BMJ Open. 2022 Nov 28;12(11):e050590. doi: 10.1136/bmjopen-2021-050590.

ABSTRACT

INTRODUCTION: Novel therapies such as small protein molecule inhibitors and immunotherapies are tested in early phase trials before moving to later phase trials and ultimately standard practice. A key aim of these clinical trials is to define a toxicity profile, however, the emphasis is often on safety with measurements of organ toxicity. Other subjective side effects can be under-reported because they are not measured formally within the trial protocols. The concern from clinical practice is that cognitive toxicity is poorly studied and may be under-reported in this context. This could lead to toxicity profiles of new treatments not being fully described and patients with unmet need in terms of acknowledgement and support of symptoms. This protocol outlines a framework of an exploratory study with feasibility aspects to investigate the impact and experience of cognitive changes for patients on phase I trials.

METHODS AND ANALYSIS: This is a mixed-methods study, combining quantitative and qualitative approaches. The sample is 30 patients with advanced cancer who are participating in phase I trials of novel therapies in the early clinical trials unit of a specialist cancer centre. A test battery of validated cognitive assessments will be taken alongside patient reported outcome measures at three time points from baseline, day eight and day 28 post start of treatment. At day 28, a semi-structured interview will be conducted and the narrative thematically analysed. Results will be integrated to offer a comprehensive description of cognitive function in this patient group.

ETHICS AND DISSEMINATION: The study has received full HRA and ethical approval. It is the first study to introduce formal cognitive assessments in a cancer phase I trial context. The study has the potential to highlight previously unreported side effects and more importantly unmet need in terms of care for patients who are participating in the trials.

PMID:36442900 | DOI:10.1136/bmjopen-2021-050590

Oncotarget. 2022 Nov 17;13:1259-1270. doi: 10.18632/oncotarget.28310.

ABSTRACT

PURPOSE/OBJECTIVES: Cancer treatment survivors often report impaired functioning and increased falls. Not all survivors experience the same symptom burden, suggesting individual susceptibilities. APOE genotype is a potential genetic risk factor for cancer treatment related side effects. Lifestyle factors such as physical activity can mitigate the effect of APOE genotype on measures of clinical interest in individuals without a history of cancer. We tested the hypothesis that APOE genotype influences cancer treatment related side effects and symptoms as well as response to exercise intervention.

MATERIALS AND METHODS: Data from a subsample of a study of fall prevention exercise in post-treatment female cancer survivors aged 50-75 years old (https://clinicaltrials.gov NCT01635413) were used to conduct a secondary data analysis. ApoE genotype was determined by serum sampling. Physical functioning, frequency of falls, and symptom burden were assessed using survey instruments.

RESULTS: Data from 126 female cancer survivors a median of 49 months out from cancer diagnosis were analyzed. ApoE4 carriers trended toward a higher fall rate at baseline (p = 0.059), but after exercise intervention had a fall rate lower than E4 non-carriers both immediately after structured intervention (p = 0.013) and after 6 months of follow up (p = 0.002). E2 carriers did not show improved measures of depressive symptoms and self-report disability after exercise intervention. E3 homozygotes showed increased self report physical activity after the 6 month exercise intervention, but E4 and E2 carriers did not.

CONCLUSIONS: APOE genotype may modulate cancer treatment related side effects and symptoms and response to exercise intervention.

PMID:36441715 | DOI:10.18632/oncotarget.28310

Front Immunol. 2022 Nov 10;13:1016730. doi: 10.3389/fimmu.2022.1016730. eCollection 2022.

ABSTRACT

Drug hypersensitivity reactions induced by small molecule drugs encompass a broad spectrum of adverse drug reactions with heterogeneous clinical presentations and mechanisms. These reactions are classified into allergic drug hypersensitivity reactions and non-allergic drug hypersensitivity reactions. At present, the hapten theory, pharmacological interaction with immune receptors (p-i) concept, altered peptide repertoire model, and altered T-cell receptor (TCR) repertoire model have been proposed to explain how small molecule drugs or their metabolites induce allergic drug hypersensitivity reactions. Meanwhile, direct activation of mast cells, provoking the complement system, stimulating or inhibiting inflammatory reaction-related enzymes, accumulating bradykinin, and/or triggering vascular hyperpermeability are considered as the main factors causing non-allergic drug hypersensitivity reactions. To date, many investigations have been performed to explore the underlying mechanisms involved in drug hypersensitivity reactions and to search for predictive and preventive methods in both clinical and non-clinical trials. However, validated methods for predicting and diagnosing hypersensitivity reactions to small molecule drugs and deeper insight into the relevant underlying mechanisms are still limited.

PMID:36439170 | PMC:PMC9684170 | DOI:10.3389/fimmu.2022.1016730

Front Immunol. 2022 Nov 10;13:953210. doi: 10.3389/fimmu.2022.953210. eCollection 2022.

ABSTRACT

BACKGROUND: To conduct a meta-analysis with the aim of comparing the outcomes of antiviral prophylaxis and preemptive therapy for the prevention of cytomegalovirus (CMV) infection in liver transplant (LT) recipients.

METHODS: We searched databases for qualified studies up until March 2022. Finally, a meta-analysis was carried out using a fixed-effect or random-effect model based on the heterogeneity.

RESULTS: With a total of 1834 LT patients, the pooled incidence of CMV infection and CMV disease in the overall LT recipients using antiviral prophylaxis and preemptive therapy were 24.7% vs. 40.4% and 6.4% vs. 9.4%, respectively. Our meta-analysis exhibited a significant reduction in the incidence of CMV infection due to antiviral prophylaxis when compared to preemptive therapy in the high-risk group (OR: 6.67, 95% CI: 1.73, 25.66; p = 0.006). In contrast, there was a significant reduction in the incidence of late-onset of CMV disease in preemptive therapy compared to antiviral prophylaxis in the high-risk group (OR: 0.29, 95% CI: 0.12, 0.74; p = 0.009). However, the incidence of CMV disease, allograft rejection, graft loss, drug related adverse effects, opportunistic infections and mortality did not differ significantly between both the interventions (all p> 0.05).

CONCLUSIONS: We found the use of antiviral prophylaxis, compared with preemptive therapy, is superior in controlling CMV infection and prolonging the time to CMV disease in LT recipients without an increased risk of opportunistic infections, allograft rejection, graft loss, drug related adverse effects, development of drug resistance, and mortality.

PMID:36439159 | PMC:PMC9685424 | DOI:10.3389/fimmu.2022.953210

BMJ Open Gastroenterol. 2022 Nov;9(1):e001001. doi: 10.1136/bmjgast-2022-001001.

ABSTRACT

OBJECTIVE: This study aimed to evaluate the safety and tolerability of OP-724, a CREB-binding protein/β-catenin inhibitor, in patients with advanced primary biliary cholangitis (PBC).

DESIGN: An open-label, non-randomised, phase 1 trial was conducted at two hospitals in Japan. Patients with advanced PBC classified as stage III or higher according to the Scheuer classification by liver biopsy between 4 September 2019 and 21 September 2021 were enrolled. Seven patients received intravenous OP-724 infusions at escalating dosages of 280 and 380 mg/m2/4 hours two times weekly for 12 weeks. The primary endpoint was the incidence of serious adverse events (SAEs). The secondary endpoints were the incidence of AEs and the improvement in the modified Histological Activity Index (mHAI) score.

RESULTS: Seven patients (median age, 68 years) were enrolled. Of these seven patients, five completed twelve cycles of treatment, one discontinued prematurely for personal reasons in the 280 mg/m2/4 hours cohort, and one in the 380 mg/m2/4 hours cohort was withdrawn from the study due to drug-induced liver injury (grade 2). Consequently, the recommended dosage was determined to be 280 mg/m2/4 hours. SAEs did not occur. The most common AEs were abdominal discomfort (29%) and abnormal hepatic function (43%). OP-724 treatment was associated with histological improvements in the fibrosis stage (2/5 (40%)) and mHAI score (3/5 (60%)) on histological analysis.

CONCLUSION: Administration of intravenous OP-724 infusion at a dosage of 280 mg/m2/4 hours two times weekly for 12 weeks was well tolerated by patients with advanced PBC. However, further evaluation of antifibrotic effects in patients with PBC is warranted.

TRIAL REGISTRATION NUMBER: NCT04047160.

PMID:36442892 | DOI:10.1136/bmjgast-2022-001001

Front Pharmacol. 2022 Nov 9;13:1008946. doi: 10.3389/fphar.2022.1008946. eCollection 2022.

ABSTRACT

The traditional Japanese (Kampo) medicine, kakkonto with shosaikotokakikyosekko, has antiviral and anti-inflammatory effects. In this randomized trial, patients with mild and moderate coronavirus disease (COVID-19) were randomly allocated to the control group receiving conventional treatment for symptom relief such as antipyretics and antitussives or the Kampo group receiving mixed extract granules of kakkonto (2.5 g) and shosaikotokakikyosekko (2.5 g) three times a day for 14 days in addition to conventional treatment. The main outcome was the number of days until total symptom relief. The secondary outcome was the number of days until each symptom's relief and whether the disease progressed to respiratory failure. We enrolled a total of 161 patients (Kampo group, n = 81; control group, n = 80). The results from Kaplan-Meier estimates of symptom relief showed that there are no significant differences between the groups. However, covariate-adjusted cumulative incidence of fever relief considering competitive risk showed that the recovery was significantly faster in the Kampo group than in the control group (HR 1.76, 95% CI 1.03-3.01). Additionally, the risk of disease progression to moderate COVID-19 requiring oxygen inhalation was lower in the Kampo group than in the control group (Risk Difference -0.13, 95% CI -0.27-0.01). No significant drug-related side effects were observed. Kakkonto with shosaikotokakikyosekko is effective for fever relief with suppression of disease progression in COVID-19 patients. Clinical Trial Registration: https://jrct.niph.go.jp/en-latest-detail/jRCTs021200020, identifier [jRCTs021200020].

PMID:36438822 | PMC:PMC9682103 | DOI:10.3389/fphar.2022.1008946

Psychiatry Clin Neurosci. 2022 Nov 27. doi: 10.1111/pcn.13511. Online ahead of print.

ABSTRACT

INTRODUCTION: Impulse control disorders (e.g., pathological gambling, hypersexuality) may develop as adverse reactions to drugs. Pathogenetic hypotheses have mainly focused on D3-receptor agonism, and switching to alternatives with different pharmacologic mechanisms represents a common management strategy. Nonetheless, treatment failure is common and gaining pathophysiological insights is needed.

AIM: We aimed to identify targets potentially contributing to pathologic impulsivity.

METHOD: We performed a pharmacovigilance-pharmacodynamic study on dopamine agonists and antipsychotics using the Food and Drug Administration Adverse Event Reporting System (January 2004-December 2021). We estimated disproportionate reporting using the Bayesian information component. Using online public databases (IUPHAR, ChEMBL, PDSP, DrugBank), we calculated drug occupancies. To identify the targets potentially contributing to impulsivity, we fitted univariate regression models interpolating information components and occupancies within dopamine agonists and antipsychotics. Sensitivity analyses were performed to check for the robustness of the results.

RESULTS: Among 19,887 reports of impulsivity, 5,898 recorded an antipsychotic, and 3,100 a dopamine agonist. The more robust signals concerned aripiprazole (N=3,091; median information component [95% confidence interval] = 4.51[4.45-4.55]) and brexpiprazole (229; 4.00[3.78-4.16]) for antipsychotics, pergolide (105; 5.82[5.50-6.06]) and pramipexole (2009; 5.43[5.36-5.48]) for dopamine agonists. Robust, significant positive associations between drug occupancy and impulsivity reporting were found for D3 within dopamine agonists (beta=1.52; p-value=0.047) and 5-HT1a within antipsychotics (1.92, 0.029).

CONCLUSION: Our results supported the role of D3-receptor agonism in inducing impulsivity in dopamine receptor agonists and identified a potential role of 5-HT1a receptor agonism in antipsychotics. Investigating these receptors may drive towards a better management of drug-induced impulsivity. This article is protected by copyright. All rights reserved.

PMID:36436204 | DOI:10.1111/pcn.13511

BMC Public Health. 2022 Nov 25;22(1):2182. doi: 10.1186/s12889-022-14573-z.

ABSTRACT

PURPOSE: To determine the prevalence and associated factors of self-reported medication information needs among medication users in a general population aged 40 years and above - The Tromsø Study.

METHODS: Cross-sectional study of medication users (n = 10,231) among participants in the Tromsø Study, a descriptive analysis of questionnaire data and multivariable logistic regression (n = 9,194).

RESULTS: Sixteen percent of medication users expressed a need for more information about own medications. Overall, medication users agreed to a higher degree to have received information from the GP compared to the pharmacy. Concerned medication users and those disagreeing to have received information about side effects had the highest odds for needing more information (OR 5.07, 95% CI 4.43-5.81) and (OR 2.21, 95% CI 1.83-2.68), respectively. Medication users who used heart medications (e.g., nitroglycerin, antiarrhythmics, anticoagulants) (OR 1.71, 95% CI 1.46-2.01), medication for hypothyroidism (OR 1.36, 95% CI 1.13-1.64) or had moderately health anxiety had expressed need for medication information. Whereas medication users with lower education, those that never used internet to search for health advice, and medication users who disagreed to have received information about reason-for-use were associated with lower odds (OR 0.75, 95% CI 0.62-0.91), (OR 0.85, 95% CI 0.74-0.98) and (OR 0.68, 95% CI 0.53-0.88), respectively.

CONCLUSION: This study demonstrated that there is need for more information about own medications in a general population aged 40 years and above and shed light on several characteristics of medication users with expressed information need which is important when tailoring the right information to the right person.

PMID:36434564 | DOI:10.1186/s12889-022-14573-z

Nutrients. 2022 Nov 9;14(22):4723. doi: 10.3390/nu14224723.

ABSTRACT

In modern society, where new diseases and viruses are constantly emerging, drugs are still the most important means of resistance. However, adverse effects and diminished efficacy remain the leading cause of treatment failure and a major determinant of impaired health-related quality of life for patients. Clinical studies have shown that the disturbance of the gut microbial structure plays a crucial role in the toxic and side effects of drugs. It is well known that probiotics have the ability to maintain the balance of intestinal microecology, which implies their potential as an adjunct to prevent and alleviate the adverse reactions of drugs and to make medicines play a better role. In addition, in the past decade, probiotics have been found to have excellent prevention and alleviation effects in drug toxicity side effects, such as liver injury. In this review, we summarize the development history of probiotics, discuss the impact on drug side effects of probiotics, and propose the underlying mechanisms. Probiotics will be a new star in the world of complementary medicine.

PMID:36432410 | DOI:10.3390/nu14224723

Molecules. 2022 Nov 16;27(22):7926. doi: 10.3390/molecules27227926.

ABSTRACT

Globally, plastics are used in various products. Concerns regarding the human body's exposure to plastics and environmental pollution have increased with increased plastic use. Microplastics can be detected in the atmosphere, leading to potential human health risks through inhalation; however, the toxic effects of microplastic inhalation are poorly understood. In this study, we examined the pulmonary toxicity of polystyrene (PS), polypropylene (PP), and polyvinyl chloride (PVC) in C57BL/6, BALB/c, and ICR mice strains. Mice were intratracheally instilled with 5 mg/kg of PS, PP, or PVC daily for two weeks. PS stimulation increased inflammatory cells in the bronchoalveolar lavage fluid (BALF) of C57BL/6 and ICR mice. Histopathological analysis of PS-instilled C57BL/6 and PP-instilled ICR mice showed inflammatory cell infiltration. PS increased the NLR family pyrin domain containing 3 (NLRP3) inflammasome components in the lung tissue of C57BL/6 and ICR mice, while PS-instilled BALB/c mice remained unchanged. PS stimulation increased inflammatory cytokines, including IL-1β and IL-6, in BALF of C57BL/6 mice. PP-instilled ICR mice showed increased NLRP3, ASC, and Caspase-1 in the lung tissue compared to the control groups and increased IL-1β levels in BALF. These results could provide baseline data for understanding the pulmonary toxicity of microplastic inhalation.

PMID:36432032 | DOI:10.3390/molecules27227926

Int J Mol Sci. 2022 Nov 17;23(22):14207. doi: 10.3390/ijms232214207.

ABSTRACT

Asthma is a common inflammatory disease of the lungs. The prevalence of asthma is increasing worldwide, and the tendency indicates that the number of asthma sufferers will soar in the coming years for several reasons, in particular, the lifestyles we have adopted that expose us to risk factors. Salbutamol is the first selective short-acting β2-agonist (SABA) used as an alternative reliever in the treatment of asthma. Its therapeutic effect is based on its potent smooth muscle relaxant properties, which allow the inhibition of bronchial smooth muscle contraction and subsequent bronchodilation. Salbutamol can be administered orally, intravenously (IV), intramuscularly (IM), subcutaneously, or by inhalation. For this reason, the pharmacokinetic (PK) parameters-absorption, distribution, metabolism, and elimination-are highly diverse and, consequently, the efficacy and adverse effects also differ between each formulation. Here, we review the pharmacological profile of different salbutamol formulations, focusing on their efficacy and adverse effects for its original application, asthma.

PMID:36430683 | DOI:10.3390/ijms232214207

Int J Mol Sci. 2022 Nov 15;23(22):14121. doi: 10.3390/ijms232214121.

ABSTRACT

Myocardial protection against ischemia/reperfusion injury (IRI) is mediated by various ligands, activating different cellular signaling cascades. These include classical cytosolic mediators such as cyclic-GMP (c-GMP), various kinases such as Phosphatydilinositol-3- (PI3K), Protein Kinase B (Akt), Mitogen-Activated-Protein- (MAPK) and AMP-activated (AMPK) kinases, transcription factors such as signal transducer and activator of transcription 3 (STAT3) and bioactive molecules such as vascular endothelial growth factor (VEGF). Most of the aforementioned signaling molecules constitute targets of anticancer therapy; as they are also involved in carcinogenesis, most of the current anti-neoplastic drugs lead to concomitant weakening or even complete abrogation of myocardial cell tolerance to ischemic or oxidative stress. Furthermore, many anti-neoplastic drugs may directly induce cardiotoxicity via their pharmacological effects, or indirectly via their cardiovascular side effects. The combination of direct drug cardiotoxicity, indirect cardiovascular side effects and neutralization of the cardioprotective defense mechanisms of the heart by prolonged cancer treatment may induce long-term ventricular dysfunction, or even clinically manifested heart failure. We present a narrative review of three therapeutic interventions, namely VEGF, proteasome and Immune Checkpoint inhibitors, having opposing effects on the same intracellular signal cascades thereby affecting the heart. Moreover, we herein comment on the current guidelines for managing cardiotoxicity in the clinical setting and on the role of cardiovascular confounders in cardiotoxicity.

PMID:36430599 | DOI:10.3390/ijms232214121

Int J Mol Sci. 2022 Nov 14;23(22):14058. doi: 10.3390/ijms232214058.

ABSTRACT

Colorectal cancer (CRC) is the third most common cancer in men and the second most common in women. Treatment of metastatic CRC consists of highly toxic chemotherapeutic drug combinations that often negatively affect patient quality of life (QoL). Moreover, chemotherapy-induced toxicity and chemotherapy resistance are among the most important factors limiting cancer treatment and can lead to the interruption or discontinuation of potentially effective therapy. Several preclinical studies have demonstrated that curcumin acts through multiple cellular pathways and possesses both anti-cancer properties against CRC and the capacity to mitigate chemotherapy-related side effects and overcome drug resistance. In this review article, we suggest that the addition of curcumin to the standard chemotherapeutic treatment for metastatic CRC could reduce associated side-effects and overcome chemotherapy resistance, thereby improving patient QoL.

PMID:36430537 | DOI:10.3390/ijms232214058

Int J Mol Sci. 2022 Nov 11;23(22):13913. doi: 10.3390/ijms232213913.

ABSTRACT

Targeting specific pathologic pro-inflammatory cytokines or related molecules leads to excellent therapeutic effects in inflammatory arthritis, including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. Most of these agents, known as biologic disease-modifying anti-rheumatic drugs (bDMARDs), are produced in live cell lines and are usually monoclonal antibodies. Several types of monoclonal antibodies target different pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-17A, IL-6, and IL-23/12. Some bDMARDs, such as rituximab and abatacept, target specific cell-surface molecules to control the inflammatory response. The therapeutic effects of these bDMARDs differ in different forms of inflammatory arthritis and are associated with different adverse events. In this article, we summarize the therapeutic utility and adverse effects of bDMARDs and suggest future research directions for developing bDMARDs.

PMID:36430392 | DOI:10.3390/ijms232213913

Int J Environ Res Public Health. 2022 Nov 11;19(22):14842. doi: 10.3390/ijerph192214842.

ABSTRACT

We explored the interaction of the United Nation's sustainable development goals to facilitate human sustainability using occupational health and sustainable HRM perspectives. In Study 1 (n = 246), we assessed the preconditions to empirically confirm the distinctiveness of the dimensions of health harm of work from other study constructs. Subsequently, we tested the hypotheses across two studies (n = 332, Study 2; n = 255, Study 3). In alignment with the ceiling effect of human energy theory, the three-way interaction results across the samples consistently indicate that high supervisory political support (SPS) significantly strengthens the negative interactions of psychological health risk factors and high job tension as adverse working conditions (SDG-8) on working-condition-related well-being as the human sustainability dimension (SDG-3). Similarly, synergistic effects were found of the side effects of work on health, high job tension, and high SPS on well-being in sample 3. We discuss theoretical and future research for human sustainability from occupational health and sustainable HRM perspectives.

PMID:36429568 | DOI:10.3390/ijerph192214842

Cells. 2022 Nov 11;11(22):3561. doi: 10.3390/cells11223561.

ABSTRACT

Chemotherapy-induced neuropathic pain is a debilitating and dose-limiting side effect. Oxaliplatin is a third-generation platinum and antineoplastic compound that is commonly used to treat colorectal cancer and commonly yields neuropathic side effects. Available drugs such as duloxetine provide only modest benefits against oxaliplatin-induced neuropathy. A particularly disruptive symptom of oxaliplatin is painful cold sensitivity, known as cold allodynia. Previous studies of the Conus regius peptide, RgIA, and its analogs have demonstrated relief from oxaliplatin-induced cold allodynia, yielding improvement that persists even after treatment cessation. Moreover, underlying inflammatory and neuronal protection were shown at the cellular level in chronic constriction nerve injury models, consistent with disease-modifying effects. Despite these promising preclinical outcomes, the underlying molecular mechanism of action of RgIA4 remains an area of active investigation. This study aimed to determine the necessity of the α9 nAChR subunit and potential T-cell mechanisms in RgIA4 efficacy against acute oxaliplatin-induced cold allodynia. A single dose of oxaliplatin (10 mg/kg) was utilized followed by four daily doses of RgIA4. Subcutaneous administration of RgIA4 (40 µg/kg) prevented cold allodynia in wildtype mice but not in mice lacking the α9 nAChR-encoding gene, chrna9. RgIA4 also failed to reverse allodynia in mice depleted of CD3+ T-cells. In wildtype mice treated with oxaliplatin, quantitated circulating T-cells remained unaffected by RgIA4. Together, these results show that RgIA4 requires both chrna9 and CD3+ T-cells to exert its protective effects against acute cold-allodynia produced by oxaliplatin.

PMID:36428990 | DOI:10.3390/cells11223561

Cells. 2022 Nov 8;11(22):3530. doi: 10.3390/cells11223530.

ABSTRACT

N-methyl-D-aspartate (NMDA) receptors have been implicated in L-Dopa-induced dyskinesias (LID) in Parkinson's disease patients, but the use of antagonists that directly inhibit this receptor is associated with severe side effects. L-4-chlorokynurenine (4-Cl-KYN or AV-101) is a pro-drug of 7-chlorokynurenic acid (7-Cl-KYNA), a potent and specific antagonist of the glycine (GlyB) co-agonist site of NMDA receptors. The 7-Cl-KYNA has limited ability to cross the blood-brain barrier, whereas AV-101 readily accesses the brain. We investigated if AV-101 reduces LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys while maintaining the antiparkinsonian activity of L-Dopa. A first pilot study using three dyskinetic MPTP monkeys showed that acute AV-101 treatment (250 and 450 mg/kg) reduced LID and maintained the antiparkinsonian activity of L-Dopa. The main study using six additional dyskinetic MPTP monkeys showed that repeated AV-101 treatment (250 mg/kg, b.i.d. for 4 consecutive days) maintained their L-Dopa antiparkinsonian response. We measured significantly less LID when AV-101 was combined with L-Dopa treatment. AV-101 alone or with L-Dopa had no non-motor adverse effects in MPTP monkeys. Our study showed antidyskinetic activity of AV-101 in MPTP monkeys was comparable to amantadine tested previously in our laboratory in this model. We observed no adverse effects with AV-101, which is an improvement over amantadine, with its known side effects.

PMID:36428960 | DOI:10.3390/cells11223530

Molecules. 2022 Nov 16;27(22):7929. doi: 10.3390/molecules27227929.

ABSTRACT

BACKGROUND: Carfilzomib (Cfz) is an anti-cancer drug related to cardiorenal adverse events, with cardiovascular and renal complications limiting its clinical use. Despite the important progress concerning the discovery of the underlying causes of Cfz-induced nephrotoxicity, the molecular/biochemical background is still not well clarified. Furthermore, the number of metabolomics-based studies concerning Cfz-induced nephrotoxicity is limited.

METHODS: A metabolomics UPLC-HRMS-DIA methodology was applied to three bio-sample types i.e., plasma, kidney, and urine, obtained from two groups of mice, namely (i) Cfz (8 mg Cfz/ kg) and (ii) Control (0.9% NaCl) (n = 6 per group). Statistical analysis, involving univariate and multivariate tools, was applied for biomarker detection. Furthermore, a sub-study was developed, aiming to estimate metabolites' correlation among bio-samples, and to enlighten potential mechanisms.

RESULTS: Cfz mostly affects the kidneys and urine metabolome. Fifty-four statistically important metabolites were discovered, and some of them have already been related to renal diseases. Furthermore, the correlations between bio-samples revealed patterns of metabolome alterations due to Cfz.

CONCLUSIONS: Cfz causes metabolite retention in kidney and dysregulates (up and down) several metabolites associated with the occurrence of inflammation and oxidative stress.

PMID:36432029 | DOI:10.3390/molecules27227929

IEEE/ACM Trans Comput Biol Bioinform. 2022 Nov 25;PP. doi: 10.1109/TCBB.2022.3224734. Online ahead of print.

ABSTRACT

Combination therapy, which can improve therapeutic efficacy and reduce side effects, plays an important role in the treatment of complex diseases. Yet, a large number of possible combinations among candidate compounds limits our ability to identify effective combinations. Though many studies have focused on predicting potential drug combinations, the existing methods are not entirely satisfactory in terms of performance and scalability. In this study, we propose a new computational pipeline, called DCMGCN, which integrates diverse drug-related information, to predict novel drug combinations. Specifically, DCMGCN first learns low-dimensional representations of drugs from the drug attributes and similarity networks. Then, by quantifying the degree of the nodes in the known drug-drug network and the similarity between connected nodes, we found the drug-drug network has heterophily and sparseness, which may limit the effectiveness of the graph convolutional network (GCN). Therefore, we introduce two designs to modify GCN. Finally, the drug representations are optimized using modified GCN (MGCN) and used to predict drug combinations. The tests on multiple drug combination datasets show that DCMGCN achieved substantial improvements over state-of-the-art methods. Importantly, our model may embed the mechanism of ground-truth drug pairs into the low-dimensional representation of each drug, which may help to further clarify the understanding of mechanisms of drug action.

PMID:36427284 | DOI:10.1109/TCBB.2022.3224734

Arch Acad Emerg Med. 2022 Sep 24;10(1):e76. doi: 10.22037/aaem.v10i1.1622. eCollection 2022.

ABSTRACT

INTRODUCTION: Rare serious complications have been documented after COVID-19 vaccination as clinical research proceeded and new target populations, such as children and ‎pregnant women, were included. In this study, we attempted to review the literature relevant to ‎pregnancy complications and maternal outcomes of COVID-19 immunization in pregnant women. ‎.

METHODS: We searched the databases of PubMed, Scopus, Cochrane, and Web of Science on 31 August 2022. The records were downloaded and underwent a two-step screening; 1) title/abstract and then 2) full-text screening to identify the eligible studies. We included English original studies that evaluated the adverse effects of COVID-19 vaccines during pregnancy. Information such as the type of ‎study, geographical location, type of vaccine injected, gestational age, maternal underlying diseases, and ‎complications following the vaccination were extracted into pre-designed tables.

RESULTS: According to the findings of included studies, in most of them vaccination had a positive impact and no negative effects were observed. Also, no medical history was reported in 11 articles, and pregnant women had no underlying diseases. Some serious adverse events were reported after ‎vaccination, including miscarriage, paresthesia, uterine contraction, vaginal bleeding, preterm birth, major ‎congenital anomalies, intrauterine growth restriction, and seizure. ‎.

CONCLUSION: Because of limited data availability and the cross-sectional design of most studies, we could neither infer ‎causation between vaccines and incidence of adverse effects nor comment with certainty about any ‎possible adverse outcome of COVID-19 vaccines in vaccinated pregnant women. Consequently, more longitudinal and experimental studies are needed to define the exact adverse effects of COVID-19 vaccines in pregnant women.

PMID:36426163 | PMC:PMC9676695 | DOI:10.22037/aaem.v10i1.1622