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PloS One 2024Pheochromocytoma, or paraganglioma (PPGL), is a tumor that arises from catecholamine-producing chromaffin cells of the adrenal medulla or paraganglion. Systemic therapy,...
Evaluation of pharmacokinetics, safety, and efficacy of [211At] meta-astatobenzylguanidine ([211At] MABG) in patients with pheochromocytoma or paraganglioma (PPGL): A study protocol.
BACKGROUND
Pheochromocytoma, or paraganglioma (PPGL), is a tumor that arises from catecholamine-producing chromaffin cells of the adrenal medulla or paraganglion. Systemic therapy, such as the combination of cyclophosphamide, vincristine, and dacarbazine or therapeutic radiopharmaceuticals such as [131I] meta-iodobenzylguanidine (MIBG), may be administered in cases of locally advanced tumors or distant metastases. However, the current therapies are limited in terms of efficacy and implementation. [211At] meta-astatobenzylguanidine (MABG) is an alpha-emitting radionuclide-labeled ligand that has demonstrated remarkable tumor-reducing effects in preclinical studies, and is expected to have a high therapeutic effect on pheochromocytoma cells.
METHODS
We are currently conducting an investigator-initiated first-in-human clinical trial to evaluate the pharmacokinetics, safety, and efficacy of [211At] MABG. Patients with locally unresectable or metastatic PPGL refractory to standard therapy and scintigraphically positive [123I] MIBG aggregation are being recruited, and a 3 + 3 dose escalation design was adopted. The initial dose of [211At] MABG is 0.65 MBq/kg, with a dose escalation in a 1:2:4 ratio in each cohort. Dose-limiting toxicity is observed for 6 weeks after a single bolus dose of [211At] MABG, and the patients are observed for 3 months to explore safety and efficacy profiles. The primary endpoint is dose-limiting toxicity to determine both maximum tolerated and recommended doses. The secondary endpoints include radiopharmacokinetics, urinary radioactive excretion rate, urinary catecholamine response rate, objective response rate, progression free survival, [123I] MIBG scintigraphy on reducing tumor accumulation, and quality of life.
TRIALS REGISTRATION
jRCT2021220012 registered on 17 June 2022.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Adrenal Gland Neoplasms; Guanidines; Paraganglioma; Pheochromocytoma; Radiopharmaceuticals; Treatment Outcome; Clinical Trials, Phase I as Topic
PubMed: 38805424
DOI: 10.1371/journal.pone.0303623 -
Substance Use & Addiction Journal Jul 2024The United States is grappling with an unprecedented overdose crisis, exacerbated by the proliferation of potent synthetic opioids like illicitly manufactured fentanyl....
Methadone's Resurgence in Bridging the Treatment Gap in the Overdose Crisis: Position Statement of AMERSA, Inc (Association for Multidisciplinary Education, Research, Substance Use, and Addiction).
BACKGROUND
The United States is grappling with an unprecedented overdose crisis, exacerbated by the proliferation of potent synthetic opioids like illicitly manufactured fentanyl. Despite the efficacy of methadone treatment in managing opioid use disorder, regulatory barriers hinder its widespread utilization. This article examines the complex landscape of methadone regulation across federal, state, and local levels, highlighting disparities and opportunities for reform.
ISSUE
The COVID-19 public health emergency prompted temporary flexibility in methadone regulations, including expanded take-home doses and telehealth counseling, leading to improved treatment experiences and retention. Permanent revisions to federal guidelines have since been introduced by the Substance Abuse and Mental Health Services Administration, reflecting a progressive shift toward patient-centered care and streamlined access. State regulations, managed by Single State Agencies and State Opioid Treatment Authorities, vary widely, often imposing additional restrictions that impede access to methadone treatment. Local OTP clinics further exacerbate barriers through stringent policies, despite federal and state guidelines advocating for flexibility.
RECOMMENDATIONS
Coordinated efforts among policymakers, healthcare providers, and communities are needed to promote the development of accountability measures, incentives, and community involvement to ensure equitable access and quality of care. To truly meet the demand needed to end the existing overdose crisis and enhance accessibility and comprehensive healthcare services, methadone treatment expansion beyond traditional OTP settings into primary care offices and community pharmacies should take place.
Topics: Humans; Methadone; Opiate Substitution Treatment; United States; Opioid-Related Disorders; COVID-19; Drug Overdose; Analgesics, Opioid; Health Services Accessibility
PubMed: 38804606
DOI: 10.1177/29767342241255480 -
Narra J Apr 2024Diabetes is closely related to immune response problems when it occurs chronically. Pegagan () is a medicinal plant with active compounds. Madecassoside is beneficial in...
Diabetes is closely related to immune response problems when it occurs chronically. Pegagan () is a medicinal plant with active compounds. Madecassoside is beneficial in treating diabetes, and nanoparticle technology is expected to enhance the medicinal potential and availability of pegagan compounds. The aim of this study was to determine the effect of chitosan-coated pegagan nanoparticles on the cytokine profile of chronic diabetic mice, which included CD4+TNF-α+, CD8+TNF-α+, CD4+IFN-γ+, CD8+IFN-γ+ and IL-6+. An experimental study with a randomized complete block design (CRD) consisting of six treatments with seven replicates was conducted. The groups were: healthy mice as negative control; diabetic mice treated with distilled water as positive control and diabetic mice treated with nanoparticle coated with chitosan (NPC) 20 mg/kg, 30 mg/kg, 40 mg/kg, and metformin 130 mg/kgBW. The data were tested using one-way analysis of variance (ANOVA) with a significance level of 5% and continued with the Duncan's multiple range test. The results showed that pegagan NPC could significantly reduce the relative number of CD4+TNF-α+, CD8+TNF-α+, CD4+IFN-γ+ and CD8+IFN-γ+ and IL-6 in the dose of 20 mg/kg, 30 mg/kg and 40 mg/kg (<0.05). The treatment dose of 20 mg/kg reduced CD4+TNF-α+, CD8+TNF-α+, CD4+IFN-γ+, CD8+IFN-γ+ to the levels of healthy mice and a dose of 30 mg/kg could reduce IL-6 as in healthy mice. These findings suggest that chitosan-coated pegagan nanoparticles are a promising therapy for diabetes, as they have the potential to modulate the immune response associated with chronic diabetes.
Topics: Animals; Chitosan; Nanoparticles; Mice; Centella; Cytokines; Diabetes Mellitus, Experimental; Male; Triterpenes; Hypoglycemic Agents; Interleukin-6; Plant Extracts; Metformin
PubMed: 38798839
DOI: 10.52225/narra.v4i1.697 -
Narra J Apr 2024The antiproliferative properties of metformin and silodosin have been observed in prostate cancer. Furthermore, it is hypothesized that the molecular pathways related to...
Effects of metformin and silodosin as supplementary treatments to abiraterone on human telomerase reverse transcriptase (hTERT) level in metastatic castration-resistant prostate cancer (mCRPC) cells: An in vitro study.
The antiproliferative properties of metformin and silodosin have been observed in prostate cancer. Furthermore, it is hypothesized that the molecular pathways related to these drugs may impact the levels of human telomerase reverse transcriptase (hTERT) in prostate cancer cells. The aim of this study was to assess the effect of metformin and silodosin on the levels of hTERT in metastatic castration-resistant prostate cancer (mCRPC) cells. The present study employed an experimental design with a post-test-only control group. This study utilized the PC3 cell line as a model for mCRPC. A viability experiment was conducted using the CCK-8 method to determine the inhibitory concentration (IC50) values of metformin, silodosin, and abiraterone acetate (AA) after a 72-hour incubation period of PC3 cells. In order to investigate the levels of hTERT, PC3 cells were divided into two control groups: a negative control and a standard therapy with AA. Additionally, three experimental combination groups were added: metformin with AA; silodosin with AA; and metformin, silodosin and AA. The level of hTERT was measured using sandwich ELISA technique. The difference in hTERT levels was assessed using ANOVA followed by a post hoc test. The IC values for metformin, silodosin, and AA were 17.7 mM, 44.162 mM, and 66.9 μM, respectively. Our data indicated that the combination of metformin with AA and the combination of metformin, silodosin and AA decreased the hTERT levels when compared to control, AA, and silodosin with AA. The administration of metformin resulted in a reduction of hTERT levels in the PC3 cell line, but the impact of silodosin on hTERT levels was not statistically significant compared to AA group.
Topics: Humans; Metformin; Telomerase; Male; Prostatic Neoplasms, Castration-Resistant; Indoles; Cell Line, Tumor; Cell Proliferation; PC-3 Cells; Cell Survival; Antineoplastic Agents; Androstenes
PubMed: 38798828
DOI: 10.52225/narra.v4i1.680 -
Antiviral Research Jul 2024The most widely used class of antivirals available for Influenza treatment are the neuraminidase inhibitors (NAI) Oseltamivir and Zanamivir. However, amino acid (AA)...
The most widely used class of antivirals available for Influenza treatment are the neuraminidase inhibitors (NAI) Oseltamivir and Zanamivir. However, amino acid (AA) substitutions in the neuraminidase may cause reduced inhibition or high antiviral resistance. In Mexico, the current state of knowledge about NAI susceptibility is scarce, in this study we report the results of 14 years of Influenza surveillance by phenotypic and genotypic methods. A total of 255 isolates were assessed with the NAI assay, including Influenza A(H1N1)pdm09, A(H3N2) and Influenza B (IBV). Furthermore, 827 sequences contained in the GISAID platform were analyzed in search of relevant mutations.Overall, five isolates showed highly reduced inhibition or reduced inhibition to Oseltamivir, and two showed reduced inhibition to Zanamivir in the NAI assays. Additionally, five A(H1N1)pdm09 sequences from the GISAID possessed AA substitutions associated to reduced inhibition to Oseltamivir and none to Zanamivir. Oseltamivir resistant A(H1N1)pdm09 harbored the H275Y mutation. No genetic mutations were identified in Influenza A(H3N2) and IBV. Overall, these results show that in Mexico the rate of NAI resistance is low (0.6%), but it is essential to continue the Influenza surveillance in order to understand the drug susceptibility of circulating strains.
Topics: Drug Resistance, Viral; Antiviral Agents; Mexico; Humans; Influenza B virus; Influenza, Human; Oseltamivir; Zanamivir; Neuraminidase; Influenza A Virus, H1N1 Subtype; Mutation; Influenza A Virus, H3N2 Subtype; Adult; Influenza A virus; Adolescent; Child; Amino Acid Substitution; Young Adult; Middle Aged; Female; Child, Preschool; Genotype; Male; Aged; Microbial Sensitivity Tests; Viral Proteins
PubMed: 38795911
DOI: 10.1016/j.antiviral.2024.105918 -
Nutrients May 2024Jacq. is traditionally applied in folk medicine in Brazil and in several Latin American countries. The leaves are used in tea form, especially in the treatment of...
INTRODUCTION
Jacq. is traditionally applied in folk medicine in Brazil and in several Latin American countries. The leaves are used in tea form, especially in the treatment of respiratory disorders, acting as an expectorant. It also has activity in gastrointestinal disorders, and it is anti-inflammatory, antioxidant, sedative, and estrogenic, among others.
AIMS
To investigate the gastroprotective activity of the methanol extract of the leaves of Jacq. (MEJP) in different experimental models of gastric ulcers.
MATERIALS AND METHODS
The adult leaves of Jacq. were collected and cultivated in beds, with an approximate spacing of 40 × 40 cm, organic fertilization, irrigation with potable water and without shelter from light. The MEJP was prepared from the dried and pulverized leaves and concentrated under reduced pressure in a rotary evaporator. For the experimental model of gastric ulcer, Swiss male albino mice were used. The inputs used in the experiment were MEJP at three different concentrations (250, 500 and 1000 mg/kg p.o.), cimetidine (50 mg/kg p.o.), indomethacin (50 mg/kg s.c.) and vehicle (10 mL/kg p.o.).
RESULTS
MEJP (250, 500 and 1000 mg/kg p.o.) demonstrated gastroprotective activity, with levels of protection of 45.65%, 44.80% and 40.22%, respectively, compared to the control (vehicle). Compared with cimetidine (48.29%), MEJP showed similar gastroprotective activity.
CONCLUSIONS
This study demonstrated the gastroprotective activity of MEJP and contributes to validate the traditional use the species for gastric disorders and provides a pharmacological basis for its clinical potential.
Topics: Animals; Plant Extracts; Mice; Stomach Ulcer; Plant Leaves; Male; Anti-Ulcer Agents; Methanol; Justicia; Disease Models, Animal; Cimetidine; Acanthaceae; Indomethacin; Brazil; Gastric Mucosa
PubMed: 38794668
DOI: 10.3390/nu16101430 -
Pharmaceuticals (Basel, Switzerland) Apr 2024It has been shown that the Medication Regimen Complexity Index (MRCI) is a useful and reliable tool for calculating the complexity of the pharmacotherapeutic regimen...
It has been shown that the Medication Regimen Complexity Index (MRCI) is a useful and reliable tool for calculating the complexity of the pharmacotherapeutic regimen (CPR). Furthermore, a high MRCI is associated with lower adherence. However, the MRCI of opioid-dependent patients (ODP) has not been studied. The aim of this study is to calculate the Methadone Maintenance Program (MMP) persistence and the MRCI score in a ODP cohort. Second, to analyze its relationship and association with other variables. To accomplish this research, an observational study including adults with a confirmed diagnosis of opiate-dependency according to the DSM-5 in a MMP center was carried out. To define MMP-persistence, a group was created by the researchers who defined five weighted items according to their agreed importance. Our first contribution was to create a new definition of MMP-persistence. This study also identified age, comorbidities, and received methadone maintenance doses as successful predictors for MMP-persistence. We have also shown that the MRCI does not seem to be a useful tool to determine MMP-persistence, probably because there are multiple factors that influence it in addition to the CPR. It is necessary to continue searching for more precise selection and stratification tools for ODP to improve their persistence.
PubMed: 38794137
DOI: 10.3390/ph17050567 -
Molecules (Basel, Switzerland) May 2024Methylglyoxal-induced ROS elevation is the primary cause of neuronal damage. Metformin is a traditional hypoglycemic drug that has been reported to be beneficial to the...
Synergistic Effect of Flavonoids and Metformin on Protection of the Methylglyoxal-Induced Damage in PC-12 Neuroblastoma Cells: Structure-Activity Relationship and Potential Target.
Methylglyoxal-induced ROS elevation is the primary cause of neuronal damage. Metformin is a traditional hypoglycemic drug that has been reported to be beneficial to the nervous system. In this study, flavonoids were found to enhance the protective effect of metformin when added at a molar concentration of 0.5%. The structure-activity relationship (SAR) analysis indicated that ortho- substitution in the B ring, and the absence of double bonds between the 2 and 3 position combined with the gallate substitution with R configuration at the 3 position in the C ring played crucial roles in the synergistic effects, which could be beneficial for designing a combination of the compounds. Additionally, the mechanism study revealed that a typical flavonoid, EGCG, enhanced ROS scavenging and anti-apoptotic ability via the BCL2/Bax/Cyto C/Caspase-3 pathway, and synergistically inhibited the expression of GSK-3β, BACE-1, and APP in PC-12 cells when used in combination with metformin. The dose of metformin used in the combination was only 1/4 of the conventional dose when used alone. These results suggested that ROS-mediated apoptosis and the pathways related to amyloid plaques (Aβ) formation can be the targets for the synergistic neuroprotective effects of flavonoids and metformin.
Topics: Metformin; Pyruvaldehyde; Rats; Flavonoids; PC12 Cells; Animals; Structure-Activity Relationship; Drug Synergism; Apoptosis; Reactive Oxygen Species; Neuroblastoma; Neuroprotective Agents; Signal Transduction
PubMed: 38792167
DOI: 10.3390/molecules29102306 -
International Journal of Molecular... May 2024This work investigated the cocatalytic activity of recently prepared guanidinium salts containing an oxanorbornane subunit in an ()-proline-catalyzed aldol reaction. The...
This work investigated the cocatalytic activity of recently prepared guanidinium salts containing an oxanorbornane subunit in an ()-proline-catalyzed aldol reaction. The activity was interpreted by the diastereoselectivity of the reaction (/ ratio) and for the most interesting polycyclic guanidinium salt, the enantioselectivity of the reaction was determined. The results indicated a negative impact on the oxanorbornane unit if present as the flexible substituent. For most of the tested aldehydes, the best cocatalysts provided enantioselectivities above 90% and above 95% at room temperature and 0 °C, respectively, culminating in >99.5% for 4-chloro- and 2-nitrobenzaldehyde as the substrate. The barriers for forming four possible enantiomers were calculated and the results for two enantiomers are qualitatively consistent with the experiment. Obtained results suggest that the representatives of furfurylguanidinium and rigid polycyclic oxanorbornane-substituted guanidinium salts are good lead structures for developing new cocatalysts by tuning the chemical space around the guanidine moiety.
Topics: Catalysis; Proline; Guanidines; Stereoisomerism; Aldehydes; Norbornanes; Guanidine; Molecular Structure
PubMed: 38791607
DOI: 10.3390/ijms25105570 -
International Journal of Molecular... May 2024Human malignancies are one of the major health-related issues throughout the world and are anticipated to rise in the future. Despite huge investments made in anticancer...
Human malignancies are one of the major health-related issues throughout the world and are anticipated to rise in the future. Despite huge investments made in anticancer drug development, limited success has been obtained and the average number of FDA approvals per year is declining. So, an increasing interest in drug repurposing exists. Metformin (MET) and aspirin (ASP) possess anticancer properties. This work aims to test the effect of these two drugs in combination on colorectal cancer (CRC) cells in vitro. The effects of MET and/or ASP on cell proliferation, viability, migratory ability, anchorage-independent growth ability (colony formation), and nutrient uptake were determined in two (HT-29 and Caco-2) human CRC cell lines. Individually, MET and ASP possessed antiproliferative, cytotoxic, and antimigratory effects and reduced colony formation in HT-29 cells (- and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α ()-mutant), although MET did not affect either H-deoxy-D-glucose or C-butyrate uptake and lactate production, and ASP caused only a small decrease in C-butyrate uptake. Moreover, in these cells, the combination of MET and ASP resulted in a tendency to an increase in the cytotoxic effect and in a potentiation of the inhibitory effect on colony formation, although no additive antiproliferative and antimigratory effects, and no effect on nutrient uptake and lactate production were observed. In contrast, MET and ASP, both individually and in combination, were almost devoid of effects on Caco-2 cells (- and -wild type). We suggest that inhibition of PI3K is the common mechanism involved in the anti-CRC effect of both MET, ASP and their combination and, therefore, that the combination of MET + ASP may especially benefit -mutant CRC cases, which currently have a poor prognostic.
Topics: Humans; Metformin; Aspirin; Colorectal Neoplasms; Cell Proliferation; Caco-2 Cells; Cell Movement; HT29 Cells; Mutation; Drug Synergism; Cell Survival; Antineoplastic Agents; Class I Phosphatidylinositol 3-Kinases; Cell Line, Tumor
PubMed: 38791419
DOI: 10.3390/ijms25105381