Curr Gastroenterol Rep. 2023 Oct 17. doi: 10.1007/s11894-023-00885-6. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICI) have revolutionized cancer care and work primarily by blocking CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), and/or PD-1 (programmed cell death protein 1), and/or PD-L1 (programmed death-ligand 1), thereby providing highly efficacious anti-tumor activity. However, this unmitigated immune response can also trigger immune related adverse events (irAEs) in multiple organs, with pancreatic irAEs (now referred to as type 3 Autoimmune pancreatitis (AIP) being infrequent.

RECENT FINDINGS: Type 3 AIP is a drug-induced, immune mediated progressive inflammatory disease of the pancreas that may have variable clinical presentations viz., an asymptomatic pancreatic enzyme elevation, incidental imaging evidence of pancreatitis, painful pancreatitis, or any combination of these subtypes. Management is largely supportive with intravenous fluid hydration, pain control and holding the inciting medication. Steroids have not been shown to demonstrate a clear benefit in acute management. A rapid development pancreatic atrophy is observed on imaging as early as 1 year post initial injury. Type 3 AIP is a chronic inflammatory disease of the pancreas that though predominantly asymptomatic and mild in severity can lead to rapid organ volume loss regardless of type of clinical presentation and despite steroid therapy.

PMID:37845557 | DOI:10.1007/s11894-023-00885-6

Cureus. 2023 Sep 13;15(9):e45180. doi: 10.7759/cureus.45180. eCollection 2023 Sep.

ABSTRACT

Euglycemic diabetic ketoacidosis (DKA) is a rare, but clinically important, presentation that can lead to significant morbidity and mortality in patients with diabetes mellitus. It has been associated with multiple etiologies, including sodium-glucose cotransport-2 (SGLT2) inhibitor use. This case report details the presentation of a 28-year-old male patient who was recently diagnosed with non-ST elevated myocardial infarction (NSTEMI) status post-percutaneous coronary intervention (PCI) to left anterior descending (LAD) and type 2 diabetes mellitus (T2DM) and discharged on a new medical regiment that included an SGLT2 inhibitor. The patient presented five days later with dyspnea, nausea, and vomiting. On initial evaluation, he had tachycardia and hypertension. Lab work revealed hyperkalemia, metabolic anion gap acidosis, and the presence of ketones and glucose in the urine, which led to the diagnosis of euglycemic DKA. The patient was started on intravenous (IV) insulin, bicarbonate, and D5 ½ normal saline (NS) and required five days of continuous treatment for the anion gap to close. Considering studies have shown that SGLT2 inhibitors are associated with euglycemic DKA, it is proposed that the use of an SGLT2 inhibitor in this newly diagnosed, post-PCI patient led to the development of euglycemic DKA. DKA most commonly resolves within 24 hours of treatment; however, our patient did not recover until after 120 hours of treatment. Recent studies have suggested that SGLT2-inhibitor euglycemic DKA may be associated with longer recovery time; however, there is still a need to further research the consistency of these findings and quantify the estimated duration of treatment across populations. There is also a need for investigation into how co-morbid factors, such as a recent NSTEMI and PCI, may affect recovery times or predispose patients who are taking SGLT2-inhibitors to develop euglycemic DKA as SGLT2 inhibitors are being more widely prescribed. This case report highlights the importance of creating more detailed and evidence-based guidelines for prescribing SGLT2 inhibitors for patients with diabetes and encourages more research into the expected duration of treatment for patients with SGLT2-induced euglycemic DKA and factors that may affect it.

PMID:37842482 | PMC:PMC10575758 | DOI:10.7759/cureus.45180

EBioMedicine. 2023 Oct 13;97:104814. doi: 10.1016/j.ebiom.2023.104814. Online ahead of print.

ABSTRACT

BACKGROUND: Ivermectin's mosquitocidal effect and in vitro activity against Plasmodium falciparum asexual stages are known. Its in vivo blood-schizonticidal efficacy is unknown. Ivermectin's tolerability and efficacy against P. falciparum infections in Gabonese adults were assessed.

METHODS: The study consisted of a multiple dose stage and a randomized, double-blind, placebo-controlled stage. Adults with asymptomatic P. falciparum parasitaemia (200-5000 parasites/μl) were enrolled. First, three groups of five participants received 200 μg/kg ivermectin once daily for one, two, and three days, respectively, and then 34 participants were randomized to 300 μg/kg ivermectin or placebo once daily for 3 days. Primary efficacy outcome was time to 90% parasite reduction. Primary safety outcomes were drug-related serious and severe adverse events (Trial registration: PACTR201908520097051).

FINDINGS: Between June 2019 and October 2020, 49 participants were enrolled. Out of the 34 randomized participants, 29 (85%) completed the trial as per protocol. No severe or serious adverse events were observed. The median time to 90% parasite reduction was 24.1 vs. 32.0 h in the ivermectin and placebo groups, respectively (HR 1.38 [95% CI 0.64 to 2.97]).

INTERPRETATION: Ivermectin was well tolerated in doses up to 300 μg/kg once daily for three days and asymptomatic P. falciparum asexual parasitaemia was reduced similarly with this dose of ivermectin compared to placebo. Further studies are needed to evaluate plasmodicidal effect of ivermectin at higher doses and in larger samples.

FUNDING: This study was funded by the Centre de Recherches Médicales de Lambaréné and the Centre for Tropical Medicine of the Bernhard Nocht Institute for Tropical Medicine.

PMID:37839134 | DOI:10.1016/j.ebiom.2023.104814

Am J Med Sci. 2023 Oct 12:S0002-9629(23)01375-7. doi: 10.1016/j.amjms.2023.10.004. Online ahead of print.

ABSTRACT

Adverse drug reactions can be either dose-dependent (Type A) or idiosyncratic (Type B). Type B adverse drug reactions tend to be extremely rare and difficult to predict. They are usually immune-mediated. Examples include severe skin reactions and drug-induced liver injury. For many commonly prescribed drugs (such as antibiotics), the risk of developing an idiosyncratic adverse drug reaction is influenced by variability in the human leukocyte antigen (HLA) genes. Because these HLA-mediated adverse drug reactions can be lethal, there is growing interest in defining which specific drug-gene relationships might benefit from pre-emptive HLA genotyping and automated clinical decision support. This review summarizes the literature for HLA-mediated adverse reactions linked to common drugs.

PMID:37838157 | DOI:10.1016/j.amjms.2023.10.004

Expert Opin Drug Saf. 2023 Oct 14. doi: 10.1080/14740338.2023.2271834. Online ahead of print.

ABSTRACT

BACKGROUND: To detect and analysis risk signals of the drug-related adverse events (AEs) of 4 gadolinium-based contrast agents (GBCAs) (gadopentetate dimeglumine (Gd-DTPA), gadobenate dimeglumine (Gd-BOPTA), gadoteridol (Gd-HP-DO3A), and gadobutrol (Gd-BT-DO3A)) according to the US Food and Drug Administration Adverse Event Reporting System (FAERS) database and ensure the clinical safety.

RESEARCH DESIGN AND METHODS: The AEs that associated with the 4 GBCAs were collected from the FAERS database from 2004Q1 to 2022Q3. The risk signals were mined using reporting odds ratio (ROR) and proportional reporting ratio (PRR).

RESULTS: 424 risk signals were excavated, in which 151 risk signals were associated with Gd-DTPA, 93 risk signals were related to Gd-BOPTA, 79 risk signals were relevant to Gd-HP-DO3A, and 101 risk signals were associated with Gd-BT-DO3A. The AE signals involved 20 system organ classes (SOCs). Two of the top four SOCs were identical, namely 'skin and subcutaneous tissue disorders' and 'general disorders and administration site conditions.'

CONCLUSIONS: The safety signals of 4 GBCAs were detected, and the SOCs associated with the AEs of the 4 GBCAs were different. Besides, some AEs obtained in this study were not mentioned in the package inserts, which need more attention and research to ensure the clinical safety.

PMID:37837355 | DOI:10.1080/14740338.2023.2271834

Cancers (Basel). 2023 Oct 9;15(19):4904. doi: 10.3390/cancers15194904.

ABSTRACT

BACKGROUND: Poly ADP-ribose polymerase inhibitors (PARPis) are an important class of therapeutics for metastatic castration-resistant prostate cancer (mCRPC). Unlike hormone-based treatments for mCRPC, PARPis are not without drug-related hematological adverse events.

OBJECTIVE: To review the evidence on hematological toxicities, including anemia, thrombocytopenia, and neutropenia from PARPis in prostate cancer.

STUDY METHODOLOGY: A systematic review and meta-analysis using the PRISMA guidelines was performed for phase II and III randomized controlled trials (RCTs) of PARPis in prostate cancer. PubMed, Embase, and Ovid All EBM reviews-Cochrane were queried from inception to 9 June 2023. The Mantel-Haenszel method was used to report risk ratios (RR) and 95% confidence intervals (CI) for all-grade and high-grade anemia, thrombocytopenia, and neutropenia toxicities.

RESULTS: The systematic review retrieved eight phase II and III RCTs; specifically, eight were included in the anemia, five in the all-grade thrombocytopenia and neutropenia, and four in the high-grade thrombocytopenia and neutropenia outcomes. Compared to a placebo and/or other non-PARPi treatments, PARPi use was associated with an increased risk of all-grade anemia (RR, 3.37; 95% CI, 2.37-4.79; p < 0.00001), thrombocytopenia (RR, 4.54; 95% CI, 1.97-10.44; p = 0.0004), and neutropenia (RR, 3.11; 95% CI, 1.60-6.03; p = 0.0008). High-grade anemia (RR, 6.94; 95% CI, 4.06-11.86; p < 0.00001) and thrombocytopenia (RR, 5.52; 95% CI, 2.80-10.88; p < 0.00001) were also associated with an increased risk, while high-grade neutropenia (RR, 3.63; 95% CI, 0.77-17.23; p = 0.10) showed no significant association. Subgroup stratification analyses showed differences in various all-grade and high-grade toxicities.

CONCLUSION: PARPis were associated with an increased risk of hematological AEs. Future studies with more pooled RCTs will enhance this understanding and continue to inform patient-physician shared decision-making. Future studies may also have a role in improving the current management strategies for these AEs.

PMID:37835597 | DOI:10.3390/cancers15194904

Medicine (Baltimore). 2023 Oct 13;102(41):e35327. doi: 10.1097/MD.0000000000035327.

ABSTRACT

BACKGROUND AND PURPOSE: Treating vitiligo in clinical practice is challenging. Furthermore, oral drugs used in Western medicine have considerable side effects and are unsuitable for long-term treatment. In contrast, Chinese patent medicines (CPMs) are more suitable for long-term oral vitiligo treatment, but medical evidence of their efficacy and safety is lacking. Therefore, in this study, the efficacy and safety of CPMs were evaluated and ranked using a Bayesian network meta-analysis.

METHODS: Seven Chinese and English databases were searched for all relevant articles published up to February 2023. The Bayesian network meta-analysis method was used to analyze the extracted data to evaluate efficacy and safety.

RESULTS: Six common CPMs for treating vitiligo were selected in our study, and 48 targeted articles and 4446 patients were included. This study showed that Qubai Babuqi tablets (QT) were the most effective for short-term treatment of vitiligo, and that vitiligo capsules or pills (VCP) were the most effective for long-term treatment, together with compound Quchong Banjiuju pills (QP). In terms of surface area under the cumulative ranking curve (SUCRA) values, the order of efficacy of each treatment was as follows: QT (92.18%) > Taohong Qingxue pills (TP) (63.81%) > VCP (55.53%) > QP (50.72%) > Bailing tablets or capsules (BTC) (49.01%) > Baishi pills (BP) (35.69%)>routine therapy (RT) (3.1%) in terms of total effective rate and QT (92.05%) > VCP (71.50%) > QP (66.60%) > TP (42.95%) > BTC (39.66%) > BP (36.60%)>RT (0.6%) in terms of improvement rate. In addition, the safety of the 6 CPMs did not significantly differ in terms of adverse effects. The SUCRA values indicated that QT performed slightly worse than other drugs.

DISCUSSION: In treating vitiligo, QT is most effective but only suitable for short-term administration owing to its poor safety. VCP and QP could be used as first-choice long-term medications. TP may positively affect repigmentation in patients with limited lesion areas.

PMID:37832097 | PMC:PMC10578774 | DOI:10.1097/MD.0000000000035327

Drug Ther Bull. 2023 Oct 13:dtb-2023-000054. doi: 10.1136/dtb.2023.000054. Online ahead of print.

NO ABSTRACT

PMID:37833039 | DOI:10.1136/dtb.2023.000054

Nucleic Acids Res. 2023 Oct 13:gkad832. doi: 10.1093/nar/gkad832. Online ahead of print.

ABSTRACT

Leveraging genetics insights to promote drug repurposing has become a promising and active strategy in pharmacology. Indeed, among the 50 drugs approved by FDA in 2021, two-thirds have genetically supported evidence. In this regard, the increasing amount of widely available genome-wide association studies (GWAS) datasets have provided substantial opportunities for drug repurposing based on genetics discoveries. Here, we developed PharmGWAS, a comprehensive knowledgebase designed to identify candidate drugs through the integration of GWAS data. PharmGWAS focuses on novel connections between diseases and small-molecule compounds derived using a reverse relationship between the genetically-regulated expression signature and the drug-induced signature. Specifically, we collected and processed 1929 GWAS datasets across a diverse spectrum of diseases and 724 485 perturbation signatures pertaining to a substantial 33609 molecular compounds. To obtain reliable and robust predictions for the reverse connections, we implemented six distinct connectivity methods. In the current version, PharmGWAS deposits a total of 740 227 genetically-informed disease-drug pairs derived from drug-perturbation signatures, presenting a valuable and comprehensive catalog. Further equipped with its user-friendly web design, PharmGWAS is expected to greatly aid the discovery of novel drugs, the exploration of drug combination therapies and the identification of drug resistance or side effects. PharmGWAS is available at https://ngdc.cncb.ac.cn/pharmgwas.

PMID:37831083 | DOI:10.1093/nar/gkad832

MMW Fortschr Med. 2023 Oct;165(18):13. doi: 10.1007/s15006-023-3071-0.

NO ABSTRACT

PMID:37828306 | DOI:10.1007/s15006-023-3071-0

Cureus. 2023 Sep 10;15(9):e44984. doi: 10.7759/cureus.44984. eCollection 2023 Sep.

ABSTRACT

INTRODUCTION: Anticancer agents are responsible for a majority of adverse drug reactions (ADRs) in cancer patients. ADR reporting with anticancer drugs is very rare in India due to the lack of awareness and knowledge about the Pharmacovigilance Programme of India. Hence, this study was done to assess the pattern of ADRs with anticancer agents in cancer patients and to increase awareness about ADR monitoring among healthcare professionals.

MATERIALS AND METHODS: This is an observational, retrospective and non-interventional study conducted in an ADR monitoring centre (AMC) in Govt. Guru Gobind Singh Medical College and Hospital, Faridkot, Punjab, North India. Voluntarily reported ADR forms with anticancer drugs as suspected drugs over a period of seven years from January 2016 to December 2022 were analyzed. Various parameters were analyzed, which include demographic details of the patients, type of ADR, department reporting ADR and suspected drug. Causality assessment, severity assessment and preventability assessment were done according to the World Health Organization Uppsala Monitoring Centre (WHO-UMC) scale, modified Hartwig and Siegel scale and modified Schumock and Thornton scale, respectively.

RESULTS: The maximum numbers of ADRs were reported in the age group of 41-60 years (68.29%) and in females (59.75%). The maximum number of ADRs was reported with the use of taxanes (docetaxel and paclitaxel) (24.39%), targeted drugs (geftinib, imatinib, bortezomib, bevacizumab, rituximab and pazopanib) (24.39%) and platinum co-ordination complexes (cisplatin, oxaliplatin and carboplatin) (17.07%). Majority of the ADRs reported were shivering and ADRs on the skin. Majority of the ADRs were probable (64.70%), mild in nature (85.29%), definitely preventable (45.58%) and probably preventable (45.58%).

CONCLUSION: ADR monitoring is needed to increase the outcome of anticancer drug treatment in cancer patients. The quality of treatment in cancer patients can be improved through the timely management of these ADRs. It is a need of the present era to inform healthcare professionals about the Pharmacovigilance Programme to increase the reporting of ADRs due to anticancer drugs.

PMID:37822427 | PMC:PMC10562879 | DOI:10.7759/cureus.44984

Drug Saf. 2023 Oct;46(10):1021-1037. doi: 10.1007/s40264-023-01342-z. Epub 2023 Oct 11.

ABSTRACT

BACKGROUND AND OBJECTIVE: Medication safety problems are common post-hospital discharge, and an important global healthcare improvement target. The Transfers of Care Around Medicines (TCAM) service was launched by a National Health Service Trust in the North-West of England, initially focusing on patients with new or existing Monitored Dosage Systems (MDS). The TCAM service is designed to enable the prompt transfer of medication information, with referrals made by hospitals at discharge to a named community pharmacy. This study aimed to explore the utilisation and impact of the TCAM service on medication safety.

METHODS: The evaluation included a descriptive analysis of 3033 anonymised patient referrals to 71 community pharmacies over a 1-year period alongside an assessment of the impact of the TCAM service on unintentional medication discrepancies and adverse drug events using a retrospective before-and-after study design. Impact data were collected across 18 general practices by 16 trained clinical pharmacists.

RESULTS: Most patient referrals (70%, 2126/3033) were marked as 'completed' by community pharmacies, with 15% of completed referrals delayed beyond 30 days. Screening of 411 patient records by clinical pharmacists yielded no statistically significant difference in unintentional medication discrepancies or adverse drug event rates following TCAM implementation using a multivariable regression analysis (unintentional medication discrepancies adjusted odds ratio = 0.79 [95% confidence interval 0.44-1.44, p = 0.46]; and adverse drug events adjusted odds ratio = 1.19 [95% confidence interval 0.57-2.45, p = 0.63]), although there remained considerable uncertainty.

CONCLUSIONS: The TCAM service facilitated a number of community pharmacy services offered to patients with monitored dosage systems; but the impact of the intervention on unintentional medication discrepancies and adverse drug event rates post-hospital discharge for this patient group was uncertain. The results of this exploratory study can inform the ongoing implementation of the TCAM service at hospital discharge and highlight the need to understand service implementation in different contexts, which may influence its impact on medication safety.

PMID:37819463 | PMC:PMC10584716 | DOI:10.1007/s40264-023-01342-z

J Pak Med Assoc. 2023 Sep;73(9):1891-1893. doi: 10.47391/JPMA.6322.

ABSTRACT

Word Health Organization declared COVID 19 infection as pandemic in 2020. Since then different countries had started working on vaccination. After multiple trials different vaccinations got approved. The first vaccine to be received in Pakistan was Sinopharm and was provided to nearly all health care professionals on priority basis. The safety profile of different vaccines were satisfactory and there were very few side effects reported till date. We are reporting the first case in Pakistan where a female health care professional developed vaccination induced deranged liver function test with delayed but complete recovery. Extensive workup was done to rule out all other differentials of deranged liver function test.

PMID:37817706 | DOI:10.47391/JPMA.6322

Ophthalmology. 2023 Oct 9:S0161-6420(23)00716-9. doi: 10.1016/j.ophtha.2023.10.004. Online ahead of print.

ABSTRACT

We classified drug-induced uveitis related to Immune Checkpoint inhibitors (ICIs) and MAP-kinase pathway inhibitors (MAPKi), including BRAF-inhibitors (BRAFi) and MEK-inhibitors (MEKi), according ophthalmological examination. Cases were retrieved from the French pharmacovigilance database (FPVD) which included all adverse drug reactions (ADR) registred by the French Regional Pharmacovigilance Network. We collected 113 cases of drug-induced uveitis (46 ICI-related and 67 MAPKi-related). The classification analysis identified four clusters. ICI were associated with anterior, posterior and panuveitis with severe manifestations such as retinal vasculitis and optic neuropathy. BRAFi were associated with anterior and panuveitis. MEKi inhibitors were associated with early serous-retinal detachment.

PMID:37820932 | DOI:10.1016/j.ophtha.2023.10.004

Clin Cancer Res. 2023 Oct 11. doi: 10.1158/1078-0432.CCR-23-2005. Online ahead of print.

ABSTRACT

BACKGROUND: Combining gemcitabine with CHK1 inhibition has shown promise in preclinical models of pancreatic ductal adenocarcinoma (PDAC). Here, we report the findings from a phase I expansion cohort study (NCT02632448) investigating low-dose gemcitabine combined with the CHK1 inhibitor LY2880070 in patients with previously treated advanced PDAC.

METHODS: Patients with metastatic PDAC were treated with gemcitabine intravenously at 100 mg/m2 on days 1, 8, and 15, and LY2880070 50 mg orally twice daily on days 2-6, 9-13, and 16-20 of each 21-day cycle. Pre-treatment tumor biopsies were obtained from each patient for correlative studies and generation of organoid cultures for drug sensitivity testing and biomarker analyses. >Results: Eleven patients with PDAC were enrolled in the expansion cohort between August 27, 2020 and July 30, 2021. Four patients (36%) experienced drug-related grade 3 adverse events. No objective radiological responses were observed, and all patients discontinued the trial by 3.2 months. In contrast to the lack of efficacy observed in patients, organoid cultures derived from biopsies procured from two patients demonstrated strong sensitivity to the gemcitabine/LY2880070 combination and showed treatment-induced upregulation of replication stress and DNA damage biomarkers, including pKAP1, pRPA32, and γ-H2AX, as well as induction of replication fork instability.

CONCLUSIONS: No evidence of clinical activity was observed for combined low dose gemcitabine and LY2880070 in this treatment refractory PDAC cohort. However, the gemcitabine/LY2880070 combination showed in vitro efficacy, suggesting that drug sensitivity for this combination in organoid cultures may not predict clinical benefit in patients.

PMID:37819936 | DOI:10.1158/1078-0432.CCR-23-2005

Haemophilia. 2023 Oct 11. doi: 10.1111/hae.14880. Online ahead of print.

ABSTRACT

INTRODUCTION: Emicizumab mimicking the cofactor function of activated factor VIII (FVIII) restores haemostasis.

METHODS: This nationwide observational study aimed to retrospectively investigate efficacy, safety, and cost in 1 year before and up to 3 years after emicizumab prophylaxis for haemophilia A (HA) patients with FVIII inhibitors.

RESULTS AND DISCUSSION: A total of 39 severe HA patients with a median age of 23.0 years were enrolled. The median historical peak FVIII inhibitor titre was 174.2 BU/mL with an interquartile range of 56.5-578.8 BU/mL. The median annualized bleeding rate reduced from 24 to 0 events in the first year after emicizumab prophylaxis (p < .01) and sustained in the second and third years. The median annualized joint bleeding rate reduced to 0 and maintained up to 3 years (p < .01). Twenty-seven patients (69.2%) had target joints before emicizumab prophylaxis and only seven patients (17.9%) of them had target joints after prophylaxis. Medical costs, including cost of haemostatic therapy, frequency of outpatient department visits, emergency room visits and hospital admission, were significantly reduced after emicizumab prophylaxis (p < .01). FVIII inhibitor titre decreased after emicizumab prophylaxis. Overall, three (7.7%) patients experienced 202 grade 1 drug-related adverse events after emicizumab prophylaxis. No serious adverse events were reported during emicizumab prophylaxis period. The adherence to emicizumab prophylaxis was 100% up to 3 years.

CONCLUSIONS: HA patients with FVIII inhibitors treated with emicizumab prophylaxis resulted in a significant reduction in treated bleeds and associated costs. No new safety events were observed.

PMID:37819166 | DOI:10.1111/hae.14880

J Pediatric Infect Dis Soc. 2023 Oct 10:piad078. doi: 10.1093/jpids/piad078. Online ahead of print.

ABSTRACT

BACKGROUND: IMPAACT 2014 study is a phase I/II, multicenter, open-label, non-randomized study of doravirine (DOR) co-formulated with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF) as fixed dose combination (DOR FDC) in adolescents with HIV-1. We report the efficacy, safety, and tolerability of DOR FDC through 96 weeks.

METHODS: Participants were adolescents aged 12 to <18 years who weighed at least 45 kg and who were either antiretroviral (ARV)-naïve or virologically suppressed without documented resistance mutations to DOR/3TC/TDF. The efficacy endpoint was the proportion of participants with HIV-1 RNA <40 copies/mL assessed at week 48 and 96 using the observed failure approach. Safety and tolerability outcomes were incidence of adverse events and treatment discontinuations.

RESULTS: A total of 45 adolescents, median age 15 (range, 12 - 17) years, 58% females, were enrolled, 2 (4.4%) participants were ARV-naïve. Of the 45 participants, 42 (93.3%) completed the study and 41 (91.1%) completed study treatment. At week 48, 41/42 (97.6%; 95% confidence interval [CI], 87.4 - 99.9) and week 96, 37/40 (92.5%; 95% CI, 79.6 - 98.4) participants had achieved or maintained HIV-1 RNA <40 copies/mL. There were no treatment-related discontinuations due to adverse events and no drug-related adverse events ≥ grade 3 or deaths.

CONCLUSIONS: We found once daily dosing of DOR FDC to be safe and well tolerated for maintaining viral suppression through 96 weeks in adolescents living with HIV-1.

PMID:37815035 | DOI:10.1093/jpids/piad078

Per Med. 2023 Sep;20(5):417-424. doi: 10.2217/pme-2023-0033. Epub 2023 Oct 9.

ABSTRACT

Epilepsy is characterized by repeated seizure activity. Valproate, a commonly used antiepileptic drug, shows large inter-individual variation in plasma valproic levels and causes many adverse drug reactions. Aim: To find the influence of CYP2C9*2 and *3 polymorphisms on valproate-associated adverse drug reactions and plasma valproic acid levels in people with epilepsy. Methods: We recruited 158 people with epilepsy (79 cases and 79 controls) from an epilepsy clinic. Steady-state plasma valproic acid levels were measured using liquid chromatography-mass spectrometry and genotyping of CYP2C9 variants was carried out with helps of RT-PCR. Results: The presence of a mutant heterozygous genotype showed an odds ratio (OR) of 2.82 (95% CI: 1.10-7.24) and the adjusted OR was 5.39 (95% CI: 1.69-17.16). There was no significant difference in steady-state plasma valproate concentration between genotypes. Conclusion: The presence of a mutant heterozygous CYP2C9 genotype possesses five-times the risk of developing adverse drug reactions to valproate in people with epilepsy.

PMID:37811569 | DOI:10.2217/pme-2023-0033

Nat Commun. 2023 Oct 9;14(1):6243. doi: 10.1038/s41467-023-41893-4.

ABSTRACT

G protein-coupled receptors are important drug targets that engage and activate signaling transducers in multiple cellular compartments. Delineating therapeutic signaling from signaling associated with adverse events is an important step towards rational drug design. The glucagon-like peptide-1 receptor (GLP-1R) is a validated target for the treatment of diabetes and obesity, but drugs that target this receptor are a frequent cause of adverse events. Using recently developed biosensors, we explored the ability of GLP-1R to activate 15 pathways in 4 cellular compartments and demonstrate that modifications aimed at improving the therapeutic potential of GLP-1R agonists greatly influence compound efficacy, potency, and safety in a pathway- and compartment-selective manner. These findings, together with comparative structure analysis, time-lapse microscopy, and phosphoproteomics, reveal unique signaling signatures for GLP-1R agonists at the level of receptor conformation, functional selectivity, and location bias, thus associating signaling neighborhoods with functionally distinct cellular outcomes and clinical consequences.

PMID:37813859 | PMC:PMC10562414 | DOI:10.1038/s41467-023-41893-4

J Patient Rep Outcomes. 2023 Oct 9;7(1):99. doi: 10.1186/s41687-023-00640-5.

ABSTRACT

BACKGROUND: Patient-reported outcomes (PROs) are getting widely implemented, but little is known of the impact of applying PROs in specific cancer diagnoses. We report the results of a randomized controlled trial (RCT) of the active use of PROs in patients with locally advanced or metastatic bladder cancer (BC) undergoing medical oncological treatment (MOT) with focus on determining the clinical effects of using PROs during chemo- or immunotherapy compared to standard of care.

METHODS: We recruited patients from four departments of oncology from 2019 to 2021. Inclusion criteria were locally advanced or metastatic BC, initiating chemo- or immunotherapy. Patients were randomized 1:1 between answering selected PRO-CTCAE questions electronically once weekly with a built-in alert-algorithm instructing patients of how to handle reported symptoms as a supplement to standard of care for handling of side effects (intervention arm (IA)) vs standard procedure for handling of side effects (control arm (CA)). No real-time alerts were sent to the clinic when PROs exceeded threshold values. Clinicians were prompted to view the completed PROs in the IA at each clinical visit. The co-primary clinical endpoints were hospital admissions and treatment completion rate. Secondary endpoints were overall survival (OS), quality of life (EORTC's QLQ-C30 and QLQ-BLM30) and dose reductions.

RESULTS: 228 patients with BC were included, 76% were male. 141 (62%) of the patients had metastatic disease. 51% of patients in the IA completed treatment vs. 56% of patients in the CA, OR 0.83 (95% CI 0.47-1.44, p = 0.51). 41% of patients in the IA experienced hospitalization vs. 32% in the CA, OR 1.48 (95% CI 0.83-2.65, p = 0.17). OS was comparable between the two arms (IA: median 22.3mo (95% CI 17.0-NR) vs. CA: median 23.1mo (95% CI 17.7-NR). Patient and clinician compliance was high throughout the study period (80% vs 94%).

CONCLUSIONS: This RCT did not show an effect of PRO on completion of treatment, hospitalizations or OS for BC patients during MOT despite a high level of patient and clinician compliance. The lack of real-time response to alerts remains the greatest limitation to this study.

PMID:37812306 | DOI:10.1186/s41687-023-00640-5