Modulation of Angiotensin II-Induced Cellular Hypertrophy by Cannflavin-C: Unveiling the Impact on Cytochrome P450 1B1 and Arachidonic Acid Metabolites.

This research aimed to clarify the impacts of cannflavin-C on angiotensin II (Ang II)-induced cardiac hypertrophy and their potential role in modulating cytochrome P450 1B1 (CYP1B1) and arachidonic acid (AA) metabolites. Currently there is no evidence to suggest that cannflavin-C; a prenylated flavonoid, has any significant effects on the heart or cardiac hypertrophy. The metabolism of arachidonic acid (AA) into midchain hydroxyeicosatetraenoic acids (HETEs), facilitated by CYP1B1 enzyme, plays a role in the development of cardiac hypertrophy which is marked by enlarged cardiac cells. Adult human ventricular cardiomyocytes cell line (AC16) were cultured and exposed to cannflavin-C in the presence and absence of Ang II. The assessment of mRNA expression pertaining to cardiac hypertrophic markers and CYPs was conducted via real-time polymerase chain reaction (PCR) while the quantification of CYPs protein levels was carried out through western blot analysis. Ang II induced hypertrophic markers myosin heavy chain (ß/α-MHC), atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) and increased cell surface area, while cannflavin-C mitigated these effects. Gene and protein expression analysis revealed that cannflavin-C downregulated CYP1B1 gene expression, protein level as well as the enzyme activity assessed by 7-methoxyresorufin O-deethylase (MROD). Arachidonic acid metabolites analysis, using LC-MS/MS, demonstrated that Ang II increased midchain (R/S)-HETEs concentrations, which were attenuated by cannflavin-C. This study provides novel insights into the potential of cannflavin-C in modulating arachidonic acid metabolites and attenuating Ang II-induced cardiac hypertrophy, highlighting the importance of this compound as potential therapeutic agents for cardiac hypertrophy. Significance Statement This study demonstrates that cannflavin-C offers protection against cellular hypertrophy induced by Ang II. The significance of this research lies in its novel discovery, which elucidates a mechanistic pathway involving the inhibition of CYP 1B1 by cannflavin-C. This discovery opens up new avenues for leveraging this compound in the treatment of heart failure.

Evolving attitudes toward online education in Peruvian university students: A quantitative approach.

Introduction: The COVID-19 pandemic has accelerated universities' adaptation process toward online education, and it is necessary to know the students' attitudes toward this online education. Objective: To describe the evolution of the attitude toward online education among social science students at a public university in Peru in the academic year 2020, in the context of the COVID-19 pandemic. Methods: The study uses a quantitative approach, a descriptive level, a non-experimental design, and a longitudinal trend. The sample consisted of 1063 students at the beginning of the class period, 908 during the classes, and 1026 at the end of the class period. The questionnaire for data collection was the Attitude scale toward online education for university students during the COVID-19 pandemic. The data was collected using Google Forms. Results: As a result, the attitude towards online education was predominantly weak negative at the beginning (51.1 %) and during the classes (49.1 %), and weak positive (48.1 %) at the end of the class period. The changes were not significant when comparing the three moments, the levels of attitude toward, intention to adopt, ease of use, technical and pedagogical support, stressors, and need for online education (p-value <0.05). Conclusion: The evolution of the attitude towards online education in the sample had a non-significant positive trend. In the initial and process stages, a weak negative attitude prevailed due to the institution's inexperience and poor digital infrastructure; in the end, the attitude became weak and positive due to the adaptation and need for online education.

South American Validation of a Survey to Assess Eco-Anxiety in Adults (ECO-ANS-LATAM).

Background: climate change is a reality, and more and more people are becoming aware of this global problem, which has generated anxiety in some populations. To validate a short survey to assess eco-anxiety in adults in South America. Methods: It is an instrumental study, and the validation was based on a previous survey, which had six questions and was generated by 217 respondents in the USA in 2021. These questions were subjected to a validation process with expert judgment, pilot and application, and then statistics were obtained. It was validated with 1907 people in six countries in South America, where the mean, standard deviation, skewness and kurtosis were adequate. Results: The initial confirmatory factorial model obtained unsatisfactory goodness-of-fit indices, so the indices were modified through a re-specification, where two items were eliminated, after which adequate values were obtained (χ2 = 22.34, df = 2, p = 0.00; RMR = 0.020; GFI = 0.990; CFI = 0.990; TLI = 0.990; and RMSEA = 0.070). Finally, the overall Cronbach's α was calculated to be 0.88 (95% CI = 0.86-0.89). Conclusions: The test was validated in a large South American population and found that only four questions can efficiently measure anxiety about the effects of climate change. The instrument can be used with other tests to screen different age groups, ethnicities and realities.

Effect of polyphenols against complications of COVID-19: current evidence and potential efficacy.

The COVID-19 pandemic that started in 2019 and resulted in significant morbidity and mortality continues to be a significant global health challenge, characterized by inflammation, oxidative stress, and immune system dysfunction.. Developing therapies for preventing or treating COVID-19 remains an important goal for pharmacology and drug development research. Polyphenols are effective against various viral infections and can be extracted and isolated from plants without losing their therapeutic potential. Researchers have developed methods for separating and isolating polyphenols from complex matrices. Polyphenols are effective in treating common viral infections, including COVID-19, and can also boost immunity. Polyphenolic-based antiviral medications can mitigate SARS-CoV-2 enzymes vital to virus replication and infection. Individual polyphenolic triterpenoids, flavonoids, anthraquinonoids, and tannins may also inhibit the SARS-CoV-2 protease. Polyphenol pharmacophore structures identified to date can explain their action and lead to the design of novel anti-COVID-19 compounds. Polyphenol-containing mixtures offer the advantages of a well-recognized safety profile with few known severe side effects. However, studies to date are limited, and further animal studies and randomized controlled trials are needed in future studies. The purpose of this study was to review and present the latest findings on the therapeutic impact of plant-derived polyphenols on COVID-19 infection and its complications. Exploring alternative approaches to traditional therapies could aid in developing novel drugs and remedies against coronavirus infection.

Development of a Novel In Vitro Model to Study Lymphatic Uptake of Drugs via Artificial Chylomicrons.

The lymphatic system plays a crucial role in the absorption of lipophilic drugs, making it an important route for drug delivery. In this study, an in vitro model using Intralipid® was developed to investigate the lymphatic uptake of drugs. The model was validated using cannabidiol, halofantrine, quercetin, and rifampicin. Remarkably, the uptake of these drugs closely mirrored what would transpire in vivo. Furthermore, adding peanut oil to the model system significantly increased the lymphatic uptake of rifampicin, consistent with meals containing fat stimulating lymphatic drug uptake. Conversely, the inclusion of pluronic L-81 was observed to inhibit the lymphatic uptake of rifampicin in the model. This in vitro model emerges as a valuable tool for investigating and predicting drug uptake via the lymphatic system. It marks the first phase in developing a physiologically based predictive tool that can be refined further to enhance the precision of drug interaction predictions with chylomicrons and their subsequent transport via the lymphatic system. Moreover, it can be employed to explore innovative drug formulations and excipients that either enhance or hinder lymphatic drug uptake. The insights gained from this study have significant implications for advancing drug delivery through the lymphatic system.

Pharmacokinetics of cycloheximide in rats and evaluation of its effect as a blocker of intestinal lymph formation.

Cycloheximide (CHX) has been used to reduce the flow of intestinal lymph and as a non-surgical tool to study drug absorption via the intestinal lymphatics. Pharmacokinetic information on the agent, and its relationship to effect and toxicity, have not been examined. The goal of this study was to provide pharmacokinetic data and link it to lymph-blocking and toxicological effects. Jugular-vein cannulated (JVC) adult Sprague-Dawley male rats were administered 0.5 mg/kg CHX by oral, intraperitoneal (ip), and intravenous routes followed by blood draws, and CHX was assayed using LC-MS/MS. Another four JVC rats were given peanut oil (2 mL/kg) without and then with CHX to measure effects on lipid absorption as a surrogate indicator of lymph flow. One-week later plasma biochemistry measures were obtained. The results indicated that CHX had a high clearance and volume of distribution, and oral absolute bioavailability of 0.47 with 0.5 mg/kg. CHX was associated with dose- and route-dependent pharmacokinetics. The relative bioavailability after ip doses was over 3. CHX had low plasma protein binding and minor urinary excretion. Metabolism appeared to be occur by oxidation and glucuronidation. Reductions in plasma lipids (24-40 %) were seen after 2.5 mg/kg orally with signs of inflammation and increased liver enzymes persisting for a week after the dose. CHX was associated with a reduction in lipid absorption after oral doses of 2.5 mg/kg, which seems to justify its use as a non-surgical tool to evaluate the lymphatic pathway of absorption of drugs. However, it also possesses hepatotoxicity, which should be taken into consideration in its use.

Analytical determination, antioxidant and anti-inflammatory activities of Bhamrung-Lohit a traditional Thai medicine.

Background and purpose: Bhamrung-Lohit (BRL) remedy is a traditional Thai medicine (TTM). There are few reports of biological activity, the activity of its constituent plants, or quantitative analytical methods for the content of phytochemicals. In this study, we investigated antioxidant, anti-inflammatory activity, and total phenolic and flavonoid content and validated a new analytical method for BRL. Experimental approach: Antioxidant activity was evaluated by a 2,2-diphenyl-1-picrylhydrazyl (DPPH and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging. The cellular antioxidant activity was evaluated by inhibition of the superoxide anion (O2●-) production from HL-60 cells and anti-inflammatory activity by inhibition of nitric oxide production in RAW264.7 cells. The total phenolic and flavonoid contents were analyzed using the Folin-Ciocalteu method and an aluminum chloride colorimetric assay, respectively. Validated analytical procedures were conducted according to International Conference on Harmonization (ICH) guidelines. Findings/Results: An ethanolic extract of BRL exerted potent DPPH radical scavenging activity and moderate antioxidant and anti-inflammatory activity. Caesalpinia sappan exerted the greatest effect and the highest content of total phenolics and flavonoids. The HPLC method validated parameters that complied with ICH requirements. Each peak showed selectivity with a baseline resolution of 2.0 and precision was less than 2.0% CV. The linearity of all compounds was > 0.999 and the recovery % was within 98.0%-102.0%. The validated results demonstrated specificity/selectivity, linearity, precision, and accuracy with appropriate LOD and LOQ. Conclusion and implication: BRL remedy, a TTM demonstrated antioxidant and anti-inflammatory properties. This study is the first report on the biological activity and the validation of an HPLC method for BRL remedy.

Formulation design and physicochemical evaluation of an anti-inflammatory hydrogel patch containing Crinum asiaticum L. extract.

Background and purpose: Crinum asiaticum L. has long been used in Thai traditional medicine to treat osteoarthritis and inflammation by placing it on painful areas without further formulation design which is suboptimal for therapeutic use. Thus, this research aims to formulate a topical hydrogel patch containing C. asiaticum L. extracts (CAE) for anti-inflammatory effects. Experimental approach: The hydrogel patches are made from carrageenan, locust bean gum, with glycerin as a plasticizer and contain CAE formulated by using response surface methodology based on Box-Behnken design for design, determination of the effect of independent factors on the tensile strength, and optimization of the hydrogel patch formulation. In vitro release and skin permeation studies using a modified Franz diffusion cell and anti-inflammatory activity were evaluated. Findings/Results: The optimized CAE hydrogel patch showed a good correlation between predicted and observed tensile strength values and exerted its maximum cumulative lycorine release and permeation at 69.38 ± 2.78% and 48.51 ± 0.45%, respectively which were fit to Higuchi's kinetic model. The release rates were found to decrease with an increase in the polymer proportion of carrageenan and locust bean gum. In addition, the patch exerted potent in vitro anti-inflammatory activity with an IC50 value of 21.36 ± 0.78 µg/mL. Conclusion and implication: The optimized CAE hydrogel patch application was successfully formulated with excellent mechanical properties, cumulative release, permeation, and anti-inflammatory effects. Thus, it has the potential to be further developed as a herbal application to relieve pain and inflammation. The in vivo anti-inflammatory effect of this delivery system should be further investigated.

A validated method for detection of cannflavins in hemp extracts.

A selective and sensitive liquid chromatography mass spectrometry assay was developed for the detection of cannflavin A, B, and C in hemp extract specimens. A deuterated analog cannabidiol-D3 was used as the internal standard and the isocratic method used a mobile phase consisting of acetonitrile and water with 0.1 % formic acid [83:17]. Detection was carried out by electrospray positive ionization in single-ion monitoring mode through a C-18 analytical column. The assay (total run time <20 min) had excellent linearity and a lower limit of quantification of 0.5 µg/mL and a limit of detection of 0.25 µg/mL with a 10 µL injection. The method possessed suitable measures of stability, sensitivity, and selectivity for detecting cannflavins in several specimen types. The method was successfully applied to the analysis of samples of cannflavin release from prototype topical formulations.

Therapeutic Potential and Predictive Pharmaceutical Modeling of Stilbenes in Cannabis sativa.

Cannabis sativa is a plant used for recreational and therapeutic purposes; however, many of the secondary metabolites in the plant have not been thoroughly investigated. Stilbenes are a class of compounds with demonstrated anti-inflammatory and antioxidant properties and are present in cannabis. Many stilbenes present in cannabis have been investigated for their therapeutic effects. Fourteen stilbenes have been identified to be present in cannabis, all of which are structurally dihydrostilbenoids, with half possessing a prenylated moiety. The stilbenes summarized in this analysis show varying degrees of therapeutic benefits ranging from anti-inflammatory, antiviral, and anti-cancer to antioxidant effects. Many of the identified stilbenes have been researched to a limited extent for potential health benefits. In addition, predictive in silico modeling was performed on the fourteen identified cannabis-derived stilbenes. This modeling provides prospective activity, pharmacokinetic, metabolism, and permeability data, setting the groundwork for further investigation into these poorly characterized compounds.

Phytochemical Profiles and Anticancer Effects of Calophyllum inophyllum L. Extract Relating to Reactive Oxygen Species Modulation on Patient-Derived Cells from Breast and Lung Cancers.

Reactive oxygen species (ROS) contribute to cancer growth and metastasis. Using antioxidants to modulate cellular ROS levels is a promisingstrategy for cancer prevention and treatment. Calophyllum inophyllum L., or tamanu, is a medicinal plant renowned for its anti-inflammatory, antioxidant, and anticancer properties in traditional medicine systems. However, the anticancer effects of C. inophyllum extract on cellular ROS remain unexplored. This study represents the first report on such effects and provides the potential mechanisms underlying the anticancer properties of C. inophyllum extract. The branches of C. inophyllum were extracted, and the extract was comprehensively analyzed for phytochemical constituents, antioxidant capacity, total phenolic content, and total flavonoid content. Subsequently, the extract's potential anticancer properties were evaluated using patient-derived cells from breast and lung cancer. The results revealed that the C. inophyllum extract possesses notable antioxidant activity and demonstrated no cytotoxicity within the initial 24 h of treatment. However, after 72 h, it exhibited significant antiproliferative effects. Moreover, the extract exhibited inhibitory properties against migration and invasion at concentrations below the IC50, which corresponded to the expression of related genes. Notably, these effects correlated with the reduction of intracellular ROS levels. Overall, our findings highlight the anticancer potential of C. inophyllum extract, emphasize its ability to modulate cellular ROS levels and target key molecular pathways involved in cancer progression. This study sheds light on the promising therapeutic implications of C. inophyllum extract as a novel agent for cancer treatment, which is safe for normal cells.

Sub-cellular sequestration of alkaline drugs in lysosomes: new insights for pharmaceutical development of lysosomal fluid.

Background and purpose: Lysosomal-targeted drug delivery can open a new strategy for drug therapy. However, there is currently no universally accepted simulated or artificial lysosomal fluid utilized in the pharmaceutical industry or recognized by the United States Pharmacopeia (USP). Experimental procedure: We prepared a simulated lysosomal fluid (SLYF) and compared its composition to a commercial artificial counterpart. The developed fluid was used to test the dissolution of a commercial product (Robitussin®) of a lysosomotropic drug (dextromethorphan) and to investigate in-vitro lysosomal trapping of two model drugs (dextromethorphan and (+/-) chloroquine). Findings/Results: The laboratory-prepared fluid or SLYF contained the essential components for the lysosomal function in concentrations reflective of the physiological values, unlike the commercial product. Robitussin® passed the acceptance criteria for the dissolution of dextromethorphan in 0.1 N HCl medium (97.7% in less than 45 min) but not in the SLYF or the phosphate buffer media (72.6% and 32.2% within 45 min, respectively). Racemic chloroquine showed higher lysosomal trapping (51.9%) in the in-vitro model than dextromethorphan (28.3%) in a behavior supporting in-vivo findings and based on the molecular descriptors and the lysosomal sequestration potential of both. Conclusion and implication: A standardized lysosomal fluid was reported and developed for in-vitro investigations of lysosomotropic drugs and formulations.

Prevalence of post-traumatic stress disorder risk post-COVID-19 in 12 countries in Latin America: a cross-sectional survey.

Introduction: Latin America was the region most affected by COVID-19 in the second quarter of 2020, and consequently, the impact on mental health requires evaluation. The aim of this study was to assess the risk of post-traumatic stress disorder (PTSD) caused by bereavement due to COVID-19 in 12 countries in Latin America. Methods: The current study was an analytical cross-sectional study. Validated tests were applied for PTSD, depression, anxiety, and stress (DASS-21), questions about the respondent's condition or their environment, and demographic questions, as well as the length of the mourning period of suffering. Results: The outcomes demonstrated that the PTSD risk increased for women (p < 0.001), when a friend or acquaintance had COVID-19 (p = 0.002), when a close relative died from COVID-19 (p = 0.010), having severe depression (p <0.001), severe anxiety (p <0.001), severe stress (p <0.001), residing in Chile (p <0.001), Paraguay (p <0.001), Bolivia (p <0.001), Costa Rica (p <0.001) or El Salvador (p = 0.005). On the other hand, there was less risk of PTSD at an older age (p <0.001) or if respondents had a sentimental partner (p = 0.025). In the case of severe PTSD, there was a greater gender risk for women (p <0.001), a close relative dying from COVID-19 (p = 0.017), having severe depression (p <0.001), severe anxiety (p <0.001), severe stress (p <0.001), residing in Chile (p <0.001), Paraguay (p <0.001), Bolivia (p <0.001) and Costa Rica (p = 0.002). It was also observed that there was less risk of severe PTSD at an older age demographic (p <0.001). Discussion: It can be concluded that the percentages of PTSD are high in its clinical presentation as severe, especially among Latin American women.

Garcinia mangostana hydrogel patch: bactericidal activity and clinical safety for acne vulgaris treatment.

Background and purpose: Garcinia mangostana, simply known as mangosteen, has long been used by Thai traditional medicine because of its reported antibacterial and anti-inflammatory activities for the treatment of skin infections. In this study, mangosteen pericarps were developed into a hydrogel patch to eradicate acne-inducing bacteria. Experimental procedure: The G. mangostana extract was investigated for bactericidal activity. A hydrogel patch containing the extract was examined for mechanical properties, antibacterial activity, in vitro release, skin permeation, and a phase I clinical study of skin irritation and allergic testing by a closed patch test. Finding/Results: The G. mangostana hydrogel patch made from carrageenan and locust bean gum powders was yellow in color, smooth, durable, and flexible. This G. mangostana hydrogel patch was effective against Cutibacterium acnes, Staphylococcus epidermidis, and Staphylococcus aureus. The active ingredient, α-mangostin, was released and permeated from the G. mangostana hydrogel patch within the first 30 min at 33.16 ± 0.81% and 32.96± 0.97%, respectively. The G. mangostana hydrogel patch showed no irritation in 30 healthy volunteers. However, two volunteers had delayed allergic contact dermatitis to 0.5% (w/w) G. mangostana hydrogel patch. Conclusion and implication: This hydrogel patch containing G. mangostana ethanolic extract is not recommended for patients who have any reaction to mangosteen but has utility as an anti-acne facial mask.

Exploring in vitro anti-proliferative and anti-inflammatory activities of Prasachandaeng remedy, and its bioactive compounds.

BACKGROUND: Prasachandaeng (PSD) remedy has been empirically used in Thai traditional medicine to treat fever in bile duct and liver and cancer patients through Thai folk doctors. However, there have been no scientific reports on the bioactive compounds and bioactivities related to inflammation-associated carcinogenesis or cytotoxicity against cancer cell lines. In this study, we investigated the chemical content of the remedy, and evaluated its cytotoxic activity against two cancer cell lines in comparison with a non-cancerous cell line and determined tumor necrosis factor-alpha (TNF-α) production in a murine macrophage cell line (RAW 264.7) to evaluate anti-inflammatory activity. A novel HPLC method was used for quality control of its chemical content. METHODS: Pure compounds from the EtOH extract of D. cochinchinensis were isolated using bioassay-guided fractionation and chemical content of the PSD remedy was determined using HPLC. The cytotoxic activity against the hepatocarcinoma cell line (HepG2) and cholangiocarcinoma cell line (KKU-M156), in comparison with non-cancerous cell line (HaCaT), were investigated using antiproliferative assay (SRB). The anti-inflammatory activity measured by TNF-α production in RAW 264.7 was determined using ELISA. RESULTS: All crude extracts and isolated compounds exhibited significant differences from vincristine sulfate (****p < 0.0001) in their cytotoxic activity against HepG2, KKU-M156, and HaCaT. The PSD remedy exhibited cytotoxic activity against HepG2 and KKU-M156 with IC50 values of 10.45 ± 1.98 (SI = 5.3) and 4.53 ± 0.74 (SI = 12.2) µg/mL, respectively. Some constituents from C. sappan, D. cochinchinensis, M. siamensis, and M. fragrans also exhibited cytotoxic activity against HepG2 and KKU-M156, with IC50 values less than 10 µg/mL. The isolated compounds, i.e., Loureirin B (1), 4-Hydroxy-2,4'-dimethoxydihydrochalcone (2), and Eucomol (3) exhibited moderate cytotoxicity against two cancer cell lines. None of the crude extracts and isolated compounds showed cytotoxicity against HaCaT. D. cochinchinensis and PSD remedy exhibited higher anti-inflammatory activity measured as TNF-α production than acetaminophen. CONCLUSION: The findings provide evidence of bioactivity for EtOH extracts of PSD remedy and the isolated compounds of D. Cochinchinensis. The results consistent the use clinical activity and use of PSD remedy as a antipyretic treatment for liver and bile duct cancer patients by Thai traditional practitioners.

Labeling of Genetically Modified (GM) Foods in Peru: Current Dogma and Insights of the Regulatory and Legal Statutes.

The COVID-19 pandemic has affected and afflicted human lives and been a transformative catalyst leading to closure of many companies, disrupting mental health, and reducing access to food and exacerbating food insecurity. This presents an opportunity to reflect on and examine genetically modified (GM) foods and their effective legislative regulation for the benefit of consumers. This review presents a detailed analysis of GM foods' regulation in Peru and the analysis of certain specific cases that show the need for greater regulation of the industry.

Development and optimization of Benjakul microemulsion formulations for enhancing topical anti-inflammatory effect and delivery.

Background and purpose: Benjakul (BJK) is a combination of five botanical herbal constituents widely used in Thai traditional medicine as an anti-inflammatory remedy. This study aimed to develop a novel topical microemulsion containing BJK for clinical use. Experimental approach: The microemulsions were produced by a phase inversion temperature (PIT) methodology. Physicochemical properties and stability were evaluated to determine an optimal formula. The stable BJK-loaded microemulsion formulas were then subjected to in vitro studies for their anti-inflammatory activity, skin cell toxicity, drug permeation, and stability. Finding/Results: Two novel formulations containing isopropyl myristate (ME1-BJK and ME2-BJK) passed the compendial stability test. BJK constituents were completely dissolved in the oil phase and incorporated into the microemulsion base Transcutol® and Labrasol® avoiding the use of alcohol, both microemulsion formulations demonstrated high anti-inflammatory activity with IC50 values of 3.41 ± 0.36 and 3.95 ± 1.73 µg/mL, respectively. However, dissolution of ME1-BJK showed a superior release profile through both lipophilic and hydrophilic membranes with the highest accumulated amount at 4 h of 25.13% and 38.06%, respectively. All tested formulations of BJK extract demonstrated no apparent skin cell toxicity at concentrations up to 50 µg/mL. After six-month storage under accelerated conditions, there were no significant changes in anti-inflammatory activity. Conclusions and implications: A novel and stable BJK-loaded microemulsion formulation was successfully developed with excellent release and stability properties. Further clinical research to evaluate pain reduction, edema, and skin irritation using this formulation in animal models is ongoing.

Novel, First-in-Human, Oral PCLX-001 Treatment in a Patient with Relapsed Diffuse Large B-Cell Lymphoma.

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) have limited treatment options, particularly if they are transplantation or chimeric antigen receptor (CAR) T-cell ineligible, and novel therapeutics are needed. An 86-year-old woman with relapsed DLBCL received a novel, first-in-class small molecule inhibitor of N-myristoyltransferase (NMT) as the initial patient on a phase I dose escalation trial. Daily oral administration of 20 mg PCLX-001 tablets produced a pharmacokinetic profile suitable for single daily dosing: rapid oral absorption, followed by an apparent elimination half-life of 16 h, without systemic accumulation of drug by day 15. Pharmacodynamic tests showed no clear change in NMT1 and NMT2 levels or selected NMT substrate Lyn and HGAL protein levels in normal circulating blood mononuclear cells, suggesting a higher dose will be required for normal tissue toxicity. The patient did not experience any dose-limiting toxicities but had disease progression after 28 days of study therapy. Dose escalation continues in other patients in this first-in-human study of a new class of anticancer drug. We conclude that PCLX-001 oral monotherapy has suitable pharmacokinetic parameters for dose escalation, and that higher doses are required to achieve pharmacodynamic evidence of on-target activity in normal tissues. The current protocol is appropriately designed to achieve these ends, and the study proceeds without modification.

Investigations of the antipyretic effect and safety of Prasachandaeng, a traditional remedy from Thailand national list of essential medicines.

Prasachandaeng (PSD) remedy from the Thailand National List of Essential Medicines (NLEM) has been used as an antipyretic for chronic fever in both adults and children for centuries. Its therapeutic effect in treating fever and its safety have not been studied in animal models. We evaluated its antipyretic activity on lipopolysaccharide (LPS)-induced fever and safety in the liver in comparison with acetaminophen (ACP). Correlation between biochemistry of liver function and the level of cytochrome P450 (CYP2E1) was also evaluated using an ELISA kit. All doses of PSD powder (PSDP) and a 95% ethanol extract of PSD (PSDE) (50, 200, and 400 mg/kg) showed a significant antipyretic effect (* p < 0.05) as compared to ACP. We investigated clinical biochemistry of liver and kidney functions, histopathology, and concentrations of CYP2E1. All treatment groups demonstrated a normal range of clinical biochemistry of liver and kidney functions in comparison with ACP on days 1, 3, 7, and 10. Serum AST, ALP, and LDH levels of PSDE and PSDP showed mean values less than that of ACP on the corresponding days (* p < 0.05). None of the treatment groups showed evidence of hepatocellular damage, nor did they affect CYPE21. The results of histopathology on liver tissue correlated with the biochemistry of liver functions which indicated no hepatotoxicity effect in liver tissue during the seven day treatment. These findings suggest that both forms of PSD remedy possessed marked antipyretic activity and were not hepatotoxic during the seven days of administration in rats.