Curr Med Res Opin. 2023 Mar 13:1-14. doi: 10.1080/03007995.2023.2189855. Online ahead of print.

ABSTRACT

OBJECTIVE: To measure the incidence of neuropsychiatric adverse drug reactions (ADRs) in individuals living with HIV who initiated antiretroviral therapy (ART) with first-line regimens containing dolutegravir (DTG) or efavirenz (EFV) and associated factors.

METHODS: Prospective cohort study with individuals living with HIV who started ART with DTG or EFV associated with tenofovir disoproxil and lamivudine in Belo Horizonte, Brazil. Sociodemographic, clinical, and laboratory data were collected from September/2015 to October/2018 in three specialized HIV care services through interviews, clinical records, and computerized systems. We analyzed the frequency of neuropsychiatric ADRs recorded in clinical records 12 months after starting antiretroviral use, and the associated factors were investigated using binary logistic regression.

RESULTS: A total of 152 (35.1%) of the 433 individuals included had neuropsychiatric ADRs. The incidence density was 35.3/100 person-years. The subjects mainly had sleep disorders and disturbances (21.3%), neurological disorders (13.9%), headaches (8.1%), and anxiety disorders and symptoms (3.0%), more frequently in individuals using EFV. A lower likelihood of neuropsychiatric ADRs was associated with using a DTG-based antiretroviral regimen (OR = 0.24; 95% CI = 0.14-0.40) and anxiety or depression signs and symptoms at the onset of treatment (OR = 0.57; 95% CI = 0.37-0.89).

CONCLUSION: The incidence of neuropsychiatric ADRs was high in individuals starting ART with a lower likelihood of using a DTG-based regimen. The DTG-based regimen had a better safety profile for neuropsychiatric ADRs than the EFV-based regimen.

PMID:36912019 | DOI:10.1080/03007995.2023.2189855

Aging Med (Milton). 2023 Feb 22;6(1):82-97. doi: 10.1002/agm2.12243. eCollection 2023 Mar.

ABSTRACT

Neurodegenerative illnesses refer to the gradual, cumulative loss of neural activity. Neurological conditions are considered to be the second leading cause of mortality in the modern world and the two most prevalent ones are Parkinson's disease and Alzheimer's disease. The negative side effects of pharmaceutical use are a major global concern, despite the availability of many different treatments for therapy. We concentrated on different types of neurological problems and their influence on targets, in vitro, in vivo, and in silico methods toward neurological disorders, as well as the molecular approaches influencing the same, in the first half of the review. The bulk of the second half of the review focuses on the many categories of treatment possibilities, including natural and artificial. Nevertheless, herbal treatment solutions are piquing scholarly attention due to their anti-oxidative properties and accessibility. However, more quality investigations and innovations are undoubtedly needed to back up these conclusions.

PMID:36911087 | PMC:PMC10000287 | DOI:10.1002/agm2.12243

J Emerg Med. 2023 Feb;64(2):253-254. doi: 10.1016/j.jemermed.2022.12.032.

NO ABSTRACT

PMID:36906377 | DOI:10.1016/j.jemermed.2022.12.032

Molecules. 2023 Feb 23;28(5):2097. doi: 10.3390/molecules28052097.

ABSTRACT

The anti-inflammatory drug ibuprofen is considered to be an emerging contaminant because of its presence in different environments (from water bodies to soils) at concentrations with adverse effects on aquatic organisms due to cytotoxic and genotoxic damage, high oxidative cell stress, and detrimental effects on growth, reproduction, and behavior. Because of its high human consumption rate and low environmental degradation rate, ibuprofen represents an emerging environmental problem. Ibuprofen enters the environment from different sources and accumulates in natural environmental matrices. The problem of drugs, particularly ibuprofen, as contaminants is complicated because few strategies consider them or apply successful technologies to remove them in a controlled and efficient manner. In several countries, ibuprofen's entry into the environment is an unattended contamination problem. It is a concern for our environmental health system that requires more attention. Due to its physicochemical characteristics, ibuprofen degradation is difficult in the environment or by microorganisms. There are experimental studies that are currently focused on the problem of drugs as potential environmental contaminants. However, these studies are insufficient to address this ecological issue worldwide. This review focuses on deepening and updating the information concerning ibuprofen as a potential emerging environmental contaminant and the potential for using bacteria for its biodegradation as an alternative technology.

PMID:36903343 | PMC:PMC10004696 | DOI:10.3390/molecules28052097

Int J Mol Sci. 2023 Mar 6;24(5):5058. doi: 10.3390/ijms24055058.

ABSTRACT

Oral mucositis is a common side effect of cancer treatment, and in particular of treatment with the mTORC1 inhibitor everolimus. Current treatment methods are not efficient enough and a better understanding of the causes and mechanisms behind oral mucositis is necessary to find potential therapeutic targets. Here, we treated an organotypic 3D oral mucosal tissue model consisting of human keratinocytes grown on top of human fibroblasts with a high or low dose of everolimus for 40 or 60 h and investigated (1) the effect of everolimus on microscopic sections of the 3D cell culture for evidence of morphologic changes and (2) changes in the transcriptome by high throughput RNA-Seq analysis. We show that the most affected pathways are cornification, cytokine expression, glycolysis, and cell proliferation and we provide further details. This study provides a good resource towards a better understanding of the development of oral mucositis. It gives a detailed overview of the different molecular pathways that are involved in mucositis. This in turn provides information about potential therapeutic targets, which is an important step towards preventing or managing this common side effect of cancer treatment.

PMID:36902486 | PMC:PMC10003620 | DOI:10.3390/ijms24055058

Int J Mol Sci. 2023 Mar 6;24(5):5011. doi: 10.3390/ijms24055011.

ABSTRACT

In the course of the SARS-CoV-2 pandemic, vaccination safety and risk factors of SARS-CoV-2 mRNA-vaccines were under consideration after case reports of vaccine-related side effects, such as myocarditis, which were mostly described in young men. However, there is almost no data on the risk and safety of vaccination, especially in patients who are already diagnosed with acute/chronic (autoimmune) myocarditis from other causes, such as viral infections, or as a side effect of medication and treatment. Thus, the risk and safety of these vaccines, in combination with other therapies that could induce myocarditis (e.g., immune checkpoint inhibitor (ICI) therapy), are still poorly assessable. Therefore, vaccine safety, with respect to worsening myocardial inflammation and myocardial function, was studied in an animal model of experimentally induced autoimmune myocarditis. Furthermore, it is known that ICI treatment (e.g., antibodies (abs) against PD-1, PD-L1, and CTLA-4, or a combination of those) plays an important role in the treatment of oncological patients. However, it is also known that treatment with ICIs can induce severe, life-threatening myocarditis in some patients. Genetically different A/J (most susceptible strain) and C57BL/6 (resistant strain) mice, with diverse susceptibilities for induction of experimental autoimmune myocarditis (EAM) at various age and gender, were vaccinated twice with SARS-CoV-2 mRNA-vaccine. In an additional A/J group, an autoimmune myocarditis was induced. In regard to ICIs, we tested the safety of SARS-CoV-2 vaccination in PD-1-/- mice alone, and in combination with CTLA-4 abs. Our results showed no adverse effects related to inflammation and heart function after mRNA-vaccination, independent of age, gender, and in different mouse strains susceptible for induction of experimental myocarditis. Moreover, there was no worsening effect on inflammation and cardiac function when EAM in susceptible mice was induced. However, in the experiments with vaccination and ICI treatment, we observed, in some mice, low elevation of cardiac troponins in sera, and low scores of myocardial inflammation. In sum, mRNA-vaccines are safe in a model of experimentally induced autoimmune myocarditis, but patients undergoing ICI therapy should be closely monitored when vaccinated.

PMID:36902442 | PMC:PMC10002951 | DOI:10.3390/ijms24055011

Int J Environ Res Public Health. 2023 Mar 3;20(5):4505. doi: 10.3390/ijerph20054505.

ABSTRACT

The safety of pharmacotherapy for geriatric patients is an essential aspect of the demographic perspective in view of the increasing size of this population. Non-opioid analgesics (NOAs) are among the most popular and often overused over-the-counter medications (OTC). The reasons for drug abuse are common in the geriatric population: musculoskeletal disorders, colds, inflammation and pain of various origins. The popularity of self-medication and the ability to easily access OTC drugs outside the pharmacy creates the danger of their misuse and the incidence of adverse drug reactions (ADRs). The survey included 142 respondents aged 50-90 years. The relationship between the prevalence of ADRs and the NOAs used, age, presence of chronic diseases, and place of purchasing and obtaining information about the mentioned drugs were evaluated. The results of the observations were statistically analyzed using Statistica 13.3. The most commonly used NOAs among the elderly included paracetamol, acetylsalicylic acid (ASA) and ibuprofen. Patients consumed the medications for intractable headaches, toothaches, fevers, colds and joint disorders. Respondents indicated the pharmacy as the main location for purchasing medications, and the physician as the source of information for selecting the therapy. ADRs were reported most frequently to the physician, and less frequently to the pharmacist and nurse. More than one-third of respondents indicated that the physician during the consultation did not take a medical history and did not ask about concomitant diseases. It is necessary to extend pharmaceutical care to geriatric patients that includes advice on adverse drug reactions, especially drug interactions. Due to the popularity of self-medication, and the availability of NOAs, long-term measures should be taken to increase the role of pharmacists in providing effective, safe health care to seniors. We are targeting pharmacists with this survey to draw attention to the problem of the prevalence of selling NOAs to geriatric patients. Pharmacists should educate seniors about the possibility of ADRs and approach patients with polypragmasy and polypharmacy with caution. Pharmaceutical care is an essential aspect in the treatment of geriatric patients, which can contribute to better results in their existing treatment and increase the safety of medication intake. Therefore, it is important to improve the development of pharmaceutical care in Poland in order to enhance patient outcomes.

PMID:36901514 | PMC:PMC10001525 | DOI:10.3390/ijerph20054505

J Clin Med. 2023 Mar 2;12(5):1985. doi: 10.3390/jcm12051985.

ABSTRACT

BACKGROUND: Acquired hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal condition characterized by hyperactivation of macrophages and cytotoxic lymphocytes, combining a series of non-specific clinical symptoms and laboratory disorders. Etiologies are multiple: infectious (mainly viral) but also oncologic, autoimmune or drug-induced. Immune checkpoint inhibitors (ICI) are recent anti-tumor agents associated with a novel profile of adverse events triggered by immune system over-activation. Here, we sought to provide a comprehensive description and analysis of HLH cases reported with ICI since 2014.

METHODS: Disproportionality analyses were performed in order to further explore the association between ICI therapy and HLH. We selected 190 cases, 177 from the World Health Organization pharmacovigilance database and 13 from the literature. Detailed clinical characteristics were retrieved from the literature and from the French pharmacovigilance database.

RESULTS: The cases of HLH reported with ICI concerned men in 65% of cases with a median age of 64 years. HLH occurred in an average of 102 days after the initiation of ICI treatment and mostly concerned nivolumab, pembrolizumab and nivolumab/ipilimumab combination. All cases were considered serious. Most cases presented a favorable outcome (58.4%); however, death was reported for 15.3% of patients. Disproportionality analyses showed that HLH was seven times more frequently reported with ICI therapy than with other drugs and three times more than with other antineoplastic agents.

CONCLUSIONS: Clinicians should be aware of the potential risk of ICI-related HLH to improve the early diagnosis of this rare immune-related adverse event.

PMID:36902771 | DOI:10.3390/jcm12051985

Hum Vaccin Immunother. 2023 Dec 31;19(1):2184756. doi: 10.1080/21645515.2023.2184756. Epub 2023 Mar 10.

ABSTRACT

Human papillomavirus (HPV) infection is associated with the risk of developing certain cancers, including cancers of the cervix, vulva, vagina, penis, anus, rectum, and oropharynx. In 2016, the bivalent HPV-16/18 vaccine was included in the Korea National Immunization Program. This vaccine protects against HPV types 16 and 18 and other oncogenic HPV types predominant in cervical and anal cancers. This post-marketing surveillance (PMS) study assessed the safety of the HPV-16/18 vaccine in Korea. The study was conducted in males and females aged between 9 and 25 years, from 2017 to 2021. Safety was measured in terms of frequency and intensity of adverse events (AEs), adverse drug reactions (ADRs), and serious adverse events (SAEs) after each vaccine dose. The safety analysis included all participants who were vaccinated as per prescribing information and who completed a 30-day follow-up after at least one dose. Data were collected using individual case report forms. The total safety cohort included 662 participants. A total of 220 AEs were reported in 144 subjects (21.75%), and there were 158 ADRs in 111 subjects (16.77%), with the most common being injection site pain in all cases. No SAEs or serious ADRs were reported. Most AEs were reported after the first dose and were injection site reactions with mild intensity that recovered. No individuals required hospitalization or an emergency department visit. Safety results showed that the HPV-16/18 vaccine was generally well tolerated in the Korean population, and no safety concerns were identified.ClinicalTrials.gov Identifier: NCT03671369.

PMID:36896702 | DOI:10.1080/21645515.2023.2184756

BMC Infect Dis. 2023 Mar 10;23(1):150. doi: 10.1186/s12879-023-08103-4.

ABSTRACT

BACKGROUND: This study aimed to evaluate the reactogenicity effects of COVID-19 vaccines, used in Iran.

METHODS: At least 1000 people were followed up with phone calls or self-report in a mobile application within 7 days after vaccination. Local and systemic reactogenicities were reported overall and by subgroups.

RESULTS: The presence of one or more local and systemic adverse effects after the first dose of vaccines was 58.9% [(95% Confidence Intervals): 57.5-60.3)] and 60.5% (59.1-61.9), respectively. These rates were reduced to 53.8% (51.2-55.0) and 50.8% (48.8-52.7) for the second dose. The most common local adverse effect reported for all vaccines was pain in the injection site. During the first week after the first dose of vaccines, the frequency of the pain for Sinopharm, AZD1222, Sputnik V, and Barekat was 35.5%, 86.0%, 77.6%, and 30.9%, respectively. The same rates after the second dose were 27.3%, 66.5%, 63.9%, and 49.0%. The most common systemic adverse effect was fatigue. In the first dose, it was 30.3% for Sinopharm, 67.4% for AZD1222, 47.6% for Sputnik V, and 17.1% for Barekat. These rates were reduced to 24.6%, 37.1%, 36.5%, and 19.5%, in the second dose of vaccines. AZD1222 had the highest local and systemic adverse effects rates. The odds ratio of local adverse effects of the AZD1222 vaccine compared to the Sinopharm vaccine were 8.73 (95% CI 6.93-10.99) in the first dose and 4.14 (95% CI 3.32-5.17) in the second dose. Barekat and Sinopharm had the lowest frequency of local and systemic adverse effects. Compared to Sinopharm, systemic adverse effects were lower after the first dose of Barekat (OR = 0.56; 95% CI 0.46-0.67). Reactogenicity events were higher in women and younger people. Prior COVID-19 infection increased the odds of adverse effects only after the first dose of vaccines.

CONCLUSIONS: Pain and fatigue were the most common reactogenicities of COVID-19 vaccination. Reactogenicities were less common after the second dose of the vaccines. The adverse effects of AZD1222 were greater than those of other vaccines.

PMID:36899326 | PMC:PMC10000357 | DOI:10.1186/s12879-023-08103-4

S D Med. 2023 Mar;76(3):124-127.

ABSTRACT

Polypharmacy is defined as concurrent use of multiple drugs for one or more conditions. The occurrence of polypharmacy in vulnerable populations, particularly the elderly, is frequent. Increased incidents of adverse drug reactions and drug-drug interactions plus high costs are not offset by a noticeable improvement in outcome. The practice of polypharmacy persists despite frequent adverse outcomes and reduced effectiveness. We present a case in which an elderly woman presented with falls and delirium. She was taking multiple medications for anxiety and depression in addition to several psychoactive medications for pain, restless leg syndrome, muscle spasms, blood pressure and many nonpsychoactive medications for other conditions. In total, she was taking 24 medications, many of which were likely contributing to her presenting problems.

PMID:36898199

Obstet Gynecol. 2023 Mar 9. doi: 10.1097/AOG.0000000000005114. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the safety, tolerability, and effect of fezolinetant on endometrial health over 52 weeks.

METHODS: We conducted a phase 3, randomized, double-blind, 52-week safety study (SKYLIGHT 4 [Study to Find Out How Safe Long-term Treatment With Fezolinetant is in Women With Hot Flashes Going Through Menopause]) of placebo, fezolinetant 30 mg, and fezolinetant 45 mg once daily (1:1:1). Participants were postmenopausal and seeking treatment for vasomotor symptoms associated with menopause. Primary endpoints were treatment-emergent adverse events, percentage of participants with endometrial hyperplasia, and percentage with endometrial malignancy. Endometrial hyperplasia or malignancy was evaluated according to U.S. Food and Drug Administration guidance (point estimate of 1% or less with an upper bound of one-sided 95% CI of 4% or less). Secondary endpoints included change in bone mineral density (BMD) and trabecular bone score. A sample size of 1,740 was calculated to enable observation of one or more events (≈80% probability for events with background rate of less than 1%).

RESULTS: A total of 1,830 participants were randomized and took one or more medication dose (July 2019-January 2022). Treatment-emergent adverse events occurred in 64.1% (391/610) of the placebo group, 67.9% (415/611) of the fezolinetant 30-mg group, and 63.9% (389/609) of the fezolinetant 45-mg group. Treatment-emergent adverse events leading to discontinuation were similar across groups (placebo, 26/610 [4.3%]; fezolinetant 30 mg, 34/611 [5.6%]; fezolinetant 45 mg, 28/609 [4.6%]). Endometrial safety was assessed in 599 participants. In the fezolinetant 45-mg group, 1 of 203 participants had endometrial hyperplasia (0.5%; upper limit of one-sided 95% CI 2.3%); there were no cases in the placebo (0/186) or fezolinetant 30 mg (0/210) group. Endometrial malignancy occurred in 1 of 210 in the fezolinetant 30-mg group (0.5%; 95% CI 2.2%) with no cases in the other groups. Liver enzyme elevations more than three times the upper limit of normal occurred in 6 of 583 placebo, 8 of 590 fezolinetant 30 mg, and 12 of 589 fezolinetant 45 mg participants; no Hy's law cases were reported (ie, no severe drug-induced liver injury with alanine aminotransferase or aspartate aminotransferase more than three times the upper limit of normal and total bilirubin more than two times the upper limit of normal, with no elevation of alkaline phosphatase and no other reason to explain the combination). Changes in BMD and trabecular bone score were similar across groups.

CONCLUSION: Results from SKYLIGHT 4 confirm the 52-week safety and tolerability of fezolinetant and support its continued development.

FUNDING SOURCE: Astellas Pharma Inc.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04003389.

PMID:36897180 | DOI:10.1097/AOG.0000000000005114

Expert Opin Drug Saf. 2023 Mar 10. doi: 10.1080/14740338.2023.2189235. Online ahead of print.

ABSTRACT

BACKGROUND: BRAF and MEK inhibitor combination therapy have significantly improved the outcome of several BRAF-mutation tumors, but it also confers the risk of drug-induced ocular adverse events (oAEs). However, very few studies focused on this risk.

METHODS: The United States Food and Drug Administration Adverse Event Reporting System (FAERS) data from Quarter 1-2011 to Quarter 2-2022 were searched to detect signs of oAEs of three marketed BRAF and MEK inhibitor combination therapies: vemurafenib plus cobimetinib (V+C), dabrafenib plus trametinib (D+T), and encorafenib plus binimetinib (E+B). Disproportionality analyses were performed by calculating the proportional reporting ratio (PRR), χ2 (chi-square), and reporting odds ratios (RORs) with a 95% confidence interval (CI).

RESULTS: A series of oAEs were identified, including 42 preferred terms, which could be classified into 8 aspects. In addition to previously reported oAEs, several unexpected oAE signals were detected. Moreover, differences in oAE profiles were found among three combination therapies (V+C, D+T, and E+B).

CONCLUSIONS: Our findings support an association between several oAEs and BRAF and MEK inhibitor combination therapies, including several new oAEs. In addition, oAEs profiles may vary across the treatment regimens. Further studies are needed to better quantify these oAEs.

PMID:36896641 | DOI:10.1080/14740338.2023.2189235

Front Toxicol. 2023 Feb 21;5:1113032. doi: 10.3389/ftox.2023.1113032. eCollection 2023.

ABSTRACT

More than fifteen million women with the human immunodeficiency virus type-1 (HIV-1) infection are of childbearing age world-wide. Due to improved and affordable access to antiretroviral therapy (ART), the number of in utero antiretroviral drug (ARV)-exposed children has exceeded a million and continues to grow. While most recommended ART taken during pregnancy suppresses mother to child viral transmission, the knowledge of drug safety linked to fetal neurodevelopment remains an area of active investigation. For example, few studies have suggested that ARV use can be associated with neural tube defects (NTDs) and most notably with the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG). After risk benefit assessments, the World Health Organization (WHO) made recommendations for DTG usage as a first and second-line preferred treatment for infected populations including pregnant women and those of childbearing age. Nonetheless, long-term safety concerns remain for fetal health. This has led to a number of recent studies underscoring the need for biomarkers to elucidate potential mechanisms underlying long-term neurodevelopmental adverse events. With this goal in mind, we now report the inhibition of matrix metalloproteinases (MMPs) activities by INSTIs as an ARV class effect. Balanced MMPs activities play a crucial role in fetal neurodevelopment. Inhibition of MMPs activities by INSTIs during neurodevelopment could be a potential mechanism for adverse events. Thus, comprehensive molecular docking testing of the INSTIs, DTG, bictegravir (BIC), and cabotegravir (CAB), against twenty-three human MMPs showed broad-spectrum inhibition. With a metal chelating chemical property, each of the INSTI were shown to bind Zn++ at the MMP's catalytic domain leading to MMP inhibition but to variable binding energies. These results were validated in myeloid cell culture experiments demonstrating MMP-2 and 9 inhibitions by DTG, BIC and CAB and even at higher degree than doxycycline (DOX). Altogether, these data provide a potential mechanism for how INSTIs could affect fetal neurodevelopment.

PMID:36896351 | PMC:PMC9988942 | DOI:10.3389/ftox.2023.1113032

J Dtsch Dermatol Ges. 2023 Mar;21(3):239-243. doi: 10.1111/ddg.14961. Epub 2023 Mar 9.

ABSTRACT

Colchicine, which was already used by the ancient Egyptians, has recently experienced a renaissance in various medical disciplines, including dermatology. However, due to the potentially significant side effects of systemic use, many clinicians are cautious in their use of colchicine. This review provides a practical overview of the data on the established and emerging use of systemic and topical colchicine in dermatologic diseases.

PMID:36892188 | DOI:10.1111/ddg.14961

S D Med. 2022 Nov;75(11):500-502.

ABSTRACT

Within most electronic medical records, automated decision support helps health care providers reduce the frequency of adverse drug reactions. Historically, this decision support has been used to prevent drug-drug interactions (DDIs). More recently, the clinical and scientific communities have been moving toward the use of this approach to predict and prevent drug-gene interactions (DGIs). Genetic variation in cytochrome P450 2D6 (CYP2D6) is known to impact clinical outcome for many drugs, including opioids. Randomized trials have been initiated to assess the utility of CYP2D6 gene-based dosing versus usual care. We review the use of this approach to guide opioid prescribing in the post-operative setting.

PMID:36893027

Nat Commun. 2023 Mar 9;14(1):1299. doi: 10.1038/s41467-023-36686-8.

ABSTRACT

mRNA-based vaccines dramatically reduce the occurrence and severity of COVID-19, but are associated with rare vaccine-related adverse effects. These toxicities, coupled with observations that SARS-CoV-2 infection is associated with autoantibody development, raise questions whether COVID-19 vaccines may also promote the development of autoantibodies, particularly in autoimmune patients. Here we used Rapid Extracellular Antigen Profiling to characterize self- and viral-directed humoral responses after SARS-CoV-2 mRNA vaccination in 145 healthy individuals, 38 patients with autoimmune diseases, and 8 patients with mRNA vaccine-associated myocarditis. We confirm that most individuals generated robust virus-specific antibody responses post vaccination, but that the quality of this response is impaired in autoimmune patients on certain modes of immunosuppression. Autoantibody dynamics are remarkably stable in all vaccinated patients compared to COVID-19 patients that exhibit an increased prevalence of new autoantibody reactivities. Patients with vaccine-associated myocarditis do not have increased autoantibody reactivities relative to controls. In summary, our findings indicate that mRNA vaccines decouple SARS-CoV-2 immunity from autoantibody responses observed during acute COVID-19.

PMID:36894554 | PMC:PMC9996559 | DOI:10.1038/s41467-023-36686-8

J Clin Pharmacol. 2023 Mar 9. doi: 10.1002/jcph.2233. Online ahead of print.

ABSTRACT

This article discusses the rare but serious occurrence of sedative hypnotic drug induced sexual thoughts. We searched PubMed from the earliest date to 2/7/2023. Articles were selected if they provided data on sexual assault hallucinations or sexual fantasies associated with the use of sedative hypnotic drugs including benzodiazepines, propofol, nitric oxide, ether, chloroform, ketamine, or esketamine. Twenty-two citations provided useful information, including 87 cases of hallucinations about sexual assault or sexual fantasy. In several of the cases, the environment and monitoring made the actual occurrence of sexual assault unlikely but there was still significant anguish for the patients and the accused clinicians. In many of the cases, the places of the body where procedures were conducted coincided the area of the body where the patients perceived the sexual assault or fantasy occurred. The higher the dose of sedative hypnotic administered, the greater the risk of experiencing a hallucination about sexual assault or sexual fantasy. The FDA Adverse Events Reporting System has numerous occurrences where "excessive sexual fantasies" and "abnormal dreams" were associated with the use of sedative hypnotic medication but also occurrences of "sexual abuse" as well. While sexual assault hallucinations or fantasies associated with sedative hypnotics are rare, it is imperative that healthcare providers take the necessary precautions and follow recommendations to provide safety for themselves and their patients. This article is protected by copyright. All rights reserved.

PMID:36895011 | DOI:10.1002/jcph.2233

Lancet Infect Dis. 2023 Mar 6:S1473-3099(23)00048-8. doi: 10.1016/S1473-3099(23)00048-8. Online ahead of print.

ABSTRACT

BACKGROUND: WHO has underlined the need for a child-friendly treatment for schistosomiasis, a prevalent parasitic disease in low-income and middle-income countries. After successful phase 1 and 2 trials, we aimed to evaluate the efficacy, safety, palatability, and pharmacokinetics of arpraziquantel (L-praziquantel) orodispersible tablets for preschool-aged children.

METHODS: This open-label, partly randomised, phase 3 study was conducted at two hospitals in Côte d'Ivoire and Kenya. Children with a minimum bodyweight of 5 kg in those aged 3 months to 2 years and 8 kg in those aged 2-6 years were eligible. In cohort 1, participants aged 4-6 years infected with Schistosoma mansoni were randomly assigned (2:1) to receive a single dose of oral arpraziquantel 50 mg/kg (cohort 1a) or oral praziquantel 40 mg/kg (cohort 1b) using a computer-generated randomisation list. Cohorts 2 (aged 2-3 years) and 3 (aged 3 months to 2 years) infected with S mansoni, and the first 30 participants in cohort 4a (aged 3 months to 6 years) infected with Schistosoma haematobium, received a single dose of oral arpraziquantel 50 mg/kg. After follow-up assessments, arpraziquantel was increased to 60 mg/kg (cohort 4b). Laboratory personnel were masked to the treatment group, screening, and baseline values. S mansoni was detected using a point-of-care circulating cathodic antigen urine cassette test and confirmed using the Kato-Katz method. The primary efficacy endpoint was clinical cure rate at 17-21 days after treatment in cohorts 1a and 1b, measured in the modified intention-to-treat population and calculated using the Clopper-Pearson method. This study is registered with ClinicalTrials.gov, NCT03845140.

FINDINGS: Between Sept 2, 2019, and Aug 7, 2021, 2663 participants were prescreened and 326 were diagnosed with S mansoni or S haematobium. 288 were enrolled (n=100 in cohort 1a, n=50 in cohort 1b, n=30 in cohort 2, n=18 in cohort 3, n=30 in cohort 4a, and n=60 in cohort 4b), but eight participants received antimalarial drugs and were excluded from the efficacy analyses. The median age was 5·1 years (IQR 4·1-6·0) and 132 (47%) of 280 participants were female and 148 (53%) were male. Cure rates with arpraziquantel were similar to those with praziquantel (87·8% [95% CI 79·6-93·5] in cohort 1a vs 81·3% [67·4-91·1] in cohort 1b). No safety concerns were identified during the study. The most common drug-related treatment-emergent adverse events were abdominal pain (41 [14%] of 288 participants), diarrhoea (27 [9%]), vomiting (16 [6%]), and somnolence (21 [7%]).

INTERPRETATION: Arpraziquantel, a first-line orodispersible tablet, showed high efficacy and favourable safety in preschool-aged children with schistosomiasis.

FUNDING: The Global Health Innovative Technology Fund, the European and Developing Countries Clinical Trials Partnership, and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).

PMID:36893784 | DOI:10.1016/S1473-3099(23)00048-8

Front Oncol. 2023 Feb 20;13:1003565. doi: 10.3389/fonc.2023.1003565. eCollection 2023.

ABSTRACT

INTRODUCTION: Many systemic treatment options are available for patients with human epidermal growth factor 2 (HER2)-positive breast cancer brain metastases. However, it is unclear which pharmacological treatment option is the most beneficial.

METHODS: We searched databases, such as PubMed, Embase, and Cochrane Library, and conference abstracts according to keywords. We extracted progression-free survival (PFS), overall survival (OS) data, and overall response rate (ORR) from randomized controlled trials and single-arm studies of HER2-positive breast cancer brain metastasis treatment for meta-analysis and analyzed different drug-related adverse events (AEs).

RESULTS: Three randomized controlled trials and seven single-arm clinical studies with 731 patients with HER2-positive brain metastases from breast cancer involving at least seven drugs were included. In randomized controlled trials, our results showed that trastuzumab deruxtecan significantly improved PFS and OS in patients and was superior to other drug regimens. In the single-arm study, the ORR was more pronounced for the trastuzumab deruxtecan and pyrotinib plus capecitabine regimens (ORR, 73.33%; 95% confidence intervals [CI], 44.90%-92.21%; ORR, 74.58%; 95% CI, 61.56%-85.02%, respectively). We found that the main AEs of antibody-drug conjugate (ADC) were nausea and fatigue, while the main AE of small-molecule tyrosine kinase inhibitor (TKI) drugs and large monoclonal antibodies was diarrhea.

CONCLUSIONS: Trastuzumab deruxtecan was shown to be the most significant in improving survival in patients with HER2-positive breast cancer brain metastases in network meta-analysis, and in single-arm study, patients with HER2-positive breast cancer brain metastases treated with trastuzumab deruxtecan and pyrotinib plus capecitabine regimen had the highest ORR. The main AEs associated with ADC, large monoclonal antibodies, and TKI drugs were nausea, fatigue, and diarrhea, respectively.

PMID:36890831 | PMC:PMC9986525 | DOI:10.3389/fonc.2023.1003565