Physiological, Pathological and Pharmacological Interactions of Hydrogen Sulphide and Nitric Oxide in the Myocardium of Rats with Left Ventricular Hypertrophy

Left ventricular hypertrophy (LVH) is characterized by increased myocardium thickness due to increased oxidative stress and downregulation of cystathione γ lyase (CSE) endothelial nitric oxide synthase (eNOS). Upregulation of CSE by hydrogen sulphide (H2S) and ENOS by L-arginine can arrest the progression of LVH individually. The present study explored the combined treatment of H2S and NO in the progression of LVH, and demonstrated that the response is due to H2S, NO or formation of either new molecule in physiological, pathological, and pharmacological in vivo settings of LVH. Exogenous administration H2S+NO in LVH significantly reduced (all p < 0.05) systolic blood pressure (SBP) and mean arterial pressure (MAP), LV index, heart index and oxidative stress when compared to the LVH group. There was downregulation of CSE mRNA and eNOS in the heart, and exogenous administration of H2S+NO groups upregulated eNOS MRNA while CSE MRNA remained downregulated in the hearts of the LVH group. Similar trends were observed with concentrations of H2S and NO in the plasma and tissue. It can be concluded that combined treatment of LVH with H2S and NO significantly ameliorate the progression of LVH by attenuating systemic hemodynamic and physical indices, and by decreasing oxidative stress. Molecular expression data in the myocardium of LVH depicts that combined treatment upregulated eNOS/NO while it downregulated CSE/H2S pathways in in vivo settings, and it is always eNOS/NO pathways which play a major role.

Preliminary Evidence of the Efficacy of Nitric Acid Treatment in Onychomycosis

Onychomycosis is the main cause of toenail disorders and is produced by a fungal infection. It is becoming more prevalent because of new lifestyles and immunosuppression statuses. The therapeutic approach to onychomycosis is under considerable study because of the lengthy treatments that require strong patient commitment, the limited efficacy of treatments, the inclusion of active substances that can be hepatotoxic and cause pharmacological interactions, and/or the questionable efficacy of treatments due to a lack of clinical trials. This study responds to the demand for rapid treatment with minimal pharmacological interactions. Methods: The efficacy of nitric acid 60% treatment in patients with onychomycosis was monitored and studied. The antifungal efficacy of nitric acid was measured by microbiological culture before and after treatment and the clinical evolution of nail dystrophy was quantitatively measured by monitoring with the Onychomycosis Severity Index (OSI). Results: The results show that, with the protocol used, nitric acid 60% painlessly cured 40% (microbiologic cure) of the cases treated, and in all cases, clinical improvement was observed (p = 0.011). Conclusions: The treatment with nitric acid 60% is as efficient as conventional treatments, requires less patient compliance of the treatment and produces no pharmacological interactions, providing alternative treatment in the case of hepatotoxicity.

Frontline treatment in CLL: the case for time-limited treatment

Over the last decade, the advent of Bruton tyrosine kinase inhibitors (BTKi) has profoundly modified the therapeutic strategy in chronic lymphocytic leukemia (CLL), introducing the concept of treatment until progression. Initially, the bcl-2 inhibitor venetoclax (VEN) was used as a single agent and then was rapidly combined in VEN-based regimens associated with either anti-CD20 or with BTKi. These regimens yielded a high rate of complete remission, leading to their use as a fixed duration treatment. The decision between continuous treatment with BTKi and VEN-based combinations relies mostly on comorbidities, comedications, and patient/physician preferences. Notably, with BTKi, cardiovascular comorbidities, hypertension, and potential pharmacological interactions should be carefully evaluated. On the other hand, the risk of tumor lysis syndrome with VEN should be monitored at treatment initiation. TP53 alteration and IGHV mutational status should also be assessed, as they remain important for therapeutic decisions. Fit patients with a TP53 wild type and IGHV-mutated CLL may still benefit from fludarabine-cyclophosphamide-rituximab chemoimmunotherapy (CIT), as it may result in a very long remission duration. VEN-based treatments are well tolerated, and no additional toxicity has been observed when combined with anti-CD20 or BTKi. The 1-year fixed-duration association of VEN plus obinutuzumab was evaluated in frontline for older adult patients. Nonetheless, considering the favorable outcome, an extension of indication for fit younger patients is expected. The association of VEN and BTKi is promising, even if the follow-up is still short. It is currently being tested against CIT, BTKi continuous treatment, and VEN plus anti-CD20.

Deep Learning for Alzheimer’s Disease Drug Repurposing using Knowledge Graph and Multi-level Evidence

ABSTRACTDeveloping drugs for treating Alzheimer’s disease (AD) has been extremely challenging and costly due to limited knowledge on underlying biological mechanisms and therapeutic targets. Repurposing drugs or their combination has shown potential in accelerating drug development due to the reduced drug toxicity while targeting multiple pathologies. To address the challenge in AD drug development, we developed a multi-task machine learning pipeline to integrate a comprehensive knowledge graph on biological/pharmacological interactions and multi-level evidence on drug efficacy, to identify repurposable drugs and their combination candidates. We developed and computationally validated a heterogeneous graph representation model with transfer learning from universal biomedical databases and with joint optimization with AD risk genes. Using the drug embedding from the heterogeneous graph representation model, we ranked drug candidates based on evidence from post-treatment transcriptomic patterns, mechanistic efficacy in preclinical models, population-based treatment effect, and Phase II/III clinical trials. We experimentally validated the top-ranked candidates in neuronal cells, identifying drug combinations with efficacy in reducing oxidative stress and safety in maintaining neuronal viability and morphology. Our neuronal response experiments confirmed several biologically efficacious drug combinations (e.g., Galantamine + Mifepristone). This pipeline showed that harmonizing heterogeneous and complementary data/knowledge, including human interactome, transcriptome patterns, experimental efficacy, and real-world patient data shed light on the drug development of complex diseases.

Safer prescription of drugs: impact of the PREFASEG system to aid clinical decision-making in primary care in Catalonia

Background In 2008, the Institut Català de la Salut (ICS, Catalan Health Institute) implemented a prescription decision support system in its electronic clinical workstation (ECW), which automatically generates online alerts for general practitioners when a possible medication-related problem (MRP) is detected. This tool is known as PREFASEG, and at the time of beginning a new treatment, it automatically assesses the suitability of the treatment for the individual patient. This analysis is based on ongoing treatments, demographic characteristics, existing pathologies, and patient biochemical variables. As a result of the assessment, therapeutic recommendations are provided. The objective of this study is to present the PREFASEG tool, analyse the main alerts that it generates, and determine the degree of alert acceptance. Methods A cross-sectional descriptive study was carried out to analyse the generation of MRP-related alerts detected by PREFASEG during 2016, 2017, and 2018 in primary care (PC) in Catalonia. The number of MRP alerts generated, the drugs involved, and the acceptance/rejection of the alerts were analysed. An alert was considered "accepted" when the medication that generated the alert was not prescribed, thereby following the recommendation given by the tool. The MRP alerts studied were therapeutic duplications, safety alerts issued by the Spanish Medicines Agency, and drugs not recommended for use in geriatrics. The prescriptions issued by 6411 ICS PC physicians who use the ECW and provide their services to 5.8 million Catalans through 288 PC teams were analysed. Results During the 3 years examined, 67.2 million new prescriptions were analysed, for which PREFASEG generated 4,379,866 alerts (1 for every 15 new treatments). A total of 1,222,159 alerts (28%) were accepted. Pharmacological interactions and therapeutic duplications were the most detected alerts, representing 40 and 30% of the total alerts, respectively. The main pharmacological groups involved in the safety alerts were nonsteroidal anti-inflammatory drugs and renin-angiotensin system inhibitors. Conclusions During the period analysed, 28% of the prescriptions wherein a toxicity-related PREFASEG alert was generated led to treatment modification, thereby helping to prevent the generation of potential safety MRPs. However, the tool should be further improved to increase alert acceptance and thereby improve patient safety.

Onychomycosis in patients with diabetes mellitus: Etiology, clinical features, and treatment response

Background: Onychomycosis accounts for 30% of all superficial mycoses and 50% of all nail diseases. One of the most studied predisposing factors is diabetes mellitus, with a frequency of onychomycosis of 31.5% in these patients. Many show resistance to standard therapeutics and have “polypharmacy”, which represents a risk for pharmacological interactions. Objective: The objective was to assess the clinical response to therapy, evaluate with histopathology, direct examination with KOH and white-calcofluor, and culture the most frequent etiologic agents associated with the development of onychomycosis in patients with diabetes mellitus. Materials and Methods: A non-randomized, uncontrolled, open-ended, prospective cohort study was conducted on 46 patients with onychomycosis and diabetes mellitus. Treatment was assigned according to clinical findings and specific indications for treatment. Results: From the samples taken for direct examination with KOH and calcofluor-white, culture, and histopathological study, positive results were: 39 (84.1%) patients to the direct examination, 32 (69.6%) to the culture, 27 (65.2%) with a positive histopathological study, and 17 (54.86%) to the calcofluor-white. On clinical evaluation, we found no treatment response in 8 patients (20%), a partial response in 14 patients (25%), and a complete response in 18 patients (45%). Out of the 46 patients evaluated initially, 25 persisted with onychomycosis after six months of follow-up. Conclusion: The prevalence of onychomycosis is increasing and requires correct diagnosis since there are other non-fungal diseases of the nails that resemble onychomycosis. Presumably, the immunosuppression of diabetes, its systemic affection, and the foot abnormalities of a diabetic patient cause more nail dystrophy, an increased fungal load, and treatment resistance.

Shedding Light on the Pharmacological Interactions between μ-Opioid Analgesics and Angiotensin Receptor Modulators: A New Option for Treating Chronic Pain

The current protocols for neuropathic pain management include µ-opioid receptor (MOR) analgesics alongside other drugs; however, there is debate on the effectiveness of opioids. Nevertheless, dose escalation is required to maintain their analgesia, which, in turn, contributes to a further increase in opioid side effects. Finding novel approaches to effectively control chronic pain, particularly neuropathic pain, is a great challenge clinically. Literature data related to pain transmission reveal that angiotensin and its receptors (the AT1R, AT2R, and MAS receptors) could affect the nociception both in the periphery and CNS. The MOR and angiotensin receptors or drugs interacting with these receptors have been independently investigated in relation to analgesia. However, the interaction between the MOR and angiotensin receptors has not been excessively studied in chronic pain, particularly neuropathy. This review aims to shed light on existing literature information in relation to the analgesic action of AT1R and AT2R or MASR ligands in neuropathic pain conditions. Finally, based on literature data, we can hypothesize that combining MOR agonists with AT1R or AT2R antagonists might improve analgesia.

Novel Use of Intraarticular Granulocyte Colony Stimulating Factor (hG-CSF) Combined with Activated Autologous Peripheral Blood Stem Cells Mobilized with Systemic hG-CSF: Safe and Efficient in Early Osteoarthritis

Osteoarthritis (OA) tends to occur in older individuals frequently burdened with comorbidities and diverse pharmacological interactions. As articular cartilage has low regenerative power, potent local tissue engineering approaches are needed to support chondrogenic differentiation. Acellular preparation methods as well as approaches to coax endogenous reparative cells into the joint space appear to have limited success. Supported by our in-vitro and clinical studies, we propose that our novel intra-articular administration of human granulocyte colony stimulating factor (IA-hG-CSF) combined with autologous activated peripheral blood stem cells (AAPBSC) is safe and offers treatment advantages not seen with other cellular interventions in early osteoarthritis.