Tmax Values Research Articles

PDE5 inhibitors against synaptic and cognitive impairment in Alzheimer’s disease and related dementia

AbstractBackgroundGene transcription mechanisms leading to synaptic plasticity and memory formation, including phosphorylation of the transcription factor CREB, are perturbed in Alzheimer’s disease (AD). In this regard, cyclic guanosine monophosphate (cGMP), which activates cGMP‐dependent protein kinases that, in turn, phosphorylate CREB, has been implicated in the memory and synaptic plasticity impairment occurring in the disease. Sildenafil (Viagra®), the well‐known FDA approved inhibitor of phosphodiesterase 5 (PDE5I), the enzyme that degrades cGMP, has shown efficacy in AD animal models (Zuccarello et al, Biochem Pharmacol. 2020) and was recently significantly associated with a reduced risk of AD in an unbiased study including 7.23 million individuals (Fang et al, Nat. Aging 2020).MethodFollowing the development of a library of small molecules inhibiting phosphodiesterase 5 (PDE5), compound efficacy was tested in different animal models of Aβ and tau elevation. Specifically, these animals were tested using a combination of biochemical (western blotting of proteins involved with gene transcription machinery), electrophysiological [analysis of long‐term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation], and behavioral (assessment of spatial and associative memory through radial arm water maze and fear conditioning) techniques.ResultStructure activity relationship (SAR) analysis of existing PDEI scaffolds led to the design and synthesis of compound 7a, a quinoline customized for AD with improved physiochemical properties compared to existing inhibitors. The molecule has outstanding inhibitory activity against PDE5 (IC50 = 0.27nM) and selectivity against all other PDE isoforms (PDE5/PDEs > 1000). It also crosses the blood brain barrier (AUC0‐tratio = 0.41) and has similar Tmax values in the brain and plasma, indicating that its distribution to the brain is fast. Moreover, similar to other PDE5Is, 7a re‐established normal LTP and both spatial and associative memory after Aβ and tau elevation. Finally, the compound re‐established normal increase of CREB phosphorylation and cGMP levels after memory induction in the presence of Aβ and tau.ConclusionUp‐regulation of CREB activation through PDE5 inhibitors might be beneficial against Aβ and tau‐induced synaptic and memory dysfunctions.

A DFT approach towards understanding the thermal stability of TKX-50 and their key precursors through band gaps and MESP.

TKX-50 (dihydroxylammonium 5,5'-bistetrazolate-1,1'-dioxide) is a recent time invention by Klapotke et. al. in the field of high energy materials, and it outperforms all the existing materials by means of performance parameters. It is rising as potential energetic material due to favorable thermal insensitivity, low toxicity and safe handling. The decomposition temperature (Tmax) values of precursors such as glyoxime (I), 1,2-dichloroglyoxime (II), 1,2-diazidoglyoxime (III), and bistetrazoledihydroxide (IV) and ending products TKX-50 (V) and ABTOX (VI) have been attempted to correlate with the results obtained from molecular electrostatic potentials and band gaps calculated from the difference of ionization potential and electron affinity. The molecular electrostatic potential values of azido attached -NO group of III are much less than that of hydro/chloro attached -NO group of I/II and that of tetrazole groups IV, V, and VI. The band gaps calculated from stability trend in the increasing order of III < II < I < IV < V < VI are well corroborated with stability trend drawn from experimentally determined decomposition temperatures. Further, employing conceptual density functional theory (DFT) molecular descriptors, band gap values were calculated via the difference of ionization potential and electron affinity to understand the thermal stability of TKX-50, ABTOX, and its precursors.

Ring inserts as a useful strategy to prepare tip-loaded microneedles for long-acting drug delivery with application in HIV pre-exposure prophylaxis

The role of microneedle array patches (MAPs) and, in particular, dissolving MAPs in transdermal drug delivery has increased exponentially over the last decade. MAPs are able to form drug depots in the viable skin from where poorly soluble drugs dissolve in a long-acting fashion, showing promise in the management of multiple diseases. The manufacture of these systems can present some challenges, including the presence of bubbles in the baseplates and consequent lack of uniformity in microneedle formation and drug content. Here, we present a simple method based on ring inserts to produce tip-loaded MAPs using the antiretroviral drug cabotegravir sodium (CAB). The obtained MAPs presented a high uniformity in terms of microneedle formation, and a suitable insertion capability, as per the mechanical characterisation performed. An optimisation based on design of experiments revealed that centrifugation parameters had a significant impact on the skin deposition of the MAPs in excised neonatal porcine skin using Franz cells, with values ranging from 62.24 ± 47.13 µg to 174.13 ± 41.10 µg of CAB. Pharmacokinetic studies carried out in rats evidenced the capacity of the MAPs to maintain therapeutic plasma levels of CAB for 14 days, with Tmax values reached between 5 and 8 days.

The Development and Evaluation of Phase Transition Microemulsion for Ocular Delivery of Acetazolamide for Glaucoma Treatment

The aim of this study was to develop microemulsion (ME) formulation with possible phase transition into liquid crystals upon ocular application to enhance acetazolamide bioavailability. Pseudoternary phase diagrams were constructed using olive oil or castor oil (oily phase), Tween 80 (surfactant), and sodium carbonate solution (aqueous phase). Microemulsion and liquid crystal (LC) formulations were selected from the constructed phase diagrams and were evaluated for rheological properties and in vitro drug release. The efficacy of the developed formulations in reducing intraocular pressure (IOP) was assessed in vivo. In vitro release study showed slower release rate from LC and ME compared with drug solution with the release from LC being the slowest. Ocular application of acetazolamide ME formulations or aqueous solution resulted in significant reduction in IOP from baseline. The recorded Tmax values indicated faster onset of action for acetazolamide aqueous solution (1 h) compared with ME systems (3 h). However, the duration of action was prolonged and the reduction in IOP continued for up to 10 h in case of MEs, while that of aqueous solution was only for 4–5 h. The study suggested ME formulations for ocular delivery of acetazolamide with enhanced efficacy and prolonged duration of action.

Variety-specific sugarcane yield simulations and climate change impacts on sugarcane yield using DSSAT-CSM-CANEGRO model

Crop simulation models are still little used for sugarcane crops due to the lack of understanding of their capabilities and experience in calibration as compared to other crops. Realistic assessment of future environmental change effects on crop production is also necessary for successful agricultural management and planning. The objective of this study is to provide DSSAT-CANEGRO simulated variety-wise sugarcane yield models for twelve different locations of Muzaffarnagar District of India. The CANEGRO model calibration is performed under three different dates of planting (early, mid, late) during the spring season 2013–2014. The results of the models are validated for consecutive two years datasets (2014–15 and 2015–16). The model shows the best calibration and validation results under the mid planting date scenario (simulated yield +0.85 %, +2.80 % and +5.20 %). The impact of climate change (sensitivity analysis) on yield of sugarcane has also been made putting different values of Tmax ( ± 1 to ± 3 ºC), Tmin ( ± 1 to ± 3 ºC), solar radiation ( ± 1 to ± 3MJ/m2/day), and atmospheric CO2 concentration of 380 ppm (720 ppm scenario A2, 500 ppm scenario B2). The study highlighted that Sugarcane yield simulation mid-planting model presenting the highest R (0.81, 0.83), and D (0.88, 0.91), and the lowest errors (RMSE = 8.37 q ha-1, 10.70 q ha-1 and MAPE = 1.10 %, 1.30 %) for the years 2014–15 and 2015–16 as compared to the other two models. The CANEGRO model simulated yield under incremental values of Tmax and Tmin in the range of (+1 to +3 ºC) shows gradual decrement in the yield ranges while, gradual increment of solar radiation from 1 to 3 MJ/m2/day showed a yield increment.

Potential petroleum prospects in the middle Benue trough, central Nigeria: Inferences from integrated applications of geological, geophysical and geochemical studies

The Middle Benue Trough (MBT) is the least well-known of the three major sub-divisions of the Benue Trough (BT) and therefore poorly understood geologically. This paper presents preliminary results of an integrated geological, aeromagnetic, gravity and geochemical studies carried out as a first step approach to petroleum exploration in the central portion (MBT) of the Benue Trough, Nigeria, so as to be able to; 1. Appraise the regional geologic setting of the MBT with a view to understanding the stratigraphy and its oil generation characteristics; 2. Determine the basin configuration and sediment thicknesses and; 3. identify and delineate “leads” or prospect areas for further detailed exploration that could lead to significant commercial discoveries of hydrocarbon in the MBT. Results have revealed the existence of petroleum systems in the MBT with the interbedded shales of the Bima and Yolde formations at the upper portions and the shales of the Asu River Group, Awe, Ezeaku and Agwu formations corresponding to the potential source rocks. The main local potential reservoir rocks are the Bima Sandstones and sandstones of the Yolde Formation coupled with the interbedded arkosic sandstones of the Awe and Keana Formations, while potential regional seals are the shales of Pindiga Formation and the arkosic sandstones overlying the shales of the Asu River Group and the basal shales of the Ezeaku formation and the upper shales horizon of the Agwu formation. Geophysical studies (Aeromagnetic/gravity survey) revealed the variability of the surface to Basement depths within the Middle Benue Trough ranging from 3 – 6 km with the deepest portions of up to 8.2 km towards the Northeastern portion of the MBT. The thick sediment piles coupled with the favorable petroleum systems, provide the conditions necessary for hydrocarbon generation, migration and accumulation. The prominent lineament structure is the NE-SW directional Keana anticline which extends along a strike for more than 100 Km from the south of Makurdi to Zurak in the northern portion. Trans tensional and trans compressional fault systems in the basin have given rise to sub-surface and extensive lineament structures systems which could either constitute major structural traps or pathways for fluid (hydrocarbon) flow. The analysis of a wide range of geochemical data from the MBT revealed TOC values ranging from 0.43 to 3.90wt% for shales/coaly shales and 14.78–79.10wt% for shaly coal/coal facies embedded in the Agwu formation with Tmax values corresponding to immature to mature stages of thermal maturation. Their petroleum potential in terms of HI values ranges from 14 to 267mgHC/gTOC in shale/coaly shale facies and 36–157mgHC/gTOC in shaly coal/coal facies, corresponding to the predominance of type III (gas-prone) in addition to type II (oil and gas-prone) organic matter suggestive of having both oil and gas generating potential. The recent discovery of significant quantity of oil (+gas) in the well Kolmani River-1 in the Gongola Sub-basin, is in strong support of its occurrence in the MBT. The paper has recommended selected prospect areas favorable for further detail hydrocarbon exploration.

November 2022 Stroke Highlights

HomeStrokeVol. 53, No. 11November 2022 Stroke Highlights Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBNovember 2022 Stroke Highlights José Rafael Romero José Rafael RomeroJosé Rafael Romero https://orcid.org/0000-0002-1101-2950 Search for more papers by this author Originally published24 Oct 2022https://doi.org/10.1161/STROKEAHA.122.041383Stroke. 2022;53:3249is related toPrevalence and Predictors of Food Insecurity Among Stroke Survivors in the United StatesIs It About the Destination or About the Journey?Importance of Delayed Reperfusions in Patients With Incomplete ThrombectomyPrevalence and Predictors of Food Insecurity Among Stroke Survivors in the United StatesFood insecurity (FI) may interfere with adequate secondary stroke prevention. Kim-Tenser and colleagues assessed FI prevalence and trends using data from the US National Health and Nutrition Examination Survey survey (1999–2015). Food security was categorized as full, marginal, low, or very low, with the last 2 categories constituting FI. Stroke data were based on self-report. Among 48 242 participants, 1877 reported a stroke. FI was reported in 17% of participants with stroke and 12% of those without stroke. Predictors of FI included Black race, Hispanic ethnicity, low education, low income, non-married status, diabetes, smoking, and obesity. In age-adjusted analysis, FI increased over the study period from 7.8% to 42.1% in stroke survivors, and 8% to 17% in stroke-free participants. This study highlights FI as a growing adverse social determinant of health and modifiable social factor for stroke prevention targeting vulnerable groups. See p 3369.Yield of Dual Therapy with Statin and Ezetimibe in the Treat Stroke to Target TrialAmarenco and colleagues conducted a post-hoc analysis of the Treat Stroke to Target trial which randomized patients to dual therapy (statin and ezetimibe) versus statin monotherapy to achieve target LDL (low-density lipoprotein) <100 or LDL <70 mg/dl and assessed recurrent major cardiovascular events. Patients had ischemic stroke or transient ischemic attack and established atherosclerotic disease (aortic, intra or extracranial large artery or coronary arteries). There were differences in statin intensity between the LDL target groups, and other lipid-lowering treatments were allowed in the monotherapy group. Target LDL levels were achieved in the groups, but there was higher compliance in the dual therapy group. Overall, the dual therapy group targeting LDL <70 mg/dL had lower event rates across all major adverse cardiovascular outcomes, including intracerebral hemorrhage. Although this study suggests a benefit of dual therapy over monotherapy and target of lower LDL levels, confirmatory randomized clinical trials are needed. See p 3260.Importance of Delayed Reperfusions in Patients with Incomplete ThrombectomyIncomplete revascularization after mechanical thrombectomy in acute large vessel occlusion ischemic strokes occurs in a substantial proportion of patients. Mujanovic and colleagues conducted a single-center study to assess the relation of delayed reperfusion (DR) with tissue and functional outcomes after incomplete recanalization with mechanical thrombectomy for the treatment of acute ischemic stroke due to large vessel occlusion. Incomplete recanalization was defined as extended Thrombolysis in Cerebral Infarction (eTICI) score 2a or lower. Patients included also had a follow-up cerebral perfusion study at 24 hours. DR was defined as absence of a focal perfusion delay with values of Tmax≥4 seconds on contrast-enhanced follow-up perfusion imaging within the territory of the initially occluded vessel. Among 566 patients studied, DR occurred in 40.3% patients with incomplete recanalization and in none of the patients with complete recanalization (eTICI 3). DR and persistent perfusion deficits were related to eTICI score with higher DR rates associated with higher eTICI score. DR was related to preserved tissue (ie, no new infarction) while persistent perfusion deficit was related to new infarct on follow-up imaging. In multivariable analysis adjusted for relevant confounders, patients with DR had better functional outcomes regardless of eTICI score achieved (adjusted odds ratio, 2.37 [95% CI, 1.34–4.23]) and lower mortality (adjusted hazard ratio, 0.60 [95% CI, 0.39–0.91]). This study needs replication but suggests that DR is an important measure of tissue fate and correlated with functional outcome. DR may be a relevant marker for patient selection, and potential target for randomized clinical trials in patients with acute ischemic stroke undergoing mechanical thrombectomy. See p 3350. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesPrevalence and Predictors of Food Insecurity Among Stroke Survivors in the United StatesAmytis Towfighi, et al. Stroke. 2022;53:3369-3374Is It About the Destination or About the Journey?Dylan Blacquiere, et al. Stroke. 2022;53:3268-3269Importance of Delayed Reperfusions in Patients With Incomplete ThrombectomyAdnan Mujanovic, et al. Stroke. 2022;53:3350-3358 November 2022Vol 53, Issue 11 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.122.041383 Originally publishedOctober 24, 2022 PDF download Advertisement SubjectsCerebrovascular Disease/StrokeRevascularization

A Pharmacokinetic Profile and Antihyperlipidemic Effectiveness of Nanoemulsion and Ethanol Extract from Parang Romang Leaves (Boehmeria virgata)

Background: Parang Romang has an antihyperlipidemic effect, but the use of herbs has limitations with poor solubility in water, causing failure in the clinical phase due to low bioavailability. Bioavailability can be increased with nanotechnology, one of which is nanoemulsion. Objectives: This study aimed to determine the pharmacokinetic profile and effectiveness of antihyperlipidemic from nanoemulsion preparation and ethanol extract from parang romang leaves. Methods: Pharmacokinetic study with 10 rats each given 100 mg/kg BW of nanoemulsion and ethanol extract from parang romang leaves. The blood was taken at 0.5; 1; 1.5; 2; 2.5; 3; 3.5; 4 hours to measure tmax, Cpmax, and AUC. Study of antihyperlipidemic with 30 rats divided into 5 groups with normal control group I which was given Na CMC suspension, group II negative control given high fat feed + streptozotocin, group III positive control given high fat feed + streptozotocin &amp; simvastatin 0.9 mg/ kg BW, group IV was given high fat feed + streptozotocin + ethanol extract of parang romang leaves 100 mg/kg BW and group V was given high fat feed + streptozotocin + nanoemulsion of ethanol extract of parang romang 100 mg/kg BW, Then blood was taken on day 0,14,21, 28 and 35. Results: The results of the pharmacokinetic profile test showed that the values ​​of tmax, Cpmax, and AUC for nanoemulsions and extract were respectively; 0.5 hours, 96.68 g/ml and 297.57 and 1-hour, 15.44 g/ml and 93.53 and The statistical results obtained a significant value (P &lt; 0,05 ) which showed a significant effect between nanoemulsion and ethanol extract from parang romang to reduce cholesterol levels Conclusions: There are differences in pharmacokinetic profile and antihyperlipidemic effectiveness between nanoemulsion preparations and ethanol extracts from parang roman leaves.

Burial history and thermal maturity of the atypical petroleum system of the Paraná Basin (Irati and Ponta Grossa formations), Brazil

The main characteristic of the intracratonic sedimentary Paraná Basin, southern Brazil, is the atypical hydrocarbon generation through the heat from basic intrusive rocks. Potential hydrocarbon source shales from the Irati and Ponta Grossa formations were identified and characterised via stratigraphic data, total organic carbon (TOC - LECO) analyses and pyrolysis (Rock-Eval 6) of well samples. Geochemical analyses showed that in wells under study, the Irati Formation has organically rich shales, and the Ponta Grossa Formation has low potential for hydrocarbon generation. 1D generation modelling using 16-well 1D and PetroMod® software was developed aiming to establish the thermal and subsidence history in the area and to determine hydrocarbon generation and expulsion. Geochemical data from the wells was used, and information on sedimentology and stratigraphy was obtained from the literature. Thermal history was calibrated using values of vitrinite reflectance, Tmax and downhole temperature, and the geothermal gradient used in the models was 28–42 °C/km. The relative erosive thicknesses of the stratigraphic units were estimated. The results showed that in regions without igneous intrusions, the Irati shales are immature for hydrocarbon generation and do not have an organic matter transformation rate, which is consistent with the results of Rock-Eval pyrolysis and %Ro. However, in wells containing igneous intrusive rocks in the Irati shales, the transformation rates varied according to the thickness and number of intrusions, reaching 100% organic matter transformation; due to its quality (Type I kerogen), this rate is favourable for oil and gas generation. The Ponta Grossa source rock showed thermal maturation by subsidence corresponding to the oil generation window, with higher maturation anomalies near igneous intrusions. The organic matter transformation rate reached 70% in the absence of igneous intrusions and nearly 100% in the presence of igneous intrusions. Despite having good maturity, the characteristics regarding the quantity and quality of organic matter suggest a moderate potential for gas generation in the Ponta Grossa Formation in the study area. The depositional history model showed that the highest subsidence rate occurred during the Early Cretaceous and was related to the burial associated with the basalt thickness of the Serra Geral Formation.

Predictive performance and verification of physiologically based pharmacokinetic model of propylthiouracil.

Background: Propylthiouracil (PTU) treats hyperthyroidism and thyroid crisis in all age groups. A variety of serious adverse effects can occur during clinical use and require attention to its pharmacokinetic and pharmacodynamic characteristics in various populations. Objective: To provide information for individualized dosing and clinical evaluation of PTU in the clinical setting by developing a physiologically based pharmacokinetic (PBPK) model, predicting ADME characteristics, and extrapolating to elderly and pediatric populations. Methods: Relevant databases and literature were retrieved to collect PTU’s pharmacochemical properties and ADME parameters, etc. A PBPK model for adults was developed using PK-Sim® software to predict tissue distribution and extrapolated to elderly and pediatric populations. The mean fold error (MFE) method was used to compare the differences between predicted and observed values to assess the accuracy of the PBPK model. The model was validated using PTU pharmacokinetic data in healthy adult populations. Result: The MFE ratios of predicted to observed values of AUC0-t, Cmax, and Tmax were mainly within 0.5 and 2. PTU concentrations in various tissues are lower than venous plasma concentrations. Compared to healthy adults, the pediatric population requires quantitative adjustment to the appropriate dose to achieve the same plasma exposure levels, while the elderly do not require dose adjustments. Conclusion: The PBPK model of PTU was successfully developed, externally validated, and applied to tissue distribution prediction and special population extrapolation, which provides a reference for clinical individualized drug administration and evaluation.

Simultaneous Analysis of a Combination of Anti-Hypertensive Drugs, Fimasartan, Amlodipine, and Hydrochlorothiazide, in Rats Using LC-MS/MS and Subsequent Application to Pharmacokinetic Drug Interaction with Red Ginseng Extract.

Fimasartan, amlodipine, and hydrochlorothiazide are commonly used in combination therapies as antihypertensive drugs. This study aimed to develop and validate an analytical method for fimasartan, its active and major metabolite fimasartan-amide, amlodipine, and hydrochlorothiazide in rat plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The standard calibration curves for fimasartan (1–500 ng/mL), its active and major metabolite fimasartan-amide (0.3–100 ng/mL), amlodipine (0.5–200 ng/mL), and hydrochlorothiazide (5–5000 ng/mL) were linear with R2 > 0.9964, and the inter- and intra-day accuracy and precision and stability were within the acceptable criteria. Using this validated analytical method, the pharmacokinetic interaction of these triple combination drugs between single administration and concomitant administration of the triple combination was investigated; the results did not reveal a significant difference in any of the pharmacokinetic parameters. Based on these results, we investigated the effects of red ginseng extract (RGE) on the pharmacokinetics of fimasartan, fimasartan-amide, amlodipine, and hydrochlorothiazide after oral administration of the combination in rats. No significant difference was observed in the pharmacokinetic parameters of fimasartan, fimasartan-amide, amlodipine, and hydrochlorothiazide, except for the Tmax values of amlodipine. The delayed Tmax value of amlodipine was attributed to its decreased intestinal permeability after repeated RGE treatments. In conclusion, using a combination of antihypertensive drugs and simultaneous analytical methods, we established efficient drug interaction and toxicokinetic studies using a small number of animals.

Hydrocarbon Potential of Middle Jurassic Sediments (Stefanets Mb. of Etropole Fm.) from the Western Part of Balkan Orogenic System, Bulgaria

Sediments of Stefanets Mb. (Etropole Fm.), consisting mainly of shale and siltstones, are investigated by Rock-Eval pyrolysis. The samples from the Middle Jurassic section (Bajocian in age), outcropping within the western part of the Balkan orogenic system in Bulgaria, were analyzed to study their hydrocarbon generative potential. The obtained TOC contents are in the range of 0.69–1.97 wt.%. Inorganic carbon (TIC) and total sulphur (TS) contents are low and coincide with previously published data. The values of S1 and S2 are between 0.01 and 0.10 (mg HC/g rock) because of the high thermal maturity level, as indicated by Tmax values of 566-610 °C. The rocks are in the postmature stage and consequently the HI values are very low (&lt; 10 mg HC/g TOC). The fair to good quantity, low quality, as well as the high level of thermal maturity of the organic matter, assume minor remaining gas-prone generation potential of Stefanets Mb.

Assessment of hydrocarbon generation potential and thermal maturity of the deep offshore Lamu Basin, Kenya

In this study, the secondary well data for Cretaceous to Miocene cutting samples in four deep offshore exploration wells, i.e., Pomboo-1 in the north, Kubwa-1 in the central, Simba-1 and Kiboko-1 in the south of the deep offshore Lamu Basin were assessed for identifying source rock presence and examining thermal maturity of the source rocks. The 2D basin modelling was used to analyse the bulk gas transformation in the basin. Total organic carbon (TOC) content values for the wells range from 0.09 wt % to 2.23 wt % with an average of 0.78 wt %. The average organic richness is higher in the Upper Cretaceous (0.83 wt %) than in the Palaeogene (0.65 wt %), Lower Cretaceous (0.28 wt %) and Upper Jurassic (0.30 wt %). The S1 averages for the Upper Cretaceous are 3.76 mg HC/g rock in Pomboo-1 and 0.31mg HC/g rock in Kubwa-1. The S2 averages for the Upper Cretaceous are 5.00 mg HC/g rock in Pomboo-1 and 0.72 mg HC/g rock in Kubwa-1. Hydrogen index (HI) values vary between 4 and 512 mg HC/g TOC with an average of 157.09 mg HC/g TOC. Organic matters were identified as mixed types of II-III (oil and gas prone) and III-IV (gas prone) kerogen in the potential source rocks. The HI and S2 yield values are exceptionally high for the observed TOC values in Pomboo-1. The vitrinite reflectance and Tmax values of deep offshore Lamu Basin are in the ranges of 0.38%–0.72% and 360–441 °C, respectively. It suggests the existence of both immature and mature source rocks. Vitrinite reflectance maturity favours near coastal region in the Upper Cretaceous. These results explain why Pomboo-1, Kubwa-1, Simba-1 and Kiboko-1 wells were dry. The temperatures are still cool for hydrocarbon generation in deep offshore. The critical risk for deep offshore Lamu Basin is charge, primarily source presence, and a lack of definitive evidence of a deep-water marine source rock being present. The four wells penetrate good quality reservoir and seal rocks, but source rock presence and maturity remain the critical play risk in the deep offshore Lamu Basin.

FORMULATION AND EVALUATION OF NOVEL INSITU GEL SYSTEM IN THE MANAGEMENT OF RHEUMATOID ARTHRITIS

Objective: To develop in-situ gel formulations of Lornoxicam for sustained release to reduce the dosing frequency in the treatment of rheumatoid arthritis. Methods: The method of ion-sensitive in-situ gel formation was used in this study. Lornoxicam in situ gel formulations were prepared by varying concentrations of sodium alginate as a bio-degradable gel-forming polymer, CaCl2 as a cross-linking agent, and chitosan, HPMCK4, HPMCK15, guar gum, gellan gum, xanthan gum, pectin were used as drug release rate controlling polymers. The formulations F11-F18 were assessed for physical appearance, pH, in vitro drug release, viscosity, in vitro gelling capacity, and drug content. FTIR, DSC, and in vivo drug kinetics studies were conducted for lornoxicam pure drug and optimized formulation. Results: Formulations showed an optimum viscosity that will allow ease of administration and swallowing. All formulations were shown pH between 6.7 to 7.3, floating lag time was 2-3 sec and floated for 12 h. In vitro, drug release studies were reporting that commercial sustained release formulation of lornoxicam released 99.92% drug in 8 h, and optimized formulation F11 released 99.52% of the drug over a 12 h extended period. FTIR studies revealed no interaction between drugs and excipients used. The results of in vivo kinetic studies are approving the better performance of the optimized formulation. The Cmax, Tmax, t1/2, and AUC values are confirming the same thing. Conclusion: Lornoxicam oral in situ gel containing chitosan as a drug release controlling polymer is a promising approach for the treatment of rheumatoid arthritis in a convenient dosage form with better patient compliance and therapeutic response.

Maturity trends for the Late Devonian Duvernay Formation and identification of the Willesden-Green Maturity High

Maturity trends appearing in the literature for the Late Devonian Duvernay Formation within the Western Canada Sedimentary Basin (WCSB) are inconsistent and do not reflect hydrocarbon production. To address these inconsistencies and more accurately delineate Duvernay maturity trends, this study produces solid-state 13C Nuclear Magnetic Resonance (NMR) spectroscopy and Rock-Eval Tmax data from 38 wells throughout the WCSB. The Duvernay is divided into three different assessment areas that include, from east to west, Innisfail, Willesden-Green, and Kaybob. Based upon the proportion of aromatic to aliphatic carbon of the source rock organic matter, the Duvernay maturity generally increases towards the southwest and mimics structural depth, except within the Willesden-Green area. The Innisfail area has the shallowest depths and only the southern portion reaches oil maturity. The Willesden-Green and Kaybob areas range from oil to dry gas maturity. Although Willesden-Green and Kaybob have similar structural depths (P = 0.24), they have a significant difference in solid-state 13C NMR proportion of aromatic to aliphatic (P = 0.05) and Tmax values (P = 0.00). The average residuals from the depth vs solid-state 13C NMR proportion of aromatic carbon and Tmax best fit line show an increase of 0.09 and 10 °C respectively in Willesden-Green compared to Kaybob. Maps of the maturity indicators show the increase in maturity within Willesden-Green is perpendicular to structural strike. This study names this anomalous feature the Willesden-Green Maturity High.

Field attributes and organic geochemical analysis of shales from early to middle Permian Dohol Formation, Peninsular Malaysia: Implications for hydrocarbon generation potential

The early to middle Permian Dohol Formation falls under the Eastern Belt of Peninsular Malaysia. This formation is part of the Palaeozoic rock sequence in East Johor, composed of several metasedimentary, metamorphic, volcanic, and siliciclastic rocks. The Dohol Formation is said to have abundant black shales; however, the previous studies done in the area does not focus on the field attributes and the ability of the shales to generate hydrocarbons. Detailed traditional fieldwork was conducted in East Johor to characterize the shale facies of the formation. Different types of shale facies have been identified and interpreted in this study: (i) dark grey shale facies, (ii) light grey shale facies, (iii) red shale facies, and (iv) dark brown shale facies. XRD analysis was used to evaluate the mineralogy of the rock samples; the results show that the shales are primarily composed of kaolinite, illite, and quartz. The organic geochemical analysis also revealed that the samples collected had low TOC content, with an average TOC value of 0.40 wt%, with type II and type III kerogen predominating. The Ro and Tmax values and plots indicated that the samples are mature, with most already generating oil. The findings of this study suggest that the Dohol Formation has a low potential for generating hydrocarbons in commercial quantities, and also, the rocks are from a deep marine depositional setting.

A method for assigning pre-exponential factors for kerogen kinetics, calibrated with Easy%RoDL, and comparison with EASY%Ro

Modeling hydrocarbon-generation processes requires reliable kinetic models for the thermal decomposition of kerogens. To improve confidence and accuracy in modeling of generation, this study employs data from both natural and laboratory maturation to quantify thermal stress and strain for kerogens in 11 source-rock data sets. The method yields kinetic parameters (pre-exponential factor and Ea) for hydrocarbon generation that are constrained to make accurate predictions about thermal stress (quantified here as Ro-equivalent) and thermal strain (quantified as Hydrogen Index) under both laboratory and natural conditions. Methods for converting Tmax values to Ro-equivalents were examined and are discussed briefly. Vitrinite reflectance values were calculated at geological heating rates using the Easy%RoDL kinetic formulation, and were then compared with previous results obtained using EASY%Ro. The large differences observed between the EASY%Ro and Easy%RoDL evaluations are attributed to the differences in the pre-exponential factors in those two Ro-kinetic formulations. Understanding this relationship gives us a way to choose kinetic parameters for hydrocarbon generation that will work well for modeling under geological conditions. The single best A factor for hydrocarbon-generation when using EASY%Ro is 1e13 s−1 , while that for Easy%RoDL is 2e14 s−1 . The minor variation in A factors observed within each of the data sets may or may not be real. Using these results and concepts, more reliable hydrocarbon-generation windows in terms of either Ro-equivalent or Transformation Ratio can be achieved and cross-correlated. These results thus have the potential to increase both the accuracy of hydrocarbon-generation modeling, and the confidence in its results. Cited as: Waples, D. W., Yang, S. A method for assigning pre-exponential factors for kerogen kinetics, calibrated with Easy%RoDL, and comparison with EASY%Ro. Advances in Geo-Energy Research, 2023, 7(1): 1-6. https://doi.org/10.46690/ager.2023.01.01

Integrated metabolism, network pharmacology, and pharmacokinetics to explore the exposure differences of the pharmacodynamic material basis in vivo caused by different extraction methods for Saussurea involucrata

Ethnopharmacological relevanceSaussurea involucrata Kar.et Kir. (S.I.) has long been used as a precious national medicine and clinically proven to be an effective treatment for rheumatoid arthritis (RA) and cardiovascular diseases. In clinical practice, two extraction methods of S.I., including water decoction and alcohol extraction, are prescribed to treat the same conditions. Nevertheless, no study has been performed on the exposure differences of the pharmacodynamic material basis in vivo caused by different extraction methods. Aim of the studyBased on the integrated strategy of metabolism, network pharmacology, and pharmacokinetics, we aimed to reveal exposure differences in pharmacodynamic substances caused by different extraction methods. Materials and methodsUltra-high-performance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS) was employed to identify the chemical constituents of S.I. extracts and the metabolites in vivo after administration. Based on the analysis of prototype components in vivo, the major exposure active constituents, potential therapeutic targets and possible pharmacological mechanisms in RA treatment were investigated using network pharmacological analysis. Seven critical active components, including quercetin, hispidulin, apigenin, chlorogenic acid, arctigenin, syringin, and umbelliferone, were quantitatively compared between the alcohol, and aqueous extraction methods, which had been confirmed by the reference substance. ResultsThe chemical comparison demonstrated that the types of chemicals in the two extracts were identical, mainly flavonoids, phenylpropanoids, coumarins, lignins, sesquiterpene lactones, and others, but the contents of the primary constituents in the aqueous extract were lower than those of the alcohol extract. A total of 30 prototype components and 174 metabolites were analyzed and identified in rat plasma, urine, fecal, and bile samples. Twenty-three prototype components were analyzed by network pharmacology, and seven critical active components were selected as representative markers for the pharmacokinetic study. Pharmacokinetic studies had shown that the Tmax values of apigenin, hispidulin, chlorogenic acid, arctigenin, and syringin after the oral administration of the alcohol extract were lower than those after the oral administration of the aqueous extract, and the above components in the alcohol extract could increase the absorption. Compared with the aqueous extract group, the Tmax and T1/2 of quercetin and umbelliferone were longer; it was suggested that alcohol extraction might have a slow-release and long-term effect on these two components. The relative bioavailability of apigenin, hispidulin, quercetin, chlorogenic acid, and umbelliferone in the alcohol extract group were higher than those in the aqueous extract group, which was consistent with the traditional clinical experience that alcohol extract could improve the efficacy of S.I. ConclusionsThe major exposure active constituents in vivo were screened. The representative components that could be used in pharmacokinetics were determined by integrating network pharmacology and metabolism studies. The critical active compounds were quantitatively compared between the alcohol and aqueous extraction methods. This study clarified that flavonoids, coumarin, and phenylpropanoids might be the primary material basis that caused the exposure differences between aqueous and alcoholic extracts from S.I.. This research aimed to provide the basis of metabolism in vivo for further studying these pharmacodynamic differences.

Adjusting sowing date improves the photosynthetic capacity and grain yield by optimizing temperature condition around flowering of summer maize in the North China Plain.

Adjusting the sowing date to optimize temperature conditions is a helpful strategy for mitigating the adverse impact of high temperature on summer maize growth in the North China Plain (NCP). However, the physiological processes of variation in summer maize yield with sowing date-associated changes in temperature conditions around flowering remain to be poorly understood. In this study, field experiments with two maize varieties and three sowing dates (early sowing date, SD1, 21 May; conventional sowing date, SD2, 10 June; delay sowing date, SD3, 30 June) were conducted at Xinxiang of Henan Province in 2019 and 2020. Early sowing markedly decreased the daily mean temperature (Tmean), maximum temperature (Tmax), and minimum temperature (Tmin) during pre-silking, while delay sowing markedly decreased those temperatures during post-silking. Under these temperature conditions, both varieties under SD1 at 12-leaf stage (V12) and silking stage (R1) while under SD3 at R1 and milking stage (R3) possessed significantly lower malondialdehyde (MDA) content in leaf due to higher activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) compared to SD2. Therefore, SD1 at V12 and R1 stages and SD3 at R1 and R3 stages for both varieties showed significantly higher photosynthetic capacity, including higher SPAD, Fv/Fm, Pn, Tr, and Gs, which promoted greater pre-silking dry matter (DM) accumulation for SD1 to increase the kernel number, and promoted greater post-silking DM accumulation for SD3 to increase the kernel weight, eventually increased the grain yield of SD1 and SD3 compared to SD2. Results of regression analysis demonstrated that Tmean, Tmax, and Tmin values from V12 to R1 stages lower than 26.6, 32.5, and 20.3°C are necessary for improving the kernel number, while Tmean, Tmax, Tmin, and accumulated temperature (AT) values from R1 to R3 stages lower than 23.2, 28.9, 17.3, and 288.6°C are necessary for improving the kernel weight. Overall, optimal temperature conditions around flowering can be obtained by early (21 May) or delay (30 June) sowing to improve the kernel number or kernel weight due to improved photosynthetic capacity, eventually increasing the grain yield of summer maize in the NCP.

Pharmacokinetic and metabolomic studies with a BIO 300 Oral Powder formulation in nonhuman primates

BIO 300, a pharmaceutical formulation of genistein, is being developed as a radiation countermeasure to treat hematopoietic acute radiation syndrome (H-ARS) and the delayed effects of acute radiation exposure (DEARE). Several studies have affirmed its safety and efficacy in alleviating the damaging effects of ionizing radiation. However, dose optimization of any drug has always been an important area of research because unnecessarily high drug doses may result in serious complications. In this study, we assessed the pharmacokinetics (PK) and metabolic profiles of two different doses of a novel solid-dosage formulation of BIO 300 (BIO 300 Oral Powder; 100 mg/kg and 200 mg/kg), when administered orally to nonhuman primates (NHPs). While the Tmax values of both doses remained the same, the area under the curve at 48 h (AUC0-48) was tripled by doubling the dose. Additionally, we monitored serum samples for global metabolomic/lipidomic changes using high resolution mass spectrometry followed by functional pathway analysis prior to and at various time points up to 48 h post drug administration. Interestingly, the metabolomic profiles of sera from NHPs that received the lower dose demonstrated a transient perturbation in numerous metabolites between the 4 and 12 h time points. Eventually, the metabolite abundance reverted to near-normal by 48 h. These study results are consistent with our previous studies focused on the PK and metabolomic analysis for parenteral and oral aqueous nanosuspension formulations of BIO 300. This study affirms that administration of a single dose of up to 200 mg/kg of BIO 300 Oral Powder is safe in NHPs and conferred no metabolomic-mediated safety features.