Design of Oral Sustained-Release Pellets by Modeling and Simulation Approach to Improve Compliance for Repurposing Sobrerol

Sobrerol, an oral mucolytic agent, in a recent study showed promise for treating multiple sclerosis. A human equivalent dose of 486 mg of sobrerol administered thrice daily (i.e., 1459 mg of daily dose) demonstrated the highest therapeutic efficacy for repurposing use, which also points out the poor compliance of administration. In this study, oral sustained-release pellets of sobrerol were successfully developed with evaluated manufacturing conditions and drug release kinetics. For design of the target drug product, we used a modeling and simulation approach to establish a predictive model of oral pharmacokinetic profile, by exploring the characteristics and correlations corresponding to the pharmacokinetics and pharmacodynamics of sobrerol, such as absorption lag time (0.18 h), time-scaling in vitro–in vivo correlation (tin-vitro = 0.494 tin-vivo − 0.0904), gastrointestinal transit time (8 h), minimum effective concentration (1.61 μg/mL), and duration of action (12.8 h). Results showed that the frequency of administration and the daily dose remarkably reduced by 33.3% (i.e., from thrice to twice daily) and 22.8%, respectively, which indicates that this prototype approach can be adopted for rapidly developing a modified-release dosage form of sobrerol, with improvement of compliance of administration and therapeutic efficacy.

UHPLC analysis and in vitro biological activities of Areca triandra Roxb. ex Buch.-Ham.: a substitute of areca nut

Areca triandra Roxb. ex Buch.-Ham. (Arecaceae) distributed in Assam, North Bengal plains, Meghalaya andaman and Nicobar Islands is used as a substitute for A. catechu L. (Areca Nut). A. catechu is widely used as masticator in South Asia. The present study was conducted to find out the phenolic acids present in A. triandra and potential of it in inhibiting the reactive oxygen species (ROS). Plant extracts obtained from leaf and nut were analyzed qualitatively, quantitatively and phenolic acids were identified and quantified using reverse phase chromatography method developed on through Hypersil Gold aQ C18 column in Thermo Scientific Dionex Ultimate 3000 UHPLC. Three antioxidant assays viz. DPPH, ABTS and reducing power assay were performed to assess the potential of A. triandra as an antioxidant. Antifungal susceptibility test was performed by Clinical Laboratory Standard Institute (CLSI) recommended broth microdilution assay and disk diffusion susceptibility assay using Tinidazole as standard. Total catechin content was 19.51% of total phenolic content in NME. The antioxidant property was observed in NME only for DPPH, ABTS and RPA assays. In antifungal activity, minimum effective concentration (MEC) was observed in NME at the concentration of 1.0mg/ml and above whereas in LME, no MEC was observed up to tested concentrations. A. triandra possesses high catechin content and has promising potential as an antioxidant agent.

Rational use of corticosteroids in the treatment of ophthalmic herpes

The article discusses the issues of rational use of corticosteroid preparations for herpes infection of the eye. On the basis of scientific literature data and our own clinical observations given in the work, corticosteroid preparations are recommended for use in ophthalmic herpes only in the absence of ulceration and violation of the integrity of the cornea. It is advisable to prescribe them in micro doses, mainly in the form of instillations and, less often, parabulbar injections, with caution, under the strict supervision of an ophthalmologist, in the minimum effective concentration and in a short course. Key words: ophthalmic herpes, therapy, rational use corticosteroids.

Mechanistic Modeling of Maternal Lymphoid and Fetal Plasma Antiretroviral Exposure During the Third Trimester

Pregnancy-induced changes in plasma pharmacokinetics of many antiretrovirals (ARV) are well-established. Current knowledge about the extent of ARV exposure in lymphoid tissues of pregnant women and within the fetal compartment is limited due to their inaccessibility. Subtherapeutic ARV concentrations in HIV reservoirs like lymphoid tissues during pregnancy may constitute a barrier to adequate virological suppression and increase the risk of mother-to-child transmission (MTCT). The present study describes the pharmacokinetics of three ARVs (efavirenz, dolutegravir, and rilpivirine) in lymphoid tissues and fetal plasma during pregnancy using materno-fetal physiologically-based pharmacokinetic models (m-f-PBPK). Lymphatic and fetal compartments were integrated into our previously validated adult PBPK model. Physiological and drug disposition processes were described using ordinary differential equations. For each drug, virtual pregnant women (n = 50 per simulation) received the standard dose during the third trimester. Essential pharmacokinetic parameters, including Cmax, Cmin, and AUC (0–24), were computed from the concentration-time data at steady state for lymph and fetal plasma. Models were qualified by comparison of predictions with published clinical data, the acceptance threshold being an absolute average fold-error (AAFE) within 2.0. AAFE for all model predictions was within 1.08–1.99 for all three drugs. Maternal lymph concentration 24 h after dose exceeded the reported minimum effective concentration (MEC) for efavirenz (11,514 vs. 800 ng/ml) and rilpivirine (118.8 vs. 50 ng/ml), but was substantially lower for dolutegravir (16.96 vs. 300 ng/ml). In addition, predicted maternal lymph-to-plasma AUC ratios vary considerably (6.431—efavirenz, 0.016—dolutegravir, 1.717—rilpivirine). Furthermore, fetal plasma-to-maternal plasma AUC ratios were 0.59 for efavirenz, 0.78 for dolutegravir, and 0.57 for rilpivirine. Compared with rilpivirine (0 h), longer dose forgiveness was observed for dolutegravir in fetal plasma (42 h), and for efavirenz in maternal lymph (12 h). The predicted low lymphoid tissue penetration of dolutegravir appears to be significantly offset by its extended dose forgiveness and adequate fetal compartment exposure. Hence, it is unlikely to be a predictor of maternal virological failure or MTCT risks. Predictions from our m-f-PBPK models align with recommendations of no dose adjustment despite moderate changes in exposure during pregnancy for these drugs. This is an important new application of PBPK modeling to evaluate the adequacy of drug exposure in otherwise inaccessible compartments.

The minimum effective concentration (MEC90) of ropivacaine for ultrasound-guided caudal block in anorectal surgery. A dose finding study

Background Caudal epidural block (CEB) provides reliable anesthesia for adults undergoing anorectal surgery. Despite the widely utilization, the minimum effective concentration for 90% patients (MEC90) of ropivacaine for CEB remains unknown. Objective To estimate MEC of ropivacaine for CEB in anorectal surgery. Design A prospective dose-finding study using biased coin design up-and-down sequential method. Setting Operating room and postoperative recovery area of Chengdu Shangjin Nanfu Hospital, from October 2019 to January 2020. Patients 50 males and 51 females scheduled for anorectal surgery. Interventions We conducted two independent biased coin design up-and down trials by genders. The concentration of ropivacaine administered to the first patient of male and female were 0.25% with fixed volume of 14ml for male and 12ml for female patients based on our previous study. In case of failure, the concentration was increased by 0.05% in the next subject. Otherwise, the next subject was randomized to a concentration 0.05% less with a probability of 0.11, or the same concentration with a probability of 0.89. Success was defined as complete sensory blockade of perineal area 15 min after the block evidenced by the presence of a lax anal sphincter and pain-free surgery. Main outcome measures The MEC of ropivacaine to achieve a successful CEB in 90%(MEC90) of the patients. Results The MEC90 of ropivacaine for CEB were estimated to be 0.35% (95% CI 0.29 to 0.4%) for male and 0.353% (95%CI 0.22 to 0.4%) for female. By extrapolation to MEC in 99% of subjects (MEC99) and pooled adjacent violators algorithm (PAVA) adjusted responses, it would be optimal to choose 0.4% ropivacaine with a volume of 14ml for male and 12ml for female. Conclusions A concentration of 0.35% ropivacaine with a volume of 14ml provided a successful CEB in 90% of the male patients, while 0.353% ropivacaine with a volume of 12ml provided a successful CEB in 90% of the female patients. A concentration of 0.4% and a volume of 14ml for male and 12 ml for female would be successful in 99% of the patients. Trial registration Chictr.org.cn identifier: No. ChiCTR 1900024315.

Novel Scale Inhibitor Extends Treatment Lifetimes in Permian EOR

Background A new extended-release (ER) scale-inhibitor technology showing significantly increased lifetimes has been applied in the Permian Basin. Tomson Technologies and Group 2 Technologies, in partnership with Occidental Petroleum (Oxy), implemented a scale-squeeze program for this carrier system. It allows for fewer squeeze treatments, which results in lower chemical usage, decreased plugging risk, and reduced environmental impact. Squeeze programs are an effective field treatment strategy to prevent scale formation in wells for extended periods of time. However, in some cases, squeeze lifetimes can be short, leading to frequent re-squeezing and production decreases, lowering overall economic recoveries. The ER phosphonate-based chemistry (SI1313) was used in selected wells where incumbent (previous chemical provider) treatment lifetimes were shorter than expected. The incumbent squeeze volumes and additives were used, and the scale-inhibitor (SI) chemistry was replaced with SI1313 to obtain directly comparable results. The wells selected are vertical wells, with predominantly carbonate mineralogy and 14–18% porosity and 9–16 mD permeability. Bottomhole temperature is 105°F (40°C). These wells are under continuous CO2 flooding operations, and the scales of interest are calcium carbonate and calcium sulfate predominantly. The selected wells were targeted to have a good squeeze history for comparison and stable water production. Pre-Job Validation Work Coreflood laboratory experiments were performed to simulate the adsorption and desorption under these specific Oxy Permian conditions. The coreflood showed over 10,000 pore volume (PV) of flow with inhibitor concentration remaining above the minimum effective concentration (MEC) during the entire run. Once greater than two times incumbent performance was reached, the coreflood was stopped, although the return concentration was still above MEC. For reference, corefloods with incumbent phosphonate chemistry under the same conditions usually drop below MEC around approximately 3,000–5,000 PVs. The adsorption of SI1313 to core material was measured during the coreflood experiment and the results show 12.5 mg of inhibitor adsorbed per gram of core material. As a comparison, a typical incumbent phosphonate scale inhibitor adsorbs 1–2 mg of inhibitor per gram of core material. This increase in adsorption is considered a large improvement over traditional chemistry. The carrier platform’s superior adsorption, when combined with controlled desorption, is the basis for extending the lifetimes of scale- inhibitor treatments. The corefloods results validate the ER characteristics expected from SI1313 and allowed for field squeezes to be conducted. Field Application Group 2 Technologies provided SI1313 to be squeezed for Oxy in January 2020, into five vertical conventional wells. The selected wells are in one area where CO2 flooding is in place and there is risk of calcium carbonate (CaCO3) and calcium sulfate (CaSO4) scaling. These wells have had many scale squeezes performed on them, yielding an excellent data set to compare against. The goal of this trial was to show significant lifetime extension compared to previous incumbent squeeze lifetimes.

A 20-Year Antifungal Susceptibility Surveillance (From 1999 to 2019) for Aspergillus spp. and Proposed Epidemiological Cutoff Values for Aspergillus fumigatus and Aspergillus flavus: A Study in a Tertiary Hospital in China

The emergence of resistant Aspergillus spp. is increasing worldwide. Long-term susceptibility surveillance for clinically isolated Aspergillus spp. strains is warranted for understanding the dynamic change in susceptibility and monitoring the emergence of resistance. Additionally, neither clinical breakpoints (CBPs) nor epidemiological cutoff values (ECVs) for Aspergillus spp. in China have been established. In this study, we performed a 20-year antifungal susceptibility surveillance for 706 isolates of Aspergillus spp. in a clinical laboratory at Peking University First Hospital from 1999 to 2019; and in vitro antifungal susceptibility to triazoles, caspofungin, and amphotericin B was determined by the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method. It was observed that Aspergillus fumigatus was the most common species, followed by Aspergillus flavus and Aspergillus terreus. Forty isolates (5.7%), including A. fumigatus, A. flavus, A. terreus, Aspergillus niger, and Aspergillus nidulans, were classified as non-wild type (non-WT). Importantly, multidrug resistance was observed among A. flavus, A. terreus, and A. niger isolates. Cyp51A mutations were characterized for 19 non-WT A. fumigatus isolates, and TR34/L98H/S297T/F495I was the most prevalent mutation during the 20-year surveillance period. The overall resistance trend of A. fumigatus increased over 20 years in China. Furthermore, based on ECV establishment principles, proposed ECVs for A. fumigatus and A. flavus were established using gathered minimum inhibitory concentration (MIC)/minimum effective concentration (MEC) data. Consequently, all the proposed ECVs were identical to the CLSI ECVs, with the exception of itraconazole against A. flavus, resulting in a decrease in the non-WT rate from 6.0 to 0.6%.

Determination of Optimal Doses and Minimum Effective Concentrations of Tricaine Methanesulfonate, 2-Phenoxyethanol and Eugenol for Laboratory Managements in Nile Tilapia (Oreochromis niloticus)

Anesthetic agents are often used in fish experiments to reduce the stress and struggle and to improve animal welfare. The present study aimed to determine the optimal doses and serum minimum effective concentration (MEC) of tricaine methanesulfonate (MS-222), 2-phenoxyethanol (2-PE), and eugenol (EUG) in Nile tilapia. Twenty-one fish were immersed in three different doses of each anesthetic and the minimal dose that produce stage III anesthesia within 5 min, maintain anesthesia status for 3 min, and recover within 5 min was considered the optimal dose. The serum concentrations of anesthetics immediately after the fish reached stage III anesthesia was defined as the MEC. The results revealed that the anesthetics dose-dependently shorten the induction time while the effect of doses on the recovery times were variable. The determined optimal doses for MS-222, 2-PE, and EUG were 300, 900, and 90 ppm, respectively. The MECs were 70, 263, and 53 µg/mL, respectively, about two to four times lower than the optimal doses and were independent of the doses. After immersion stopped, the serum concentrations decreased by >90% within the first hour and >99% after 4 h. Our research provides useful information for a smooth fish handling and design for researches requiring stage III anesthesia.