Lack Of Efficacy Research Articles

Ginsenoside Compound K Alleviates Brain Aging by Inhibiting Ferroptosis through Modulation of the ASK1-MKK7-JNK Signaling Pathway

Background: Aging of the brain is a major contributor to the onset and progression of neurodegenerative diseases. Conventional treatments for these diseases are often limited by significant side effects and a lack of efficacy in halting disease progression. Ginsenoside compound K (CK), a bioactive secondary metabolite derived from ginseng, has shown promise because of its potent antioxidant properties. Purpose: This study aimed to elucidate the molecular mechanisms underlying the impact of CK on brain senescence, with a particular focus on its role in modulating oxidative stress and related signaling pathways. Methods: We employed a d-galactose (D-gal)-induced PC-12 senescent cell model and a mouse brain aging model to explore the antioxidant properties of CK in the context of brain aging. The effects of CK on mitochondrial dysfunction associated with brain aging were assessed using immunofluorescence and western blotting techniques. The potential molecular mechanisms by CK influences brain aging were investigated using transcriptomic analysis and western blotting. Additionally, CK's regulatory effect on apoptosis signal-regulating kinase 1 (ASK1) was validated by molecular docking, microscale thermophoresis, and small interfering RNA transfection. Results: Our findings demonstrate that CK effectively alleviates cognitive decline associated with brain aging. CK reduces the number of senescent cells, alleviates neuronal damage, and enhances the activity of key antioxidant enzymes, including catalase, superoxide dismutase, and glutathione peroxidase. Additionally, CK restores mitochondrial function and upregulated the expression of solute carrier family 7 member 11 and glutathione peroxidase 4, thereby inhibiting ferroptosis. Furthermore, CK targets ASK1 and suppresses the hyperphosphorylation of MAPK kinase 7 (MKK7) and c-Jun N-terminal kinase (JNK). This suppression promotes the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), effectively reducing ferroptosis and oxidative damage linked to brain aging. Conclusion: In summary, our research demonstrates that CK effectively delays brain aging by inhibiting the ASK1-MKK7-JNK signaling pathway, enhancing nuclear Nrf2 expression, and suppressing the ferroptosis response. These findings highlight CK as a promising therapeutic agent for slowing brain aging and alleviating neurodegenerative diseases.

Does wearing facemasks during small animal surgery reduce the incidence of surgical site infections?

Question In small animals undergoing theatre-based surgical procedures does having all theatre personnel masked, compared with not having all theatre personnel masked, result in a reduced incidence of surgical site infections? Clinical bottom line The category of research question was: Incidence. The number and type of study designs that were critically appraised were: Zero. No records relevant to the PICO question were retrieved from the literature search. Critical appraisal of the selected papers meeting the inclusion criteria collectively provide zero/weak/moderate/strong evidence in terms of their experimental design and implementation: Zero. The outcomes reported are summarised as follows… There is no published evidence specific to small animals that assesses the effect of wearing facemasks during surgical procedures on the rate of postoperative surgical site infections. In view of the strength of evidence and the outcomes from the studies the following conclusion is made… In small animals undergoing theatre-based surgical procedures, there is no published evidence evaluating the effect of having all theatre personnel masked compared with not having all theatre personnel masked on the incidence of surgical site infections. However, this lack of evidence should not be interpreted as lack of efficacy.

Effectiveness and safety analysis of ketogenic diet therapy for drug-resistant epilepsy caused by structural pathology.

To explore the effectiveness and safety of the ketogenic diet (KD) in children with drug resistant epilepsy (DRE) caused by structural etiology. The children were categorized into acquired brain injury group and malformations of cortical development (MCD) group based on the etiology. Follow-up assessments were performed at 1, 3, and 6 months after KD treatment to observe seizure reduction, behavioral and cognitive improvements, adverse reactions events, and reasons for discontinuation withdrawal. Statistical analysis was conducted on the results. We found the seizure-free rates at 1, 3, and 6 months were 4.8% (2/42), 19% (8/42), and 21.4% (9/42), respectively. The seizure control effective rates were 42.9% (18/42), 52.4% (22/42), and 54.8% (23/42) at the corresponding time points. Compared to the acquired brain injury group, the MCD group showed a higher seizure control effective rate. Further analysis within the MCD group revealed the highest efficacy in focal cortical dysplasia (FCD). At the 3-month follow-up, cognitive and behavioral improvements were observed in 69% (29/42) of children. The main reasons for discontinuation were lack of efficacy and poor compliance. Finally, we get that KD is a safe and effective treatment for drug resistant epilepsy caused by structural etiology, with the added benefit of improving behavioral and cognitive abilities in children. The efficacy is higher in children with MCD, particularly in cases of FCD. Early intervention with KD is recommended for this population.

Treatment patterns for advanced therapies in Canadians with moderate-to-severe inflammatory bowel disease: a retrospective cohort analysis

Abstract Many patients with inflammatory bowel disease (IBD) show an inadequate response or experience a loss of response to advanced therapies. Guidelines recommend dose optimization and switching among therapies until an optimal treatment response is attained. With several advanced treatments available, we aimed to evaluate the persistence of different therapeutic sequences in IBD. The RECORDED study was a retrospective cohort study of Canadians with moderate-to-severely active ulcerative colitis (UC) or Crohn’s disease (CD) who had been exposed to more than 1 advanced therapy between May 2015 and April 2021 for UC, and May 2016 and April 2021 for CD. The primary endpoint was time to permanent discontinuation of the first advanced treatment. Overall, 330 patients had CD and 344 had UC. The most common first-line treatments for CD and UC were adalimumab and infliximab, respectively. The median (95% CI) time to permanent discontinuation of first-line treatment was 12.3 (10.9, 13.6) months in patients with CD and 9.2 (8.2, 10.8) months for those with UC. The most common reason for treatment change across both diseases was lack of efficacy. First-line advanced treatments were optimized in 191 (58.1%) CD patients and 202 (59.1%) UC patients prior to permanent discontinuation. Second-line therapy was typically from a different class compared with the first-line treatment choice. The RECORDED study provides insights into the real-world sequencing and optimization patterns of advanced treatments in patients with moderate-to-severe IBD in Canada. Lack of efficacy was the most cited reason for switching to a different therapy.

Unveiling pharmacogenomics: insights from Portuguese pharmacists on quaternary prevention

Abstract Background Public health genomics recognises the potential of genomic knowledge for enhancing population health. Adverse drug reactions (ADR) and lack of efficacy have significant clinical and economic burdens, which can be mitigated by pharmacogenomics (PGx) testing. Pharmacists can play a vital role in facilitating the implementation of PGx into routine clinical care. This will promote quaternary prevention, to protect individuals from medical intervention that can cause more harm than good. Objectives To assess attitudes, opinions, expectations, practices, and concerns of Portuguese pharmacists regarding PGx implementation. Methods An observational cross-sectional web-based survey was developed based on literature review, adapted to the national context, and validated in a focus group. The target population were adults residing in Portugal with a degree in Pharmaceutical Sciences or equivalent, with convenience sampling. Descriptive statistics were performed. Results From 303 participants, 98% believe that PGx is an important area of pharmaceutical sciences and 97% indicate that PGx should be included in continuing education. Almost all (99%) anticipate that PGx implementation will prevent the administration of ineffective drugs and inappropriate doses, 98% expect PGx will reduce ADR. Major concerns are related with direct-to-consumer sale of PGx tests via internet (78%) and unauthorized access to test results (91%). Currently, 25% are familiar with reliable sources of information on PGx, but only 11% feel qualified to recommend PGx testing, and 10% have analysed PGx reports. Conclusions There are positive opinions and expectations regarding the potential benefits of PGx tests. However, there are regulatory concerns and lack of readiness for immediate application. Pharmacists express interest in learning more about PGx, highlighting the need for continuous education and training to integrate it effectively into routine pharmaceutical practice. Key messages • Pharmacists recognize the benefits of PGx implementation for quaternary prevention. • Regulatory concerns and readiness gaps in PGx emphasise a need for training and life-long education of pharmacists.

Switching biologics in chronic rhinosinusitis with nasal polyps: A multicenter Canadian experience.

Type 2 biologics have been used increasingly for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP). However, patterns of biologic switching are understudied, and established guidelines for sequential or simultaneous use do not yet exist. This is a Canadian multicenter retrospective study of real-world patient data. Patients were included if they had recurrent CRSwNP despite maximal medical and surgical management, and received at least one dose of a type 2 biologic. Patients who remained on their initial biologic comprised the continuous group. Patients with sequential or simultaneous use of more than one biologic comprised the switched group. We compared the characteristics of patients who continued and switched biologics. Note that 225 consecutive patients were included. Thirty-six (16%) switched biologics at least once, and six (3%) switched twice. The most common switch was from mepolizumab to dupilumab, with poor control of CRSwNP symptoms being the leading cause for this switch. Lack of efficacy was the main reason for switching off mepolizumab and omalizumab, while adverse events were the leading cause for switching off dupilumab. Additionally, mepolizumab patients were more likely to switch biologics late in their treatment, while dupilumab patients rarely switched after 12 months of therapy (p-value<0.001). Switching biologics for CRSwNP is frequent in Canadian rhinology practices, with 16% of patients switching at least once. The most common switch is from mepolizumab to dupilumab with inadequate CRSwNP control driving this switch. This study may help guide sequential or simultaneous use of biologics in CRSwNP patients.

Factors influencing the discontinuation of biologic therapies in patients with ulcerative colitis

BackgroundThe therapeutic landscape for ulcerative colitis (UC) has recently broadened to include anti-TNFα, anti-integrin, and anti-IL-12/23p40 antibody agents. These biological agents are tailored to individual patient profiles. However, some patients cease biological treatment. This study investigates factors influencing the discontinuation of biological treatment in UC patients.MethodsThis retrospective single-cohort study encompasses UC patients who commenced treatment with biological agents like infliximab, adalimumab, golimumab, vedolizumab, and ustekinumab from April 2019 to March 2022. Patients were categorized into continuation and discontinuation groups based on their one-year treatment status. Baseline characteristics were compared between the groups.ResultsOf the 116 UC patients, 102 were included in the study. Among these, 74 (72.5%) continued and 28 (27.5%) discontinued biological therapy. Discontinuation rates for infliximab, adalimumab, golimumab, vedolizumab, and ustekinumab were 33.3%, 25.0%, 50.0%, 30.2%, and 15.6%, respectively. The primary discontinuation reason was lack of efficacy (85.7%), followed by adverse events (7.1%), pregnancy (3.6%), and death (3.6%). The discontinuation group had a significantly lower rate of concomitant thiopurine compared to the continuation group (28.6% vs. 56.8%, p = 0.0132). Multivariable analysis revealed that concomitant thiopurine was independently associated with therapy continuation (p = 0.0075).ConclusionThe study indicates that concomitant thiopurine significantly correlates with the continuation of biological therapies in UC patients, underscoring the importance of concomitant thiopurine in sustaining biological therapy. Further studies are warranted to assess the efficacy of combination therapy.

Polyploidy as an outcome of anticancer therapies and a contributing cause of their lack of efficacy

In addition to innate and gained resistance poliploidy of cancer cells is described as a mechanism responsible for lack of response or cancer relapses after initial patient recovery. Formation of these cells is induced by cyto- and genotoxic agents, which trigger endoreduplication, cytokinesis failure, cell fusion or canibalism. These processes lead to amplification of DNA, cell cycle arrest and escape from death. Cancer reinitiation results from depolyploidization by neosis, amitotic and meiotic-like divisions. In this paper we review the known mechanisms, which drive cancer cell transition to poliploidy, major features of these cells and their role in cancer progression. We also depict the current approaches, which target metabolic and signaling pathways that are crucial for survival and functioning of polyploid cells. The combination of chemotherapy and radiotherapy with agents capable of inhibiting or eliminating polyploid cells could substantially improve the success rate and efficacy of anticancer therapies.

Real-world utilisation and switching between Janus kinase inhibitors in Australian patients with rheumatoid arthritis in the OPAL dataset.

To describe use and treatment persistence for Janus kinase inhibitors (JAKi) in rheumatoid arthritis (RA) by line of therapy, and the mechanism of action for the drug switched to after JAKi discontinuation. This was a retrospective, observational analysis using the OPAL dataset, a large collection of deidentified electronic medical records from 112 rheumatologists around Australia. Adult patients with RA were included if they initiated tofacitinib (TOF), baricitinib (BARI) or upadacitinib (UPA) between 1 October 2015 and 30 September 2021. Data were summarised using descriptive statistics. Kaplan-Meier survival was used to analyse treatment persistence. 5,900 patients initiated JAKi within the study window (TOF n=3,662, BARI n=1,875, UPA n=1,814). Median persistence was similar across JAKi within each line of therapy where there was sufficient follow-up, and almost 3 years for first-line: 34.9 months (95% CI 30.8, 40.7; n=1,408) for TOF, 33.6 months (95% CI 25.7, not reached; n=545) for BARI. While JAKi to JAKi switching occurred across all lines of therapy, switches to a tumour necrosis factor inhibitor (TNFi) were more frequent after first- or second-line JAKi. JAKi monotherapy use at baseline increased with line of therapy, and was highest at follow-up after switching to another JAKi. 'Lack of efficacy' was the most common reason for discontinuing JAKi. In this large analysis of Australian real-world practice separated by line of therapy, treatment persistence for JAKi was high overall subject to differential follow-up, but declined in later lines. JAKi to JAKi switching was observed across all lines of therapy.

Inhibition of ATGL alleviates MASH via impaired PPARα signalling that favours hydrophilic bile acid composition in mice

Background and AimsAdipose triglyceride lipase (ATGL) is an attractive therapeutic target in insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD). This study investigated the effects of pharmacological ATGL inhibition on the development of metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis in mice. MethodsStreptozotocin-injected male mice were fed an HFD to induce MASH. Mice receiving the ATGL inhibitor, Atglistatin (ATGLi), were compared to controls using liver histology, lipidomics, metabolomics, 16s rRNA, and RNA sequencing. Human ileal organoids, HepG2 cells, and Caco2 cells treated with the human ATGL inhibitor NG-497, HepG2 ATGL knockdown cells, gel-shift, and luciferase assays were analysed for mechanistic insights. We validated its benefits on steatohepatitis and fibrosis in a low-methionine choline-deficient mouse model. ResultsATGLi improved serum liver enzymes, hepatic lipid content, and histological liver injury. Mechanistically, ATGLi attenuated PPARα signalling, favouring hydrophilic bile acid (BA) synthesis with increased Cyp7a1, Cyp27a1, Cyp2c70, and reduced Cyp8b1 expression. Additionally, reduced intestinal Cd36 and Abca1, along with increased Abcg5 expression, were consistent with reduced levels of hepatic TAG-species containing PUFAs like linoleic acids as well as reduced cholesterol levels in the liver and plasma. Similar changes in gene expression associated with PPARα signaling and intestinal lipid transport were observed in ileal organoids treated with NG-497. Furthermore, HepG2 ATGL knockdown cells revealed reduced expression of PPARα target genes and upregulation of genes involved in hydrophilic BA synthesis, consistent with reduced PPARα binding and luciferase activity in the presence of the ATGL inhibitors. ConclusionsInhibition of ATGL attenuates PPARα signalling, translating into hydrophilic BAs, interfering with dietary lipid absorption, and improving metabolic disturbances. The validation with NG-497 opens a new therapeutic perspective for MASLD. Impact and ImplicationsThe global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is a crucial public health concern. Since adherence to behavioural interventions is limited, pharmacological strategies are necessary, as highlighted by the recent FDA approval of resmetirom. However, since our current mechanistic understanding and pathophysiology-oriented therapeutic options for MASLD are still limited, novel mechanistic insights are urgently needed.Our present work uncovers that pharmacological inhibition of ATGL, the key enzyme in lipid hydrolysis using Atglistatin (ATGLi), improves metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and associated key features of metabolic dysfunction in a mouse model of MASH and MCD-induced liver fibrosis. Mechanistically, we demonstrated that attenuation of PPARα signalling in the liver and gut favours hydrophilic bile acid composition, ultimately interfering with dietary lipid absorption. One of the drawbacks of ATGLi is its lack of efficacy against human ATGL, thus limiting its clinical applicability. Against this backdrop, we could show that ATGL inhibition using the human inhibitor NG-497 in human primary ileum-derived organoids, Caco2 cells, and HepG2 cells translated into therapeutic mechanisms similar to ATGLi. Collectively, these findings open a new avenue for MASLD treatment development by inhibiting human ATGL activity.

Emotion Regulation and Academic Burnout Among Youth: a Quantitative Meta-analysis

Emotion regulation (ER) represents an important factor in youth’s academic wellbeing even in contexts that are not characterized by outstanding levels of academic stress. Effective ER not only enhances learning and, consequentially, improves youths’ academic achievement, but can also serve as a protective factor against academic burnout. The relationship between ER and academic burnout is complex and varies across studies. This meta-analysis examines the connection between ER strategies and student burnout, considering a series of influencing factors. Data analysis involved a random effects meta-analytic approach, assessing heterogeneity and employing multiple methods to address publication bias, along with meta-regression for continuous moderating variables (quality, female percentage and mean age) and subgroup analyses for categorical moderating variables (sample grade level). According to our findings, adaptive ER strategies are negatively associated with overall burnout scores, whereas ER difficulties are positively associated with burnout and its dimensions, comprising emotional exhaustion, cynicism, and lack of efficacy. These results suggest the nuanced role of ER in psychopathology and well-being. We also identified moderating factors such as mean age, grade level and gender composition of the sample in shaping these associations. This study highlights the need for the expansion of the body of literature concerning ER and academic burnout, that would allow for particularized analyses, along with context-specific ER research and consistent measurement approaches in understanding academic burnout. Despite methodological limitations, our findings contribute to a deeper understanding of ER's intricate relationship with student burnout, guiding future research in this field.

From Traditional Use to Modern Evidence: The Medicinal Chemistry of Antimalarials from Genus Artemisia.

While the use of plants in traditional medicine dates back to 1500 B.C., modern advancements led to the development of innovative therapeutic techniques. On the other hand, in the field of anti-infective agents, lack of efficacy and the onset of resistance stimulate the search for novel agents. Genus Artemisia is one of the most diverse among perennial plants with a variety of species, properties, and chemical components. The genus is known for its therapeutic values and, in particular, for its role in the origin of antimalarial agents derived from artemisinin. In this review, we aim to provide an updated overview of the evolution of natural and natureinspired compounds related to the genus Artemisia that have been proven, in vitro and in vivo, to possess antimalarial properties. An overview of the chemical composition and a description of the ethnopharmacological aspects will be presented, as well as an updated report on in vitro and in vivo evidence that allowed the translation of artemisinin and its derivatives from traditional chemistry into modern medicinal chemistry. The biological and structural properties will be discussed, also dedicating attention to the challenging tasks that still are open, such as the identification of optimal combination strategies, the routes of administration, and the full assessment of the mechanism of action.

Novel Diacyl-hydrazide Compounds as Potential Therapeutics for Visceral Leishmaniasis.

Visceral leishmaniasis is a neglected tropical disease with the highest mortality among different forms of leishmaniasis manifestation in humans. The disease is caused by the parasitic protists Leishmania donovani and Leishmania infantum, and treatments remain unsuitable due to high costs, complicated administration, lack of efficacy, variable patient susceptibility, toxic side effects, and rising parasitic resistance. Herein, we report a structure-activity relationship (SAR) exploration of the diacyl-hydrazide scaffold identified to have antiparasitic activity from a high-throughput screen against L. donovani, Trypanosoma cruzi, and Trypanosoma brucei. This SAR study revealed new structural insights into this scaffold related to bioactivity resulting in a new series of lead compounds with nanomolar activity against L. donovani and no toxicity against human THP-1 macrophages. These optimized diacyl-hydrazide compounds set the stage for future drug development and hold promise for a new treatment avenue for visceral leishmaniasis.

Modulation of brain energy metabolism in hepatic encephalopathy: impact of glucose metabolic dysfunction.

Cerebral function is linked to a high level of metabolic activity and relies on glucose as its primary energy source. Glucose aids in the maintenance of physiological brain activities; as a result, a disruption in metabolism has a significant impact on brain function, launching a chain of events that leads to neuronal death. This metabolic insufficiency has been observed in a variety of brain diseases and neuroexcitotoxicity disorders, including hepatic encephalopathy. It is a significant neurological complication that develops in people with liver disease, ranging from asymptomatic abnormalities to coma. Hyperammonemia is the main neurotoxic villain in the development of hepatic encephalopathy and induces a wide range of complications in the brain. The neurotoxic effects of ammonia on brain function are thought to be mediated by impaired glucose metabolism. Accordingly, in this review, we provide an understanding of deranged brain energy metabolism, emphasizing the role of glucose metabolic dysfunction in the pathogenesis of hepatic encephalopathy. We also highlighted the differential metabolic profiles of brain cells and the status of metabolic cooperation between them. The major metabolic pathways that have been explored are glycolysis, glycogen metabolism, lactate metabolism, the pentose phosphate pathway, and the Krebs cycle. Furthermore, the lack of efficacy in current hepatic encephalopathy treatment methods highlights the need to investigate potential therapeutic targets for hepatic encephalopathy, with regulating deficient bioenergetics being a viable alternative in this case. This review also demonstrates the importance of the development of glucose metabolism-focused disease diagnostics and treatments, which are now being pursued for many ailments.

Efficacy, safety, and tolerability of adjunctive Lacosamide therapy for focal seizures in young children aged ≥1 month to ≤4 years: A real-world study.

To evaluate the efficacy, safety, and tolerability of adjunctive lacosamide therapy against focal seizures in young children (1 month - 4 years). This non-randomized, open-label, and self-controlled real-world study included 105 children (1 month-4 years) with focal seizures treated with adjunctive lacosamide therapy at Children's Hospital of Chongqing Medical University. (1) The 50% response rates at 3, 6, 9, and 12 months of follow-up were 58.1%, 61.0%, 57.1%, and 56.2%, while the seizure-free rates were 27.6%, 34.3%, 32.4%, and 37.1%, respectively. The 50% response rate of the first addition of lacosamide for focal seizures was much higher than the second and later added treatment at 3 months (p = 0.038). After 1 year of follow-up, these children showed an improvement in neurodevelopmental levels (p < 0.05). (2) Lacosamide retention rate was 72.7% (64/88) after 1 year of follow-up. Lack of efficacy and serious adverse events were independent risk factors for the lacosamide retention rate. (3) During adjunctive lacosamide therapy, 13 (12.4%) patients reported adverse events and five (4.7%) patients withdrew due to adverse events, including vomiting drowsiness, ataxia (0.94%), neck itching with eczema (0.94%), irritability (1.88%), and gastrointestinal discomfort (0.94%). Adjunctive lacosamide therapy was effective, safe, and well-tolerated in young Chinese children with focal seizures in this study.

Use of medications for migraine in Aotearoa New Zealand.

To document and assess acute and preventive medication use in people with migraine disease in Aotearoa New Zealand. Online survey of people with migraine in Aotearoa New Zealand (n=530), run from 22 August to 7 October 2022, including questions on current and previous acute and preventive medication use, reasons for medication discontinuation and use of new migraine medications. Most respondents had used simple analgesics for acute treatment; 55% were currently using a triptan; 27% were currently using an opioid. Overall, 27% of survey respondents had over-used at least one acute medication in the last month. Half of respondents were taking at least one preventive medication but only 57% of those eligible for preventive treatment were currently taking it. In those who had previously tried preventives, side effects and lack of efficacy were common reasons for stopping. Cost, lack of knowledge and awareness were the main barriers to use of new migraine medications. Many people with migraine in Aotearoa New Zealand are not receiving optimal treatment, which increases the burden and cost of migraine disease. More effective and tolerable acute and preventive medications are needed that are affordable and available in Aotearoa New Zealand. Greater awareness of best practice prescribing is also needed.

A biological pharmacology network to secure the risk of drug–drug interaction with nirmatrelvir/ritonavir

Nirmatrelvir/ritonavir is a protease inhibitor antiviral drug indicated in the treatment of severe acute respiratory syndrome coronavirus-2 infections in high-risk patients for a severe disease. Unfortunately, ritonavir, used to boost nirmatrelvir pharmacokinetics, can also inhibit or induce the metabolism of other co-administered drugs substrates. This may lead to a subsequent risk of adverse drug reaction and lack of efficacy. In this study, we aimed at describing the expert advices provided by the biological pharmacology network of the SFPT (i.e., the therapeutic drug monitoring specialists working in the laboratories of the pharmacology departments in France/Belgium). From February to August 2022, we collected all specialized advices provided by the biological pharmacology network of the SFPT. Seven pharmacology departments actively participated in the study (Brussels Saint-Luc Hospital in Belgium, Caen, Dijon, Nantes, Nancy, Rennes and Toulouse in France). We collected the following data: patient's age, date of nirmatrelvir/ritonavir initiation, clinical department requiring the expert advice, patient's treatments, and advice provided. One hundred and six expert advice on 753 drugs were provided during the seven months of data collection. Two centers provided 83% of all the expert advice (around 8/month). Patients originated form a transplantation department in 65% of the cases. The most common request were for cardiac drugs (28%), immunosuppressive drugs (24%) and endocrine drugs (18%). The advice were distributed as follows: treatment continuation, treatment discontinuation during the antiviral course, dosage adjustment, and treatment switch in 59%, 28%, 11%, and 1.6% of the cases, respectively. Only 2 pieces of advice (0.3%) constituted treatment contra-indications. Drug monitoring was proposed in 10% of prescription lines. Expert advice provided by the biological pharmacology network of the SFPT allows securing the combination of nirmatrelvir/ritonavir with other concomitant drugs. Most of eligible patients to the antiviral drug can benefit from it despite the risk of drug-drug interaction.

Efficacy of scrambler therapy in chronic neuropathic pain: pairwise and dose-response meta-analysis

Chronic neuropathic pain (CNP) affects 7% of the world’s population and is challenging to control since existing medications are inadequate and have negative effects. Electrocutaneous devices, such as scrambler therapy (ST), have emerged as a possible option and have shown promising results in multiple randomized controlled trials (RCTs). However, the long-term efficacy of ST remains unknown. We aimed to evaluate the efficacy of ST in CNP reduction over time. We used the data sources including PubMed, Embase, Scopus, and Cochrane Central Register of Controlled Trials from inception to September 2023. Five placebo and three routine-care controlled RCTs were selected among the screened abstracts. Two authors independently extracted the data. Data was pooled using a model under the common parameters assumption. The studies were evaluated for methodological quality using the MethodologicAl STandard for Epidemiological Research (MASTER) scale. The primary outcome measure was pain reduction; pain was converted to a common 0 to 10 scale, and a weighted mean difference of more than 2 points on a 10-point pain scale was considered clinically important. Eight RCTs that evaluated the effect of ST on CNP were included, with a total sample size of 350 participants. None of the participants withdrew in all these trials owing to adverse events or lack of efficacy. There was high-quality evidence that ST reduced pain in the short term, with a mean difference of –3 points. The dose-response meta-analysis demonstrated a significant reduction in pain scores post-treatment, with a peak reduction at day 40. The effect of ST remained below the baseline values for 90 days, although with limited certainty. This study is the first dose-response meta-analysis to assess the duration of efficacy of ST in the treatment of CNP. The results demonstrated a clinically significant and more sustained reduction in pain created by ST compared to conventional treatments. Our findings indicate that ST could be used as a safe and effective alternative for managing CNP.

Pharmacokinetic Modeling of the Effect of Tariquidar on Ondansetron Disposition into the Central Nervous System

PurposeSerotonin (5-HT3) receptor antagonists are promising agents for treatment of neuropathic pain. However, insufficient drug exposure at the central nervous system (CNS) might result in lack of efficacy. The goal of this study was to evaluate the impact of administration of a Pgp inhibitor (tariquidar) on ondansetron exposure in the brain, spinal cord, and cerebrospinal fluid in a wild-type rat model.MethodsOndansetron (10 mg/kg) and tariquidar (7.5 mg/kg) were administered intravenously, plasma and tissue samples were collected and analyzed by HPLC. A mathematical model with brain, spinal cord, cerebrospinal fluid and two systemic disposition compartments was developed to describe the data.ResultsThe results demonstrate that tariquidar at 7.5 mg/kg resulted in a complete inhibition of Pgp efflux of ondansetron in the brain and spinal cord. The compartmental model successfully captured pharmacokinetics of ondansetron in wild type and Pgp knockout (KO) animals receiving the drug alone or in wild type animals receiving the ondansetron and tariquidar combination.ConclusionsThe study provided important quantitative information on enhancement of CNS exposure to ondansetron using co-administration of Pgp Inhibitor in a rat model, which will be further utilized in conducting a clinical study. Tariquidar co-administration resulted in ondansetron CNS exposure comparable to observed in Pgp KO rats. Results also highlighted the effect of tariquidar on plasma disposition of ondansetron, which may not be dependent on Pgp inhibition, and should be evaluated in future studies.

Complications and Mortality Rate of Vagus Nerve Stimulation for Drug-Resistant Epilepsy.

The goal of this study is to evaluate the complications and mortality associated with vagus nerve stimulation (VNS). We retrospectively reviewed medical records of patients who underwent VNS implantation for the treatment of drug-resistant epilepsy (DRE) between 2000 and 2023. The mean follow-up time was 10.6 years, ranging from three months to 22 years. In total, 55 adult and pediatric patients received VNS therapy with 117 procedures performed over 23 years. The most common early complications were hoarseness and cough which were reported in eight adult patients (6.8%). Four children with intellectual disability (ID) had infection (3.4%), eight patients had lead breakage (6.8%), and two had device migration (1.7%). Fourof all patients (7.3%) demonstrated late complications due to chronic nerve stimulation including vocal cord dysfunction, late-onset severe AV block, and obstructive sleep apnea (OSA). Three patients (5.5%) had VNS deactivated permanently due to complications and/or lack of efficacy. Two patients died from probable sudden unexpected death in epilepsy (SUDEP) with an incidence of 3.4/1000 person-years. VNS therapy is safe over long-term follow-up but not without risks. Most post-operative complications are minor and transient for adults. Children with ID tend to have infection and device migration. Late-onset cardiac complications and OSA can develop in some patients during VNS therapy and should not be overlooked. The SUDEP rate may decrease with VNS therapy over time.