-controlled, double-blind feasibility trial. One hundred pregnant women with a history of depression and/or anxiety/PDA will be recruited and randomized into one of four arms, which could include the following: receiving a daily dose of both investigational products and dietary counseling on increasing dietary fiber, receiving a daily dose of both investigational drugs only, receiving fish oil investigational product and placebo, and a control arm with no intervention. The study involves six study visits, all of which can be conducted virtually every 3 months from the time of enrollment. At all study visits, information on diet, mental health, physical activity, and sleep quality will be collected. Additionally, all participants will provide a stool sample at each visit. It is anticipated that pregnant women with a history of depression and anxiety will be particularly interested in partaking in this trial, resulting in favorable recruitment rates. Given the positive findings of omega-3 fatty acids (O3FAs) and probiotic supplements on mental health symptoms in nonpregnant adults, we expect a similar trend in PDA symptoms, with a low likelihood of adverse events. This study will build the foundation for larger powered studies to further contribute evidence for the efficacy of this potential preventative treatment option. This trial was registered at ClinicalTrials/gov on October 6, 2023; NCT06074250. Trial Sponsor: The Canadian College of Naturopathic Medicine, 1255 Sheppard Ave E, Toronto, ON M2K 1E2, 416-498-1255.

Treatment with Sacubitril/Valsartan Effectively Manages Hypertension and Ameliorates Left Ventricular Hypertrophy in Hemodialysis Patients

Introduction: The aim of this study was to investigate the role of sacubitril/valsartan in managing hypertension and cardiac remodeling in patients undergoing hemodialysis. Methods: Hemodialysis patients with stable blood pressure control were enrolled in the study. Sacubitril/valsartan was prescribed to replace previously used angiotensin-converting enzyme inhibitor/angiotensin receptor blocker or other antihypertensive drugs. During a 6-month follow-up period, pre-dialysis blood pressure, routine biochemical markers, and N-terminal pro-brain natriuretic peptide levels were measured. Volume status was assessed using bioelectrical impedance analysis. Endothelial damage was evaluated by measuring asymmetric dimethylarginine expression, while echocardiography and life quality assessed by Short Form-12 Health Survey were conducted at baseline and after treatment. Results: The median daily dose of sacubitril/valsartan in 32 participants was 200 mg, and no obvious adverse reactions were reported. The defined daily dose of other antihypertensive drugs (baseline 2.00 ± 1.18, end point 1.46 ± 1.30, t = 3.216, p = 0.003) reduced significantly. After treatment with sacubitril/valsartan, left ventricular ejection fraction significantly increased from 64.81 ± 8.16% to 67.55 ± 5.85% (t = −4.022, p ≤ 0.001) and the thickness of posterior wall of the left ventricle reduced from 1.05 ± 0.14 cm to 1.00 ± 0.11 cm (t = 2.063, p = 0.048). The interventricular septal thickness (baseline 1.08 ± 0.16 cm, endpoint 1.02 ± 0.12 cm, t = 2.260, p = 0.031) remarkably reduced by the end of follow-up. The tricuspid regurgitation pressure gradient decreased from 28.47 ± 8.26 mm Hg at baseline to 23.79 ± 6.61 mm Hg (t = 2.531, p = 0.020) after treatment. Conclusion: Sacubitril/valsartan effectively manages hypertension in hemodialysis patients and may also independently improve left ventricular hypertrophy and systolic function, regardless of changes in the blood pressure or the volume load.

FEASIBILITY OF SUBTYPING OF PRIMARY ALDOSTERONISM BY ADRENAL VEIN SAMPLING DURING MINERALOCORTICOID RECEPTOR ANTAGONIST TREATMENT

Objective: Current guidelines and consensus documents recommend withdrawal of mineralocorticoid receptor antagonists (MRA) before primary aldosteronism (PA) subtyping by adrenal venous sampling (AVS), but this practice can cause severe hypokalemia and/or uncontrolled high blood pressure (BP) values in PA patients. The aim of the study was to investigate if identification of unilateral PA (uPA) by means of AVS is feasible in patients on MRA treatment. Design and method: We compared the rate of uPA identification between patients with and without MRA treatment in two large datasets of patients who were submitted to AVS from 2000 to 2023 without renin-angiotensin system blockers and beta-blockers. In sensitivity analyses, the between-groups differences of lateralization index (LI) values after propensity score matching and the rate of uPA identification in subgroups with undetectable (< 2 mUI/L), suppressed (< 8.2 mUI/L) and unsuppressed (> 8.2 mUI/L), direct renin concentration (DRC) levels were also evaluated. Results: A minority of the PA patients (n = 61, 7.3%) underwent AVS on MRA treatment, while the majority were off MRA (n = 779, 92.7%). Compared to non-MRA patients, those with MRA showed a higher daily drug dose (2.25 vs 1.5, p = 0.001), a higher rate of adrenal nodules at imaging (82 vs 67, p = 0.022) and of adrenalectomy (72 vs 54%, p = 0.01). The AUROC of lateralization index (LI) showed no significant differences between groups, either under unstimulated conditions (0.960 vs 0.937, p = 0.590) or after cosyntropin (0.923 vs 0.917, p = 0.938). Sensitivity analyses confirmed these results after propensity score matching in several adjusted models and in patients with undetectable, suppressed or unsuppressed renin levels. Conclusions: MRAs, at doses that controlled blood pressure and potassium levels in PA patients, did not preclude the identification of uPA at AVS.

Safety evaluation of 8 drug degradants present in over-the-counter cough and cold medications

Although the United States Food & Drug Administration (FDA) has provided guidance on the control of drug degradants for prescription drugs, there is less guidance on how to set degradant specifications for FDA OTC monograph drugs. Given that extensive impurity testing was not part of the safety paradigm in original OTC monographs, a weight of evidence (WOE) approach to qualify OTC degradants is proposed. This approach relies on in silico tools and read-across approaches alongside standard toxicity testing to determine safety. Using several drugs marketed under 21 CFR 341 as case studies, this research demonstrates the utility of a WOE approach across data-rich and data-poor degradants. Based on degradant levels ranging from 1 to 4% of the maximum daily doses of each case study drug and 10th percentile body weight data for each patient group, children were recognized as having the highest potential exposure relative to adults per body mass. Depending on data availability and relationship to the parent API, margins of safety (MOS) or exposure margins were calculated for each degradant. The findings supported safe use, and indicated that this contemporary WOE approach could be utilized to assess OTC degradants. This approach is valuable to establish specifications for degradants in OTCs.

Effect of CYP3A4/5, ABCB1 gene polymorphisms on the residual equilibrium concentration of apixaban and bleeding in patients with non-valvular atrial fibrillation and deep vein thrombosis

Effect of CYP3A4/5, ABCB1 gene polymorphisms on the residual equilibrium concentration of apixaban and bleeding in patients with non-valvular atrial fibrillation and deep vein thrombosis

Defined Daily Dose (DDD): An Essential Metric in the Antimicrobial Stewardship Programmes (AMSPs) in the Healthcare Sector

Antimicrobial stewardship programmes (AMSPs) decrease antimicrobial resistance, optimize usage of antimicrobials, and enhance patient outcomes. The Anatomical Therapeutic Chemical (ATC) is the foundation of the World Health Organization (WHO) global methodology, which groups the pharmacologically active substances of antimicrobials according to their therapeutic, pharmacological, and chemical characteristics and the organ or system on which they work. Since varied unit doses of daily administration of antimicrobials are prescribed, it is best to utilize a standard approach to measure antimicrobial intake. The Defined Daily Dose (DDD) is awarded to active ingredients with an active ingredient code currently in effect. It is the anticipated average daily maintenance dose of an antimicrobial drug or substances used for their primary indication in adults. The ATC/DDD approach was created to enhance patient care by tracking antimicrobial usage and conducting research. Healthcare facilities would benefit immensely from establishing an antimicrobial stewardship programme, and more research is required to determine the baseline of antimicrobial consumption in the country.

Dosage Optimisation of Trimethoprim and Sulfamethoxazole for the Treatment of an Avian Pathogenic Strain of Escherichia coli in Broiler Chickens.

Based on pharmacokinetic studies carried out according to the methodologies defined by the European Medicines Agency (EMA) using mass spectrometry analysis, a new formulation of a veterinary drug for the treatment of broiler chickens is proposed. Currently, the traditional trimethoprim-sulfamethoxazole drug used for broilers is applied in a 1:5 ratio, and the recommended dose is 45 mg kg-1 of live weight administered at 24 h intervals for 3 to 5 days. In this study, we propose a novel combination containing similar active substances in a newly established ratio of 1:4, with a recommended dosage of 20 mg kg-1 of live weight administered at 24 h intervals for 3 to 5 days. With this method, the currently recommended dose of the traditional trimethoprim-sulfamethoxazole drug used for broilers can be reduced by more than half. The efficacy of the newly designed formulation and dosage of the drug was verified in a bioassay for the treatment of broilers experimentally infected with an avian pathogenic strain of Escherichia coli. In the experiment, we compared the newly designed dosage with the traditional dosage in terms of efficacy and dosage. There were no statistically significant differences between the two drugs in efficacy regarding the survival of chickens after experimental infection or changes in their health status. The experimental results suggest that a significant reduction in the recommended daily dose of drugs containing trimethoprim and sulfamethoxazole for the treatment of bacterial infections in broilers is possible and can support the prudent use of antimicrobials, including the limitation of their overuse.

MANAJEMEN HIPERTENSI DENGAN TREATMENT NON-FARMAKOLOGI

Management of hypertension therapy must be carried out throughout life, both pharmacological and non-pharmacological therapy, to reduce the risk of complications and improve the quality of life of the elderly. This causes the need for assistance through providing education for elderly people who suffer from hypertension in order to achieve controlled blood pressure and reduce the symptoms of hypertension so that the risk of complications can be reduced. The design of this research is a systematic review. The search for articles discussed in this study used several databases, including Pubmed, Proquest, and ScienceDirect, with a time span of 2012 to 2022. The keywords used to search for these articles were hypertension management, hypertension treatment, non-pharmacological treatment. The type of article used is a research article. The articles collected were then re-selected using inclusion criteria, namely: 1) the aim of the article was to analyze the effectiveness of non-pharmacological treatment in hypertension management, 2) it was experimental research, as well as exclusion criteria, namely 1) it was not a full text article, 2) the article did not use English. Based on 23 selected articles, non-pharmacological interventions help reduce the daily dose of antihypertensive drugs and delay the progression from prehypertension to the hypertensive stage.

Vosoritide therapy in children with achondroplasia aged 3−59 months: a multinational, randomised, double-blind, placebo-controlled, phase 2 trial

Vosoritide is a recombinant C-type natriuretic peptide analogue that increases annualised growth velocity in children with achondroplasia aged 5-18 years. We aimed to assess the safety and efficacy of vosoritide in infants and children younger than 5 years. This double-blind, randomised, placebo-controlled, phase 2 trial was done in 16 hospitals across Australia, Japan, the UK, and the USA. Children younger than 60 months with a clinical diagnosis of achondroplasia confirmed by genetic testing and who had completed a baseline growth study or observation period were enrolled into one of three sequential cohorts based on age at screening: 24-59 months (cohort 1); 6-23 months (cohort 2); and 0-5 months (cohort 3). Each cohort included sentinels who received vosoritide to determine appropriate daily drug dose, with the remainder randomly assigned (1:1) within each age stratum (except in Japan, where participants were randomly assigned within each cohort) to receive daily subcutaneous injections of vosoritide (30·0 μg/kg for infants aged 0-23 months; 15·0 μg/kg for children aged 24-59 months) or placebo for 52 weeks. Participants, caregivers, investigators, and the sponsor were masked to treatment assignment. The first primary outcome was safety and tolerability, assessed in all participants who received at least one study dose. The second primary outcome was change in height Z score at 52 weeks from baseline, analysed in all randomly assigned participants. This trial is registered with EudraCT, 2016-003826-18, and ClinicalTrials.gov, NCT03583697. Between May 13, 2018, and March 1, 2021, 75 participants were recruited (37 [49%] females). 11 were assigned as sentinels, whereas 32 were randomly assigned to receive vosoritide and 32 placebo. Two participants discontinued treatment and the study: one in the vosoritide group (death) and one in the placebo group (withdrawal). Adverse events occurred in all 75 (100%) participants (annual rate 204·5 adverse events per patient in the vosoritide group and 73·6 per patient in the placebo group), most of which were transient injection-site reactions and injection-site erythema. Serious adverse events occurred in three (7%) participants in the vosoritide group (decreased oxygen saturation, respiratory syncytial virus bronchiolitis and sudden infant death syndrome, and pneumonia) and six (19%) participants in the placebo group (petit mal epilepsy, autism, gastroenteritis, vomiting and parainfluenza virus infection, respiratory distress, and skull fracture and otitis media). The least-squares mean difference for change from baseline in height Z score between the vosoritide and placebo groups was 0·25 (95% CI -0·02 to 0·53). Children with achondroplasia aged 3-59 months receiving vosoritide for 52 weeks had a mild adverse event profile and gain in the change in height Z score from baseline. BioMarin Pharmaceutical.

Abstract 17563: Serial ABPM, Antihypertensive Drug Treatment, and Pregnancy Outcomes in Women With Hypertension Found Early During Pregnancy

Introduction: Few data are available on serial ambulatory blood pressure monitoring (ABPM) throughout pregnancyand antihypertensive drug treatment required for good blood pressure (BP) control in hypertensivepregnant women. Hypothesis: Evaluation of BP control, antihypertensive drug treatment intensity, and pregnancy outcomes in patients with hypertension (HTN) found early during pregnancy. Methods: We studied 49 consecutive pregnant patients (mean age 33.4±4.8 years, BMI before pregnancy24.5±3.7 kg/m2) referred for office HTN found early during pregnancy who gave birth to 50 children (1 twin pregnancy) in 2011-2015. Gestational HTN was previouslydiagnosed in 39 women, and 9 women had a history of previous miscarriage or stillbirth, with multipleprevious pregnancies lost in some patients. ABPM was repeated at 5-10-15-20-25-30-33-35-37 weeksof pregnancy. We calculated overall antihypertensive treatment intensity in standard daily drug doses per patient (standard doses: labetalol 200 mg, methyldopa 750 mg, metoprolol 50 mg, nifedipine 20mg, verapamil 120 mg). Statistical analysis was performed using ANOVA. Results: All children were born alive (24 vaginal delivery, 26 cesarean section) and are well at follow-up.Gestational age was 38.0±2.5 (range 29-40) weeks, and birth weight was 3215±653g (range 955-4200). Preeclampsia/eclampsia occurred in 10/3 patients. Four patients had normal BP values by ABPM throughout pregnancy and did not receive antihypertensive drugs. Most patients were treatedwith labetalol and methyldopa. Throughout pregnancy, BP remainedwell controlled (24h mean SBP/DBP 120.3-126.0/75.3-77.1 mmHg), the number of treated patientsincreased from 25 at 5 weeks to 42 at 25-35 weeks, and the average number of daily antihypertensivedrug doses in treated pts increased from 1.82 at 5 weeks to 2.98 at 37 weeks. Conclusions: Serial ABPM-guided antihypertensive drug treatment started early during pregnancywas associated with favorable outcomes. The number of patients requiring treatment increased throughout the pregnancy. No physiological BP fall atthe end of 1 st trimester was observed. Our findings help estimate the expected treatment intensity required in pregnant patients with preexisting hypertension.

Study of the dynamics of the vitamin D level increase and the development of a method for calculating the required duration of cholecalciferol intake

Pandemic D-avitaminosis swept the planet. Among the inhabitants of the northern hemisphere, about 45 % are deficient, and 32 % have insufficient vitamin D serum levels. In Russia, the situation is even more tense: the level of deficiency was registered in 56.4 % of the population, and insufficiency in 27.87 % of our fellow citizens. Maintaining an optimal concentration of vitamin D in the blood serum reduces the risk and severity of autoimmune, cardiovascular diseases, many types of cancer, dementia, type 1 and 2 diabetes, respiratory tract infections, improves dental and oral health, and increases physical performance. The problem of the increased prevalence of vitamin D deficiency during pregnancy, which has serious consequences not only for the mother, but also for the child throughout later life, requires special attention. A review of the documents regulating the intake of vitamin D supplements suggests that there is some uncertainty in the instructions, which leads to a wide variability in medical recommendations to patients on the choice of the type of drug, its dosage and the duration of vitamin D intake. Recommendations on the required duration of vitamin D supplementation, in our opinion, look the most vulnerable and insufficiently substantiated, therefore, in this work, on the basis of international clinical practice, studies of the dynamics of the increment in the level of vitamin D were carried out and a method was developed for calculating the required duration of taking the most common vitamin D3 preparations at present. The analysis of domestic and foreign practice of increasing the level of vitamin D in the blood serum, as well as the conducted statistical studies, allow, with some caution, to draw the following conclusions. When taking vitamin D3 preparations, the increase in the level of 25(OH)D over time is quite correctly described by an exponential equation. As the duration of taking vitamin D3 preparations increases, the rate of increase in the level of 25(OH)D in the blood serum decreases. The current calcifediol level when taking in vitamin D3 preparations in asymptotical persons, is associated with a power-law dependence on the daily drug dose and increases as it increases. As shown by numerous results of clinical trials, the main increase in the level of 25(OH)D occurs within 30–90 days under different conditions. The multiple regression equation we obtained indicates that the time of blood serum saturation with vitamin D3 is inversely related to the daily dose of the drug, the patient’s age, and the initial level of 25(OH)D in the blood serum. The method developed by the authors makes it possible to estimate the dynamics of the increase in the level of 25(OH)D in the patient’s blood serum as vitamin D3 preparations are taken and to determine the required duration of the drug intake.

Effect of Bariatric Surgery on Metabolic Syndrome in Chinese Patients with Low Body Mass Index: a Propensity Score Matching Study.

Bariatric surgery (BS) is known to improve the components of metabolic syndrome (MS) in patients with obesity. However, few studies have evaluated the effect of BS on patients with MS at low BMI levels. The study aims to assess the effect of BS on MS in patients with low BMI by comparing BS with medical therapy(MT). A total of 271 patients with MS who underwent BS and MT at a single institution were reviewed in this retrospective cohort study. A 1:1 propensity score matching was performed for the BS and MT groups with BMI<35 kg/m2. We analyzed the 5 years effect of BS versus MT on the remission of MS, its components, atherosclerotic cardiovascular disease (ASCVD) risk, and medication used. Patients in the MT group showed a decrease in the prevalence of MS to 62% at the 1st year and 10% at the 5th year. In the BS group, MS prevalence in patients with BMI<35 kg/m2 decreased to 30% and 9% at the 1st and 5th year, whereas in patients with BMI≥35 kg/m2 was 26% and 7%, respectively. The 10-year ASCVD risk and the lifetime ASCVD were significantly decreased 5 years after BS in patients with BMI<35 kg/m2. The number and daily drug dose of hypoglycemic drugs, antihypertensive medications, and lipid-lowering drugs were reduced from baseline in both BS and MT groups. Bariatric surgery significantly improves MS remission rates and long-term cardiovascular risk in Chinese patients with metabolic syndrome and a BMI <35 kg/m2.

Artificial Neural Network Analysis of Determinants of Tacrolimus Pharmacokinetics in Liver Transplant Recipients.

The efficacy and toxicity of tacrolimus are closely related to its trough blood concentrations. Identifying the influencing factors of pharmacokinetics of tacrolimus in the early postoperative period is conducive to the optimization of the individualized tacrolimus administration protocol and to help liver transplant (LT) recipients achieve the target blood concentrations. This study aimed to develop an artificial neural network (ANN) for predicting the blood concentration of tacrolimus soon after liver transplantation and for identifying determinants of the concentration based on Shapley additive explanation (SHAP). In this retrospective study, we enrolled 31 recipients who were first treated with liver transplantation from the Department of Liver Transplantation and Hepatic Surgery, the First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital) from November 2020 to May 2021. The basic information, biochemical indexes, use of concomitant drugs, and genetic factors of organ donors and recipients were used for the ANN model inputs, and the output was the steady-state trough concentration (C0) of tacrolimus after oral administration in LT recipients. The ANN model was established to predict C0 of tacrolimus, SHAP was applied to the trained model, and the SHAP value of each input was calculated to analyze quantitatively the influencing factors for the output C0. A back-propagation ANN model with 3 hidden layers was established using deep learning. The mean prediction error was 0.27 ± 0.75 ng/mL; mean absolute error, 0.60 ± 0.52 ng/mL; correlation coefficient between predicted and actual C0 values, 0.9677; and absolute prediction error of all blood concentrations obtained by the ANN model, ≤3.0 ng/mL. The results indicated that the following factors had the most significant effect on C0: age, daily drug dose, genotype at CYP3A5 polymorphism rs776746 in both recipient and donor, and concomitant use of caspofungin. The predicted C0 value of tacrolimus in LT recipients increased in a dose-dependent manner when the daily dose exceeded 3 mg, whereas it decreased with age when LT recipients were older than 48 years. The predicted C0 was higher when recipients and donors had the genotype CYP3A5*3*3 than when they had the genotype CYP3A5*1. The predicted C0 value also increased with the use of caspofungin or Wuzhi capsule. The established ANN model can be used to predict the C0 value of tacrolimus in LT recipients with high accuracy and good predictive ability, serving as a reference for personalized treatment in the early stage after liver transplantation.

Early extubation in extracorporeal life support patients: a propensity score matched study.

Extubation strategy in extracorporeal life support patients remains unclear, and literature only reports studies with significant biases. To explore the prognostic impact of an early ventilator-weaning strategy in assisted patients after controlling for confounding factors. A 10-year retrospective study included 241 patients receiving extracorporeal life support for at least 48 hours, corresponding to a total of 977 days spent on assistance. The a priori probability of extubation for each day of assistance was calculated according to daily biological examinations, drug doses, clinical observations and admission data to pair each day containing an extubation with one on which the patient was not extubated. The primary outcome was survival at day 28. The secondary outcomes were survival at day 7, respiratory infections and safety criteria. Two similar cohorts of 61 patients were generated. Survival at day 28 was better in patients extubated under assistance in univariate and multivariate (HR=0.37[0.2-0.68], p-value=0.002) analyses. Patients who underwent failed early extubation did not have a different prognosis from those without early extubation. Successful early extubation was associated with a better outcome than a failed or no attempt at early extubation. Survival at day 7 and the rate of respiratory infections were better in early-extubated patients. Safety data did not differ between the two groups. Early extubation during assistance was associated with a superior outcome in our propensity-matched cohort study. The safety data were reassuring. However, due to the lack of prospective randomized studies, the causality remains uncertain.

Electrodermal measurement of acupuncture points for testing daily doses of sofosbuvir in patients with chronic hepatitis C virus infection

Acupuncture has been practiced widely for treating different medical conditions. The basis of the acupuncture method is the doctrine of acupuncture points, one of the features of which is their unique electrical properties on the measurement of which the methods of electropuncture diagnostics are based. The purpose of the study was to explore the possibilities of a medicament testing technique for determining daily doses of the antiviral drug Sofosbuvir and comparing the tested daily doses of Sofosbuvir with the level of viral load in the blood of patients with chronic hepatitis C virus infection. Medicament testing of Sofosbuvir was performed on two points of point of acupunctures. This pilot study included 61 patients diagnosed with chronic hepatitis C virus infection. Electrodermal measurement points of acupuncture of Liver meridian and EAV Circulation meridian and the correlation between tested doses of Sofosbuvir and viral load in the patients’ blood were analyzed. The points of acupuncture of Liver and EAV Circulation meridians demonstrated the possibility to apply them as measuring points to determine daily doses of Sofosbuvir. Patients with chronic hepatitis C virus infection showed a significant positive correlation between tested daily doses of Sofosbuvir and viral load, which was gradually lost with an increase in viral load. The mean values of the tested doses of Sofosbuvir did not vary in different PA and significantly differed depending on viral load. This study showed that points of acupuncture serve as a diagnostic window in a process of medicament testing and can help to determine the daily doses of the antiviral drugs and also serve as an indirect method for assessing the level of viral load in patients with chronic hepatitis C virus infection. There is the correlation between the tested doses of Sofosbuvir and viral load levels in these patients.

Prevalence and Risk Factors of Hydroxychloroquine Retinopathy in Rheumatic Patients with Dry Eye Symptoms

Purpose: Hydroxychloroquine is widely used for long-term treatment of rheumatic diseases, but the drug can trigger irreversible toxic retinopathy. We studied the prevalence of, and the risk factors for, hydroxychloroquine retinopathy in rheumatic patients with dry eye symptoms and we introduce a representative case.Methods: We retrospectively studied a cohort of 133 rheumatological patients who had taken hydroxychloroquine for at least 12 months and who visited our ophthalmology clinic with dry eye symptoms from April 2016 to December 2021. Hydroxychloroquine retinopathy was diagnosed via fundus photography, spectral-domain optical coherence tomography, the Humphrey visual field test, autofluorescence fundus photography, and multifocal electroretinography. The principal outcomes were the prevalence of retinopathy at the first screening and the risk factors.Results: Of the 133 patients, hydroxychloroquine retinopathy was diagnosed in seven (5.2%) at the first screenings. The Mann-Whitney U-test revealed that older age; higher daily doses; longer dosing duration; greater cumulative doses; and higher daily and cumulative doses/kg were statistically significant in terms of retinopathy development. On multivariate logistic regression analysis, the average daily dose (odds ratio [OR] 6.02; 95% confidence interval [CI] 1.64-22.12, 100 mg increments) and duration of dosing (OR 3.39; 95% CI 1.19-9.62, 5 years increments) remained statistically significant (P = 0.021, P = 0.007 respectively)Conclusions: Ophthalmologists should enquire about any history of hydroxychloroquine therapy, and perform a retinal examination, when encountering dry eye in patients with rheumatic disease. Early detection of hydroxychloroquine retinopathy followed by discontinuation of hydroxychloroquine is the only way to prevent visual loss. High daily drug doses and long dosing durations are risk factors for retinopathy.

Pharmacoeconomical affordability of antipsychotic drugs for patients with mental disorders in the structure of dementia at the regional level

Objective. To analyze the pharmacoeconomical affordability of antipsychotic drugs (APD) in patients with mental disorders in the structure of dementia at the level of the Gomel region of the Republic of BelarusMaterials and methods. The study used data from the State Register of Medicines of the Republic of Belarus (2022); Clinical Protocol for providing medical care to patients with mental and Behavioral Disorders (2010); website data https://myfin.by about the average pension amount and the minimum subsistence budget of the Gomel region for 2022; data from «State Register of Medicines of the Republic of Belarus» website. For the analysis, the price list for medicines (drugs) of the largest pharmacy chains in Belarus was used, which included the state pharmacies of the Gomel UP «Pharmacy» and commercial pharmacies of the well-known brands in Belarus «ADEL» and «Dobrya Leki». Parameters such as the price affordability of the APD and 4 availability coefficients (Cd) were determined, allowing to correlate the average cost of antipsychotic drugs packaging and the cost of the average daily dose of antipsychotic drugs with the consumer income, as well as the total affordability coefficient (Cd total.).Results. According to all criteria, the most economically affordable drug from the group of typical APD was the generic Haloperidol–Ozone (Ozon, Russia), and the least affordable from the group of atypical ones was the generic Olanzapine (Belmedpreparaty, Republic of Belarus).Conclusion. There is a large selection of APD on the pharmaceutical market of the Gomel region. Generic APD predominate on sale, which are more affordable compared to the original APD. But one should not forget about the advantages of the original drugs – efficiency, safety, innovativeness, reproducibility of the effect and strict quality control, confirmed in clinical trials. However, the genetic drug Olanzapine (Belmedpreparations, RB) is not in any way more superior in terms of affordability, but even inferior to some drugs. This study allowed us to establish that in the Gomel region of the Republic of Belarus, a patient with dementia is provided with a wide choice of APD and the ability to determine the criteria for preference when buying a specific drug.

Therapeutic drug monitoring of antipsychotic drugs in routine psychiatric practice

To evaluate the relationship between daily doses of antipsychotic drugs, their serum concentrations, and characteristics of patients treated for schizophrenia or schizophreniform disorder in day-to-day clinical practice. A total of 187 patients were included in the study, 77 (41.1%) patients were on monotherapy, and 110 (58.9%) patients received two or more antipsychotics. Patients age was 27.8±8.1 years, and their body weight was 79.8±15.6 kg. The sample was represented mainly by young men (93.0%). The proportion of smokers was 37.4%. The appropriate HPLC-MS/MS method was used for the simultaneous analysis of 8 antipsychotics and its active metabolites. Serum concentrations of the drugs aripiprazole (ARI), chlorpromazine (CPZ), haloperidol (HAL), zuclopenthixol (ZUC), clozapine (CLO), risperidone (RIS), quetiapine (QUE), olanzapine (OLA), norclozapine (N-desmethylclozapine, NOR), 9-hydroxyrisperidone (9-OH-RIS), dehydroaripiprazole (DGA) were measured. The serum concentration/dose ratio (C/D) was employed as the primary outcome measure, as doses were not kept constant during the study. The active antipsychotic fraction (drug+active metabolite, active moiety - AM) was also evaluated for RIS and ARI. In addition, the metabolite/parent ratio (MPR) was evaluated for RIS and ARI. A total of 265 biological samples were obtained, 421 and 203 measurements of the concentration of drugs and their metabolites were carried out, respectively. Overall, 48% of antipsychotics levels were in the expected therapeutic ranges, 30% were below therapeutic ranges, and 22% were above them. A total of 55 patients underwent dose adjustments or drug changes due to ineffectiveness or side-effects. It has been found that smoking reduces the level of C/D for CLO (p<0.01, Mann-Whitney test). We have established that comedication with CLO significantly increases the C/D ratio of QUE (p<0.05, Mann-Whitney test). We have not revealed any influence of weight and age of the subjects on the C/D. The dose-concentration regression relationships are formalized for all AP. Therapeutical drug monitoring (TDM) is an essential tool to personalize antipsychotic therapy. Careful analysis of TDM data can contribute significantly to the study of the impact of individual patient characteristics on systemic exposure to these drugs.