Pharmacotherapeutic Strategies Research Articles

Influence of the Type of Antiretroviral Treatment on the Time to Reach High Pharmacotherapy Complexity in People Living With HIV.

The introduction of antiretroviral therapy (ARV) has significantly improved the survival of people living with HIV (PLWH), increasing the proportion of individuals over 50 years old. This aging trend poses challenges, such as the development of age-related comorbidities and a higher prevalence of polypharmacy. The pharmacotherapeutic complexity, assessed using the Medication Regimen Complexity Index (MRCI), is crucial for identifying and optimizing treatment, especially in elderly and polymedicated patients. The main objective was to assess the association between different ARV regimens and the time required to reach a high level of pharmacotherapeutic complexity in PLWH. A single-center observational analytical research study was conducted, including adult PLWH on active ARV from January 2010 to December 2021 with follow-up until December 2023. An analysis of the time to reach MRCI ≥11.25 was performed, followed by a Cox regression model to determine the influence of ARV on high MRCI. A total of 789 PLWH were included, median age of 52 years (interquartile range: 45-58). Overall, 195 patients had an MRCI value ≥11.25 with a mean time to reach it of 181.86 months (95% confidence interval [CI]: 176.24 to 187.49). Significant differences were observed in sex, advanced age, AIDS stage, presence of comorbidities, polypharmacy, and ARV-related variables. A multivariate Cox proportional hazards model showed an association between integrase inhibitor (INSTI)-containing regimens (hazard ratio [HR]: 1.83; 95% CI: 1.08 to 3.10) and non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens (HR: 0.72; 95% CI: 0.52 to 0.98) with the time to reach high MRCI. In summary, NNRTI-based regimens were associated with a lower likelihood of developing high MRCI compared to INSTI-based regimens, which was associated with a higher likelihood. These conclusions are based on a profile of PLWH that included advanced age and a high prevalence of comorbidities and polypharmacy. Identifying high MRCI may help us implement pharmacotherapeutic optimization strategies to improve health outcomes.

Pharmacotherapy Effectiveness in Treating Mental Disorders in Kosovo's Specialized Institutions

Abstract: In various global regions, specialized institutions rigorously supervise pharmacological treatments for mental health disorders. In Kosovo, the absence of such dedicated infrastructure highlights the need for continuous evaluations to refine and enhance treatment practices. Objective: This study evaluates the effectiveness of pharmacotherapeutic strategies for mental health disorders at specialized centers in Kosovo. Methodology: The research followed the protocols set by the World Health Organization (WHO). Patient data were collected from medical records. A total of 400 patients were analyzed, selected randomly from different cities with sample sizes ranging from 50 to 90 per city. Results: Medication was administered orally in 106.8% of the cases, with no significant differences in administration methods between centers (Chi-Test = 36, p > 0.22) (Tab. 4). Most prescribed medications were classified as non-essential (85.9%). Of the medications prescribed, 69.2% were antipsychotics, 22.3% were anxiolytics, and 14.8% were antidepressants, making up 100% of all drugs used. Conclusion: In Kosovo's mental health facilities, oral administration is the predominant method (PO), with 22.9% of cases involving parenteral administration. The majority of prescribed medications were non-essential (85.9%). Antipsychotics were the most commonly prescribed (69.2%). Often, second-line medications are used as the initial treatment choice. The use of effective but high-risk medications is common (e.g., Clozapine at 100.0% from the SDA group). Ineffective medications were observed in 2.50% of cases, and a misalignment between treatment and drug indications occurred in 7.50% of cases.

Off-Label Use of Lamotrigine and Naltrexone in the Treatment of Ketamine Use Disorder: A Case Report.

Ketamine is a dissociative anesthetic increasingly utilized in United States medical settings for the treatment of mental health conditions. Additionally, it is increasingly used in nonmedical settings for its dissociative properties. While nonmedical ketamine use and ketamine use disorder (KUD) have been observed internationally, KUD, and approaches to its treatment, have not been previously described in the US. We present the case of a 32-year-old man with KUD who experienced severe cravings despite receipt of residential and intensive outpatient substance use disorder treatment. He resumed use after an initial period of abstinence and was subsequently started on lamotrigine and naltrexone for treatment of depressive symptoms and cravings. This combination altered his experience while on ketamine, resulting in nausea and decreased hallucinogenic effects. In addition, it substantially decreased his cravings, aiding him in achieving longer-term abstinence in combination with receipt of dialectical behavioral therapy, familial support, and involvement in 12-step programming. KUD is a poorly described condition that may become more prevalent as US ketamine use increases. Combining treatment of depressive symptoms and cravings, in this case with lamotrigine and naltrexone, may be a promising pharmacotherapeutic strategy. Lamotrigine, an antiepileptic with glutamate modulating effects, has been utilized to decrease cravings in a variety of substance use disorders. Naltrexone is an opioid antagonist approved for alcohol use disorder and opioid use disorder and is used off-label for stimulant use disorder. This combination offers a possible pharmacotherapeutic option for KUD with more research needed to further evaluate.

Pharmacotherapy for Coronary Artery Disease and Acute Coronary Syndrome in the Aging Population.

To provide a comprehensive summary of relevant studies and evidence concerning the utilization of different pharmacotherapeutic and revascularization strategies in managing coronary artery disease and acute coronary syndrome specifically in the older adult population. Approximately 30% to 40% of hospitalized patients with acute coronary syndrome are older adults, among whom the majority of cardiovascular-related deaths occur. When compared to younger patients, these individuals generally experience inferior clinical outcomes. Most clinical trials assessing the efficacy and safety of various therapeutics have primarily enrolled patients under the age of 75, in addition to excluding those with geriatric complexities. In this review, we emphasize the need for a personalized and comprehensive approach to pharmacotherapy for coronary heart disease and acute coronary syndrome in older adults, considering concomitant geriatric syndromes and age-related factors to optimize treatment outcomes while minimizing potential risks and complications. In the realm of clinical practice, cardiovascular and geriatric risks are closely intertwined, with both being significant factors in determining treatments aimed at reducing negative outcomes and attaining health conditions most valued by older adults.

Review of Pharmacotherapeutic Targets in Alzheimer's Disease and Its Management Using Traditional Medicinal Plants.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. While there is currently no cure for AD, several pharmacotherapeutic targets and management strategies have been explored. Additionally, traditional medicinal plants have gained attention for their potential role in AD management. Pharmacotherapeutic targets in AD include amyloid-beta (Aβ) aggregation, tau protein hyperphosphorylation, neuroinflammation, oxidative stress, and cholinergic dysfunction. Traditional medicinal plants, such as Ginkgo biloba, Huperzia serrata, Curcuma longa (turmeric), and Panax ginseng, have demonstrated the ability to modulate these targets through their bioactive compounds. Ginkgo biloba, for instance, contains flavonoids and terpenoids that exhibit neuroprotective effects by reducing Aβ deposition and enhancing cerebral blood flow. Huperzia serrata, a natural source of huperzine A, has acetylcholinesterase-inhibiting properties, thus improving cholinergic function. Curcuma longa, enriched with curcumin, exhibits anti-inflammatory and antioxidant effects, potentially mitigating neuroinflammation and oxidative stress. Panax ginseng's ginsenosides have shown neuroprotective and anti-amyloidogenic properties. The investigation of traditional medicinal plants as a complementary approach to AD management offers several advantages, including a lower risk of adverse effects and potential multi-target interactions. Furthermore, the cultural knowledge and utilization of these plants provide a rich source of information for the development of new therapies. However, further research is necessary to elucidate the precise mechanisms of action, standardize preparations, and assess the safety and efficacy of these natural remedies. Integrating traditional medicinal-plant-based therapies with modern pharmacotherapies may hold the key to a more comprehensive and effective approach to AD treatment. This review aims to explore the pharmacotherapeutic targets in AD and assess the potential of traditional medicinal plants in its management.

The Most Effective Drugs in the Treatment of Myocarditis Disease


 Myocarditis, characterized by inflammation of the heart muscle, presents a complex and challenging clinical scenario. This review explores the landscape of pharmacological interventions in the treatment of myocarditis, aiming to identify the most effective drugs in managing this inflammatory cardiac condition. A comprehensive analysis of current literature encompasses clinical trials, observational studies, and experimental models to evaluate the efficacy of various drug classes. From immunosuppressive agents to anti-inflammatory medications, the review delineates the mechanisms of action, safety profiles, and clinical outcomes associated with different drug interventions. The synthesis of evidence provides valuable insights into the pharmacotherapeutic strategies that demonstrate the highest efficacy in mitigating inflammation, preserving cardiac function, and improving patient outcomes in myocarditis

Synergistic effect of potential alpha-amylase inhibitors from Egyptian propolis with acarbose using in silico and in vitro combination analysis

BackgroundType 2 Diabetes mellitus (DM) is an affliction impacting the quality of life of millions of people worldwide. An approach used in the management of Type 2 DM involves the use of the carbohydrate-hydrolyzing enzyme inhibitor, acarbose. Although acarbose has long been the go-to drug in this key approach, it has become apparent that its side effects negatively impact patient adherence and subsequently, therapeutic outcomes. Similar to acarbose in its mechanism of action, bee propolis, a unique natural adhesive biomass consisting of biologically active metabolites, has been found to have antidiabetic potential through its inhibition of α-amylase. To minimize the need for ultimately novel agents while simultaneously aiming to decrease the side effects of acarbose and enhance its efficacy, combination drug therapy has become a promising pharmacotherapeutic strategy and a focal point of this study.MethodsComputer-aided molecular docking and molecular dynamics (MD) simulations accompanied by in vitro testing were used to mine novel, pharmacologically active chemical entities from Egyptian propolis to combat Type 2 DM. Glide docking was utilized for a structure-based virtual screening of the largest in-house library of Egyptian propolis metabolites gathered from literature, in addition to GC–MS analysis of the propolis sample under investigation. Thereafter, combination analysis by means of fixed-ratio combinations of acarbose with propolis and the top chosen propolis-derived phytoligand was implemented.ResultsAucubin, identified for the first time in propolis worldwide and kaempferol were the most promising virtual hits. Subsequent in vitro α-amylase inhibitory assay demonstrated the ability of these hits to significantly inhibit the enzyme in a dose-dependent manner with an IC50 of 2.37 ± 0.02 mM and 4.84 ± 0.14 mM, respectively. The binary combination of acarbose with each of propolis and kaempferol displayed maximal synergy at lower effect levels. Molecular docking and MD simulations revealed a cooperative binding mode between kaempferol and acarbose within the active site.ConclusionThe suggested strategy seems imperative to ensure a steady supply of new therapeutic entities sourced from Egyptian propolis to regress the development of DM. Further pharmacological in vivo investigations are required to confirm the potent antidiabetic potential of the studied combination.

Pharmacological characterization of SAGE-718, a novel positive allosteric modulator of N-methyl-d-aspartate receptors.

Select neuroactive steroids tune neural activity by modulating excitatory and inhibitory neurotransmission, including the endogenous cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-HC), which is an N-methyl-d-aspartate (NMDA) receptor positive allosteric modulator (PAM). NMDA receptor PAMs are potentially an effective pharmacotherapeutic strategy to treat conditions associated with NMDA receptor hypofunction. Using in vitro and in vivo electrophysiological recording experiments and behavioural approaches, we evaluated the effect of SAGE-718, a novel neuroactive steroid NMDA receptor PAM currently in clinical development for the treatment of cognitive impairment, on NMDA receptor function and endpoints that are altered by NMDA receptor hypoactivity and assessed its safety profile. SAGE-718 potentiated GluN1/GluN2A-D NMDA receptors with equipotency and increased NMDA receptor excitatory postsynaptic potential (EPSP) amplitude without affecting decay kinetics in striatal medium spiny neurons. SAGE-718 increased the rate of unblock of the NMDA receptor open channel blocker ketamine on GluN1/GluN2A in vitro and accelerated the rate of return on the ketamine-evoked increase in gamma frequency band power, as measured with electroencephalogram (EEG), suggesting that PAM activity is driven by increased channel open probability. SAGE-718 ameliorated deficits due to NMDA receptor hypofunction, including social deficits induced by subchronic administration of phencyclidine, and behavioural and electrophysiological deficits from cholesterol and 24(S)-HC depletion caused by 7-dehydrocholesterol reductase inhibition. Finally, SAGE-718 did not produce epileptiform activity in a seizure model or neurodegeneration following chronic dosing. These findings provide strong evidence that SAGE-718 is a neuroactive steroid NMDA receptor PAM with a mechanism that is well suited as a treatment for conditions associated with NMDA receptor hypofunction.

Estimating the extent to which chronic kidney disease mediates the association between metabolic syndrome and heart failure: the Atherosclerosis Risk in Communities (ARIC) Study

Abstract Background/Introduction Metabolic Syndrome (MetS) is linked to increased risk of developing heart failure (HF), underscoring a need to implement more aggressive lifestyle and pharmacotherapeutic HF prevention strategies. Chronic kidney disease (CKD) is associated with MetS and is a risk factor for HF; however, therapies protective against both kidney function decline and HF risk such as ACEi/ARBs and SGLT2i are underutilized among individuals with MetS. A potential contributor to this underutilization is that creatinine (Cr)- based estimates of glomerular filtration rate (eGFR) may underestimate the role of CKD as a mediator of HF risk relative to Cystatin-C (CysC) based eGFR. Purpose To compare estimations of the relationship between MetS and kidney function, and of the extent to which eGFR mediates the link between MetS and incident HF, using CysC-based versus Cr-based eGFR. Methods Among ARIC Visit 4 (1996-1998) participants without baseline HF, we used linear regression to assess the cross-sectional association of MetS severity (measured using an established z-score, modeled in quartiles and continuously) with eGFR, with comparisons across 3 different eGFR equations (CKD-Cr 2021, CKD-Cr-CysC 2021 and CKD-CysC 2012). In prospective analyses, we used Cox regression and mediation analyses to estimate the extent to which kidney function mediated the association between MetS and incident HF after Visit 4 through 12/31/2019, with comparisons across the 3 eGFR equations. Results Among 8,582 participants (mean age 63.1 years, 56.9% women, 18.4% Black adults), 1,803 developed HF over a median follow-up of 21 years. MetS was more strongly associated with eGFR when using eGFR estimates that included CysC, with the 4th vs 1st quartile of MetS Z-score associated with an adjusted eGFR difference of -2.55 ml/min/1.73m2 (95% CI -3.36 to -1.73) for CKD-Cr, -8.07 ml/min/1.73m2 (95% CI -8.95 to -7.19) for CKD-Cr-CysC and -10.74 ml/min/1.73m2 (95% CI -11.67 to -9.80) for CKD-CysC. In prospective analyses, we also estimated greater mediation by kidney function of the association between MetS and incident HF when using eGFR equations that included CysC. The strength of the association between MetS and HF potentially mediated by kidney function increased from 3.0% to 15.2% to 24.2%, respectively, when using eGFR-Cr vs eGFR-Cr-CysC vs eGFR-CysC (Table and Figure). These estimates were not significantly attenuated after additional adjustment for coronary heart disease and C-reactive protein. Conclusion(s) The degree of kidney function reduction associated with MetS, and the subsequent implications of kidney dysfunction for HF risk in those with MetS, are underestimated using eGFR-Cr equations compared to eGFR equations including CysC. Greater appreciation by clinicians of the impact of kidney disease on HF risk among individuals with MetS could help increase utilization of kidney-protective therapies that can lower HF risk.

Pharmacotherapeutic management of advanced therapy medicinal products

Advanced therapy medicinal products have emerged In recent years as new pharmacotherapeutic strategies. In this context, hospital pharmacy services have had to adapt to the new challenges posed by the inclusion of advanced therapies in their roster of services against the background of the complex pharmacotherapeutic process patients typically go through.All the activities carried out in the hospital pharmacy services must abide by the rules established in the Spanish legislation and ensure both the quality of the different drugs they manage and the safety of every single patient.Advanced therapy medicinal products are associated certain peculiarities, including the need to select and evaluate potential candidates to receive them; recourse to financing mechanisms based on risk sharing; and their extreme fragility, which means that the personnel in charge of handling them must be properly trained to maintain their viability and that special storage conditions, involving temperatures below 180 °C in the case of chimeric antigen receptor T cell therapies, must be maintained.In addition, use of advanced therapy medicinal products in the clinical setting has made it necessary for scientific societies to produce consensus documents recognizing the pivotal role of hospital pharmacists as indispensable members of the multidisciplinary healthcare team and ensuring the same traceability, conservation, custody and pharmacotherapeutical monitoring standards imposed on other drugs to provide for adequate pharmaceutical care. Scientific societies have also highlighted the importance of intensifying clinical research, an essential requirement for the safe incorporation of new therapeutic targets.The present document is intended to describe the challenges pharmacists may face when using advanced therapy medicinal products at the different stages or processes in the patient's clinical journey.

Significant use of non-evidence-based therapeutics in a cohort of Australian fibromyalgia patients.

Fibromyalgia is a common condition characterised by chronic widespread musculoskeletal pain and central sensitivity features. Appropriate management requires a multidisciplinary approach prioritising non-pharmacological strategies. Evidence-based fibromyalgia medications are not always easily available, effective or tolerated. To characterise actual medication usage in Australian fibromyalgia patients. Demographic and clinical data, including medication use information, were gathered by chart review from patients attending the Monash Fibromyalgia Clinic between January 2019 and June 2022. Eligible patients were invited to complete an anonymous questionnaire between June and August 2022 to assess current therapeutic use. The questionnaire assessed fibromyalgia clinical features by using the Revised Fibromyalgia Impact Questionnaire and the 2016 modified American College of Rheumatology Fibromyalgia criteria. The chart review included 474 patients, and 108 participants completed the questionnaire. Most chart review (78.7%) and questionnaire participants (85.2%) reported using at least one medication for their fibromyalgia. 48.5% of chart review patients and 58.3% of questionnaire participants reported using at least one evidence-based medication, usually amitriptyline, duloxetine or pregabalin. However, the most common individual medications for questionnaire participants were non-steroidal anti-inflammatory drugs (48.2%), paracetamol (59.3%) and opioids (34.3%), with most opioids being typical opioids. Among questionnaire participants, 14.8% reported using cannabinoids, and 70.4% reported using at least one supplement, vitamin or herbal/naturopathic preparation. Not all medication or substance use was recorded during clinic appointments. Fibromyalgia patients engage in various pharmacotherapeutic strategies that are not always evidence-based or disclosed to their treating clinicians.

Depressive disorders and their pharmacotherapy in routine clinical practice

Depression is one of the most common medical causes of disability and mortality in patients of all ages. Depressive disorders are common in the practice of physicians of a variety of specialties, including psychiatrists, neurologists, and physicians. This paper provides a summary review of the literature on modern ideas about the epidemiology, classification, and clinical picture of depression. Current approaches to the diagnosis and treatment of depressive disorders in neurological and psychiatric practice are discussed. Modern pharmacotherapeutic strategies for the treatment of depression in various patient populations are described in detail. Current clinical practice indicates the high importance of an interdisciplinary approach in the diagnosis and management of patients with depressive symptoms in Russia. The paper suggests organizational and educational strategies that can be recommended to improve the effectiveness of medical care for patients with depressive disorders.

Pharmacotherapy in patients with vasomotor disorders.

Anginal symptoms in patients with non-obstructive coronary artery disease are frequently related to vasomotor disorders of the coronary circulation. Although frequently overlooked, a distinct diagnosis of different vasomotor disorders can be made by intracoronary function testing. Early detection and treatment seems beneficial, but little evidence is available for the medical treatment of these disorders. Nevertheless, there are several pharmacotherapeutic options available to treat these patients and improve quality of life. We performed an extensive yet non-systematic literature search to explore available pharmacotherapeutic strategies for addressing vasomotor disorders in individuals experiencing angina and non-obstructive coronary artery disease. This article presents a comprehensive overview of therapeutic possibilities for patients exhibiting abnormal vasoconstriction (such as spasm) and abnormal vasodilation (like coronary microvascular dysfunction). Treatment of vasomotor disorders can be very challenging, but a general treatment algorithm based on the existing evidence and the best available current practice is feasible.

Unrevealing the role of miRNA in successful TNBC treatment: A pilot study to explore the chemotherapy drugs for timely treatment of TNBC

Objectives: Worldwide, breast cancer is the most prevalent and common type of cancer. Physical examination and mammography with a range of sensitivities are currently used as screening methods. Triple-negative breast cancer (TNBC) lacks estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) gene expression. MicroRNAs (miRNA) as potential prognostic and diagnostic biomarkers, miRNA 125, 200c, 221, 21, and 34a were selected for study. Materials and Methods: Here, 25 consenting TNBC patients with negative ER/PR/HER-2 status and compatible history were accrued from the Department of Oncosurgery, All India Institutes of Medical Sciences (AIIMS) Bhopal. Serum from participants and 25 controls was collected for quantitative estimation of miRNA by quantitative real-time polymerase chain reaction. After being treated with epirubicin, capecitabine, and paclitaxel, the MDA-MB-231 cell line’s expression of these miRNA subtypes was also examined. Statistical Analysis: All statistical analyses, pie charts, dot plots, and box-whisker plots were performed using EZR (Easy R), R Commander version 2.7-1. Bar graphs were created using Microsoft Excel 2019 software. Heat map graphics were produced using Graph Prism Version 9. Results: miRNA125 (p< 0.0001) and miRNA21 (p< 0.05) were found to be statistically significant. miR125 (DCt [cycle threshold] 2.77) was seen to be upregulated and miR21 (DCt -1.61) was seen to be downregulated in TNBC patients. Epirubicin treatment caused miR125 to be downregulated, but capecitabine treatment caused miR125 to be upregulated. Paclitaxel was seen to downregulate miR21. All three chemotherapeutic agents were seen to downregulate miR34a. Conclusion: miRNAs can be developed into a reliable biomarker and prognostic tool with more research. They can also help develop and improve pharmaco-therapeutic strategies.

Ethnicity-dependent effect of rs1799971 polymorphism on OPRM1 expression in the postmortem brain and responsiveness to antipsychotics

Schizophrenia is associated with aberration of inhibitory neurons. Although the mu-opioid receptor (MOR) is an essential modulator of inhibitory neurons, the effect of rs1799971 polymorphism in the MOR gene on risk of schizophrenia is controversial. Moreover, the disturbance of opioids systems in patients with schizophrenia has not been fully examined. We firstly conducted preliminary meta-analyses integrating Asian and European populations separately over 12,000 subjects to assess the effect of rs1799971 on risk of schizophrenia. Based on the above result, we also investigated the effect on the expression levels of MOR mRNA in the prefrontal cortex (PFC) and caudate nucleus of 41 postmortem brains. In addition, we determined whether these levels were related to antemortem schizophrenia symptoms and pharmacotherapeutic effects. The rs1799971 G-allele reduced the risk of schizophrenia in Asian populations (OR: 0.56, 95%CI: 0.32–0.98, p = 0.042) but increased it in European populations (OR: 1.66, 95%CI: 1.08–2.56, p = 0.022). It decreased MOR mRNA levels in PFC in the Japanese population (p = 0.031). Increased MOR mRNA level in PFC correlated with higher total score of antemortem schizophrenia symptoms (p = 0.017). Furthermore, the pharmacotherapeutic effect of first-generation antipsychotics was higher for genotype AA than AG/GG of rs1799971 (p = 0.036). The rs1799971 affects risk of schizophrenia and MOR mRNA expression and the effect varies according to ethnicity. Overexpression of MOR might induce severe schizophrenia symptoms. Therefore, MOR modulation may be the key clue for treating antipsychotics-resistant schizophrenia, and genotyping rs1799971 may provide a better pharmacotherapeutic strategy.

Involvement of opioid antagonists on COX-2 activity

Pain is a complex process involving complex molecular and cellular mechanisms and pharmacotherapeutic strategies including nonsteroidal anti-inflammatory drugs (NSAIDs). The main mechanism of action of them, both for their adverse and therapeutic effects, is the inhibition of cyclooxygenases (COXs), one of its isoforms is COX-2 with selective inhibitors such as celecoxib, rofecoxib, and etoricoxib. The objective of this study was to evaluate the nociceptive interaction of COX-2 NSAIDs with other drugs due to the scarce information available in this regard. Antinociception was assessed by the formalin hind paw test evaluated from dose-response curves obtained before and after the i.p. administration of 1,0 mg/kg of naltrexone (NTX), or naltrindole (NTI), or nor-binaltorphimine (nor-BNI) in the assay, using at least 6-8 animals for each of at least 4 doses. Analgesic ratio (AR) expressed as the relation between ED50 of phase II / phase I of FHP indicates the following order of relative potency: celecoxib > parecoxib > etoricoxib. Administration of naltrexone or naltrindole induced a significant reduction of the analgesic activity of celecoxib, etoricoxib and parecoxib, reflected by an increase in the respective ED50 in both phases of FHP assay. However, norbinaltorphimine lack of effect. The results of the work demonstrate that opioid receptors MOR and DOR play a key role in coxib-induced antinociception in the FHP trial and while the KOR opioid receptor seems not to be involved in this antinociception.

Attenuation of Microglial Activation and Pyroptosis by Inhibition of P2X7 Pathway Promotes Photoreceptor Survival in Experimental Retinal Detachment.

Photoreceptor (PR) death is the ultimate cause of irreversible vision loss in retinal detachment (RD). Although microglial infiltration in the subretinal space (SRS) was observed after RD, the molecular mechanism underlying microglial activation and the outcomes of infiltrating microglia remain unclear. We aimed to uncover the mechanism of initiation of microglial activation to help explore potential therapy to promote PR survival. An RD model was conducted by injecting sodium hyaluronate into SRS of C57BL/6J wild type mice. Adenosine triphosphate (ATP) was measured by a ATP Microplate Assay Kit. Bioinformatics analysis was used to evaluate the upregulated receptor relating to ATP binding in human datasets and mouse transcriptomes of RD. Expression of P2X7, its downstream signaling pathways, and microglial pyroptosis were confirmed by qPCR, WB, and immunofluorescence in vivo and in vitro. The cell viability of PR was measured by cell counting kit-8. Brilliant Blue G, a P2X7 antagonist, was subretinally or intraperitoneally injected to inhibit microglial activation in vivo and was applied for microglia cell line treatment in vitro. The decrease in microglial activation and pyroptosis was detected by immunofluorescence and WB. The protective effect on PR was measured by hematoxylin and eosin staining, TUNEL assay, and electroretinogram analysis. The results showed that extracellular ATP released in the SRS after RD triggered P2X7 activation and attracted microglia. The downstream cascade of inflammasome activation induced by P2X7 activation contributed to microglial pyroptosis and then to PR death. ATP-activated microglia led to PR death in vitro. P2X7 blockade rescued PR morphologically and functionally by inhibiting microglial activation and pyroptosis. These results elucidate that ATP-induced P2X7-mediated microglial activation leads to microglial pyroptosis, contributing to PR death. Appropriate inhibition of microglial pyroptosis might serve as a pharmacotherapeutic strategy for decreasing PR death in RD.

Current treatment strategies for EGFR-mutated non-small cell lung cancer: from first line to beyond osimertinib resistance.

Osimertinib, a third-generation EGFR TKI, is the standard therapy for previously untreated EGFR-mutated non-small cell lung cancer patients following the landmark FLAURA study. However, resistance inevitably hinders patient prognosis, increasing the need for new therapeutic strategies beyond osimertinib. Frontline osimertinib-based combination strategies (platinum-based chemotherapy and angiogenesis inhibitors) are currently being tested primarily to prevent initial resistance. In the later-line setting after osimertinib, many next-line therapeutic candidates have been actively examined in clinical trials. Notably, several drugs with novel mechanisms of action, such as antibody-drug conjugates and EGFR -MET bispecific antibodies, have shown promising efficacy despite the resistance mechanisms and are close to clinical application. In addition, genotype-based target strategies have been investigated for a better understanding of osimertinib resistance mechanisms based on molecular profiling tests at relapse. The C797S mutation and MET gene alterations are commonly identified following osimertinib resistance, for which targeting strategies are actively tested. This review describes current pharmacotherapeutic strategies for EGFR-mutated non-small cell lung cancer based on the results of clinical trials and the latest published data, broadly grouped into two sections: 1) EGFR TKIs-based combination therapy in the front-line setting and 2) novel therapeutic strategies after osimertinib resistance.

LRP1 Deficiency Promotes Mitostasis in Response to Oxidative Stress: Implications for Mitochondrial Targeting after Traumatic Brain Injury.

The brain undergoes oxidative stress and mitochondrial dysfunction following physiological insults such as Traumatic brain injury (TBI), ischemia-reperfusion, and stroke. Pharmacotherapeutics targeting mitochondria (mitoceuticals) against oxidative stress include antioxidants, mild uncouplers, and enhancers of mitochondrial biogenesis, which have been shown to improve pathophysiological outcomes after TBI. However, to date, there is no effective treatment for TBI. Studies have suggested that the deletion of LDL receptor-related protein 1 (LRP1) in adult neurons or glial cells could be beneficial and promote neuronal health. In this study, we used WT and LRP1 knockout (LKO) mouse embryonic fibroblast cells to examine mitochondrial outcomes following exogenous oxidative stress. Furthermore, we developed a novel technique to measure mitochondrial morphometric dynamics using transgenic mitochondrial reporter mice mtD2g (mitochondrial-specific Dendra2 green) in a TBI model. We found that oxidative stress increased the quantity of fragmented and spherical-shaped mitochondria in the injury core of the ipsilateral cortex following TBI, whereas rod-like elongated mitochondria were seen in the corresponding contralateral cortex. Critically, LRP1 deficiency significantly decreased mitochondrial fragmentation, preserving mitochondrial function and cell growth following exogenous oxidative stress. Collectively, our results show that targeting LRP1 to improve mitochondrial function is a potential pharmacotherapeutic strategy against oxidative damage in TBI and other neurodegenerative diseases.

Preclinical Models and Promising Pharmacotherapeutic Strategies in Liver Fibrosis: An Update.

Liver fibrosis represents one of the greatest challenges in medicine. The fact that it develops with the progression of numerous diseases with high prevalence (NAFLD, viral hepatitis, etc.) makes liver fibrosis an even greater global health problem. Accordingly, it has received much attention from numerous researchers who have developed various in vitro and in vivo models to better understand the mechanisms underlying fibrosis development. All these efforts led to the discovery of numerous agents with antifibrotic properties, with hepatic stellate cells and the extracellular matrix at the center of these pharmacotherapeutic strategies. This review focuses on the current data on numerous in vivo and in vitro models of liver fibrosis and on various pharmacotherapeutic targets in the treatment of liver fibrosis.