Class Of Drugs Research Articles

Design, Docking, Synthesis, and In vitro Evaluation of Potent Anti-tubercular Agents Targeting DNA Gyrase

Background: Tuberculosis caused by Mycobacterium tuberculosis has been reported to infect about two-third of the global population and to continuously develop multidrug resistance. DNA gyrase, a type II topoisomerase, is a promising target of the quinolone class of drugs in the treatment of tuberculosis. Objective: The present study is focused on the design and synthesis of newer nitrogen heterocyclics containing indole, n-methyl piperazine, piperidine, and pyrrolidine ring structures. Methods: Initially designed compounds were evaluated for their affinity to the DNA gyrase target. The molecular docking performed using FlexX indicated compounds IIb5 (1-(R)-(4-hydroxyphenyl)(4- methylpiperazin-1-yl)methyl)-3-((S)-(4-hydroxyphenyl)(4-methylpiperazin-1-yl)methyl)urea and IIc5 ((1-(R)-(4-hydroxyphenyl)(4-methylpiperazin-1-yl)methyl)-3-((S)-(4-hydroxyphenyl)(4-methylpiperazin- 1-yl)methyl) thiourea to exhibit promising binding affinity (dock score of -15.01 and -13.77) respectively when compared to the reference MFX moxifloxacin (dock score -4.40) with the target 5BS8 (DNA gyrase). Further, the best 10 compounds were synthesized by one-pot synthesis employing the reaction of indole/N-methyl piperazine/piperidine/pyrrolidine with N-substituted benzaldehydes in the presence of acetamide/urea/thiourea to afford the compounds in 54.60% to 85.47% yield. The synthesized compounds were suitably characterized using chromatographic and spectroscopic tools. Results: In the microplate Alamar Blue assay (MABA), compounds IIb1, IIIc2, IIIb1, and IIb5 exhibited good minimum inhibitory concentrations of 1.6 μg/mL, 3.12 μg/mL, and 12.5 μg/mL, respectively, when compared to the standard rifampicin with 0.8 μg/mL inhibitory concentration. The MTB gyrase supercoiling assay performed using Mycobacterium tuberculosis gyrase supercoiling assay kit demonstrated compound IIb5 at a concentration of 300 μg/mL to show gyrase inhibition in comparison to MFX at 60 μg/mL. In the MTT assay performed using the human breast cancer cell line MCF-7, compounds IIc2, IIb5, and IIb1 showed IC50 values of 2.57 μM, 12.54 μM, and 12.75 μM, respectively, compared to doxorubicin (1.10 μM) at 7-48 hrs and 72 hrs of the study. Conclusion: Based on these observations, N-methyl piperazine class of compounds can serve as a lead/pharmacophore for the rational design of potent molecules against MTB gyrase to combat the growing issue of MDR-TB.

Distinguishing DRESS syndrome from drug rash and eosinophilia: beyond the RegiSCAR criteria

BackgroundDiagnosing drug reaction with eosinophilia and systemic symptoms (DRESS) can be challenging. ObjectivesTo identify clinical and laboratory features outside of the RegiSCAR criteria which distinguish patients with probable DRESS (RegiSCAR >/=4) from those who have drug rash and eosinophilia (DRE). MethodsUsing International coding classification of drug induced fever, generalised skin eruption due to medications and eosinophilia, a retrospective audit of hospitalized patients was performed from 2008 to 2023. ResultsForty-four cases of DRESS were compared to 80 cases of DRE. In addition to the RegiSCAR distinguishing factors for DRESS were longer drug latency prior to symptom onset (median 21 vs 5 days, p<0.001)and higher alanine transaminase (ALT) levels (increase by a factor of 2.49 (95% CI: 1.56, 4.00; p=0.009). Follow-up (mean 5.67 years) revealed a low rate of statewide drug alert reporting (29.6%) and drug allergy testing in DRESS (20.5%). Inadvertent re-exposure to a culprit or structurally-related drug resulted in recurrent DRESS in three patients (7.5%), and tolerance of structurally related drugs in 8 patients (17.5%). ConclusionThis is the largest study to date evaluating DRE patients that don’t meet RegiSCAR criteria for DRESS. We highlight additional factors outside the RegiSCAR which may help clinicians differentiate DRESS which is critical for optimal and timely patient management. Our study also highlights the need for development of local protocols to ensure appropriate allergy labeling and testing is performed to prevent recurrent DRESS.

P035 SOCIAL DETERMINANTS OF HEALTH AND CONTROL OF HYPERTENSION

Background and Objectives: Recent national blood pressure (BP) survey data of adults in Canada and United States show a troubling decline in the control of hypertension, particularly in women, the elderly and those with low income, less education and under-using health services. Social determinants of health (SDH) can be important barriers to controlling hypertension. Studies assessing associations of BP control and SDH have focused on one or a few domains. Objectives of this study are to screen treated hypertensive patients for a wide range of SDH, test for correlations and assess the effects of high-quality treatment on SDH and BP control relationship. Method: We created and applied a screening tool to gather personal information on 14 SDH from consecutive consenting eligible patients attending a complex hypertension care clinic. Logistic regression was used to assess association of each SDH domain with BP control. Results: Of 90 patients enrolled, 88 completed the 6-month study. At baseline, mean age (standard deviation) was 64 (14) years, 64% male, 69% white, 25% experiencing financial hardship, mean BMI 30.4 kg/m2 (5.9), mean automated office BP 138/78 (23/14), mean number of co-morbid conditions 4.2 (2.0) and 55% had treatment-resistant hypertension. From baseline to exit, BP fell to 127/73 (17/12), p&lt;0.001, mean number of antihypertensive drug classes increased from 3.06 (1.43) to 3.23 (1.30), p=0.049 but BMI remained unchanged. There were no associations between uncontrolled hypertension and any of the 14 SDOH domains at baseline. However, at exit financial status was associated with uncontrolled hypertension on univariate analysis (p=0.022) and on multivariate analysis. Stress (p=0.063) and optimism status (p=0.085] showed a similar trend. These analyzes indicated better BP control among those with poorer financial status, higher stress levels or more pessimistic outlook. Conclusion: None of the SDOH were associated with uncontrolled hypertension at baseline. However good medical care and follow-up appeared to have improved BP control, noticeably in those experiencing financial hardship. Explanation of findings requires further study.

Real-world effectiveness and tolerability of switching to doravirine-based antiretroviral therapy in people with HIV: a nationwide, matched, prospective cohort study

Currently, real-world data on doravirine are scarce. In a national prospective cohort, we assessed the effectiveness and tolerability of switching to doravirine-based antiretroviral therapy (ART) in people with HIV. We did a nationwide, matched, prospective cohort study of people with HIV without previous virological failure and stable for at least 12 months on non-doravirine-containing triple or dual ART switching to doravirine before Sept 1, 2020 (exposed group). Participants in the exposed group were matched 1:2 to individuals continuing stable non-doravirine-containing ART, on age, sex, HIV acquisition category, time since ART initiation, calendar time, pre-ART CD4-count, pre-ART plasma viral load (PVL) and anchor drug class before switching. The primary outcome was protocol-defined virological failure (PDVF; PVL of ≥200 copies per mL) in the intention-to-treat (ITT) population at week 104, with participants modifying their regimen or becoming lost to follow-up considered as PDVF (non-inferiority margin +5%). In contrast, in the on-treatment population, those who modified their regimen or became lost to follow-up were censored from that moment onwards. Tolerability was a secondary outcome. In total, 590 participants in the exposed group and 1180 participants in the unexposed group (of whom 55·3% used integrase strand transfer inhibitor-based regimens) were included. In the ITT analysis, PDVF occurred in 135 (22·9%) exposed participants and in 295 (25·0%) unexposed participants (risk difference -2·12%, upper limit of the one-sided 95% CI +1·40%). In the on-treatment analysis, 10 (2·2%) of 455 non-censored exposed participants and 26 (2·9%) of 885 non-censored unexposed participants had PDVF (risk difference -0·70%, upper limit of the one-sided 95% CI +0·73%). All exposed participants with a PVL of 200 copies or more per mL resuppressed without regimen modification: no confirmed virological failure (two consecutive PVLs of ≥200 copies per mL) was observed. 104 (17·6%) exposed participants and 211 (17·9%) unexposed participants modified their regimen. 73 (12.4%) exposed participants discontinued doravirine due to adverse events: abnormal dreams (1·7%) and insomnia (1·5%) were most common. Switching to doravirine in well suppressed people with HIV without previous virological failure was non-inferior compared with continuing non-doravirine-containing regimens after 2 years in a real-world setting. None.

P044 TEAM-BASED CARE TO MANAGE COMPLEX CASES OF HYPERTENSION

Background and Objectives: Team-based care that uses home blood pressure (BP) telemonitoring to facilitate hypertension management is safe and effective in lowering BP in routine primary care. However, its usefulness to manage more complex cases of hypertension is uncertain. This 6-month study explores its use in such patients attending a hypertension clinic. Methods: BP telemonitoring consisted of smartphone with BP app paired with wireless home BP device to transmit BP readings to a central server, accessible to patients and clinic staff. Patients were asked to contact the clinic about worrisome home BP readings, treatment problems and technical issues. Home readings were integrated into clinical decision-making. Outcomes were patients’ experience and clinical measures. Results: Of 90 enrolled patients, 38% had grade 3 or 4 chronic kidney disease, 23% diabetes, 31% heart disease, 12% stroke and 12% aortic dissection. Mean number (standard deviation) of co-morbid conditions was 4.2 (2.0). Most patients were at very high (30%) or high risk (50%) for a cardiovascular event. During follow-up, one patient died and one dropped-out of care. Mean number of in-person and virtual assessments by a physician were 1.6 (0.6) and 2.0 (1.8), respectively. Eighty-three percent (n=75) contacted clinic staff. Mean number of contacts for technical reasons was 1.2 (1.8), treatment-related issues 0.5 (1.0) and personal support 4.2 (5.9). From baseline to exit mean automated office BP fell (p&lt;0.001), BP control improved (p&lt;0.001) and mean number of antihypertensive drug classes increased (p=0.049). Most patients, 91% (80/88), felt BP telemonitoring to be a valuable tool for managing their hypertension. Nonetheless, 38% also considered cost to be potentially a barrier to long-term use. Only 6% had data security concerns. Conclusions: Team-based care was highly rated by patients to manage their hypertension and may account for the low drop-out rate, high number of patient-provider contacts, good patient acceptance of more intensified pharmacological treatment and better BP control. However, cost potentially may be a barrier for long-term use.

P210 ASSOCIATION BETWEEN FOLLOW-UP BLOOD PRESSURE AND BLOOD PRESSURE CONTROL: A META-REGRESSION ANALYSIS

Background: Blood pressure (BP) control is typically defined as BP values under certain thresholds, most commonly &lt;140/90 mmHg – but there is widespread uncertainty about how mean BP is related to BP control, and what mean BP is required to achieve BP control in 80% of patients. Objective: To assess the association between follow-up mean systolic BP (SBP) and BP control from randomised clinical trials (RCTs). Methods: We systematically searched multiple databases for relevant RCTs. We included double-blind individual RCTs (iRCTs) of adults with hypertension, randomised to BP-lowering drugs from five major antihypertensive classes for ≥2 to ≤ 26 weeks, and which reported data for follow-up mean SBP and BP control (clinic BP &lt;140/90 mmHg) at the last follow-up visit. We also included cluster RCTs (cRCTs), of adults with hypertension, randomised to any BP-lowering intervention, for any duration. The association between follow-up mean SBP and BP control at the last follow-up visit was assessed using a linear regression model. The coefficient was interpreted as the increase in percentage of patients with BP control for every 1 mmHg decrease in follow-up mean SBP. Results: Seventy iRCTs (45,836 participants) and 36 cRCTs (28,154 participants) were included. Each 1 mmHg decrease in follow-up mean SBP was associated with about 2% improvement in BP control in both iRCTs and cRCTs (R2= 78% and 76%, respectively). This finding was broadly consistent in the subgroups of BP-lowering drug classes, baseline SBP categories, and pre-trial BP-lowering treatment status in iRCTs, and country income and baseline SBP categories in cRCTs. Mean SBP levels of 125, 130, and 135 mmHg were associated with BP control rates of 78%, 67%, and 55%, respectively, in iRCTs and 80%, 68%, and 56% in cRCTs. Conclusion: Mean SBP levels of 125 mmHg are required for achieving BP control of &lt;140/90 mmHg in about 80% of the patients. These findings should inform clinical care, guideline recommendations and hypertension control programs.

Changes in the Use of Hydrochlorothiazide and Other Antihypertensive Drugs in Switzerland in Association With the Swissmedic Safety Alert Regarding Non-melanoma Skin Cancer: An Interrupted Time-Series Analysis Using Swiss Claims Data.

Long-term use of hydrochlorothiazide increases the risk of non-melanoma skin cancer. We aimed to evaluate potential changes in the use of hydrochlorothiazide in Switzerland after a direct healthcare professional communication (DHPC) in November 2018 by Swissmedic. We performed interrupted time-series analyses using a large Swiss healthcare claims database (2015-2021). Within monthly intervals, we quantified the total number of claims and the total dispensed 'defined daily doses' (DDD) for preparations containing (1) hydrochlorothiazide, (2) angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II-receptor blockers (ARB), (3) calcium-channel blockers (CCB) and (4) thiazide-like diuretics per 10 000 persons. Using segmented linear regression, we quantified the pre-DHPC trend, the immediate change and the post-DHPC change in trend for total claims and DDD for the four drug classes weighted for the demographic distribution of the Swiss population. ACE inhibitors and ARB were the most frequently claimed antihypertensive drugs with 300-400 claims per 10 000 persons, which increased by 5.4% during the study period. The average number of hydrochlorothiazide claims (157/10 000 persons in 2015) declined by 35% between 2015 and 2021. The decrease started prior to the DHPC, but the DHPC was associated with an immediate 6.1% decline and an accelerated decline in claims over time after the DHPC (similar results for DDD). This coincided with a 23% increase in claims of CCB (dihydropyridine type) over 7 years, whereas use of other antihypertensives increased less. Our results suggest that the DHPC by Swissmedic in 2018 accelerated a pre-existing decline in the use of hydrochlorothiazide in Switzerland.

Rimegepant - a breakthrough drug for migraine treatment - literature review

Migraine is a chronic condition that manifests itself periodically. It is characterized by recurrent, severe, often hemiplegic, throbbing headaches accompanied by autonomic symptoms in the form of nausea, vomiting, hypersensitivity to noise and light. For many years, triptans have been the gold standard in the treatment of migraine, acting by constricting blood vessels and inhibiting the release of neuropeptides. However, their efficacy is not satisfactory for all patients, especially those with cardiovascular disease. In response to the need for effective and safe therapies, gepants, a new class of drugs that block the calcitonin gene-related peptide (CGRP) receptor, have emerged. Rimegepant, one of the newest representatives of gepant, has been approved for the treatment of migraine both in the acute attack phase and prophylactically. Clinical trials have shown its effectiveness in reducing the number of days with migraine and alleviating associated symptoms. Rimegepant also has a favorable safety profile, making it a promising therapeutic option for migraine patients. This article aims to discuss in detail rimegepant as a new treatment option for migraine, including its mechanism of action, efficacy, safety profile, clinical trial and outlines the benefits of introducing this drug into standard clinical practice.

Novel inhibitors of bromodomain and extra-terminal domain trigger cell death in breast cancer cell lines

Small molecule inhibitors targeting the bromodomain and extra-terminal domain (BET) family proteins have emerged as a promising class of anti-cancer drugs. Nevertheless, the clinical advancement of these agents has been significantly hampered by challenges related to their potency, oral bioavailability, or toxicity. In this study, virtual screening approaches were employed to discover novel inhibitors of the bromodomain-containing protein 4 (BRD4) by analyzing their comparable chemical structural features to established BRD4 inhibitors. Several of these compounds exhibited inhibitory effects on BRD4 activity ranging from 60 % to 70 % at 100 µM concentrations, while one compound also exhibited an 84 % inhibition of Sirtuin 2 (SIRT2) activity. Furthermore, a subset of structurally diverse compounds from the BRD4 inhibitors was selected to investigate their anti-cancer properties in both 2D and 3D cell cultures. These compounds exhibited varying effects on cell numbers depending on the specific cell line, and some of them induced cell cycle arrest in the G0/G1 phase in breast cancer (MDA-MB-231) cells. Moreover, all the compounds studied reduced the sizes of spheroids, and the most potent compound exhibited a 90 % decrease in growth at a concentration of 10 µM in T47D cells. These compounds hold potential as epigenetic regulators for future studies.

Development of a Formulation and In Vitro Evaluation of a Pulmonary Drug Delivery System for a Novel Janus Kinase (JAK) Inhibitor, CPL409116

The pursuit of targeted therapies for cytokine-dependent diseases has led to the discovery of Janus kinase (JAK) inhibitors, a promising class of drugs. Among them, CPL409116, a selective dual JAK and rho-associated protein kinase inhibitor (ROCK), has demonstrated potential for treating conditions such as pulmonary fibrosis exacerbated by the COVID-19 pandemic. This study investigated the feasibility of delivering CPL409116 via inhalation, with the aim of minimizing the systemic adverse effects associated with oral administration. Two micronization methods, jet milling and spray drying, were assessed for CPL409116, with spray drying chosen for its ability to produce an amorphous form of the compound. Moreover, parameters such as the mixing energy, drug load, and force control agent significantly influenced the fine particle fraction (FPF), a critical parameter for pulmonary drug delivery. This study provides insights into optimizing the formulation parameters to enhance the delivery efficiency of CPL409116 to the lungs, offering potential for improved therapeutic outcomes in cytokine-dependent pulmonary diseases.

Forget me not: The effect of doxycycline on human declarative memory

Investigations into neuroprotective drugs are in high demand for the treatment of neurodegenerative diseases, such as multiple sclerosis or Alzheimer's disease, but also psychiatric disorders, such as depression, trauma, and substance use. One potential drug class being investigated are tetracyclines impacting on a variety of neuroprotective mechanisms. At the same time, tetracyclines like doxycycline have been suggested to affect human fear and spatial memory as well as reducing declarative memory retention. Based on the assumed necessity for synaptic consolidation in hippocampus-dependent learning, we hypothesised declarative memory may be similarly impaired by doxycycline as fear and spatial memory. Therefore, in this study we investigate the potential diminishing effects of doxycycline on consolidation of declarative memory in healthy humans. Additionally, to test for effect specificity we assessed motor memory, sustained attention, and processing speed. We administered a neuropsychological test battery in three independent randomized placebo-controlled double-blind trials (RCTs), in which healthy young volunteers (total N = 252) either received a single oral dose doxycycline (200 mg, n = 126) or placebo (n = 126) in a between-subject design. We found no evidence for a detrimental effect of doxycycline on declarative memory; instead, doxycycline improved declarative learning (p-value=0.022, Cohen's d=0.15) and memory consolidation (p=0.040, d=0.26). Contrarily, doxycycline slightly reduced motor learning (p=0.001, d=0.10) but subtly strengthened long-term motor memory (p=0.001, d=0.10). These results suggest that doxycycline can improve declarative learning and memory without having long term negative effects on other cognitive domains in healthy humans. Our results give hope to further investigate doxycycline in neuroprotective treatment applications.

A high-throughput sample preparation approach for the determination of nonsteroidal anti-inflammatory drugs in urine samples through membrane-based microextraction employing a green supramolecular solvent

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of drugs with antipyretic, analgesic, and anti-inflammatory effects widely used worldwide. This study aimed at developing an environmentally friendly and high-throughput sample preparation method for the determination of six NSAIDs in urine samples followed by high-performance liquid chromatography coupled to diode-array detection (HPLC-DAD). The experimental workflow consisted of hollow-fiber microporous membrane liquid-liquid extraction (HF-MMLLE) using a supramolecular solvent immobilized into the porous of polypropylene hollow membranes (1 cm length). These membranes were attached to a 96-well plate system to permit multiple extractions simultaneously. Under the optimized conditions, limits of detection (LODs) and limits of quantification (LOQs) ranged from 6.06 to 30.3 µg/L and from 20 to 100 µg/L, respectively. The linear ranges varied from 20 to 1000 µg/L for indomethacin and diclofenac, from 50 to 1000 µg/L for ketoprofen and ibuprofen, and from 100 to 1000 µg/L for naproxen and fenoprofen. The coefficients of determination (R²) ranged from 0.9735 to 0.9997. Intraday precision ranged from 6.13 to 20.11 %, interday precision varied from 2.87 to 20.72 %, and accuracy ranged from 92.49 to 126.89 %. Moreover, the recently proposed Sample Preparation Metric of Sustainability (SPMS) was employed to evaluate the greenness of the sample preparation technique resulting in a score of 8.0, which is highly satisfactory according to the concepts of green analytical chemistry.

Analogues of the anti-malaria drug mefloquine have broad spectrum antifungal activity and are efficacious in a model of disseminated Candida auris infection.

Only three classes of antifungal drugs are currently in clinical use. Here, we report that derivatives of the malarial drug mefloquine have broad spectrum antifungal activity including difficult to treat molds and endemic fungi. Pharmacokinetic and efficacy studies of NSC-4377 indicate it penetrates the central nervous system and is active against Candida auris in vivo. These data strongly support the further development of mefloquine analogs as a potentially new class of antifungal molecules.

Cytotoxic Activity of Novel GnRH Analogs Conjugated with Mitoxantrone in Ovarian Cancer Cells.

The gonadotropin-releasing hormone (GnRH) receptor (GnRH-R) is highly expressed in ovarian cancer cells (OCC), and it is an important molecular target for cancer therapeutics. To develop a new class of drugs targeting OCC, we designed and synthesized Con-3 and Con-7 which are novel high-affinity GnRH-R agonists, covalently coupled through a disulfide bond to the DNA synthesis inhibitor mitoxantrone. We hypothesized that Con-3 and Con-7 binding to the GnRH-R of OCC would expose the conjugated mitoxantrone to the cellular thioredoxin, which reduces the disulfide bond of Con-3 and Con-7. The subsequent release of mitoxantrone leads to its intracellular accumulation, thus exerting its cytotoxic effects. To test this hypothesis, we determined the cytotoxic effects of Con-3 and Con-7 using the SKOV-3 human OCC. Treatment with Con-3 and Con-7, but not with their unconjugated GnRH counterparts, resulted in the accumulation of mitoxantrone within the SKOV-3 cells, increased their apoptosis, and reduced their proliferation, in a dose- and time-dependent manner, with half-maximal inhibitory concentrations of 0.6-0.9 µM. It is concluded that Con-3 and Con-7 act as cytotoxic "prodrugs" in which mitoxantrone is delivered in a GnRH-R-specific manner and constitute a new class of lead compounds for use as anticancer drugs targeting ovarian tumors.

Patterns of Transmitted Drug Resistance Mutations and HIV-1 Subtype Dynamics in ART-Naïve Individuals in Veneto, Italy, from 2017 to 2024

This study investigates the prevalence and patterns of transmitted drug resistance mutations (TDRMs) and HIV-1 subtypes among antiretroviral therapy (ART) naïve individuals in Veneto, Italy, from 2017 to 2024. This research aims to understand the dynamic landscape of TDRMs and HIV-1 genetic diversity to inform treatment strategies effectively. We included all adult ART-naïve people with HIV (PWH) from seven infectious disease units in Veneto, Italy. We collected the genotypic resistance testing conducted to predict drug susceptibility and subtype distribution using the Stanford HIVdb algorithm. We included 762 PWH, showing a slight but statistically significant decline in the B subtype among Italian PWH (p = 0.045) and an increase in non-B subtypes among foreigners, though it was not statistically significant (p = 0.333). The most frequent mutations were in Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs), especially in non-B subtypes, with a notable rise from 10.7% in 2017–2019 to 15.5% in 2020–2024. Notably, TDRMs were consistently detected, highlighting an ongoing challenge despite the stable prevalence observed over the years. In addition, the data revealed a concerning rise in mutations against newer drug classes, such as integrase inhibitors. Conclusively, the study underscores the necessity of continuous surveillance of HIV subtypes and resistance patterns to adapt ART regimens optimally. Despite the stable levels of drug resistance, the emergence of resistance against newer drugs necessitates ongoing vigilance and possible adjustment in treatment protocols to enhance clinical outcomes and manage HIV drug resistance effectively.

Dynamic changes in seizure state and anxiety-like behaviors during pentylenetetrazole kindling in rats

IntroductionExcessive anxiety is a mental disorder, and its treatment involves the use of benzodiazepines, a class of drugs that enhance the effects of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor. Anxiety disorders are frequent comorbidities in patients with epilepsy, and it has been speculated that anxiety disorders and epileptic seizures share common neurobiological mechanisms. However, conflicting results regarding anxiolytic and anxiogenic effects have been reported in animal models of epilepsy induced by pentylenetetrazole (PTZ) injections, and the causes of this discrepancy are unknown. We hypothesized that anxiety-like behaviors would change dynamically according to the changes in epilepsy susceptibility that occur during the PTZ kindling process. Therefore, we attempted to change anxiety-like behaviors bidirectionally depending on the number of PTZ injections. MethodsAdult male rats were injected with PTZ 20 times every other day, and stages of seizure onset were classified according to the Racine staging system. Anxiety-like behaviors were measured after 10 and 20 injections. The control group was injected with an equal volume of saline solution. Anxiety-like behaviors were investigated using the open-field, light/dark transition, elevated plus maze, and social interaction tests. ResultsBimodal changes in seizure stage were observed in response to PTZ kindling. The increase in the seizure stage was transiently suppressed after 10 injections, and this decrease in epileptic sensitivity disappeared after 20 injections. However, none of the rats reached a fully kindled state after 20 PTZ injections. After 10 PTZ injections, anxiety-like behaviors decreased compared with those of the control group in the open field, light/dark transition, and elevated plus-maze tests. The anxiolytic effects correlated with the seizure stage in individual rats. After 20 PTZ injections, anxiety-like behaviors returned to control levels. ConclusionPTZ kindling induced bimodal changes in the seizure stage. Anxiety-like behaviors decreased with transient decrease in epileptic sensitivity and returned to control levels with the disappearance of these states. These findings suggest a common neurobiological mechanism underlying anxiety disorders and epileptic seizures. In addition, the discrepancy in the previous studies, in which anxiety levels increase or decrease in PTZ-kindled animals, may be due to examination at different phases of the kindling process.

Take-home naloxone administered in emergency settings: feasibility of intervention implementation in a cluster randomized trial

BackgroundOpioids kill more people than any other class of drug. Naloxone is an opioid antagonist which can be distributed in kits for peer administration. We assessed the feasibility of implementing a Take-home Naloxone (THN) intervention in emergency settings, as part of designing a definitive randomised controlled trial (RCT).MethodsWe undertook a clustered RCT on sites pairing UK Emergency Departments (ED) and ambulance services. At intervention sites, we recruited emergency healthcare practitioners to supply THN to patients presenting with opioid overdose or related condition, with recruitment across 2019–2021. We assessed feasibility of intervention implementation against four predetermined progression criteria covering site sign up and staff training; identification of eligible patients; issue of THN kits and Serious Adverse Events.ResultsAt two intervention sites, randomly selected from 4, 299/687 (43.5%) clinical staff were trained (ED1 = 107, AS1 = 121, ED2 = 25, AS2 = 46). Sixty THN kits were supplied to eligible patients (21.7%) (n: ED1 = 36, AS1 = 4, ED2 = 16, AS2 = 4). Across sites, kits were not issued to eligible patients on a further 164 occasions, with reasons reported including: staff forgot (n = 136), staff too busy (n = 15), and suspected intentional overdose (n = 3), no kit available (n = 2), already given by drugs nurse (n = 4), other (n = 4). Staff recorded 626 other patients as ineligible but considered for inclusion, with reasons listed as: patient admitted to hospital (n = 194), patient absconded (n = 161) already recruited (n = 64), uncooperative or abusive (n = 55), staff not trained (n = 43), reduced consciousness level (n = 41), lack of capacity (n = 35), patient in custody (n = 21), other (n = 12). No adverse events were reported.ConclusionStaff and patient recruitment were low and varied widely by site. This feasibility study did not meet progression criteria; a fully powered RCT is not planned.Trial RegistrationISRCTN13232859 (Registered 16/02/2018).

Pharmacotherapy of motor symptoms in early and mid-stage Parkinson's disease: guideline "Parkinson's disease" of the German Society of Neurology.

There are multiple pharmacological treatment options for motor symptoms of Parkinson's disease (PD). These comprise multiple drug classes which are approved for the condition, including levodopa, dopamine agonists, COMT inhibitors, MAO-B inhibitors, NMDA-receptor antagonists, anticholinergics, and others. Some of the drugs are approved for monotherapy and combination therapy while others are only approved as adjunctive therapy to levodopa. Furthermore, treatment for special treatment situations, e.g., rescue medication for off-phases, for tremor, treatment during pregnancy and breast feeding is discussed and recommendations are given with further details. The recommendations were based on systematic literature reviews, drafted by expert teams, consented in online polls followed by online consensus meetings of the whole German Parkinson's Guideline Group, and publicly released in November 2023. In the new S2k (i.e., consensus-based) guidelines, the pharmacotherapy of the motor symptoms of PD is discussed in five chapters. These comprise "Parkinson medication", "Initial monotherapy", "Early combination therapy", "Fluctuations and dyskinesia", and "Parkinsonian tremor". Furthermore, there is a chapter for special treatment situations, including perioperative management, freezing of gait, and pregnancy and breastfeeding. The recommendations for the pharmacotherapy of motor symptoms of PD have been updated. Newly available drugs have been added, while other drugs (e.g., ergoline dopamine agonists, anticholinergics, budipine) have been removed from the recommendations.

Infliximab (Remsima SC)

Reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada’s federal, provincial, and territorial governments, with the exception of Quebec. This review assesses Description infliximab (Remsima SC), 120 mg/mL solution for subcutaneous injection. Indication: Maintenance treatment of adults with moderately to severely active Crohn disease who have had an inadequate response to or were intolerant of conventional therapy. Remsima SC should be used only as maintenance therapy after the completion of an induction period with IV infliximab.

Sulindac exhibits anti-proliferative and anti-invasive effects in uterine serous carcinoma cells

PurposeUterine serous carcinoma (USC) is a highly aggressive and frequently recurring subtype of endometrial cancer with limited treatment options for advanced or recurrent stages. Sulindac, a classic non-steroidal anti-inflammatory drug, has demonstrated anti-tumor activity in several pre-clinical tumor models. This study aims to evaluate the effect of sulindac on cell proliferation and invasion in USC cells.MethodsHuman USC cell lines ARK-1 and SPEC2 were treated with different concentrations of sulindac. Cell proliferation was assessed using MTT and colony formation assays. ELISA assays measured cellular stress, cleaved caspase 3 activity, antioxidant ability, and adhesion. Cell cycle arrest was evaluated by Cellometer. The invasive capability was detected by wound healing assay. Western blotting was used to analyze the changes in protein expression induced by sulindac.ResultsExposure to sulindac decreased cellular viability in a dose-dependent manner in ARK-1 and SPEC2 cells. Sulindac effectively inhibited cell cycle progression, increased cellular stress, caused apoptosis, and reduced cell adhesion and invasion in USC cells. Additionally, sulindac decreased the expression of COX-2 and blocked phosphorylation of NF-κB induced by TNF-α.ConclusionSulindac is a potential therapeutic agent for USC that deserves further exploration in pre-clinical studies and potentially future clinical trials.