Selective suppression of normal modes in coupled oscillators

P03-60 - Levetiracetam showed lower depression, insomnia and mood instability incidence than phenytoin after supratentorial tumour neurosurgery

A highly tumor-specific light-triggerable drug carrier responds to hypoxic tumor conditions for effective tumor treatment

BackgroundObesity is a worldwide epidemic affecting millions of people. The current pharmacological treatment of obesity remains limited and ineffective due to drugs’ undesirable side effects. Hence, there is a need for novel or improved strategies for long-term therapies that will help prevent the disease progression into other chronic diseases. Nanotechnology holds the future for the treatment of obesity because of its versatility, as shown by improved drug efficiency and safety in cancer clinical trials. Nano-based drug delivery systems could potentially do the same for obesity through targeted drug delivery. This study investigated the use of peptide-functionalized quantum dots (QDs) for the imaging of prohibitin (PHB)-expressing cells in vitro and in diet-induced obese rats, which could potentially be used as nanocarriers of antiobesity drugs.MethodsCadmium (Cd)-based QDs were functionalized with an adipose homing peptide (AHP) and injected intravenously into lean and obese Wistar rats. Biodistribution of the QDs was analyzed by an IVIS® Lumina XR imaging system and inductively coupled plasma optical emission spectroscopy (ICP-OES). For in vitro studies, PHB-expressing (Caco-2 and MCF-7) and non-PHB-expressing (KMST-6 and CHO) cells were exposed to either unfunctionalized QDs (QD625) or AHP-functionalized QDs (AHP-QD625) and analyzed by fluorescence microscopy.ResultsAHP-QD625 accumulated significantly in PHB-expressing cells in vitro when compared with non-PHB-expressing cells. In vivo data indicated that QD625 accumulated mainly in the reticuloendothelial system (RES) organs, while the AHP-QD625 accumulated mostly in the white adipose tissues (WATs).ConclusionAHP-functionalized QDs were successfully and selectively delivered to the PHB-expressing cells in vitro (Caco-2 and MCF-7 cells) and in the WAT vasculature in vivo. This nanotechnology-based approach could potentially be used for dual targeted drug delivery and molecular imaging of adipose tissues in obese patients in real time.

Background: Deep brain stimulation (DBS) is a widely employed treatment for Parkinson’s disease. However, conventional DBS utilizing ring-shaped leads can often result in undesirable side effects by stimulating nearby brain structures, thus limiting its effectiveness. To address this issue, a novel DBS electrode was developed to allow for directional stimulation, avoiding neighboring structures. Objective: This literature review aims to analyze the disparities between conventional and directional DBS and discuss the benefits and limitations associated with this innovative electrode design, focusing on the stimulation-induced side effects it can or cannot mitigate. Methods: A comprehensive search was conducted in MEDLINE/PubMed, ScienceDirect, and EBSCO databases using the Boolean search criteria: "Deep brain stimulation" AND "Parkinson" AND "Directional." Following the application of inclusion and exclusion criteria, the selected articles were downloaded for full-text reading. Subsequently, the results were organized and analyzed to compose this article. Results: Numerous studies have demonstrated that directional DBS effectively reduces side effects associated with brain stimulation, prevents the stimulation of non-targeted structures, and expands the therapeutic window, among other advantages. However, it has been observed that directional DBS may be more challenging to program and requires higher energy consumption. Furthermore, there is a lack of standardization among different manufacturers of directional DBS electrodes. Various stimulation-induced side effects, including dysarthria, dyskinesia, paresthesias, and symptoms of pyramidal tract activation, have been shown to be mitigated with the use of directional DBS. Moreover, directional electrodes offer a wider therapeutic window and a reduced incidence of undesired effects, requiring the same or lower minimum current for symptom relief compared to conventional DBS. Conclusion: The utilization of directional leads in DBS offers numerous advantages over conventional electrodes without significant drawbacks for patients undergoing directional DBS therapy.

Although whole body cooling is used widely to provide therapeutic hypothermia for the brain, there are undesirable clinical side effects. Selective brain cooling may allow for rapid and controllable neuroprotection while mitigating these undesirable side effects. We evaluated an innovative cerebrospinal fluid (CSF) cooling platform that utilizes chilled saline pumped through surgically implanted intraventricular catheters to induce hypothermia. Magnetic resonance thermal imaging of the healthy sheep brain (n = 4) at 7.0T provided dynamic temperature measurements from the whole brain. Global brain temperature was 38.5 ± 0.8°C at baseline (body temperature of 39.2 ± 0.4°C), and decreased by 3.1 ± 0.3°C over ∼30 min of cooling (p < 0.0001). Significant cooling was achieved in all defined regions across both the ipsilateral and contralateral hemispheres relative to catheter placement. On cooling cessation, global brain temperature increased by 3.1 ± 0.2°C over ∼20 min (p < 0.0001). Rapid and synchronized temperature fall/rise on cooling onset/offset was observed reproducibly with rates ranging from 0.06-0.21°C/min, where rewarming was faster than cooling (p < 0.0001) signifying the importance of thermoregulation in the brain. Although core regions (including the subcortex, midbrain, olfactory tract, temporal lobe, occipital lobe, and parahippocampal cortex) had slightly warmer (∼0.2°C) baseline temperatures, after cooling, temperatures reached the same level as the non-core regions (35.6 ± 0.2°C), indicating the cooling effectiveness of the CSF-based cooling device. In summary, CSF-based intraventricular cooling reliably reduces temperature in all identified brain regions to levels known to be neuroprotective, while maintaining overall systemic normothermia. Dynamic thermal mapping provides high spatiotemporal temperature measurements that can aid in optimizing selective neuroprotective protocols.

Rationale Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling in pulmonary arterioles. Increased activation of receptor tyrosine kinase (RTK)-mediated signaling pathways lead to increased proliferation and chemotaxis of pulmonary arterial smooth muscle cells (PASMCs). In previous studies, we identified phosphatidylinositol-3-kinase (PI3K) as a key enzyme for these processes. Since systemic PI3K inhibition is potentially associated with undesired side effects, we here for the first time tested the efficacy of the novel PI3K inhibitor CL27c to impede growth factor-mediated cellular effects in human PASMCs. CL27c is topically applicable and as a prodrug it is intracellularly activated and thus offers optimal efficacy in target cells while at the same time minimizing undesired effects in non-target cells. Methods Using Western blotting and immunohistochemistry, activation of the central PI3K effector AKT in human and murine lung tissue was investigated. Quantification of cell proliferation was performed by 5-bromo-2-deoxyuridine (BrdU) incorporation assay. PASMCs were incubated with CL27c [0.1; 0.3; 1; 3; 10μM] and stimulated either with PDGF-BB [30ng/ml] or with a growth factor combination (GFC) [PDGF-BB 30ng/ml, FGF 2ng/ml, EGF 0.5ng/ml, insulin 0.5μg/ml, FCS 5%]. Chemotaxis was quantified using modified Boyden chambers. The signal transduction cascade was investigated by Western blotting. Results Analysis of AKT activation revealed hyperphosphorylation in both the vascular wall and complete lung homogenates from PAH patients and hypoxia-treated mice. Examination of the mitogenic signal transduction revealed a markedly reduced phosphorylation of AKT and GSK3β in CL27c pretreated PASMCs. In addition, central cell cycle events, such as expression of cyclin D1, were reduced. This was in line with a CL27c concentration-dependent significant reduction of PDGF- and GFC-induced proliferation (control: 2.53±0.26 vs. CL27c: 0.73±0.14 and control: 5.27±0.61 vs. CL27c: 2.80±0.71 both at 10μM, p&lt;0.001). Furthermore, PDGF- and GFC-induced chemotaxis were as well significantly reduced (100% ± 19 vs. CL27c: 24.43% ± 8.58 and 100% ± 5.76 vs CL27c: 25.23% ± 10.57 at 10μM p&lt;0.001). Conclusion These results indicate that CL27c reduces both proliferation and chemotaxis of PASMCs. As these processes play a key role in the development and progression of PAH, this approach is currently being investigated in preclinical models for its therapeutic potential. This “prodrug” approach could avoid non-specific effects and systemic side effects of Pan-PI3K inhibition, especially since the substance is suitable for topical application (inhalation). Thus, CL27c represents a promising treatment option.

Long-acting reversible contraception (LARC) is increasingly used by adolescents and young adults (AYAs). Subsequent to LARC insertion, AYAs are presenting to their primary care providers with LARC concerns. This article seeks to equip primary care clinicians with the tools necessary to assess and manage common LARC-associated side effects. Side effects are common with progestin-only LARC, and can precipitate early discontinuation of an otherwise effective, low-maintenance form of contraception. Abnormal uterine bleeding, pelvic pain, acne, and weight change are often cited as progestin-only LARC side effects, yet the causes are poorly understood despite extensive research. While most side effects improve with time, therapeutic interventions are available for patients with undesirable side effects that prefer medical management. Research emphasizes the importance of proper patient counseling and clinical follow-up. Counseling remains essential in the management of LARC-associated side effects. However, options are available to temporarily mitigate such side effects and increase LARC satisfaction. While these therapeutic options are prescribed based on expert opinion, such regimens remain inadequately studied in AYA populations.

Although videonystagmography (VNG) is a useful test for evaluating patients with vestibular symptoms, it may cause undesirable side effects. The aim of this study was to measure cerebral tissue oxygen saturation in patients with vertigo undergoing VNG and assess its relationship with clinical parameters, including the severity of the procedure-related side effects. Continuous measurement of regional oxygen saturation (rSO2) from both hemispheres during VNG with caloric stimulation was performed in patients with chronic vertigo using a near-infrared spectroscopy sensor. This sensor, connected to a regional oximetry system (O3™, Masimo, Irvine, CA), was placed on the participant's forehead. During and after the VNG procedure, patient-perceived dizziness, discomfort, headache, and nausea-side effects related to VNG testing-were assessed using a 0-to-10 visual analog scale (VAS). A total of 23 patients were enrolled, with a mean age of 54.27 years and an average duration of vertigo of 5.96 years. Of these, 11 patients experienced VNG-related side effects. No significant differences in oximetry parameters were observed before and after the caloric test, regardless of whether cold or hot water was used or whether the left or right ear was stimulated. We found a positive correlation between the overall change in oxygenation values in both hemispheres during the whole VNG test (delta) and the severity of side effects symptoms (VAS). The correlation coefficient between delta and VAS was higher in the right hemisphere than in the left (accordingly 0.69 vs. 0.62, p < 0.05). Caloric stimulation does not influence regional brain oxygenation as measured by a regional oximetry system. However, fluctuations in rSO2 values during the whole VNG procedure, predominantly on the right side, may be associated with the side effects of the procedure.

Glucocorticoids, such as dexamethasone and prednisone, play a crucial role in the treatment of childhood acute lymphoblastic leukemia (ALL). Dexamethasone is currently the preferred glucocorticoid and is administered during maintenance therapy for five days every 3-4 weeks over 1.5 years of treatment. However, dexamethasone is associated with various undesirable side effects, including neurobehavioral and sleep problems, increased hunger, dyslipidemia, and adiposity. The prevalence of these side effects varies among patients, and there are no clear risk factors identified. The first aim of this thesis was to enhance our understanding of the prevalence and determinants of dexamethasone-induced side effects in children with ALL. Our systematic literature review suggested that the type or dose of steroid wasn't related to neurobehavioral problems but might be to sleep problems. Younger patients appeared at risk for behavioral problems, while older patients were at risk for sleep problems. Parental stress and medical history had not been well-studied, and genetic susceptibility associations required further validation. Our prospective cohort study involving 105 children with ALL found that parents frequently reported clinically relevant neurobehavioral (67%) and sleep problems (59%). Surprisingly, parenting stress, and not dexamethasone pharmacokinetics, genetics, demographics, or disease and treatment factors, emerged as a significant determinant for parent-reported dexamethasone-induced neurobehavioral and sleep problems. This highlights the potential for addressing parenting stress to reduce these issues. Our study also demonstrated that just five days of dexamethasone led to a notable increase in leptin (a hormone regulating satiety), hunger scores, and fat mass. However, there were no correlations between these measurements, suggesting the possibility of dexamethasone-induced acute leptin resistance, which is of concern given the increased risk of metabolic adverse events in children with ALL. Despite the well-known side effects of dexamethasone, there is currently no pharmacological treatment to mitigate them. Previous research showed that hydrocortisone may be beneficial in reducing neurobehavioral and sleep problems in those patients who suffer most. The second aim of this thesis was to validate the finding that hydrocortisone addition leads to a reduction in clinically relevant dexamethasone-induced neurobehavioral and sleep problems. However, our study found that there was no significant difference between hydrocortisone and placebo in reducing these problems. Instead, it suggested that a placebo effect influenced both patients and families, providing some relief from dexamethasone-induced neurobehavioral problems. Lastly, this thesis explored the cytotoxic effects of hydrocortisone and the role of mineralocorticoid receptors in steroid-induced cytotoxicity. Preclinical research revealed that hydrocortisone can induce the expression of steroid-regulated genes through both glucocorticoid and mineralocorticoid receptors and effectively induce cell death in leukemic cell lines. Patient samples indicated a less pronounced role of the mineralocorticoid receptor in steroid-induced cytotoxicity. In conclusion, this research offers important insights into the prevalence and determinants of dexamethasone-induced side effects in childhood ALL. While no pharmacological treatment currently exists to eliminate these side effects, our findings suggest potential approaches for alleviating the burden, including addressing parental stress. Additionally, the placebo effect may provide some relief to patients and families facing these challenges during the course of ALL treatment.

BackgroundPatient treatment satisfaction is likely to be a highly relevant outcome measure in pulmonary arterial hypertension (PAH), a condition for which the benefits of treatment must be weighed against frequent, undesirable side effects, inconvenience, and complications associated with therapy. In this study, we sought to evaluate the psychometric properties of a patient-reported treatment satisfaction measure and its relationship to quality of life (QoL) among patients transitioning from inhaled iloprost (iILO) to inhaled treprostinil (iTRE).MethodsWe studied treatment satisfaction among 66 subjects with PAH in a single-arm, open-label, multi-center trial of iTRE following transition from iILO. Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM, version 1.4) administered to subjects immediately before and 12 weeks after transition of inhaled therapy. The TSQM is comprised of 4 domains: effectiveness, side effects, convenience, and global satisfaction. Scores range from 0 to 100 with higher scores indicating greater satisfaction. Six-minute walk distance (6MWD), functional class, adverse events, drug administration time, and PAH-specific QoL (CAMPHOR) were concurrently assessed.ResultsDomains of the TSQM demonstrated evidence of strong internal consistency at baseline and at 12 weeks (Cronbach α = 0.88-0.93). Transition from iILO to iTRE was associated with an improvement in 3 of 4 TSQM domains: effectiveness (+20 ± 21, p < 0.0001), side effects (0 ± 22, p = 0.97), convenience (+39 ± 26, p < 0.0001), and global satisfaction (+20 ± 24, p = 0.0005). Change in effectiveness scores correlated with change in 6MWD (r = 0.43, p = 0.0004) and side effects scores at 12 weeks correlated inversely with number of severity-weighted treatment-emergent adverse events (r = −0.44, p = 0.0002). In multiple regression models adjusted for baseline characteristics, changes in effectiveness and convenience satisfaction scores were significantly associated with improvement in PAH-specific QoL (p = 0.002 and p = 0.01).ConclusionsThe TSQM demonstrated acceptable performance characteristics in patients with PAH. Changes in treatment satisfaction resulting from transitioning from iILO to iTRE were associated with improvements in PAH-specific QoL.

Opioids are the gold-standard treatment for severe pain. However, potentially life-threatening side effects decrease the safety and effectiveness of these compounds. The addiction liability of these drugs has led to the current epidemic of opioid abuse in the US. Extensive research efforts have focused on trying to dissociate the analgesic properties of opioids from their undesirable side effects. Splice variants of the mu opioid receptor (MOR), which mediates opioid actions, have unique pharmacological properties and anatomic distributions that make them attractive candidates for therapeutic pain relief. In this issue of the JCI, Xu et al. show that specific C-terminal regions of the MOR can modulate side effects without altering analgesia. This discovery greatly improves our understanding of opioid side effects and suggests intriguing therapeutic approaches that could improve both the safety and long-term effectiveness of opioids.

Levodopa is the most useful drug for treatment of Parkinson's disease today. But after continued use for several years, the effectiveness declines, and the undesirable side effects become more frequent, leading to unsatisfactory control. Once the treatment failure emerges, further management is difficult and often unsuccessful. One alternative for preventing side effects and treatment failure is to use a low dose. We are reporting our 12-year experience on uninterrupted treatment with levodopa, 3 grams (approximate) daily. The improvement was comparable with the best reports on higher dosage, and the side effects were significantly less frequent. The frequency of dyskinesia and on-off phenomena showed a strong correlation with duration of treatment. Psychiatric side effects were more common on treatment, but frequency of dementia did not correlate with duration of therapy. Improvement reached a peak after 6 months and remained statistically significant for 3.5 years. By the end of 5 years, the disability profile in the group was similar to that prior to levodopa treatment. So far, there is no satisfactory method for preventing treatment failure. From our observations, low dosage of levodopa is a desirable alternative, but not the answer to therapeutic failure. We recommend that levodopa use be delayed until the patient has a functional and/or psychological handicap that cannot be satisfactorily controlled with less potent antiparkinsonian agents.

Seizures are common in patients with gliomas, and phenytoin (PHT) is frequently used to control tumor-related seizures. PHT, however, has many undesirable side effects (SEs) and drug interactions with glioma chemotherapy. Levetiracetam (LEV) is a newer antiepileptic drug (AED) with fewer SEs and essentially no drug interactions. We performed a pilot study testing the safety and feasibility of switching patients from PHT to LEV monotherapy for postoperative control of glioma-related seizures. Over a 13-month period, 29 patients were randomized in a 2:1 ratio to initiate LEV therapy within 24 h of surgery or to continue PHT therapy. 6 month follow-up data were available for 15 patients taking LEV and for 8 patients taking PHT. In the LEV group, 13 patients (87%) were seizure-free. In the PHT group, 6 patients (75%) were seizure-free. Reported SEs at 6 months was as follows (%LEV/%PHT group): dizziness (0/14), difficulty with coordination (0/29), depression (7/14) lack of energy or strength (20/43), insomnia (40/43), mood instability (7/0). The pilot data presented here suggest that it is safe to switch patients from PHT to LEV monotherapy following craniotomy for supratentorial glioma. A large-scale, double-blinded, randomized control trial of LEV versus PHT is required to determine seizure control equivalence and better assess differences in SEs.

Attention-deficit/hyperactivity disorder (ADHD) is a common developmental neuropsychiatric disorder. Although ADHD can often be treated with stimulant class medications to alleviate symptoms, such treatments may cause undesirable side effects. Recently, Traditional Chinese medicine (TCM) has been gaining interest with treatment potential for ADHD and the lack of the stimulant-associated undesirable side effects. Animal models are useful for study the efficacy and mechanisms of TCM treatment for ADHD, however, previous studies of TCM on ADHD animal models, in general, have not considered appropriate experiemental designs. There were many concerns regarding the choice and source of the model and control animals, drug administration methods, behavioral and biochemical testing criteria, humane use of animals, and statistical power, etc. In this review, we discuss these issues present in the previous literature of animal research, and propose guidelines for future studies in particular consideration with the unique characteristic of Chinese medicine itself.

The successful therapy strategy of gastric cancer is defined as devastating the cancerous cells without exposing systematic toxicity and undesirable side effects. One strategy to overcome cancer treatment related difficulties could be combination therapy with natural products with anticancer drugs to introduce effective antitumor effects in addition to reduce undesirable side effects. In this regard, different extracts of mulberry leaf, isoquercetin and rutin as the extracted flavonoids from Morus alba, mulberry, in single dose as well as in combination with cisplatin against gastric cancer cell line were applied. This innovative treatment led to cytotoxic effect on gastric cancer cells in a synergistic manner. The findings anticipated that these herbal products have exceptional potential for future gastric cancer investigations and therapy.