Effects Of Drugs Research Articles

Internalization and mechanisms of toxicity of lipid nanocapsules in HepG2 and HepaRG hepatoma cells upon acute and chronic exposures

Lipid nanocapsules (LNCs) used as nanomedicine have been developed to enhance pharmacokinetics and decrease side effects of drugs, particularly for cancer therapies. After intravenous administration, LNCs possess an important hepatic tropism however, few data exist about their toxicity and even less after repeated exposure. This study aimed to assess the in vitro toxicity and internalization of unloaded LNCs, of 50 and 100 nm size, on HepG2 and HepaRG liver cell lines. Internalization of the 50 nm LNCs was slower compared to the 100 nm LNCs and both LNCs exhibited a higher toxicity on cancerous HepG2 cells compared to differentiated HepaRG cells. LNCs were mainly internalized via caveolin-mediated endocytosis in both cell lines. Upon chronic exposure, the toxicity of LNCs on HepaRG cells increased, although the pathways of internalization remained unchanged. Cell death studies have demonstrated an involvement of ferroptosis, but not of apoptosis. After acute and repeated exposures on HepaRG cells, the 100 nm LNCs showed a good safety profile. Finally, LNCs induced a more significant toxicity associated with faster internalization in the HepG2 cancerous model than in the differentiated HepaRG cells. This provides good evidence for LNCs to potentialize the cytotoxic effects of an active drug on liver cancer cells.

RISK FACTORS FOR THE OCCURRENCE OF DENTOFACIAL ANOMALIES AND DEFORMITIES IN CHILDREN

801 patients diagnosed with anomalies and deformations of the dental system in children under 18 years of age, their mother's illnesses during pregnancy, their age, the degree of kinship between their parents, the effect of drugs taken by the mother during this period of pathology were studied and analyzed.

Assessment of human abuse potential of an unflavored, sucralose-sweetened electronic cigarette in combustible cigarette smokers.

Despite the popularity of electronic cigarettes (ECIGs), limited research has examined the role of sweeteners, independent of other flavors, in shaping ECIG human abuse potential (HAP). This study examined the effects of sucralose and nicotine in unflavored ECIG liquid solutions to provide a basic understanding of the effects of sweeteners on ECIG HAP compared to combustible cigarettes. Individuals who smoked cigarettes daily (N = 14) completed five within-subject, Latin-square ordered study sessions that differed by product used: (a) own-brand combustible cigarettes (OB), (b) 0 mg/mL nicotine, unsweetened liquid, (c) 0 mg/mL nicotine, sucralose-sweetened liquid, (d) 15 mg/mL nicotine, unsweetened liquid, and (e) 15 mg/mL nicotine, sucralose-sweetened liquid. Participants completed subjective questionnaires and behavioral tasks following a 10-puff directed use bout during which puff topography was measured, and blood was sampled for later measurement of plasma nicotine concentration. On average, the OB condition had a greater increase in plasma nicotine concentration and produced more pronounced subjective effects compared to the ECIG conditions. The 15 mg/mL nicotine ECIGs delivered significantly more nicotine and produced greater drug effects and reductions in tobacco abstinence symptoms than the 0 mg/mL nicotine ECIGs. Sucralose-containing solutions increased ECIG product appeal, puff duration, and puff volume during the 10-puff directed bout. Findings revealed greater HAP for OB cigarettes relative to all ECIGs tested and suggest that adding sucralose and nicotine elevates ECIG HAP via different mechanisms; sucralose appears to influence HAP through product appeal, while nicotine influences HAP through drug effects and tobacco/nicotine abstinence symptom suppression. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Clinical efficacy and safety of new compound single tablet antiviral drugs in the treatment of HIV/AIDS

AimsGenvoya, Biktarvy and Dovato are novel single-tablet antiretroviral therapy(ART). The aim of this study is to explore the therapeutic effects of these novel drugs on HIV/AIDS. Main methodsThis retrospective cohort study, conducted at a single center, included a total of 200 HIV-treated patients who transitioned to these new antiretroviral drugs from July 2021 to August 2023. Data were extracted from electronic medical records at Ditan Hospital. The Genvoya group comprised 22 patients, and all subsequent switches in this group were to Biktarvy. The primary HAART group consisted of 178 patients initially treated with a first-line triple Highly Active Antiretroviral Therapy (HAART) regimen during the same period. This group was further subdivided into HAART+Dovato, HAART+Biktarvy, and HAART+Genvoya groups based on the switching regimen. The primary outcomes focused on changes in viral load and immune efficacy, while secondary safety indicators included blood/liver function, lipid parameters, renal function, blood glucose, blood uric acid, etc. Key findingsThe viral suppression rate was 100 % after the drug change treatment, and CD4+ T cell counts increased significantly across all four groups. Over the 6-month treatment period, there were increases in creatinine (Cr), low-density lipoprotein (LDL), high-density lipoprotein (HDL), erythrocyte count, and glomerular filtration rate (eGFR). Conversely, Alanine transaminase (ALT), Aspartate aminotransferase (AST), C-reactive protein (CRP), albumin (ALB), and blood glucose (Glu) levels decreased. SignificanceGenvoya, Biktarvy and Dovato are recommended for the treatment of HIV/AIDS and have a good safety profile.

Prospective, randomized, double-blind trial to validate the efficacy of an oral herbal gel on pain in the newborn during minor diagnostic-therapeutic procedures.

Term and preterm infants are frequently exposed to painful procedures and stimuli during hospitalization in the Neonatal Intensive Care Unit (NICU). Pain is widely recognized to cause short- and long-term effects in the newborn. In recent years there has been a growing medical interest and a strong demand from parents for phytotherapeutic drugs, but literature data are limited, and excellent methodological studies are necessary to evaluate the importance of phytotherapy in the neonatal period. We evaluated the use of an oral phytotherapeutic gel based on chamomile, angelica and oats in the management of full term and preterm infant pain caused by minor diagnostic or therapeutic procedures. We enrolled full term infants (>37 weeks gestational age [GA]) and preterm infants with higher GA than 28 weeks, weighing more than 1000 grams. Assessed painful procedures were minor diagnostic or therapeutic ones. Newborns were double-blind randomized into two groups (A and B) to orally receive the phytotherapeutic gel (solution A) and a gel of the same consistency and aroma (solution B) before the painful procedure. The group of newborns to whom solution A had been administered showed significantly lower scores in the Pain Scale (P<0.01) during painful procedure. This figure indicates that the herbal medicine has been effective in reducing pain experience in the population of examined newborns. To the best of our literature research, our work is the first scientific study highlighting the possibility of preventive beneficial effects of phytotherapeutic drugs on pain control.

PH responsive and zwitterionic micelle for enhanced cellular uptake and antitumor performance

The side effects of small molecule chemotherapeutic drugs (SMCD) have brought great pain to the cancer patients. Many nanodrug carriers can relieve the shortcomings of SMCD, but they have complex synthesis processes and lack biodegradability. To overcome both problems, we synthesized a pH responsive biodegradable zwitterionic molecules (EK-D) by linking zwitterionic polypeptide (EK7) and dodecyl acrylate through a simple click reaction. Subsequently, doxorubicin (DOX) was physically encapsulated within the EK-D micelles to produce EK-D-DOX micelles, and polyethylene glycol monooleate (POO) employed as a comparative group for the preparation of POO-DOX micelles. The results show that EK-D-DOX micelles have good aqueous stability and anti-protein non-specific adsorption performance at pH 7.4, but EK-D-DOX micelles aggregate under the condition of pH = 5.5 due to the biodegradability of EK-D. The tumor cell uptake rate of EK-D-DOX micelles is higher than that of POO-DOX micelles and free DOX, which makes EK-D-DOX micelles the highest cytotoxic. Additionally, EK-D-DOX micelles release more DOX in a slightly acidic environment than at pH 7.4, and the release of DOX reaches a significant cumulative value of 75.20 % under pH conditions of 5.5. More importantly, EK-D-DOX micelles exhibit superior in vivo tumor inhibitory efficacy compared to free DOX, resulting in a remarkable tumor inhibition rate of 95.7 %. EK-D-DOX micelles not only have lower biological toxicity to normal tissues than free DOX, but also have a longer blood circulation time in mice. The method of EK-D-DOX micelles preparation represents a new method to prepare biodegradable zwitterionic nanodrug.

Striosomes control dopamine via dual pathways paralleling canonical basal ganglia circuits.

Balanced activity of canonical direct D1 and indirect D2 basal ganglia pathways is considered a core requirement for normal movement, and their imbalance is an etiologic factor in movement and neuropsychiatric disorders. We present evidence for a conceptually equivalent pair of direct D1 and indirect D2 pathways that arise from striatal projection neurons (SPNs) of the striosome compartment rather than from SPNs of the matrix, as do the canonical pathways. These striosomal D1 (S-D1) and D2 (S-D2) pathways target substantia nigra dopamine-containing neurons instead of basal ganglia motor output nuclei. They modulate movement with net effects opposite to those exerted by the canonical pathways: S-D1 is net inhibitory and S-D2 is net excitatory. The S-D1 and S-D2 circuits likely influence motivation for learning and action, complementing and reorienting canonical pathway modulation. A major conceptual reformulation of the classic direct-indirect pathway model of basal ganglia function is needed, as well as reconsideration of the effects of D2-targeting therapeutic drugs.

Inclusion of phase III clinical trial costs in health economic evaluations

IntroductionProtocol-driven trial activities contribute to the utility gain demonstrated in the phase III clinical trial of a new drug. If this utility gain cannot be distinguished from the effects of the new drug itself, protocol-driven trial costs cannot be easily dismissed for consistency reasons. This study aims to estimate the impact of including per-patient costs of phase III clinical trials on the incremental cost-effectiveness ratio (ICER).MethodsThe analysis utilized a modeling approach with secondary data from an ad-hoc literature review, considering both societal and payer perspectives. While the costs of phase III clinical trials may cancel out during the period of “normal” life-years due to the incremental cost calculation, they do not cancel out when differential early treatment termination occurs (e.g., due to differential mortality). Assuming the presence of differential mortality, per-patient phase III trial costs were calculated for the period of added life-years. These costs were then included in the ICER of a new drug, under the assumption that direct patient-related costs constitute 30–70% of the total trial costs. Capital costs were also incorporated from a societal perspective.ResultsBased on assumptions of $40,000 out-of-pocket expenses per patient enrolled in a phase III trial and a life expectancy gain of three months, incremental costs increased by $27,000 from a societal perspective. From a payer perspective, the estimate was $12,000.ConclusionsThe costs of phase III trials are a relevant component of the ICER, and excluding it is generally not appropriate for consistency reasons. Properly considering these trial costs is essential for a comprehensive evaluation of a new drug’s cost-effectiveness.

P2.11B.05 Effect of Dysbiosis-Inducing Drugs on the Response to Immune Checkpoint Inhibitors in Patients with NSCLC

P2.11B.05 Effect of Dysbiosis-Inducing Drugs on the Response to Immune Checkpoint Inhibitors in Patients with NSCLC

Herbs for the Therapy of Diabetes Mellitus: A Thorough Analysis with Particular Emphasis on Preclinical, Clinical Trials, and their Hypothesised Mechanisms

Background: In recent times, herbal medicines have experienced an expansion in both developing and developed countries due to their natural origin and low incidence of adverse effects. A systematic review was performed to gather information regarding herbal plants used to treat diabetes mellitus. Objective: The aim of this article was to review evidence from preclinical and clinical trials and the proposed mechanism of herbal drugs in diabetes mellitus. Methods: A literature survey was carried out mainly focused on scientific papers published in recent years. The search strategy involved interrelated keywords, like “Diabetes mellitus,” “Herbs,” “Hyperglycaemia,” and other uniterms. Electronic databases used were Scopus, Web of Science, PubMed, and Elsevier. Results: Twenty studies, including preclinical and clinical trials, were selected for evaluating the mechanism of the anti-hyperglycaemic effect of herbal drugs in diabetes mellitus. Conclusion: Through clinical and preclinical research as well as an analysis of the mechanism of action of herbs, the current review provides preliminary evidence for possible anti-diabetic benefits of herbal medicines.

Systematic Review on Herbal Preparations for Controlling Visceral Hypersensitivity in Functional Gastrointestinal Disorders.

Visceral hypersensitivity (VH) is an overreaction of the gastrointestinal (GI) tract to various stimuli and is characterized by hyperalgesia and/or allodynia. VH contributes to the etiology of many GI dysfunctions, particularly irritable bowel syndrome (IBS). Although the exact mechanisms underlying VH are yet to be found, inflammation and oxidative stress, psychosocial factors, and sensorimotor alterations may play significant roles in it. In this review, we provide an overview of VH and its pathophysiological function in GI disorders. Adverse effects of synthetic drugs may make herbal agents a good candidate for pain management. Therefore, in this review, we will discuss the efficacy of herbal agents in the management of VH with a focus on their anti-inflammatory and antioxidant potentials. Data were extracted from clinical and animal studies published in English between 2004 and June, 2020, which were collected from PubMed, Google Scholar, Scopus, and Cochrane Library. Overall, Radix, Melissia, Glycyrrhizae, Mentha, and Liquorice were the most efficient herbals for VH management in IBS and dyspepsia, predominantly through modulation of the mRNA expression of transient receptor potential vanilloid type-1 (TRPV1) and suppression of 5- hydroxytryptamine 3 (5-HT3) or the serotonin receptors. Considering the positive effects of herbal formulations in VH management, further research on novel herbal and/or herbal/chemical preparations is warranted.

Evaluation of thiopyrano[2,3-d]thiazole derivatives as potential anticonvulsant agents.

Anticonvulsant drug discovery has achieved significant progress; however, pharmacotherapy of epilepsy continues to be a challenge for modern medicine and pharmacy. To expand the chemical space of heterocycles as potential antiepileptic agents, herein we report on the synthesis and evaluation of anticonvulsant properties of a series of thiopyrano[2,3-d]thiazoles. The studied heterocycles are characterized by satisfactory drug-likeness and pharmacokinetics properties, calculated in silico using SwissADME. The anticonvulsant activity of thiopyrano[2,3-d]thiazole derivatives was evaluated in vivo using the subcutaneous pentylenetetrazole test. Three hits, that is, compounds 12, 14, and 16, that caused a pronounced anticonvulsant effect were identified. Derivatives 12, 14, and 16 positively affected the latent period of onset of clonic seizures, number of seizures, mortality rate, and duration of the seizure period of animals under experimental conditions. The anticonvulsant properties of compound 14 were equivalent to the effect of the reference drug, sodium valproate. All hit compounds are characterized by satisfying toxicity properties in the human lymphocytes and HEK293 cell line. The most active hit 14 possesses a potential affinity with the GABAA receptor in the molecular docking study and forms a stable complex in the molecular dynamics experiments equal to diazepam. Preliminary SAR results were obtained and discussed based on screening data.

Physician-dentist dual referral model concept for coordinated bone anabolic therapy

BackgroundBone anabolic drugs used for the pharmacologic treatment of osteoporosis have the potential to enhance alveolar bone regeneration to improve implant success. There are no US Food and Drug Administration–approved drugs indicated to improve oral bone density around teeth or implants. MethodsThe authors summarized expert opinions on a novel coordinated treatment approach leveraging the effects of systemic bone anabolic drugs to enhance dental implant therapy in patients with osteoporosis and a dual referral model for physicians and dentists to address the clinical needs of patients with osteoporosis from a comprehensive perspective of oral-systemic health. Interviews of key opinion leaders were conducted with a bone health specialist group consisting of specialists in orthopedic surgery, internal medicine, geriatrics, endocrinology, and clinical densitometry and a surgical dental specialist group consisting of periodontists and oral surgeons. ResultsOverall, both groups shared positive feedback on the idea of strategically timing administration of anabolic osteoporosis drugs with dental treatment. Both groups expressed interest in the dual referral model. ConclusionsThe feedback of key opinion leaders supported the coordinated bone anabolic therapy concept and identified a need for improved interdisciplinary collaboration, education, and communication to realize the synergies of physician-dentist clinical cooperation. Practical ImplicationsStrategic timing of osteoporosis therapy could improve skeletal bone health and reduce fracture risk while offering adjunctive dental benefits.

Brain mitochondrial damage attenuation by quercetin and N-acetyl cysteine: peripheral and central antiemetic effects.

Nausea serves as a protective mechanism in organisms to prevent excessive consumption of toxic substances. Due to the adverse effects of chemical anti-nausea drugs, there is a growing interest in using herbal remedies and natural antioxidants. In this study, we evaluated the neuroprotective effects of quercetin (QU) and N-acetylcysteine (NAC) against oxidative damage induced by nausea. Emesis was induced in chickens using ipecac and copper sulfate (600 and 60mg/kg, orally, respectively). QU and NAC (with doses of 50, 100, 200mg/kg), and their combination were administered, along with a standard therapy (metoclopramide; MET 2mg/kg) for one-time. Mitochondrial function, lipid peroxidation (LPO), protein carbonyl (PC), glutathione level (GSH), and reactive oxygen species (ROS) as oxidative damage biomarkers were evaluated in the chicken's brain mitochondria. QU and NAC significantly reduced emesis induced by copper sulfate and ipecac compared to the control group (P<0.001). Significant differences in oxidative damage were observed in the groups received of copper sulfate and ipecac compared with control group. Levels of LPO, ROS, and PC were significantly decreased after the administration of QU and NAC in emesis induced by copper sulfate and ipecac. While, mitochondrial function and GSH levels were increased after the administration of QU and NAC. Combination therapy with QU and NAC yielded the most effective results. This study suggests that QU and NAC possess antiemetic effects through both peripheral and central mechanisms and exhibit neuroprotective effects against oxidative brain damage induced by emesis by increasing plasma antioxidants or scavenging free radicals.

Valacyclovir-Induced Crystal Kidney Failure: An Underestimated Adverse Effect of a Well-Known Drug

Valacyclovir-Induced Crystal Kidney Failure: An Underestimated Adverse Effect of a Well-Known Drug

Effect of vasoactive drugs used for management of hypotension during pregnancy on uterine hemodynamic parameters: A systematic review and meta-analysis of preclinical and clinical studies

Effect of vasoactive drugs used for management of hypotension during pregnancy on uterine hemodynamic parameters: A systematic review and meta-analysis of preclinical and clinical studies

Basal cortisol level modulates stress-induced opioid-seeking behavior

In preclinical studies and our human laboratory, the α2-noradrenergic autoreceptor antagonist yohimbine was found to promote drug-seeking behavior. This study evaluated effects of dose-combinations of yohimbine and the glucocorticoid receptor agonist hydrocortisone to model intensity-dependent effects of stimulating each neurochemical system, alone and together, on stress-reactivity and opioid-seeking. Twelve regular heroin-using participants diagnosed with opioid use disorder (OUD) were stabilized on sublingual buprenorphine (8-mg/day), then passed a hydromorphone 18-mg vs. placebo intramuscular reinforcement screen. Across 9 experimental conditions (3 × 3 within-subject, randomized crossover, placebo-controlled, double-blind design) during inpatient buprenorphine maintenance, combinations of oral pretreatment doses of yohimbine (0, 27, 54-mg; t = 0 min) then hydrocortisone (0, 20, 40-mg; t = 45 min) were administered. In each condition, subjective drug and mood effects, cardiovascular responses, and saliva cortisol and α-amylase levels were assessed to evaluate stress-reactivity, and participants completed a 12-trial choice progressive ratio task during which they could earn units of hydromorphone (1.5-mg intramuscular) and/or money ($2.00). Yohimbine dose-dependently increased blood pressure, α-amylase, and anxiety scores, and decreased opioid agonist symptoms; hydrocortisone dose-dependently increased cortisol levels. Yohimbine/hydrocortisone dose-combinations significantly shifted within-session responding from money to opioid-seeking among participants with lower basal cortisol levels. These findings replicate yohimbine effects on stress biomarkers and demonstrate that noradrenergic/glucocorticoid-potentiated opioid-seeking is modulated by basal cortisol level. In persons with OUD stabilized on buprenorphine, basal HPA-axis activity and acute stressors can enhance opioid relative reinforcing efficacy. These factors may limit OUD treatment efficacy and highlight the need for novel interventions that prevent stress-induced opioid-seeking.

Clinical benefit evaluation of drug treatment regimens for advanced lung cancer-based on ASCO-VF and ESMO-MCBS

BackgroundWith the increasing use of novel targeted drugs and immune checkpoint inhibitors (ICIs) for lung cancer (LC), the life expectancy of patients with LC has notably increased. In China, many drugs with the same mechanism of action have been approved by the National Medical Products Administration (NMPA) through phase III randomized controlled trials (RCTs). However, differences occur in these drugs’ efficacy and adverse effects, all of which have been compared with standard treatments, and data from head-to-head studies are lacking. MethodsThe key RCTs of EGFR tyrosine kinase inhibitors (EGFR-TKIs), ALK-TKIs, and ICIs approved by NMPA in advanced LC in China were searched and divided into five groups. The American Society of Clinical Oncology Value Framework (ASCO-VF v2) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS v1.1) were used to evaluate the net health benefits (NHB) of RCTs, including efficacy, adverse reactions, and patient-reported outcomes (PROs), etc. The consistency of the ASCO-VF and ESMO-MCBS was compared. ResultsAs of September 2024, 37 RCTs have been included in the ASCO-VF and ESMO-MCBS. NHB scores ranged from 12.30 to 93.25. Nineteen trials met the ASCO-VF “substantial benefit”, and 28 trials achieved the ESMO-MCBS “substantial benefit”. Except for icotinib, dacomitinib, and befotertinib, all EGFR-TKIs and ALK-TKIs met the threshold of two frameworks. In the ICI regimens, eight regimens met the threshold of “ substantial benefit ” as defined by the two frameworks and nine studies showed conflicting results. The correlation coefficient of the 37 pairs of scores in the advanced LC study was estimated to be 0.473(Spearman), and the consistency analysis showed fair agreement.(κ = 0.265, p = 0.001). ConclusionsASCO-VF and ESMO-MCBS focus on clinical efficacy and consider the adverse effects of drugs and PROs. We look forward to head-to-head studies on the different treatment options and advocate refining the ESMO-MCBS.

An Improved Framework for Drug-Side Effect Associations Prediction via Counterfactual Inference-Based Data Augmentation.

Detecting side effects of drugs is a fundamental task in drug development. With the expansion of publicly available biomedical data, researchers have proposed many computational methods for predicting drug-side effect associations (DSAs), among which network-based methods attract wide attention in the biomedical field. However, the problem of data scarcity poses a great challenge for existing DSAs prediction models. Although several data augmentation methods have been proposed to address this issue, most of existing methods employ a random way to manipulate the original networks, which ignores the causality of existence of DSAs, leading to the poor performance on the task of DSAs prediction. In this paper, we propose a counterfactual inference-based data augmentation method for improving the performance of the task. First, we construct a heterogeneous information network (HIN) by integrating multiple biomedical data. Based on the community detection on the HIN, a counterfactual inference-based method is designed to derive augmented links, and an augmented HIN is obtained accordingly. Then, a meta-path-based graph neural network is applied to learn high-quality representations of drugs and side effects, on which the predicted DSAs are obtained. Finally, comprehensive experiments are conducted, and the results demonstrate the effectiveness of the proposed counterfactual inference-based data augmentation for the task of DSAs prediction.

Evaluation of the prevalence and influencing factors on poly-pharmacy among elderly patients - A review

ABSTRACT The evaluation of adverse effects caused by poly-pharmacy (PHP) in patients, especially in the elderly group, is very important. The purpose of the present study was to evaluate the prevalence and factors affecting PHP in elderly patients. This study was conducted as a narrative review. Related articles were downloaded using reliable international databases and specialized mesh terms. Finally, the results of 29 articles were extracted based on the authors’ names, study location, sample size, and key results. The findings of the study showed that the prevalence of PHP in the elderly was higher after discharge from the hospital than during hospitalization. In addition, the prevalence of PHP in the elderly who lived in care centers was higher than in those who lived at home. Based on the findings, there was a relationship between the source of obtaining information about drugs and the pattern of PHP consumption. The findings of the present study showed that PHP leads to serious complications in the elderly. Based on the results of the study, it can be concluded that some variables such as age, sex, health level, financial status, place of residence, type of disease, number of simultaneous diseases, hospitalization, duration of hospitalization, level of awareness of the elderly and their caregivers, the care place of elderly, and the number of visits of the elderly to the physician can be effective in the prevalence of PHP. Strategies such as choosing treatment goals for each patient in preventing unnecessary drug use, identifying at-risk groups, and periodically monitoring the benefits and side effects of drugs can be effective in reducing drug complications caused by PHP in the elderly.