Significant Drug Effects Research Articles

Assessing the health implications of anticholinergic drugs in older people

In this narrative review, we analyzed the existing literature on the pros and cons of anticholinergic medications, focusing on their prevalence, underlying mechanisms, and methods of assessment. Our review underscores the significant adverse effects of anticholinergic drugs, particularly on cognition and functional abilities in older adults. These effects include the exacerbation of various cognitive states, increased psychiatric symptoms, heightened risk of delirium, functional decline, elevated hospitalization rates, greater likelihood of institutionalization, and increased mortality. While anticholinergic medications provide therapeutic benefits, their use in older adults requires careful evaluation due to these considerable risks. Discontinuation of anticholinergic therapy offers both benefits and challenges. We propose practical guidelines for their use in clinical contexts such as dementia, schizophrenia, depression, anxiety, Parkinson’s disease, cardiovascular conditions, and urinary incontinence.

"Expectancy-Mood Neural Dynamics Predict Mechanisms of Short- and Long-Term Antidepressant Placebo Effects".

Acute experimental models of antidepressant placebo effects suggest that expectancies, encoded within the salience network (SN), are reinforced by sensory evidence and mood fluctuations. However, whether these dynamics extend to longer timescales remains unknown. To answer this question, we investigated how SN and default mode network (DMN) functional connectivity during the processing of antidepressant expectancies facilitates the shift from salience attribution to contextual cues in the SN to belief-induced mood responses in the DMN, both acutely and long-term. Sixty psychotropic-free patients with major depressive disorder (MDD) completed an acute antidepressant placebo fMRI experiment manipulating placebo-associated expectancies and their reinforcement while assessing trial-by-trial mood improvement, before entering an 8-week double-blind, randomized, placebo-controlled trial (RCT) of a selective serotonin reuptake inhibitor (SSRI) or placebo. Learned antidepressant expectancies predicted by a reinforcement learning model modulated SN-DMN connectivity. Acutely, greater modulation predicted higher effects of expectancy and reinforcement manipulations on reported expectancies and mood. Over 8 weeks, no significant drug effects on mood improvement were observed. However, participants who believed they were receiving an antidepressant exhibited significantly greater mood improvement, irrespective of the actual treatment received. Moreover, increased SN-DMN connectivity predicted mood improvement, especially in placebo-treated participants who believed they received an SSRI. SN-DMN interactions may play a critical role in the evolution of antidepressant response expectancies, drug-assignment beliefs, and their effects on mood.

Insights into mitochondrial creatine kinase: examining preventive role of creatine supplement in doxorubicin-induced cardiotoxicity

Doxorubicin (Dox) is an effective and commonly used anticancer drug; however, it leads to several side effects including cardiotoxicity which contributes to poor quality of life for cancer patients. Creatine (Cr) is a promising intervention to alleviate Dox-induced cardiotoxicity. This study aimed to examine the effects of Cr beforeDox on cardiac mitochondrial creatine kinase (MtCK). Male rats were randomly assigned to one of two 4-week Cr feeding interventions (standard Cr diet or Cr loading diet) or a control diet (Con, n = 20). Rats in the standard Cr diet (Cr1, n = 20) were fed 2% Cr for 4-weeks. Rats in the Cr loading diet (Cr2, n = 20) were fed 4% Cr for 1-week followed by 2% Cr for 3-weeks. After 4-weeks, rats received either a bolus injection of 15 mg/kg Dox or a placebo saline injection (Sal). Five days post-injections left ventricle (LV) was excised and analyzed for MtCK expression using Western blot and ELISA. A significant drug effect was observed for LV mass (p < 0.05), post hoc testing revealed LV mass of Con + Dox and Cr2 + Dox was significantly lower than Con + Sal (p < 0.05). A significant drug effect was observed for MtCK (p = 0.03) through Western blot. A significant drug effect (p = 0.03) and interaction (p = 0.02) was observed for MtCK using ELISA. Post hoc testing revealed that Cr2 + Dox had significantly higher MtCK than Cr1 + Sal and Cr2 + Sal. Data suggest that a reduction in LV mass and MtCK may contribute to Dox-induced cardiotoxicity, and Cr supplementation may play a potential role in mitigating cardiotoxicity by preserving mitochondrial CK.

Protective effect of carbon dots as antioxidants on intestinal inflammation by regulating oxidative stress and gut microbiota in nematodes and mouse models

Inflammatory bowel disease (IBD) is a recurrent chronic colitis disease with increasing incidence and prevalence year by year. The single efficacy and significant side effects of traditional IBD treatment drugs have promoted the flourishing development of new drugs. Inspired by many health benefits of carbon dots (CDs) based nanomedicine in biomedical applications, a metal-free carbon dots (CP-CDs) was synthesized from citric acid and polyethylene polyamine to treat colitis. Oxidative stress tests at the cellular and nematode levels demonstrated CP-CDs have good antioxidant effects, while the toxicity of CP-CDs to cells and nematodes is low. CP-CDs were further applied to dextran sodium sulfate (DSS)-induced colitis in mice models, and it was found that CP-CDs can reduce the disease activity index (DAI) score of colon tissue and restore the intestinal barrier. Further, the anti-colitis mechanisms of CP-CDs were explored, one of which is to regulate intestinal oxidative stress in inflammatory mice, further reducing the expression of inflammatory cytokines, and thus alleviating colitis. Notably, 16S rRNA sequence analysis showed that the abundance of beneficial bacteria (Ligilactobacillus and Enterorhabdus) in the intestinal tract increased, while that of harmful bacteria (unclassified_Clostridia_UCG_014) decreased after CP-CDs treatment, indicating that CP-CDs rebalancing the gut microbiota destroyed by DSS is another important mechanism. In short, these non-toxic carbon dots not only have the potential for multi-factor combined relief of colitis but also offer an alternative therapy medicine for patients suffering from IBD.

Evaluation of outcomes of calcitonin gene-related peptide (CGRP)-targeting therapies for acute and preventive migraine treatment based on patient sex.

Women show increased prevalence and severity of migraine compared to men. Whether small molecule calcitonin gene-related peptide receptor (CGRP-R) antagonists (i.e., gepants) and monoclonal antibodies targeting either the CGRP-R or the CGRP peptide might show sexually dimorphic outcomes for acute and preventive therapy has not been established. We conducted a subpopulation analysis of available published data from FDA reviews to evaluate potential sex differences in the response rates of ubrogepant, rimegepant and zavegepant for acute migraine therapy. Available data from FDA reviews of erenumab, fremanezumab, galcanezumab and eptinezumab, approved CGRP-R and CGRP monoclonal antibodies and of atogepant were examined for prevention outcomes based on patient sex. Preventive outcomes were analyzed separately for patients with episodic migraine and chronic migraine. In women, the three approved gepants produced statistically significant drug effects regardless of dose tested on the FDA mandated co-primary endpoints, the proportion of patients achieving two-hour pain-freedom and the proportion of patients free of their most bothersome symptom at two hours post-dose. In women, the average placebo-subtracted two-hour pain-freedom proportion was 9.5% (CI: 7.4 to 11.6) and the average numbers needed to treat was 11. The free from most bothersome symptom at two hours outcomes were also significant in women. The gepant drugs did not reach statistically significant effects on the two-hour pain-freedom endpoint in the men, with an average drug effect of 2.8% (CI: -2.5 to 8.2) and an average number needed to treat of 36. For freedom from most bothersome symptom at two hours post-dose endpoint, differences were not significant in male patients. The treatment effect in each of the gepant studies was always numerically greater in women than in men. In evaluation of prevention outcomes with the antibodies or atogepant using the change from the specified primary endpoint (e.g., monthly migraine days), the observed treatment effect for episodic migraine patients almost always favored drug over placebo in both women and men. For chronic migraine patients the treatment effects of antibodies were similar in men and women and always favored the drug treated group.Conclusion/Interpretation: Small molecule CGRP-R antagonists are effective in acute migraine therapy in women but available data do not demonstrate effectiveness in men. CGRP-targeting therapies are effective for migraine prevention in both male and female episodic migraine patients but possible sex differences remain uncertain. In male and female chronic migraine patients, CGRP/CGRP-R antibodies were similarly effective. The data highlight possible differential effects of CGRP targeted therapies in different patient populations and the need for increased understanding of CGRP neurobiology in men and women.

Research progress of nanoparticles in diagnosis and treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is among the most common malignant liver tumors. Despite progress in anticancer drugs and surgical approaches, early detection of HCC remains challenging, often leading to late-stage diagnosis where rapid disease progression precludes surgical intervention, leaving chemotherapy as the only option. However, the systemic toxicity, low bioavailability, and significant adverse effects of chemotherapy drugs often lead to resistance, rendering treatments ineffective for many patients. This article outlines how nanoparticles, following functional modification, offer high sensitivity, reduced drug toxicity, and extended duration of action, enabling precise targeting of drugs to HCC tissues. Combined with other therapeutic modalities and imaging techniques, this significantly enhances the diagnosis, treatment, and long-term prognosis of HCC. The advent of nanomedicine provides new methodologies and strategies for the precise diagnosis and integrated treatment of HCC.

Dry Eyes Illness in Psychiatric Patients Placed on Antipsychotic Medications

Introduction: Psychosis is used to describe conditions that affect the mind where there has been loss of contact with reality. Most psychotic disorders are treated with a combination of medications and psychotherapy. A significant ocular side effect of anti-psychotic drugs is dry eyes which often do not get adequate attention thus leading to great discomfort to the patient. Methodology: The study was a hospital-based, case-control prospective study where patients diagnosed with a psychotic disorders within the age groups of 18 to 70 years and who have been on anti-psychotic treatment for at least one year were examined by a consultant ophthalmologist. Healthy adults were enrolled from the Ophthalmology outpatient clinic as the control for the study. Result: The case group comprised 53(44.9%) males and 65(55.1%) females. The age group with the highest representation amongst the cases- 29.7% was the 29-38-year-olds. On the medication history, 65(55.1%) started taking antipsychotic drugs within 1-5 years. 65.3% of the respondents were on antipsychotic monotherapy-commonly Olanzapine tablets. Schirmer’s test was normal in most of the participants in both cases 50.8% and control 53.4% but those that have been on medication for 5 years or less demonstrated the highest occurrence of severe dry eyes with a prevalence rate of 23.1% while those on medication for over 10 years showed a higher prevalence of mild dry eyes accounting for 20.8% of the cases. Tear film Break-up Time (TBUT) showed Dry eyes in 50.8% of cases. A significant proportion (56.9%) of those who had been on medication for 1-5 years were found to be exhibiting dry eyes. Conclusion: An association was observed between Dry eye disease and antipsychotic medication as early as within 1-5 years of using the medication. Ophthalmic assessment should be incorporated early in the course of treatment.

The Characterization of Non-oncologic Chronic Drug Therapy in Bladder Cancer Patients and the Impact on Recurrence-Free and Cancer-Specific Survival: A Prospective Study

We aimed to characterize non-oncologic chronic drug therapy of bladder cancer (BC) patients and evaluate a possible impact on recurrence-free (RFS) and cancer-specific survival (CSS). Patients with a first diagnosis (FD) of BC or radical cystectomy (RC) were included in a prospective, monocentric, observational study. Drugs and medical data was assessed at start and three-monthly for 24 months. Drugs were classified by anatomical-therapeutic-chemical code (ATC). Endpoints for outcome analysis were RFS and CSS in univariate (Kaplan–Meier curves and log-rank test, Cox regression for Hazard Ratio (HR)) and multivariate (Cox regression models) analyses. Of 113 patients, 52 had FD and 78 RC. Median age was 74 and 72 years, 83% and 82% were male. Drugs of 114 ATC classes were taken by 48 (92%) FD patients (median number 4.5/IQR 2–7.5) and 73 (94%) of RC patients (median 5/IQR 2–9). In univariate analysis (log-rank test (p)/Cox regression (HR, 95% CI, p)), polypharmacy (p = 0.036/HR = 2.83, 95% CI = 1.02–7.90, p = 0.047), calcium channel blockers (p = 0.046/HR = 2.47, 95% CI = 0.97–6.27, p = 0.057) and proton pump inhibitors (p = 0.015/HR = 3.16, 95% CI = 1.18–8.41, p = 0.022) had a significant negative impact on RFS in RC patients, statins (p = 0.025/HR = 0.14, 95% CI = 0.02–1.06, p = 0.057) a positive effect on RFS in FD patients, angiotensin-converting enzyme inhibitors (p = 0.008/HR = 10.74, 95% CI = 1.20–96.17, p = 0.034) and magnesium (p = 0.042/HR = 5.28, 95% CI = 0.88–31.59, p = 0.067) a negative impact on CSS in FD patients. In multivariate analysis, the only significant drug effects were the negative impact of angiotensin-converting enzyme inhibitors (HR = 15.20, 95% CI = 1.30–177.67, p = 0.030) and magnesium (HR = 22.87, 95% CI = 1.57–333.81), p = 0.022) on CSS in FD patients, and the positive impact of statins (HR = 0.12, 95% CI = 0.01–0.97, p = 0.047) on RFS in FD patients. Impact of non-oncologic drugs on RFS and CSS was small in this prospective study. Thus, appropriate treatment of comorbidities is encouraged.

Short-term cognitive effects of repeated-dose esketamine in adolescents with major depressive disorder and suicidal ideation: a randomized controlled trial

BackgroundKetamine and its enantiomer have rapid and robust effects on depressive symptom and suicidal ideation. Little is known about their cognitive effects in adolescents. We aimed to evaluate the short-term effect of esketamine on cognition in adolescents with major depressive disorder (MDD) and suicidal ideation.MethodIn this randomized-controlled trial, 51 participants aged 13–18 with MDD and suicidal ideation received three intravenous infusions of either esketamine (0.25 mg/kg) or midazolam (0.02 mg/kg). Four dimensions of the MATRICS Consensus Cognitive Battery (MCCB), including processing speed, working memory, verbal learning and visual learning, were assessed at Days 0, 6 and 12.ResultsIn the linear mixed model, a significant time main effect (F = 12.803, P < 0.001), drug main effect (F = 6.607, P = 0.013), and interaction effect (F = 3.315, P = 0.041) was found in processing speed. Other dimensions including working memory and verbal learning showed significant time main effect (all P < 0.05), but no significant drug or interaction effect (all P > 0.05). Esketamine group showed improvement in processing speed from baseline to Days 6 and 12, and working memory from baseline to Day 12 (all P < 0.05). The generalized estimation equation showed no significant association between baseline cognition and antidepressant or antisuicidal effect (both P > 0.05).ConclusionsThe present study suggested that three-dose subanesthetic esketamine infusions did not harm cognition among adolescents with MDD and suicidal ideation. Instead, esketamine may be associated with improvement in processing speed.Trial registration: This trial was registered in the Chinese Clinical Trials Registry (http://www.chictr.org.cn, ChiCTR2000041232).

An exploration of actigraphy in the context of ketamine and treatment-resistant depression.

This study explored the potential of non-parametric and complexity analysis metrics to detect changes in activity post-ketamine and their association with depressive symptomatology. Individuals with treatment-resistant depression (TRD: n=27, 16F, 35.9±10.8years) and healthy volunteers (HVs: n=9, 4F, 36.4±9.59years) had their activity monitored during an inpatient, double-blind, crossover study where they received an infusion of ketamine or saline placebo. All participants were 18-65years old, medication-free, and had a MADRS score ≥20. Non-parametric metrics averaged over each study day, metrics derived from complexity analysis, and traditionally calculated non-parametric metrics averaged over two weeks were calculated from the actigraphy time series. A separate analysis was conducted for a subsample (n=17) to assess the utility of these metrics in a hospital setting. In HVs, lower intradaily variability was observed within daily rest/activity patterns post-ketamine versus post-placebo (F=5.16(1,15), p=0.04). No other significant effects of drug or drug-by-time or correlations between depressive symptomatology and activity were detected. Weak associations between non-parametric variables and ketamine were found but were not consistent across actigraphy measures. ClinicalTrials.gov, NCT00088699.

The influence of atorvastatin, amlodipine and ethoxidol on ubiquinol and ubiquinone endogenous plasma concentrations in patients with chronic heart failure.

Coenzyme Q10 is a key component of the mitochondrial respiratory chain and a fat-soluble endogenous antioxidant performing many vital functions in the human body. Many researchers studied the plasma concentrations of ubiquinol, ubiquinone, total CoQ10 and the redox state (ubiquinol/ubiquinone ratio) of CoQ10 in healthy volunteers. However, these parameters in the plasma of patients with chronic heart failure (CHF) remain almost uninvestigated. The aim of this case-control study was to investigate the effect of atorvastatin, amlodipine and ethoxidol on endogenous plasma concentrations of ubiquinol, ubiquinone, total CoQ10 and its redox state in patients with CHF. The study included 62 patients with CHF divided into four groups depending on the prescribed therapy. For the quantitative determination of ubiquinol, ubiquinone, and total CoQ10 in the plasma of patients, HPLC-MS/MS was used. It was established that the endogenous plasma concentration of total CoQ10 in patients with CHF is significantly lower than in healthy volunteers, and the ratio of reduced and oxidized forms of CoQ10 is shifted towards ubiquinone. It was a statistically significant effect of drugs with different physicochemical structures and pharmacological action on the plasma concentrations of ubiquinol, ubiquinone and total CoQ10: atorvastatin administration led to a decrease in the concentration of ubiquinol (-33.3Δ%), and total CoQ10 (-15Δ%), administration of amlodipine contributed to an increase in the levels of ubiquinol (+27.7Δ%) and total CoQ10 (+18.2Δ%), and the administration of ethoxidol caused an increase in the concentration of ubiquinol (+25Δ%), ubiquinone (+17.7Δ%) and total CoQ10 (+20.2Δ%). Amlodipine is able to neutralize the negative effect of atorvastin on the redox balance of CoQ10 in patients with CHF. An additional prescription of the antioxidant ethoxidol to standard therapy for patients with CHF was substantiated. Determination of the redox state of CoQ10 in plasma can be used to diagnose and assess the degree of oxidative stress in patients with cardiovascular diseases, as well as to assess the efficacy and safety of ongoing pharmacotherapy.

Nephroprotective Properties of Antidiabetic Drugs.

Chronic kidney disease (CKD) is associated with increased morbidity and mortality, especially from cardiovascular (CV) causes, and especially in people with diabetes mellitus (DM). Already the presence of DM increases CV risk and potentiates the risk of CKD. Therefore, besides glycemic control, prevention and treatment of CKD to slow its progression are of clinical importance. A significant nephroprotective effect of novel antidiabetic drugs, namely sodium-glucose cotransporter 2 inhibitors (SGLT2-I) and glucagon-like peptide 1 receptor agonists (GLP1-RA), has been shown on top of their glucose-lowering effects and was confirmed in cardiovascular outcome trials. GLP1-RA mainly reduced the risk of macroalbuminuria, whereas SGLT2-I were also associated with a lower risk of declining glomerular filtration rate (GFR) over time. The nephroprotective effects of SGLT2-I are also evident in people without DM. According to current guidelines, SGLT2-I and/or GLP1-RA are recommended for people with DM who have chronic kidney disease and/or increased cardiovascular risk. However, other antidiabetic drugs offer nephroprotective properties, which will also be discussed in this review.

Interaction of the synthetic cannabinoid WIN55212 with tramadol on nociceptive thresholds and core body temperature in a chemotherapy-induced peripheral neuropathy pain model.

Chemotherapy-induced peripheral neuropathy (CIPN) is a significant adverse effect of many anticancer drugs. Current strategies for the management of CIPN pain are still largely unmet. The aim of this study is to investigate the antinociceptive potential of combining tramadol with the synthetic cannabinoid WIN55212, and to evaluate their associated adverse effects, separately or in combination, in a CIPN rat model, and to investigate their ability to modulate the transient receptor potential vanilloid 1 (TRPV1) receptor activity. Von Frey filaments were used to determine the paw withdrawal threshold in adult male Sprague-Dawley rats (200-250 g) following intraperitoneal (i.p) injection of cisplatin. Single cell ratiometric calcium imaging was used to investigate WIN55212/tramadol combination ability to modulate the TRPV1 receptor activity. Both tramadol and WIN55212 produced dose-dependent antinociceptive effect when administered separately. The lower dose of tramadol (1 mg/kg) significantly enhanced the antinociceptive effects of WIN55212 without interfering with core body temperature. Mechanistically, capsaicin (100 nM) produced a robust increase in [Ca 2+ ] i in dorsal root ganglia (DRG) neurons ex vivo . Capsaicin-evoked calcium responses were significantly reduced upon pre-incubation of DRG neurons with only the highest concentration of tramadol (10 µM), but not with WIN55212 at any concentration (0.1, 1 and 10 µM). However, combining sub-effective doses of WIN55212 (1 µM) and tramadol (0.1 µM) produced a significant inhibition of capsaicin-evoked calcium responses. Combining WIN55212 with tramadol shows better antinociceptive effects with no increased risk of hypothermia, and provides a potential pain management strategy for CIPN.

Update Management of Chemotherapy-Induced Neutropenia: A Narrative Literature Review

One of the most frequent and significant complicated side effects of myelosuppressive drugs is neutropenia. Neutropenia is not only associated with high morbidity but also mortality. Generally, the onset of neutropenia occurs within 3-7 days after the administration of anticancer agents. Approximately 5-30% of patients will develop febrile neutropenia. The highest incidence occurs during the first cycle of chemotherapy. This literature review aimed to describe chemotherapy-induced neutropenia and its prevention and management. Administration of granulocyte colony-stimulating factor as prophylaxis can prevent neutropenia-induced anticancer drugs. The use of granulocyte colony-stimulating factor (G-CSF) as therapeutic is contradictive, and some guidelines recommend not to use the G-CSF for therapeutic purposes. Up to 70% of mortality among these populations was associated with gram-negative sepsis, therefor empirical antibiotics, and antifungals are the keys to the management of neutropenia. In conclusion, prevention and appropriate management of neutropenia are extremely important in the treatment of patients with cancer.

Drugs and high hospitalization rate: are they related?

IntroductionSubstance use continues to be an important problem among mental health patients either as main diagnosis or as comorbidity. Acute care visits, including emergency department visits and hospitalizations, related to substance use disorders (SUD) are increasing and can be opportunities to engage individuals to get proper treatment (Suen LW et al. J Gen Intern Med 2022; 37(10):2420–2428). Both mental disorders and SUD lead to subsequent chronic physical conditions, premature death, suicide or overdose (Bennett AC. Public Health Rep 2019; 134(1):17-26) that can be accidental or not.24% to 32% of patients with Substance Induced Psychosis develop later a schizophrenia spectrum disorder or bipolar disorder (Starzer MSK et al. Am J Psychiatry 2018;175(4):343–350) leading to a chronic use of medication and, in several instances, to a necessity of psychiatric in-patient treatment with long hospital stays and high readmission rates (Khan S. Health Reports (2017) 28(8)3-8).ObjectivesOur goal was to analyze if substance use is associated with higher psychiatric hospitalization rates.MethodsAn independent-samples t-test was run to determine if there were more hospitalizations among patients with substance use. Afterwards, the Cohen’s D was calculated to measure the effect size and to see the magnitude of the experimental effect.ResultsA sample of 2604 in-patient treatment episodes was used. The sample had 1696 female patients, 908 male patients and 823 patients had substance use. We found that patients with substance use had a statistically significant higher hospitalization rate (6.82±5.27) than the ones without it (5.32±4.84), t(1483)=6.945, p&lt;0.001. Cohen’s effect size value (d=.30) suggested a small practical significance.ConclusionsOur findings go mainly accordingly the literature; we found a significant effect of drugs on readmission rates (Böckmann V et al. Front Psychiatry 2019; 10:828) but we might have thought it would be bigger. That could be explain by undiagnosed substance use (refusal to admit the use, drugs not detected on lab tests, not requesting toxic lab tests) or higher sample percentage of confounding comorbid diagnoses.However, is undoubtable the several risks that drugs bring to our health and so the authors aim to raise awareness among the medical community to the importance being alert for signs of use or psychiatric symptoms to avoid reaching a no turning point. It’s known that doctors frequently fail to diagnose SUD in hospitalized patients and given the linkage between use of certain substances and particular medical reasons for admission, it would be well-advised to search for SUD in certain admission diagnoses (Weintraub E et al. Am J Addict 2001;10(2):167-77). Knowledge of substance use behavior may help reducing relapse rates and to reduce the risk of developing a SUD (Andersson HW et al. Nordic Journal of Psychiatry, 75:3, 160-169).Disclosure of InterestNone Declared

Synthesis of PAMAM dendrimers anchored to WS2 nano-sheets for controlled delivery of docetaxel: Design, characterization and in vitro drug release

The oral delivery of anti-cancer agents is typically challenging due to low bioavailability and significant gastrointestinal side effects of drugs. Docetaxel is a lipophilic anti-cancer agent used to treat some cancers, such as metastatic breast and prostate cancer. Herein, we represent a highly effective strategy for the delivery of docetaxel using a near-infrared responsive nano-carrier based on WS2 nano-sheets. To do this, Poly (N-vinylcaprolactam) and allyl amine were grafted on the surface of nano-sheets as thermo-sensitive polymer and functional monomer, respectively. Next, three generations of PAMAM dendrimers were anchored to the grafted polymer chains by using methyl acrylate and ethylenediamine. The produced nano-carrier was characterized by using FT-IR, TGA, XRD, FE-SEM systems. The adsorption isotherm and kinetic results were well fitted to Langmuir and second-order models. The results of thermodynamic factors including Gibb's free energy, enthalpy, and entropy supported the drug adsorption process. The thermo-sensitive nano-carrier released a maximum of 88.25% and 32.94% drug in the simulated human blood fluid at 50 °C and 37 °C within 6 h. The in vitro release curves were analyzed using several mathematical models to determine the drug release mechanism. Using the near-infrared irradiation, the drug release was reached at 100% in 12 min, which was about 4.4 times faster than without laser irradiation. The findings show that the produced smart nano-carrier could be a promising choice for sustained delivery of docetaxel.

Pharmacological investigations of effort-based decision-making in humans: Naltrexone and nicotine.

Many mental health disorders are characterized by an impaired ability, or willingness, to exert effort to obtain rewards. This impairment is modeled in effort-based decision tasks, and neuropharmacological studies implicate dopamine in this process. However, other transmitter systems such as opioidergic and cholinergic systems have received less attention. Here, in two separate studies we tested the acute effects of naltrexone and nicotine on effort-based decision-making in healthy adults. In Study 1, we compared naltrexone (50mg and 25mg) to placebo, and in Study 2, a pilot study, we compared nicotine (7mg) to placebo. In both studies, participants completed the Effort Expenditure for Rewards Task (EEfRT), which measured effort-based decision-making related to monetary rewards. Although subjects expended greater effort for larger reward magnitude and when there was a higher probability of receiving the reward, neither naltrexone nor nicotine affected willingness to exert effort for monetary rewards. Although the drugs produced significant and typical drug effects on measures of mood and behavior, they did not alter effort-based decision-making. This has implications both for the clinical use of these drugs, as well as for understanding the neuropharmacology of effort-related behavior.

Expectation for stimulant type modifies caffeine's effects on mood and cognition among college students.

Caffeine is regularly used by college students to enhance mood and academic performance. Although high doses confer risk for negative consequences, moderate doses of caffeine may lead to acute improvements in mood and cognitive functioning. Notably, the pharmacological effects of caffeine may be enhanced by expectancy effects. College students may also engage in nonmedical prescription stimulant use for similar purposes, as students expect strong cognitive enhancement from prescription stimulants and consider them to be more efficacious than caffeine. The purpose of the current study was to examine whether the pharmacological effects of caffeine on mood/drug effects and cognitive performance are enhanced when expecting a conceivably stronger stimulant (i.e., Adderall) compared to when expecting caffeine. Sixty-five undergraduate students were randomized to condition across two variables: drug ingested (placebo or 200 mg caffeine) and drug expected (caffeine or Adderall). Participants completed self-report measures of mood and drug effects pre- and post-drug, as well as cognitive assessments post-drug. There were significant main effects of drug ingested and drug expected on several post-drug measures. Subjects receiving caffeine reported feeling more high, stimulated, anxious, and motivated than subjects receiving placebo. Further, subjects expecting Adderall reported stronger amphetamine effects and feeling more high, and performed better on a working memory test, than those expecting caffeine. Effects tended to be strongest in participants receiving caffeine and expecting Adderall. Modifying expectancies, in conjunction with the pharmacological properties of caffeine at moderate doses, may be one mechanism by which college students may experience differential effects of caffeine. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer’s disease: systematic review and meta-analysis

BackgroundDysfunction of the locus coeruleus-noradrenergic system occurs early in Alzheimer’s disease, contributing to cognitive and neuropsychiatric symptoms in some patients. This system offers a potential therapeutic target, although noradrenergic treatments...

The Role of Geranylgeraniol in Managing Bisphosphonate-Related Osteonecrosis of the Jaw.

Medication-related osteonecrosis of the jaw (ONJ) is a rare but significant adverse side effect of antiresorptive drugs. Bisphosphonate-related ONJ (BRONJ) is the most prevalent condition due to the extensive use of the drug in cancer and osteoporosis treatment. Nitrogen-containing bisphosphonates suppress osteoclastic resorption by inhibiting farnesyl pyrophosphate synthase in the mevalonate pathway, leading to deficiency of the substrate for GTPase prenylation. The bone remodelling process is uncoupled, subsequently impairing bone healing and causing ONJ. Targeted administration of geranylgeraniol (GGOH) represents a promising approach to mitigate BRONJ because GGOH is a substrate for GTPase prenylation. In the current review, the in vitro effects of GGOH on osteoclasts, osteoblasts and other related cells of the jaw are summarised. We also present and appraise the current in vivo evidence of GGOH in managing BRONJ in animal models. Lastly, several considerations of using GGOH in the clinical management of BRONJ are highlighted. As a conclusion, GGOH is a promising topical agent to manage BRONJ, pending more research on an effective delivery system and validation from a clinical trial.