Impact of Azithromycin on Forsythiaside Pharmacokinetics in Rats: A Population Modeling Method.

OBJECTIVE: Lianhuaqingwen and Shuanghuanglian are drug treatment options for Corona Virus Disease 2019 (COVID-19). In China, use of traditional Chinese medicine with Shuanghuanglian or Lianhuaqingwen (for them, forsythiaside is the active antiviral and antibacterial component) in combination with azithromycin is common for the treatment of pediatric pneumonia. It is important to understand the reason why the combination of these compounds is better than a single drug treatment. This study aimed to explore the pharmacokinetic interaction between forsythiaside and azithromycin. METHODS: Twelve male Sprague-Dawley rats were randomly divided into an experimental group (Forsythia suspensa extract and azithromycin) and a control group (a single dose of Forsythia suspensa extract in 5% glucose solution). Plasma samples were collected at scheduled time points, and the high-performance liquid chromatography combined with ultraviolet method was used to determine the plasma forsythiaside concentration. Non-compartmental analysis and population pharmacokinetic methods were used to investigate the forsythiaside pharmacokinetic difference between the experimental and control group. RESULTS: Compared with a single administration, the area under the curve and half-life of forsythiaside increased, and forsythiaside clearance decreased significantly after co-administration with azithromycin. The in vivo behavior of forsythiaside could be described by the one compartment model. The forsythiaside clearance decreased when combined with azithromycin. Visual evaluation and bootstrap results suggested that the final model was precise and stable. CONCLUSION: Co-administration of azithromycin can significantly decrease the forsythiaside clearance and increase drug exposure. A lower dose of azithromycin can obtain sufficient forsythiaside concentration to provide antiviral and antibacterial activity.

Impact of Electroacupuncture Stimulation on Postoperative Constipation for Patients Undergoing Brain Tumor Surgery.

BACKGROUND: Constipation is frequently encountered in patients undergoing brain tumor resection. Constipation has negative effects on daily living, well-being, and individuals' quality of life. We examined the impact of acupuncture and electroacupuncture (EA) stimulation on postoperative constipation for patients undergoing brain tumor resection. METHODS: Patients undergoing brain tumor resection (n = 150) were randomly divided into a nontreatment group, an acupuncture group, and an EA group. Rome III Diagnostic Criteria, Cleveland Clinic Constipation Score, symptom assessment, Patient Assessment of Constipation Quality of Life questionnaire, Self-Rating Anxiety Scale, and a Self-Rating Depression Scale were collected. RESULTS: Acupuncture and EA were effective in relieving postoperative constipation. Electroacupuncture decreased constipation and improved quality of life scores. CONCLUSION: Acupuncture and EA are novel adjuvant therapies to treat constipation.

Pharmacokinetic interaction of Forsythia suspensa extract and azithromycin injection after single and co-intravenous administration in rats.

Azithromycin and Chinese medicine forsythia are often used together to treat pediatric mycoplasma infections in China. We aimed to investigate the pharmacokinetic interaction of Forsythia suspensa extract and azithromycin after single and co-intravenous administration in rats. Male Sprague-Dawley rats received single (Forsythia suspensa extract or azithromycin) treatment or co-administration of Forsythia suspensa extract and azithromycin. Blood samples were collected at scheduled times, and drug concentrations were determined by HPLC-UV or HPLC-MS/MS methods. Both non-compartmental analyses and nonlinear mixed-effects modeling approaches were applied to fit pharmacokinetic data and evaluate the impact of co-administration. Pharmacokinetic analysis showed that the area under the curve of azithromycin and forsythiaside increased, and clearance decreased significantly (P < 0.05), after co-administration. The in vivo behavior of both azithromycin and forsythiaside could be appropriately described by the two-compartmental model. The final population pharmacokinetic model indicated that co-administration decreased the central volume of azithromycin and forsythiaside clearance significantly. Co-administration of Forsythia suspensa extract and azithromycin significantly decreased the clearance and increased exposure for both drugs. Pharmacokinetic data suggest that drug co-administration may increase efficiency.

Pharmacokinetic interaction between shuanghuanglian and azithromycin injection: a nonlinear mixed-effects model analysis in rats.

1. This study aimed to evaluate the pharmacokinetic interaction of shuanghuanglian (SHL) and azithromycin in rats, and to provide experimental support for rational drug use in clinics. 2. High-performance liquid chromatography with ultraviolet detection (HPLC-UV) and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) approaches were respectively developed to detect the forsythiaside (active component of SHL) and azithromycin concentrations. Both non-compartmental and compartmental analyzes were employed to calculate pharmacokinetic parameters. A nonlinear mixed-effects modeling method was applied to fit the drug concentration-time data. The influence of drug coadministration on pharmacokinetic parameters was tested using forward inclusion and backward elimination procedures. 3. After drug co-administration, areas under the drug concentration-time curve (AUC) and half-lives (T1/2) of both azithromycin and forsythiaside increased significantly, meanwhile, the drug clearance (CL) decreased compared to single drug administration. Both forsythiaside and azithromycin exposures increased after coadministration. Two-compartment models were suitable to describe the in vivo behavior of both azithromycin and forsythiaside. The coadministration of SHL could significantly decrease the central volume of azithromycin (VCA) and forsythiaside clearance (CLF) decreased after co-intravenous administration of azithromycin. 4. Co-intravenous administration of forsythiaside and azithromycin could significantly increase drug exposures for both drugs. Lower dose can provide sufficient drug exposure to obtain antibacterial activity. The coadministration may be a potential method to increase therapy efficiency while decrease adverse drug reactions.

Alterations of amino Acid level in depressed rat brain.

Amino-acid neurotransmitter system dysfunction plays a major role in the pathophysiology of depression. Several studies have demonstrated the potential of amino acids as a source of neuro-specific biomarkers could be used in future diagnosis of depression. Only partial amino acids such as glycine and asparagine were determined from certain parts of rats' brain included hippocampi and cerebral cortex in previous studies. However, according to systematic biology, amino acids in different area of brain are interacted and interrelated. Hence, the determination of 34 amino acids through entire rats' brain was conducted in this study in order to demonstrate more possibilities for biomarkers of depression by discovering other potential amino acids in more areas of rats' brain. As a result, 4 amino acids (L-aspartic acid, L-glutamine, taurine and γ-amino-n-butyric acid) among 34 were typically identified as potentially primary biomarkers of depression by data statistics. Meanwhile, an antidepressant called Fluoxetine was employed to verify other potential amino acids which were not identified by data statistics. Eventually, we found L-α-amino-adipic acid could also become a new potentially secondary biomarker of depression after drug validation. In conclusion, we suggested that L-aspartic acid, L-glutamine, taurine, γ-amino-n-butyric acid and L-α-amino-adipic acid might become potential biomarkers for future diagnosis of depression and development of antidepressant.

Development and validation of a highly sensitive LC-ESI-MS/MS method for the determination of hyperoside in beagle dog plasma: application to a pharmacokinetic study.

A highly sensitive, rapid assay method has been developed and validated for the analysis of hyperoside in beagle dog plasma with liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive-ion mode. The assay procedure involves extraction of hyperoside and ginsenoside Re (IS) from beagle dog plasma. Chromatographic separation was carried out on an Agilent Zorbax XDB-C18 (100 × 2.1 mm, 1.8 µm) column by isocratic elution with acetonitrile and water (50:50, v/v) at a flow rate of 0.25 mL/min with a total run time of 2.0 min. The MS/MS ion transitions monitored were 464.4 → 463.4 for hyperoside and 947.12 → 969.60 for IS. Linear responses were obtained for hyperoside ranging from 10 to 5000 ng/mL. The intra-and inter-day precisions (RSDs) were <5.38 and 3.39% and the extraction recovery ranged from 94.39 to 100.78% with an RSD <3.82%. Stability studies showed that hyperoside was stable in preparation and analytical process. The results indicated that the validated method was successfully used to determine the concentration-time profiles of hyperoside.

Altered plasma and brain disposition of isopropylidene shikimic acid liposome in rats and the brain protection in cerebral ischemia-reperfusion.

CONTEXT: Cerebral ischemia-reperfusion (I/R) injury is a secondary injury caused by oxidative stresses and inflammatory responses after recovery from cerebral ischemia. Brain protective drugs were used to reduce the injury. In order to improve the distribution in brain and enhance the brain-protective efficacy, some pharmaceutical technologies were used to achieve brain targeting delivery. OBJECTIVE: To investigate the physiological disposition of ISA liposome, and provide references for the further study about high-efficacy brain-protective preparations for I/R injury. MATERIALS AND METHODS: Comparative studies were carried out. The pharmacodynamics in t-MCAO model rats were studied first, and then the pharmacokinetics and brain distribution of the two preparations were determined. RESULTS: At the same dose, the efficacy of ISA liposome was better (P < 0.05). The efficacy was dose dependent, with significant difference of 20 mg/kg (P < 0.01) and indistinctive difference of 10 mg/kg (P = 0.22), compared with vehicle-treated rats. The parameters, T(1/2ß), MRT and AUC were different significantly between the two preparations. The enhancement of brain distribution for ISA in the liposome was obvious, with the maximum concentration 7.18 µg/g, while close to zero for the solution group. DISCUSSION AND CONCLUSION: ISA liposome could increase the distribution in brain and enhance the efficacy significantly. The results revealed that the liposomal DDS was potential as a novel strategy for the treatment of cerebral I/R injury. In addition, further targeted modification, such as PEG-modified liposomes, which possess a long circulating property in the bloodstream, would further improve the targeting delivery to the brain and lead to more significant efficacy.