Dose Range Research Articles

Psilocybin Facilitates Fear Extinction: Importance of Dose, Context, and Serotonin Receptors.

A variety of classic psychedelics and MDMA have been shown to enhance fear extinction in rodent models. This has translational significance because a standard treatment for post-traumatic stress disorder (PTSD) is prolonged exposure therapy. However, few studies have investigated psilocybin's potential effect on fear learning paradigms. More specifically, the extents to which dose, timing of administration, and serotonin receptors may influence psilocybin's effect on fear extinction are not understood. In this study, we used a delay fear conditioning paradigm to determine the effects of psilocybin on fear extinction, extinction retention, and fear renewal in male and female mice. Psilocybin robustly enhances fear extinction when given acutely prior to testing for all doses tested. Psilocybin also exerts long-term effects to elevate extinction retention and suppress fear renewal in a novel context, although these changes were sensitive to dose. Analysis of sex differences showed that females may respond to a narrower range of doses than males. Administration of psilocybin prior to fear learning or immediately after extinction yielded no change in behavior, indicating that concurrent extinction experience is necessary for the drug's effects. Cotreatment with a 5-HT2A receptor antagonist blocked psilocybin's effects for extinction, extinction retention, and fear renewal, whereas 5-HT1A receptor antagonism attenuated only the effect on fear renewal. Collectively, these results highlight dose, context, and serotonin receptors as crucial factors in psilocybin's ability to facilitate fear extinction. The study provides preclinical evidence to support investigating psilocybin as a pharmacological adjunct for extinction-based therapy for PTSD.

SAFER: sub-hypergraph attention-based neural network for predicting effective responses to dose combinations

BackgroundThe potential benefits of drug combination synergy in cancer medicine are significant, yet the risks must be carefully managed due to the possibility of increased toxicity. Although artificial intelligence applications have demonstrated notable success in predicting drug combination synergy, several key challenges persist: (1) Existing models often predict average synergy values across a restricted range of testing dosages, neglecting crucial dose amounts and the mechanisms of action of the drugs involved. (2) Many graph-based models rely on static protein–protein interactions, failing to adapt to dynamic and higher-order relationships. These limitations constrain the applicability of current methods.ResultsWe introduce SAFER, a Sub-hypergraph Attention-based graph model, addressing these issues by incorporating complex relationships among biological knowledge networks and considering dosing effects on subject-specific networks. SAFER outperformed previous models on the benchmark and the independent test set. The analysis of subgraph attention weight for the lung cancer cell line highlighted JAK-STAT signaling pathway, PRDM12, ZNF781, and CDC5L that have been implicated in lung fibrosis.ConclusionsSAFER presents an interpretable framework designed to identify drug-responsive signals. Tailored for comprehending dose effects on subject-specific molecular contexts, our model uniquely captures dose-level drug combination responses. This capability unlocks previously inaccessible avenues of investigation compared to earlier models. Furthermore, the SAFER framework can be leveraged by future inquiries to investigate molecular networks that uniquely characterize individual patients and can be applied to prioritize personalized effective treatment based on safe dose combinations.

Novel Relaxin Receptor RXFP1 Agonist AZD3427 in the Treatment of Heart Failure: A Phase 1a/b, First-in-Human, Randomized, Single-Blind, Placebo-Controlled Study.

Heart failure mortality remains high despite recent progress in pharmacological treatment. AZD3427 is a selective long-acting analog of relaxin, a vasodilatory hormone with antifibrotic effects. We assessed the safety, pharmacokinetics, and pharmacodynamics of AZD3427 in healthy volunteers and patients with heart failure on standard-of-care therapy. In this first-in-human, phase 1a/b, randomized, single-blind, placebo-controlled study, healthy volunteers were randomized 6:2 to receive a single dose of AZD3427 or placebo by subcutaneous injection in 5 mixed-ethnicity cohorts (5, 10, 30, 90, or 270 mg) and 1 Japanese-descent cohort (270 mg), or by intravenous injection in 1 cohort (15 mg). After confirming safety and tolerability in healthy volunteers, 3 cohorts of patients with heart failure and left ventricular ejection fraction ≤40% and 3 cohorts with ejection fraction ≥41% were randomized 6:2 to receive 5 weekly doses of AZD3427 (5, 15, or 45 mg) or placebo by subcutaneous injection. In total, 56 healthy volunteers and 48 patients with heart failure were randomized. AZD3427 was well tolerated at all doses. After subcutaneous administration, AZD3427 was absorbed slowly, and exposure was approximately linear across the dose range. In patients with heart failure, AZD3427 terminal half-life was 13 to 14 days and there were numerical increases in stroke volume and estimated glomerular filtration rate. No treatment-emergent antidrug antibodies were detected. AZD3427 had favorable safety and pharmacokinetic profiles. Hemodynamic changes in patients with heart failure were consistent with the anticipated effects of a relaxin analog. These findings support further development of AZD3427 as a novel long-term treatment for patients with heart failure. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04630067.

A Model-Informed Drug Development Approach Supporting the Approval of an Unstudied Valbenazine Dose for Patients With Tardive Dyskinesia.

Valbenazine is a highly potent and selective inhibitor of synaptic vesicular monoamine transporter 2. The current therapeutic doses of valbenazine for tardive dyskinesia (TD) are 40, 60, or 80 mg capsules, given orally, once daily (QD). While 40 and 80 mg were investigated in phase 3 KINECT® 3 trial and initially approved, the approval of valbenazine 60mg was based on the analysis utilizing the Model-informed drug development (MIDD) approach, facilitated through the US Food and Drug Administration's MIDD Pilot Program. This study aimed to demonstrate the efficacy of 60 mg QD dose through model simulations using an established exposure-response (E-R) relationship between valbenazine active metabolite [+]-α-dihydrotetrabenazine exposure and the change from baseline in Abnormal Involuntary Movement Scale total score (AIMS-CFB). A longitudinal E-R model was constructed based on the 40 and 80 mg data from the KINECT 3 trial. The final Emax model adequately predicted dose-dependent improvement in the primary endpoint and was used to interpolate AIMS-CFB for 60 mg at week 6. The efficacy of the unstudied 60 mg dose regimen is expected to be within the range of doses studied clinically with predicted mean AIMS-CFB (95% confidence interval) of -2.69 (-3.30, -2.13) between observed mean AIMS-CFB for 40 mg of -1.92 and 80 mg of -3.39. Results from this analysis provided the key evidence to establish efficacy of 60 mg QD without the need for an additional clinical trial. The availability of valbenazine 60mg dose fills an existing medical need for patients with TD who could benefit from this third effective dose.

Exploring the thermoluminescence characteristics of smartphone screen safety glasses for retrospective dosimetry applications

In clinical settings, standard dosimeters might miss radiation mishaps. Retrospective dosimeters could help to track personnel (such as patients and other staff who don't wear dosimeters) exceeding safe limits and assess long-term exposure trends. This study has investigated key thermoluminescence (TL) dosimetric characteristics, including the glow curve structure, dose-response, energy dependence, sensitivity and fading of various safety glasses that are used as screen protectors of smartphones subjected to photon irradiation. Among the studied glasses, the HD Anti-Peep safety glass for iPhone has been found to exhibit a linear dose-response with a regression coefficient of 99% within the dose range of 2–10 Gy. Moreover, all the safety glasses showed independence with respect to photon energy of 6 MV and 10 MV. The TL glow curves of the samples showed a broad glow peak between 125 °C and 325 °C at 10 Gy. The TL kinetic parameters of the safety glasses were also studied by analyzing the glow curves using the peak shape and initial rise method. The geometric factor (μg) is found to be within the range of 0.43–0.53, which indicates the suitability of applying Chen's general-order formula to calculate the kinetic parameters such as activation energy, frequency factor and trap lifetime. The activation energy (E) and frequency factor (s) are found in the range of 0.31–0.54 eV and 4.55 × 103 to 2.12 × 106 s−1 respectively obtained via the peak shape method. The relatively long trap lifetime and observed thermoluminescence features indicate that the HD Anti-Peep safety glass offers a better option to estimate dose retrospectively to ensure the safety of human health.

Influence of α-lipoic acid on longevity and stress resistance in Drosophila melanogaster fed with a high-fat diet.

Consumption of a high-fat diet is accompanied by the risks of obesity and early onset of age-associated complications for which dietary interventions are imperative to combat. α-lipoic acid has been shown to hinder diet-induced obesity and induce lifespan-extending efficacy in model organisms. In this study, α-lipoic acid was investigated for its efficacy in improving lifespan and stress resistance in the Canton-S strain of Drosophila melanogaster fed with a high-fat diet. Furthermore, as mating status significantly impacts survival in fruit flies, flies were reared in two experimental groups-group one, in which males and females were bred together, and group two, in which males and females were bred separately. In group one, α-lipoic acid improved the mean lifespan, reduced the fecundity of females, and reduced the mean body weight of flies at a dose range of 2-2.5mM, respectively. In group two, α-lipoic acid improved the mean lifespan, reduced the fecundity of females, and reduced the mean body weight of flies at a dose range of 1-2.5mM, respectively. Improved climbing efficiency was observed with α-lipoic acid at the dose range of 1.5-2.5mM in flies of group one and 1-2.5mM in flies of group two, respectively. Administration of α-lipoic acid improved resistance to oxidative stress in only female flies of group one at 2.5mM, whereas in group two, both male and female flies exhibited enhanced resistance to oxidative stress with α-lipoic acid at a dose range of 2-2.5mM, respectively. Male and female flies of only group one showed improved resistance to heat shock stress with α-lipoic acid at a dose range of 2-2.5mM. Only female flies of group two exhibited a slight improvement in recovery time following cold shock with α-lipoic acid only at 2.5mM. No significant change in resistance to starvation stress was observed with any dose of α-lipoic acid in either group of flies. To summarize, data from this study suggested a probable dose and gender-dependent efficacy of α-lipoic acid in flies fed with a high-fat diet, which was significantly influenced by the mating status of flies due to varied rearing conditions.

Dose-response of daridorexant in insomnia disorder: An analysis of Phase 2 and 3 studies

ObjectiveDaridorexant is approved for the treatment of insomnia at two dose levels (25 and 50 mg). Dose-efficacy and -safety response relationships were evaluated using Phase 2 and 3 data. MethodsData (N = 2153) from one Phase 2 (daridorexant 5, 10, 25, 50 mg, placebo once daily for 1 month) and two Phase 3 studies (daridorexant 10 and 25 or 25 and 50 mg, placebo once daily for 3 months) were pooled. Dose-response analyses at 1 month of double-blind treatment were performed using a linear regression and a two-stage meta-analysis approach. Efficacy endpoints were polysomnography-derived wake after sleep onset, latency to persistent sleep (LPS), self-reported total sleep time and the Insomnia Daytime Symptoms and Impacts Questionnaire total score (only Phase 3 data for the latter). Safety endpoints were the incidence of total adverse events (AEs) and AEs corresponding to somnolence/fatigue. ResultsDose-responses for all efficacy endpoints were significant in the observed dose range (both statistical approaches, p < 0.01). All dose-response relationships were linear except for LPS (two-stage meta-analysis) which showed a change in slope above 10 mg without reaching a plateau. No significant dose-response was observed for any AE (both approaches, p > 0.05). The incidence of AEs corresponding to somnolence/fatigue was low at all doses and, without linear assumption (two-stage meta-analysis) there was no dose-dependency (p = 0.369). ConclusionsThe data support the use of 50 mg as the preferred daridorexant dose in patients with insomnia disorder to provide the greatest opportunity for efficacy with no increased risk for AEs, including somnolence/fatigue, compared to lower doses.

Intravenous initial bolus during prophylactic norepinephrine infusion to prevent spinal hypotension for cesarean delivery: A randomized controlled, dose-finding trial

BackgroundPrevious studies have shown that a 0.05 μg/kg/min of norepinephrine infusion in combination with an initial bolus reduces the incidence of spinal hypotension during cesarean delivery. The initial norepinephrine bolus influences the incidence of spinal hypotension during continuous norepinephrine infusion; however, the ideal initial bolus dose for 0.05 μg/kg/min of continuous infusion remains unknown. MethodsThis randomized, controlled, dose-finding study randomly allocated 120 parturients scheduled for elective cesarean delivery to receive initial bolus doses of 0, 0.05, 0.10, and 0.15 μg/kg of norepinephrine, followed by continuous infusion at a rate of 0.05 μg/kg/min. The primary outcome was the dose-response relationship of the initial norepinephrine bolus in preventing the incidence of spinal hypotension. Spinal hypotension was defined as systolic blood pressure (SBP) decreased to <80% of the baseline value or to an absolute value of <90 mmHg from intrathecal injection to delivery, and severe spinal hypotension was defined as SBP decreased to <60% of the baseline value. The secondary outcomes included the incidence of nausea and/or vomiting, hypertension, and bradycardia, as well as the Apgar scores and results of the umbilical arterial blood gas analysis. The effective dose (ED) 90 and ED95 were estimated using probit regression. ResultsThe per-protocol analysis included 117 patients. The incidence of spinal hypotension varied significantly among the groups: Group 0 (51.7%), Group 0.05 (44.8%), Group 0.10 (23.3%), and Group 0.15 (6.9%). The ED90 and ED95 values were 0.150 μg/kg (95% confidence interval [CI], 0.114–0.241 μg/kg) and 0.187 μg/kg (95% CI, 0.141–0.313 μg/kg), respectively. However, the ED95 value fell outside the dose range examined in this study. The incidence of severe spinal hypotension differed significantly (P = 0.02) among Groups 0 (17.2%), 0.05 (10.3%), 0.10 (3.3%), and 0.15 (0.0%); however, the incidence of hypertension and bradycardia did not. The incidence of nausea and/or vomiting decreased with an increase in the initial bolus dose (P = 0.03). The fetal outcomes were comparable among the groups. ConclusionsAn initial bolus of 0.150 μg/kg of norepinephrine may be the optimal dose for preventing spinal hypotension during cesarean delivery with a continuous infusion rate of 0.05 μg/kg/min, and does not significantly increase the incidence of hypertension but substantially reduces the risk of nausea and/or vomiting.

Luminescence and Dosimetry Investigations of Eu(III) Doped Ca2CeVO6 Novel Double Perovskite

A novel composition of vanadate double perovskite Ca2CeVO6 doped with Eu3+ was successfully synthesized using combustion synthesis, wherein the doping levels of Eu3+ ranged from 1 to 6 mol%. The Rietveld refinement of the powder X-ray diffraction (XRD) data confirmed the orthorhombic structure of the phosphors. Scanning electron microscopy (SEM) and energy-dispersive X-ray analysis (EDAX) were employed to investigate the surface morphology and elemental distribution in the phosphor, respectively. Under the excitation at 280 nm and 467 nm, the phosphor exhibited strong down-conversion red photoluminescence (PL) emission, attributed to Eu3+ transitions (5D0-7FJ, where J=0-3) originating from its 4f states. The intensity of PL emission shows increasing trend with increasing doping concentration. However, exceeding the threshold doping concentrations led reduction in PL intensity due to multipolar interaction effects. Additionally, the Eu3+ doped Ca2CeVO6 phosphors were subjected to irradiation with a radioactive 90Sr/90Y beta source to explore their thermoluminescence (TL) properties. Post-irradiation, the phosphors displayed prominent TL glow curves, with the most intense peak at around 94°C, followed by peaks at 160°C and 288°C. The TL intensity of these peaks exhibited a linear dose response within the dose range of 1 Gy to 50 Gy. Besides, the TL fading and reproducibility tests showed satisfactory results. Furthermore, Tmax-Tstop experiments revealed the presence of three trap centres within the trap depth range of 0.7-2.1 eV in the Ca2CeVO6:Eu3+ phosphor. Additionally, the glow curve deconvolution (GCD) was employed to determine trapping parameters, providing valuable insights into the TL behaviour of the phosphor. Overall, the results suggest that the novel phosphor under study holds promise for its applications in lighting devices and TL dosimetry (TLD).

Effectiveness and mechanisms of mesenchymal stem cell therapy in preclinical animal models of hepatic fibrosis: a systematic review and meta-analysis

BackgroundLiver damage due to long-term viral infection, alcohol consumption, autoimmune decline, and other factors could lead to the gradual development of liver fibrosis. Unfortunately, until now, there has been no effective treatment for liver fibrosis. Mesenchymal stem cells, as a promising new therapy for liver fibrosis, can slow the progression of fibrosis by migrating to the site of liver injury and by altering the microenvironment of the fibrotic area.AimBy including all relevant studies to date to comprehensively assess the efficacy of mesenchymal stem cells for the treatment of hepatic fibrosis and to explore considerations for clinical translation and therapeutic mechanisms.MethodsData sources included PubMed, Web of Science, Embase, and Cochrane Library, and were constructed until October 2023. Data for each study outcome indicator were extracted for comprehensive analysis.ResultsThe overall meta-analysis showed that mesenchymal stem cells significantly improved liver function. Moreover, it inhibited the expression level of transforming growth factor-β [SMD = 4.21, 95% CI (3.02,5.40)], which in turn silenced hepatic stellate cells and significantly reduced the area of liver fibrosis [SMD = 3.61, 95% CI (1.41,5.81)].ConclusionSeveral outcome indicators suggest that mesenchymal stem cells therapy is relatively reliable in the treatment of liver fibrosis. The therapeutic effect is cell dose-dependent over a range of doses, but not more effective at higher doses. Bone-marrow derived mesenchymal stem cells were more effective in treating liver fibrosis than mesenchymal stem cells from other sources.Systematic Review RegistrationIdentifier CRD42022354768.

Pharmacokinetic/pharmacodynamic model-based optimization of temocillin dosing strategies for the treatment of systemic infections.

Temocillin is increasingly considered as an alternative to carbapenems. However, there is no consensus on optimal dosing strategies and limited data on temocillin efficacy in systemic infections. We compared temocillin dosing strategies using pharmacokinetic/pharmacodynamic (PK/PD) modelling and simulation based on plasma exposure and in vitro time-kill data. Temocillin effects on four Escherichia coli strains were evaluated using static time-kill experiments and the hollow-fibre infection model, in which unbound plasma concentrations following intermittent and continuous infusion regimens of 4 and 6 g daily were replicated over 72 h. A PK/PD model was developed to describe the time-kill data. The PK/PD model was coupled to a population PK model of temocillin in critically ill patients to predict bacterial killing and resistance development following various dosing regimens. Amplification of resistant subpopulations was observed within 24 h for all strains. The PK/PD model described the observed bacterial kill kinetics and resistance development from both experimental systems well. Simulations indicated dose-dependent bacterial killing within and beyond the currently used daily dose range, and a superiority of continuous compared with intermittent infusions. However, regrowth of resistant subpopulations was frequently observed. For two strains, bacteriostasis over 72 h was predicted only with doses that are higher than those currently licensed. Continuous infusions and 6 g daily doses of temocillin kill E. coli more effectively than 4 g daily doses and intermittent infusions, and may increase efficacy in the treatment of systemic infections. However, higher daily doses may be required to suppress resistance development.

Clinical factors influencing the success rate of radioiodine treatment for Graves' disease.

To investigate the impact of various clinical factors associated with Graves' disease on the success rate of radioiodine (RAI) therapy for Graves' disease within 3 years, and to determine the optimal range of iodine dosage per unit volume that yields the highest cure rate for Graves' disease within 1 year. This retrospective study included patients diagnosed with Graves' disease who underwent RAI therapy at the Second Affiliated Hospital of Anhui Medical University between October 2012 and October 2022. The cumulative success rate was analysed using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression models were employed to evaluate factors associated with successful treatment of Graves' disease. Outcomes were categorized as either success or failure for all patients. Overall, 1994 patients were enrolled in this study, including 594 (29.8%) male and 1399 (70.2%) female patients. The success and failure groups comprised 1645 (82.4%) and 349 patients (17.6%), respectively, after a 3-year follow-up period. Multivariate regression analysis demonstrated that sex, antithyroid drug (ATD) use before RAI therapy, age, thyroid receptor antibody (TRAb) levels, iodine dose, thyroid mass, and early ATD use before RAI therapy were independent influencing factors for Graves' disease cure. We found that female patients and those with TRAbs ≥31.83 IU/L and thyroid mass ≥ 73.42 g had a lower cure rate. Therefore, thyroid size, disease severity, and duration of disease should be comprehensively considered when making treatment decisions and iodine dose selection in clinical practice.

Evaluation of potential punishing effects of 2,5-dimethoxy-4-methylamphetamine (DOM) in rhesus monkeys responding under a choice procedure.

There has been substantial and growing interest in the therapeutic utility of drugs acting at serotonin 2A subtype (5-HT2A) receptors, increasing the need for characterization of potential beneficial and adverse effects of such compounds. Although numerous studies have evaluated the possible rewarding and reinforcing effects of 5-HT2A receptor agonists, there have been relatively few studies on potential aversive effects. The current study investigated punishing effects of 2,5-dimethoxy-4-methylamphetamine (DOM) in four rhesus monkeys responding under a choice procedure in which responding on one lever delivered a sucrose pellet alone and responding on the other lever delivered a sucrose pellet plus an intravenous infusion of a range of doses of fentanyl (0.1-3.2 µg/kg/infusion), histamine (3.2-100 µg/kg/infusion), or DOM (3.2-100 µg/kg/infusion). When fentanyl was available, responding for a pellet plus an infusion increased dose dependently in all subjects, indicating a positive reinforcing effect of fentanyl. When histamine was available, responding for a pellet plus an infusion decreased in three of four subjects, indicating a punishing effect of histamine. Whether available before or after histamine, DOM did not systematically alter choice across the range of doses tested. These results suggest that the 5-HT2A receptor agonist DOM has neither positive reinforcing nor punishing effects under a choice procedure that is sensitive to both processes.

An investigation of 60Co gamma radiation induced damage in N-channel MOSFETS at cryogenic temperature.

N-channel depletion metal oxide semiconductor field effect transistors (MOSFETs) were irradiated with 60Co gamma radiation in the dose range of 100 krad to 6Mrad at cryogenic (77K) and room temperatures (300K). The MOS devices irradiated at 77K and 300K were characterized at 77K and 300K respectively. The different electrical parameters of MOSFET such as threshold voltage (Vth), density of interface trapped charges (ΔNit), density of oxide trapped charges (ΔNot) and mobility of the charge carriers (μ) were studied as a function of total dose. A considerable increase in ΔNit and ΔNot and decrease in Vth was observed after irradiation. The 77K irradiation results were then compared with 300K irradiation results and found that the degradation in the electrical characteristics is more for the devices irradiated at 300K.

60Co gamma radiation effects on NPN transistor at cryogenic temperature.

The 60Co gamma radiation effects on the DC electrical characteristics of silicon NPN transistor were studied in the dose range of 100krad to 6Mrad at room temperature (300K) and cryogenic temperature (77K). The measurements were carried out at both 300 and 77K temperature. The electrical characteristics such as Gummel characteristics, excess base current (ΔIB), current gain (hFE), transconductance (gm) and output characteristics were studied in situ as a function of total dose. The results show that there is a considerable degradation in the electrical parameters of the device irradiated both at 300 and 77K as a consequence of increase in excess base current (ΔIB) because of the formation of generation and recombination centers in the emitter-base spacer oxide (SiO2). At cryogenic temperature irradiation, the degradation in electrical characteristics is less because of the physical phenomena such as carrier freezeout effect, decreased recombination rate, reduced charge yield, decreased electron mobility, etc.

Analysis of glycoalkaloid distribution in the tissues of mealworm larvae (Tenebrio molitor)

Solanine (SOL) and chaconine (CHA) are glycoalkaloids (GAs) produced mainly by Solanum plants. These plant secondary metabolites affect insect metabolism; thus, they have the potential to be applied as natural plant protection products. However, it is not known which GA concentration induces physiological changes in animals. Therefore, the aim of this study was to perform a quantitative analysis of SOL and CHA in the larvae of Tenebrio molitor using LC‒MS to assess how quickly they are eliminated or metabolised. In this experiment, the beetles were injected with 2 μL of 10−5 M SOL or CHA solution, which corresponds to a dosage range of 0.12–0.14 ng/mg body mass. Then, 0.5, 1.5, 8, and 24 h after GA application, the haemolymph (H), gut (G), and the remainder of the larval body (FB) were isolated. GAs were detected in all samples tested for 24 h, with the highest percentage of the amount applied in the FB, while the highest concentration was measured in the H sample. The SOL and CHA concentrations decreased in the haemolymph over time, while they did not change in other tissues. CHA had the highest elimination rate immediately after injection, while SOL slightly later. None of the GA hydrolysis products were detected in the tested samples. One possible mechanism of the detoxification of GAs may be oxidation and/or sequestration. They may be excreted by Malpighian tubules, with faeces or with cuticles during moulting. The results presented are significant because they facilitate the interpretation of studies related to the effects of toxic substances on insect metabolism.

ANTI-INFLAMMATORY AND ANTIMICROBIAL ACTIVITIES OF THE LEAVES OF ACALYPHA WILKESIANA MUELL. ARG. (EUPHORBIACEAE) FORMULATED AS HERBAL CREAM

The use of some traditional creams in Nigeria is associated with negative outcomes. In order to tackle this problem, we conducted a study on the antibacterial and anti-inflammatory characteristics of Acalypha wilkesiana leaves, which were utilized in the creation of a herbal cream. Standard methods were employed to conduct analytical procedures for the analysis of the phytochemical and chromatographic content of A. wilkesiana leaves. The anti-inflammatory efficacy of the unrefined ethanol extract was assessed using the egg albumin technique, throughout a dosage range of 15.6 to 500 mg/ml. The effectiveness of the herbal cream and the raw ethanol extract of A. wilkesiana in killing specific bacteria were evaluated. A comprehensive evaluation was carried out to determine the physicochemical characteristics of the herbal cream formulation using appropriate methodologies. The phytochemical examination of A. wilkesiana which gave a yield of 12.6 % indicated the existence of alkaloids, tannins, and saponins. The anti-inflammatory properties of the crude extract derived from A. wilkesiana had a comparable effect to that of aspirin, a commonly prescribed medicine at doses of 125, 250 and 500 mg/kg. The herbal cream (25.5 ± 0.22) and crude extract (19.5 ± 0.01) had the greatest antibacterial effectiveness against Candida albicans at 200 mg/ml. The physicochemical examination of the cream that was created: pH (5.6 ± 0.64); consistency (5 mm); viscosity (22 x 106 cps); spreadability (36 g.cm/sec); Extrudability (510 gm) showed similarities to the commercially available Gentamycin cream. The herbal cream containing A. wilkesiana has demonstrated substantial promise and could function as a practical alternative to traditional creams for treating skin infections.

The damage and remineralization strategies of dental hard tissues following radiotherapy

ObjectivesThis study pursued two main purposes. The first aim was to expound on the microscopic factors of radiation-related caries (RRC). Further, it aimed to compare the remineralization effect of different remineralizing agents on demineralized teeth after radiotherapy.MethodsThe enamel and dentin samples of bovine teeth were irradiated with different doses of radiation. After analysis of scanning electron microscope (SEM), X-Ray diffraction (XRD), and energy dispersive spectrometer (EDS), the samples irradiated with 50 Gy radiation were selected and divided into the demineralization group, the double distilled water (DDW) group, the Sodium fluoride (NaF) group, the Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) group, the NaF + CPP-ACP group, and the Titanium tetrafluoride (TiF4) group. After demineralization, remineralizing agents treatment, and remineralization, the samples were evaluated using SEM, atomic force microscope (AFM), EDS, and transverse microradiography (TMR).ResultsA radiation dose of 30 Gy was sufficient to cause damage to the dentinal tubules, but 70 Gy radiation had little effect on the microstructure of enamel. Additionally, the NaF + CPP-ACP group and the TiF4 group significantly promoted deposit formation, decreased surface roughness, and reduced mineral loss and lesion depth of demineralized enamel and dentin samples after radiation.ConclusionsRadiation causes more significant damage to dentin compared to enamel. NaF + CPP-ACP and TiF4 had a promising ability to promote remineralization of irradiated dental hard tissues.Advances in knowledgeThis in vitro study contributes to determining a safer radiation dose range for teeth and identifying the most effective remineralization approach for RRC.

Establishment and activity of the planning and acting network for low dose radiation research in Japan (PLANET): 2016-2023.

The Planning and Acting Network for Low Dose Radiation Research in Japan (PLANET) was established in 2017 in response to the need for an all-Japan network of experts. It serves as an academic platform to propose strategies and facilitate collaboration to improve quantitative estimation of health risks from ionizing radiation at low-doses and low-dose-rates. PLANET established Working Group 1 (Dose-Rate Effects in Animal Experiments) to consolidate findings from animal experiments on dose-rate effects in carcinogenesis. Considering international trends in this field as well as the situation in Japan, PLANET updated its priority research areas for Japanese low-dose radiation research in 2023 to include (i) characterization of low-dose and low-dose-rate radiation risk, (ii) factors to be considered for individualization of radiation risk, (iii) biological mechanisms of low-dose and low-dose-rate radiation effects and (iv) integration of epidemiology and biology. In this context, PLANET established Working Group 2 (Dose and Dose-Rate Mapping for Radiation Risk Studies) to identify the range of doses and dose rates at which observable effects on different endpoints have been reported; Working Group 3 (Species- and Organ-Specific Dose-Rate Effects) to consider the relevance of stem cell dynamics in radiation carcinogenesis of different species and organs; and Working Group 4 (Research Mapping for Radiation-Related Carcinogenesis) to sort out relevant studies, including those on non-mutagenic effects, and to identify priority research areas. These PLANET activities will be used to improve the risk assessment and to contribute to the revision of the next main recommendations of the International Commission on Radiological Protection.

A phase 1, randomized, double-blind, placebo-controlled, dose escalation study to evaluate the safety, tolerability, pharmacokinetics and immunogenicity of SHR-1905, a long-acting anti-thymic stromal lymphopoietin antibody, in healthy subjects.

Thymic stromal lymphopoietin (TSLP) is integral to inducing innate and T helper two cell inflammation that leads to clinical symptoms of asthma. SHR-1905 is a humanized immunoglobulin G1 kappa monoclonal antibody that inhibits TSLP bioactivity, developed for the treatment of severe uncontrolled asthma. This phase 1, randomized, double-blind, placebo-controlled single ascending dose study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of subcutaneous SHR-1905 in healthy subjects. Five dose cohorts were planned (50, 100, 200, 400, and 600mg) and subjects were randomized (8:2) in each cohort to receive SHR-1905 or placebo with a follow-up period up to Day 253. The majority of treatment-emergent adverse events (TEAEs) were mild and the incidence of TEAEs was comparable between the SHR-1905 and the placebo groups. The maximum serum concentration was reached 7.0-17.6days after injection. The serum concentration of SHR-1905 increased with increasing dose level, and SHR-1905 exposure exhibited in a slightly greater-than-dose-proportional manner from 50 to 600mg. SHR-1905 had a prolonged serum half-life around 80days supporting every 6-month dosing. In SHR-1905 treated subjects, 15% tested positive for anti-drug antibodies post-dose with no apparent effect on corresponding PK profiles or safety. SHR-1905 demonstrated a good safety and tolerability profile with a long half-life in healthy subjects after a single administration in the dose range of 50-600mg. clinicaltrials.gov, identifier NCT04800263.