Major Adverse Effects Research Articles

Deciphering the roles of cellular and extracellular non-coding RNAs in chemotherapy-induced cardiotoxicity.

Chemotherapy-induced cardiotoxicity is a major adverse effect, driven by multiple factors in its pathogenesis. Notably, RNAs have emerged as significant contributors in both cancer and heart failure (HF). RNAs carry genetic and metabolic information that mirrors the current state of cells, making them valuable as potential biomarkers and therapeutic tools for diagnosing, predicting, and treating a range of diseases, including cardiotoxicity. Over 97% of the genome is transcribed into non-coding RNAs (ncRNAs), including ribosomal RNA (rRNAs), transfer RNAs (tRNAs), and newly identified microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs). NcRNAs function not only within their originating cells but also in recipient cells by being transported through extracellular compartments, referred to as extracellular RNAs (exRNAs). Since ncRNAs were identified as key regulators of gene expression, numerous studies have highlighted their significance in both cancer and cardiovascular diseases. Nevertheless, the role of ncRNAs in cardiotoxicity remains not fully elucidated. The study aims to review the existing knowledge on ncRNAs in Cardio-Oncology and explore the potential of ncRNA-based biomarkers and therapies. These investigations could advance the clinical application of ncRNA research, improving early detection and mitigating of chemotherapy-induced cardiotoxicity.

Regadenoson stress echocardiography: a road ahead

Abstract Introduction Drugs used in stress echocardiography (SE) have important limitations due to side effects and contraindications. Since its approval in 2008, Regadenoson has seen a significant increase in usage. This is largely attributed to its good safety profile and diagnostic accuracy, making it the preferred drug for stress tests in many European centers. However, despite its expanding use and major advantages, current guidelines don't place it as the first choice for SE, probably because the reported experience with this drug remains limited. The aim of the present study was to assess the safety and short-medium term prognosis of patients who underwent Regadenoson SE. Methods Retrospective observational study. Patients who underwent Regadenoson SE between 2017 and 2023 were included. Safety was assessed by monitoring immediate adverse effects following Regadenoson infusion and the need for using an antidote (Aminophylline). A positive test result was defined by the occurrence of any of the following: wall motion abnormalities, left ventricle dilatation, electrocardiographic changes or symptoms of ischemia. During the follow up, we registered the incidence of ischaemic events (admission for unstable angina, acute myocardial infarction (AMI) or cardiovascular (CV) death) and other CV events such as admission for heart failure (HF) and stroke. Additionally, we evaluated patients in both groups who underwent coronary angiography (by computerized tomography or coronary catheterization) during the follow up period. The groups with negative SE (NSE) and positive SE (PSE) were compared. Results The total number of patients was 344, with a median follow up of 29 months. Basal population characteristics and events by group (NSE and PSE) are shown in Figure 1. We needed to use the antidote in only one case, because of ventricular bigeminism, with no other major adverse effects reported. SE was positive in 37 (11%) patients. In this group, patients were more likely to present ischaemic events (16% vs. 3%, p<0.01) and admissions for HF (24% vs. 5%, p <0.01), compared to the NSE one. In those who underwent coronary angiography, revascularization was needed in 14 patients of the PSE group, and only in 7 of the NSE group (38% vs 2%, p < 0.05). The indications for these last cases were persistent angina in 5 patients (2 of them with history of coronary artery disease) and revascularization following an AMI in 2 patients. (Figure 2). Conclusions The probability of an ischaemic event after a negative Regadenoson SE remains very low, unlike positive studies. Regadenoson SE showed to be both safe in assessing ischemic cardiomyopathy and very useful for its prognostic value. These findings encourage its expanding use in the stress echo lab.

The renoprotective efficacy and safety of genetically-engineered human bone marrow-derived mesenchymal stromal cells expressing anti-fibrotic cargo

BackgroundKidney fibrosis is a hallmark of chronic kidney disease (CKD) and compromises the viability of transplanted human bone marrow-derived mesenchymal stromal cells (BM-MSCs). Hence, BM-MSCs were genetically-engineered to express the anti-fibrotic and renoprotective hormone, human relaxin-2 (RLX) and green fluorescent protein (BM-MSCs-eRLX + GFP), which enabled BM-MSCs-eRLX + GFP delivery via a single intravenous injection.MethodsBM-MSCs were lentiviral-transduced with human relaxin-2 cDNA and GFP, under a eukaryotic translation elongation factor-1α promoter (BM-MSCs-eRLX + GFP) or GFP alone (BM-MSCs-eGFP). The ability of BM-MSCs-eRLX + GFP to differentiate, proliferate, migrate, produce RLX and cytokines was evaluated in vitro, whilst BM-MSC-eRLX + GFP vs BM-MSCs-eGFP homing to the injured kidney and renoprotective effects were evaluated in preclinical models of ischemia reperfusion injury (IRI) and high salt (HS)-induced hypertensive CKD in vivo. The long-term safety of BM-MSCs-RLX + GFP was also determined 9-months after treatment cessation in vivo.ResultsWhen cultured for 3- or 7-days in vitro, 1 × 106 BM-MSCs-eRLX + GFP produced therapeutic RLX levels, and secreted an enhanced but finely-tuned cytokine profile without compromising their proliferation or differentiation capacity compared to naïve BM-MSCs. BM-MSCs-eRLX + GFP were identified in the kidney 2-weeks post-administration and retained the therapeutic effects of RLX in vivo. 1–2 × 106 BM-MSCs-eRLX + GFP attenuated the IRI- or therapeutically abrogated the HS-induced tubular epithelial damage and interstitial fibrosis, and significantly reduced the HS-induced hypertension, glomerulosclerosis and proteinuria. This was to an equivalent extent as RLX and BM-MSCs administered separately but to a broader extent than BM-MSCs-eGFP or the angiotensin-converting enzyme inhibitor, perindopril. Additionally, these renoprotective effects of BM-MSCs-eRLX + GFP were maintained in the presence of perindopril co-treatment, highlighting their suitability as adjunct therapies to ACE inhibition. Importantly, no major long-term adverse effects of BM-MSCs-eRLX + GFP were observed.ConclusionsBM-MSCs-eRLX + GFP produced greater renoprotective and therapeutic efficacy over that of BM-MSCs-eGFP or ACE inhibition, and may represent a novel and safe treatment option for acute kidney injury and hypertensive CKD.

Mode of action exploration for prostate epithelial cell injury caused by bisphenol A

Bisphenol A (BPA) is a typical food chemical contaminant with various detrimental effects, especially on reproductive system. Male prostate damage is also one of its major adverse health effects, of which mode of action (MOA) remains unclear. This study aims to explore the MOA for prostate toxicity of BPA using human normal prostate epithelial cell RWPE-1 for 28-day human-relevant-level exposure. A physiological based pharmacokinetic model was used to determine the concentration of BPA based on the actual oral exposure in China. The possible key events were identified by high-throughput transcriptome sequencing and validated by qPCR, Western blot and cell cycle assay, and the benchmark concentration analysis were conducted. The enriched KEGG pathways include the endocytosis, cell cycle, cellular senescence, MAPK and TNF signaling pathways. With increasing BPA concentrations, the increased mRNA and/or protein expressions of MAPKAPK2, c-JUN and c-fos in the MAPK signaling pathway, the increased mRNA expressions of CCND1 and CDKN1A, the decreased mRNA expression of CDC25C, the increased proportion of G0/G1 phase and S phase, as well as the decreased proportion of G2/M phase, were observed. The lowest value of benchmark concentration lower confidence limit (BMCL) was retrieved from G2/M phase ratio, with 110.580 and 175.862 nM for BMCL5 and BMCL10, respectively, much higher than the male gonad maximum concentration of 0.019 nM of BPA at the current exposure level of adult Chinese males. In conclusion, the MOA of BPA induced male prostatic toxicity at human-relevant levels may include: key event (KE)1-MAPK signaling pathway activation, KE2-disorder of cell cycle regulatory gene expression (increased expression of CCND1 and CDKN1A, decreased expression of CDC25C), and KE3-disturbance of cell cycle (increased proportion of G0/G1 and S phases, decreased proportion of G2/M phases). However, more studies are needed to validate and complete the MOA.

Efficacy and Safety of Ivabradine for Patients With AcuteHeart Failure: Meta-Analysis of Randomized Controlled Trials.

The efficacy and safety of Ivabradine for patients with acute heart failure (AHF) is controversial, and there are few clinical trials addressing this topic. We performed this meta-analysis to evaluate efficacy and safety of Ivabradine treatment for patients with acute heart failure. We obtained data for controlled trials using the PubMed, Cochrane Library, EMBASE, and Clinical Trials.gov databases. The efficacy endpoints included change in heart rate, brain natriuretic peptide (BNP) levels, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, ejection fraction (EF) values, and a 6-min walk distance. The safety endpoints included mortality, cardiogenic mortality, incidents of hospital readmission, bradycardia, and atrial fibrillation. Ten randomized controlled trials (RCTs) met our criteria, and data from 656 patients were included for the study. Ivabradine treatment significantly decreased heart rate and BNP and NT-proBNP levels compared with those seen in the control group. EF values were significantly increased upon ivabradine treatment. No significant differences were observed in the endpoints of the 6-min walk distance, all-cause mortality, cardiogenic mortality, incidents of hospital readmission, bradycardia, and atrial fibrillation data between ivabradine treated and control groups. Ivabradine can reduce heart rate and BNP and NT-pro BNP levels and elevate EF values and 6-min walk distance data significantly in acute heart failure patients. It also exhibits a stable safety profile, with similar risks of all-cause mortality, cardiogenic mortality, incidents of readmission, and major adverse cardiovascular effects compared with those of the control group.

Hereditary angioedema due to C1-inhibitor deficiency: current therapeutic approaches.

For decades, treatment options for hereditary angioedema (HAE) were limited by major adverse effects, insufficient efficacy, and difficult routes of administration. However, the growing body of knowledge regarding HAE pathophysiology has led to the development of innovative drugs for self-administered, on-demand therapy and for short- and long-term prophylaxis. This review provides a comprehensive overview of the approved drugs and the development of HAE treatments. The implementation of new therapies will improve the application of individualized action plans based on the key goals of minimizing the number of attacks and meeting the complex needs of patients. HAE is a rare genetic disease with a high impact on patients' quality of life due to the unpredictability and variable severity of attacks. Advances in HAE research have allowed optimization of attack management and individualization of therapeutic approaches.

Alpha-Lipoic Acid: Biological Mechanisms and Health Benefits.

Alpha-lipoic acid (ALA) is a bioactive molecule with significant health effects. The biological action of ALA has been ascribed to the characteristic antioxidant properties of the oxidized form (ALA) and its reduced counterpart the dihydrolipoic acid (DHLA) system. The ALA/DHLA combination represents an ideal antioxidant since it can quench radicals, is able to chelate metals, is amphiphilic, and has no major adverse effects. This unique system is able to scavenge reactive oxygen species, exerting a major effect on tissue levels of reduced forms of other antioxidants, including glutathione. For this reason, ALA is also known as the "antioxidant of antioxidants". This review analyzes the antioxidant, anti-inflammatory, and neuroprotective effects of ALA and discusses its applications as an ameliorative tool for chronic diseases and those associated with oxidative stress. Results from in vitro and in vivo studies demonstrated that ALA modulates various oxidative stress pathways suggesting its application, alone or in combination with other functional substances, as a useful support in numerous conditions, in which the balance oxidant-antioxidant is disrupted, such as neurodegenerative disorders. Based on several successful clinical studies, it has been also established that oral ALA supplements are clinically useful in relieving the complications of diabetes and other disorders including cardiovascular diseases and nerve discomforts suggesting that ALA can be considered a useful approach to improving our health.

Anti-tumor activity of camptothecin analog conjugate of a RSPO4-based peptibody targeting LGR4/5/6 in preclinical models of colorectal cancer.

Antibody-drug conjugates (ADCs) have emerged as a major modality of targeted cancer therapy, yet no ADC has been approved for colorectal cancer (CRC). LGR4/5/6 (leucine-rich repeat containing, G protein-coupled receptor 4, 5, 6) are three related receptors that are expressed at high levels together or alternately in nearly all cases of CRC. ADCs targeting LGR5 have been shown to have robust anti-tumor potency, but not all CRC cells express LGR5 and LGR5-positive tumor cells may lose LGR5 expression due to cancer cell plasticity. R-spondin 4 (RSPO4) is a natural protein ligand of LGR4/5/6 with high affinity for all three receptors. We fused a mutant form of RSPO4 that retains high affinity binding to LGR4/5/6 to IgG1 Fc to create a peptibody designated R462. Conjugation of R462 with a camptothecin analog (CPT2) at eight drugs per peptibody led to the synthesis of R462-CPT2 that showed highly potent cytotoxic activity in vitro in CRC cell lines expressing any of LG4/5/6. In cell line xenograft and PDX models of CRC, R462-CPT2 demonstrated robust anti-tumor effect. Importantly, R462-CPT2 showed no major adverse effect at therapeutically effective dose levels. These results strongly support the use of RSPO ligand drug-conjugates that target LGR4/5/6 simultaneously for the treatment of CRC.

Clinical Benefits and Safety of Medical Cannabis Products: A Narrative Review on Natural Extracts.

Interest in medical cannabis and cannabis-based medicinal products (CBMPs) has increased greatly in recent years. Two cannabinoids are of principal importance; delta-9-tetrahydrocannabinol (∆9-THC), the primary psychoactive component, and also cannabidiol (CBD), considered non-intoxicating. Each has distinct mechanisms of action and different therapeutic potentials. CBMPs differ in their ∆9-THC and CBD components; predominantly ∆9-THC, balanced formulations with equivalent ∆9-THC and CBD elements, and CBD-predominant products. In this narrative review, we evaluate the published evidence for the clinical benefits of CBMPs and overall benefits in well-being. We also review the overall safety profile and discuss the potential for dependence with CBMPs. Evidence can be drawn from a wide range of randomized and other controlled studies and from observational real-world studies. Most data from observational registry studies are supportive of ∆9-THC-based products (∆9-THC-predominant or balanced CBMPs) in the management of chronic neuropathic pain. Balanced products are also effective in reducing spasticity in multiple sclerosis. Most CBMPs show benefit in providing symptomatic benefits in reducing anxiety, nausea, and in improving sleep, but the place of specific products is more subtle, and choice guided by specific circumstances. Symptomatic improvements are accompanied by improved quality of life and well-being. Safety data indicate that CBMPs are generally well tolerated in most patients without specific contraindications. The majority of adverse effects are non-serious, and transient; most are principally associated with ∆9-THC and are dose-dependent. In contrast to recreational cannabis use, there is little evidence from clinical studies that CBMPs have any potential for dependence.

Efficacy of Low-Dose Deflazacort with Tamsulosin in the Medical Expulsive Therapy of Distal Ureterolithiasis: A Randomized Controlled Trial

Introduction: Distal ureterolithiasis, characterized by stones in the lower ureter, poses significant challenges in clinical management. Medical expulsive therapy (MET) using Tamsulosin is a common non-invasive treatment, but its efficacy can be limited, especially for stones larger than 5 mm. Deflazacort, a corticosteroid with anti-inflammatory properties, may enhance the effectiveness of Tamsulosin by reducing ureteral inflammation and facilitating stone passage. Methods: This prospective, randomized controlled trial enrolled 80 patients with distal ureteral stones <8 mm. Participants were randomly assigned to receive either Tamsulosin alone or Tamsulosin with Deflazacort for 28 days. Primary outcomes included stone expulsion rate and time, while secondary outcomes were pain reduction, analgesic use, and adverse effects. Results: The combination therapy group showed a higher expulsion rate (85% vs. 70%) and significantly faster expulsion time (10.1 days vs. 13.9 days, p=0.006). Pain reduction was greater in the Deflazacort group, with fewer colic episodes and reduced analgesic requirements. Adverse effects were comparable between the groups, with no significant increase in major side effects in the combination therapy group. Conclusion: The addition of low-dose Deflazacort to Tamsulosin significantly improves stone expulsion rates, reduces expulsion time, and lowers pain levels in patients with distal ureterolithiasis, without increasing major adverse effects. This combination may represent a superior treatment option in MET for distal ureteral stones.

Efficacy of Rectal Versus Oral Chloral Hydrate in Pediatric Auditory Brainstem Response: Randomized Controlled Trial.

To compare sedation success rates between rectal (RCH) and oral chloral hydrate (OCH) administration in children undergoing auditory brainstem response (ABR) testing and assess the incidence of adverse effects. Randomized controlled trial, performed between May 2023 and August 2023. Ear, Nose, and Throat Outpatient Department at tertiary care hospital. Pediatric patients aged 1 to 5 years, who were indicated for ABR testing were enrolled and randomly divided into 2 groups. The control group received 10% wt/vol chloral hydrate orally at a dose of 50 mg/kg, while the other group received the same dose through rectal administration. Onset of sedation, duration of sedation, recovery time, vital signs, and adverse effects were recorded and analyzed to assess sedative effectiveness and safety. Eighty-eight children were randomly assigned to RCH or OCH administration groups, the sedation success rates of RCH and OCH groups were 84.09% and 90.91%, respectively (P = .33). Adverse effects were detected in 11 children (12.5%), with a vomiting rate of 20.45% in the oral group versus 0% in the rectal group (P = .002). The diarrhea rate was 4.55% in the rectal group versus 0% in the oral group (P = .16). In either group, no serious adverse effects were documented. RCH and OCH are both safe and effective for short-term sedation in pediatric patients during ABR testing. Interestingly, RCH administration offers a high success rate without vomiting or major adverse effects. This study established the effectiveness of RCH for sedation in children under specialized supervision.

Efficacy, Safety, and Tolerability of a Very Low-Calorie Ketogenic Diet in Women with Obesity and Symptomatic Knee Osteoarthritis: A Pilot Interventional Study.

Obesity is a major risk factor for knee osteoarthritis (OA), and weight loss is crucial for its management. This pilot study explores the effects of a Very Low-Calorie Ketogenic Diet (VLCKD) in women with obesity and symptomatic knee OA. Women with symptomatic knee OA and obesity, defined as a body mass index (BMI) ≥ 30 kg/m2, were eligible for the VLCKD protocol. The intervention included a ketogenic phase from baseline (T0) to the 8th week (T8), followed by a progressive reintroduction of carbohydrates over the next 12 weeks, ending at the 20th week (T20). Body mass index (BMI), the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index, the EuroQol 5D (EQ-5D), and the 36-item Short Form Health Survey (SF-36) were assessed at all time points. Generalized estimating equations were used to analyze the association between BMI and patient-reported outcomes across the study period. Twenty participants started the study, but four discontinued the intervention, with two of these being due to adverse effects. The mean age of the 16 patients who completed the 20-week program was 57.3 ± 5.5 years, and their mean BMI was 40.0 ± 4.8 kg/m2. The mean BMI significantly decreased to 37.5 ± 4.5 at T4, 36.3 ± 4.6 at T8, and 34.8 ± 4.8 at T20 (all p < 0.001 compared to baseline). The total WOMAC score improved from a mean of 43.6 ± 16.9 at T0 to 30.2 ± 12.8 at T4 (p = 0.005) and further to 24.7 ± 10.6 at T8 (p = 0.001) and to 24.8 ± 15.9 at T20 (p = 0.005). The reduction in BMI was significantly correlated with the improvements in WOMAC, EQ-5D, and SF-36 over time. No major adverse effects were observed. A 20-week VLCKD in women with obesity and knee OA significantly reduced their weight and improved their outcomes, warranting further research. This trial is registered with number NCT05848544 on ClinicalTrials.gov.

Semaglutide for the management of diabesity: The real-world experience.

Diabesity (diabetes as a consequence of obesity) has emerged as a huge healthcare challenge across the globe due to the obesity pandemic. Judicious use of antidiabetic medications including semaglutide is important for optimal management of diabesity as proven by multiple randomized controlled trials. However, more real-world data is needed to further improve the clinical practice. To study the real-world benefits and side effects of using semaglutide to manage patients with diabesity. We evaluated the efficacy and safety of semaglutide use in managing patients with diabesity in a large academic hospital in the United States. Several parameters were analyzed including demographic information, the data on improvement of glycated hemoglobin (HbA1c), body weight reduction and insulin dose adjustments at 6 and 12 months, as well as at the latest follow up period. The data was obtained from the electronic patient records between January 2019 to May 2023. 106 patients (56 males) with type 2 diabetes mellitus (T2DM), mean age 60.8 ± 11.2 years, mean durations of T2DM 12.4 ± 7.2 years and mean semaglutide treatment for 2.6 ± 1.1 years were included. Semaglutide treatment was associated with significant improvement in diabesity outcomes such as mean weight reductions from baseline 110.4 ± 24.6 kg to 99.9 ± 24.9 kg at 12 months and 96.8 ± 22.9 kg at latest follow up and HbA1c improvement from baseline of 82 ± 21 mmol/mol to 67 ± 20 at 12 months and 71 ± 23 mmol/mol at the latest follow up. An insulin dose reduction from mean baseline of 95 ± 74 units to 76.5 ± 56.2 units was also observed at the latest follow up. Side effects were mild and mainly gastrointestinal like bloating and nausea improving with prolonged use of semaglutide. Semaglutide treatment is associated with significant improvement in diabesity outcomes such as reduction in body weight, HbA1c and insulin doses without major adverse effects. Reviews of largescale real-world data are expected to inform better clinical practice decision making to improve the care of patients with diabesity.

Conorphin-66 produces peripherally restricted antinociception via the kappa-opioid receptor with limited side effects

With the current unmet demand for effective pain relief, analgesics without major central adverse effects are highly appealing, such as peripherally restricted kappa-opioid receptor (KOR) agonists. In this study, Conorphin-66, an analog of the selective KOR peptide agonist Conorphin T, was pharmacologically characterized in a series of experiments, with CR845 serving as the reference compound. Firstly, in vitro functional assay indicated that Conorphin-66 selectively activates KOR and exhibits weak β-arrestin2 signaling bias (−1.54 versus −4.35 for CR845). Additionally, subcutaneous Conorphin-66 produced potent antinociception in mouse pain models with ED50 values ranged from 0.02 to 3.28 μmol/kg, including tail-flick test, post-operative pain, formalin pain, and acetic acid-induced visceral pain. Similarly, CR845 exert potent antinociception in mouse pain models ranged from 0.15 to 1.47 μmol/kg. Notably, antagonism studies revealed that the analgesic effects of Conorphin-66 were mainly mediated by the peripheral KOR. Furthermore, Conorphin-66 produced non-tolerance-forming antinociception over 8 days. Unlike CR845, subcutaneous Conorphin-66 did not promote the sedation, anxiogenic effects, depressive-like effects, but did exhibit diuretic activity. Further study showed that Conorphin-66 does not have apparent antipruritic effects in an acute itch model. Overall, Conorphin-66 emerges as a novel peripherally restricted KOR agonist that produced potent antinociception with reduced side effects.

Effectiveness and safety of intravenous labetalol in severe pre-eclampsia and eclampsia at a teaching institution in Chhattisgarh.

Severe hypertension in pregnancy deserves prompt recognition and urgent effective reduction in order to reduce the risk of complications such as eclampsia and HELLP syndrome and to achieve desirable neonatal outcomes. There is a need for effective and safe parenteral antihypertensive treatment. We studied the effectiveness and safety of intravenous labetalol use in severe hypertension in pregnancy and post-partum period in a teaching hospital in Chhattisgarh in 101 women. IV labetalol was given as bolus doses till the blood pressures were controlled. Neonatal outcomes were recorded, and adverse effects such as hypotension, hypoglycemia, and neonatal asphyxia were documented. Intravenous labetalol given as a single bolus of 20 mg was efficacious in controlling blood pressures in 93 out of 101 (93%) women, and the rest were controlled with 1 or 2 additional doses in 1-3 hours. No neonatal deaths happened beyond the 13 intrauterine fetal deaths at presentation. No women developed any episodes of hypotension, tachycardia of more than 100, or nausea or vomiting on labetalol. Intravenous labetalol, even as a single bolus dose, is highly efficacious and is free of any major adverse effects.

CMG901, a Claudin18.2-specific antibody-drug conjugate, for the treatment of solid tumors

Claudin18.2 has been recently recognized as a potential therapeutic target for gastric/gastroesophageal junction or pancreatic cancer. Here, we develop a Claudin18.2-directed antibody-drug conjugate (ADC), CMG901, with a potent microtubule-targeting agent MMAE (monomethyl auristatin E) and evaluate its preclinical profiles. Invitro studies show that CMG901 binds specifically to Claudin18.2 on the cell surface and kills tumor cells through direct cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and bystander killing activity. Invivo pharmacological studies show significant antitumor activity in patient-derived xenograft (PDX) models. Toxicity studies show that the major adverse effects related to CMG901 are reversible hematopoietic changes attributed to MMAE. The highest non-severely toxic dose (HNSTD) is 6mg/kg in cynomolgus monkeys and 10mg/kg in rats once every 3weeks. CMG901's favorable preclinical profile supports its entry into the human clinical study. CMG901 is currently under phase 3 investigation in patients with advanced gastric/gastroesophageal junction adenocarcinoma expressing Claudin18.2 (NCT06346392).

Thrombolysis with tenecteplase in acute ischaemic stroke in a tertiary care setting in Sri Lanka: A retrospective study

Introduction: Alteplase (ALT) is the standard thrombolytic treatment in acute ischaemic stroke (AIS). Tenecteplase (TNK) is proven to be effective in acute coronary syndrome, is relatively cheap, widely available and can easily be given as a single intravenous (IV) bolus. Despite evidence for its use, there is equivocal guidance for the use of TNK in AIS. On the background of a global reduction in stroke admissions, treatment interventions and prolonged treatment time metrics due to the COVID-19 pandemic, this study highlights the experience with TNK in a tertiary care setting in Sri Lanka, during the pandemic.Objectives: To describe the outcomes at 48 hours among stroke patients who underwent thrombolysis with TNK at District General Hospital Hambantota, Sri Lanka over a period of one year.Methods: We retrospectively reviewed records of adults with AIS thrombolysed with 0.25 mg/kg TNK. The National Institutes of Health Stroke Scale (NIHSS) was assessed on admission and at 24-hours following treatment. Patients were observed for 48-hours for potential adverse events.Results: We thrombolysed 20 consecutive patients over one-year. The baseline mean NIHSS was 9.7 (standard deviation (SD)=4.4; range 4-22), and the 24h-post thrombolysis mean NIHSS was 6.0 (SD=7.3; range 0-28). Seventy percent (n=14) showed an improved NIHSS of at least 1-point after thrombolysis (mean difference=3.7; SD=6.46), and 55%(n=11) displayed a major clinical improvement (change in NIHSS ≥ 4). Ten percent (n=2) developed major adverse effects (one intra-cranial haemorrhage; one haemorrhagic transformation). There were no deaths.Conclusions: TNK 0.25mg/kg for the treatment of AIS appeared efficacious and safe in our case series. The limitation in this study was the low number of patients who underwent thrombolysis during the study period, as a probable effect of the COVID-19 pandemic. Thrombolysis with TNK could be a cost-effective alternative to alteplase in resource-limited South Asian settings.

Evaluating Cardiovascular Benefits of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) in Type 2 Diabetes Mellitus: A Systematic Review.

Cardiovascular risks and complications remain elevated in patients with type 2 diabetes even after appropriate control of contributing factors like glycemic control, hypertension, and lipid profile. More efficient methods are needed to address this issue in type 2 diabetics. Newer drugs like glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown a cardioprotective effect in addition to glycemic control. This systematic review aims to study the latest literature findings on the cardiovascular effects of GLP-1 RAs in patients with type 2 diabetes. We used PubMed, Google Scholar, Science Direct, and Biomed Central databases for our data collection. Our review adheres to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. The outcomes evaluated in the review include major adverse cardiovascular events (MACE), heart failure, stroke, all-cause mortality, and effects on cardiovascular risk factors. After careful inspection and quality check, we included 14 articles in the systematic review. GLP-1 RAs were associated with a significant reduction in cardiovascular mortality, all-cause mortality, nonfatal myocardial infarction (MI), and nonfatal stroke, especially in patients with existing cardiovascular risk factors. However, more evidence is required to determine if these benefits extend to those without such risk factors. Limited data suggest that GLP-1 RAs might have a protective effect on arrhythmias, but this area needs further investigation. Despite their potential, several barriers hinder the widespread use of GLP-1 RAs. In conclusion, GLP-1 RAs significantly reduce cardiovascular mortality, all-cause mortality, nonfatal MI, and stroke, with minor effects on hospitalization due to heart failure. Benefits are greater in patients with cardiovascular risk factors. A comprehensive, multilevel approach to policy development and implementation is necessary to optimize the use of these medications in eligible populations.

Intra-articular Therapies for Hand Osteoarthritis: a Systematic Review and Network Meta-analysis

Abstract Objective Intra-articular injection therapy for hand osteoarthritis has inconclusive evidence regarding the effectiveness of different regimens. A systematic review and network meta-analysis of randomized controlled trials (RCTs) was conducted to examine the effectiveness of different injectants. Design The PubMed, Cochrane Library, Embase, ClinicalKey, and Scopus databases were searched for studies from inception to July 15, 2023. RCTs that applied intra-articular injection to hand osteoarthritis patients were included, and the outcomes of pain scores and functional scales were assessed. Results 14 RCTs with 674 patients met the inclusion criteria; 11 RCTs were included in the network meta-analysis. Intra-articular injected platelet-rich plasma (PRP) and dextrose significantly improved pain scores (mean difference [MD] = −4.03, 95% confidence interval [CI] = −6.51 to −1.56 for PRP; MD = −1.06, 95% CI = −2.1 to −0.02 for dextrose) and hand function (standard mean difference [SMD] = −0.93, 95% CI = −1.81 to −0.05 for PRP; SMD = −0.84, 95% CI = −1.58 to −0.09 for dextrose) in the long-term (≥6 months after treatment completion). The ranking probabilities revealed the highest effectiveness of PRP, followed by dextrose. No major adverse effects were reported. Conclusion Intra-articular injected PRP and dextrose can be recommended for treating hand osteoarthritis.

Efficacy of sequential primary motor and prefrontal cortices intermittent Theta burst stimulation in persistent somatoform PAIN disorder (TAP-PAIN): A randomized sham-controlled pilot trial

Aim: There is a need to elucidate intermittent Theta burst stimulation (iTBS) as a novel treatment in persistent somatoform pain disorder (PSPD). Methods: Twenty patients were randomly allocated to active iTBS (n = 11) and sham iTBS (n = 9) and received 10 iTBS sessions, 2 sessions per day, sequentially to primary motor and dorsolateral prefrontal cortices for 5 days in a week. Each iTBS session comprised of 2 sec. per train of 10 bursts (3 pulses per burst at 50 Hz; total 30 pulses) and were given with a gap of 5 Hz, total of 20 trains, and 600 pulses. Visual Analogue Scale, Brief Pain Inventory and Global Pain Scale (GPS), Montgomery and Asberg Depression Rating Scale, Hamilton Anxiety Rating Scale - Anxiety, World Health Organization Quality-of-Life Scale-brief, and Pittsburgh Sleep Quality Index were applied at baseline, after last session, and at 2 weeks after last TBS session. Intention to treat analysis was conducted. Results: Both groups were comparable for baseline psychopathology scores including clinical variables like age (t = 0.865; P = 0.398), duration of illness (t = 1.600; P = 0.127), and motor threshold (t = 0.304; P = 0.765). On repeated measures ANOVA, a significant within-group time effect for VAS, BPI-Severity, BPI-Interference, BDI – II, MADRS, HAM-A, and WHOQOL- BREF was found for active and sham TBS groups, respectively. GPS scores had significant within-group (active) * time interaction (F = 11.651; P = .001; ηp2 = 0.538) and between-group * time interaction (F = 3.407; P = 0.044; ηp2 = 0.159). However, between-group * time effect interaction was lost after covariance (F = 1.726; P = 0.196; ηp2 = 0.110). Conclusion: No major adverse effects were reported. Our pilot trial concludes that safe therapeutic efficacy of iTBS in PSPD is inconclusive. Lower total number of sessions along with small sample size may limit the study findings.