Background: Memantine, an uncompetitive and voltage-dependent N-methyl-D-aspartate (NMDA) receptor antagonist, is clinically established for moderate-to-severe Alzheimer's disease. Its pharmacodynamic profile, low-to-moderate affinity, rapid open-channel block, and strong voltage dependency allows selective inhibition of pathological NMDA overactivation while preserving physiological neurotransmission. Increasing evidence shows that these same mechanistic principles operate in the peripheral nervous system, where NMDA receptors contribute to excitotoxicity, oxidative stress, neuroinflammation, and maladaptive nociceptive signaling. Purpose: To synthesize emerging preclinical and clinical evidence demonstrating memantine's modulatory and neuroprotective actions in peripheral neurons and glia and to outline implications for drug repurposing across neurology, pain medicine, oncology, supportive care, and ophthalmology. Methodology: A narrative integration of mechanistic studies, in vivo preclinical models, and heterogeneous clinical trials evaluating memantine's effects on peripheral sensory neurons, autonomic neurons, Schwann cells, retinal ganglion cells, and neuromuscular junction physiology. Evidence was examined across conditions involving excitotoxicity, oxidative injury, mitochondrial dysfunction, apoptotic signaling, neuroinflammation, and neuropathic pain amplification. Results: Memantine consistently attenuates peripheral excitotoxic calcium influx, suppresses NOX-2-mediated ROS generation, stabilizes mitochondrial membrane potential, modulates Bax/Bcl-2 signaling, and reduces neuroinflammatory cytokine activity. It also inhibits dorsal horn wind-up selectively under neuropathic conditions. These convergent mechanisms yield protective effects across chemotherapy-induced peripheral neuropathy (CIPN), diabetic neuropathy, traumatic nerve injury, phantom limb pain, retinal ganglion cell excitotoxicity, and organophosphate-induced neuromuscular toxicity. Clinical evidence includes improved multimodal neuropathy outcomes in diabetic neuropathy when combined with gabapentin, reduced phantom limb pain prevalence and intensity at six months, and a five-fold reduction in post-mastectomy neuropathic pain with pre-emptive administration. Conclusions: Memantine should be conceptually reframed as a system-wide neuroprotective agent with substantial translational potential beyond the CNS. Priorities for future development include NR2B-selective peripheral NMDA antagonists, peripherally restricted formulations, single-cell transcriptomic mapping of peripheral NMDA receptor subtypes, and adequately powered PNS-specific randomized trials.
The amide functional group remains a cornerstone of medicinal chemistry, serving as an indispensable scaffold in the design of modern therapeutics. This review presents an analysis of FDA-approved drugs (small molecules and peptides with MW < 1300 Da) containing amide functionality between 2021 and 2025, highlighting its continued and evolving role in addressing contemporary medical challenges. An analysis of these novel therapeutics reveals the remarkable functional versatility of the amide bond. In antiviral agents like nirmatrelvir (Paxlovid®), amides form the structural backbone of peptidomimetics, enabling high-affinity binding to a viral protease. In precision oncology, as seen with adagrasib (Krazati®), the amide acts as a critical, metabolically stable linker that positions a covalent warhead for selective inhibition of a mutant kinase. This analysis underscores that amide's unique combination of planarity, resonance stabilization, and capacity for robust hydrogen bonding continues to make it an essential element in the medicinal chemist's toolkit, underpinning the development of next-generation therapeutics across oncology, infectious diseases, and neurology. To provide a practical framework for drug discovery, the synthetic routes for each drug are detailed, with particular emphasis placed on the key amide-forming strategies employed.
Background: Obesity is a chronic, relapsing disease that often proves resistant to lifestyle measures alone. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), are reshaping treatment, yet prospective real-world data remain limited. Objective: To prospectively assess the effects of once-weekly Semaglutide on weight, body composition, and metabolic health in obesity. Methods: An exploratory observational study of 37 patients initiating Semaglutide (mean age 31 years; 11 children and adolescents; 22 females) was conducted. All met obesity criteria (baseline BMI 34.7 kg/m2). Anthropometry, bioimpedance body composition, and fasting biochemistry were obtained at baseline and 3 months. Variables were reported as mean ± SD or median (IQR) according to normal/non-normal distribution, whether a parametric test or a Wilcoxon one was used. Parametric or non-parametric paired tests (two-sided α = 0.05) were applied. We also explored tri-ponderal mass index (TMI, kg/m3) and its correlations with metabolic markers. Results: At 3 months, body weight decreased by a median 8.0 kg (p < 0.001), BMI by 1.6 kg/m2 (p < 0.001). Body fat percentage declined: 43.4% to 42.8% (p = 0.009), with a small reduction in skeletal muscle mass (-0.6 kg; p = 0.035). Fasting glucose improved (p = 0.030) and HOMA-IR fell significantly. HbA1c changes were minimal, consistent with near-normal baseline values. Triglycerides decreased, while total cholesterol, LDL-C, HDL-C, liver enzymes, creatinine, uric acid, and 25-OH vitamin D remained stable. Baseline TMI (median 20.13 kg/m3; IQR 3.80) correlated strongly with HOMA-IR (r = 0.766, p < 0.001) and moderately-to-strongly with body fat percentage (r = 0.621, p < 0.001). Conclusions: In this real-world cohort, Semaglutide produced rapid, clinically meaningful improvements in weight, adiposity, and insulin resistance within 3 months. Findings suggest that Semaglutide may represent a promising adjunct to lifestyle therapy in obesity management.
Methicillin-resistant Staphylococcus aureus (MRSA) remains a major cause of serious infection and is associated with substantial morbidity and mortality. Clinical presentations range from localized disease to severe, life-threatening infections, including bacteremia and sepsis with metastatic complications such as infective endocarditis and osteoarticular involvement. MRSA bacteremia carries a high risk of dissemination and death, underscoring the importance of early recognition and effective management. Optimal treatment requires timely initiation of appropriate antimicrobial therapy in conjunction with source control when indicated. Despite advancements in treatment, persistent MRSA bacteremia continues to pose significant clinical challenges. Given the complexity of these infections, a clear understanding of current treatment strategies is essential for clinicians. In this narrative review, we summarize contemporary guideline-based approaches to the management of MRSA bacteremia, highlight key pharmacologic considerations of available antimicrobial agents, and discuss knowledge gaps and recent developments in both established and emerging therapies aimed at improving outcomes in these challenging infections.
Background: Debate continues to swirl around the effectiveness of novel nicotine-delivery products such as snus and e-cigarettes as tobacco cessation aids. The purpose of this review is to quantify the state of research on modern products, including e-products, and established or developing pharmaceuticals on assisting nicotine users in achieving cessation. Methods: This study relied on a comprehensive assessment of research articles, clinical trials, drug approvals, and textbook material available via PubMed, Ovid Wolters Kluwer, and Wiley. We utilized Python 3.14.2, Anaconda3, the ShinyWeb App, and Py.Litstudy to investigate the selected literature. Our key study elements are product evolution and cessation behavior associated with e-cigarettes, snus, nicotine gum, nicotine dermal patches, bupropion, varenicline, and cytisine. Results: This manuscript assessed 144 manuscripts published between 1952 and 2025. E-cigarettes and snus, while containing some limited cessation benefit, were not identified to be effective enough at attaining cessation (when used exclusively) to be prescribed as cessation tools. Cytisine was identified as having very similar cessation outcomes to established pharmaceuticals such as varenicline. Conclusions: Since their iteration, e-cigarettes and snus products were marketed as cessation aids. This review found that there is scant evidence to support that modern snus and e-cigarette products work as cessation aids when used in exclusion of other more traditional approaches to cessative aid. Additionally, more modern pharmaceuticals such as cytisine may have benefit as solo cessation tools over novel nicotine-delivery products.
Background/Objective: Ultraviolet A and B (UVAB) radiation is a major environmental factor that induces DNA damage and upregulates programmed death-ligand 1 (PD-L1) expression in skin cells, thereby contributing to immune evasion and impaired tissue repair. This study evaluated the protective effects of two purified compounds, Cinnamtannin B1 (CTB-1) and Cinnamtannin D1 (CTD-1), as well as cinnamon extract, in UVAB-irradiated human keratinocyte HaCaT cells. Methods: HaCaT cells were exposed to low (20 kJ/m2 UVA, 1.3 kJ/m2 UVB), medium (30 kJ/m2 UVA, 2 kJ/m2 UVB), and high (40 kJ/m2 UVA, 2.7 kJ/m2 UVB) UVAB doses of UVAB radiation. Dose-dependent effects of CTB-1 and CTD-1 (0, 5, 10, 25, and 50 µg/ mL) and cinnamon extract (0, 5, 10, 50, and 100 µg/mL), as well as time-dependent effects (12, 24, and 72 h), were evaluated by measuring PD-L1 expression, cell viability, and DNA damage. Results: CTD-1 was the most effective compound, significantly reducing UVAB-induced PD-L1 expression and DNA double-strand breaks without compromising cell viability. CTB-1 also demonstrated protective effects at specific doses and time points; however, higher concentrations reduced cell viability. Cinnamon extract was protective at low concentrations but cytotoxic at higher doses. Conclusions: CTD-1, CTB-1, and cinnamon extract attenuated UVAB-induced cellular damage in HaCaT cells, with CTD-1 demonstrating the most favorable protective profile. These findings support the potential of cinnamon-derived compounds as therapeutic candidates for preventing UVAB-induced skin damage and immune dysregulation.
Background/Objectives: Postoperative pain remains a significant clinical challenge, often requiring multimodal strategies to mitigate opioid-related adverse events. The fixed-dose combination (FDC) of Diclofenac, a non-steroidal anti-inflammatory drug, and Orphenadrine, a muscle relaxant, targets distinct nociceptive pathways to potentially enhance analgesia and reduce opioid consumption. This systematic review aims to evaluate the analgesic efficacy and safety profile of the fixed-dose combination of Diclofenac and Orphenadrine for postoperative pain management and quantify its opioid-sparing effect compared to standard monotherapies or placebo. Methods: A systematic search of electronic databases (MEDLINE, Scopus) and clinical trial registries (including ClinicalTrials.gov and CTIS) was conducted up to 20 September 2025. Fourteen (14) randomized controlled trials (RCTs) involving 981 adult patients undergoing various surgical procedures were included. Due to high clinical and methodological heterogeneity, a Synthesis Without Meta-analysis (SWiM) approach was utilized. The certainty of evidence was assessed using the GRADE methodology. Results: The synthesis demonstrated that the FDC may improve pain relief (measured by the Visual Analog Scale and Numeric Rating Scale scores) and may reduce opioid consumption compared to active comparators and placebo. The opioid-sparing effect could be correlated with a reduced incidence of dose-dependent adverse events, particularly nausea and vomiting. However, the overall certainty of the evidence was graded as “Very Low” due to the high risk of bias and lack of transparency in the included studies. Conclusions: The FDC of Diclofenac and Orphenadrine is a rational addition to multimodal postoperative analgesic regimens, which may potentially reduce the perioperative opioid burden without compromising pain control. Nevertheless, because almost all included studies suffer from severe methodological flaws, these apparent efficacy findings must be interpreted with caution. Future high-quality, pre-registered, and low-bias randomized controlled trials are required to draw firm clinical conclusions.
Sulforaphane, a bioactive isothiocyanate found abundantly in cruciferous vegetables, has attracted significant attention for its chemopreventive and therapeutic potential, particularly in cancer. There is now an abundance of peer-reviewed research documenting true synergies between sulforaphane and (a) cancer treatment drugs, (b) pharmaceuticals in development but not yet on the market or in the regulatory pipeline, (c) other phytochemicals, and (d) proprietary mixtures such as leaf extracts and other botanicals, as well as evidence that some cell lines resistant to various cancer drugs become more susceptible when treated with sulforaphane. Most of the published studies demonstrate evidence for synergy in cancer, including cancers of the bladder, blood, brain, breast, colon, esophagus, liver, lung, ovaries, prostate, and skin, where reducing drug dosages could yield substantial patient benefits. Importantly, non-cancer indications have also been reported, such as mitigation of cardiac toxicity, inflammation, obesity, and pain (including antihyperalgesic and antinociceptive effects). Synergistic effects are most often demonstrated in cell line models, with many studies providing robust mechanistic evidence, and some employing the gold-standard Chou–Talalay method for quantifying synergy. Current evidence on the synergistic interactions of sulforaphane with both phytochemicals and pharmaceuticals highlights underlying mechanisms such as modulation of oxidative stress, inflammation, apoptosis, and epigenetic regulation, suggesting significant clinical and therapeutic implications. By providing a comprehensive overview of sulforaphane synergies in both cancer and non-cancer contexts, we aim to inform future research and support the development of integrated therapeutic strategies.
Background: Incorporating sex as a biological variable (SBV) is recognized as essential for improving the reliability, reproducibility, and generalizability of pharmacological research. This principle is codified in international policies and guidelines, yet implementation remains uneven, especially in phytomedicine. Phytomedicines are a major component of healthcare worldwide, with 65% of the global population relying on them in both regulated and traditional contexts. Globally, phytomedicines are used by males, females, intersex and non-cis gender persons, all of whom may present specific safety and efficacy considerations and warrant full inclusion in pre-clinical to clinical research pipelines. However, in contemporary settings, phytomedicine lags in SBV best practices relative to Western allopathic standards for research design. Methods: We conducted a non-systematic review and in silico data mining to quantify sex/gender representation in recent preclinical and clinical phytomedicine studies, complemented by targeted case studies of sexually dimorphic safety/efficacy. We also summarize the historical role of women and gender-diverse people as users and providers within Traditional and Integrative Medical Systems (TIMSs). Results: Across rodent and human studies, females are under-represented relative to males, and sex is rarely reported for cell lines. Intentional inclusion of intersex and other gender-diverse populations is largely absent. Case studies illustrate plausible sex-associated differences in pharmacokinetics, pharmacodynamics, and adverse event profiles. TIMSs historically address women’s health needs and include substantial participation by female practitioners; however, contemporary SBV practices remain less standardized than in Western allopathic pipelines. Conclusions: SBV integration in phytomedicine is needed to strengthen safety, efficacy, and regulatory-grade evidence. Practical barriers include legacy datasets without sex metadata, limited intersex animal models, and uneven resources across settings. We outline feasible, stepwise practices to improve SBV adoption in a manner compatible with TIMS contexts and recommend expanding current guidelines to better support diverse research environments while maintaining scientific rigor.
Background/Objectives: A possible pharmacokinetic interaction between a single dose of aripiprazole and multiple-dose pretreatment with oxcarbazepine was investigated in vivo in Wistar albino rats. Methods: The experiment was conducted on two groups of 12 male rats each. The control group received a single oral dose of aripiprazole (8 mg/kg), while the test group was given oral oxcarbazepine (85 mg/kg/day) for 5 days, followed by a single oral dose of aripiprazole (8 mg/kg). Blood samples were automatically drawn following the administration of aripiprazole to each rat. Noncompartmental analysis was employed to determine the pharmacokinetic parameters of aripiprazole and its active metabolite, dehydroaripiprazole. Results: After the five-day oxcarbazepine pretreatment, aripiprazole’s maximum plasma concentration decreased by 51.37%, and its mean half-life was significantly reduced by 1.51-fold. In contrast, for the metabolite, the mean total area under the concentration–time curve increased by 44.66%, and the mean apparent systemic clearance decreased by 61.84%. Conclusions: Multiple-dose pretreatment with oxcarbazepine resulted in significant changes in the pharmacokinetics of a single oral dose of aripiprazole and its active metabolite in vivo in rats. The clinical implications should be further studied in human subjects, as this interaction may reduce the efficacy of aripiprazole.
Background/Objectives: Anticholinergic burden is an important risk marker in older adults, associated with cognitive decline, falls, and increased mortality. This study aimed to assess anticholinergic burden in institutionalized elderly individuals using two tools (ACB calculator and CALS—CRIDECO Anticholinergic Load Scale), as well as to analyze its relationship with pharmacotherapeutic variables like polypharmacy. Methods: A descriptive cross-sectional study was conducted by analyzing the pharmacotherapeutic profiles of institutionalized elderly individuals (≥65 years) utilizing individualized medication preparation services from a community pharmacy in Alentejo (Portugal). Participants agreed to the study and had complete, up-to-date pharmacotherapeutic profiles. Results: The pharmacotherapeutic profiles of 75 institutionalized elderly people were analyzed; the sample comprised mostly women (72%) who had experienced excessive polypharmacy (≥10 medications) (56%) and had an average age of 85.62 ± 7.62 years. It was found that 90.7% (ACB) and 89.3% (CALS—CRIDECO) of the elderly had anticholinergic burden, with mean values of 3.60 ± 2.84 and 3.33 ± 2.51, respectively. Women exhibited higher anticholinergic burden in unadjusted analyses (p < 0.05). The burden correlated moderately with the total number of medications (p < 0.05). Conclusions: The results show high exposure to anticholinergic medications in the institutionalized elderly population, reinforcing the rationale for systematic therapeutic reviews focused on the pharmacological safety of institutionalized older adults in community pharmacies.
Background/Objectives: Many products that claim to have anti-aging effects have been reported, but their relative potency is not clear. In this study, the in vitro replicative lifespan extension (RLE) activity of various groups of physiologically active substances was compared by using the updated “overlay method”. Methods: Human dermal and periodontal ligament fibroblasts (HDFa, HPLF) were inoculated into the inner 60 wells of 96-well microplate, surround by sterile water to prevent the water evaporation. At Day 1 and Day 8, the cells were overlayed with wide ranges of concentrations (0.01–100 µM) of samples without medium change. Viable cell number was measured by the MTT method at Day 15 and then corrected for the variation in cell growth due to the location of inoculated cells. The RLE value was calculated as the maximum cell proliferation rate relative to the control. Results: Cell density of HDFa and HPLFs at subculture decreased with the passage number, and their growth was stopped at 56 or 85 population doubling levels (PDLs), respectively. Hydrocortisone showed the highest RLE values among six hormones, followed by three plant extracts, sodium ascorbate and quercetin. On the other hand, other antioxidants, chlorogenic acid, phenylpropanoids, vanilloids, and bacterial products showed little or no RLE effects. However, for HPLF cells, hydrocortisone did not show RLE effects while oxytocin showed slight stimulation. Conclusions: When differences in proliferation due to cell seeding position were corrected, the biphasic dose response curve of most of the compounds significantly reduced. The present study suggests the significant role of hormones for the regulation of the long-term aging process. To confirm systemic or clinical anti-aging effects, further in vitro and in vivo experiments are needed.
Cadmium (Cd) is an environmental toxicant originating from both natural processes and human activities. Cd has been strongly associated with multiple diseases, including breast cancer (BC). Background/Objective: Environmental Cd exposure represents a significant contributor to BC onset and progression. Cd-induced breast carcinogenesis is driven by a constellation of molecular events, including DNA damage, oxidative stress (OS), and the dysregulation of key signaling pathways. These include the ERK/JNK/p38 MAPK cascade, the PI3K/AKT/mTOR axis, NF κB activation, and Wnt signaling, all of which collectively promote tumor initiation, survival, and metastasis. This review underscores the complex interplay between Cd exposure and its effects on cancer-triggering factors. Methods: The complexity of the mechanisms Cd-induced BC, underlying Cd-induced BC makes it challenging to treat, highlighting the need for novel therapeutic strategies that complement or enhance conventional chemotherapy. Therefore, this review was developed by reviewing the literature and presenting the different aspects of the challenge associated with Cd exposure and BC therapy. Results: Phytochemicals, especially phenolics, alkaloids, carotenoids, terpenoids, and related plant-derived compounds, have emerged as promising candidates for mitigating Cd-induced BC. Their antioxidants, anti-estrogenic, and anti-inflammatory properties position them as potential chemopreventive and therapeutic agents capable of counteracting Cd’s molecular toxicity. Conclusions: The review presents current evidence linking Cd exposure to BC development and highlights the protective potential of selected phytochemicals in preventing or attenuating Cd-induced BC. Understanding these interactions reinforces the importance of phytochemical-based interventions as a strategy to reduce Cd-related cancer risk and support breast health.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to reduce morbidity and mortality associated with type II diabetes mellitus, and/or obesity, and/or cardiovascular disease in multiple clinical trials. Their efficacy in reversing cardiovascular disease and mitigating the risk of major adverse cardiac and vascular events has been well studied, with outcome trials consistently demonstrating benefits such as reduced systemic inflammation, improved endothelial function, and favorable metabolic effects. These pleiotropic actions have nearly innumerable potential applications, with a progressively growing interest in using GLP-1 RAs to mitigate increased cardiovascular disease risk secondary to other off-target pharmacologic agents. Given these effects, the potential to utilize GLP-1 RAs for prophylactic cardioprotection before, during, and/or after chemotherapy regimens is of great interest. These effects are thought to be mediated in part through anti-inflammatory and antioxidant mechanisms that counter inflammation and reactive oxygen species-driven myocardial injury central to anthracycline-induced cardiotoxicity (AIC). Anthracyclines, a widely used class of chemotherapeutics for various malignancies, are frequently associated with dose-dependent and often irreversible cardiotoxicity, leading to heart failure, reduced quality of life, and adverse long-term outcomes. For the past three decades, dexrazoxane has been the sole Food and Drug Administration-approved agent for cardioprotection in this setting. However, in the current era of novel therapies with multi-system benefits—such as GLP-1 RAs—we propose a theoretical framework exploring their potential role in mitigating AIC and underscore the need for further clinical investigation in this new arena in the field of cardio-oncology.
Renal cell carcinoma (RCC) is a common tumor that heavily depends on extracellular matrix (ECM) remodeling, an essential process involved not only in normal tissue homeostasis but also in malignant growth. This article reviews the role of matrix metalloproteinases (MMPs, zinc-dependent endopeptidases) in matrix degradation and ECM reorganization in the setting of RCC. We focus on the specific role of MMP2, MMP7, and MMP9 in clear cell renal cell carcinoma (ccRCC) and major subtypes of RCC. Higher levels of these MMPs are associated with high-grade tumors, increased risk of metastasis, and poorer patient survival rates, indicating that they may have value as prognostic markers. This review also discusses how ECM composition and structure are altered in the tumor microenvironment (TME), thereby preventing cell interactions and promoting cancer growth. Finally, it compiles the existing studies to anticipate a future era in which MMPs could serve as effective prognostic biomarkers and potential treatment targets for RCC, with implications for improving diagnostic and therapeutic interventions targeting ECM remodeling to suppress cancer progression.
Background: Alcohol is associated with increased mortality and morbidity globally. Pulmonary infections with opportunistic pathogens can occur in healthy humans; however, binge alcohol intoxication (≥0.08% BAC) is a major risk factor. We have previously shown that a single dose of alcohol comparable to binge alcohol intoxication increases infection by reducing alveolar macrophage function in vivo. Sulforaphane (SFN), a phytonutrient, is a potent inducer of antioxidant production through the induction of nuclear factor erythroid 2-related factor 2 (Nrf2) and inhibition of the nuclear factor kappa-light-chain-enhancer (NF-kB) pathway. The aim of this study was to test the therapeutic potential of SFN given as a pretreatment to prevent alcohol-induced phagocytic dysfunction. Methods: Intracellular phagocytic killing was measured via colony-forming units (CFU) and cytokine expression via ELISA. G. mellonella survival was used to determine the therapeutic potential of SFN in vivo. Results: Dose–response curves indicated that SFN concentrations of less than 20 µM were not cytotoxic in either MH-S (murine) or THP-1 (human) cells. Live infection assay results showed that MH-S and THP-1 cells pretreated with SFN (5 µM) and challenged with 0.2% (v/v) alcohol for 3 or 8 h prior to live B. thailandensis or S. epidermidis infection improved intracellular pathogen killing between 12- and 20-fold compared to macrophages treated with alcohol alone. ELISA analysis indicated that SFN significantly reduced levels of Tumor necrosis factor-alpha (TNF-α) expression at 3 and 8 h compared to controls. Additionally, a Galleria mellonella larvae model demonstrated greater survivability in the prophylaxis group compared to larvae exposed to either Gram-positive or Gram-negative pathogens, as well as in groups that received alcohol prior to pathogen inoculation. Conclusions: Taken together, SFN-induced cytoprotection was extended beyond in vitro cell culture to include an in vivo G. mellonella model demonstrating protection against Gram-positive and negative opportunistic pathogens. These data demonstrate that SFN may be an effective pretreatment option to prevent alcohol-mediated innate immune dysfunction and restore macrophage phagocytic killing.
Background: Major cardiovascular events (MACEs) in people with HIV (PWH) may be partly related to antiretroviral therapy (ART) and persistent inflammation. The aim of the study was to evaluate the association between targeted variables and MACEs. Methods: Retrospective, single-center study conducted on PWH receiving ART between January 2010 and April 2024, classified according to HIV-RNA levels: virological suppression (<50 copies/mL), low-level viremia (50–200 or 200–1000 copies/mL), and non-suppression (≥1000 copies/mL). Viremia was considered as a time-dependent variable and by cumulative years in each category. A Cox proportional hazards model for multivariate time-to-event analysis assessed associations between virological status and MACEs. Results: We included 3349 PWH followed for a median time of 14 years (interquartile range, IQR 11.2–14.2). At baseline, 2794 (83.4%) were virologically suppressed, 189 (5.6%) and 90 (2.7%) presented 50–200 and 200–1000 copies/mL, respectively, and 276 (8.2%) were non-suppressed. During the follow-up, virological suppression was documented at least once in 3295 (98.4%), low-level viremia in 1579 (47.1%) with 50–200 copies/mL and 794 (23.7%) with 200–1000 copies/mL, and HIV-RNA > 1000 copies/mL in 844 (25.2%). Overall, 300 MACEs occurred, including 53 (17.7%) repeated events, with total incident rate of 0.00976 events per person-year. The risk of MACEs was significantly associated with previous MACEs (Hazard Ratio, HR 3.385, p-value < 0.001) and viremia > 1000 copies/mL at baseline (HR 2.209, p-value 0.039). Their onset was also significantly associated with greater age at baseline and years on ART, hypertension, diabetes, lower HDL, and higher triglycerides. Conclusions: PWH on ART with HIV-RNA > 1000 copies/mL at baseline and a previous MACE presented higher risk of developing MACEs.
Symptomatic male hypogonadism, defined by low serum testosterone with associated clinical symptoms, is increasingly treated with testosterone replacement therapy. Traditional oral formulations were limited by hepatotoxicity and poor bioavailability, leading to reliance on injectable and transdermal routes. Recent advances in oral testosterone undecanoate formulations have introduced safer and more effective options. This review compares Jatenzo, Tlando, and Kyzatrex, highlighting their pharmacology, efficacy, safety, and clinical utility. Clinical trial data demonstrate restoration of eugonadal testosterone levels in most patients (80–88%), with shared risks including hypertension, polycythemia, and lipid changes. Differences in dosing regimens, titration requirements, and insurance coverage influence choice of therapy and patient adherence. Kyzatrex offers flexible titration and self-pay access, Tlando provides a fixed-dose regimen, and Jatenzo combines titratability with established clinical data. Collectively, these agents expand the therapeutic landscape of hypogonadism, offering effective, non-invasive alternatives that support individualized treatment strategies.
