The Polypharmacological Effects of Cannabidiol.

Cannabidiol (CBD) is a major phytocannabinoid present in Cannabis sativa (Linneo, 1753). This naturally occurring secondary metabolite does not induce intoxication or exhibit the characteristic profile of drugs of abuse from cannabis like Δ9-tetrahydrocannabinol (∆9-THC) does. In contrast to ∆9-THC, our knowledge of the neuro-molecular mechanisms of CBD is limited, and its pharmacology, which appears to be complex, has not yet been fully elucidated. The study of the pharmacological effects of CBD has grown exponentially in recent years, making it necessary to generate frequently updated reports on this important metabolite. In this article, a rationalized integration of the mechanisms of action of CBD on molecular targets and pharmacological implications in animal models and human diseases, such as epilepsy, pain, neuropsychiatric disorders, Alzheimer's disease, and inflammatory diseases, are presented. We identify around 56 different molecular targets for CBD, including enzymes and ion channels/metabotropic receptors involved in neurologic conditions. Herein, we compiled the knowledge found in the scientific literature on the multiple mechanisms of actions of CBD. The in vitro and in vivo findings are essential for fully understanding the polypharmacological nature of this natural product.

Mast Cells Localize in Hypoxic Zones of Tumors and Secrete CCL-2 under Hypoxia through Activation of L-Type Calcium Channels.

Hypoxia is a condition that together with low pH, high amounts of reactive oxygen species (ROS), and increased adenosine levels characterize tumor microenvironment. Mast cells (MCs) are part of tumor microenvironment, but the effect of hypoxia on the production of MC-derived cytokines has not been fully described. Using the hypoxia marker pimonidazole in vivo, we found that MCs were largely located in the low-oxygen areas within B16-F1 mice melanoma tumors. In vitro, hypoxia promoted ROS production, a ROS-dependent increase of intracellular calcium, and the production of MCP 1 (CCL-2) in murine bone marrow-derived MCs. Hypoxia-induced CCL-2 production was sensitive to the antioxidant trolox and to nifedipine, a blocker of L-type voltage-dependent Ca2+ channels (LVDCCs). Simultaneously with CCL-2 production, hypoxia caused the ROS-dependent glutathionylation and membrane translocation of the α1c subunit of Cav1.2 LVDCCs. Relationship between ROS production, calcium rise, and CCL-2 synthesis was also observed when cells were treated with H2O2 In vivo, high CCL-2 production was detected on hypoxic zones of melanoma tumors (where tryptase-positive MCs were also found). Pimonidazole and CCL-2 positive staining diminished when B16-F1 cell-inoculated animals were treated with trolox, nifedipine, or the adenosine receptor 2A antagonist KW6002. Our results show that MCs are located preferentially in hypoxic zones of melanoma tumors, hypoxia-induced CCL-2 production in MCs requires calcium rise mediated by glutathionylation and membrane translocation of LVDCCs, and this mechanism of CCL-2 synthesis seems to operate in other cells inside melanoma tumors, with the participation of the adenosine receptor 2A.

Protein Tyrosine Kinase Fyn Regulates TLR4-Elicited Responses on Mast Cells Controlling the Function of a PP2A-PKCα/ß Signaling Node Leading to TNF Secretion.

Mast cells produce proinflammatory cytokines in response to TLR4 ligands, but the signaling pathways involved are not fully described. In this study, the participation of the Src family kinase Fyn in the production of TNF after stimulation with LPS was evaluated using bone marrow-derived mast cells from wild-type and Fyn-deficient mice. Fyn(-/-) cells showed higher LPS-induced secretion of preformed and de novo-synthesized TNF. In both cell types, TNF colocalized with vesicle-associated membrane protein (VAMP)3-positive compartments. Addition of LPS provoked coalescence of VAMP3 and its interaction with synaptosomal-associated protein 23; those events were increased in the absence of Fyn. Higher TNF mRNA levels were also observed in Fyn-deficient cells as a result of increased transcription and greater mRNA stability after LPS treatment. Fyn(-/-) cells also showed higher LPS-induced activation of TAK-1 and ERK1/2, whereas IκB kinase and IκB were phosphorylated, even in basal conditions. Increased responsiveness in Fyn(-/-) cells was associated with a lower activity of protein phosphatase 2A (PP2A) and augmented activity of protein kinase C (PKC)α/ß, which was dissociated from PP2A and increased its association with the adapter protein neuroblast differentiation-associated protein (AHNAK, desmoyokin). LPS-induced PKCα/ß activity was associated with VAMP3 coalescence in WT and Fyn-deficient cells. Reconstitution of MC-deficient Wsh mice with Fyn(-/-) MCs produced greater LPS-dependent production of TNF in the peritoneal cavity. Our data show that Fyn kinase is activated after TLR4 triggering and exerts an important negative control on LPS-dependent TNF production in MCs controlling the inactivation of PP2Ac and activation of PKCα/ß necessary for the secretion of TNF by VAMP3(+) carriers.

Physicians' preferences for bone metastases treatments in France, Germany and the United Kingdom.

BACKGROUND: Several bone-targeted agents (BTAs) are available for preventing skeletal-related events (SREs), but they vary in terms of efficacy, safety and mode of administration. This study assessed data on European physicians' treatment preferences for preventing SREs in patients with bone metastases from solid tumours. METHODS: Physicians completed a web-based discrete-choice experiment survey of 10 choices between pairs of profiles of hypothetical BTAs for a putative patient. Each profile included five attributes within a pre-defined range (primarily based on existing BTAs' prescribing information): time (months) until the first SRE; time (months) until worsening of pain; annual risk of osteonecrosis of the jaw (ONJ); annual risk of renal impairment; and mode of administration. Choice questions were developed using an experimental design with known statistical properties. A separate main-effects random parameters logit model was estimated for each country and provided the relative preference for the treatment attributes in the study. RESULTS: A total of 191 physicians in France, 192 physicians in Germany, and 197 physicians in the United Kingdom completed the survey. In France and the United Kingdom, time until the first SRE and risk of renal impairment were the most important attributes; in Germany, time until the first SRE and delay in worsening of pain were the most important. In all countries, a 120-min infusion every 4 weeks was the least preferred mode of administration (p < 0.05) and the annual risk of ONJ was judged to be the least important attribute. CONCLUSIONS: When making treatment decisions regarding the choice of BTA, delaying the onset of SREs/worsening of pain and reducing the risk of renal impairment are the primary objectives for physicians.

Chemoinformatic Analysis of Selected Cacalolides from Psacalium decompositum (A. Gray) H. Rob. & Brettell and Psacalium peltatum (Kunth) Cass. and Their Effects on FcεRI-Dependent Degranulation in Mast Cells.

Cacalolides are a kind of sesquiterpenoids natural compounds synthesized by Psacalium decompositum (A. Gray) H. Rob. & Brettell or Psacalium peltatum (Kunth) Cass. Antioxidant and hypoglycemic effects have been found for cacalolides such as cacalol, cacalone or maturine, however, their effects on inflammatory processes are still largely unclear. The main aim of this study was to investigate the biological activities of secondary metabolites from P. decompositum and P. peltatum through two approaches: (1) chemoinformatic and toxicoinformatic analysis based on ethnopharmacologic background; and (2) the evaluation of their potential anti-inflammatory/anti-allergic effects in bone marrow-derived mast cells by IgE/antigen complexes. The bioinformatics properties of the compounds: cacalol; cacalone; cacalol acetate and maturin acetate were evaluated through Osiris DataWarrior software and Molinspiration and PROTOX server. In vitro studies were performed to test the ability of these four compounds to inhibit antigen-dependent degranulation and intracellular calcium mobilization, as well as the production of reactive oxygen species in bone marrow-derived mast cells. Our findings showed that cacalol displayed better bioinformatics properties, also exhibited a potent inhibitory activity on IgE/antigen-dependent degranulation and significantly reduced the intracellular calcium mobilization on mast cells. These data suggested that cacalol could reduce the negative effects of the mast cell-dependent inflammatory process.

Mexican Propolis: A Source of Antioxidants and Anti-Inflammatory Compounds, and Isolation of a Novel Chalcone and ε-Caprolactone Derivative.

The propolis produced by bees are used in alternative medicine for treating inflammation, and infections, presumably due to its antioxidant properties. In this context, five propolis from México were investigated to determine their inhibitory lipid peroxidation properties. The ethyl acetate extract from a red propolis from Chiapas State (4-EAEP) was the most potent (IC50 = 1.42 ± 0.07 µg/mL) in the TBARS assay, and selected for further studies. This extract afforded two new compounds, epoxypinocembrin chalcone (6), and an ε-caprolactone derivative (10), as well as pinostrobin (1), izalpinin (2), cinnamic acid (3), pinocembrin (4), kaempherol (5), 3,3-dimethylallyl caffeate in mixture with isopent-3-enyl caffeate (7a + 7b), 3,4-dimethoxycinnamic acid (8), rhamnetin (9) and caffeic acid (11). The HPLC profile, anti-mycobacterial, and antioxidant properties of this extract was also determined. Most of the isolated compounds were also tested by inhibition of reactive oxygen species (ROS) in challenged mouse bone marrow-derived mast cells (BMMCs), and DPPH. Their anti-inflammatory activity was evaluated by TPA, and MPO (myeloperoxidase) activity by ear edema test in mice. The most potent compounds were 7a + 7b in the TBARS assay (IC50 = 0.49 ± 0.06 µM), and 2 which restored the ROS baseline (3.5 µM). Our results indicate that 4-EAEP has anti-oxidant, and anti-inflammatory properties due to its active compounds, suggesting it has anti-allergy and anti-asthma potential.

Small-Group Randomized Controlled Trial to Increase Condom Use and HIV Testing Among Hispanic/Latino Gay, Bisexual, and Other Men Who Have Sex With Men.

OBJECTIVES: To evaluate the HOLA en Grupos intervention, a Spanish-language small-group behavioral HIV prevention intervention designed to increase condom use and HIV testing among Hispanic/Latino gay, bisexual, and other men who have sex with men. METHODS: In 2012 to 2015, we recruited and randomized 304 Hispanic/Latino men who have sex with men, aged 18 to 55 years in North Carolina, to the 4-session HOLA en Grupos intervention or an attention-equivalent general health education comparison intervention. Participants completed structured assessments at baseline and 6-month follow-up. Follow-up retention was 100%. RESULTS: At follow-up, relative to comparison participants, HOLA en Grupos participants reported increased consistent condom use during the past 3 months (adjusted odds ratio [AOR] = 4.1; 95% confidence interval [CI] = 2.2, 7.9; P < .001) and HIV testing during the past 6 months (AOR = 13.8; 95% CI = 7.6, 25.3; P < .001). HOLA en Grupos participants also reported increased knowledge of HIV (P < .001) and sexually transmitted infections (P < .001); condom use skills (P < .001), self-efficacy (P < .001), expectancies (P < .001), and intentions (P < .001); sexual communication skills (P < .01); and decreased fatalism (P < .001). CONCLUSIONS: The HOLA en Grupos intervention is efficacious for reducing HIV risk behaviors among Hispanic/Latino men who have sex with men.

Healthcare resource use and costs associated with renal impairment in US patients with bone metastases from solid tumors.

Introduction During cancer progression, more than half of patients develop renal insufficiency, including chronic kidney disease. The primary and secondary objectives of this study were to estimate healthcare resource use and costs, respectively, associated with renal impairment in patients with bone metastases from solid tumors in the United States. Methods and materials This was a retrospective, observational cohort study conducted using administrative claims data for individuals with solid tumors and bone metastases. Control patients were matched to renal impairment patients using propensity scores (ratio up to 3:1) based on demographics, clinical characteristics, and baseline costs. Average per-patient per-year healthcare resource utilization and costs (total costs and cost components; 2013 dollars) were reported. Results In total, 2616 renal impairment patients were matched to 7211 control patients. Renal impairment patients had greater healthcare resource use compared with controls, including a greater mean number of hospital admissions (4.4 versus 2.1), longer average stay per hospital admission (7.4 versus 6.5 days), as well as greater mean number of physician office visits (22.9 versus 18.8), emergency department visits (3.1 versus 2.0), and hospital-based outpatient visits (18.8 versus 16.0) compared with control patients. Total costs were > $50,000 higher among renal impairment patients ($142,267 versus $88,839; P < 0.001), with hospital costs accounting for $72,557 for renal impairment patients, and $27,858 for control patients ( P < 0.001). Conclusion The healthcare resource use and costs associated with renal impairment in patients with bone metastases from solid tumors is high; efforts to reduce renal impairment in this population, including the potential avoidance of nephrotoxic agents, are warranted.

Burden of symptoms associated with development of metastatic bone disease in patients with breast cancer.

PURPOSE: Women with breast cancer frequently develop painful bone metastases. This retrospective study was designed to longitudinally characterize patterns of patient-reported symptoms among patients with breast cancer relative to the diagnosis of bone metastases. METHODS: Patient records were identified from the Oncology Services Comprehensive Electronic Records (OSCER) database which includes outpatient oncology practices across the USA. Symptom burden was assessed by Patient Care Monitor (PCM) assessments, which are administered as part of routine care in a subset of these practices. Eligible patients were women diagnosed with breast cancer (ICD-9-CM 174.xx) who developed bone metastases (ICD-9-CM 198.5) and had ≥1 PCM assessment between January 2007 and December 2012. The pre-specified endpoint was the occurrence of moderate to severe symptom burden, defined as PCM score ≥4 (0-10 scale). RESULTS: One thousand one hundred five women (median age, 61) met the eligibility criteria. Worsening of symptoms, particularly fatigue and pain, occurred in the months leading up to the diagnosis of bone metastases. After bone metastases diagnosis, the rate of increase in the proportion of patients experiencing moderate/severe symptoms slowed, but continued to climb during follow-up. Median time to moderate/severe symptoms was 0.9 month for fatigue, 1 month for pain, 2.9 months for trouble sleeping, and 7.7 months for numbness/tingling. Half of the patients received bone-targeted agents after diagnosis of bone metastases. CONCLUSIONS: Symptom burden, especially pain and fatigue, increased both before and after the diagnosis of bone metastases, highlighting the need for proactive monitoring and management of symptoms in breast cancer patients.

Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer.

PURPOSE: Zoledronic acid (ZA) or denosumab treatment reduces skeletal-related events; however, the safety of prolonged therapy has not been adequately studied. Here, we describe safety results of extended denosumab therapy in patients with bone metastases from the open-label extension phase of two phase 3 trials. METHODS: Patients with metastatic breast or prostate cancer received subcutaneous denosumab 120 mg Q4W or intravenous ZA 4 mg Q4W in a double-blinded fashion. Denosumab demonstrated superior efficacy in the blinded treatment phase; thus, patients were offered open-label denosumab for up to an additional 2 years. RESULTS: Cumulative median (Q1, Q3) denosumab exposure was 19.1 (9.2, 32.2) months in the breast cancer trial (n = 1019) and 12.0 (5.6, 21.3) months in the prostate cancer trial (n = 942); 295 patients received denosumab for >3 years. No new safety signals were identified during the open-label phase, or among patients who switched from ZA to denosumab. During the blinded treatment phase, exposure-adjusted subject incidences of osteonecrosis of the jaw (ONJ) were 49 (1.9%) and 31 (1.2%) in the denosumab and ZA groups, respectively. In total, 32 (6.9%) and 25 (5.5 %) new cases of ONJ (not adjusted for exposure) were reported for patients continuing and switching to denosumab, respectively. The incidences of hypocalcemia were 4.3 and 3.1%, in patients continuing and switching to denosumab, respectively. CONCLUSION: These results describe the safety profile of denosumab after long-term exposure, or after switching to denosumab from ZA. No new safety signals were identified. Hypocalcemia rates were similar in the blinded treatment and open-label phases. ONJ rates increased with increasing exposure to antiresorptives, consistent with previous reports.

Physicians' preferences for bone metastases drug therapy in the United States.

OBJECTIVE: Several characteristics of bone-targeted agents are considered when making treatment decisions. This study evaluated physicians' therapy preferences for preventing skeletal-related events (SREs) in patients with bone metastases secondary to solid tumors. METHODS: A Web-enabled, discrete-choice experiment online survey was conducted among physicians who treated patients with bone metastases and solid tumors in the United States. Respondents chose between pairs of hypothetical medications defined by combinations of six attributes at varying levels for two hypothetical patients. Preference weights for attribute levels were estimated using a random-parameters logit model. RESULTS: In total, 200 physicians completed the survey. Their mean age was 52 years, 57% were in practice for more than 15 years, 37% were oncologists, and 65% treated 10 or fewer patients with bone metastases weekly. Out-of-pocket cost to patients was the most important attribute overall. Among clinical outcomes, time to first SRE and risk of renal impairment were the most important attributes. Statistically significant preferences were observed for all attribute levels for time to first SRE, risk of renal impairment, and mode of administration. Predicted choice probability analysis showed that physicians preferred a hypothetical medication with attributes similar to those of denosumab over one with attributes similar to those of zoledronic acid. CONCLUSIONS: Physicians indicated that clinical attributes are important when considering bone-targeting therapy for bone metastases, but consistent with the current health care landscape, patient out-of-pocket cost was the most important. With health care costs being increasingly shifted to patients, physicians require accurate information about co-pays and assistance programs to avoid patients receiving less costly, yet potentially inferior, treatment.

Measurement of skeletal related events in SEER-Medicare: a comparison of claims-based methods.

BACKGROUND: Skeletal related events (SREs) are common in men with metastatic prostate cancer (mPC). Various methods have been used to identify SREs from claims data. The objective of this study was to provide a framework for measuring SREs from claims and compare SRE prevalence and cumulative incidence estimates based on alternative approaches in men with mPC. METHODS: Several claims-based approaches for identifying SREs were developed and applied to data for men aged [greater than or equal to] 66 years newly diagnosed with mPC between 2000 and 2009 in the SEER-Medicare datasets and followed through 2010 or until censoring. Post-diagnosis SREs were identified using claims that indicated spinal cord compression (SCC), pathologic fracture (PF), surgery to bone (BS), or radiation (suggestive of bone palliative radiation, RAD). To measure SRE prevalence, two SRE definitions were created: 'base case' (most commonly used in the literature) and 'alternative' in which different claims were used to identify each type of SRE. To measure cumulative incidence, we used the 'base case' definition and applied three periods in which claims were clustered to episodes: 14-, 21-, and 28-day windows. RESULTS: Among 8997 mPC patients, 46 % experienced an SRE according to the 'base case' definition and 43 % patients experienced an SRE according to the 'alternative' definition. Varying the code definition from 'base case' to 'alternative' resulted in an 8 % increase in the overall SRE prevalence. Using the 21-day window, a total of 12,930 SRE episodes were observed during follow up. Varying the window length from 21 to 28 days resulted in an 8 % decrease in SRE cumulative incidence (RAD: 10 %, PF: 8 %, SCC: 6 %, BS: 0.2 %). CONCLUSIONS: SRE prevalence was affected by the codes used, with PF being most impacted. The overall SRE cumulative incidence was affected by the window length used, with RAD being most affected. These results underscore the importance of the baseline definitions used to study claims data when attempting to understand relevant clinical events such as SREs in the real world setting.

Patients' preferences for bone metastases treatments in France, Germany and the United Kingdom.

PURPOSE: The aim of this study was to assess patients' preferences for efficacy, safety, and mode of administration in relation to available bone-targeted agents (BTA) for the prevention of skeletal-related events (SREs) associated with bone metastases in Europe. METHODS: Adults in France (n = 159), Germany (n = 166), and the United Kingdom (UK; n = 159) with a self-reported physician diagnosis of bone metastases secondary to a solid tumour completed an online discrete- choice experiment survey of ten questions, choosing between pairs of hypothetical BTA profiles. Profiles were defined by five treatment attributes: delay of first SRE, delay of worsening of pain, annual risk of osteonecrosis of the jaw (ONJ), annual risk of renal impairment, and mode of administration. Profiles were generated using an experimental design with known statistical properties. A main-effects random parameters logit (RPL) model was applied to relate participants' choices to the characteristics of the BTA profiles. RESULTS: The most important treatment attributes for patients across all three countries were time until first SRE, annual risk of renal complications and time until pain worsening. For these attributes, better levels of outcomes were significantly preferred to worse levels (p < 0.05). A 120-minutes infusion every 4 weeks was the least preferred mode of administration. Risk of ONJ was judged by patients in the UK and Germany to be the least important attribute. CONCLUSIONS: Patients consider delaying SREs, avoiding renal impairment and delaying pain worsening as the most important goals to consider when selecting treatment to prevent the bone complications commonly associated with bone metastases.

Patient preferences for treatments to delay bone metastases.

BACKGROUND: Most patients with advanced prostate cancer (PCa) develop bone metastases (BM) and present with bone complications like fracture. Bone-targeted agents that prevent metastasis-induced bone complications can cause adverse events. Understanding how patients view treatment options may optimize care. This study aimed to quantify how PCa patients value a hypothetical treatment that delays BM but can cause osteonecrosis of the jaw (ONJ). The study also assessed the value patients place on avoiding metastasis-induced bone complications versus increased survival. METHODS: PCa patients from the United Kingdom (n = 201) and Sweden (n = 200) on androgen-deprivation therapy or hormone therapy for ≥ 3 years completed a 10-question discrete-choice-experiment survey examining whether patients would accept a BM-delaying treatment. Two time-tradeoff questions assessed patients' willingness to tradeoff between survival and bone complications. Percentages of patients choosing treatment were summarized by levels of treatment efficacy and ONJ risk. Odds ratios from a logit model were used to evaluate how patient and medication characteristics affected treatment choice. Proportions of patients choosing each tradeoff scenario were calculated. RESULTS: A majority of patients accepted treatment at the lowest benefit level (5-month BM delay) and highest risk level (9% ONJ risk). PCa symptoms and prior treatment affected patient preferences. Nearly 80% of patients would tradeoff at least 3 months of survival to avoid bone complications. CONCLUSIONS: PCa patients in the U.K and Sweden may value a medication that delays BM, despite the risk of ONJ. Furthermore, patients were willing to tradeoff up to 5 months of survival for prevention of bone complications.

Patients with bone metastases from solid tumors initiating treatment with a bone-targeted agent in 2011: a descriptive analysis using oncology clinic data in the US.

PURPOSE: Three bone-targeted agents (BTAs) are approved in the USA for prevention of bone complications among solid tumor patients with bone metastases: two intravenous bisphosphonates (IV BP) (pamidronate and zoledronic acid), and one subcutaneous receptor activator of nuclear factor-kappaB (RANK) ligand inhibitor (denosumab). Using electronic medical record data from outpatient community and hospital-affiliated oncology clinics, we examined the characteristics of patients who initiated treatment with a BTA in 2011 and followed them for a maximum of 12 months. METHODS: Adult patients with bone metastasis secondary to solid tumors newly treated with a BTA during 2011 were identified from the Oncology Services Comprehensive Electronic Records (OSCER) database. We examined patient characteristics at BTA initiation, treatment patterns, and compliance during a 12-month period. Sensitivity analyses were performed in a subgroup of patients who had confirmed 12 months of follow-up data. RESULTS: Denosumab patients (N = 1,594) were older (65 % ≥65 years vs. 60 % ≥65 years), further along in their disease progression (time since bone metastasis diagnosis: 16 % ≥2 years vs. 10 % ≥2 years), less likely to switch BTA (overall: 6 vs. 14 %; subgroup: 8 vs. 19 %), and more compliant with treatment (overall: median doses of 7 vs. 4; subgroup: 11 vs. 8) compared to IV BP patients (N = 1,975). Findings were consistent across gender, age, tumor type, naïve, and transition strata. CONCLUSIONS: Patients receiving denosumab and IV BPs may differ. Despite higher age and more advanced disease, patients treated with denosumab are more likely to stay on treatment and have better compliance.

Synthesis and Monoamine Oxidase Inhibitory Activity of Halogenated Flavones.

Small molecule neurotransmitters containing amines are metabolized by monoamine oxidase (MAO) in the nervous system. Monoamine oxidase inhibitors are a valuable class of drugs prescribed for the management of neurological disorders, including depression. A series of halogenated flavonoids similar to the dietary flavonoid acacetin were designed as selective MAO-B inhibitors. MAO-A and -B inhibition of 36 halogenated flavones were tested. The halogens (fluorine and chlorine) were placed at positions 5 and 7 on ring A of the flavone scaffold. All compounds were selective MAO-B inhibitors with micro- and nanomolar IC50 values. Compounds 9f, 10a-c, 11a-c, 11g,h, and 11l displayed inhibitory activity toward MAO-B with IC50 values between 16 to 74 nM. We conclude that halogenated flavonoids are promising molecules in pursuit of developing new agents for neurological disorders.

Drugs and natural products for the treatment of COVID-19 during 2020, the first year of the pandemic.

This work aimed to show which treatments showed efficacy against coronavirus disease 2019 (COVID-19); therefore, the results of 37 clinical trials started in 2020 and completed in 2021 are reviewed and discussed here. These were selected from databases, excluding vaccines, computational studies, in silico, in vitro, and those with hyperimmune sera from recovered patients. We found 34 drugs, one vitamin, and one herbal remedy with pharmacological activity against symptomatic COVID-19. They reduced mortality, disease progression, or recovery time. For each treatment, the identifier and type of trial, the severity of the disease, the sponsor, the country where the trial was conducted, and the trial results are presented. The drugs were classified according to their mechanism of action. Several drugs that reduced mortality also reduced inflammation in the most severe cases. These include some that are not considered anti-inflammatory, such as Aviptadil, pyridostigmine bromide, anakinra, imatinib, baricitinib, and bevacizumab, as well as the combination of ivermectin, aspirin, dexamethasone, and enoxaparin. Nigella sativa seeds with honey have also been reported to have therapeutic activity. On the other hand, tofacitinib, novaferon with ritonavir, and lopinavir were also effective, as well as in combination with antiviral therapies such as danoprevir with ritonavir. The natural products colchicine and Vitamin D3 were only effective in patients with mild-to-moderate COVID-19, as was hydroxychloroquine. Drug repositioning has been the main tool in the search for effective therapies by expanding the pharmacological options available to patients.

El objetivo del presente trabajo fue conocer qué tratamientos mostraron efectividad contra COVID-19, para lo cual se revisan y discuten los resultados de 37 estudios clínicos iniciados durante 2020 y concluidos en 2021. Estos fueron seleccionados de bases de datos, excluyendo vacunas, estudios computacionales, in silico, in vitro y con sueros hiperinmunes de pacientes recuperados. Se documentaron 34 fármacos, una vitamina y un remedio herbolario, con actividad farmacológica ante COVID-19 sintomático. Estos redujeron la mortalidad, el progreso de la enfermedad, o el tiempo de recuperación. Para cada tratamiento se presenta identificador y tipo de estudio, la gravedad de la enfermedad, patrocinador, país donde se realizó, así como sus resultados. Los fármacos se clasificaron de acuerdo con su mecanismo de acción. Varios fármacos que redujeron la mortalidad también disminuyeron la inflamación en los casos más graves. Esto incluyendo algunos no considerados antiinflamatorios, como el aviptadil, el bromuro de piridostigmina, el anakinra, el imatinib, el baricitinib y el bevacizumab, así como la combinación de ivermectina, aspirina, dexametasona y enoxaparina. También se reportaron con actividad terapéutica las semillas de Nigella sativa con miel. Además, resultaron efectivos el tofacitinib, el novaferón con ritonavir y lopinavir, así como los antivirales en terapias combinadas como el danoprevir con ritonavir. Los productos naturales colchicina y vitamina D3, solo tuvieron actividad en los pacientes en estado leve a moderado de la COVID-19, así como la hidroxicloroquina. El reposicionamiento de fármacos fue la principal herramienta para buscar terapias efectivas ampliando las opciones farmacológicas accesibles a los pacientes.

Jacareubin inhibits TLR4-induced lung inflammatory response caused by the RBD domain of SARS-CoV-2 Spike protein.

BACKGROUND: COVID-19, the disease caused by SARS-CoV-2 virus infection, has been a major public health problem worldwide in the last 2 years. SARS-CoV-2-dependent activation of innate immune receptors contributes to the strong local and systemic inflammatory reaction associated with rapid disease evolution. The receptor-binding domain (RBD) of Spike (S) viral protein (S-RBD) is essential for virus infection and its interacting molecules in target cells are still under identification. On the other hand, the search for accessible natural molecules with potential therapeutic use has been intense and remains an active field of investigation. METHODS: C57BL6/J (control) and Toll-like receptor (TLR) 4-deficient (Lps del) mice were nebulized with recombinant S-RBD. Tumor Necrosis Factor-alpha (TNF-α) and Interleukin (IL)-6 production in bronchoalveolar lavages (BALs) was determined by enzyme-linked immunosorbent assay (ELISA). Lung-infiltrating cells recovered in BALs were quantified by hematoxylin-eosin (H&E) stain. In selected groups of animals, the natural compound Jacareubin or dexamethasone were intraperitoneally (ip) administered 2 hours before nebulization. RESULTS: A rapid lung production of TNF-α and IL-6 and cell infiltration was induced by S-RBD nebulization in control but not in Lps del mice. Pre-treatment with Jacareubin or dexamethasone prevented S-RBD-induced TNF-α and IL-6 secretion in BALs from control animals. CONCLUSIONS: S-RBD domain promotes lung TNF-α and IL-6 production in a TLR4-dependent fashion in C57BL6/J mice. Xanthone Jacareubin possesses potential anti-COVID-19 properties that, together with the previously tested anti-inflammatory activity, safety, and tolerance, make it a valuable drug to be further investigated for the treatment of cytokine production caused by SARS-CoV-2 infection.

Cost-effectiveness of proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab in patients with a history of myocardial infarction in Sweden.

AIMS: To assess the cost-effectiveness of proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab added to standard-of-care lipid-lowering treatment [maximum tolerated dose (MTD) of statin and ezetimibe] in Swedish patients with a history of myocardial infarction (MI). METHODS AND RESULTS: Cost-effectiveness was evaluated using a Markov model based on Swedish observational data on cardiovascular event rates and efficacy from the FOURIER trial. Three risk profiles were considered: recent MI in the previous year; history of MI with a risk factor; and history of MI with a second event within 2 years. For each population, three minimum baseline low-density lipoprotein cholesterol (LDL-C) levels were considered: 2.5 mmol/L (≈100 mg/dL), based on the current reimbursement recommendation in Sweden; 1.8 mmol/L (≈70 mg/dL), based on 2016 ESC/EAS guidelines; and 1.4 mmol/L (≈55 mg/dL), or 1.0 mmol/L (≈40 mg/dL) for MI with a second event, based on 2019 ESC/EAS guidelines. Proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab was associated with increased quality-adjusted life-years and costs vs. standard-of-care therapy. Incremental cost-effectiveness ratios (ICERs) were below SEK700 000 (∼€66 500), the generally accepted willingness-to-pay threshold in Sweden, for minimum LDL-C levels of 2.3 (recent MI), 1.7 (MI with a risk factor), and 1.7 mmol/L (MI with a second event). Sensitivity analyses demonstrated that base-case results were robust to changes in model parameters. CONCLUSION: Proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab added to MTD of statin and ezetimibe may be considered cost-effective at its list price for minimum LDL-C levels of 1.7-2.3 mmol/L, depending on risk profile, with ICERs below the accepted willingness-to-pay threshold in Sweden.