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Background: Combination therapy has become an attractive option in pulmonary arterial hypertension (PAH) treatment. The aim of this study was to investigate whether additional use of prostacyclin analogs could exert any additional benefits over background targeted therapies in PAH patients.Methods: Searches were performed on PubMed, Embase, and ClinicalTrials.gov from inception to 1 October 2021. Randomized controlled trials were included if patients had been treated with prostacyclin analog-containing combination therapy and compared with the use of other PAH-specific background therapies. The bias risk and statistical analysis of the enrolled studies were performed with RevMan 5.1. Sensitivity analysis and funnel plot were used to evaluate the stability and publication bias, respectively. PROSPERO registered number CRD42021284196.Results: Ten trials involving 1828 patients were included. Prostacyclin analog treatment was associated with greater improvement in clinical worsening (risk ratio [RR], 0.70; 95% confidence interval [CI], 0.57–0.86), 6-min walk distance (mean difference [MD], 37.17 m; 95% CI, 3.01–71.33 m), NYHA/WHO functional class (RR, 1.58; 95% CI, 1.21–2.05), mean pulmonary artery pressure (MD, −9.23 mmHg; 95% CI, −17.44 to −1.03 mmHg), and cardiac index (MD, 0.41 L/min/m2; 95% CI, 0.26–0.55 L/min/m2) than the control group. No significant differences in pulmonary vascular resistance (MD, −137.22 dyn·s/cm5; 95% CI, −272.61 to −1.84 dyn·s/cm5) and all-cause mortality (RR, 0.96; 95% CI, 0.57–1.61) were found between the prostacyclin analog group and control group. Of note, more adverse events (RR, 1.07; 95% CI, 1.02–1.13) occurred in the prostacyclin analog group but no significant increase in serious adverse events (RR, 1.25; 95% CI, 0.75–2.11).Conclusion: Additional prostacyclin analog treatment exerted benefits on clinical worsening, exercise capacity, functional class, mean pulmonary artery pressure, and cardiac index in PAH patients, but it was associated with overall risk of adverse events.Clinical Trial Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021284196, identifier CRD42021284196.

With the increasing demand for the radioisotope-free operations, using pulsed neutron gamma density (NGD) instead of gamma-gamma density (GGD) has become increasingly important for the development of logging while drilling (LWD) technology. However, due to the different logging mechanisms, there are huge differences between GGD and NGD in the instrument designs, measurement methods, and instrument specifications. To further promote the NGD development, a comparative study on GGD and NGD was carried out from theoretical and simulation aspects. Based on the theoretical methods, the differences between GGD and NGD in the gamma sources, field distribution, methods for density measurement and instrument specifications were systematically elaborated. Then, using the Monte Carlo simulation, the GGD and NGD models were built to quantitatively verify the theoretical results. Last, the detailed performances of NGD and GGD methods in different logging environments were compared. Results showed that the theoretical results are highly consistent with the simulation results. The density sensitivity of NGD is less than half that of GGD, but the depth of investigation (DOI) approaches twice that of GGD. The density precision and vertical resolution of NGD are less than those of GGD. Additionally, compared to GGD, NGD also has an excellent performance in different pore fluid and lithology formations, but it is easily affected by borehole factors. The research can provide quantitative performance evaluations for the NGD replacing GGD in LWD logging.

Diacerein is a symptomatic slow-acting drug used for treating osteoarthritis. This drug is completely metabolized into the active metabolite rhein before reaching the systemic circulation. This study evaluated the effects of food on the pharmacokinetics of rhein released from diacerein in healthy Chinese subjects. This was a single-center, randomized, single-dose, open-label, two-period, cross-over study. Twenty-four healthy subjects were randomly selected to receive a single oral dose of 50 mg diacerein capsule in either fasted or fed state on two separate visits. Plasma samples were analyzed with LC-MS/MS. Pharmacokinetic parameters were calculated using WinNonlin software. In the fasted and fed states, the main pharmacokinetic parameters of diacerein capsule were as follows: Cmax were (4471 ± 936), (3225 ± 755) ng/mL, t1/2 were (4.22 ± 0.42), (4.19 ± 1.05) h, tmax were (2.61 ± 1.25), (3.81 ± 1.29) h, AUC0-24 h were (24223 ± 4895), (24316 ± 5856) h·ng/mL, and AUC0-∞ were (24743 ± 5046), (25170 ± 6415) h·ng/mL. The absorption rate of diacerein capsule was obviously delayed by food intake but the absorption degree remained unaffected.

Neutron lifetime logging can measure the thermal-neutron capture cross-section of the formation using the neutron/gamma time spectrum information, and has a wide application in dynamic monitoring and recovery of remaining oil. However, the current time-spectrum processing technology is easily interfered by the borehole information and counting statistics in the neutron/gamma time spectrum, especially in a complex logging environment. To ensure the accuracy of neutron lifetime logging, a new time-spectrum processing technology based on regularized non-negative least squares (RNNLS) method was proposed. By presetting an array composed of different capture cross-section values, a multi-exponential decay function was established to describe the decay law of the time spectrum. Taking the multi-exponential decay function as a reference, an overdetermined linear equation system was constructed using time spectrum data. Finally, using the regularized non-negative least squares (RNNLS) method to solve the equation system, the contribution distribution of different cross-section values in the preset array to the time spectrum was obtained to indicate the capture cross-section of the formation. Studies show that, the new technology can automatically separate the cross-section contribution of the wellbore and formation to the time spectrum, and the cross-section contribution distribution has an obvious contribution peak which can be used for evaluating the real formation cross-section. In addition, by adopting the RNNLS method, this new method successfully gets rid of the influence of noise information and counting statistics on the capture cross-section results. Compared with the original technology, the new time-spectrum processing technology is no longer limited by the selection of time gates, and shows more accurate results in various logging environments.

Tight gas has become an important part of unconventional petroleum exploration and development. The evaluation of gas content is of great significance for reservoir prediction and oil & gas production. Pulsed neutron technology has been widely used for gas content evaluation in cased hole. The accurate evaluation of gas content under different types of gas reservoir is a huge challenge for pulsed neutron technology. In this paper, for closed gas reservoirs, the apparent gas saturation which utilizes the captured gamma ratio of near to extra-far detector is proposed to evaluate gas content. To accurately determine gas content, the responses of apparent gas saturation under different environment conditions were studied by Monte Carlo simulation. The result shows that lithology and clay content have a great influence on the use of the captured gamma ratio to calculate the apparent gas saturation. At the same time, the gas content in the wellbore is also an important interference factor. These factors should be considered in the actual evaluation of gas content. At last, the actual measurement data and interpretation results verify the validity of the method.

Hydraulic fracturing plays an important role in enhancing oil and gas production of unconventional formations. The quantitative fracture evaluation is essential for the optimization of fracturing model and production prediction of oil or gas. In this paper, based on the high thermal-neutron absorption capacity of tagged proppants containing gadolinium oxide, the thermal neutron detection technology is proposed to determine the fracture parameters including the height and width. By Monte Carlo simulation method, the spatial distributions of the thermal neutron before and after fracturing are analyzed. The relationships of the thermal neutron count versus gadolinium content and proppant filling are studied. On this basis, a mathematical relationship between the change of thermal neutron count VTn and fracture parameters was established to quantitatively evaluate the fracture height and width. In addition, the fracture responses of VTn under different formation backgrounds including porosity, salinity and lithology width were studied. Results show that the variations of porosity, salinity and lithology have non-ignorable influence on the determination of fracture width. Therefore, the better method on the fracture-width inversion is combining the thermal neutron count with the formation parameters. A simulated fracturing case with different formation porosities, lithologies and fracture conditions is given, which presented the feasibility of the method under different measurement environments. After the corrections of porosity, salinity, and other formation backgrounds, the new method shows a good performance: the calculated results of the fracture width and height are consistent with the realistic parameters, and the error in fracture calculation is less than 10%.

Repirinast is a new, synthetic, disodium cromoglycate-like antiallergic agent for oral administration in humans. This study evaluated the safety, tolerability and pharmacokinetics of repirinast tablets in healthy Chinese volunteers. This was a phase I, open-label, randomized, single- and multiple-dose study. Subjects were assigned to receive a single dose of repirinast tablet at either 150, 300, or 450 mg, or multiple doses of 150 mg twice daily for 5 days. Plasma samples were analyzed with LC-MS/MS. Pharmacokinetic parameters of active metabolite MY-1250 (deesterified repirinast) were calculated using non-compartmental analysis with WinNonlin software. Statistical analysis was performed using SPSS software. All adverse events (AEs) were mild and of limited duration. No serious adverse event (SAE), death or withdrawal from the study was observed. In the single-dose study, Cmax was reached at about 0.75 hour, and the mean t1/2 was approximately 16.21 hours. Area under curve (AUC) and Cmax increased with dose escalation, but dose proportionality was not observed over the range of 150 to 450 mg. In the multiple-dose study, the steady-state was reached within 3 days with no accumulation. Repirinast tablet was well tolerated in healthy Chinese subjects.

L-3-n-butylphthalide (L-NBP) is a naturally occurring antioxidant, which can be used for the treatment of acute ischemic stroke and vascular dementia. This study evaluated the safety, tolerability and pharmacokinetics of L-NBP tablets in healthy Chinese volunteers. This was a single-center, randomized, double-blind, placebo-controlled, single- and multiple-dose study. Subjects were assigned to receive a single dose of L-NBP tablet at either 80, 160, 320, or 480 mg (n=40), or multiple doses of 160 mg twice daily for 7 days (n=12). Plasma samples were analyzed with LC-MS/MS. Pharmacokinetic parameters of L-NBP were calculated using non-compartmental analysis with WinNonlin software. Statistical analysis was performed using SPSS software. All adverse events (AEs) were mild and of limited duration; AEs in this study occurred less frequently and more mildly than AEs listed for the DL-NBP soft capsule. No serious adverse event (SAE), death or withdrawal from the study was observed. In the single-dose study, Cmax was reached at about 1 h, and the mean t1/2 was approximately 13.76 h. Area under curve (AUC) and Cmax increased with dose escalation, but dose proportionality was not observed over the range of 160 to 480 mg. In the multiple-dose study, the steady-state was reached within 3 days with slight accumulation. In summary, the L-NBP tablet was well tolerated in healthy Chinese subjects. Slight accumulation appeared after repeated doses. L-3-n-butilftalida (L-NMP) é um antioxidante natural, que pode ser utilizado para o tratamento do acidente isquêmico agudo e demência vascular. Este estudo avaliou segurança, tolerância e farmacocinética de comprimidos de L-NBP em chineses voluntários sadios. Este foi um estudo monocêntrico, randomizado, duplo cego, com controle por placebo e doses única e múltipla. Os indivíduos receberam dose única de comprimido de L-NBP de 80, 160, 320 ou 480 mg (n=40) e doses múltiplas de 160 mg duas vezes ao dia, por sete dias (n=12). Amostras de plasma foram analisadas com LC-MS/MS. Os parâmetros farmacocinéticos do L-NBP foram calculados utilizando análise não compartimental, com o programa WinNonlin. A análise estatística foi realizada utilizando-se o programa SPSS. Todos os eventos adversos (EAs) foram moderados e de duração limitada. EAs nesse estudo ocorreram menos frequentemente e mais moderadamente do que os EAs relacionados para cápsulas moles de DL-NBP. Não se observaram eventos adversos graves (EAG), morte ou abandono do estudo. Com dose única, atingiu-se o Cmax em cerca de 1 hora e o t1/2 médio foi de, aproximadamente, 13,76 h. A área sob a curva (ASC) e o Cmax aumentaram com o aumento da dose, mas não se observou proporcionalidade na faixa acima de 160 a 480 mg. No estudo de dose múltipla, o equilíbrio foi alcançado em três dias, com pequeno acúmulo. Em resumo, o comprimido de L-NMP foi bem tolerado em indivíduos chineses saudáveis. O acúmulo pequeno apareceu após doses repetidas.

Triflusal presents comparable antiplatelet activity to aspirin while presenting a more favourable safety profile, and is used in the treatment of thrombosis. The study aimed to evaluate the pharmacokinetics and safety of triflusal and its major metabolite 2-(hydroxyl)-4-(trifluoromethyl)- benzoic acid (HTB) in healthy Chinese subjects. 30 healthy subjects were recruited in this randomized, single-center, and open-label, parallel, single ascending doses (300, 600, 900 mg) and multiple doses (600 mg, once daily for 7 days) study. Plasma samples were analyzed with a validated liquid chromatography tandem mass spectrometry (LC/MS/MS) method. Safety was assessed by adverse events, ECG, laboratory testing, and vital signs. Triflusal was safe and well tolerated. After single-dose administration, triflusal was rapidly absorbed with a mean T max of 0.55–0.92 h and a mean t 1/2 kel of 0.35–0.65 h, HTB was absorbed with a mean T max of 2.35–3.03 h and a mean t 1/2 kel of 52.5–65.57 h. C max and AUC for triflusal and HTB were approximately dose proportional over the 300–900 mg dose range. In the steady state, the accumulation index (R) indicated that the exposure of triflusal increased slightly with repeated dosing, and the exposure of HTB increased obviously. 3 adverse events certainly related to the investigational drugs occurred in the multiple-dose phase. Following oral dosing under fasting condition, triflusal is promptly absorbed and rapidly depleted from the systemic circulation. HTB is quickly generated from triflusal and slowly eliminated. Triflusal accumulates slightly in the body. HTB plasma concentration builds up progressively toward steady-state.

The chloro­phenyl group of the title compound, C18H12ClNO4, is disordered over two orientations with occupancies of 0.331 (8) and 0.669 (8). An intra­molecular hydrogen bond is formed between a hy­droxy group and the acyclic carbonyl group. In the crystal, molecules are linked into chains along [110] by O—H⋯O and C—H⋯O hydrogen bonds, forming a ladder motif.