Arch Prev Riesgos Labor. 2023 Apr 15;26(2):106-126. doi: 10.12961/aprl.2022.26.02.02.

ABSTRACT

OBJECTIVE: To compare the reactogenicity between the types of mRNA Commirnaty® (Pfizer) and Spikevax® (Moderna) vaccines against COVID-19 in a healthcare population.

METHODS: Cross sectional study of short-term adverse effects and their consequences (sick leave, limitations of daily life, etc.) after the administration of the first and second doses of both vaccines in professionals and students of a health institution. A questionnaire on symptoms and their consequences was administered seven days after each vaccination dose. The prevalence and 95% confidence interval (95%CI) were calculated. Differences between vaccines were quantified using the odds ratio (OR) and its 95%CI.

RESULTS: The questionnaire was completed by 1924 and 1170 healthcare providers (response rates 62.2% and 39.1%) after the first and second doses, respectively, of the Commirnaty® vaccine, and 410 (56.0%) and 107 (15.0%) of Spikevax®. After the first dose of Comirnaty®, 67.4% presented some adverse effect, and 76.1% for Spikevax® (OR 1.5 95%CI 1.2-1.9). In general, women and young people showed greater reactogenicity and differences between vaccinSpain. Consequences of adverse effects were more frequent for Spikevax®. The reactogenicity was higher after the second than the first dose, for both vaccines (Comirnaty®: 67.4% vs. 75.6%; Spikevax®: 76.1% vs. 87.9%.

CONCLUSIONS: The greater reactogenicity and its consequences, for the first and second dose of the Spikevax® vaccine compared to Comirnaty®, and of the second dose compared to the first dose of both vaccines, provides useful knowledge for planning vaccination against COVID-19 campaigns in healthcare settings.

PMID:37070591 | DOI:10.12961/aprl.2022.26.02.02

NPJ Breast Cancer. 2023 Apr 18;9(1):28. doi: 10.1038/s41523-023-00522-5.

ABSTRACT

In this phase I study, the safety, pharmacokinetics, and antitumour activity of the HER2-targeted antibody-drug conjugate A166 were evaluated in patients with HER2-expressing advanced solid tumours. Patients with advanced solid tumours refractory to standard therapies received A166 at doses of 0.1, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8 or 6.0 mg/kg Q3W in a standard "3 + 3" design. Dose cohorts were expanded at 4.8 and 6.0 mg/kg Q3W. Primary endpoints were assessment of the safety and tolerability of A166 and identification of the maximum tolerated dose or recommended phase II dose. In total, 81 patients were enroled and received A166 (n = 1 for 0.1 mg/kg; n = 3 for each of 0.3, 0.6, 1.2, 2.4 and 3.6 mg/kg doses; n = 27 for 4.8 mg/kg; n = 38 for 6.0 mg/kg). No dose-limiting toxicity or drug-related deaths occurred. The most common treatment-related adverse events at grade 3 or higher were corneal epitheliopathy (30.9%), blurred vision (18.5%), dry eyes (7.4%), and peripheral sensory neuropathy (6.2%). The Cmax and area under the curve of Duo-5, its free payload, were approximately 0.1% and 0.2% of those of the ADC, respectively. For all assessable HER2-positive breast cancer patients enroled in the 4.8 mg/kg and 6.0 mg/kg cohorts, the corresponding ORRs were 73.9% (17/23) and 68.6% (24/35), respectively, and the median PFS was 12.3 and 9.4 months, respectively. A166 has a recommended phase II dose of 4.8 mg/kg Q3W, manageable toxicity, good stability in the circulation and promising antitumour activities in HER2-positive breast cancer patients.

PMID:37072437 | DOI:10.1038/s41523-023-00522-5

Expert Opin Drug Saf. 2023 Apr 18. doi: 10.1080/14740338.2023.2203488. Online ahead of print.

NO ABSTRACT

PMID:37070412 | DOI:10.1080/14740338.2023.2203488

BMC Rheumatol. 2023 Apr 18;7(1):7. doi: 10.1186/s41927-023-00326-x.

ABSTRACT

BACKGROUND: Drug-related problems can negatively influence treatment outcome and well-being for patients with rheumatic diseases. Thus, it is important to support patients in preventing or resolving drug-related problems as quickly as possible. To effectively develop interventions for this purpose, knowledge on the frequency and character of drug-related problems is needed. Therefore, this study aims to quantify and characterize drug-related problems reported by patients with inflammatory rheumatic diseases along their treatment process.

METHODS: A prospective observational study was conducted in a Dutch outpatient pharmacy. Adult patients with rheumatic diseases that were prescribed medication by a rheumatologist were questioned about experienced DRPs by telephone 4 times in 8 weeks using a structured interview-guide. Patient-reported DRPs were scored on uniqueness (i.e., if a specific DRP was reported in multiple interviews by one individual, this was counted as one unique DRP) and were categorized using a classification for patient-reported DRPs and analysed descriptively.

RESULTS: In total, 52 participants (median age 68 years (interquartile range (IQR) 62-74), 52% male) completed 192 interviews with 45 (87%) participants completing all 4 interviews. The majority of patients (65%) were diagnosed with rheumatoid arthritis. Patients reported a median number of 3 (IQR 2-5) unique DRPs during interview 1. In subsequent interviews, patients reported median numbers of 1 (IQR 0-2), 1 (IQR 0-2) and 0 (IQR 0-1) unique DRPs for interviews 2-4 respectively. Participants reported a median number of 5 (IQR 3-9) unique DRPs over all completed interviews. Unique patient-reported DRPs were most frequently categorized into (suspected) side effects (28%), medication management (e.g., medication administering or adherence) (26%), medication concerns (e.g., concerns regarding long-term side-effects or effectiveness) (19%) and medication effectiveness (17%).

CONCLUSIONS: Patients with rheumatic diseases report various unique DRPs with intervals as short as two weeks. These patients might therefore benefit from more continuous support in-between contact moments with their healthcare provider.

PMID:37069634 | DOI:10.1186/s41927-023-00326-x

Res Social Adm Pharm. 2023 Apr 17:S1551-7411(23)00233-4. doi: 10.1016/j.sapharm.2023.04.118. Online ahead of print.

ABSTRACT

BACKGROUND: The CombiConsultation is a consultation with the community pharmacist for patients with diabetes, COPD and/or cardiovascular disease (CVD), aligned with the annual or quarterly consultation with the practice nurse (PN) or general practitioner (GP). The consultation is focused on the personal health-related goals of the patient.

OBJECTIVES: To assess the number and types of personal health-related goals, drug-related problems (DRPs) and interventions identified by pharmacists during a CombiConsultation and to investigate which patients can benefit most from such consultation.

METHOD: Twenty-one Dutch community pharmacies and associated GP practices were included in the CombiConsultation study. CombiConsultations were performed, involving patients with diabetes, COPD and/or (at risk of) CVD. The pharmacists set health-related goals together with the patients and identified DRPs. The number and types of personal health-related goals, DRPs and interventions were analysed. Associations between patient characteristics and the identification of at least one DRP were analysed by multivariate regression analysis.

RESULTS: In 834 patients (49% men, mean age: 70 years), 939 DRPs were identified, mostly (potential) side effects (33%), undertreatment (18%) and overtreatment (14%). In 71% of the patients, one or more DRPs were found, with a median of one DRP per patient. Pharmacists proposed 935 recommendations, of which 72% were implemented. DRPs were found more often in patients using a higher number of drugs for chronic conditions. A total of 425 personal health-related goals were set, of which 53% were (partially) attained.

CONCLUSION: The CombiConsultation can be used as a compact health service contributing to safe and effective use of medication for patients with diabetes, COPD and/or (at risk of) CVD, also in patients under 65 or with less than 5 medications in use. The output of the CombiConsultation reflects its characteristics.

PMID:37095031 | DOI:10.1016/j.sapharm.2023.04.118

Einstein (Sao Paulo). 2023 Apr 17;21:eCE0403. doi: 10.31744/einstein_journal/2023CE0403. eCollection 2023.

NO ABSTRACT

PMID:37075462 | DOI:10.31744/einstein_journal/2023CE0403

Front Immunol. 2023 Mar 29;14:1166377. doi: 10.3389/fimmu.2023.1166377. eCollection 2023.

ABSTRACT

BACKGROUND: Glioma is the most lethal and most aggressive brain cancer, and currently there is no effective treatment. Cancer immunotherapy is an advanced therapy by manipulating immune cells to attack cancer cells and it has been studied a lot in glioma treatment. Targeting the immune checkpoint CD47 or blocking the CD47-SIRPα axis can effectively eliminate glioma cancer cells but also brings side effects such as anemia. Glutaminyl-peptide cyclotransferase-like protein (QPCTL) catalyzes the pyroglutamylation of CD47 and is crucial for the binding between CD47 and SIRPα. Further study found that loss of intracellular QPCTL limits chemokine function and reshapes myeloid infiltration to augment tumor immunity. However, the role of QPCTL in glioma and the relationship between its expression and clinical outcomes remains unclear. Deciphering the role of QPCTL in glioma will provide a promising therapy for glioma cancer immunotherapy.

METHODS: QPCTL expression in glioma tissues and normal adjacent tissues was primarily analyzed in The Cancer Genome Atlas (TCGA) database, and further validated in another independent cohort from the Gene Expression Omnibus (GEO) database, Chinese Glioma Genome Atlas (CGGA), and Human Protein Atlas (HPA). The relationships between QPCTL expression and clinicopathologic parameters and overall survival (OS) were assessed using multivariate methods and Kaplan-Meier survival curves. And the proteins network with which QPCTL interacted was built using the online STRING website. Meanwhile, we use Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA) databases to investigate the relationships between QPCTL expression and infiltrated immune cells and their corresponding gene marker sets. We analyzed the Differentially Expressed Genes (DEGs) including GO/KEGG and Gene Set Enrichment Analysis (GSEA) based on QPCTL-high and -low expression tumors.

RESULTS: In contrast to normal tissue, QPCTL expression was higher in glioma tumor tissue (p < 0.05). Higher QPCTL expression was closely associated with high-grade malignancy and advanced tumor stage. Univariate and multivariate analysis indicated the overall survival of glioma patients with higher QPCTL expression is shorter than those with lower QPCTL expression (p < 0.05). Glioma with QPCTL deficiency presented the paucity of infiltrated immune cells and their matching marker sets. Moreover, QPCTL is essential for glioma cell proliferation and tumor growth and is a positive correlation with glioma cell stemness.

CONCLUSION: High QPCTL expression predicts high grades of gliomas and poor prognosis with impaired infiltration of adaptive immune cells in the tumor microenvironment as well as higher cancer stemness. Moreover, targeting QPCTL will be a promising immunotherapy in glioma cancer treatment.

PMID:37063864 | PMC:PMC10090505 | DOI:10.3389/fimmu.2023.1166377

Drug Ther Bull. 2023 Apr 17:dtb-2023-000020. doi: 10.1136/dtb.2023.000020. Online ahead of print.

ABSTRACT

Overview of: Butler CC, Hobbs FDR, Gbinigie OA, et al Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial. Lancet 2023;401:281-93.

PMID:37068918 | DOI:10.1136/dtb.2023.000020

Ann Intern Med. 2023 Apr 18. doi: 10.7326/M22-3428. Online ahead of print.

ABSTRACT

BACKGROUND: Development of safe and effective SARS-CoV-2 therapeutics is a high priority. Amubarvimab and romlusevimab are noncompeting anti-SARS-CoV-2 monoclonal antibodies with an extended half-life.

OBJECTIVE: To assess the safety and efficacy of amubarvimab plus romlusevimab.

DESIGN: Randomized, placebo-controlled, phase 2 and 3 platform trial. (ClinicalTrials.gov: NCT04518410).

SETTING: Nonhospitalized patients with COVID-19 in the United States, Brazil, South Africa, Mexico, Argentina, and the Philippines.

PATIENTS: Adults within 10 days onset of symptomatic SARS-CoV-2 infection who are at high risk for clinical progression.

INTERVENTION: Combination of monoclonal antibodies amubarvimab plus romlusevimab or placebo.

MEASUREMENTS: Nasopharyngeal and anterior nasal swabs for SARS-CoV-2, COVID-19 symptoms, safety, and progression to hospitalization or death.

RESULTS: Eight-hundred and seven participants who initiated the study intervention were included in the phase 3 analysis. Median age was 49 years (quartiles, 39 to 58); 51% were female, 18% were Black, and 50% were Hispanic or Latino. Median time from symptom onset at study entry was 6 days (quartiles, 4 to 7). Hospitalizations and/or death occurred in 9 (2.3%) participants in the amubarvimab plus romlusevimab group compared with 44 (10.7%) in the placebo group, with an estimated 79% reduction in events (P < 0.001). This reduction was similar between participants with 5 or less and more than 5 days of symptoms at study entry. Grade 3 or higher treatment-emergent adverse events through day 28 were seen less frequently among participants randomly assigned to amubarvimab plus romlusevimab (7.3%) than placebo (16.1%) (P < 0.001), with no severe infusion reactions or drug-related serious adverse events.

LIMITATION: The study population was mostly unvaccinated against COVID-19 and enrolled before the spread of Omicron variants and subvariants.

CONCLUSION: Amubarvimab plus romlusevimab was safe and significantly reduced the risk for hospitalization and/or death among nonhospitalized adults with mild to moderate SARS-CoV-2 infection at high risk for progression to severe disease.

PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

PMID:37068272 | DOI:10.7326/M22-3428

Autoimmun Rev. 2023 Apr 14:103332. doi: 10.1016/j.autrev.2023.103332. Online ahead of print.

ABSTRACT

Biotechnological monoclonal antibodies and receptor antagonists capable of targeting specific inflammatory actors, such as cytokines, cytokines receptors, co-stimulatory molecules or leukocyte populations, have emerged as an alternative to conventional therapies for treating systemic inflammatory diseases with immune pathogenesis. However, there is no doubt that, with a frequency that is not exceptionally high but also not negligible, immunotherapies can favour the development of systemic and organ-specific immune-mediated disorders. It has become increasingly evident that interference with a specific immune pathway may favour the activation of opposing compensatory signalling, which may exacerbate underlying subclinical disorders or cause immune-mediated diseases completely different from the underlying disease. The 'compensatory immunological switch' has emerged primarily in patients treated with tumor necrosis factor (TNF) -α inhibitors, the first biological drugs approved for treating systemic inflammatory diseases with immune pathogenesis. In this Review, we describe the clinical features and predisposing factors of the main TNF-α inhibitor-related immune disorders, organising them into subclinical serological autoimmunity, autoimmune disorders other than those for which TNF-α inhibitors are indicated, and paradoxical reactions. We also discuss the underlying pathogenetic mechanisms and precautions for use in the therapeutic management of these patients. Better understanding of the complex phenomenon of the 'compensatory immunological switch', which TNF-α inhibitors and other biological drugs might trigger, can help not only appropriately managing immune-mediated disorders, but also better interpreting the heterogeneity of the pathogenetic mechanisms underlying certain chronic inflammatory conditions that, although different from each other, are arbitrarily placed in the context of overly generic nosological entities.

PMID:37062440 | DOI:10.1016/j.autrev.2023.103332

Lancet Oncol. 2023 Apr 13:S1470-2045(23)00102-X. doi: 10.1016/S1470-2045(23)00102-X. Online ahead of print.

ABSTRACT

BACKGROUND: Targeted real-time imaging during robot-assisted radical prostatectomy provides information on the localisation and extent of prostate cancer. We assessed the safety and feasibility of the prostate-specific membrane antigen (PSMA)-targeted fluorescent tracer OTL78 in patients with prostate cancer.

METHODS: In this single-arm, phase 2a, feasibility trial with an adaptive design was carried out in The Netherlands Cancer Institute, Netherlands. Male patients aged 18 years or older, with PSMA PET-avid prostate cancer with an International Society of Urological Pathology (ISUP) grade group of 2 or more, who were scheduled to undergo robot-assisted radical prostatectomy with or without extended pelvic lymph node dissection were eligible. All patients had a robot-assisted radical prostatectomy using OTL78. Based on timing and dose, patients received a single intravenous infusion of OTL78 (0·06 mg/kg 1-2 h before surgery [dose cohort 1], 0·03 mg/kg 1-2 h before surgery [dose cohort 2], or 0·03 mg/kg 24 h before surgery [dose cohort 3]). The primary outcomes, assessed in all enrolled patients, were safety and pharmacokinetics of OTL78. This study is completed and is registered in the European Trial Database, 2019-002393-31, and the International Clinical Trials Registry Platform, NL8552, and is completed.

FINDINGS: Between June 29, 2020, and April 1, 2021, 19 patients were screened for eligibility, 18 of whom were enrolled. The median age was 69 years (IQR 64-70) and median prostate-specific antigen concentration was 15 ng/mL (IQR 9·3-22·0). In 16 (89%) of 18 patients, robot-assisted radical prostatectomy was accompanied by an extended pelvic lymph node dissection. Three serious adverse events occurred in one (6%) patient: an infected lymphocele, a urosepsis, and an intraperitoneal haemorrhage. These adverse events were considered unrelated to the administration of OTL78 or intraoperative fluorescence imaging. No patient died, required a dose reduction, or required discontinuation due to drug-related toxicity. The dose-normalised maximum serum concentration (Cmax/dose) in patients was 84·1 ng/mL/mg for the 0·03 mg/kg dose and 79·6 ng/mL/mg for the 0·06 mg/kg dose, the half-life was 5·1 h for the 0·03 mg/kg dose and 4·7 h for the 0·06 mg/kg dose, the volume of distribution was 22·9 L for the 0·03 mg/kg dose and 19·5 L for the 0·06 mg/kg dose, and the clearance was 3·1 L/h for the 0·03 mg/kg dose and 3·0 L/h for the 0·06 mg/kg dose.

INTERPRETATION: This first-in-patient study showed that OTL78 was well tolerated and had the potential to improve prostate cancer detection. Optimal dosing was 0·03 mg/kg, 24 h preoperatively. PSMA-directed fluorescence imaging allowed real-time identification of visually occult prostate cancer and might help to achieve complete oncological resections.

FUNDING: On Target Laboratories.

PMID:37062295 | DOI:10.1016/S1470-2045(23)00102-X

Sci Rep. 2023 Apr 15;13(1):6167. doi: 10.1038/s41598-023-33110-5.

ABSTRACT

Kidneys are complex organs, and reproducing their function and physiology in a laboratory setting remains difficult. During drug development, potential compounds may exhibit unexpected nephrotoxic effects, which imposes a significant financial burden on pharmaceutical companies. As a result, there is an ongoing need for more accurate model systems. The use of renal organoids to simulate responses to nephrotoxic insults has the potential to bridge the gap between preclinical drug efficacy studies in cell cultures and animal models, and the stages of clinical trials in humans. Here we established an accessible fluorescent whole-mount approach for nuclear and membrane staining to first provide an overview of the organoid histology. Furthermore, we investigated the potential of renal organoids to model responses to drug toxicity. For this purpose, organoids were treated with the chemotherapeutic agent doxorubicin for 48 h. When cell viability was assessed biochemically, the organoids demonstrated a significant, dose-dependent decline in response to the treatment. Confocal microscopy revealed visible tubular disintegration and a loss of cellular boundaries at high drug concentrations. This observation was further reinforced by a dose-dependent decrease of the nuclear area in the analyzed images. In contrast to other approaches, in this study, we provide a straightforward experimental framework for drug toxicity assessment in renal organoids that may be used in early research stages to assist screen for potential adverse effects of compounds.

PMID:37061575 | PMC:PMC10105743 | DOI:10.1038/s41598-023-33110-5

Med Oncol. 2023 Apr 15;40(5):150. doi: 10.1007/s12032-023-02014-9.

ABSTRACT

L-Asparaginase is an antileukemic drug long approved for clinical use to treat childhood acute lymphoblastic leukemia, the most common cancer in this population worldwide. However, the efficacy and its use as a drug have been subject to debate due to the variety of adverse effects that patients treated with it present, as well as the prompt elimination in plasma, the need for multiple administrations, and high rates of allergic reactions. For this reason, the search for new, less immunogenic variants has long been the subject of study. This review presents the main aspects of the L-asparaginase enzyme from a structural, pharmacological, and clinical point of view, from the perspective of its use in chemotherapy protocols in conjunction with other drugs in the different treatment phases.

PMID:37060469 | DOI:10.1007/s12032-023-02014-9

Iran J Kidney Dis. 2023 Mar;1(2):79-85.

ABSTRACT

INTRODUCTION: Despite great advances in hemodialysis, complications during dialysis remain in force. Accurate assessment of dry weight is a determining factor in the prevention of hemodialysis complications. This study is designed to evaluate the effect of adjustment of ultrafiltration rate, on hemodialysis complications, based on dry weight calculation, by measuring the pre-dialysis serum sodium.

METHODS: In this single-blind clinical trial 50 patients were included. The patients were randomly divided into case and control groups. First, in the intervention group, the blood sodium level was measured before dialysis. Then, the dry weight of the patients was determined, ultrafiltration was adjusted according to the dry weight, and the patients' dialysis program was performed. In the control group, dry weight was determined routinely. Blood pressure, muscle cramps, nausea, and vomiting were recorded in both groups for 3 months.

RESULTS: The results showed a significant difference between the two groups in the rate of postoperative nausea and vomiting (P < .05) and muscle cramps during dialysis (P < .05). There were no significant differences between the two groups in blood pressure drop during dialysis and fatigue after hemodialysis in the first, second, and third months (P > .05).

CONCLUSION: Accurate assessment of dry weight by the pre-dialysis blood sodium formula, reduces muscle cramps, nausea, and, vomiting. DOI: 10.52547/ijkd.7170.

PMID:37060341

Hum Vaccin Immunother. 2023 Dec 31;19(1):2196893. doi: 10.1080/21645515.2023.2196893. Epub 2023 Apr 14.

ABSTRACT

Patients received kidney transplantation (KTR) have a low seroconversion rate after vaccination. Our objective was to compare the seroconversion rates and adverse effects of additional different vaccinations in KTR patients in existing studies. Databases such as PubMed, Cochrane Library, Web of Science, Embase, ClinicalTrials.gov and others. Three high-quality RCT were included and showed no statistical difference in seroconversion rates between the two vaccines (RR = 0.93[0.76,1.13]). There was no statistical difference in seroconversion rates between the sexes, for men (RR = 0.93[0.69,1.25]) and women (RR = 0.91[0.62,1.33]). Among the adverse effects there was no statistically significant difference in fever (RR = 1.06[0.44,2.57]), while for injection site pain there was a statistically significant difference (RR = 1.14[1.18,1.84]). There was no significant difference in seroconversion rates in patients with KTR who received the two additional vaccines. Patients injected with the viral vector vaccine were less painful than those injected with the mRNA vaccine.

PMID:37057765 | PMC:PMC10120468 | DOI:10.1080/21645515.2023.2196893

Cochrane Database Syst Rev. 2023 Apr 14;4(4):CD010961. doi: 10.1002/14651858.CD010961.pub2.

ABSTRACT

BACKGROUND: Epilepsy is one of the most common neurological disorders. Approximately 30% of people with epilepsy are considered to be drug-resistant, and usually need treatment with a combination of other antiepileptic drugs. Perampanel is a newer antiepileptic drug that has been investigated as add-on therapy for drug-resistant focal epilepsy.

OBJECTIVES: To evaluate the benefits and harms of perampanel as add-on therapy for people with drug-resistant focal epilepsy.

SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 20 October 2022.

SELECTION CRITERIA: We included randomised controlled trials comparing add-on perampanel with placebo.

DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was 1. 50% or greater reduction in seizure frequency. Our secondary outcomes were 2. seizure freedom, 3. treatment withdrawal due to any reason, 4. treatment withdrawal due to adverse effects, and 5.

ADVERSE EFFECTS: We used an intention-to-treat population for all primary analyses. We presented the results as risk ratios (RR) with 95% confidence intervals (CIs), except for individual adverse effects, which we reported with 99% CIs to compensate for multiple testing. We used GRADE to assess certainty of evidence for each outcome.

MAIN RESULTS: We included seven trials involving 2524 participants, all aged over 12 years. The trials were double-blind, randomised, placebo-controlled trials with treatment duration of 12 to 19 weeks. We assessed four trials at overall low risk of bias, and three trials at overall unclear risk of bias, due to risk of detection, reporting, and other biases. Compared with placebo, participants receiving perampanel were more likely to achieve a 50% or greater reduction in seizure frequency (RR 1.67, 95% CI 1.43 to 1.95; 7 trials, 2524 participants; high-certainty evidence). Compared to placebo, perampanel increased seizure freedom (RR 2.50, 95% CI 1.38 to 4.54; 5 trials, 2323 participants; low-certainty evidence) and treatment withdrawal (RR 1.30, 95% CI 1.03 to 1.63; 7 trials, 2524 participants; low-certainty evidence). Participants treated with perampanel were more likely to withdraw from treatment due to adverse effects compared to those receiving placebo (RR 2.36, 95% CI 1.59 to 3.51; 7 trials, 2524 participants; low-certainty evidence). A higher proportion of participants receiving perampanel reported one or more adverse effects when compared to participants who received placebo (RR 1.17, 95% CI 1.10 to 1.24; 7 trials, 2524 participants; high-certainty evidence). Compared with placebo, participants receiving perampanel were more likely to experience ataxia (RR 14.32, 99% CI 1.09 to 188.31; 2 trials, 1098 participants; low-certainty evidence), dizziness (RR 2.87, 99% CI 1.45 to 5.70; 7 trials, 2524 participants; low-certainty evidence), and somnolence (RR 1.76, 99% CI 1.02 to 3.04; 7 trials, 2524 participants). Subgroup analysis indicated that a larger proportion of participants who received perampanel at a dose of 4 mg/day (RR 1.38, 95% CI 1.05 to 1.83; 2 trials, 710 participants), 8 mg/day (RR 1.83, 95% CI 1.51 to 2.22; 4 trials, 1227 participants), or 12 mg/day (RR 2.38, 95% CI 1.86 to 3.04; 3 trials, 869 participants) achieved a 50% or greater reduction in seizure frequency compared to placebo; however, treatment with perampanel 12 mg/day also increased treatment withdrawal (RR 1.77, 95% CI 1.31 to 2.40; 3 trials, 869 participants).

AUTHORS' CONCLUSIONS: Add-on perampanel is effective at reducing seizure frequency and may be effective at maintaining seizure freedom for people with drug-resistant focal epilepsy. Although perampanel was well-tolerated, there was a higher proportion of treatment withdrawals with perampanel compared with placebo. Subgroup analysis suggested that 8 mg/day and 12 mg/day are the most efficacious perampanel doses; however, the use of 12 mg/day would likely increase the number of treatment withdrawals. Future research should focus on investigating the efficacy and tolerability of perampanel with longer-term follow-up, as well as exploring an optimal dose.

PMID:37059702 | PMC:PMC10103545 | DOI:10.1002/14651858.CD010961.pub2

Carbohydr Polym. 2023 Jul 15;312:120797. doi: 10.1016/j.carbpol.2023.120797. Epub 2023 Mar 11.

ABSTRACT

Now-a-days, the polysaccharides are extensively employed for the delivery of small-molecule drugs ascribed to their excellent biocompatibility, biodegradability and modifiability. An array of drug molecules is often chemically conjugated with different polysaccharides to augment their bio-performances. As compared to their therapeutic precursors, these conjugates could typically demonstrate an improved intrinsic solubility, stability, bioavailability and pharmacokinetic profiles of the drugs. In current years, various stimuli-responsive particularly pH and enzyme-sensitive linkers or pendants are also exploited to integrate the drug molecules into the polysaccharide backbone. The resulting conjugates could experience a rapid molecular conformational change upon exposure to the microenvironmental pH and enzyme changes of the diseased states, triggering the release of the bioactive cargos at the targeted sites and eventually minimize the systemic side effects. Herein, the recent advances in pH and enzyme -responsive polysaccharide-drug conjugates and their therapeutic benefits are systematically reviewed, following a brief description on the conjugation chemistry of the polysaccharides and drug molecules. The challenges and future perspectives of these conjugates are also precisely discussed.

PMID:37059536 | DOI:10.1016/j.carbpol.2023.120797

BMJ. 2023 Apr 14;381:p855. doi: 10.1136/bmj.p855.

NO ABSTRACT

PMID:37059463 | DOI:10.1136/bmj.p855

PLoS One. 2023 Apr 14;18(4):e0284439. doi: 10.1371/journal.pone.0284439. eCollection 2023.

ABSTRACT

BACKGROUND: Drug therapy problems (DTPs) are common among patients suffering from chronic kidney disease (CKD). However, there is a lack of information about DTPs and its predictors among CKD patients from Pakistan.

OBJECTIVES: To evaluate the frequency, type and predictors of various types of DTPs among CKD patients at a tertiary-care hospital in Pakistan.

METHODOLOGY: This was a cross-sectional study carried out at Sandeman Provincial Hospital, Quetta between 1-11-2020 and 31-1-2021. It included 303 non-dialysis ambulatory patients of CKD-stage 3 and above. Cipolle et al., criterion was used for classifying the DTPs and a clinician at the study site checked the identified DTPs for accuracy. Data were analyzed by SPSS 23. Multivariate analysis was conducted to find the predictors of individual types of DTPs. A p-value <0.05 was considered statistically significant.

RESULTS: The patients received a total of 2265 drugs with a median of eight drugs per patient (range: 3-15 drugs). A total of 576 DTPs were identified among 86.1% patients with a median of two DTPs (interquartile range 1-3) per patient. Dosage too high (53.5%) was the most common DTP followed by adverse drug reactions (ADRs) (50.5%) and need of additional drug therapy (37.6%). In multivariate analysis, patients' age of >40 years emerged as a predictor of unnecessary drug therapy and dosage too high. The odds of needing a different drug product was significantly high in patients with cardiovascular diseases (CVD) and diabetes mellitus (DM). The dosage too low had significant association with CVD. The risk of ADRs was significantly high in elderly patients (>60 years) and those with CVD. The presence of hypertension, DM and CKD stage-5 emerged as predictors of dosage too high.

CONCLUSION: This study revealed a high prevalence of DTPs among CKD patients. Targeted interventions in high risk patients may reduce the frequency of DTPs at the study site.

PMID:37058504 | PMC:PMC10104314 | DOI:10.1371/journal.pone.0284439

Anal Cell Pathol (Amst). 2023 Apr 4;2023:1714884. doi: 10.1155/2023/1714884. eCollection 2023.

ABSTRACT

Acetaminophen has always been at the center of attention as a non-steroidal anti-inflammatory drug, which is generally associated with the serious side effects on liver and the hematological parameters. This study aimed to compare the effect of N-acetyl cysteine (NAC) and thyme extract on rat models of acetaminophen-induced toxicity. The present experimental study was conducted on 48 Wistar rats randomized into six groups, including the control group (no treatment); the Ac group (470 mg/kg of acetaminophen); the Ac + 100Ex, Ac + 200Ex, and Ac + 400Ex groups (acetaminophen + thyme extract at doses of 100, 200, 400 mg/kg); and Ac + NA group (acetaminophen + NAC). After weighing, a blood sample was taken from heart at the end of the period. The measured parameters were hematological, liver biochemical, and oxidative stress profiles. A part of the liver tissue was also fixed for the pathological examinations. The bone marrow was aspirated to check for cellular changes as well. The lowest mean of the final weight and liver weight to body weight ratio was observed in the Ac group. Weight loss was compensated in Ac + NA and Ac + 200Ex groups (P = 0.035). White blood cell (WBC), red blood cell (RBC), Hemoglobin (Hgb), and Hematocrit (HCT) in Ac and Ac + 400Ex groups showed significant differences from those of the other test groups (P < 0.001). Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) enzymes in Ac + 200Ex and Ac + NA groups showed a significant decrease compared to those of the other treatment groups (P = 0.043). Total antioxidant capacity (TAC) and glutathione peroxidase (GPx) had the lowest levels in Ac and Ac + 400Ex groups, while malondialdehyde (MDA) had the highest content. In this regard, the liver histopathological indices (necrosis, hyperemia, and hemorrhage) in the Ac + 200Ex and Ac + NA groups reached their lowest grades in the treatment groups. The mean number of erythroid and myeloid cells in the Ac group reached the lowest (17.40 ± 3.48). The microscopic appearance of the bone marrow cells was different from normocytosis in the control group to hypocytosis in the Ac and Ac + 400Ex groups. Thymol, as an effective ingredient in thyme extract at a dose of 200 mg/kg compared to NAC, had a unique effect on reducing bone marrow and liver cell-tissue changes due to the acetaminophen toxicity.

PMID:37056637 | PMC:PMC10089780 | DOI:10.1155/2023/1714884