Do Chinese HIV-infected Adult Patients with altered renal function need to adjust Tenofovir Disoproxil Fumarate Dosage? A Population Pharmacokinetics analysis.

Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir(TFV), is an effective drug in treating patients infected with human immunodeficiency virus(HIV). Previous population pharmacokinetics(PPK) studies have showed the large variabilities in PK of TFV. Furthermore, limited information was known in Chinese populations. Therefore, the aim of this study was to characterize PPK of TDF in Chinese and identify factors that may affect its PK. TFV concentrations (n = 552) from 30 healthy subjects and 162 HIV-infected Chinese adult patients were pooled for PPK analysis by a nonlinear mixed-effects method. The PK of TFV was adequately described as a two-compartment model with first order absorption and elimination. The typical apparent clearance(CL/F) of TFV in 70-kg adults was 137 L/h, higher than that reported in Caucasians and Blacks(45.8-93L/h). Estimated glomerular filtration rate was identified to be a significant factor influencing CL/F. Monte Carlo simulation showed that the exposure of standard dosing regimen of TDF 300mg every 24 hours in Chinese people with mild renal impairment(60 to 90 ml/min/1.73m2) was close to that in individuals with normal renal function(90 mL/min). Dose adjustment is not required for patients with mild renal impairment. Our study might offer new clues for optimal dosing strategies in Chinese patients with HIV-infected.

Tenofovir Concentration Is Not Enough in Intraocular Tissues of Patients With HIV infection.

OBJECTIVE: To determine tenofovir (TFV) penetration into intraocular tissues using ultra high-performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS). METHODS: Nineteen participants taking tenofovir in combination antiretroviral therapy (cART) regimen who underwent pars plana vitrectomy (PPV) surgery were enrolled in the observational retrospective study between January 2019 and August 2021. The participants were divided into mild, moderate, and severe groups according to retinal manifestations. Basic information was recorded during PPV surgery. Paired blood plasma and vitreous humor samples (n = 19) were collected for UHPLC-MS/MS. RESULTS: The median plasma and vitreous tenofovir concentrations were 106.00 ng/mL (interquartile range[IQR], 54.6-142.5) and 41.40 ng/mL (IQR 9.4-91.6), respectively. The median vitreous/plasma concentration ratio from the paired samples was 0.42 (IQR 0.16-0.84). The plasma and vitreous tenofovir concentrations were significantly correlated (r = 0.483, P = 0.036). The median vitreous tenofovir concentration was the lowest in the mild group (4.58 ng/mL). Six vitreous samples were below 50% inhibitory concentration (IC50) (11.5 ng/mL), and 2 of them were undetectable. Significant differences were noted in vitreous/plasma and vitreous tenofovir concentrations ( P = 0.035 and P = 0.045, respectively) among the 3 groups but not in plasma tenofovir concentration ( P = 0.577). No correlation was noted between vitreous HIV-1 RNA and vitreous tenofovir concentrations (r = 0.049, P = 0.845). CONCLUSION: Vitreous tenofovir did not reliably or consistently achieve concentrations sufficient to inhibit viral replication in intraocular tissues due to poor penetration of the blood-retinal barrier (BRB). The higher vitreous tenofovir concentrations were associated with moderate or severe disease compared with mild disease, indicating an association with the severity of BRB disruption.

Population pharmacokinetics and model-informed precision dosing of lamivudine in Chinese HIV-infected patients with mild and moderate impaired renal function.

BACKGROUND: Lamivudine is a first-line medication used for human immunodeficiency virus (HIV) treatment. To date, the population pharmacokinetics of lamivudine in Chinese HIV-infected adults have not been assessed. This study aimed to develop a population pharmacokinetic model for oral lamivudine in Chinese HIV-infected adults and to determine the optimal lamivudine dosage regimens. RESEARCH DESIGN AND METHODS: A total of 1113 samples, from 828 Chinese HIV-infected patients treated with lamivudine 300 mg every 24 hours, were pooled from two open-label, prospective clinical trials. A population pharmacokinetics analysis was performed using a nonlinear mixed-effects modeling method. A Monte Carlo simulation was conducted to optimize lamivudine dosing. RESULTS: A two-compartment model adequately described the population pharmacokinetics of lamivudine. The typical population estimate for apparent clearance was 28.3 L/h. Creatinine clearance was identified as a significant factor influencing apparent clearance. According to the Monte Carlo simulation, patients with creatinine clearance between 50 and 70 mL/min should receive lamivudine 200 mg every 24 h or 300 mg every 36 h, to achieve optimal lamivudine exposure. CONCLUSIONS: No obvious ethnic differences were observed in lamivudine pharmacokinetics between Chinese and Caucasian populations. Additionally, a model-informed dosage regimen is recommended for patients with impaired renal function.

Preparation of V-type cold water-swelling starch by ethanolic extrusion.

Ethanolic extrusion was used to prepare V-type cold water-swelling starch (VCWSS). Effects of extrusion temperature, ratio of starch to ethanol, and ratio of starch to water on the properties of VCWSS were investigated. It was found that when the extrusion temperature was 100 °C, the ratio of starch to ethanol was 1:0.30, and the ratio of starch to water was 1:0.60, the resulting VCWSS could quickly swell into paste in cold water with the highest V-type relative crystallinity (12.90%) and cold paste viscosity (3058 cP). Then the formation mechanism of cold paste viscosity of VCWSS was evaluated. The cold paste viscosity of VCWSS was positively related to its V-type relative crystallinity. Extrusion destroyed the granular morphology of native starch, and VCWSS particles exhibited rock-like morphology that is much larger than the granules of native starch. Formation of the V-amylose-ethanol complex during extrusion was the direct cause of rapid hydration of VCWSS.

Simultaneous determination of first-line anti-tuberculosis drugs and one metabolite of isoniazid by liquid chromatography/tandem mass spectrometry in patients with human immunodeficiency virus-tuberculosis coinfection.

The incidence rate of tuberculosis (TB) in patients with human immunodeficiency virus (HIV) infection is 26 times higher than that in other patients. Patients with both infections require long-term combination therapy, which increases therapy complexity and might lead to serious adverse reactions and drug-drug interactions. To optimize therapy for patients with HIV and TB coinfection, we developed an ultra-high-performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS) method to simultaneously quantify four anti-tuberculosis drugs and one isoniazid (INH) metabolite. Blood samples (n = 32) from 16 patients with HIV and TB coinfection were collected. Plasma protein precipitation with acetonitrile was followed by a hydrazine reaction between INH and cinnamaldehyde (CA) to produce phenylhydrazone (CA-INH) and dilution with heptafluorobutyric acid. The separation was performed on an Acquity UHPLC HSS T3 1.8 µm column (2.1 × 100 mm, Waters) with a mobile phase consisting of 10 mmol/L ammonium formate (pH = 4) in water (solvent A) and 0.1 % formic acid in methanol (solvent B) in a gradient elution. The compounds were detected using a positive multiple reaction monitoring model. INH, acetyl-INH (AC-INH), rifampicin (RIF), ethambutol (EMB), and pyrazinamide (PZA) showed good linear relationships in their quantitative ranges, with lower limits of quantification of 48, 192, 200, 96, and 480 ng/mL, respectively. The inter- and intraday precision was within 15 %, and the accuracy was between 85 % and 115 %. The mean plasma concentrations of INH, AC-INH, RIF, EMB, and PZA in patients were 1990.23 (24-16 600), 863.06 (96-2880), 3507.05 (229-9800), 808.10 (149-2130), and 18 838.33 (240-34 800) ng/mL, respectively. The plasma concentrations detected in the 16 patients were lower than the targeted concentrations in HIV-negative TB patients. In summary, we developed a simple UHPLC-MS/MS method for simultaneous quantification of first-line TB drugs, and successfully applied it for therapeutic drug monitoring in patients with HIV and TB coinfection. This method will facilitate monitoring of TB drugs in the future.

Preparation of V-type porous starch by amylase hydrolysis of V-type granular starch in aqueous ethanol solution.

In this paper, a novel porous starch with a V-type crystalline structure and high adsorption capacity was obtained by enzymatic hydrolysis of V-type granular starch (VGS) in an aqueous ethanol solution. The effects of different starch concentrations, reaction temperatures, and ethanol concentrations on the microstructure, crystal morphology, crystallinity and adsorption properties of VGS before and after enzymatic hydrolysis were studied, and native normal corn starch (NNCS) and A-type porous starch (APS) prepared by enzymatic hydrolysis of NNCS were used as controls. The results showed that compared with NNCS, VGS was easier to hydrolyze with a higher hydrolysis degree and the corresponding V-type porous starch (VPS) had more and larger pores and thus showed better adsorption performance than APS. Under the same enzymatic hydrolysis time, temperature and rotation speed, VPS prepared with a starch concentration of 20%, reaction temperature of 140 °C and ethanol concentration of 70% showed an irregular spongelike porous structure, highest V-type relative crystallinity of 25.09%, highest oil adsorption capacity of 241.70% and water adsorption capacity of 805.59%.

A robust and scalable active-matrix driven digital microfluidic platform based on printed-circuit board technology.

Two-dimensional digital microfluidic platforms, on which droplets are actuated by electrowetting on dielectrics, have merits such as dynamic reconfigurability and ease for automation. However, concerns for digital microfluidic platforms based on low-cost printed circuit boards, such as the scalability of the electrode array and the reliability of the device operation, should be addressed before high throughput and fully automatic applications can be realized. In this work we report the progress in addressing those issues by using active-matrix circuitry to automatically drive a large electrode array with enhanced device reliability. We describe the design and the fabrication of a robust and scalable active-matrix driven digital microfluidic platform based on printed-circuit board technology. Reliable actuation of aqueous and organic droplets is achieved using a free-standing double-layer hydrophobic membrane. To demonstrate the versatility of the digital microfluidic platform, a pentapeptide is synthesized on the device within 30 minutes. With these improvements, a fully automatic, scalable, robust, reusable, and low-cost digital microfluidic platform capable of parallel manipulation of a large number of droplets can find numerous applications in chemical engineering, bioengineering and biomedical engineering.

Vitamin C supplementation is necessary for patients with coronavirus disease: An ultra-high-performance liquid chromatography-tandem mass spectrometry finding.

To administer vitamin C (VC) with precision to patients with the coronavirus disease (COVID-19), we developed an ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to assess plasma VC concentrations. 31 patients with COVID-19 and 51 healthy volunteers were enrolled. VC stability was evaluated in blood, plasma, and precipitant-containing stabilizers. A proportion of 7.7 % of VC was degraded in blood at room temperature (RT) (approximately 20-25 °C) at 1.5 h post administration with respect to the proportion degraded at 0.5 h, but without statistical difference. VC was stable in plasma for 0.75 h at RT, 2 h at 4 °C, 5 days at -40 °C, and 4 h in precipitant-containing stabilizer (2 % oxalic acid) at RT. The mean plasma concentration of VC in patients with COVID-19 was 2.00 mg/L (0.5-4.90) (n = 8), which was almost 5-fold lower than that in healthy volunteers (9.23 mg/L (3.09. 35.30)) (n = 51). After high-dose VC treatment, the mean VC concentration increased to 13.46 mg/L (3.93. 34.70) (n = 36), higher than that in healthy volunteers, and was within the normal range (6-20 mg/L). In summary, we developed a simple UPLC-MS/MS method to quantify VC in plasma, and determined the duration for which the sample remained stable. VC levels in patients with COVID-19 were considerably low, and supplementation at 100 mg/kg/day is considered highly essential.