Efficacy Of Drug Treatment Research Articles

Baohuoside I inhibits resistance to cisplatin in ovarian cancer cells by suppressing autophagy via downregulating HIF-1α/ATG5 axis.

Since chemotherapy's therapeutic impact is diminished by drug resistance, treating ovarian cancer is notably challenging. Thereafter, it is critical to develop cutting-edge approaches to treating ovarian cancer. Baohuoside I (derived from Herba Epimedii) is reported to have antitumor properties in various malignancies. It is unknown, however, what role Baohuoside I plays in cisplatin (DDP)-resistant ovarian cancer cells.3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT), colony formation, and flow cytometry assay were used to investigate the impact of Baohuoside I on ovarian cancer A2780 cells and DDP-resistant A2780 (A2780/DDP) cells. The level of microtubule associated protein 1 light chain 3 (LC3) was determined using immunofluorescence staining. Utilizing the mRFP-GFP-LC3B tandem fluorescent probe allowed us to analyse the autophagy flux. Analysis of mRNA and protein level was performed using RT-qPCR and Western blot analysis, respectively. The interaction between hypoxia inducible factor 1 subunit alpha (HIF-1α) and autophagy related 5 (ATG5) promoter was investigated by dual luciferase and ChIP assay. Additionally, evaluation of Baohuoside I's role in ovarian cancer was performed using a nude mouse xenograft model.Baohuoside I decreased the viability and proliferation and triggered the apoptosis of both A2780 and A2780/DDP cells in a concentration-dependent manner. Baohuoside I also increased the sensitivity of A2780/DDP cells to DDP. Concurrently, HIF-1α could promote A2780/DDP cells resistance to DDP. In addition, HIF-1α could induce the autophagy of A2780/DDP cells through transcriptionally activating ATG5, and Baohuoside I imporved the chemosensitivity of A2780/DDP cells to DDP by downregulating HIF-1α. Moreover, Baohuoside I could inhibit the chemoresistance to DDP in ovarian cancer in vivo.Baohuoside I sensitizes ovarian cancer cells to DDP by suppressing autophagy via downregulating the HIF-1α/ATG5 axis. Consequently, Baohuoside I might be evaluated as a new agent for enhancing the chemotherapeutic efficacy of drug treatment for ovarian cancer.

Effect of clinical pharmacists participating in nutritional therapy for patients with acute cerebral infarction complicated with dysphagia.

To explore the effect of clinical pharmacists participating in nutritional therapy for patients with acute cerebral infarction (ACI) complicated with dysphagia. This is a Clinical comparative study. A total of 82 patients with ACI complicated with dysphagia treated in Baoding No.1 Central Hospital from May 2021 to February 2022 were included as subjects. They were divided into control group (n= 40, without clinical pharmacists) and experimental group (n= 42, with clinical pharmacists) using a random number table. The effect of nutritional therapy and the incidence of adverse reactions were compared between the two groups. In the experimental group, PALB and ALB were both higher than those in the control group on the seven and 14-day after treatment (p< 0.05), while HB was higher than that in the control group only on the 14-day after treatment (p< 0.05). After treatment for 14-day, MAMC and TSF in the experimental group were higher than those in the control group (p< 0.05), while NIHSS score was lower than that in the control group (p< 0.05). The incidence of adverse events in the experimental group was lower than that in the control group (p< 0.05). Pharmaceutical intervention in nutritional therapy for patients with ACI complicated with dysphagia has positive significance in further improving the nutritional status and nutritional indexes, enhancing the efficacy of drug treatment and reducing the risk of adverse events, and is worthy of promotion.

The Role of Natural Products in the Improvement of Cancer-Associated Cachexia.

The enormous library of natural products and herbal medicine prescriptions presents endless research avenues. However, the lack of research evidence and trials on cancer-induced cachexia limit the therapeutic potential of natural products. Cancer-induced cachexia is a systemic wasting syndrome characterized by continuous body weight loss with skeletal muscle and adipose tissue atrophy. Cancer cachexia is a problem in itself and reduces the quality of life by lessening the treatment efficacy of anticancer drugs. This review summarizes single natural product extracts for cancer-induced cachexia, not compounds derived from natural products and herbal medicine prescriptions. This article also discusses the effect of natural products on cachexia induced by anticancer drugs and the role of AMPK in cancer-induced cachexia. The article included the mice model used in each experiment to encourage researchers to utilize animal models for research on cancer-induced cachexia in the future.

Quantitative comparison of the efficacy of clinical drug treatments for primary progressive multiple sclerosis

ObjectiveThis study proposes a comprehensive quantitative evaluation of the efficacy of drugs and placebo in clinical trials for primary progressive multiple sclerosis (PPMS). MethodsA literature search was conducted using the PubMed, EMBASE, and Cochrane library databases and the clinical studies reporting drug efficacy in the treatment of PPMS were included in the analyses. The cumulative proportion of patients without confirmed disability progression (wCDP%) was used as the main efficacy endpoint. The model-based meta-analysis method was used to describe the time course of each drug (as well as placebo) in order to rank the drug efficacy for the treatment of PPMS. ResultsFifteen studies involving 3779 patients were included, of which, nine were placebo-controlled and six were single-arm trials. Twelve drugs were included in the study. The results showed that, except for biotin, interferon β-1a, and interferon β-1b, whose efficacy was comparable to the placebo, the efficacy of the other 9 drugs were significantly better than placebo. Among these, ocrelizumab showed outstanding performance, with wCDP% of 72.6 at 96 weeks, while the proportions of rest of the drugs ranged between approximately 55–70%. ConclusionThe results of this study provide the necessary quantitative information for both the rational clinical use of drugs and future clinical trials in primary progressive multiple sclerosis.

Evaluation of serum VIP and aCGRP during pulmonary exacerbation in cystic fibrosis: A longitudinal pilot study of patients undergoing antibiotic therapy.

Objective monitoring of improvement during treatment of pulmonary exacerbation can be difficulty in children when pulmonary function testing cannot be obtained. Thus, the identification of predictive biomarkers to determine the efficacy of drug treatments is of high priority. The major aim of the current study was to investigate the serum levels of vasoactive intestinal peptide (VIP) and alpha calcitonin gene related peptide (aCGRP) of cystic fibrosis pediatric patients during pulmonary exacerbation and post-antibiotic therapy, and possible associations of their levels with different clinicopathological parameters. 21 patients with cystic fibrosis were recruited at onset of pulmonary exacerbation. Serum was collected at time of admission, three days post-antibiotic therapy, and two weeks post-antibiotic therapy (end of antibiotic therapy). Serum VIP and aCGRP levels were measured using ELISA. Overall least square means of serum aCGRP level but not VIP changed from time of exacerbation to completion of antibiotic therapy (p = 0.005). Serum VIP was significantly associated with the presence of diabetes mellitus (p = 0.026) and other comorbidities (p = 0.013), and with type of antibiotic therapy (p = 0.019). Serum aCGRP level was significantly associated with type of antibiotic therapy (p = 0.012) and positive Staphylococcus aureus microbiology test (p = 0.046). This study could only show significant changes in serum aCGRP levels following treatment of pulmonary exacerbations. Future studies with larger sample size are required to investigate the clinical importance of VIP and aCGRP in cystic fibrosis patients.

Intrathecal chemotherapy combined with systemic therapy in patients with refractory leptomeningeal metastasis of non-small cell lung cancer: a retrospective study

BackgroundLeptomeningeal metastasis (LM) is the most devastating complication of non-small cell lung cancer (NSCLC), and its incidence is increasing. There is currently no standard treatment for LM, and the efficacy of traditional intravenous drug treatment is low, making refractory LM a difficult problem. In this study, we evaluated the efficacy and safety of intrathecal chemotherapy (IC)-based regimens in patients with refractory LM.MethodsWe retrospectively enrolled NSCLC patients with confirmed LM who received IC and systemic therapy at the Second Affiliated Hospital of Nanchang University from December 2017 to July 2022. We analysed overall survival (OS), intracranial progression-free survival (iPFS), clinical response, and safety in these patients.ResultsA total of 41 patients were enrolled. The median number of IC treatments was seven (range: 2–22). Seven patients received intrathecal methotrexate, and 34 patients received intrathecal pemetrexed. Clinical manifestations related to LM improved after IC and systemic therapy in 28 (68.3%) patients. The median iPFS in the whole cohort was 8 months (95% confidence interval [CI]: 6.4–9.7 months), and the median OS was 10.1 months (95% CI: 6.8–13.4 months). Multivariate analysis of the 41 patients with LM using a Cox proportional risk model showed that bevacizumab was an independent prognostic factor in patients treated with combination therapy (p = 0.002; hazard ratio [HR] 0.240; 95% CI: 0.097–0.595). Poor ECOG performance status remained a significant predictor of poor prognosis for survival (p = 0.048; HR 2.560; 95% CI: 1.010–6.484). Myelosuppression was the major adverse event over all IC dose levels. There were 18 cases of myelosuppression, 15 cases of leukopenia, and nine cases of thrombocytopenia. Eleven patients had myelosuppression above grade 3, including four with thrombocytopenia and seven with leukopenia.ConclusionsCombination therapy based on IC had good curative effects, was safe to use, and was associated with prolonged survival in NSCLC patients with LM. The use of bevacizumab is a good prognostic factor for NSCLC LM patients with combination therapy.

Application of nanotechnology in reversing therapeutic resistance and controlling metastasis of colorectal cancer.

Colorectal cancer (CRC) is the most common digestive malignancy across the world. Its first-line treatments applied in the routine clinical setting include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, resistance to therapy has been identified as the major clinical challenge that fails the treatment method, leading to recurrence and distant metastasis. An increasing number of studies have been attempting to explore the underlying mechanisms of the resistance of CRC cells to different therapies, which can be summarized into two aspects: (1) The intrinsic characters and adapted alterations of CRC cells before and during treatment that regulate the drug metabolism, drug transport, drug target, and the activation of signaling pathways; and (2) the suppressive features of the tumor microenvironment (TME). To combat the issue of therapeutic resistance, effective strategies are warranted with a focus on the restoration of CRC cells' sensitivity to specific treatments as well as reprogramming impressive TME into stimulatory conditions. To date, nanotechnology seems promising with scope for improvement of drug mobility, treatment efficacy, and reduction of systemic toxicity. The instinctive advantages offered by nanomaterials enable the diversity of loading cargoes to increase drug concentration and targeting specificity, as well as offer a platform for trying the combination of different treatments to eventually prevent tumor recurrence, metastasis, and reversion of therapy resistance. The present review intends to summarize the known mechanisms of CRC resistance to chemotherapy, radiotherapy, immunotherapy, and targeted therapy, as well as the process of metastasis. We have also emphasized the recent application of nanomaterials in combating therapeutic resistance and preventing metastasis either by combining with other treatment approaches or alone. In summary, nanomedicine is an emerging technology with potential for CRC treatment; hence, efforts should be devoted to targeting cancer cells for the restoration of therapeutic sensitivity as well as reprogramming the TME. It is believed that the combined strategy will be beneficial to achieve synergistic outcomes contributing to control and management of CRC in the future.

Abstract 2674: Synergistic combinations of lurbinectedin with irinotecan and ONC212 in pancreatic cancer

Abstract Pancreatic cancer is a devastating disease with a five-year survival rate below 10% according to the American Cancer Society. Novel chemotherapeutics and targeted therapies in pancreatic cancer have shown limited success, illustrating the urgent need for new treatments. Lurbinectedin is a chemotherapeutic synthetic tetrahydroisoquinoline alkaloid that inhibits active transcription by binding to guanine rich sequences in the minor groove of DNA. Lurbinectedin has been shown to reduce oncogenic transcription by stalling and degrading RNA Polymerase II while also inducing single- and double-stranded breaks to DNA, causing subsequent apoptosis. Lurbinectedin received accelerated FDA approval in 2020 for metastatic small cell lung cancer on or after platinum-based chemotherapy and is currently undergoing clinical trials in a variety of tumor types. We recently described a synergistic interaction between lurbinectedin and ONC201/TIC10, a compound that induces the TRAIL pathway, in killing SCLC cell lines associated with activation of p-Chk1 and the integrated stress response. We now demonstrate lurbinectedin’s efficient killing of pancreatic tumor cells as a single agent in PANC-1, BxPC-3, and HPAF-II cell lines, with IC-50s corresponding to sub-nanomolar concentrations. We also demonstrate that a combination of lurbinectedin and irinotecan, a topoisomerase I inhibitor with FDA approval for advanced pancreatic cancer, results in synergistic killing of pancreatic tumor cells in vitro. We further demonstrate a combination of lurbinectedin and ONC212, an imipridone, the same class of compounds as ONC201, also results in synergistic killing of pancreatic tumor cells. Cell viability was measured using the CellTiterGlo assay at varying drug concentrations. We hypothesize a combination therapy of lurbinectedin and irinotecan or ONC212 can enhance immune cell killing of pancreatic tumor cells. This is being explored by co-culturing CD8+ T lymphoblast cells with pancreatic tumor cells treated with lurbinectedin, irinotecan, ONC212, and combination, along with molecular mechanisms of cell death and effects on cytokines in the tumor microenvironment. Our results are developing insights regarding molecular mechanisms underlying therapeutic efficacy of a novel combination drug treatment for pancreatic cancer. Citation Format: Tej Tummala, Arielle De La Cruz, Ash Uruchurtu, Nicholas R. Liguori, Abbas E. Abbas, Leiqing Zhang, Christopher G. Azzoli, Lanlan Zhou, Wafik S. El-Deiry. Synergistic combinations of lurbinectedin with irinotecan and ONC212 in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2674.

Abstract 3242: Efficacy evaluation by novel humanized mouse models for preclinical study of ADCs combined with immunotherapy

Abstract Antibody-drug conjugates (ADCs) are effective anti-tumor therapies with high specificity, with little toxicity and side effects. Xenograft tumor models based on immunodeficient mice have been used for evaluating the human anti-tumor efficacy of ADCs. However, the antibody-mediated immune response of ADCs is not well evaluated in immunodeficient mice. To this end, we have developed BALB/c-hPD1 humanized mouse model to evaluate the efficacy of ADCs in combination with immunotherapy. Trastuzumab deruxtecan (T-DXd, DS-8201a) is a HER2-targeting ADC. In vitro efficacy studies showed that T-DXd effectively bound to the HER2-positive cell line SK-BR-3, resulting in strong endocytosis and induction of apoptosis. It has also been shown to kill HER2-negative MDA-MB-468 cells through a bystander effect both in vitro and in vivo. In vivo efficacy studies have demonstrated that ADCs can effectively inhibit human tumor cell growth in immunodeficient mice. In addition to human tumor cell lines, the efficacy of ADCs was also studied in BALB/c-hPD1mice engrafted with murine colon cancer cells model, and the results showed that T-DXd and Keytruda could significantly inhibit CT26-hHER2 tumor growth, with the tumor growth inhibition rates being 57% and 66%, respectively, Tumor growth inhibition rate of the combined treatment group was about 91%, which was superior compared to the efficacy of single drug treatment. The evaluation of Fc segment-mediated effect (such as ADCC, CDC and ADCP) of ADCs antibodies was carried out in humanized immune system mouse models, such as NCG-hIL15 and NCG-hSGM3. In summary, we have established a drug evaluation platform using various humanized mouse models to study the synergistic anti-tumor effects of ADCs combined with immune checkpoint blockade antibodies. Citation Format: Fang Zhu, Hongyan Sun, Qian Lu, Yuan Fang, Jianming Xu, Cunxiang Ju, Hongyu Wang, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao. Efficacy evaluation by novel humanized mouse models for preclinical study of ADCs combined with immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3242.

Comparison of Pronase versus Manual Dechorionation of Zebrafish Embryos for Small Molecule Treatments.

Zebrafish are a powerful animal model for small molecule screening. Small molecule treatments of zebrafish embryos usually require that the chorion, an acellular envelope enclosing the embryo, is removed in order for chemical compounds to access the embryo from the bath medium. For large-scale studies requiring hundreds of embryos, manual dechorionation, using forceps, can be a time-consuming and limiting process. Pronase is a non-specific protease that is widely used as an enzymatic alternative for dechorionating zebrafish embryos. However, whether pronase treatments alter the effects of subsequent small molecule treatments has not been addressed. Here, we provide a detailed protocol for large-scale pronase dechorionation of zebrafish embryos. We tested whether pronase treatment can influence the efficacy of drug treatments in zebrafish embryos. We used a zebrafish model for Duchenne muscular dystrophy (DMD) to investigate whether the efficacies of trichostatin-A (TSA) or salermide + oxamflatin, small molecule inhibitors known to ameliorate the zebrafish dmd muscle degeneration phenotype, are significantly altered when embryos are treated with pronase versus manual dechorionation. We also tested the effects of pronase on the ability of the anthracycline cancer drug doxorubicin to induce cardiotoxicity in zebrafish embryos. When comparing pronase- versus forceps-dechorionated embryos used in these small molecule treatments, we found no appreciable effects of pronase on animal survival or on the effects of the small molecules. The significant difference that was detected was a small improvement in the ability of salermide + oxamflatin to ameliorate the dmd phenotype in pronase-treated embryos when compared with manual dechorionation. Our study supports the use of pronase treatment as a dechorionation method for zebrafish drug screening experiments.

Drug treatment efficacy in 32 children with streptococcal toxic shock syndrome

To study the efficacy of different drug treatment regimens in children with streptococcal toxic shock syndrome (STSS). Clinical data of children diagnosed with STSS confirmed by bacterial culture and treated in Hunan Children's Hospital and Chenzhou First People's Hospital from January 2009 to April 2023 were retrospectively collected. The efficacy of different drug treatment regimens was analyzed. The children were divided into four groups based on the treatment regimens: standard group (regimens containing penicillin), Group A (carbapenem + glycopeptides/linezolid), Group B (carbapenems, broad-spectrum antibiotics, glycopeptides/linezolid used alone or in combination, excluding the regimens in Group A), and Group C (macrolides/not receiving antimicrobial drugs). A total of 32 cases of STSS were included. Antimicrobial susceptibility testing showed that all strains were sensitive to beta-lactam antibiotics such as ampicillin and vancomycin, while resistant to clindamycin, erythromycin, and tetracycline. There was a statistically significant difference in the efficacy rate among the four groups (P<0.05). The standard group exhibited the highest efficacy rate (100%), while the efficacy rates for Group A, Group B, and Group C were 40%, 40%, and 0%, respectively. The use of antimicrobial regimens containing penicillin can improve the therapeutic efficacy of STSS in children.

Proteomics reveals that cell density could affect the efficacy of drug treatment

In vitro cell biology study plays a fundamental role in biological and drug development research, but the repeatability and accuracy of cell studies remain to be low. Various uncertainties during the cell culture process could introduce bias into drug research. In this study, we evaluate the potential effects and underlying mechanisms induced by cell number differences in the cell seeding process. Normally, drug experiments are initiated 24 h after cell seeding, and the difference in the cell number at the time of inoculation leads to the difference in cell confluence (cell density) when drug research is conducted. While cell confluence is closely related to intercellular communication, surface protein interaction, cell autocrine as well as paracrine protein expression of cells, it might have a potential impact on the effect of biological studies such as drug treatment. This study used proteomics technology to comprehensively explore the different protein expression patterns between cells with different confluences. Due to the high sensitivity and high throughput of liquid chromatography-mass spectrometry (LC-MS/MS) detection, it was hired to evaluate the protein expression differences of Hep3B cells with 3 different confluences (30%, 50%, and 70%). The differential expressed proteins were analyzed by the Reactome pathway and the Gene Ontology (GO) pathway. Significant differences were identified across three confluences in terms of the number of proteins identified, the protein expression pattern, and the expression level of certain KEGG pathways. We found that those proteins involved in the cell cycle pathway were differently expressed: the higher the cell confluence, the higher these proteins expressed. A cell cycle inhibitor palbociclib was selected to further verify this observation. Palbociclib in the same dose was applied to cells with different confluence, the results indicated that the growth inhibition effect of palbociclib increases along with the increasing trend of cell cycle protein expression. The result indicated that cell density did influence the effect of drug treatment. Furthermore, three other drugs, cisplatin, paclitaxel, and imatinib, were used to treat the three liver cancer cell lines Hep3B, SUN387, and MHCC97, and a similar observation was obtained that drug effect would be different when the cell confluences were different. Therefore, selecting an appropriate number of cells for plating is vitally important at the beginning of a drug study.

A rapid multiplex assay of human malaria parasites by digital PCR

BackgroundBlood smear examination through traditional optical microscopy is the gold standard for malaria diagnosis. However, it imposes strict requirements for operational staff and its sensitivity cannot perfectly satisfy the needs of clinical requirements. More sensitive and accurate modern technologies should be applied to this field. Digital PCR (dPCR), as an absolute quantification detection method, can serve as an effective tool to facilitate the diagnosis and classification of different malaria species. ObjectiveWe aimed to establish a new multiplex dPCR detection system for four main Plasmodium species: P. vivax, P. falciparum, P. ovale and P. malariae, which can distinguish exact species of malaria by one PCR reaction. MethodsA total of 39 patients were identified as malaria-positive by microscopic examination in Huashan Hospital from 2016 to 2021; seventy blood samples from these patients were collected. Additionally, 20 healthy individuals, 20 patients with fever and 6 patients with other types of blood parasites infection were also included in this study. Each blood sample was subjected to examination by both blood smears and dPCR. By optimizing four different fluorescence-labeled probes in one reaction system, dPCR permitted the performance of accurate quantitation and working out the exact number of copies of malaria DNA per microliter in whole blood. Rapid diagnostic tests were also conducted to verify part of the results obtained by dPCR. ResultsThe dPCR system was able to make rapid diagnosis and quantification of malaria DNA samples. The analytical sensitivity of multiplex dPCR was as low as 0.557 copies/μL (95% CI 0.521 to 0.607), and it had a sensitivity of 98.0% and a specificity of 100% in clinical samples. Additionally, three multiple malaria co-infection samples have been detected by this dPCR system, including one triple malaria infection case. By testing consecutive daily blood samples of Patient 39, dPCR facilitated monitoring the efficacy of drug treatment. It showed that the DNA concentrations of P. falciparum ranged from 5474 copies/μL to 0 copies/μL, which can reflect the efficacy of antimalarials in real time. This study also found that haemocyte samples (plasma removed) rather than whole blood had higher malaria detection capability and an enhanced positive rate. ConclusionThe multiplex dPCR system newly established here made a substantial contribution in detecting malaria infection at low concentrations. It is suitable for mixed-infection diagnosis and multi-sample continuous monitoring, and presents a promising candidate as an absolute quantitative tool in clinical practice.

The Prevalence and Control of Lungworms of Pastoral Ruminants in Iran.

Lungworms of the genera Dictyocaulus, Muellerius, Protostrongylus, and Cystocaulus are common helminths of domestic and wild ruminants with substantial veterinary and economic importance. Several studies have assessed the presence and prevalence of lungworm infections in ruminants in Iran. This report compiles the available scientific information about the occurrence of lungworms in domestic and wild ruminants in Iran between 1931 and June 2022 to give an insight into their epidemiology, and where possible to describe drug treatment efficacy. For this purpose, national and international scientific databases were searched. Overall, 54 publications comprising 33 articles in peer-reviewed journals, 8 conference papers, and 13 dissertations were evaluated regarding prevalence data; and an additional 4 peer-reviewed articles were evaluated regarding drug efficacy. Seven species of lungworms, namely Dictyocaulus filaria, Dictyocaulus viviparus, Dictyocaulus eckerti, Protostrongylus rufescens, Protostrongylus raillietti, Muellerius capillaris, and Cystocaulus ocreatus have been recorded from different ruminant hosts in Iran. Thirty-three studies conducted on small ruminant (sheep and goat) lungworms reported prevalences of lungworm infection of 11.6%, 45.81% and 66.29% using abattoir meat inspection, Baermann technique and fecal flotation, respectively. Eight studies conducted on large ruminants (cattle and water buffalo) reported prevalences of infection of 14.83%, 13.98% and 5% using abattoir meat inspection, the Baermann technique and fecal flotation, respectively. The prevalence of infection in wild ruminants was variable across examined species; 38% in urial, 37% in wild goats, 5% in goitered gazelles and 67% in red deer, in addition to a single case report in roe deer. There are few contemporary studies assessing the efficacy of currently available broad-spectrum anthelmintic compounds against lungworms in Iran. The high prevalence of multiple lungworm species in Iran, combined with a lack of information about drug efficacy, supports the need to improve the understanding of these important nematode parasites and inform the development of sustainable control strategies. The aim of this review and meta-analysis is to provide a baseline for future conventional parasitology and next generation molecular epidemiological studies of lungworm infection in pastoral ruminants in Iran.

Thermosensitive In Situ Gels for Joint Disorders: Pharmaceutical Considerations in Intra-Articular Delivery.

The intra-articular administration of conventional drug solutions or dispersions in joint diseases such as osteoarthritis has a relatively short retention time and, therefore, limited therapeutic effect. Thermosensitive polymer solutions that exhibit a sol-gel phase transition near body temperature after injection can prolong drug retention by providing a depot from which the drug release is sustained while relieving inflammation and preventing degradation of the joint complex. Thermosensitive hydrogels have in recent times garnered considerable attention in the intra-articular therapeutics of joint diseases such as osteoarthritis. Among the stimuli-responsive gelling systems, most research has focused on thermosensitive hydrogels. These gels are preferred over other stimuli-sensitive hydrogels since they have well-controlled in situ gelling properties and are also easier to load with drugs. Temperature-sensitive polymers, such as block copolymers or poloxamers, are frequently used to modify their gelation properties, usually in combination with other polymers. They are compatible with most drugs but may pose formulation challenges in terms of their low-response time, highly fragile nature, and low biocompatibility. The stability and biodegradability of implant hydrogels can control the drug release rate and treatment efficacy. This review stresses the application of thermosensitive gels in joint disorders and summarizes recent developments for intra-articular application, including the incorporation of nanoparticles. The hydrogel composition, drug release mechanisms, and the challenges involved in their formulation and storage are also discussed.

Identifying critical transitions in major depression with fuzzy recurrence entropy

ABSTRACT Detection of mood changes can be useful for the efficacy of drug treatment of psychiatric disorders in major depression. This paper presents an approach for detecting major time points of mood transitions under the influence of antidepressants. These time points, which are indicated by critical fluctuations in time series, can be discovered using change point detection and time-frequency analysis of fuzzy recurrence entropy of mood data. The mood transitions identified by the fuzzy recurrence entropy agree with results that were clinically validated and reported in literature. The proposed approach can detect early mood transitions in a fully objective way that does not require the manual analysis of fluctuations in the signal dynamics.

Modeling the effect of different drugs and treatment regimen for hookworm on cure and egg reduction rates taking into account diagnostic error.

BackgroundHookworm infections, caused by Ancylostoma duodenale and Necator americanus, are of considerable public health importance. The World Health Organization recommends preventive chemotherapy as the key strategy for morbidity control. Meta-analyses have been conducted to estimate treatment efficacy of available drugs and drug combinations. However, in most studies, the relation between the diagnostic error and infection intensity have not been considered, resulting in an overestimation of cure rates (CRs).MethodologyA Bayesian model was developed to compare the ‘true’ CR and egg reduction rate of different treatment regimens for hookworm infections taking into account the error of the recommended Kato-Katz thick smear diagnostic technique. It was fitted to the observed egg count data which was linked to the distribution of worms, considered the day-to-day variation of hookworm egg excretion and estimated the infection intensity-dependent sensitivity. The CR was obtained by defining the prevalence of infection at follow-up as the probability of having at least one fertilized female worm. The model was applied to individual-level egg count data available from 17 treatments and six clinical trials.Principal findingsTaking the diagnostic error into account resulted in considerably lower CRs than previously reported. Overall, of all treatments analyzed, mebendazole administered in six dosages of 100 mg each was the most efficacious treatment with a CR of 88% (95% Bayesian credible interval: 79-95%). Furthermore, diagnostic sensitivity varied with the infection intensity and sampling effort. For an infection intensity of 50 eggs per gram of stool, the sensitivity is close to 60%; for two Kato-Katz thick smears it increased to approximately 76%.Conclusions/significanceOur model-based estimates provide the true efficacy of different treatment regimens against hookworm infection taking into account the diagnostic error of the Kato-Katz method. Estimates of the diagnostic sensitivity for different number of stool samples and thick smears are obtained. To accurately assess efficacy in clinical trials with the Kato-Katz method, at least two stool samples on consecutive days should be collected.

Gene panel to guide antiseizure medication prescribing: Does the cost justify the benefits?

Pharmacogenomics hold the potential to identify variants associated with adverse drug reactions and treatment efficacy of anti-seizure medications. A model-based cost-utility analysis by Gordon and colleagues showed that genetically-guided therapy costs more, yielded higher quality-adjusted life years outcomes, and was considered to be cost-effective compared to usual care. The study provided preliminary evidence on the value of pharmacogenetic testing in patients with drug-resistant epilepsy. However, data input for the model was based on assumptions that need to be empirically tested. Further, there are many other factors that may affect the cost-effectiveness of pharmacogenetic testing that need to be considered, including the model of service delivery, its implementation in complex clinical service, whether clinicians will modify treatment decisions based on pharmacogenetic information, and the fidelity with which recommendation on testing is adhered to in the real-world. The cost-effectiveness analysis should be repeated when more robust data on the effectiveness of pharmacogenetics are available and conducted alongside a budget impact analysis, incorporating the direct health care resources required to implement widespread testing and potential subsequent changes in treatment.

Severe drug-induced liver injury (DILI) associated with benznidazole therapy for Chagas' disease.

Chagas’ disease (CD), a neglected tropical disease caused by Trypanosoma cruzi, endemic in Latin America and sporadic in many parts of the world, affects 6–7 million people.1 Although the efficacy of drug treatment of late-stage CD remains uncertain,2 it is expected to prevent severe cardiac, intestinal and/or neurological complications. Since 1970, only two drugs have been available for CD treatment: benznidazole and nifurtimox. Benznidazole is highly metabolized by the liver.3 Both drugs are associated with a high rate of drug discontinuation due to side effects, such as skin reactions, leucopenia and neuropathy. A mild elevation of transaminases is sometimes observed. Discontinuation of benznidazole due to serious toxic effects is rarely necessary, and adverse effects usually disappear when treatment is stopped.4–6 Here we describe the case of a patient treated with benznidazole for CD who developed severe liver toxicity. A 68-year-old woman who was born in El Salvador and migrated in Italy in 2010, taking levetiracetam (500 mg twice per day) for epilepsy, was diagnosed in June 2021 with chronic CD according to WHO criteria. The disease staging did not reveal organ involvement. Liver ultrasonography showed a mild hyperechogenic structure.

Gut reactions: emerging mechanisms of abdominal pain from food intake.

Abdominal pain, which is a form of visceral pain, is a highly prevalent symptom worldwide frequently occurring following food ingestion. Its pathophysiology is complex, and many factors, including intestinal environmental cues, the immune system, or the molecular composition of foods, can influence the development of postprandial abdominal pain. Because of the poor efficacy of drug treatments, current strategies are often limited to the exclusion of culprit food(s) from the diet. However, there are two important limitations to this approach. First, patients suffering from food-induced abdominal pain usually recognize several food items as the cause of their gastrointestinal symptoms. Second, not all offending foods can always be identified by these patients. Newly identified mechanisms involving neuroimmune interactions and their communication with the intestinal microbiota shed light on the development of new therapeutic strategies. In this Mini-Review, these novel mechanisms and relevance of such findings are highlighted.