BACKGROUND: Although the levonorgestrel 52 mg intrauterine device is locally active and has low systemic hormone exposure, hormonal intrauterine device users sometimes report hormone-related side effects.
OBJECTIVE: Evaluate hormone-related adverse event rates among all participants and compare these among those who used combined hormonal or no hormonal contraception in the month before enrollment.
METHODS: A total of 1714 women aged 16-45 years old received a levonorgestrel 52 mg intrauterine device in a multicenter phase 3 trial to evaluate contraceptive efficacy and safety for up to 10 years. This analysis evaluated a subset of participants who used combined hormonal or no hormonal contraception in the month prior to device placement. We assessed all non-expulsion, non-bleeding-related events with ≥1% incidence at 180 days with a plan to include weight increase regardless of incidence; we excluded events considered non-hormonal. We computed 180-day side effect frequency rates based on the number of days a side effect was reported during the study period. We created a multivariable model for side effect incidence at 180 days based on age, race, ethnicity, body mass index at enrollment, parity, and contraception use in the month before enrollment. For those side effects with a p-value <0.2 on univariate comparison between combined-hormonal and no-hormonal contraception users, we secondarily evaluated 360-day event rates.
RESULTS: Overall, 644 participants used combined hormonal contraception (primarily oral [n=499, 77.5%]) and 855 used no hormonal method before IUD placement. Individual side effect rates over the first 180 days did not differ between prior combined-hormonal and no-hormonal contraception users except for acne (84 [13.0%] versus 73 [8.5%], respectively), p=0.006, OR 1.61 (95% CI 1.15-2.24). However, this association was weaker after adjustment for age, race, ethnicity, obesity status, and parity (aOR 1.40, 95% CI 0.99-1.98) At 360 days, prior combined hormonal contraception users were more likely to report acne (101 [15.7%] vs. 91 [10.6%], respectively, p=0.005) and orgasm/libido problems (20 [3.1%] vs. 12 [1.4%], respectively, p=0.03). Over the first 180 days, all side effects other than acne were reported in less than 3% of days; acne was reported an average of 13 days (7.4%) per prior combined hormonal contraception user and 9 days (5.0%) per prior non-hormonal contraception user (p<0.0001). Discontinuation for evaluated side effects occurred in 83 (5.5%) participants with no difference between those who used combined hormonal (36 [5.6%]) or no hormonal contraception (47 [5.5%]), p=1.0) before study entry.
CONCLUSIONS: Using combined hormonal contraception prior to levonorgestrel 52 mg intrauterine device placement is only weakly associated with reporting hormonally related side effects like acne. Only a small percentage of levonorgestrel 52 mg intrauterine device users experienced potentially hormone-related side effects during the initial 6 months of use that resulted in discontinuation.

Benign prostatic hyperplasia is one of the most common diseases in men, with a prevalence rate of 50% in their 50s to 80% in their 80s, and is mostly treated with chronic drug therapy. The aim of this study was to analyze adverse drug reactions (ADR) to drugs used in benign prostate hyperplasia (BPH) treatment reported to HALMED from 2008 to 2021. Data on ADR reports in Croatia were obtained from the VigiFlow national database and on the use of drugs for BPH in Croatia from Drug Utilization Reports from HALMED. In the observed period, the number of reports on each BPH drug, total number of reports, seriousness of reported ADR, patient age and sex, type of reporter, and most reported ADRs were analyzed. Results showed that 438 ADR reports were received, of which 45.95% on tamsulosin as the most frequently used drug for BPH. Of all reports, 84% were non-serious, 96% were reported in men and 82% in patients older than 45 years. The most frequently reported ADRs were consistent with the known safety profile of BPH drugs. Pharmacists were the most common (47%) reporters of ADRs for BPH drugs, while 33% were reported by physicians. Analysis of the reported ADRs showed that most frequently reported ones were in line with the known safety profile of BPH drugs. However, given the prevalence of the disease and the extent of the use of BPH drugs, it could be argued that the number of reports could be higher (i.e., 34 reports/year). Reporting on ADRs is necessary to better understand the safety profile of drugs in the post-authorization period, and more information on the safe use of medicines could be collected by raising awareness of healthcare professionals.

BACKGROUND: Many factors contribute to quality of life (QoL) in patients with schizophrenia, yet limited research examined these factors in patients in China. This cross-sectional study explores subjective QoL and its associated factors in patients.
METHODS: The QoL was assessed using the Schizophrenia Quality of Life Scale (SQLS). Clinical symptoms were evaluated using the Brief Psychiatric Rating Scale (BPRS) and seven factors were extracted. Patient Health Questionnaire-9 (PHQ-9), and Generalized Anxiety Disorder Scale (GAD-7) were used to assess depression and anxiety. Cognitive impairment was assessed using the Ascertain Dementia 8 (AD8). The Treatment Emergent Symptom Scale (TESS) and Rating Scale for Extrapyramidal Side Effects (RSESE) were used to evaluate the side effects of medications.
RESULTS: We recruited 270 patients (male:142,52.6%, mean age:41.9 ± 9.4 years). Positive correlations were observed between SQLS and its subdomains with the total score of BPRS, PHQ-9, GAD-7, AD8, TESS, and RSESE (all P < 0.005). Patients who were taking activating second-generation antipsychotics (SGAs) had lower scores on total SQLS, Motivation/ Energy domain of SQLS (SQLS-ME) as well as Symptoms/ Side effects domain of SQLS (SQLS-SS) compared to those taking non-activating SGAs (all P < 0.005). Multiple regression analysis showed that depressive/ anxiety symptoms and cognitive impairment had significant negative effects on QoL (P ≤ 0.001), while activating SGAs had a positive effect (P < 0.005). Blunted affect and unemployment were inversely associated with the motivation/energy domain (P < 0.001).
CONCLUSIONS: Our findings emphasize the important role of depression/anxiety symptoms and cognitive impairment in the QoL of patients with chronic schizophrenia. Activating SGAs and employment may improve the QoL of these individuals.
BACKGROUND: This protocol was registered at chictr.org.cn (Identifier: ChiCTR2100043537).

BACKGROUND: Seizures are considered to be one of the dreaded side effects of clozapine, and due to this, the use of clozapine is avoided in patients with treatment-resistant schizophrenia. Resultantly, there is little information about the use of clozapine among patients with seizure disorder.
OBJECTIVE: To assess the safety of clozapine in patients with history of seizures in their lifetime before starting clozapine and receiving clozapine for the management of psychotic disorders.
RESULTS: Out of the 958 patients, 35 (3.65 %) had a history of at least one seizure episode before starting clozapine, with a mean of 5.06 (SD: 7.23; Median: 3.00) seizures before starting clozapine. The mean duration between the last seizure and the starting of clozapine was 123.75 (SD: 124.99; Median: 84) months, with nine patients having an episode of seizure in the previous 12 months and 15 patients being seizure-free for more than ten years. About one-fourth (25.7 %; nine out of 35) of the patients had recurrence of seizure while receiving clozapine for a mean duration of about five years. When the recurrence of seizure after starting clozapine was evaluated in patients receiving antiepileptics along with clozapine, the incidence of at least one seizure was 26.67 % (4 out of 15), and among those not receiving antiepileptics, the incidence of at least one seizure was 25 % (5 out of 20). The dose of clozapine at which seizure was noted ranged from 12.5 mg to 600 mg/day with a mean of 236.25 (SD: 169.04; Median: 162.5) mg/day. In none of the patients, clozapine had to be stopped due to the continuation of seizures.
CONCLUSIONS: About one-fourth of the patients with history of an episode of seizure have recurrence of seizure while receiving clozapine. The demographic and clinical variables do not differ between those who develop and who do not develop seizures after starting clozapine, including concomitant use of antiepileptics.

This paper investigates the relationship between the experiences of mass vaccinations against two pandemic viruses: the swine flu in 2009-2010 and COVID-19 in the early 2020s. We show how distressing memories from the swine flu vaccination, which led to the rare but severe adverse effect of narcolepsy in approximately 500 children in Sweden, were triggered by the COVID-19 pandemic. The narcolepsy illness story has rarely been told in academic contexts; therefore, we will provide space for this story. It is presented through a dialogue with the aim of shedding light on the interrelationship between pandemics-and between mass vaccinations-to investigate what could be termed cultural wounds that influence societies because they are characterized by the difficulty of talking about them. The paper explores the multiple shocks of illness in life and what can be learned from them by sharing them.

Objectives: This real-life study aimed to evaluate the safety of acetazolamide (ACZ), a carbonic anhydrase inhibitor with diuretic effects. ACZ has recently been proven to improve decongestion in the context of patients hospitalized for acute heart failure (HF). However, data in terms of safety are lacking. Methods: We conducted a monocentric observational prospective study from November 2023 to February 2024 in a 12-bed cardiology department, recording adverse events (hypotension, severe metabolic acidosis, severe hypokalemia and renal events) during in-hospital HF treatment. All patients hospitalized for acute HF during the study period treated with ACZ (500 mg IV daily for 3 days) on top of IV furosemide (n = 28, 48.3%) were compared with patients who have been treated with IV furosemide alone (n = 30, 51.7%). Results: The patients treated with ACZ were younger than those without (median age 78 (range 67-86) vs. 85 (79-90) years, respectively, p = 0.01) and had less frequent chronic kidney disease (median estimated glomerular fraction rate (60 (35-65) vs. 38 (26-63) mL/min, p = 0.02). As concerned adverse events during HF treatment, there were no differences in the occurrences of hypotension (three patients [10.7%] in the ACZ group vs. four [13.3%], p = 0.8), renal events (four patients [14.3%] in the ACZ group vs. five [16.7%], p = 1) and severe hypokalemia (two [7.1%] in the ACZ group vs. three [10%], p = 1). No severe metabolic acidosis occurred in either group. Conclusions: Although the clinical characteristics differed at baseline, with younger age and better renal function in patients receiving ACZ, the tolerance profile did not significantly differ from patients receiving furosemide alone. Additional observational data are needed to further assess the safety of ACZ-furosemide combination in the in-hospital management of HF, especially in older, frail populations.

In clinical trials, laboratory values are assessed with high frequency. This can be stressful for patients, resource intensive, and difficult to implement, for example in office-based settings. In the prospective, multicentre phase 2 TITAN-RCC trial (NCT02917772), we investigated how many relevant changes in laboratory values would have been missed if laboratory values had been assessed less frequently. Patients with metastatic renal cell carcinoma (n = 207) received a response-based approach with nivolumab and nivolumab+ipilimumab boosts for non-response. We simulated that laboratory values were obtained before every second dose instead of every dose of the study drug(s). We assessed elevated leukocyte counts, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, amylase, lipase, and thyroid-stimulating hormone. Dose delay and discontinuation criteria were defined according to the study protocol. With the reduced frequency of laboratory analyses, dose delay criteria were rarely missed: in a maximum of <0.1% (3/4382) of assessments (1% [2/207] of patients) during nivolumab monotherapy and in a maximum of 0.2% (1/465) of assessments (1% [1/132] of patients) during nivolumab+ipilimumab boosts. An exception was lipase-related dose delay which would have been missed in 0.6% (25/4204) of assessments (7% [15/207] of patients) during nivolumab monotherapy and in 0.8% (4/480) of assessments (3% [4/134] of patients) during nivolumab+ipilimumab boosts, but would have required the presence of symptoms. Discontinuation criteria would have only been missed for amylase (<0.1% [1/3965] of assessments [0.5% (1/207) of patients] during nivolumab monotherapy, none during nivolumab+ipilimumab boosts) and lipase (0.1% [5/4204] of assessments [2% (4/207) of patients] during nivolumab monotherapy; 0.2% [1/480] of assessments [0.7% (1/134) of patients] during nivolumab+ipilimumab boosts). However, only symptomatic patients would have had to discontinue treatment due to amylase or lipase laboratory values. In conclusion, a reduced frequency of laboratory testing appears to be acceptable in asymptomatic patients with metastatic renal cell carcinoma treated with nivolumab or nivolumab+ipilimumab.

The outcome of multiple myeloma (MM) has significantly improved in the last few decades due to several factors such as new biological discoveries allowing to better stratify disease risk, development of more effective therapies and better management of side effects related to them. However, handling all these aspects requires an interdisciplinary approach involving multiple knowledge and collaboration of different specialists. The hematologist, faced with a patient with MM, must not only choose a treatment according to patient and disease characteristics but must also know when therapy needs to be started and how to monitor it during and after treatment. Moreover, he must deal not only with organ issues related to MM such as bone disease, renal failure or neurological disease but also with adverse events, often very serious, related to novel therapies, particularly new generation immunotherapies such as CAR T cell therapy and bispecific antibodies. In this review, we provide an overview on the newer MM diagnostic and monitoring strategies and on the main side effects of MM therapies, focusing on adverse events occurring during treatment with CAR T cells and bispecific antibodies.

The development of multitarget opioid drugs has emerged as an attractive approach for innovative pain management with reduced side effects. In the present study, a novel hybrid peptide BNT12 containing the opioid and neurotensin (NT)-like fragments was synthesized and pharmacologically characterized. In acute radiant heat paw withdrawal test, intracerebroventricular (i.c.v.) administration of BNT12 produced potent antinociception in mice. The central antinociceptive activity of BNT12 was mainly mediated by μ-, δ-opioid receptor, neurotensin receptor type 1 (NTSR1) and 2 (NTSR2), supporting a multifunctional agonism of BNT12 in the functional assays. BNT12 also exhibited significant antinociceptive effects in spared nerve injury (SNI)-neuropathic pain, complete Freund\'s adjuvant (CFA)-induced inflammatory pain, acetic acid-induced visceral and formalin-induced pain after i.c.v. administration. Furthermore, BNT12 exhibited substantial reduction of acute antinociceptive tolerance, shifted the dose-response curve to the right by only 1.3-fold. It is noteworthy that BNT12 showed insignificant chronic antinociceptive tolerance at the supraspinal level. In addition, BNT12 exhibited reduced or no opioid-like side effects on conditioned place preference (CPP) response, naloxone-precipitated withdrawal response, acute hyperlocomotion, motor coordination, gastrointestinal transit, and cardiovascular responses. The present investigation demonstrated that the novel hybrid peptide BNT12 might serve as a promising analgesic candidate with limited opioid-like side effects.

BACKGROUND: With a wide therapeutic index, efficacy, ease of use, and other neuroprotective and respiratory benefits, caffeine citrate(CC) is currently the drug of choice for preterm neonates (PTNs). Caffeine-induced excessive energy expenditure, diuresis, natriuresis, and other CC-associated potential side-effects (CC-APSEs) result in lower daily-weight gain (WG) in premature neonates. This study aimed to evaluate the risk factors for daily-WG in neonates exposed to different dose regimens of caffeine in ICU.
METHODS: This retrospective cohort study included neonates of ≤ 36weeks gestational age (GA) and received CC-therapy. The same participants were followed for data analysis in two postnatal phases: 15-28 and 29-42 days of life (DOL). Based on daily CC-dose, formed group-I (received; standard-doses = 5 mg/kg/day), group-II (received;>5-7 mg/kg/day), and group-III (received;>7 mg/kg/day). Prenatal and postnatal clinical characteristics, CC-regimen, daily-WG, CC-APSEs, and concomitant risk-factors, including daily-caloric intake, Parenteral-Nutrition duration, steroids, diuretics, and ibuprofen exposure, were analyzed separately for group-II and group-III using group-I as standard. Regression analysis was performed to evaluate the risk factors for daily-WG.
RESULTS: Included 314 PTNs. During 15-28 DOL, the mean-daily-WG(MD-WG) was significantly higher in group-I than group-II [19.9 ± 0.70 g/kg/d vs. 17.7 ± 0.52 p = 0.036] and group-III [19.9 ± 0.70 g/kg/d vs. 16.8 ± 0.73 p < 0.001]. During 29-42 DOL the MD-WG of group-I was only significantly higher than group-III [21.7 ± 0.44 g/kg/d vs. 18.3 ± 0.41 g/kg/d p = 0.003] and comparable with group-II. During 15-28 DOL, observed CC-APSEs was significantly higher in group-II and III but during 29-42 DOL it was only significant in group-III. In the adjusted regression analysis for daily-WG during 15-28DOL, with respect to standard-dose, 5-7 mg/kg/day (β=-1.04; 95%CI:-1.62,-0.93) and > 7-10 mg/kg/day (β=-1.36; 95%CI:-1.56,-1.02) were associated with a lower daily-WG. However, during 29-42DOL, this association was present only for > 7-10 mg/kg/day (β=-1.54; 95%CI:-1.66,-1.42). The GA ≤ 27weeks (β=-1.03 95%CI:-1.24, -0.88) was associated with lower daily-WG only during 15-28DOL. During both periods of therapy, higher cumulative-caffeine dose and presence of culture proven sepsis, tachypnea, hyponatremia, and feeding intolerance were significantly associated with lower daily-WG. Conversely, daily kcal intake was found to be linked with an increase in daily-WG in both periods.
CONCLUSIONS: In this study cohort exposure to higher caffeine daily and cumulative doses is associated with lower postnatal daily-WG in PTNs than standard-daily doses, which may be due to its catabolic effects and CC-APSEs.