Test Dose Research Articles

Predicting a Positive Antibody Response After 2 SARS-CoV-2 mRNA Vaccines in Transplant Recipients: A Machine Learning Approach With External Validation.

Background.Solid organ transplant recipients (SOTRs) are less likely to mount an antibody response to SARS-CoV-2 mRNA vaccines. Understanding risk factors for impaired vaccine response can guide strategies for antibody testing and additional vaccine dose recommendations.Methods.Using a nationwide observational cohort of 1031 SOTRs, we created a machine learning model to explore, identify, rank, and quantify the association of 19 clinical factors with antibody responses to 2 doses of SARS-CoV-2 mRNA vaccines. External validation of the model was performed using a cohort of 512 SOTRs at Houston Methodist Hospital.Results.Mycophenolate mofetil use, a shorter time since transplant, and older age were the strongest predictors of a negative antibody response, collectively contributing to 76% of the model’s prediction performance. Other clinical factors, including transplanted organ, vaccine type (mRNA-1273 versus BNT162b2), sex, race, and other immunosuppressants, showed comparatively weaker associations with an antibody response. This model showed moderate prediction performance, with an area under the receiver operating characteristic curve of 0.79 in our cohort and 0.67 in the external validation cohort. An online calculator based on our prediction model is available at http://transplantmodels.com/covidvaccine/.Conclusions.Our machine learning model helps understand which transplant patients need closer follow-up and additional doses of vaccine to achieve protective immunity. The online calculator based on this model can be incorporated into transplant providers’ practice to facilitate patient-centric, precision risk stratification and inform vaccination strategies among SOTRs.

Comparing the monochromatic TL response of a high sensitivity natural quartz irradiated with β and γ rays

This study investigates the effect of the dose-rate in the thermoluminescent glow curves of a single crystal of quartz. The samples were sensitized by the γ radiation combined with the heat-treatments. The glow curves were registered in zeroed (unsensitized) and sensitized conditions using an optical filter centered in violet spectral region. Tens mGy test doses were administered with one β (90Sr/90Y) source and two γ radiation sources (60Co and 137Cs). The TL curves were deconvoluted using a first-order kinetic model. Differences in the glow curves and trapping parameters were observed between zeroed and sensitized samples. Differences were found in the TL curves comparing the three radiation sources. The principal variation is the remarkable increase in the TL signal above 350 °C, which is observed only in sensitized samples with the minor dose-rate source (137Cs). This signal seems to be associated with deep trapping states. The intensities of the components defining the first peak and the high temperature signal show a dependence on the dose-rate. The dose-rate dependence of the first-peak components is explained by the competing effects that may take place during the excitation stage. The components that fitted the sensitized peak (260 oC) do not exhibit a clear dependence on the dose-rate of radiation source.

Bioequivalence Study of Two Etoricoxib 90 mg Film-Coated Tablet Formulations

The present study was conducted to compare the bioavailability of two etoricoxib 90 mg film-coated tablet formulations (test formulation and reference formulation). This study was an open-label, randomized, single-dose, two-periods, twotreatments, and crossover study which included 24 healthy adult male and female subjects under fasting conditions. Each of the two study periods was separated by a 7 days washout. A single dose of test or reference drug was administered to the subject in each period based on the randomization scheme. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters assessed in this study were the area under the plasma concentration-time curve from time zero to 96 h (AUC0-96h), area under the plasma concentration-time curve from time zero to infinity (AUC0-∞), the peak plasma concentration of the drug (Cmax), time needed to achieve the peak plasma concentration (Tmax), and the elimination half-life (T1/2). The geometric mean ratios (90% CI) of the test drug/reference drug for etoricoxib were 102.39% (97.63% – 107.38%) for AUC0-96h and 93.23% (86.54% – 100.43%) for Cmax. The 90% Confidence Intervals (CI) calculated for AUC0-96h and Cmax of etoricoxib were within the standard bioequivalence range (80.00– 125.00% for AUC0-t and Cmax). It was concluded that the two etoricoxib film-coated tablets (test and reference drug) were bioequivalent in terms of the rate and extent of absorption

Pharmacist-Mediated Thyroid-Stimulating Hormone (TSH) Test Guideline Monitoring Program- Outcomes of a Retrospective Study In Patients On Levothyroxine

Thirty to sixty percent of individuals taking levothyroxine were either under or overtreated, which leads to organ damage and excess mortality. This study aims to assess the gaps in the “thyroid-stimulating hormone (TSH) test guideline compliance rate” and validate the scope of ambulatory care pharmacist-mediated practice in patients on levothyroxine. At the study site, pharmacists offered patient-centered telephonic counseling to patients on levothyroxine who had been non-compliant with TSH tests for more than a year. A two-month quantitative retrospective analysis of this practice was conducted to assess its impact on TSH lab test adherence and dose modification outcomes. 415 patients met the study’s inclusion criteria who received pharmacist counseling with documented intervention. Pharmacists bridged the significant gap in practice by creating new TSH lab requests with counseling in 81.2% (n = 337) of the study population who did not have TSH lab requests prior to the program. The non-compliance rate population dropped from 79.27% (n = 329) to 17.59% (n = 73) in the study population who had been non-compliant with the TSH test for 13 and 24 months. 74.5% (n = 309) were found to have performed their TSH test after the pharmacist’s intervention. Among 100, 66% (n = 66) patients with abnormal TSH values consulted their physician for advice, of which 60.6% (n=40) had their levothyroxine dose adjusted (χ2=82.702, P < 0.01. The study suggests that pharmacists can significantly mediate between patients and physicians to enhance TSH test compliance and essential dose adjustment in patients prescribed levothyroxine.

Pengaruh Ekstrak Etanol Daun Momordica Charantia L. Terhadap Aktivitas Proteksi Mukosa Lambung Tikus

Momordica charantia L. contain alkaloid, flavonoid, phenolic, tannin and saponin compounds which can protect the gastric mucosa. This study aims to determine the effect of giving the ethanol extract of bitter melon leaves (Momordica charantia L.) on the protective activity of the gastric mucosa in aspirin-induced male white rats. Momordica charantia L maceration using 70% ethanol as a solvent. The gastric mucosal protective activity test used 15 male white rats which were divided into 5 groups. The treatments were given orally for 3 days including: the positive control group was given 0.5% Na-CMC + aspirin 600 mg/kgBB, the comparison control group was given sucralfate suspension 360 mg/kgBB + aspirin 600 mg/kgBB, the test dose group 1 was given Pare leaf ethanol extract 100 mg/kgBB + aspirin 600 mg/kgBB, group 2 test dose was given ethanol extract of bitter melon leaves 200 mg/kgBB + aspirin 600 mg/kgBB and group 3 test dose was given ethanol extract of bitter melon leaves 400 mg/kgBB + aspirin 600 mg/kgBB. On day 3, the mice were dissected after 4 hours of aspirin administration, observation and the percentage of gastric mucosal protection in the rats was calculated. Data were analyzed statistically with one-way ANOVA test followed by Duncan's test. The bitter melon leaf extract had a significant effect (p &lt;0.05) on the protection of the gastric mucosa. The highest percentage of protection was shown by the dose of 400 mg / kgBW at 62.48%.

Thermoluminescence (TL), kinetic parameters and dosimetric features of Pakistani limestone

Thermoluminescence (TL), kinetic parameters and dosimetric features of Pakistani limestone (CaCO3) is reported in this study. Both compositional and structural analyses reveal that the material has a crystalline nature with rhombohedral structure and non-uniform crystallite size having major content of CaCO3. A powdered limestone sample of 30 mg is found to be the optimized weight for TL and other dosimetric studies. After irradiating the samples with a test dose of 100 Gy using a β source three composite glow peaks termed as P1, P2 and P3 are visible at 100, 230 and 330 °C respectively using a linear heating rate of 1 °C/s during the TL readout. The Coefficient of Variation (COV) is found to be about 4%. Kinetic parameters (i.e., frequency factor (f), activation energy (E), and the kinetic order (b)) are estimated using both first and second Order of kinetics using an in-house Computerized Glow Curve Deconvolution (GCD) software. The figure-of-merit (FOM) is found to be 2.12%. The distribution of continuum traps with activation energy in the range of 0.77–2.59 eV is observed in the kinetic parameter analysis of the glow peaks of the sample. The TL response in the dose range of 1–5 Gy (not reported previously) and linearity in the dose response in the dose range of 1–10 Gy is observed in samples of Pakistani limestone. The Minimum Detectable Dose (MDD) is 1.01 Gy clearly resembling the experimentally linear fitted results. After a fading study for a period of thirty days, only the first peak i.e., P1 majorly fades while no major change is observed in the amplitude of peaks P2 and P3. In addition, P1 is the main contributor fading by 92% within the first 24 h of irradiation while P2 fades by 30 %. However, P3 shows stability with a very minor fading of 0.05% within 24 h of irradiation. This study concludes that Pakistani limestone can be further assessed as a potential radiation dosimeter for various applications.

A simplified multiple aliquot regenerative dose protocol to extend the dating limit of K-feldspar pIRIR signal

The post-infrared infrared stimulated luminescence signal (pIRIR) from K-feldspar shows significantly less athermal fading than the conventional IRSL signal, thus it has been widely used for dating Quaternary deposits. With the single aliquot regenerative dose (SAR) protocol, the test dose signal is influenced by the preceding regenerative dose, and the characteristic saturation dose (D0) of the pIRIR signal is mostly in the range of 200–600 Gy, depending on the size of the test dose. According to the D0 value, the dating range of pIRIR is restricted to <300 ka with the SAR protocol. Here we present a multiple aliquot regenerative dose (MAR) protocol using low-temperature thermoluminescence (TL) signal for inter-aliquot normalisation. The multiple-elevated-temperature (MET) pIRIR signals up to 290 °C are investigated. The D0 increases to 850–1300 Gy with this protocol, which should represent the intrinsic D0 of IR or pIRIR signals of K-feldspar. Based on the higher D0, this protocol has the potential to date samples with equivalent doses (Des) up to 2000 Gy, i.e. up to ∼600 ka considering a dose rate of ∼3.5 Gy·ka−1. Applications of this MAR protocol on two loess samples from the Chinese Loess Plateau provide ages consistent with expected ages up to 350 ka, with the MET-pIRIR signal at 290 °C. However, tests on three fluvial and alluvial samples show age overestimation with the new MAR protocol as well as SAR protocol, which may result from the hard-to-bleach property of the high-temperature pIRIR signals. Simulations of fading correction indicate that the age will be over-corrected when the laboratory dose response curve has a D0 smaller than the true D0 of the signal. Caution should be taken in fading corrected ages measured with the conventional SAR protocol, as the D0 values are always underestimated in this case.

Experimental Study of the Efficacy and Safety of a New PEG-Based Laxative

Bowel-cleansing PEG-based agents, including Moviprep®, are commonly used to prepare the large intestine for diagnostic examinations. PLNV-next is a newly developed fixed combination medicinal product with a composition similar to that of Moviprep®.The aim of the study was to estimate the pharmacological efficacy and toxicity of PLNV-next.Materials and methods: The study evaluated pharmacological efficacy of four formulations of PLNV-next in comparison with Moviprep® after a single administration in a therapeutic dose to outbred rats. The evaluation was carried out based on the laxative effect of the medicinal products. The authors recorded diarrhoea onset latency and the number of defecation boluses and diarrhoea spots produced during the 6-hour observation period. Toxicity of PLNV-next was studied in the formulation containing maximum amounts of the ingredients according to the patent. In the single-dose toxicity study, PLNV-next was administered intragastrically to rats at doses of 4.2 g/kg (maximum human therapeutic dose, MHTD), 21 g/kg (5 MHTD), and 42 g/kg (10 MHTD) and to ferrets at doses of 4.2 g/kg (MHTD) and 21 g/kg (5 MHTD). In the repeated-dose toxicity study, PLNV-next was administered for 14 days at 4.2 g/kg (rats and ferrets), 21 g/kg (5 MHTD, rats), and 12.6 g/kg (3 MHTD, ferrets). Additionally, the repeated-dose toxicity study evaluated safety pharmacology parameters for the cardio-vascular, respiratory and central nervous systems.Results: All PLNV-next formulations tested exerted a laxative effect equivalent to that of Moviprep®. No clinical signs of toxicity were observed in rats, with the exception of the laxative effect. Ferrets demonstrated decreased behavioral activity and diarrhoea. Nausea or emesis were noted in 75–90% of the ferrets receiving the doses exceeding the MHTD. A single administration of PLNV-next affected blood sodium concentrations: a slight increase was noted in the 5 MHTD and 10 MHTD groups of rats and in the 5 MHTD group of ferrets. The repeated-dose toxicity study in rats revealed a slight increase in sodium levels with both test doses. After a single administration of 5 MHTD to ferrets, the authors observed a decrease in potassium levels. All the changes were mild and within physiological ranges. PLNV-next toxic effects observed in the rat and ferret studies were similar to those reported in rat and dog toxicity studies of Moviprep®. Conclusion: PLNV-next exerts a marked laxative effect and has a favourable safety profile.

Caralluma edulis (Apocynaceae): A Comprehensive Review on its Traditional Uses, Phytochemical Profile and Pharmacological Effects.

Caralluma edulis is a well-known species of the genus Caralluma from Apocynaceae, commonly known as chunga. Caralluma species are mostly succulent perennial herbs, several of which are edible species. The plant has an outstanding therapeutic background in the traditional system of treatment. It has been recommended for the treatment of a number medical disorders such as hypertension, Alzheimer's disease, rheumatism, gastric problems and leprosy. Traditionally the stem was boiled in water and this extract was then used to cure diabetes. The pharmacological effects of C. edulis have also been explored in various in vitro and in vivo experiments. In this regard, the extract of the plant exhibited strong antioxidant, and analgesic activity against inflammation as well as xylene-mediated ear edema as topical effects. The significant anti-hyperlipidemic effect of the plant extract is also reported. However, the extract was found insignificant in the reversal of alloxan-induced diabetes in the rabbit model at test doses. These pharmacological effects are strongly supported by the presence of different bioactive phytochemicals in the plant. These groups of compounds include sterols, terpenoids, flavonoids, and pregnane glycosides. C. edulis is a very potential member of the genus Caralluma with strong traditional history, phytochemistry and phytopharmacology, and needs further exploration for clinically used lead compounds. In this review, we have focused on combining different reported data on the traditional uses of the plant, its phytochemical profile and pharmacological effects in different experimental assay along with subsequent future prospects.

Assessment of antimalarial medicinal plants used in Nigerian ethnomedicine reveals antimalarial potential of Cucurbita pepo leaf extract

Medicinal plants are often used to treat malaria in different parts of Nigeria and exploiting these can unravel new therapeutic leads. This study evaluated the antiplasmodial potential of selected plants used to treat malaria in Nsukka, Enugu state, Nigeria. Leaves of three different plants (Cucurbita pepo, Hibiscus rosa-sinensis and Pennisetum purpureum) were collected for screening and two extracts viz., 70%v/v ethanol and dichloromethane/methanol (1:1 v/v), were prepared for each. An acute toxicity test was done in mice and cytotoxicity was assessed using human hepatoma cell line (HUH). The extracts were screened against chloroquine-sensitive P. falciparum (Pf3D7) in vitro, and chloroquine-resistant P. berghei ANKA in vivo using a 4 day-suppressive test in mice. Cucurbita pepo ethanol extract was further tested for hemolytic effect on human erythrocytes and in established infection in mice. Parameters assessed were post-treatment parasitemia, hematological indices, organ (brain, kidney, liver, and spleen) weights, and survival. The extracts were non-cytotoxic up to a test dose of 100 μg/ml and 2000 mg/kg fed - mice did not show acute or delayed toxicity. Cucurbita pepo ethanol extract (CpE) displayed excellent in vitro antiplasmodial activity with IC50 of 3.05 μg/ml. At an oral dose of 500 mg/kg, mice were observed to display significant (p < 0.01) ∼51% suppression of parasitemia. The extract did not produce any significant hemolytic effect up to a test concentration of 1 mg/ml. In established infection, a dose of 300 mg/kg significantly (p < 0.01) protected mice from anemia caused by low hematocrit. The extract produced significant (p < 0.05) elevation in red blood cells and platelet counts, and an increase in hemoglobin was evident at 100 and 300 mg/kg. Further, CpE in a dose-dependent manner, reversed liver and spleen weight increase seen in untreated, infected mice. These findings show C. pepo as a potential candidate for further studies to identify its bioactive principle(s) and possible mechanism(s) of antimalarial action.

Evaluation of the Antiulcer Activity of Methanolic Extract and Solvent Fractions of the Leaves of Calpurnia aurea (Ait.) Benth. (Fabaceae) in Rats.

Introduction In Ethiopia, traditionally, the leaves of Calpurnia aurea have been utilized to treat peptic ulcer disease. Therefore, the objective of the present study was to examine the antiulcer activity of Calpurnia aurea hydromethanolic leaf extract and solvent fractions in rats. Methods The ulcer-healing potential of the crude test extract was assessed in rats by adopting pyloric ligation-, acidified ethanol-, and acetic acid-induced ulcer methods; while, in solvent fractions, the acidified ethanol-induced ulcer model was used. In all models, three serial test doses (100, 200, and 400 mg/kg) were given and the antiulcer activity was investigated. Standard drugs like sucralfate (100 mg/kg), omeprazole (20 mg/kg), and cimetidine (100 mg/kg) have been used as a positive control; whereas distilled water (10 mL/kg) was used as the negative control. Parameters like ulcer index, total acidity, pH, gastric volume, and gastric mucin level were all measured. Results In an acute toxicity study, the test extract at the limit test dose (2 g/kg) was safe following a single dose administration. In pyloric ligation-induced ulcers, the plant extract at 200 and 400 mg/kg significantly reduced the ulcer index, the volume of stomach secretion, and total acidity while raising gastric pH and mucus content (P < 0.05). Likewise, in the acidified ethanol- and acetic acid-induced ulcer models, the extract at both test doses (200 and 400 mg/kg) also displayed a substantial reduction (P < 0.05) in ulcer index. Among the fractions, the ethyl acetate fraction revealed remarkable cytoprotective activity at all test doses and the aqueous fraction at 400 mg/kg (P < 0.05). In contrast, the effect of chloroform fraction was found to be negligible. The peak ulcer inhibition was noted at 400 mg/kg of ethyl acetate fraction (52.4%). Conclusion The study showed that the crude extract and solvent fractions possess remarkable antiulcer activity.

Clinical validation of novel lightning dose optimizer for gamma knife radiosurgery of irregular-shaped arteriovenous malformations and pituitary adenomas.

PurposeTo demonstrate the clinical feasibility of a novel treatment planning algorithm via lightning dose optimizer (LDO) on Leksell Gamma Knife (LGK) GammaPlan with significantly faster planning times for stereotactic radiosurgery (SRS) of the complex and difficult arteriovenous malformations (AVMs) and pituitary adenomas.Methods and materialsAfter completing the in‐house end‐to‐end phantom testing and independent dose verification of the recently upgraded LDO algorithm on GammaPlan using the MD Anderson's IROC anthropomorphic SRS head phantom irradiation credentialing, 20 previously treated GK‐SRS patients (10 AVM, average volume 3.61 cm3 and 10 pituitary adenomas, average volume 0.86 cm3) who underwent manual forward planning on GammaPlan were retrospectively replanned via LDO. These pathologies were included because of the need for adequate dose delivery with organs at risk in very close proximity. LDO finds the target curvature boundary by well‐formulated linear programing objectives and inversely optimizes the GK‐SRS plan by isocenter placement, optimization, and sequencing. For identical target coverage, the LDO and original manual plans were compared for target conformity, gradient index, dose to critical organs, and surrounding normal brain. Additionally, various treatment delivery parameters, including beam‐on time were recorded.ResultsFor both patient cohorts, LDO provided similar target coverage with better dose conformity, tighter radiosurgical dose distribution with a lower value of gradient indices (all p < 0.001), and lower dose to critical organs. For AVMs, there was a significant reduction of normal brain V 10Gy, V 12Gy, and V 14Gy by 4.74, 3.67, and 2.67 cm3 (all p < 0.001). LDO had twice the number of shots (p < 0.001), and longer beam‐on time (p = 0.012) by a factor of 1.44. For pituitary adenomas, LDO provided systematically lower values of V 10Gy, V 12Gy, and V 14Gy by 1.08, 0.86, and 0.68 cm3 (all p < 0.001), and lower maximum dose to optic pathway by 0.7 Gy (p = 0.005), but had almost twice the numbers of shots (p < 0.001) and increased beam‐on time (p = 0.005) by a factor of 1.2. However, for both patient groups, the average planning time for the LDO was <5 min, compared to the estimated 30–90 min of manual planning times.ConclusionGK‐SRS treatment on Leksell Perfexion GammaPlan using the LDO provided highly conformal target coverage with a steep dose gradient, spared critical organs, and significantly reduced normal brain dose for complex targets at the cost of slightly higher treatment times. LDO generated high‐quality treatment plans and could significantly reduce planning time. If available, the LDO algorithm is suggested for validation and clinical use for complex and difficult GK cases.

Evaluation of Antidiabetic and Antihyperlipidemic Activity of 80% Methanolic Extract of the Root of Solanum incanum Linnaeus (Solanaceae) in Mice.

Background Conventional antidiabetic drugs are linked with a number of contraindications and untoward effects. The root decoction of Solanum incanum L. has traditionally been used to treat diabetes. However, its safety and efficacy have not been scientifically authenticated yet. Hence, the study was conducted in mice to corroborate its antidiabetic potential and safety profile. Methods Using normoglycemic, oral glucose-loaded, and streptozotocin-induced diabetic mice models, the hypoglycemic and antihyperglycemic activities of 80% methanolic root extract were investigated. On streptozotocin-induced diabetic mice, the effect of the test extract on diabetic lipid profile and body weight was also investigated. Further, the in vitro α-amylase inhibition activity was assessed. Results The test extract was safe at a limit test dose of 2 g/kg. Dose-dependent α-amylase inhibition activity was seen with peak percentage inhibition of 75.95% at 700 μg/mL. In normoglycemic mice, the plant extract showed statistically significant hypoglycemic activity at 200 and 400 mg/kg (P < 0.001) at 6 h and 4 and 6 h of treatment, respectively; in oral glucose-loaded mice, at both the test doses, the glucose level was also significantly dropped at 120 (P < 0.01) and 60 and 120 min (P < 0.001), respectively; whereas, in the third model, the test extract showed significant antihyperglycemic activity at 100 mg/kg (P < 0.05) on the 14th day and at 200 (P < 0.01) and 400 mg/kg (P < 0.001) on the 7th and 14th day of treatment. Similarly, following repeated administration of the test extract at 200 and 400 mg/kg, the body weight was significantly improved on the 14th day (P < 0.05) and on the 7th and 14th day (P < 0.01), respectively, while diabetic dyslipidemia after 14 days (P < 0.05). Conclusion The study revealed that the test extract showed promising antihyperglycemic and antihyperlipidemic activity. Thus, the findings back up its use in Ethiopian remedies for diabetes.

Evaluation of In vivo antidiarrheal activity of hydro-methanolic extract of the root of Rumex nepalensis in Swiss Albino mice

BackgroundNatural products have been utilized by human beings for thousands of years to relieve a variety of ailments, including diarrhea. Conventional antidiarrheal drugs are associated with multiple adverse effects and contraindications. Traditionally, Rumex nepalensis by crushing the root, mix with water and then drunk the juice is extensively used for treating diarrhea. However, no scientific research has been done yet to support its antidiarrheal efficacy and safety. Hence, the aim of the study was to evaluate the antidiarrheal activity and safety profile of the plant in mice. MethodsThe hydro-methanolic extract was extracted through a cold maceration technique using 80% methanol. Castor oil-induced diarrheal, gastro-intestinal transit, and enteropooling models have been employed to assess the antidiarrheal activity of the test extract at doses of 100, 200, and 400 mg/kg. ResultsThe crude root extract caused no mortality at a single limit test dose of 2 g/kg throughout the first 24 h and for the rest of the 14 days. In a castor oil-induced diarrheal model, the hydro-methanolic extract markedly delayed the onset of diarrhea, reduced the weight of wet and total feces at 100 (P<.05), 200 (P<.01), and 400 mg/kg (P<.001) test doses. Meanwhile, at 200 (P<.01) and 400 mg/kg (P<.001) doses, the plant extract considerably lowered the weight and volume of intestinal contents. In the gastro-intestinal transit model, however, a dramatic inhibition in the charcoal meal travel was noticed at 100 (P<.05), 200 (P<.01), and 400 mg/kg (P<.001) test doses. The peak antidiarrheal index was exhibited at the highest dose of the test extract. ConclusionThe study speculated that Rumex nepalensis root extract possesses antidiarrheal activity, which could be owing to its inhibitory effect on both gastro-intestinal motility and fluid secretion.

Rationale for and design of a multicenter, placebo-controlled, phase 3 study to assess efficacy and safety of intranasal etripamil for the conversion of paroxysmal supraventricular tachycardia

Presently, acute pharmacological termination of paroxysmal supraventricular tachycardia (PSVT) unresponsive to patient-initiated vagal maneuvers requires in-hospital intervention. Etripamil, a fast-acting, nondihydropyridine, L-type calcium channel blocker, is formulated as an intranasal spray to rapidly terminate atrioventricular (AV) nodal-dependent PSVT in a medically unsupervised setting. The NODE-301 study did not meet its prespecified primary end point of PSVT conversion over 5 hours following a single dose of etripamil 70 mg. However, analysis at earlier time points demonstrated etripamil treatment effect during the first 30 minutes, consistent with its expected rapid onset and short duration of action. This led to the design of the RAPID study, which includes a new dosing regimen (up to 2 etripamil 70 mg doses separated by 10 minutes) to increase the exposure and pharmacodynamic effect of etripamil. The primary objective of RAPID (NCT03464019) is to determine if etripamil self-administered by patients is superior to placebo in terminating PSVT in an at-home setting. The secondary objective is to evaluate the safety of etripamil when self-administered by patients without medical supervision. Additional efficacy end points include the proportion of patients requiring additional medical intervention in an emergency department to terminate PSVT and patient-reported outcomes. After successfully completing a test dose to assess the safety of 2 70 mg doses of etripamil during sinus rhythm, approximately 500 patients will be randomized 1:1 to etripamil or placebo to accrue 180 positively adjudicated AV nodal-dependent PSVT events for treatment with the study drug. Etripamil may offer a new alternative to the current in-hospital treatment modality, providing for safe and effective at-home termination of PSVT.

Discovery of Novel Benzo[4,5]imidazo[1,2-a]pyrazin-1-amine-3-amide-one Derivatives as Anticancer Human A2A Adenosine Receptor Antagonists.

The blockade of A2A adenosine receptor (A2AAR) activates immunostimulatory response through regulating signaling in tumor microenvironment. Thus, A2AAR has been proposed as a promising target for cancer immunotherapy. In this work, we designed a new series of benzo[4,5]imidazo[1,2-a]pyrazin-1-amine derivatives bearing an amide substitution at 3-position to obtain potent antitumor antagonist in vivo. The structure-activity relationship studies were performed by molecular modeling and radioactive assay. The in vitro anticancer activities were evaluated by 3',5'-cyclic adenosine monophosphate (cAMP) functional and T cell activation assay. The most potent compound 12o·2HCl showed much higher affinity toward A2AAR (Ki = 0.08 nM) and exhibited more significant in vitro immunostimulatory anticancer activity than clinical antagonist AZD4635. More importantly, 12o·2HCl significantly inhibited the growth of triple-negative breast cancer by reversing immunosuppressive tumor microenvironment in the xenograft mouse model without severe toxicity at the testing dose. These results make 12o·2HCl a promising immunotherapy anticancer drug candidate.

Isolating a violet stimulated luminescence (VSL) signal in quartz suitable for dating: Investigating different thermal treatments and signal integration limits

The behavior of the post-blue violet stimulated luminescence (VSL) signal from quartz with respect to thermal treatments is explored. The results suggest that more than one source trap may be responsible for the VSL signal and therefore, the separation of this signal from the preceding blue stimulated luminescence (BSL) signal is challenging. Furthermore, the behavior of the VSL dose response curve (DRC) in a single aliquot regenerative (SAR) protocol is demonstrated to be influenced significantly by the test dose size and the efficacy of signal depletion prior to measurement of the test dose signal, and hence a modified VSL SAR measurement protocol is considered for further investigations in this study. The ability of this protocol to recover a given dose is tested and it is shown that by selecting different integration limits, two signals with distinct dose response characteristics can be separated from the same original VSL decay curve. Dose response curves derived from early signal integration (Signal A) saturate at ∼150 Gy and cannot recover given doses beyond this limit, whereas later signal integration (Signal B) results in a DRC that continues to grow exponentially to doses >> 500 Gy, and can recover given doses up to at least ∼3200 Gy. However, Signal B underestimates by ∼90% the equivalent dose (De) for a sample with expected De value of ∼500 Gy. This may suggest thermal instability of Signal B over geological time and needs further investigation.

Evaluation of the Potency of the Pertussis Vaccine in Experimental Infection Model with Bordetella pertussis: Study of the Case of the Pertussis Vaccine Used in the Expanded Vaccination Program in Algeria

In Algeria, vaccination against pertussis is carried out using the whole-cell pertussis vaccine combined with the diphtheria and tetanus toxoids (DTwp). The quality control of vaccines locally produced or imported is carried out before the batch release. The aim of our work was to evaluate the potency of pertussis vaccines. In the present study, five consecutive trials of potency were conducted on samples of the same batch of (DTwp) using the mouse protection test (MPT) against experimental infection of Bordetella pertussis strain 18323, based on the Kendrick test. The virulence of B. pertussis strain 18–323 was verified by the mortality of mice, with an average LD50 of 338.92, as well as the dose of the lethal test containing a mean number of LD50 of 324.43. The (MPT) test recorded a relative potency of 8.02 IU/human dose, with 95% CL of (3.56–18.05) IU/human dose. The development of the (MPT) at the laboratory of quality control of vaccines and sera at the Pasteur Institute of Algeria was effective in evaluating the potency of whole-cell pertussis vaccines. Interestingly, our study indicates that this potency is necessary for the vaccine quality assurance. Further validation is needed to strengthen the application and routine use of the test.

Neuroendoscopy in the management of pineal region tumours in children.

Pineal region tumours (PRTs) are more common in children and represent a wide variety of lesions. The practise of a radiation test dose is obsolete and a biochemical/histological diagnosis is recommended before further therapy. Many patients present with hydrocephalus. Advances in neuroendoscopic techniques have allowed safe and effective management of this obstructive hydrocephalus with an opportunity to sample cerebrospinal fluid (CSF) and obtain tissue for histopathology. Definitive surgery is required in less than a third. Endoscopic visualisation and assistance is increasingly used for radical resection, where indicated. Our experience of endoscopic surgery for paediatric PRTs from 2002 to 2021 is presented. All patients underwent MRI with contrast. Serum tumour markers were checked. If negative, endoscopic biopsy and endoscopic third ventriculostomy (ETV) were performed; and CSF collected for tumour markers and abnormal cells. For radical surgery, endoscope-assisted microsurgery procedures were performed to minimise retraction, visualise the extent of resection and confirm haemostasis. M:F ratio was 2:1. The median age of presentation was 11years. Raised ICP (88.88%) was the commonest mode of presentation. Nineteen patients had pineal tumours, one had a suprasellar and pineal tumour, one had disseminated disease, while six had tectal tumours. The ETB diagnosis rate was 95.45%, accuracy rate was 83.3% and ETV success rate was 86.96%. Neuroendoscopy has revolutionised the management of paediatric PRTs. It is a safe and effective procedure with good diagnostic yield and allows successful concurrent CSF diversion, thereby avoiding major surgeries and shunt implantation. It is also helpful in radical resection of lesions, where indicated.

AKTIVITAS HEPATOPROTEKTIF EKSTRAK ETANOL BUNGA TELANG (Clitoria ternatea L.) PADA TIKUS PUTIH YANG DIINDUKSI PARASETAMOL

Paracetamol causes liver damage if consumed more than normal limits continuously. Liver damage is characterized by increased levels of the enzymes Serum Glutamic Pyruvic Transaminase (SGPT) and Serum Glutamic Oxaloacetic Transaminase (SGOT) in the blood. Antioxidants can prevent paracetamol-induced liver damage. Telang flower (Clitoria ternatea) is a plant that has the potential to prevent liver damage because it has high antioxidant activity. This study aimed to examine the hepatoprotective activity of ethanol extract of telang flower in rats induced by paracetamol. Rats were grouped into 6 groups consisting of normal control without paracetamol induction, negative control, positive control, test doses 1, 2, and 3 were given paracetamol as much as 150 mg/200 g BW on day 1 to day 7. After 1 hour, the positive control group was given curliv 37 mg/200 g BW, test doses 1, 2, and 3 were given ethanol extract of telang flower, respectively 123 mg/200 g BW, 247 mg/200 g BW, and 370 mg/200g BW on day 1 until the 7th day. On the 8th day, the rat's blood was taken and then measured SGPT and SGOT were by an enzymatic method using a photometer. Based on the results of statistical analysis, Telang flower ethanol extract doses 1, 2, 3, and positive control showed a significantly different decrease in SGPT and SGOT compared to negative control but only dose 2 (247 mg/200 g BW) showed hepatoprotective activity equivalent to positive control.