AAPS J. 2024 Jun 17;26(4):71. doi: 10.1208/s12248-024-00935-5.

ABSTRACT

Dose selection for investigations of intrinsic and extrinsic factors of pharmacokinetic variability as well as safety is a challenging question in the early clinical stage of drug development. The dose of an investigational product is chosen considering the compound information available to date, feasibility of the assessments, regulatory requirements, and the intent to maximize information for later regulatory submission. This review selected 37 programs as case examples of recently approved drugs to explore the doses selected with focus on studies of drug interaction, renal and hepatic impairment, food effect and concentration-QTc assessment.The review found that regulatory agencies may consider alternative approaches if justified and safe as illustrated in these examples. It is thus recommendable to use the first in human trial as an opportunity to assess QT-prolongation and drug interactions using probes or endogenous markers while maximizing the DDI potential, increasing sensitivity and ensuring safety. Early understanding of dose proportionality assists dose finding and simple and fast to conduct DDI study designs are advantageous. Single dose impairment studies despite non-proportional/time-dependent PK are often acceptability.Overall, the early understanding of the drug's safety profile is essential to ensure the safety of doses selected while preventing clinical trials with unnecessary exposure when using high doses or multiple doses. The information collected in this retrospective survey is a good reminder to tailor the early clinical program to the profile and needs of the molecule and consider regulatory opportunities to streamline the development path.

PMID:38886275 | DOI:10.1208/s12248-024-00935-5

PLoS One. 2024 Jun 17;19(6):e0305215. doi: 10.1371/journal.pone.0305215. eCollection 2024.

ABSTRACT

OBJECTIVE: The growing deprescribing field is challenged by a lack of consensus around evidence and knowledge gaps. The objective of this overview of systematic reviews was to summarize the review evidence for deprescribing interventions in older adults.

METHODS: 11 databases were searched from 1st January 2005 to 16th March 2023 to identify systematic reviews. We summarized and synthesized the results in two steps. Step 1 summarized results reported by the included reviews (including meta-analyses). Step 2 involved a narrative synthesis of review results by outcome. Outcomes included medication-related outcomes (e.g., medication reduction, medication appropriateness) or twelve other outcomes (e.g., mortality, adverse events). We summarized outcomes according to subgroups (patient characteristics, intervention type and setting) when direct comparisons were available within the reviews. The quality of included reviews was assessed using A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2).

RESULTS: We retrieved 3,228 unique citations and assessed 135 full-text articles for eligibility. Forty-eight reviews (encompassing 17 meta-analyses) were included. Thirty-one of the 48 reviews had a general deprescribing focus, 16 focused on specific medication classes or therapeutic categories and one included both. Twelve of 17 reviews meta-analyzed medication-related outcomes (33 outcomes: 25 favored the intervention, 7 found no difference, 1 favored the comparison). The narrative synthesis indicated that most interventions resulted in some evidence of medication reduction while for other outcomes we found primarily no evidence of an effect. Results were mixed for adverse events and few reviews reported adverse drug withdrawal events. Limited information was available for people with dementia, frailty and multimorbidity. All but one review scored low or critically low on quality assessment.

CONCLUSION: Deprescribing interventions likely resulted in medication reduction but evidence on other outcomes, in particular relating to adverse events, or in vulnerable subgroups or settings was limited. Future research should focus on designing studies powered to examine harms, patient-reported outcomes, and effects on vulnerable subgroups.

SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020178860.

PMID:38885276 | DOI:10.1371/journal.pone.0305215

Breast Cancer. 2024 Jun 17. doi: 10.1007/s12282-024-01600-7. Online ahead of print.

ABSTRACT

BACKGROUND: In the global phase 3 DESTINY-Breast04 study (NCT03734029), the anti-human epidermal growth factor 2 (HER2) antibody-drug conjugate trastuzumab deruxtecan (T-DXd) demonstrated a statistically significant improvement in progression-free survival (PFS) and overall survival (OS), with manageable safety compared with treatment of physician's choice (TPC) in patients with HER2-low metastatic breast cancer (mBC) who had received 1-2 prior lines of chemotherapy.

METHODS: This subgroup analysis examined the efficacy and safety of T-DXd versus TPC in 213 patients from Asian countries and regions who were enrolled in the DESTINY-Breast04 trial and randomized to T-DXd (n = 147) or TPC (n = 66).

RESULTS: Median PFS with T-DXd and TPC was 10.9 and 5.3 months, respectively, in Asian patients with hormone receptor-positive mBC, and 10.9 and 4.6 months, respectively, in the overall Asian population. In both populations, median OS was not reached with T-DXd and was 19.9 months with TPC. The objective response rate was higher with T-DXd versus TPC in all Asian patients. Median treatment duration was 8.4 months with T-DXd and 3.5 months with TPC. The most common grade ≥ 3 drug-related treatment-emergent adverse events in Asian patients treated with T-DXd were neutropenia (16.3%), anemia (12.9%), and leukopenia (11.6%); the incidences of neutropenia and leukopenia were higher with TPC versus T-DXd. Adjudicated drug-related interstitial lung disease or pneumonitis with T-DXd was 14.3%; the majority of events were grade 1-2.

CONCLUSIONS: T-DXd demonstrated clinically meaningful survival benefits versus TPC in Asian HER2-low mBC patients, regardless of hormone receptor status, with no new safety signals.

CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT03734029.

PMID:38884900 | DOI:10.1007/s12282-024-01600-7

Hepatol Res. 2024 Jun 17. doi: 10.1111/hepr.14078. Online ahead of print.

ABSTRACT

With the widespread use of immune checkpoint inhibitors (ICIs), liver injury (ICI-induced liver injury) as an immune-related adverse event has become a major concern in clinical practice. Because severe cases of liver injury require administration of corticosteroids, a comprehensive evaluation is crucial, including clinical course, blood and imaging tests, and if necessary, pathological examination through liver biopsy. As with liver injury induced by other drugs, classification of injury type by R-value is useful in deciding treatment strategies for ICI-induced liver injury. Histologically, the most representative feature is an acute hepatitis-like hepatocellular injury, characterized by diffuse lobular inflammation accompanied by CD8-positive T lymphocytes. Another condition that can cause liver injury during ICI treatment is cholangitis accompanied by non-obstructive bile duct dilatation and bile duct wall thickening. Many cases of ICI-induced cholangitis are classified as non-hepatocellular injury type, and they have been reported to respond poorly to corticosteroids. It is essential that gastroenterologists/hepatologists and doctors in various departments work in cooperation to develop a system that achieves early diagnosis and appropriate treatment of ICI-induced liver injury.

PMID:38884591 | DOI:10.1111/hepr.14078

Am J Transl Res. 2024 May 15;16(5):1945-1952. doi: 10.62347/QOWN3646. eCollection 2024.

ABSTRACT

PURPOSE: To determine the clinical effectiveness and safety of Gemcitabine (GEM) plus Capecitabine (CAP) for advanced triple-negative breast cancer (aTNBC).

METHODS: Eighty aTNBC patients treated in Affiliated Hospital of Nanjing Medical University between June 2020 and June 2022 were retrospectively included and divided into an observation group (Obs; 42 cases treated with GEM + CAP) and a control group (Con; 38 cases treated with docetaxel + CAP) according to different chemotherapy regimens. The clinical effectiveness and the serum levels of tumor markers and inflammatory factors pre- and post-treatment were detected for comparative analyses. In addition, the two groups were compared in terms of side effects, 1-year survival, and quality of life after 1 month of treatment. Cox regression was performed to identify the independent risk factors affecting patient prognosis.

RESULTS: Higher clinical effectiveness was observed in the Obs group compared to the Con (P < 0.05). The pre-treatment TPS, CA153, TNF-α, and IL-6 levels were comparable between groups (all P > 0.05); however, better post-treatment TPS, CA153, and inflammatory factors were observed in the Obs group compared to the Con (all P < 0.05). The Obs group also showed markedly lower drug-induced toxicities than the Con group, with higher 1-year survival and better quality-of-life after 1 month of treatment (all P < 0.05). According to multivariate analysis, clinical stage and lymph node metastasis were independent risk factors for poor prognosis, and GEM + CAP chemotherapy was a protective prognostic factor.

CONCLUSIONS: GEM + CAP is effective in treating aTNBC and provides clinical benefit for patients, with fewer side effects and good patient tolerance.

PMID:38883354 | PMC:PMC11170573 | DOI:10.62347/QOWN3646

Transl Cancer Res. 2024 May 31;13(5):2571-2579. doi: 10.21037/tcr-23-1952. Epub 2024 Apr 19.

ABSTRACT

BACKGROUND: Programmed cell death-1 (PD-1) inhibitors and anti-angiogenic drugs have become a hotspot in research of anti-tumor programs; however, they can also cause some rare drug-related adverse reactions. Immune checkpoint inhibitors (ICIs) cause adverse reactions in the body, collectively known as immune-related adverse events (irAEs). Ocular side effects can occur in both targeted and immunotherapy patients, including dry eye, blurred vision, uveitis, conjunctivitis, retinopathy, or thyroid eye disease. To our knowledge, this is the first case report describing corneal ulcers secondary to dry eye in a patient treated with the combination of PD-1 inhibitor sintilimab and multi-targeted receptor tyrosine kinase inhibitor (TKI) anlotinib.

CASE DESCRIPTION: A 65-year-old woman with non-small cell lung cancer (NSCLC) and bone metastases, without pre-existing ocular conditions, experienced mild dry eye symptoms 1 month following treatment with sintilimab (200 mg q3w) in combination with anlotinib (12 mg q3w). Unrelieved dry eye symptoms occurred after the third cycle of chemotherapy, and she was diagnosed with dry eye syndrome. Subsequently, she received corneal protective lens, sodium hyaluronate eye drops, and prednisone treatment. Her corneal epithelial damage did not improve significantly, and within the following 2 months, her vision decreased in both eyes and progressed to bilateral corneal ulcers. Oral administration of sintilimab and anlotinib was interrupted, and treatments such as corticosteroids, anti-inflammatory drugs, and corneal repair were administered; however, both eyes presented with corneal subepithelial defect and corneal scarring. Due to a shortage of donors, no corneal transplantation surgery could be performed.

CONCLUSIONS: The development of corneal epithelial disorders in patients receiving target therapy and immunotherapy may not be reversed by reducing its dose. Although the condition is controlled with the use of glucocorticoids, some eye side effects cannot be cured. The timely detection and intervention of adverse effects of anti-tumor drugs by oncologists and ophthalmologists is critical for rational prescription. Ophthalmologists should be aware of eye side effects in patients using immunotherapy to ensure appropriate treatment and minimize potential eye complications such as dry eye, conjunctivitis, etc.

PMID:38881937 | PMC:PMC11170519 | DOI:10.21037/tcr-23-1952

J Transl Med. 2024 Jun 16;22(1):572. doi: 10.1186/s12967-024-05372-8.

ABSTRACT

BACKGROUND: Accurately identifying the risk level of drug combinations is of great significance in investigating the mechanisms of combination medication and adverse reactions. Most existing methods can only predict whether there is an interaction between two drugs, but cannot directly determine their accurate risk level.

METHODS: In this study, we propose a multi-class drug combination risk prediction model named AERGCN-DDI, utilizing a relational graph convolutional network with a multi-head attention mechanism. Drug-drug interaction events with varying risk levels are modeled as a heterogeneous information graph. Attribute features of drug nodes and links are learned based on compound chemical structure information. Finally, the AERGCN-DDI model is proposed to predict drug combination risk level based on heterogenous graph neural network and multi-head attention modules.

RESULTS: To evaluate the effectiveness of the proposed method, five-fold cross-validation and ablation study were conducted. Furthermore, we compared its predictive performance with baseline models and other state-of-the-art methods on two benchmark datasets. Empirical studies demonstrated the superior performances of AERGCN-DDI.

CONCLUSIONS: AERGCN-DDI emerges as a valuable tool for predicting the risk levels of drug combinations, thereby aiding in clinical medication decision-making, mitigating severe drug side effects, and enhancing patient clinical prognosis.

PMID:38880914 | DOI:10.1186/s12967-024-05372-8

Eur J Med Res. 2024 Jun 16;29(1):333. doi: 10.1186/s40001-024-01934-0.

ABSTRACT

BACKGROUND: Adverse drug events (ADEs) represent challenges affecting Africa's healthcare systems owing to the increased healthcare expenditure and negative health outcomes of ADEs.

OBJECTIVES: We aimed to systematically review published studies on ADEs and synthesize the existing evidence of ADE prevalence in Africa.

METHODS: Studies reporting on ADE occurrence in African settings and published from Jan 1, 2000 to Oct 1, 2023 were identified by searching PubMed, EBSCO, Science Direct, and Web of Science. Studies that either articulately investigated ADEs caused by clinical condition (such as HIV patients) or ADEs caused by exposure to specific drug(s) (such as antibiotics) were considered specific and the remaining were general. Grouped ADE prevalence rates were described using median and interquartile range (IQR). PROSPERO registration (CRD42022374095).

RESULTS: We included 78 observational studies from 15 African countries that investigated the prevalence of ADEs leading to hospital admissions (17 studies), developed during hospitalizations (30 studies), and captured in the outpatient departments (38 studies) or communities (4 studies). Twelve studies included multiple settings. The median prevalence of ADE during hospitalization was 7.8% (IQR: 4.2-21.4%) and 74.2% (IQR: 54.1-90.7%) in general and specific patients, respectively. The ADE-related fatality rate was 0.1% and 1.3% in general and specific patients. The overall median prevalence of ADEs leading to hospital admissions was 6.0% (IQR: 1.5-9.0%); in general, patients and the median prevalence of ADEs in the outpatient and community settings were 22.9% (IQR: 14.6-56.1%) and 32.6% (IQR: 26.0-41.3%), respectively, with a median of 43.5% (IQR: 16.3-59.0%) and 12.4% (IQR: 7.1-28.1%) of ADEs being preventable in general and specific patients, respectively.

CONCLUSIONS: The prevalence of ADEs was significant in both hospital and community settings in Africa. A high ADE prevalence was observed in specific patients, emphasizing important areas for improvement, particularly in at-risk patient groups (e.g., pediatrics, HIV, and TB patients) in various settings. Due to limited studies conducted in the community setting, future research in this setting is encouraged.

PMID:38880895 | DOI:10.1186/s40001-024-01934-0

Clin Drug Investig. 2024 Jun;44(6):439-453. doi: 10.1007/s40261-024-01369-9. Epub 2024 Jun 15.

ABSTRACT

BACKGROUND: Evidence on associations between drug-drug interactions (DDIs) and health outcomes in the older community-dwelling population is limited.

OBJECTIVE: We estimate potentially clinically important DDI prevalence and examine the association between DDIs and (1) adverse drug events (ADEs), (2) emergency hospital attendance and (3) health-related quality of life (HRQoL) in an older community-dwelling population in Ireland.

METHODS: This is a prospective cohort study of community-dwelling older adults (N = 904) aged ≥ 70 years from 15 general practices in Ireland recruited in 2010 (wave-1) and followed-up over 2 years (wave-2; 2012-2013), with linked national pharmacy claims data. Individuals dispensed two or more drugs (wave-1: N = 842; wave-2: N = 763) were included. DDI prevalence at baseline, follow-up and 6 months prior to each health outcome was estimated. Multi-level regression was used to model the association between DDI-exposure and health outcomes at follow-up. DDI prevalence, adjusted incidence-rate ratios (aIRR), adjusted odds ratios (aOR), β coefficients and robust standard error (RSE) from multi-level regression analyses, and 95% confidence intervals (CIs) are reported.

RESULTS: At wave-1, n = 196 (23.3% [95% CI 20.5-26.3]), individuals were potentially exposed to ≥ 1 DDI, increasing to n = 345 (45.2% [41.7-48.9]) at wave-2. At 2-year follow-up, the median number of ADEs was 3 (interquartile range [IQR 2-5]); 229 (30.1%) had ≥ 1 emergency hospital attendance, and the mean EQ-5D was 0.74 (± 0.23). Evidence for the association between DDI-exposure and emergency hospital attendance at follow-up was lacking (aOR = 1.38 [0.42-4.53]). DDI-exposure was associated with an increasing number of ADEs (aIRR = 1.26 [1.03-1.55]), and decreasing EQ-5D utility (β = - 0.07, [-0.11 to -0.04], RSE = 0.02). Aspirin-warfarin, clarithromycin-prednisolone, amiodarone-furosemide, clarithromycin-salbutamol, rosuvastatin-warfarin, amiodarone-bisoprolol, and aspirin-nicorandil were common DDIs 6 months preceding these health outcomes.

CONCLUSIONS: We found a two-fold increase in DDI prevalence between wave 1 and 2. DDI exposure was associated with increasing ADEs and declining HRQoL at 2-year follow-up. Common DDIs involved anticoagulants, cardiovascular and antimicrobial drugs, which should be targeted for medicine optimisation.

PMID:38878216 | DOI:10.1007/s40261-024-01369-9

BMC Geriatr. 2024 Jun 14;24(1):520. doi: 10.1186/s12877-024-05124-9.

ABSTRACT

BACKGROUND: Dementia is a major global public health challenge, and with the growing elderly population, its prevalence is expected to increase in the coming years. In Sweden, municipalities are responsible for providing special housing for the elderly (SÄBO), which offers services and care for older individuals needing specific support. SÄBO is both the person´s home and a care environment and workplace. Polypharmacy in patients with dementia is common and increases the risk of medication interactions. Involving clinical pharmacists in medication reviews has been shown to enhance medication safety and improve prescribing practices. However, the views of the standard care team involved in medication prescribing, administration, monitoring and documentation on integrating pharmacist services have received less attention. Thus, this study aims to explore how pharmacists' contributions can enhance medication safety, improve patient care efficiency, and potentially alleviate the workload of general practitioners for people with dementia living in special housing.

METHODS: This study has a descriptive qualitative study design using semi-structured interviews and qualitative content analysis. The study was conducted in a southern Swedish special housing and included nurses, assistant nurses, general practitioners (GPs), and a pharmacist. Due to the COVID-19 pandemic, interviews were conducted over the phone. The Swedish Ethical Review Authority approved the study.

RESULTS: The analysis revealed three main categories, and eleven subcategories.: (1) Integrating multidisciplinary approaches for holistic dementia care, (2) Strengthening dementia care through effective medication management and (3) Advancing dementia care through pharmacist integration and role expansion. Nurses focused on non-pharmacological treatments, while GPs emphasized the importance of medication reviews in assessing the benefits and side-effects of prescribed medication. Pharmacists were valued for their reliable medication expertise, appreciated by GPs for saving time and providing recommendations prior to consultations with individuals with dementia and their next-of-kin. Although medication reviews were considered beneficial, there was skepticism about their ability to solve all medication-related problems associated with dementia care.

CONCLUSIONS: This study highlights the critical role pharmacists play in enhancing medication safety and patient care efficiency in special housing for individuals with dementia. Despite the value of their contributions, communication barriers within healthcare teams pose significant challenges. Recognising potential pharmacist role expansion is essential to alleviate the workload of GPs and ensure effective collaborative practices for better patient outcomes.

PMID:38877433 | DOI:10.1186/s12877-024-05124-9

Sci Rep. 2024 Jun 13;14(1):13691. doi: 10.1038/s41598-024-64697-y.

ABSTRACT

Tafamidis is the world's first and only oral drug approved to treat the rare disease transthyretin amyloid cardiomyopathy (ATTR-CM). Medicines are known to have different adverse reactions during the course of treatment. However, the current limited clinical studies did not identify significant adverse drug reactions to tafamidis. Tafamidis has been on the market for 5 years now, a large number of adverse drug event (ADE) reports with tafamidis as the primary suspected drug have been reported in the United Food and Drug Administration's adverse event reporting system (FAERS). We retrieved 8170 adverse event reports in FAERS with tafamidis as the first suspected drug, and mined these reports for positive signals to perform risk warnings for potentially possible adverse events with tafamidis. We found that a large number of adverse events associated with the primary disease were reported due to insufficient awareness of ATTR among the reporters, leading to a large number of positive signals reported in the cardiac disorders system. We also found that tafamidis has the potential to cause an adverse event risks of ear and labyrinth disorders system and urinary tract infection bacterial, which deserve continued clinical attention.

PMID:38871835 | DOI:10.1038/s41598-024-64697-y

Expert Opin Pharmacother. 2024 Jun 13:1-7. doi: 10.1080/14656566.2024.2358131. Online ahead of print.

ABSTRACT

INTRODUCTION: In many postmenopausal women, quality of life is decreased due to vasomotor symptoms. Efficient and well-tolerated non-hormonal treatment options are needed.

AREAS COVERED: The present review summarizes what is known about the etiology of postmenopausal vasomotor symptoms as a rationale for the mechanism of action of Elinzanetant, a new neurokinin (NK)-1/-3 receptor antagonist, as well as its efficacy and side effect profile.

EXPERT OPINION: Elinzanetant likely exerts an antagonistic effect on the NK-3 receptor in the preoptic thermoregulatory zone, but also an additional antagonistic effect on the NK-1 receptor possibly leading to a reduction in vasodilatation and heat-sensing neuro-activity. Elinzanetant's reported peak drug concentrations are reached within one hour and the terminal elimination half-life is approximately 15 hours. Two phase IIb clinical trials evaluated the safety profile and efficacy of several doses. There were no serious adverse events, which also included a lack of evidence of drug-related hepatotoxicity. Overall, Elinzanetant seems to be well-tolerated. In the SWITCH-1 study, the 120 mg/day and 160 mg/day regimen showed good efficacy for the treatment of vasomotor symptoms and led to significant improvements in quality of life. Thus, 120 mg oral Elinzanetant/day was used in phase III trials, whose results have not yet been published.

PMID:38869992 | DOI:10.1080/14656566.2024.2358131

Rev Med Liege. 2024 Jun;79(5-6):455-461.

ABSTRACT

Adverse events related to drug therapy are a major cause of iatrogenicity. They are responsible of increased morbidity, leading to hospitalization, sometimes in emergency, and mortality, not only in ambulatory care but also during hospitalization itself. Causes are multiple : among them, confusion leading to an erroneous drug administration, mistakes regarding dosage, risks associated to self-medication, drug-drug interactions or even food-drug interactions. Elderly population is exposed to an increased incidence of drug iatrogenicity because older patients cumulate numerous risk factors, especially polypharmacy and cognitive disorders. Prevention of drug iatrogenicity is a key objective from a public health point of view. Preventive measures should target the prescriber (physician), the dispenser (pharmacist), the user (patient) and the supplier (pharmaceutical industry).

PMID:38869139

Eur Heart J Suppl. 2024 Apr 17;26(Suppl 1):i69-i73. doi: 10.1093/eurheartjsupp/suae021. eCollection 2024 Apr.

ABSTRACT

Brugada syndrome mainly affects young subjects with structurally normal heart and can cause x syncope or sudden death due to ventricular arrhythmias, even as the first manifestation, in approximately 5-10% of cases. To date, two questions remain open: how to recognize subjects who will experience arrhythmic events and how to treat them. The guidelines suggest treating subjects with a previous history of cardiac arrest or arrhythmogenic syncope, while they are unconclusive about the management of asymptomatic patients, who represent ∼90% of Brugada patients. We recently demonstrated that in asymptomatic patients, the presence of spontaneous Brugada type 1 electrocardiogram (ECG) pattern and inducibility of ventricular arrhythmias at electrophysiological study allows us to identify a group of patients at greater risk who deserve treatment. Regarding treatment, there are three options: implantable cardioverter defibrillator, drugs, and epicardial transcatheter ablation. Recent studies have shown that the latter is effective and free from serious side effects, thus opening a new scenario in the treatment of Brugada patients at risk. Subjects who present drug-induced-only type 1 Brugada ECG pattern, in whom a spontaneous type 1 pattern has been ruled out with repeated ECGs and 12-lead 24-h Holter monitoring, represent a very low-risk group, provided they adhere to behavioural recommendations and undergo regular follow-up.

PMID:38867864 | PMC:PMC11167981 | DOI:10.1093/eurheartjsupp/suae021

Eur J Pain. 2024 Jun 12. doi: 10.1002/ejp.2299. Online ahead of print.

ABSTRACT

BACKGROUND: The TRPV1 receptor is a key molecule in pain generation. Previous development of oral TRPV1-antagonists was halted due to systemic heat insensitivity and body temperature alterations. The present Phase 1b study investigated the efficacy, safety and plasma exposure of a topically administered TRPV1-antagonist (ACD440 Gel) in healthy subjects.

METHODS: The study comprised two parts. In part 1, 24 healthy subjects were included in this randomized double-blind, placebo-controlled, crossover trial. ACD440 Gel or Placebo was applied once daily and wiped off after 1 h, for 5 consecutive days. Assessments were done in normal skin, skin optimized for penetration (by stripping and occlusive gel application) and UVB-irradiated skin. Pain induced by thermo-nociceptive CO2 laser impulses generated laser-evoked potentials (LEPs), with readouts of peak-to-peak (PtP) amplitude in vertex-EEG and pain assessments by VAS (0-100). Endpoints include effects at 1 hour post-dose, AUC(Days 1-5) and AUC(0-24, Day 4). In UVB-irradiated skin, also pain on pinprick and skin redness were assessed. Part 2 explored the plasma pharmacokinetics of ACD440.

RESULTS: ACD440 Gel reduced LEP PtP amplitude and VAS pain, p < 0.001, in all skin conditions, versus placebo. In UVB-irradiated skin, pinprick pain was also reduced, p = 0.047. Effects were significant after 1 h, maintaining for at least 9 h. There were no adverse events or drug-induced erythema. Plasma exposures of ACD440 were too low to establish an elimination half-life of ACD400.

CONCLUSIONS: Topical ACD440 Gel demonstrated a significant analgesic effect on LEP, VAS score and pinprick pain, with low systemic exposures, supporting further clinical development.

SIGNIFICANCE: This study demonstrates that the topical administration of a TRPV1-antagonist, ACD440 Gel, has potential as a new treatment for painful conditions affecting the skin, such as chronic peripheral neuropathic pain, without any local or systemic side effects.

PMID:38864733 | DOI:10.1002/ejp.2299

Iran J Pathol. 2024 Winter;19(1):103-106. doi: 10.30699/IJP.2023.2002772.3118. Epub 2023 Dec 29.

ABSTRACT

BACKGROUND & OBJECTIVE: Antigen Ki-67 (histone-based nuclear protein) is a static marker of tumor cell proliferation and growth and is commonly measured to indicate the effect of treatment in breast cancer patients. This single-arm trial study aimed to evaluate the effect of short-term endocrine therapy (letrozole) on Ki-67 levels in menopausal women with early hormone-positive breast cancer who were referred to two university hospitals.

METHODS: Patients with a pre-treatment Ki67 of 5% or less were excluded from the study. Participants (n=25) received oral letrozole (2.5 mg daily) seven days before surgery. Ki-67% on both biopsies and the surgical specimens were measured and compared.

RESULTS AND CONCLUSION: The mean age of patients was 62±9.4 (48-83 years). Our result indicated that pre-surgery consumption of letrozole for hormone-positive breast cancer can significantly decrease the of Ki-67 labeling index (23.24±9.74 vs. 16.92±9.55, P=0.001 by paired t-test), with no drug-related adverse events.

PMID:38864079 | PMC:PMC11164301 | DOI:10.30699/IJP.2023.2002772.3118

Oxf Med Case Reports. 2024 Jun 7;2024(6):omae062. doi: 10.1093/omcr/omae062. eCollection 2024 Jun.

ABSTRACT

Ceftriaxone is a third-generation cephalosporin. Due to its wide range of activity and acceptable safety profile, it is frequently prescribed to paediatric patients. However, there are several documented cases of reports of uncommon adverse events, such as cholecystitis, linked to the use of ceftriaxone. This study discusses the case of an 8-year-old female patient who developed cholecystitis, an inflammation of the gallbladder, after being treated with ceftriaxone. The patient presented with right upper quadrant pain, associated with nausea. Imaging studies showed the presence of stones and shadowing sludge, leading to acute inflammation of the gallbladder. Prompt cessation of ceftriaxone and supportive treatment led to the resolution of cholecystitis and the complete disappearance of the sludge and stones. The study highlights that early identification and withdrawal of the antibiotic can lead to successful therapy and the avoidance of unnecessary surgical procedures.

PMID:38860015 | PMC:PMC11162581 | DOI:10.1093/omcr/omae062

Int J Nanomedicine. 2024 Jun 6;19:5317-5333. doi: 10.2147/IJN.S460890. eCollection 2024.

ABSTRACT

PURPOSE: The purpose of this study is to address the high mortality and poor prognosis associated with Acute Respiratory Distress Syndrome (ARDS), conditions characterized by acute and progressive respiratory failure. The primary goal was to prolong drug circulation time, increase drug accumulation in the lungs, and minimize drug-related side effects.

METHODS: Simvastatin (SIM) was used as the model drug in this study. Employing a red blood cell surface-loaded nanoparticle drug delivery technique, pH-responsive cationic nanoparticles loaded with SIM were non-covalently adsorbed onto the surface of red blood cells (RBC), creating a novel drug delivery system (RBC@SIM-PEI-PPNPs).

RESULTS: The RBC@SIM-PEI-PPNPs delivery system effectively extended the drug's circulation time, providing an extended therapeutic window. Additionally, this method substantially improved the targeted accumulation of SIM in lung tissues, thereby enhancing the drug's efficacy in treating ARDS and impeding its progression to ARDS. Crucially, the system showed a reduced risk of adverse drug reactions.

CONCLUSION: RBC@SIM-PEI-PPNPs demonstrates promise in ARDS and ARDS treatment. This innovative approach successfully overcomes the limitations associated with SIM's poor solubility and low bioavailability, resulting in improved therapeutic outcomes and fewer drug-related side effects. This research holds significant clinical implications and highlights its potential for broader application in drug delivery and lung disease treatment.

PMID:38859953 | PMC:PMC11164090 | DOI:10.2147/IJN.S460890

J Hepatol. 2024 Jun 7:S0168-8278(24)02303-1. doi: 10.1016/j.jhep.2024.06.003. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Survodutide is a glucagon/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH). We investigated survodutide in people with cirrhosis.

METHODS: This multinational, non-randomized, open-label, phase 1 clinical trial initially evaluated a single subcutaneous (s.c.) dose of survodutide 0.3 mg in people with Child-Pugh class A, B or C cirrhosis and healthy individuals with or without overweight/obesity matched for age, sex, and weight; the primary endpoints were the area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) and maximal plasma concentration (Cmax). Subsequently, people with overweight/obesity with or without cirrhosis and Child-Pugh class A or B received once-weekly s.c. doses escalated from 0.3 mg to 6.0 mg over 24 weeks then maintained for 4 weeks; the primary endpoint was drug-related treatment-emergent adverse events, with MASH/cirrhosis-related endpoints explored.

RESULTS: In the single-dose cohorts (n = 41), mean AUC0-∞ and Cmax were similar in those with cirrhosis compared with healthy individuals (90% confidence intervals for adjusted geometric mean ratios spanned 1). Drug-related adverse events occurred in 25.0% of healthy individuals and ≤25.0% of those with cirrhosis after single doses, and 82.4% and 87.5%, respectively, of the multiple-dose cohorts (n = 41) over 28 weeks. Liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers were generally reduced after 28 weeks of survodutide treatment.

CONCLUSIONS: Survodutide is generally tolerable in people with compensated or decompensated cirrhosis, does not require pharmacokinetic-related dose adjustment, and may improve liver-related non-invasive tests, supporting its investigation for MASH-related cirrhosis. Clinical trial number; ClinicalTrials.gov identifier: NCT05296733.

IMPACT AND IMPLICATIONS: Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH), which causes cirrhosis in ∼20% of cases. This trial delineates the pharmacokinetic and safety profile of survodutide in people with compensated or decompensated cirrhosis, and revealed associated reductions in liver fat content, markers of liver fibrosis and body weight. These findings have potential relevance for people with MASH-including those with decompensated cirrhosis, who are usually excluded from clinical trials of investigational drugs. Based on this study, further investigation of survodutide for MASH-related cirrhosis is warranted.

PMID:38857788 | DOI:10.1016/j.jhep.2024.06.003

Life Sci. 2024 Jun 8:122792. doi: 10.1016/j.lfs.2024.122792. Online ahead of print.

ABSTRACT

AIMS: Drug-induced enteropathy is often associated with the therapeutic use of certain glucuronidated drugs. One such drug is mycophenolic acid (MPA), a well-established immunosuppressant of which gastrointestinal adverse effects are a major concern. The role of bacterial β-glucuronidase (β-G) from the gut microbiota in MPA-induced enteropathy has recently been discovered. Bacterial β-G hydrolyzes MPAG, the glucuronide metabolite of MPA excreted in the bile, leading to the digestive accumulation of MPA that would favor in turn these adverse events. We therefore hypothesized that taming bacterial β-G activity might reduce MPA digestive exposure and prevent its toxicity.

MAIN METHODS: By using a multiscale approach, we evaluated the effect of increasing concentrations of MPA on intestinal epithelial cells (Caco-2 cell line) viability, proliferation, and migration. Then, we investigated the inhibitory properties of amoxapine, a previously described bacterial β-G inhibitor, by using molecular dynamics simulations, and evaluated its efficiency in blocking MPAG hydrolysis in an Escherichia coli-based β-G activity assay. The pharmacological effect of amoxapine was evaluated in a mouse model.

KEY FINDINGS: We observed that MPA impairs intestinal epithelial cell homeostasis. Amoxapine efficiently blocks the hydrolysis of MPAG to MPA and significantly reduces digestive exposure to MPA in mice. As a result, administration of amoxapine in MPA-treated mice significantly attenuated gastrointestinal lesions.

SIGNIFICANCE: Collectively, these results suggest that the digestive accumulation of MPA is involved in the pathophysiology of MPA-gastrointestinal adverse effects. This study provides a proof-of-concept of the therapeutic potential of bacterial β-G inhibitors in glucuronidated drug-induced enteropathy.

PMID:38857657 | DOI:10.1016/j.lfs.2024.122792