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Frontiers in Immunology 2024Fostemsavir is a gp120-directed attachment inhibitor approved for heavily treatment-experienced (HTE) adults with multidrug-resistant HIV-1. We provide detailed week 240... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Fostemsavir is a gp120-directed attachment inhibitor approved for heavily treatment-experienced (HTE) adults with multidrug-resistant HIV-1. We provide detailed week 240 safety results from the BRIGHTE study and evaluate the impact of immune recovery on safety outcomes.
METHODS
The phase 3 BRIGHTE trial is ongoing; data for this analysis were collected from the first participant's first visit (February 23, 2015) through the last participant's last visit for week 240 (March 22, 2021). Safety endpoints were assessed in participants who received fostemsavir + optimized background therapy. In participants with baseline CD4+ T-cell count <200 cells/mm, exposure-adjusted adverse event (AE) rates were assessed among subgroups with or without CD4+ T-cell count ≥200 cells/mm at any time during 48-week analysis periods through week 192.
RESULTS
Through a median of 258 weeks (range, 0.14-319) of treatment, discontinuations due to AEs occurred in 30/371 (8%) participants. Serious AEs were reported in 177/371 (48%) participants, including 16 drug-related events in 13 (4%) participants. Thirty-five (9%) deaths occurred, primarily related to AIDS or acute infections. COVID-19-related events occurred in 25 (7%) participants; all resolved without sequelae. Among participants with baseline CD4+ T-cell count <200 cells/mm, 122/162 (75%) achieved CD4+ T-cell count ≥200 cells/mm at week 192. Exposure-adjusted AE rates were markedly lower among participants achieving CD4+ T-cell count ≥200 cells/mm at any time vs those sustaining <200 cells/mm. No new AIDS-defining events were reported after week 48 in participants with CD4+ T-cell count ≥200 cells/mm.
CONCLUSIONS
Cumulative safety findings through the BRIGHTE 240-week interim analysis are consistent with other trials in HTE participants with advanced HIV-1 and comorbid disease. Reduced rates of AIDS-defining events and AEs were observed in participants with immunologic recovery on fostemsavir-based treatment.
CLINICAL TRIAL NUMBER
NCT02362503, https://clinicaltrials.gov/study/NCT02362503.
Topics: Humans; Adult; HIV Infections; Female; Male; CD4 Lymphocyte Count; Middle Aged; HIV-1; Anti-HIV Agents; Organophosphates; COVID-19; SARS-CoV-2; Treatment Outcome; Viral Load; Piperazines
PubMed: 38863717
DOI: 10.3389/fimmu.2024.1394644 -
Physiological Reports Jun 2024Sildenafil, a phosphodiesterase-5 (PDE5) inhibitor, has been shown to improve insulin sensitivity in animal models and prediabetic patients. However, its other metabolic...
Sildenafil, a phosphodiesterase-5 (PDE5) inhibitor, has been shown to improve insulin sensitivity in animal models and prediabetic patients. However, its other metabolic effects remain poorly investigated. This study examines the impact of sildenafil on insulin secretion in MIN6-K8 mouse clonal β cells. Sildenafil amplified insulin secretion by enhancing Ca influx. These effects required other depolarizing stimuli in MIN6-K8 cells but not in K channel-deficient β cells, which were already depolarized, indicating that sildenafil-amplified insulin secretion is depolarization-dependent and K channel-independent. Interestingly, sildenafil-amplified insulin secretion was inhibited by pharmacological inhibition of R-type channels, but not of other types of voltage-dependent Ca channels (VDCCs). Furthermore, sildenafil-amplified insulin secretion was barely affected when its effect on cyclic GMP was inhibited by PDE5 knockdown. Thus, sildenafil stimulates insulin secretion and Ca influx through R-type VDCCs independently of the PDE5/cGMP pathway, a mechanism that differs from the known pharmacology of sildenafil and conventional insulin secretory pathways. Our results reposition sildenafil as an insulinotropic agent that can be used as a potential antidiabetic medicine and a tool to elucidate the novel mechanism of insulin secretion.
Topics: Sildenafil Citrate; Animals; Insulin-Secreting Cells; Mice; Insulin Secretion; Phosphodiesterase 5 Inhibitors; Calcium; Insulin; Cell Line
PubMed: 38862270
DOI: 10.14814/phy2.16091 -
PloS One 2024High viral load during pregnancy and breastfeeding period is the risk factor for vertical transmission of human immunodeficiency virus (HIV). Currently, Dolutegravir...
BACKGROUND
High viral load during pregnancy and breastfeeding period is the risk factor for vertical transmission of human immunodeficiency virus (HIV). Currently, Dolutegravir (DTG)-based regimens are recommended to attain adequate viral load suppression (VLS) among women. However, its effect on VLS has not been investigated among women in PMTCT care in Ethiopia.
OBJECTIVE
This study aimed to investigate the rate of viral load non-suppression among women exposed to DTG-based versus Efavirenz (EFV)-based regimens in Ethiopia.
METHODS
An uncontrolled before-and-after study design was conducted among 924 women (462 on EFV-based and 462 on DTG-based regimens) enrolled in PMTCT care from September 2015 to February 2023. The outcome variable was the viral load (VL) non-suppression among women on PMTCT care. A modified Poisson regression model was employed, and the proportion was computed to compare the rate of VL non-suppression in both groups. The risk ratio (RR) with a 95% confidence interval (CI) was calculated to assess viral load non-suppression among women on DTG-based and EFV-based regimens by adjusting for other variables.
RESULTS
The overall rate of non-suppressed VL was 16.2% (95% CI: 14.0-18.8%). Mothers on DTG-based regimens had approximately a 30% (adjusted risk ratio (aRR): 0.70; 95% CI: 0.52-0.94) lesser risk of developing non-suppressed VL than women on EFV-based regimens. Besides, older women were 1.38 times (aRR: 1.38; 95% CI: 1.04-1.83); mothers who did not disclose their HIV status to their partners were 2.54 times (aRR: 2.54; 95% CI: 1.91-3.38); and mothers who had poor or fair adherence to antiretroviral (ARV) drugs were 2.11 times (aRR: 2.11; 95% CI: 1.45-3.07) at higher risk of non-suppressed VL.
CONCLUSION
Women on DTG-based regimens had a significantly suppressed VL compared to those on EFV-based regimens. Thus, administering DTG-based first-line ART regimens should be strengthened to achieve global and national targets on VLS.
Topics: Humans; Female; Cyclopropanes; Alkynes; Benzoxazines; Viral Load; Ethiopia; Pyridones; Heterocyclic Compounds, 3-Ring; Adult; HIV Infections; Piperazines; Pregnancy; Oxazines; Infectious Disease Transmission, Vertical; Young Adult; Anti-HIV Agents; Adolescent; Pregnancy Complications, Infectious
PubMed: 38857273
DOI: 10.1371/journal.pone.0305331 -
Journal of Physiological Investigation May 2024A recent study investigated the correlation between telmisartan (TEL) exposure and Alzheimer's disease (AD) risk among African Americans (AAs) and European Americans....
Perturbations of Telmisartan Alone and in Combination with Ranolazineor Dapagliflozin on the Amplitude and Gating of Voltage-gated Na + Current in Neuroblastoma Neuronal Cells.
A recent study investigated the correlation between telmisartan (TEL) exposure and Alzheimer's disease (AD) risk among African Americans (AAs) and European Americans. Their findings indicated that moderate-to-high TEL exposure was linked to a decreased incidence of AD among AAs. These results suggest a potential association between TEL and a reduced risk of AD specifically within the AA population. Here, we investigated the effects of TEL, either alone or in combination with ranolazine (Ran) or dapagliflozin (Dapa), on voltage-gated Na + currents ( INa ) in Neuro-2a cells. TEL, primarily used for treating hypertension and cardiovascular disorders, showed a stimulatory effect on INa , while Ran and Dapa reversed this stimulation. In Neuro-2a cells, we demonstrated that with exposure to TEL, the transient ( INa(T) ) and late ( INa(L) ) components of INa were differentially stimulated with effective EC 50 's of 16.9 and 3.1 μM, respectively. The research implies that TEL's impact on INa might be associated with enhanced neuronal excitability. This study highlights the complex interplay between TEL, Ran, and Dapa on INa and their potential implications for AD, emphasizing the need for further investigation to understand the mechanisms involved.
Topics: Telmisartan; Glucosides; Benzimidazoles; Ranolazine; Benzoates; Neuroblastoma; Cell Line, Tumor; Animals; Acetanilides; Piperazines; Mice; Benzhydryl Compounds; Neurons; Ion Channel Gating
PubMed: 38857206
DOI: 10.4103/ejpi.EJPI-D-24-00018 -
BMC Cancer Jun 2024Poly (ADP- ribose) polymerase inhibitors (PARPi) has been increasingly adopted for metastatic castration-resistance prostate cancer (mCRPC) patients with homologous... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Poly (ADP- ribose) polymerase inhibitors (PARPi) has been increasingly adopted for metastatic castration-resistance prostate cancer (mCRPC) patients with homologous recombination repair deficiency (HRD). However, it is unclear which PARPi is optimal in mCRPC patients with HRD in 2nd -line setting.
METHOD
We conducted a systematic review of trials regarding PARPi- based therapies on mCRPC in 2nd -line setting and performed a Bayesian network meta-analysis (NMA). Radiographic progression-free survival (rPFS) was assessed as primary outcome. PSA response and adverse events (AEs) were evaluated as secondary outcomes. Subgroup analyses were performed according to specific genetic mutation.
RESULTS
Four RCTs comprised of 1024 patients (763 harbored homologous recombination repair (HRR) mutations) were identified for quantitative analysis. Regarding rPFS, olaparib monotherapy, rucaparib and cediranib plus olaparib showed significant improvement compared with ARAT. Olaparib plus cediranib had the highest surface under cumulative ranking curve (SUCRA) scores (87.5%) for rPFS, followed by rucaparib, olaparib and olaparib plus abiraterone acetate prednisone. For patients with BRCA 1/2 mutations, olaparib associated with the highest probability (98.1%) of improved rPFS. For patients with BRCA-2 mutations, olaparib and olaparib plus cediranib had similar efficacy. However, neither olaparib nor rucaparib showed significant superior effectiveness to androgen receptor-axis-targeted therapy (ARAT) in patients with ATM mutations. For safety, olaparib showed significantly lower ≥ 3 AE rate compared with cediranib plus olaparib (RR: 0.72, 95% CI: 0.51, 0.97), while olaparib plus cediranib was associated with the highest risk of all-grade AE.
CONCLUSION
PARPi-based therapy showed considerable efficacy for mCRPC patients with HRD in 2nd -line setting. However, patients should be treated accordingly based on their genetic background as well as the efficacy and safety of the selected regimen.
TRIAL REGISTRATION
CRD42023454079.
Topics: Humans; Poly(ADP-ribose) Polymerase Inhibitors; Bayes Theorem; Prostatic Neoplasms, Castration-Resistant; Mutation; Male; Phthalazines; Network Meta-Analysis; Piperazines; BRCA2 Protein; Recombinational DNA Repair; Antineoplastic Combined Chemotherapy Protocols; Randomized Controlled Trials as Topic; Progression-Free Survival; Indoles; BRCA1 Protein; Treatment Outcome; Quinazolines
PubMed: 38851712
DOI: 10.1186/s12885-024-12388-2 -
The Brazilian Journal of Infectious... 2024We report an autochthonous case of mild unifocal chronic pulmonary paracoccidioidomycosis in a 48-year-old previously healthy woman with no history of possible...
We report an autochthonous case of mild unifocal chronic pulmonary paracoccidioidomycosis in a 48-year-old previously healthy woman with no history of possible environmental exposures in endemic rural areas, supposedly resulting from reactivation of a latent pulmonary focus secondary to the use of methotrexate for the control of Chikungunya arthropathy. Laboratory investigation ruled out other immunosuppression. Her only symptoms were a dry cough and chest pain. Diagnosis confirmed by needle lung biopsy. There were no abnormalities on physical examination nor evidence of central nervous system involvement. MRI of the total abdomen showed no involvement of other organs. Computed chest tomography showed a favorable evolution under the use of itraconazole (200 mg/day). Different tomographic presentations findings are highlighted when performed before and after treatment. CONCLUSIONS: PCM should be considered even in a woman without a history of consistent environmental exposure and in a non-endemic geographic area.
Topics: Humans; Female; Paracoccidioidomycosis; Middle Aged; Methotrexate; Lung Diseases, Fungal; Chronic Disease; Itraconazole; Tomography, X-Ray Computed; Antifungal Agents; Immunosuppressive Agents
PubMed: 38851212
DOI: 10.1016/j.bjid.2024.103768 -
Cephalalgia : An International Journal... Jun 2024The cAMP and cGMP pathways are implicated in the initiation of migraine attacks, but their interactions remain unclear. Calcitonin gene-related peptide (CGRP) triggers... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The cAMP and cGMP pathways are implicated in the initiation of migraine attacks, but their interactions remain unclear. Calcitonin gene-related peptide (CGRP) triggers migraine attacks via cAMP, whereas the phosphodiesterase-5 inhibitor sildenafil induces migraine attacks via cGMP. Our objective was to investigate whether sildenafil could induce migraine attacks in individuals with migraine pre-treated with the CGRP-receptor antibody erenumab.
METHODS
In this randomized, double-blind, placebo-controlled, cross-over study, adults with migraine without aura received a single subcutaneous injection of 140 mg erenumab on day 1. They were then randomized to receive sildenafil 100 mg or placebo on two experimental days, each separated by at least one week, between days 8 and 21. The primary endpoint was the difference in the incidence of migraine attacks between sildenafil and placebo during the 12-h observation period after administration.
RESULTS
In total, 16 participants completed the study. Ten participants (63%) experienced a migraine attack within 12 h after sildenafil administration compared to three (19%) after placebo ( = 0.016). The median headache intensity was higher after sildenafil than after placebo (area under the curve (AUC) for the 12-h observation period, = 0.026). Furthermore, sildenafil induced a significant decrease in mean arterial blood pressure (AUC, = 0.026) and a simultaneous increase in heart rate (AUC, < 0.001) during the first hour after administration compared to placebo.
CONCLUSION
These findings provide evidence that migraine induction via the cGMP pathway can occur even under CGRP receptor blockade.
TRIAL REGISTRATION
ClinicalTrials.gov: Identifier NCT05889455.
Topics: Humans; Adult; Male; Double-Blind Method; Female; Sildenafil Citrate; Cross-Over Studies; Receptors, Calcitonin Gene-Related Peptide; Migraine Disorders; Middle Aged; Cyclic GMP; Antibodies, Monoclonal, Humanized; Calcitonin Gene-Related Peptide Receptor Antagonists; Phosphodiesterase 5 Inhibitors; Young Adult
PubMed: 38850034
DOI: 10.1177/03331024241259489 -
Breast Cancer Research : BCR Jun 2024Breast cancers treated with aromatase inhibitors (AIs) can develop AI resistance, which is often driven by estrogen receptor-alpha (ERα/ESR1) activating mutations, as...
BACKGROUND
Breast cancers treated with aromatase inhibitors (AIs) can develop AI resistance, which is often driven by estrogen receptor-alpha (ERα/ESR1) activating mutations, as well as by ER-independent signaling pathways. The breast ER antagonist lasofoxifene, alone or combined with palbociclib, elicited antitumor activities in a xenograft model of ER + metastatic breast cancer (mBC) harboring ESR1 mutations. The current study investigated the activity of LAS in a letrozole-resistant breast tumor model that does not have ESR1 mutations.
METHODS
Letrozole-resistant, MCF7 LTLT cells tagged with luciferase-GFP were injected into the mammary duct inguinal glands of NSG mice (MIND model; 6 mice/group). Mice were randomized to vehicle, lasofoxifene ± palbociclib, fulvestrant ± palbociclib, or palbociclib alone 2-3 weeks after cell injections. Tumor growth and metastases were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis. The experiment was repeated with the same design and 8-9 mice in each treatment group.
RESULTS
Western blot analysis showed that the MCF7 LTLT cells had lower ERα and higher HER2 expressions compared with normal MCF7 cells. Lasofoxifene ± palbociclib, but not fulvestrant, significantly reduced primary tumor growth versus vehicle as assessed by in vivo imaging of tumors at study ends. Percent tumor area in excised mammary glands was significantly lower for lasofoxifene plus palbociclib versus vehicle. Ki67 staining showed decreased overall tumor cell proliferation with lasofoxifene ± palbociclib. The lasofoxifene + palbociclib combination was also associated with significantly fewer bone metastases compared with vehicle. Similar results were observed in the repeat experiment.
CONCLUSIONS
In a mouse model of letrozole-resistant breast cancer with no ESR1 mutations, reduced levels of ERα, and overexpression of HER2, lasofoxifene alone or combined with palbociclib inhibited primary tumor growth more effectively than fulvestrant. Lasofoxifene plus palbociclib also reduced bone metastases. These results suggest that lasofoxifene alone or combined with a CDK4/6 inhibitor may offer benefits to patients who have ER-low and HER2-positive, AI-resistant breast cancer, independent of ESR1 mutations.
Topics: Animals; Female; Humans; Mice; Aromatase Inhibitors; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Resistance, Neoplasm; Estrogen Receptor alpha; Fulvestrant; Letrozole; MCF-7 Cells; Piperazines; Pyridines; Pyrrolidines; Tetrahydronaphthalenes; Xenograft Model Antitumor Assays
PubMed: 38849889
DOI: 10.1186/s13058-024-01843-4 -
BMC Infectious Diseases Jun 2024The effectiveness of post-exposure prophylaxis (PEP) depends on participants adherence, making it crucial to assess and compare regimen options to enhance human...
BACKGROUND
The effectiveness of post-exposure prophylaxis (PEP) depends on participants adherence, making it crucial to assess and compare regimen options to enhance human immunodeficiency virus (HIV) prophylaxis strategies. However, no prospective study in China has shown that the completion rate and adherence of single-tablet regimens in HIV PEP are higher than those of multi-tablet preparations. Therefore, this study aimed to assess the completion rate and adherence of two HIV PEP regimens.
METHODS
In this single-center, prospective, open-label cohort study, we included 179 participants from May 2022 to March 2023 and analyzed the differences in the 28-day medication completion rate, adherence, safety, tolerance, and effectiveness of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and tenofovir disoproxil fumarate, emtricitabine, and dolutegravir (TDF/FTC + DTG).
RESULTS
The PEP completion rate and adherence were higher in the BIC/FTC/TAF group than in the TDF/FTC + DTG group (completion rate: 97.8% vs. 82.6%, P = 0.009; adherence: 99.6 ± 2.82% vs. 90.2 ± 25.29%, P = 0.003). The incidence of adverse reactions in the BIC/FTC/TAF and TDF/FTC + DTG groups was 15.2% and 10.3% (P = 0.33), respectively. In the TDF/FTC + DTG group, one participant stopped PEP owing to adverse reactions (1.1%). No other participants stopped PEP due to adverse events.
CONCLUSIONS
BIC/FTC/TAF and TDF/FTC + DTG have good safety and tolerance as PEP regimens. BIC/FTC/TAF has a higher completion rate and increased adherence, thus, is recommended as a PEP regimen. These findings emphasize the importance of regimen choice in optimizing PEP outcomes.
TRIAL REGISTRATION
The study was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2200059994(2022-05-14), https://www.chictr.org.cn/bin/project/edit?pid=167391 ).
Topics: Humans; HIV Infections; Prospective Studies; Male; Emtricitabine; Tenofovir; China; Adult; Female; Anti-HIV Agents; Pyridones; Amides; Heterocyclic Compounds, 3-Ring; Middle Aged; Post-Exposure Prophylaxis; Drug Combinations; Medication Adherence; Heterocyclic Compounds, 4 or More Rings; Alanine; Adenine; Young Adult; Piperazines
PubMed: 38844855
DOI: 10.1186/s12879-024-09407-9 -
Food Microbiology Sep 2024Penicillium spp. produce a great variety of secondary metabolites, including several mycotoxins, on food substrates. Chestnuts represent a favorable substrate for...
Penicillium spp. produce a great variety of secondary metabolites, including several mycotoxins, on food substrates. Chestnuts represent a favorable substrate for Penicillium spp. development. In this study, the genomes of ten Penicillium species, virulent on chestnuts, were sequenced and annotated: P. bialowiezense. P. pancosmium, P. manginii, P. discolor, P. crustosum, P. palitans, P. viridicatum, P. glandicola, P. taurinense and P. terrarumae. Assembly size ranges from 27.5 to 36.8 Mb and the number of encoded genes ranges from 9,867 to 12,520. The total number of predicted biosynthetic gene clusters (BGCs) in the ten species is 551. The most represented families of BGCs are non ribosomal peptide synthase (191) and polyketide synthase (175), followed by terpene synthases (87). Genome-wide collections of gene phylogenies (phylomes) were reconstructed for each of the newly sequenced Penicillium species allowing for the prediction of orthologous relationships among our species, as well as other 20 annotated Penicillium species available in the public domain. We investigated in silico the presence of BGCs for 10 secondary metabolites, including 5 mycotoxins, whose production was validated in vivo through chemical analyses. Among the clusters present in this set of species we found andrastin A and its related cluster atlantinone A, mycophenolic acid, patulin, penitrem A and the cluster responsible for the synthesis of roquefortine C/glandicoline A/glandicoline B/meleagrin. We confirmed the presence of these clusters in several of the Penicillium species conforming our dataset and verified their capacity to synthesize them in a chestnut-based medium with chemical analysis. Interestingly, we identified mycotoxin clusters in some species for the first time, such as the andrastin A cluster in P. flavigenum and P. taurinense, and the roquefortine C cluster in P. nalgiovense and P. taurinense. Chestnuts proved to be an optimal substrate for species of Penicillium with different mycotoxigenic potential, opening the door to risks related to the occurrence of multiple mycotoxins in the same food matrix.
Topics: Penicillium; Mycotoxins; Multigene Family; Secondary Metabolism; Genome, Fungal; Phylogeny; Food Contamination; Patulin; Fungal Proteins; Nuts; Polyketide Synthases; Food Microbiology; Corylus; Heterocyclic Compounds, 4 or More Rings; Indoles; Piperazines
PubMed: 38839238
DOI: 10.1016/j.fm.2024.104532