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

Turk J Med Sci. 2022 Oct;52(5):1425-1447. doi: 10.55730/1300-0144.5482. Epub 2022 Oct 19.

ABSTRACT

Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disease with multiple genetic and a variety of environmental risk factors. Although current drugs significantly aid in controlling the disease, many people have led to the application of complementary therapies due to the common belief that they are natural and safe, as well as due to the consideration of the side effect of current drugs. Curcumin, cannabinoids, wheatgrass, Boswellia, wormwood and Aloe vera are among the most commonly used complementary medicines in UC. However, these treatments may have adverse and toxic effects due to unintended interactions with drugs or drug-metabolizing enzymes such as cytochrome P450s; thus, being ignorant of these interactions might cause deleterious effects with severe consequences. In addition, the lack of complete and controlled long-term studies with the use of these complementary medicines regarding drug metabolism pose additional risk and unsafety. Thus, this review aims to give an overview of the potential interactions of drug-metabolizing enzymes with the complementary botanical medicines used in UC, drawing attention to possible adverse effects.

PMID:36422483 | DOI:10.55730/1300-0144.5482

Recenti Prog Med. 2022 Dec;113(12):722-732. doi: 10.1701/3914.38974.

ABSTRACT

OBJECTIVE: The results of PD-1/PD-L1 inhibitor combined with chemotherapy for TNBC are controversial. Therefore, a meta-analysis was conducted to evaluate the efficacy and safety after PD-1/PD-L1 inhibitors plus chemotherapy in TNBC patients.

METHODS: We systematically searched seven databases and several mainly oncology conferences for prospective clinical trials of chemotherapy combined with immunotherapy to treat TNBC, and we included pathologic complete response (PCR), progression-free survival (PFS), overall survival (OS) and adverse effects as outcome indicators of the study.

RESULTS: We analyzed data from six studies involving 4,187 patients. The efficacy analysis indicated that PD1/PD-L1 inhibitor combined with chemotherapy significantly increased PCR rates in neoadjuvant patients (OR: 1.60; 95% CI: 1.18-2.17; p=0.003). There was no correlation between increases in PCR rates and the expression of PD-L1, but the PCR rate was higher in PD-L1+ patients. Subgroup analysis suggested that the lymph node-positive (OR: 2.52; 95% CI: 1.69-3.77; p<0.001) and ECOG PS 0 (OR: 1.9; 95% CI: 1.42-2.53; p<0.001) subgroups benefited from the combination of PD-1/PD-L1 inhibitor plus chemotherapy. In TNBC receiving advanced rescue treatment, PFS was higher in the group receiving PD-1/PD-L1 inhibitor plus chemotherapy than in the group receiving chemotherapy alone (HR: 0.78; 95% CI: 0.70-0.86; p<0.001). Compared with chemotherapy alone, PD-1/PD-L1 inhibitors combined with chemotherapy did not increase the OS of patients (HR=0.88, 95% CI: 0.76~1.03, p=0.12). In addition, the toxicity analysis showed that more grade 3-4 adverse effects and severe adverse effects occurred in the PD-1/PD-L1 inhibitor combined with chemotherapy group.

CONCLUSIONS: PD-1/PD-L1 inhibitors combined with chemotherapy can improve the PCR and PFS rate of TNBC patients, but did not improve the OS, and had a higher risk of AEs.

PMID:36420848 | DOI:10.1701/3914.38974

S Afr Med J. 2022 Nov 1;112(11):866-870. doi: 10.7196/SAMJ.2022.v112i11.16453.

ABSTRACT

BACKGROUND: Severe theophylline toxicity requiring haemodialysis accounts for approximately one-third of drug toxicity cases admitted to the Livingstone Tertiary Hospital (LTH) intensive care unit (ICU) in Gqeberha, South Africa, imposing a significant resource burden.

OBJECTIVES: To investigate the characteristics and burden of severe theophylline toxicity in an Eastern Cape Province tertiary hospital adult ICU.

METHODS: A retrospective review of all severe theophylline toxicity admissions to the ICU from 1 January 2013 to 31 December 2018 was conducted. Demographic and clinical data were captured and analysed. The National Department of Health 2019 fees schedule was used to calculate costs based on duration of ICU stay and number of haemodialysis sessions received.

RESULTS: Of the 57 patients included in the study, 84% were cases of deliberate self-harm. The majority were aged <40 years (77%) and female (79%). The mean (standard deviation (SD)) initial serum theophylline level was 612 (269) µmol/L. Complications included convulsions (n=12; 21%), arrhythmias (n=9; 16%), need for mechanical ventilation (n=7; 12%) and death (n=4; 7%). The main risk factors for these complications were age ≥30 years, an inappropriately normal or elevated initial serum potassium level, an elevated serum creatinine kinase level and an elevated initial serum theophylline level. Receiver operator characteristic curve analysis assessing the initial serum theophylline level as a discriminator for life-threatening complications produced an area under the curve of 0.71 for serum theophylline >400 µmol/L (sensitivity 88%, specificity 12%). All the 4 patients who died had an initial serum theophylline level >1 000 µmol/L. The mean (SD) cost per admission amounted to ZAR16 897 (10 718), with a mean of one 4-hour dialysis session per admission.

CONCLUSION: Severe theophylline toxicity, usually in the context of deliberate self-harm, is a preventable yet life-threatening toxicity encountered at LTH. Demographic risk factors include young females from certain areas in and around Gqeberha. Risk factors for complications include older age, paradoxically normal or elevated serum potassium levels, elevated serum creatinine kinase levels and an initial serum theophylline level >400 µmol/L. Patients with these clinical features should be closely monitored and treated timeously at an appropriate level of care. The need for ICU admission and dialysis, both limited resources, makes the treatment of severe theophylline toxicity costly. Further studies of the underlying psychosocial drivers, local prescribing practices and preventive interventions related to severe theophylline toxicity are required.

PMID:36420723 | DOI:10.7196/SAMJ.2022.v112i11.16453

Cochrane Database Syst Rev. 2022 Nov 24;11:CD014384. doi: 10.1002/14651858.CD014384.pub2.

ABSTRACT

BACKGROUND: Antipsychotic drugs are the mainstay treatment for schizophrenia, yet they are associated with diverse and potentially dose-related side effects which can reduce quality of life. For this reason, the lowest possible doses of antipsychotics are generally recommended, but higher doses are often used in clinical practice. It is still unclear if and how antipsychotic doses could be reduced safely in order to minimise the adverse-effect burden without increasing the risk of relapse.

OBJECTIVES: To assess the efficacy and safety of reducing antipsychotic dose compared to continuing the current dose for people with schizophrenia.

SEARCH METHODS: We conducted a systematic search on 10 February 2021 at the Cochrane Schizophrenia Group's Study-Based Register of Trials, which is based on CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, PubMed, ClinicalTrials.gov, ISRCTN, and WHO ICTRP. We also inspected the reference lists of included studies and previous reviews.

SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing any dose reduction against continuation in people with schizophrenia or related disorders who were stabilised on their current antipsychotic treatment. DATA COLLECTION AND ANALYSIS: At least two review authors independently screened relevant records for inclusion, extracted data from eligible studies, and assessed the risk of bias using RoB 2. We contacted study authors for missing data and additional information. Our primary outcomes were clinically important change in quality of life, rehospitalisations and dropouts due to adverse effects; key secondary outcomes were clinically important change in functioning, relapse, dropouts for any reason, and at least one adverse effect. We also examined scales measuring symptoms, quality of life, and functioning as well as a comprehensive list of specific adverse effects. We pooled outcomes at the endpoint preferably closest to one year. We evaluated the certainty of the evidence using the GRADE approach.

MAIN RESULTS: We included 25 RCTs, of which 22 studies provided data with 2635 participants (average age 38.4 years old). The median study sample size was 60 participants (ranging from 18 to 466 participants) and length was 37 weeks (ranging from 12 weeks to 2 years). There were variations in the dose reduction strategies in terms of speed of reduction (i.e. gradual in about half of the studies (within 2 to 16 weeks) and abrupt in the other half), and in terms of degree of reduction (i.e. median planned reduction of 66% of the dose up to complete withdrawal in three studies). We assessed risk of bias across outcomes predominantly as some concerns or high risk. No study reported data on the number of participants with a clinically important change in quality of life or functioning, and only eight studies reported continuous data on scales measuring quality of life or functioning. There was no difference between dose reduction and continuation on scales measuring quality of life (standardised mean difference (SMD) -0.01, 95% confidence interval (CI) -0.17 to 0.15, 6 RCTs, n = 719, I2 = 0%, moderate certainty evidence) and scales measuring functioning (SMD 0.03, 95% CI -0.10 to 0.17, 6 RCTs, n = 966, I2 = 0%, high certainty evidence). Dose reduction in comparison to continuation may increase the risk of rehospitalisation based on data from eight studies with estimable effect sizes; however, the 95% CI does not exclude the possibility of no difference (risk ratio (RR) 1.53, 95% CI 0.84 to 2.81, 8 RCTs, n = 1413, I2 = 59% (moderate heterogeneity), very low certainty evidence). Similarly, dose reduction increased the risk of relapse based on data from 20 studies (RR 2.16, 95% CI 1.52 to 3.06, 20 RCTs, n = 2481, I2 = 70% (substantial heterogeneity), low certainty evidence). More participants in the dose reduction group in comparison to the continuation group left the study early due to adverse effects (RR 2.20, 95% CI 1.39 to 3.49, 6 RCTs with estimable effect sizes, n = 1079, I2 = 0%, moderate certainty evidence) and for any reason (RR 1.38, 95% CI 1.05 to 1.81, 12 RCTs, n = 1551, I2 = 48% (moderate heterogeneity), moderate certainty evidence). Lastly, there was no difference between the dose reduction and continuation groups in the number of participants with at least one adverse effect based on data from four studies with estimable effect sizes (RR 1.03, 95% CI 0.94 to 1.12, 5 RCTs, n = 998 (4 RCTs, n = 980 with estimable effect sizes), I2 = 0%, moderate certainty evidence). AUTHORS' CONCLUSIONS: This review synthesised the latest evidence on the reduction of antipsychotic doses for stable individuals with schizophrenia. There was no difference between dose reduction and continuation groups in quality of life, functioning, and number of participants with at least one adverse effect. However, there was a higher risk for relapse and dropouts, and potentially for rehospitalisations, with dose reduction. Of note, the majority of the trials focused on relapse prevention rather potential beneficial outcomes on quality of life, functioning, and adverse effects, and in some studies there was rapid and substantial reduction of doses. Further well-designed RCTs are therefore needed to provide more definitive answers.

PMID:36420692 | DOI:10.1002/14651858.CD014384.pub2

Front Endocrinol (Lausanne). 2022 Nov 7;13:951186. doi: 10.3389/fendo.2022.951186. eCollection 2022.

ABSTRACT

Obesity in women of reproductive age has a number of adverse metabolic effects, including Type II Diabetes (T2D), dyslipidemia, and cardiovascular disease. It is associated with increased menstrual irregularity, ovulatory dysfunction, development of insulin resistance and infertility. In women, estradiol is not only critical for reproductive function, but they also control food intake and energy expenditure. Food intake is known to change during the menstrual cycle in humans. This change in food intake is largely mediated by estradiol, which acts directly upon anorexigenic and orexigenic neurons, largely in the hypothalamus. Estradiol also acts indirectly with peripheral mediators such as glucagon like peptide-1 (GLP-1). Like estradiol, GLP-1 acts on receptors at the hypothalamus. This review describes the physiological and pathophysiological mechanisms governing the actions of estradiol during the menstrual cycle on food intake and energy expenditure and how estradiol acts with other weight-controlling molecules such as GLP-1. GLP-1 analogs have proven to be effective both to manage obesity and T2D in women. This review also highlights the relationship between steroid hormones and women's mental health. It explains how a decline or imbalance in estradiol levels affects insulin sensitivity in the brain. This can cause cerebral insulin resistance, which contributes to the development of conditions such as Parkinson's or Alzheimer's disease. The proper use of both estradiol and GLP-1 analogs can help to manage obesity and preserve an optimal mental health in women by reducing the mechanisms that trigger neurodegenerative disorders.

PMID:36419765 | PMC:PMC9677105 | DOI:10.3389/fendo.2022.951186

J Int Med Res. 2022 Nov;50(11):3000605221133988. doi: 10.1177/03000605221133988.

ABSTRACT

Lamotrigine is an antiepileptic drug that can be used to control many types of seizures as a single-agent or an add-on therapy in patients over 2 years of age. In addition to common adverse reactions, this current case report describes a paediatric male patient with a rare side-effect of persistent penile erectile due to lamotrigine. Previous studies have shown that it can improve sexual function in adult male patients. This patient suffered from refractory epilepsy and pneumonia. He had taken a variety of antiepileptic drugs for a long time and developed priapism after the dosage of lamotrigine had been increased. The priapism improved after drug withdrawal and sedation. Further research is needed to elucidate the mechanism of this rare side-effect.

PMID:36418928 | DOI:10.1177/03000605221133988

Drugs Aging. 2022 Nov 23. doi: 10.1007/s40266-022-00983-6. Online ahead of print.

ABSTRACT

BACKGROUND: Residents of aged-care facilities have high rates of adverse drug events. This study aimed to identify risk factors for adverse drug events in aged-care residents.

METHOD: This was a secondary study using data from a multicentre randomised controlled trial. Data from 224 residents for whom there was 6 months of baseline information were analysed. We assessed the risk of adverse drug events and falls (post hoc) in the subsequent 6 months. Adverse events were identified via a key word search of the resident care record and adjudicated by a multidisciplinary panel using a modified version of the Naranjo criteria. Covariates identified through univariable logistic regression, including age, sex, medicines, physical activity, cognition (Montreal Cognitive Assessment), previous adverse events and health service use were included in multivariable models.

RESULTS: Overall, 224 residents were included, with a mean age of 86 years; 70% were female. 107 (48%) residents had an adverse drug event during the 6-month follow-up. Falls and bleeding were experienced by 73 (33%) and 28 (13%) residents, respectively. Age (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.01-1.10), weight (OR 1.02, 95% CI 1.002-1.04), previous fall (OR 2.58, 95% CI 1.34-4.98) and sedative or hypnotic medicine use (OR 1.98, 95% CI 1.52-2.60) were associated with increased risk of adverse drug events. Increased cognition (OR 0.89, 95% CI 0.83-0.95) was protective. Risk factors for falls were previous fall (OR 3.27, 95% CI 1.68-6.35) and sedative or hypnotic medicines (OR 3.05, 95% CI 1.14-8.16). Increased cognition (OR 0.88, 95% CI 0.83-0.95) was protective.

CONCLUSION: Our results suggest residents with a previous fall, reduced cognition, and prescription of sedative or hypnotic medicines were at higher risk of adverse drug events and should be considered for proactive prevention.

PMID:36422825 | DOI:10.1007/s40266-022-00983-6

Subst Use Misuse. 2022 Nov 24:1-9. doi: 10.1080/10826084.2022.2148482. Online ahead of print.

ABSTRACT

Background: Although evidence shows that engaging in chemsex can be associated with poor mental health, little is known about the relationship between psychological factors and this type of drug use. We aim to explore associations between engagement in chemsex and several psychological variables (adverse life events, attachment styles, emotional regulation skills, self-care patterns) in a sample of gay, bisexual, and other men who have sex with men (GBMSM) with drug-related problems. Methods: A group of GBMSM engaged in chemsex (n = 41) and a control group of GBMSM (n = 39) completed an online survey to assess drug-related problems and the abovementioned psychological variables, in which both groups were compared. All analyses were adjusted for covariates showing significant differences between groups. Results: Compared to the control group, participants engaged in chemsex showed significantly higher frequencies of an avoidant-insecure attachment style and early adverse life events, regardless of all covariates (HIV status, job situation, and place of birth). Poorer emotional regulation and self-care patterns and a higher frequency of sexual abuse were also found in participants engaged in chemsex, though we cannot rule out the influence of HIV status on this second group of variables. Conclusions: Some people with drug-related problems engaged in chemsex might have suffered early adverse events and might have an avoidant-insecure attachment style. Moreover, those who have been diagnosed with HIV might show higher emotional dysregulation and poorer self-care patterns. These variables should be routinely evaluated in this population.

PMID:36422467 | DOI:10.1080/10826084.2022.2148482

Phytother Res. 2022 Nov 23. doi: 10.1002/ptr.7687. Online ahead of print.

ABSTRACT

Tea tree (Melaleuca alternifolia) essential oil is widely used as an antiseptic. It mainly consists of monoterpenes with terpinen-4-ol as the major constituent. The aim of this study was to review literature on safety data about tea tree oil and to assess its safety by investigating 159 cases of adverse reactions possibly caused by the oil, reported to the World Health Organization (WHO) from December 1987 until September 2021. To extract these data, VigiBase, the WHO global database of individual case safety reports maintained by the Uppsala Monitoring Centre (UMC), was used. All cases were categorized and analysed and 16 serious cases further assessed. It was concluded that tea tree oil should never be administered orally, as it can lead to central nervous system depression and pneumonitis. Applied topically, skin disorders may occur, especially when the oil had been exposed to light or air. This yields monoterpene oxidation products, being potent skin irritants. Tea tree oil stored under appropriate conditions and not exceeding the expiration date should be considered safe to use by non-vulnerable people for non-serious inflammatory skin conditions, although the occurrence of adverse reactions such as contact allergies is difficult to predict.

PMID:36420525 | DOI:10.1002/ptr.7687

Nat Commun. 2022 Nov 22;13(1):7165. doi: 10.1038/s41467-022-34744-1.

ABSTRACT

Nano-immunotherapy improves breast cancer outcomes but not all patients respond and none are cured. To improve efficacy, research focuses on drugs that reprogram cancer-associated fibroblasts (CAFs) to improve therapeutic delivery and immunostimulation. These drugs, however, have a narrow therapeutic window and cause adverse effects. Developing strategies that increase CAF-reprogramming while limiting adverse effects is urgent. Here, taking advantage of the CAF-reprogramming capabilities of tranilast, we developed tranilast-loaded micelles. Strikingly, a 100-fold reduced dose of tranilast-micelles induces superior reprogramming compared to free drug owing to enhanced intratumoral accumulation and cancer-associated fibroblast uptake. Combination of tranilast-micelles and epirubicin-micelles or Doxil with immunotherapy increases T-cell infiltration, resulting in cures and immunological memory in mice bearing immunotherapy-resistant breast cancer. Furthermore, shear wave elastography (SWE) is able to monitor reduced tumor stiffness caused by tranilast-micelles and predict response to nano-immunotherapy. Micellar encapsulation is a promising strategy for TME-reprogramming and SWE is a potential biomarker of response.

PMID:36418896 | DOI:10.1038/s41467-022-34744-1

Drug Deliv. 2022 Dec;29(1):3384-3396. doi: 10.1080/10717544.2022.2149899.

ABSTRACT

Pirfenidone (PRF) is the first FDA-approved API in the treatment of idiopathic pulmonary fibrosis (IPF). However, PRF induces serious side effects, such as photophobia and gastrointestinal disorder. PRF inhalation can be expected with a lower effective dose and reduced side effects. In this study, PRF was prepared as inhalable co-spray-dried particles for dry powder inhalation. Mannitol, L-leucine (Leu), and NaCl were used as a stabilizer. The kinds and ratios of stabilizers affecting the physicochemical properties of particles were analyzed, including particle size and surface composition, because of the surface enrichment properties of Leu, the most effective stabilizer. The co-spray-dried PRF and Leu microparticle (SD-PL1:1) have the smallest size and highest aerosol performance. The bioavailability was confirmed by in vivo pharmacokinetics (PK) studies. In addition, in vivo pharmacodynamics (PD) experiments were conducted using a bleomycin-induced IPF rat model. In vivo PK experiments demonstrated that pulmonary administration of SD-PL1:1 was 4 times more effective than the oral route. Similar to the PK results, the therapeutic effect was improved when SD-PL1:1 was administered via the pulmonary route compared to the oral route.

PMID:36415157 | DOI:10.1080/10717544.2022.2149899