Third-line Drugs Research Articles

Association between incretin-based drugs and risk of cholangiocarcinoma among patients with type 2 diabetes: A large population-based matched cohort study

AimTo examine the association between the use of incretin-based drugs [glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP-4Is)] and the risk of cholangiocarcinoma (CCA) in the United States. MethodsThis large population-based, retrospective cohort study using the TriNetX datasets included adult patients with type 2 diabetes mellitus (T2DM) who were new users of GLP-1RAs, DPP-4Is, or other second- or third-line antidiabetic drugs between 2010 and 2021. The primary outcome was the incidence of CCA. ResultsA total of 3,816,071 patients were included (mean age, 61.4 years, female, 49.3 %). A 51 % and 23 % risk reduction in CCA after 1 year of exposure to GLP-1RAs (hazard ratio 0.49; 95 % CI 0.40–0.60) and DPP4Is (0.77, 95 % CI 0.67–0.90), respectively compared to new second-or third-line users. Results were consistent at 3, 5, and 7 years of follow-up (0.66, 0.71, and 0.72 for GLP-1RAs and 0.84, 0.87, and 0.85 for DPP-4Is, respectively). Compared to new metformin users, GLP-1RA users were associated with a 42 % lower risk of developing CCA, whereas DPP-4I group was not associated with an increased risk. ConclusionsGLP-1RAs and DPP-4Is were not associated with a significantly increased risk of CCA. GLP-1RAs even showed a reduced risk of CCA development. They can be considered as safe and effective treatment options for patients with T2DM at risk of CCA.

SAPHO syndrome in the mandible: A 17-patient-based experience

SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis) syndrome is a rare inflammatory bone disorder with a remarkably low incidence. The condition's impact on the mandible is exceptionally uncommon, often resulting in a high rate of misdiagnosis and an extended duration of illness. The objective of this study was to assess patients with SAPHO syndrome in the mandible in across various stages and to dissect their distinctive features, aiming to provide future clinical experience for the disease.Methods: A retrospective analysis was performed on a cohort of 17 patients diagnosed with SAPHO syndrome affecting the mandible at the Second Affiliated Hospital of Zhejiang University from January 2020 to March 2023. Data including clinical presentations, imaging characteristics, and laboratory results were collected.Results: The median age at disease onset was 25, with a diagnostic interval of 26 months. Notably, seven individuals were prepubescent (under the age of 14). Seven patients (41.18 %) exhibited polyostotic involvement, while eight patients (47.06 %) presented with dermatological manifestations either concurrently with or subsequent to the osseous lesions. Condyle involvement was identified in six patients (35.29 %), and bilateral mandibular affection was noted in an equivalent number. The majority of patients (sixteen patients, 94.12 %) reported symptomatic relief following treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). Glucocorticoids were instrumental in managing severe pain and extreme limitations in mouth opening. For patients with refractory disease, tumor necrosis factor-alpha (TNF-α) inhibitors, Janus kinase (JAK) inhibitors and bisphosphonates were employed. Ultimately, effective pain management was achieved in the entire cohort.Conclusion: The diagnosis of SAPHO syndrome involving the mandible is exclusionary. It is important to improve diagnostic accuracy among oral and maxillofacial surgeons (OMFS), dentists, and rheumatologists to avoid unnecessary surgery and tooth extraction. TNF-α inhibitors, JAK inhibitors and bisphosphonates are recommended as third-line drugs.

Enzalutamide Prolonged the Duration of Drug Use in Comparison to Abiraterone Acetate and Cabazitaxel after Upfront Docetaxel: A Large Japanese Database Study.

In the United States, a total of 268,490 men were found to have prostate cancer in 2022, thus making it the most common cancer in men, accounting for 27% of all cancers in the male population. Among all cancers in men, it was the fifth leading cause of death, with 34,500 deaths and a mortality rate of 11%. In 2019, the total number of cases was 94,748, making it the leading cancer in males, accounting for 11% of all male cancers. In terms of mortality, it ranked seventh, with 13,217 deaths and a mortality rate of 1.6%. However, new treatment options for metastatic castration-sensitive prostate cancer (mCSPC) have emerged. Docetaxel has been shown to be effective for both mCSPC and castration-resistant prostate cancer (CRPC). Upfront docetaxel has not been approved in Japan, nor has it been validated in large-scale studies. Furthermore, several agents can be used after docetaxel treatment, but it is unclear which is the most effective. We used a large Japanese health insurance database to determine which agent would be the most effective as a next-line therapy in patients who had received docetaxel. We used data from medical institutions using the Diagnosis Procedure Combination (DPC), which provides a comprehensive evaluation of medical classifications. The Medical Data Vision database covers approximately 23% of DPC hospitals in Japan. This study analyzed 2938 patients with mCSPC who received docetaxel, followed by CRPC, between April 2008 and December 2021. The study focused on three agents: enzalutamide, abiraterone acetate, and cabazitaxel. Other agents were excluded due to the small number of patients. The following data were analyzed: age, date of CRPC diagnosis, presence of bone metastasis, drug type, and prognosis. This study included 1997 patients with CRPC after upfront docetaxel therapy for mCSPC (enzalutamide [ENZ] group, n = 998; abiraterone acetate [ABI] group, n = 617; and cabazitaxel [CBZ] group, n = 382). The overall survival (OS) time from drug initiation was 456 days in the enzalutamide group, which was significantly longer than that in the cabazitaxel group (p = 0.017, HR 0.94) (ENZ: ABI p = 0.54, HR 0.94; ABI: CBZ p = 0.14, HR 0.75). OS was also compared for the third-line drug in the group that received enzalutamide as the second-line drug, the group that used abiraterone acetate as the third-line drug (ENZ-ABI group), and the group that used abiraterone acetate as the second-line drug. OS from the start of the third-line drug was compared between the ENZ-ABI group and the ABI-ENZ group, which received enzalutamide as the third-line drug, but showed no significant difference (269 vs. 281 days, p = 0.85; HR 1.03). ENZ was shown to prolong OS relative to cabazitaxel after the cessation of docetaxel. ENZ was associated with a longer duration of drug use than ABI and CBZ.

Factors Influencing Data Quality in Electronic Health Record Systems in 50 Health Facilities in Rwanda and the Role of Clinical Alerts: Cross-Sectional Observational Study.

Electronic health records (EHRs) play an increasingly important role in delivering HIV care in low- and middle-income countries. The data collected are used for direct clinical care, quality improvement, program monitoring, public health interventions, and research. Despite widespread EHR use for HIV care in African countries, challenges remain, especially in collecting high-quality data. We aimed to assess data completeness, accuracy, and timeliness compared to paper-based records, and factors influencing data quality in a large-scale EHR deployment in Rwanda. We randomly selected 50 health facilities (HFs) using OpenMRS, an EHR system that supports HIV care in Rwanda, and performed a data quality evaluation. All HFs were part of a larger randomized controlled trial, with 25 HFs receiving an enhanced EHR with clinical decision support systems. Trained data collectors visited the 50 HFs to collect 28 variables from the paper charts and the EHR system using the Open Data Kit app. We measured data completeness, timeliness, and the degree of matching of the data in paper and EHR records, and calculated concordance scores. Factors potentially affecting data quality were drawn from a previous survey of users in the 50 HFs. We randomly selected 3467 patient records, reviewing both paper and EHR copies (194,152 total data items). Data completeness was >85% threshold for all data elements except viral load (VL) results, second-line, and third-line drug regimens. Matching scores for data values were close to or >85% threshold, except for dates, particularly for drug pickups and VL. The mean data concordance was 10.2 (SD 1.28) for 15 (68%) variables. HF and user factors (eg, years of EHR use, technology experience, EHR availability and uptime, and intervention status) were tested for correlation with data quality measures. EHR system availability and uptime was positively correlated with concordance, whereas users' experience with technology was negatively correlated with concordance. The alerts for missing VL results implemented at 11 intervention HFs showed clear evidence of improving timeliness and completeness of initially low matching of VL results in the EHRs and paper records (11.9%-26.7%; P<.001). Similar effects were seen on the completeness of the recording of medication pickups (18.7%-32.6%; P<.001). The EHR records in the 50 HFs generally had high levels of completeness except for VL results. Matching results were close to or >85% threshold for nondate variables. Higher EHR stability and uptime, and alerts for entering VL both strongly improved data quality. Most data were considered fit for purpose, but more regular data quality assessments, training, and technical improvements in EHR forms, data reports, and alerts are recommended. The application of quality improvement techniques described in this study should benefit a wide range of HFs and data uses for clinical care, public health, and disease surveillance.

Нудота та блювання під час вагітності: огляд сучасних можливостей

Nausea and vomiting of pregnancy (NVP) are the most frequent and characteristic symptoms of pregnancy for the first trimester that potentially may cause substantial negative consequences for the physical and emotional health of a woman. According to various studies, from 50 to 90% of women suffer from NVP. Usually, the symptoms of NVP begin at 5-6 weeks after the last menstrual period and disappear in most cases by the 16th-20th week of pregnancy, but sometimes they persist and may be observed until the third trimester, and in rare cases - even until childbirth. The doctor's main task in providing assistance to a pregnant woman with NVP is the timely application of an adequate treatment strategy, both effective and safe for a mother and a fetus, as well as ensuring the highest achievable life quality for a woman. The aim of this article is to analyze modern management opportunities for pregnant women with NVP, including an assessment of the advantages and disadvantages of different treatment strategies, for a comprehensive understanding of the NVP problem and the main principles and ways for solving it. This review is based on national guidelines (updated Royal College of Obstetricians and Gynecologists (RCOG) Green-top clinical guideline 2024, Society of Obstetricians and Gynecologists of Canada (SOGC) Guideline 2016), the results of various studies, and review articles (database of the Cochrane Library, UpToDate, EMBASE, MEDLINE). Conclusion: a combination of pyridoxine and doxylamine can be prescribed for the prevention of NVP since the diagnosis of pregnancy in a high-risk group of women. In case of already existing symptoms of NVP, the objective assessment of complaints, as well as a response to the prescribed therapy, are facilitated by the unified scales. In most cases, lifestyle modification and first-line drug therapy effectively reduce the severity of NVP symptoms and improve a woman's quality of life. In case of insufficient response, other drugs are added to the treatment regimen, including second and third-line drugs, with a consideration of possible drug interactions. Some patients might need admission, and in addition to antiemetic therapy, they might need intravenous rehydration, electrolyte balance restoration, and thromboprophylaxis. The authors declare that there is no conflict of interest.

Survival benefit with regorafenib and/or trifluridine/tipiracil sequencing to rechallenge with anti-EGFR-based third-line regimens in metastatic colorectal cancer: A multicenter retrospective real-world subgroups comparison.

e15553 Background: Rechallenge with anti-EGFR drugs has recently proven therapeutic activity in a subset of RAS wild type (wt) metastatic colorectal cancer (mCRC) patients who had previously benefited from cetuximab- or panitumumab-based first-line regimen. Regorafenib (R) and Trifluridine/tipiracil (T) have been found to improve survival in patients with refractory mCRC. This real-life subgroup survival analysis focused on treatment with R and T, sequential or not, in patients who had received prior third-line anti-EGFR therapy. Methods: Clinical data of patients diagnosed with mCRC who received R and/or T between July 2012 and March 2022, were retrospectively collected from 13 Italian cancer institutes. The objective of this subgroup analysis was to compare overall survival (OS) and progression-free survival (PFS) in patients who received late-line R and/or T according to prior third-line anti-EGFR-based treatment. Results: The entire study enrolled 866 patients. 146 (16.8%) of them received the T/R sequence (T/R), 116 (13.3%) the reverse sequence (R/T), 325 (37.5%) T, and 279 (32.5%) R. For the purpose of this subgroup analysisi we identified 338 RAS wt patients (39%) who were eligible. Of these, 290/338 patients (85.8%) did not receive the previous third-line anti-EGFR therapy, while 48 patients (14.2%) did it (12 T/R, 10 R/T, 13 T, 13 R). When comparing T/R to R/T in patients who did not previously received third-line anti-EGFR drug rechallenge, we observed a statistically significant and clinically meaningful improvement in PFS. In detail, the median PFS benefit was 67,5% when treating patients with T/R sequence vs. the reverse sequence (11,4 vs. 3,7 months, respectively, ∆ = 7,7 months; p = &lt; 0,0001; HR = 0,17; 95% CI = 0,09-0,32). In patients who received T/R or R/T following rechallenge with anti-EGFR drug, we also observed a comparable, albeit smaller and non-statistically significant, improvement in PFS (8.1 vs. 7.8 months, respectively; p = 0.22; HR 0,51; 95% CI = 0,17-1,50). There were no statistically significant differences in OS between these groups. Anti-EGFR rechallenge data analysis showed that the non-sequential administration of R and T had no statistically significant impact on survival outcomes. Conclusions: With the limit of the sample size, our retrospective subgroup analysis failed to validate the promising beneficial effects of anti-EGFR rechallenge prior to R and/or T treatment. A statistically significant longer PFS was only observed in patients with refractory metastatic colorectal cancer receiving T/R sequence without prior cetuxumab- or panitumumab-based regimens.

Sodium-glucose cotransporter-2 inhibitors and the risk of atrial fibrillation in patients with type 2 diabetes: a population-based cohort study.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have a direct cardiac effect that is likely to be independent of its glucose lowering renal effect. Previous research has shown that SGLT2-is mitigate heart failure and prevent arrhythmic cardiac death. Our objective is to determine whether SGLT-2is reduce atrial fibrillation (AF) in comparison to other second-to third-line antidiabetic drugs in type 2 diabetes. We conducted a population-based, new-user active comparator cohort study using data from the UK Clinical Practice Research Datalink. We identified a cohort of patients initiating a new antidiabetic drug class between January 2013 and September 2020. This cohort included patients initiating their first ever non-insulin antidiabetic drug, as well as those who switched to or added-on an antidiabetic drug class not previously used in their treatment history. Individuals with a diagnosis of AF or atrial flutter at any time before cohort entry were excluded. Cox regression analysis with time-dependent covariates was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) of AF comparing SGLT-2-is with other second-line to third-line antidiabetic drugs. Stratified analyses were performed according to sex, diabetes duration (<5 or≥5 years), body mass index (BMI), HbA1c, and presence of heart failure.The cohort comprised 142447 patients. SGLT-2is were associated with a statistically significant reduced hazard of AF compared to other second-line to third-line antidiabetic drugs (adjusted HR: 0.77 [95% CI: 0.68-0.88]). This reduced risk was present in both sexes but was more prominently among women (adjusted HRwomen: 0.60 [95% CI: 0.45-0.79]; HRmen: 0.85 [95% CI: 0.73-0.98]; P-value interaction: 0.012). There was no evidence for effect modification when stratifying on duration of diabetes, BMI, HbA1c, or presence of heart failure. SGLT-2is were associated with a reduced risk of AF in patients with type 2 diabetes compared to other second-line to third-line antidiabetic drugs. This reduced risk occurs in both sexes but more prominently among women.

Abstract 557: Clofarabine inhibits U87MG glioblastoma cell line proliferation through CD99 signaling pathway

Abstract The present work aimed to test the efficacy of clofarabine in glioblastoma (GBM) cells that express high levels of CD99. GBMs are the most malignant with the poorest prognosis among tumors of the central nervous system. Patients have a median survival of 12 to 15 months despite surgical, radio, and chemotherapy. CD99 is a cell surface receptor overexpressed in several types of tumors, including GBMs, justifying the interest of studies in CD99 as a possible therapeutic target. Our group has previously demonstrated that knockout of CD99 in the U87MG GBM cell line promoted a decrease in cell adhesion, migration, and invasion. Clofarabine is a third-line drug used in the treatment of refractory/relapsed childhood acute lymphoblastic leukemia. It is a purine analog that is transported into intracellular space, phosphorylated, and incorporated into DNA chain, inhibiting DNA synthesis and ultimately inducing cell death by apoptosis. The clofarabine effect has also been demonstrated in cells from solid tumors, such as breast, gastric, and bladder. Clofarabine action on the proliferation of Ewing sarcoma cells in vitro and in vivo was proved to be by direct binding to CD99 and independent of the drug internalization. In addition, clofarabine also had an effect on cells from other tumor types that express CD99. The present work demonstrated the significant action of clofarabine on the high CD99-expressing U87MG cells by inhibiting cell proliferation, adhesion, and migration, and by inducing cell cycle arrest and apoptosis. U87MG cells knocked out for CD99 expression were more resistant to clofarabine action on proliferation. RNAseq analysis of U87MG cells treated with clofarabine and compared to control showed downregulated genes involved in cell cycle regulation and mitosis, while upregulated genes were enriched in extracellular proteins, cell adhesion, locomotion, p53 signaling pathway, and apoptosis. Our data indicates clofarabine as a potential CD99 inhibitor to treat GBM patients. Citation Format: Camila Cristina de Souza, Roseli da Silva Soares, Antonio Marcondes Lerario, Suely Kazue Marie, Sueli Mieko Oba-Shinjo. Clofarabine inhibits U87MG glioblastoma cell line proliferation through CD99 signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 557.

Efficacy and Safety of Anlotinib in EGFR-Positive Patients with Advanced Lung Adenocarcinoma Compared with Chemotherapy: A Retrospective Study.

There are no standard third-line or beyond treatments for patients with driver mutation-positive advanced lung adenocarcinoma (LUAD). Anlotinib was approved as a third-line multitarget drug in China in 2018. Limited data are available regarding the efficacy and safety of anlotinib compared with chemotherapy. To investigate the efficacy and safety of anlotinib compared with traditional chemotherapy in patients with epidermal growth factor receptor (EGFR)-positive advanced LUAD. We conducted a retrospective study of 83 EGFR mutation-positive patients with advanced LUAD between 2011 and 2022. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints, whereas the objective response rate (ORR) and disease control rate (DCR) were the secondary endpoints. Anlotinib-related adverse events (AEs) were recorded to evaluate the safety of anlotinib. 39 patients with LUAD received anlotinib and 44 patients with LUAD received chemotherapy were enrolled in the study. Patients treated with anlotinib exhibited longer PFS (11.2 vs 4.5 months, P < .01) and OS (18.8 vs 15.8 months, P < .05) than patients treated with chemotherapy. There were no significant differences in ORR (7.9% vs 20.5%, P = .129) or DCR (100% vs 93.2%, P = .120) between the two groups. Anlotinib-related AEs grading 3-4 level were observed in 2 (5.1%) patients, no anlotinib-related death was recorded. Cox regression analyses of PFS and OS showed that brain metastases and age < 30 years at diagnosis had negative effects on clinical outcomes. Anlotinib is effective and safe in patients with EGFR-positive advanced LUAD. Patients without brain metastases had better clinical outcomes.

Mycobacterial β-carbonic anhydrases: Molecular biology, role in the pathogenesis of tuberculosis and inhibition studies.

Mycobacterium tuberculosis (Mtb), which causes tuberculosis (TB), is still a major global health problem. According to the World Health Organization (WHO), TB still causes more deaths worldwide than any other infectious agent. Drug-sensitive TB is treatable using first-line drugs; treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB requires second- and third-line drugs. However, due to the long duration of treatment, the noncompliance of patients with different levels of resistance of Mtb to these drugs has worsened the situation. Previously developed anti-TB drugs targeted the replication machinery, protein synthesis, and cell wall biosynthesis pathways of Mtb. Therefore, novel drugs targeting alternate pathways crucial for the survival and pathogenesis of Mtb in the human host are needed. The genome of Mtb encodes three β-carbonic anhydrases (CAs) that are fundamental for pH homeostasis, hypoxia, survival, and pathogenesis. Recently, several studies have shown that the β-CAs of Mtb could be inhibited both in vitro and in vivo using small chemical molecules, suggesting that these enzymes could be novel targets for developing anti-TB compounds that are devoid of resistance by Mtb. In addition, homologs of β-CAs are absent in humans; therefore, drugs developed to target these enzymes might have minimal off-target effects. In this work, we describe the roles of β-CAs in Mtb and discuss bioinformatics and cheminformatics tools used in development and discovery of novel inhibitors of these enzymes. In addition, we summarize the in vitro and in vivo studies demonstrating that the β-CAs of Mtb are indeed druggable targets.

Trends and Differences in Status Epilepticus Treatment of Children and Adults Over 10 Years: A Comparative Study of Medical Records (2012-2021) from a University Hospital in Germany.

Over the last decade, significant advancements have been made in status epilepticus (SE) management, influenced by landmark trials such as ESETT and RAMPART. The objectives of this study were to explore the evolution of drug treatments for patients with SE, to investigate its association with outcomes and mortality, and to evaluate differences in treatment patterns between adults and children for a potential shift in medication trends due to the above mentioned trials. The medical records of patients with SE treated at University Hospital Frankfurt between 2012 and 2021 were evaluated for medication trends and outcomes. Children and adults were analyzed separately and jointly. This study included 1151 SE episodes in 1021 patients (mean age = 53.3 ± 28.3 years; 52.5 % female [n = 533]). The overall percentage of patients with SE treated prehospital was stable over the last decade. More than half (53.6 %) of children were treated prehospital, compared with less than one-third (26.7 %) of adults. Prehospital midazolam use increased over time, while diazepam use decreased. Lorazepam was the most commonly used benzodiazepine in hospitals in 2012-2013, used in 40.8 % of all episodes. However, its use declined to 27.2 % in 2020-2021, while midazolam use increased to 44.0 %. While the use of older antiseizure medications (ASMs) such as phenobarbital (p = 0.02), phenytoin (p < 0.001), and valproate (p < 0.001) decreased, the use of newer ASMs such as levetiracetam and lacosamide significantly increased (p < 0.001). Propofol and continuous midazolam infusion remained the most used third-line therapy drugs. Overall mortality was 16.5 % at discharge and 18.9 % at 30 days. Mortality rates did not change between 2012 and 2021. Midazolam has become the preferred benzodiazepine in pre- and in-hospital settings, both in children and adults. The same applies to the increased use of levetiracetam and lacosamide over time in children and adults, while phenobarbital, phenytoin, and valproate use decreased. Continuous midazolam infusion and propofol remain the most frequently used anesthetic drugs. Mortality and outcome remain stable despite changes in medication patterns.

Long-term outcomes of highly experienced people with HIV undergoing salvage therapy with raltegravir.

Raltegravir and other third-line drugs have shown promise in improving outcomes in treatment-experienced patients. However, the efficacy and tolerability of these agents vary. This study assessed real-life virologic success, long-term survival, and adverse events in patients receiving raltegravir or other third-line drugs as salvage regimens. This retrospective cohort study included adults who experienced treatment failure (human immunodeficiency syndrome-1 RNA plasma viral load >1000 copies/mL) and subsequently initiated raltegravir or other third-line drugs (darunavir/ritonavir, maraviroc, or etravirine). Propensity score matching methods were employed to account for differences at the time of switching from failing antiretroviral therapy regimens. The matched subset was analyzed using the Kaplan-Meier method and Generalized Wilcoxon tests to evaluate the probability of achieving virologic suppression (plasma viral load <50 copies/mL). Mortality rates, toxicity, treatment interruption, virologic failure, and loss to follow-up were determined using Poisson regression. One hundred and sixty-eight patients initiating salvage regimens were included, with 123 receiving raltegravir and 45 other third-line drugs. Propensity score matching resulted in a subset of 90 patients, 45 in each group. During the follow-up period, there were no significant differences observed between the groups in terms of virologic suppression (77.8% vs 82.2%, P = .73), mortality rates (4.04 vs 6.18 persons per 100 person-years [p-y]; P = .67), drug toxicity (0.00 vs 2.06 persons per 100 p-y; P = .49), treatment interruption (8.07 vs 0.00 persons per 100 p-y; P = .06), virologic failure (2.02 vs 4.12 persons per 100 p-y; P = .61), and loss of follow-up (6.05 vs 4.12 persons per 100 p-y; P = .70). Our findings indicate comparable survival and virological success rates between raltegravir and other drugs used in salvage regimens. Similar rates of drug toxicity, treatment interruption, virologic failure, and loss of follow-up were also observed. These results suggest that raltegravir may be a viable option for salvage therapy, demonstrating outcomes comparable to other third-line drugs in real life.

Refractory and super-refractory status epilepticus and evidence for the use of ketamine: a scope review

Status epilepticus (SE) is a neurological emergency with serious consequences for neuronal tissues, therefore, it is considered the most serious manifestation of epilepsy. The response to treatment, its evolution time and duration, and the need to use one or more antiseizure drugs define SE as refractory or super-refractory. Ketamine has been used in SE management since the 90s when an article describing its use in treating SE was published. Since then, at least 24 publications have reported the use of ketamine for the treatment of SE in both adult and pediatric patients. This scoping review seeks to synthesize information on the use of drugs in super-refractory SE, specifically ketamine. Twenty articles were chosen for the final document construction. Few studies have investigated the use of ketamine in refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE). Most of the information comes from retrospective case series studies, mostly with small sample sizes, and although the information is heterogeneous, it points to the efficacy of ketamine as a third-line drug in RES and SRSE, in controlling seizures.

The Downregulation of Opioid Receptors and Neuropathic Pain

Neuropathic pain (NP) refers to pain caused by primary or secondary damage or dysfunction of the peripheral or central nervous system, which seriously affects the physical and mental health of 7-10% of the general population. The etiology and pathogenesis of NP are complex; as such, NP has been a hot topic in clinical medicine and basic research for a long time, with researchers aiming to find a cure by studying it. Opioids are the most commonly used painkillers in clinical practice but are regarded as third-line drugs for NP in various guidelines due to the low efficacy caused by the imbalance of opioid receptor internalization and their possible side effects. Therefore, this literature review aims to evaluate the role of the downregulation of opioid receptors in the development of NP from the perspective of dorsal root ganglion, spinal cord, and supraspinal regions. We also discuss the reasons for the poor efficacy of opioids, given the commonness of opioid tolerance caused by NP and/or repeated opioid treatments, an angle that has received little attention to date; in-depth understanding might provide a new method for the treatment of NP.

Psoriasiform lesions as a side effect of SGLT-2 therapy

SGLT-2 inhibitors (flozins) are one of the new classes of anti-diabetic drugs, used from 2012. They are highly recommended in case of intolerance or contraindication of metformin, but in Poland they are used usually as third-line drug after metformin and sulfonylurea. They growing popularity is caused by their significance in cardiovascular risk reduction and preventive role in according to diabetes complications like chronic kidney disease, or diabetes-induced dementia. The aid of this article is to summarize the knowledge on the risk of psoriasis development in diabetic patients cured with flozins.&#x0D; In according to the newest studies, flozins may be considered as a pro-psoriatic factor, increasing the risk of this skin disease, especially in patients with diabetic kidney disease. But on the other hand, SGLT-2 inhibitors have significantly decreasing effect on cardiovascular risk, which is increased in psoriatic patients.

Comparative evaluation of effect of various means of basic and genetically engineered biological therapy on clinical course, rate of development of osteodestructive changes, quality of life and state of stress resistance in patients with rheumatoid arthritis (open observational study)

Objective. To study the effect of various basic and genetic engineering biological therapies (infliximab, rituximab, tocilizumab) used as first, second- and third-line drugs in combination with methotrexate on clinical course, quality of life (QOL), and the evolution of articular erosions and synovitis in patients with rheumatoid arthritis (RA) during 12 months of follow-up.Material and methods. This paper is an open observational study of the efficacy and safety of various basic and genetic engineering biological therapy agents (bDMARD) in patients with early active RA who are in the Mechnikov North-West State Medical University registry. Included are 151 patients with early RA (eRA), the average age is 58.2 ± 5.5 years, the disease duration is 6.5 ± 0.3 months, DAS 28-CRP – 4.48 ± 0.87. At the first stage, basic therapy was administered to patients with eRA by random sampling: sulfasalazine (CC) 2 g per day (group I – 55 patients), methotrexate (MT) – 20 mg per week (group II – 55 patients), or leflunomide (LF) 20 mg per day (group III – 41 patients). The follow-up was 12 months. At the second stage, 101 patients with persisting moderate (DAS 28: 3.2–5.1) and high levels of RA activity (DAS 28 &gt; 5.1) despite ongoing therapy with DMARDs were assigned MT at a dose of 25 mg per week (subgroup 1–25 patients), or MT – 20 mg per week in combination with infliximab (INF) – 3 mg/kg (subgroup of 2–25 patients), or – MT 20 mg per week and rituximab (RM) – two infusions of 1000 mg at the week 0 and 2 and then at the week 52nd and 54th with a duration of observation of 12 months. In the third stage, 20 patients (16 women and 4 men aged 28 to 67 years) with a high disease activity DAS 28-CRP despite previous therapy with MT and INF or RM were transferred to therapy with an IL6 – tocilizumab receptor blocker as a second-line or third-line drug. The duration of observation ranged from 6 months to five years.Results. By 12 months of treating DMARDs, clinical remission was achieved more often in the MT group than in the LF group (43.2 and 32.4 %) (p &lt; 0.05), and was accompanied by a decrease in the expression of markers of early activation of T-lymphocytes, IL-1β, IL-2 and IL-4. In the SS group, clinical remission was not observed, while there was a significant increase in the median of the total Sharpe score and erosion score relative to the baseline. The prescription of INF or PM as the first bDMARD after 12 months led to a significant increase in the physical and psychological components of the patients' QL and positive dynamics of the HAQ index compared to baseline values. The use of tocilizumab as a second-line and third-line drug in patients with active RA and the ineffectiveness of previous therapy for DMARD and bDMARD contributed to a significant decrease in DAS 28-CRP by as early as 24 weeks of follow-up. Cases of serious adverse reactions (AE) are not marked.Conclusions. There were no statistically significant differences in the dynamics of CRP, ESR, circulating immune complex and X-ray progression indicators between the groups of patients who received biological therapy of INF and RM, which confirms the possibility of ‘switching’ therapy from the first bDMARD to the drugs of subsequent lines with an increase in the clinical activity of RA. Tocilizumab can be a second- and third-line drug with an ‘escape’ effect from other bDMARDs.

Ein Update zur Leishmaniose des Hundes: Diagnostik, Therapie und Monitoring

Canine infections with Leishmania (L.) infantum are gaining significance in Germany due to rising numbers of dogs imported from endemic countries, frequent travel and changing of climatic conditions in Central Europe. Dogs without any clinical signs suspicious for vector-borne infections imported from other countries to Germany should be tested immediately after import and 6 months later. In dogs with clinical signs suspicious for leishmaniosis, direct and indirect detection methods of the pathogen as well as hematology, biochemistry, serum protein electrophoresis and C-reactive protein are recommended. For treatment and monitoring of canine leishmaniosis, the LeishVet-guidelines are highly recommended. Different therapeutic options include first-line, second-line, and third-line drugs. For dose adjustments of allopurinol, the "step plan" should be taken in consideration. Due to climatic changes, habitats of sandflies as transmitting vectors of leishmaniosis are expanding. Next to vectorial transmission mating, transplacental infections, bite wounds, and blood transfusions were described in canine leishmaniosis. Additionally, L. infantum is a zoonotic vector-borne infectious pathogen, which is important regarding the "One-health"-aspect.

Drug-Resistant Tuberculosis Types and Their Treatment Regimens Using First-Line, Second-Line Injectable, Third-Line, Fluoroquinolones, Aminoglycosides, Cyclic Polypeptides, Novel and Repurposed Anti-Tuberculosis Drugs

Drug-Resistant Tuberculosis (DR-TB) causes high mortality and morbidity rates globally. DR-TB and COVID-19 pandemic are posing a major risk to global public health and economic security, and are jeopardizing efforts in the control, prevention and elimination of TB globally. Mycobacterium tuberculosis (MTB) has continued to evolve resistance to anti-TB drugs. Different types of DR-TB have been defined and they include; mono drug-resistant TB, Multi Drug-Resistant TB (MDR-TB), poly drug-resistant TB, pre-Extensively Drug-Resistant TB (pre-XDR TB), Extensively Drug-Resistant TB (XDR-TB), Extremely Drug-Resistant TB (XXDR-TB), and Totally Drug-Resistant TB (TDR-TB). DR-TB is caused by several factors which include: non-adherence, poor compliance, low efficacy anti-TB drugs, delayed diagnosis, interrupted supply, stock-outs, inadequate infection control, HIV co-infection, spontaneous mutations, and chromosomal replication errors. Global TB targets have gone off-track and years of progress reversed due to DR-TB and the COVID-19 pandemic. Treatment failure, death and costs incurred are higher among patients suffering from DR-TB than among those with susceptible TB. For this reason, susceptible TB needs to be diagnosed quickly and treated effectively to prevent its progression to DR-TB. Treatment for susceptible TB requires the use of first-line anti-TB drugs; rifampicin, isoniazid, pyrazinamide, and ethambutol. While DR-TB is treated using the second- and third-line anti-TB drugs. Effective treatment of TB is dependent on: prompt and accurate diagnosis of TB and recognition of drug-resistance; adherence to treatment; robust contact tracing and prophylactic treatment of TB contacts; and screening for TB infection in high-risk groups.

Use of sodium-glucose cotransporter-2 inhibitors and the risk for sudden cardiac arrest and for all-cause death in patients with type 2 diabetes mellitus.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are antidiabetic agents that can have direct cardiac effects by impacting on cardiac ion transport mechanisms that control cardiac electrophysiology. We studied the association between SGLT-2i use and all-cause mortality and the risk of sudden cardiac arrest (SCA) in patients with type 2 diabetes. Using data from the UK Clinical Practice Research Datalink, a cohort study among patients initiating a new antidiabetic drug class on or after January 2013 through September 2020 was conducted. A Cox regression with time-dependent covariates was performed to estimate the hazard ratios (HRs) of SCA and all-cause mortality comparing SGLT-2is with other second- to third-line antidiabetic drugs. Stratified analyses were performed according to sex, diabetes duration (<5 or ≥5 years), and the presence of cardiovascular disease. A total of 152 591 patients were included. Use of SGLT-2i was associated with a reduced HR of SCA when compared with other second- to third-line antidiabetic drugs after adjustment for common SCA risk factors, although this association marginally failed to reach statistical significance [HR: 0.62, 95% confidence interval (95% CI): 0.38-1.01]. The HR of all-cause mortality associated with SGLT-2i use when compared with other second- to third-line antidiabetics was 0.43 (95% CI: 0.39-0.48) and did not vary by sex, diabetes duration, or the presence of cardiovascular disease. SGLT-2i use remained associated with lower all-cause mortality in patients without concomitant insulin use (HR: 0.56, 95% CI: 0.50-0.63). SGLT-2i use was associated with reduced all-cause mortality in patients with type 2 diabetes. The association between use of SGLT-2i and reduced risk of SCA was not statistically significant.

Efficacy and Safety of Apatinib in Advanced Hepatocellular Carcinoma: A Multicenter Real World Retrospective Study.

Background and Purpose: Apatinib is a novel antiangiogenic agent that can target vascular endothelial cell growth factor 2. The aim of our study was to evaluate the efficacy and safety of apatinib mesylate in the treatment of advanced hepatocellular carcinoma (HCC) in the real world. Methods: We retrospectively analyzed 178 patients with advanced HCC who had been treated with apatinib mesylate from January 2017 to March 2020. The primary outcome indexes were progression-free survival (PFS) and overall survival (OS), and the secondary outcome indexes were overall response rate (ORR), disease control rate (DCR), and incidence of treatment-related adverse reactions. Results: Univariate analysis showed that patients with third-line treatment (p <0.001), alpha fetoprotein (AFP) ≥400 ng/ml (p <0.05), distant metastasis (p <0.05), portal vein tumor thrombus (PVTT) (p <0.05), and apatinib monotherapy (p <0.001) had shorter survival. Multivariate analysis confirmed that third-line drugs, PVTT, and combination therapy were independent prognostic factors for PFS in all patients. Univariate analysis showed that Eastern Cooperative Oncology Group (ECOG) scores (p <0.05), line of apatinib (p <0.001), AFP (p <0.001), tumor progression (p <0.05), PVTT (p <0.05), and combination therapy (p <0.001) may impact the OS. Multivariate analysis proved that AFP, PVTT, and combination therapy were independent prognostic factors for OS. The most common adverse reactions were secondary hypertension (29.21%), symptoms of fatigue (16.85%), hand and foot syndrome (16.29%), vomiting (14.04%), liver dysfunction (6.18%), and proteinuria (6.74%). Most of the adverse reactions were Grade 1 or 2. Conclusion: Apatinib mesylate is an effective treatment for advanced HCC, and its adverse reactions are relatively mild. Line of apatinib, PVTT, AFP level, and combination therapy were independent prognostic factors for patients with advanced HCC who were treated with apatinib.