The Impact of Proton Pump Inhibitors on the Efficacy of Immune Checkpoint Inhibitor Combinations in Patients with HBV-Associated Advanced Hepatocellular Carcinoma.

Purpose: There is limited research on whether Proton Pump Inhibitors (PPIs) will affect the efficacy of immune checkpoint inhibitors (ICIs) in treating hepatocellular carcinoma (HCC).This study aimed to determine whether PPIs affect the survival outcomes of patients with HBV-associated advanced HCC receiving combination therapy based on ICIs. Methods: We retrospectively analyzed patients with hepatitis B virus (HBV)-associated advanced HCC who underwent ICIs combination therapy from January 1, 2020, to December 30, 2022. Patients were stratified into PPI and non-PPI groups based on whether they received PPI treatment within 30 days before or after ICIs therapy. Patients' survival and the risk of PPI-associated mortality was assessed. Adverse events were also evaluated. Results: A total of 183 patients with HBV-associated HCC treated with ICI combination therapy were included. The median survival time (12.5 months vs 13.7 months, P = 0.285) and incidence of adverse events (P = 0.729) did not significantly differ between the PPI and non-PPI groups. Even after propensity score matching, the difference in median overall survival (OS) between the two groups was not significant (10.7 months vs 11.4 months; P = 0.596) and the patient's OS is not significantly related to the dosage of PPI application (P > 0.05).However, according to our subgroup analysis, among HCC patients with a serum HBV DNA concentration ≥ 200 IU/mL, the use of PPIs significantly increased the risk of mortality in patients receiving ICI combination therapy (P = 0.024). Conclusion: PPIs do not notably influence the survival prognosis of patients receiving ICI combination therapy for HBV-associated advanced HCC. However, among patients with high levels of HBV DNA, PPIs increase the risk of mortality. Therefore, antiviral therapy should be intensified in the patients with HBVDNA > 200 IU/mL. Additionally, PPIs do not impact the incidence of adverse reactions in these patients.

Effects of vitamin C on the pharmacokinetics and pharmacodynamics of nimodipine in rats.

In recent years, researchers have shown a growing interest in the interactions between different pharmaceutical agents. An intriguing instance lies in the possible interaction between nimodipine and vitamin C. To investigate the pharmacokinetic and pharmacodynamic effects of vitamin C on nimodipine in rats, rats were randomly divided into a nimodipine only group and a combination group (nimodipine + vitamin C). The two groups were given intragastric administration and nimodipine blood concentrations were determined using high-performance liquid chromatography-tandem mass spectrum at different time points. Blood pressure and heart rate were measured via carotid artery cannulation. Pharmacokinetic differences were observed between the nimodipine only group and the combination group at the same dose. Compared with the nimodipine only group, the combination group's main pharmacokinetic parameters of peak concentration and area under the curve increased significantly, and the difference was statistically significant (p < 0.05); furthermore, the combination group exhibited a significant reduction in average blood pressure, while no significant effects on heart rate were observed. Vitamin C did not affect the activity of CYP450 in rat liver. The pharmacokinetic characteristics and pharmacodynamics of nimodipine were changed by vitamin C administration in rats.

Liver Injury and Its Impact on Prognosis in Patients with HBV-Related Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization Combined with Tyrosine Kinase Inhibitors Plus Immune Checkpoint Inhibitors.

Purpose: Recently, the triple therapy of transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs) has become a new treatment option for advanced or unresectable hepatocellular carcinoma (HCC) patients. We aimed to explore the liver injury and its effect on overall survival (OS) in patients treated with this combination therapy. Patients and Methods: Patients with HBV-related HCC who were treated with TACE-TKIs-ICIs from January 2020 to December 2021 were enrolled. Liver injury and survival time were the main endpoints of the study. Logistic regression analysis was used to analyze the factors associated with liver injury. Cox regression and Kaplan-Meier analysis were used to determine prognostic factors for OS. Results: As of March 2022, 52 of the 119 enrolled patients developed any grade hepatotoxicity: 15 cases with grade 1, 19 cases with grade 2, 16 cases with grade 3 and 2 cases with grade 4. Our analysis indicated that lack of antiviral prevention was a risk factor for liver injury (OR = 0.149; 95% CI: 0.050-0.442; P = 0.001). The findings suggested that liver injury events (HR = 1.912; 95% CI: 1.031-3.546; P = 0.040) was associated with patient death. The median OS of patients without liver injury, grade 1-2 and grade 3-4 liver injury were undefined, 13.7 months and 11.1 months, respectively (log-rank P = 0.034). Conclusion: Liver injury adverse events are common in HBV-related HCC patients treated with TACE-TKIs-ICIs. Patients who developed liver injury had a poor prognosis. For HBV-related HCC patients, effective prophylactic antiviral therapy and regular liver function testing are required before and during this triple therapy.

Comparing the interactions of nitrendipine with lysozyme or human serum albumin and the effects of vitamin C and naringin on these interactions by spectroscopy and molecular docking methods.

The interactions between drugs and proteins play a pivotal role in determining the pharmacological effects and disposition of drugs within the human body. This study focuses on exploring the interaction between nitrendipine and lysozyme/human serum albumin. Spectroscopic analysis indicated a compound static quenching, indicative of the formation of stable complexes between the drug and proteins. The addition of vitamin C or naringin resulted in a decrease of the binding constant between nitrendipine and lysozyme/human serum albumin. The presence of these compounds may disrupt the interactions between the drug and proteins, potentially leading to an increased concentration of free nitrendipine in the bloodstream. Nitrendipine binds more easily to human serum albumin at 310 K, and human serum albumin has an average binding site ratio with nitrendipine approximately 0.1 higher than that with lysozyme. Vitamin C has a greater impact on the binding constant of nitrendipine to human serum albumin and lysozyme. Compared to the binary system of proteins with the drug, the ternary system with the addition of vitamin C at 310 K reduces the binding constants of lysozyme and human serum albumin by 85%. In conclusion, this study explores the significance of considering drug-protein interactions in understanding drug behavior and potential drug-food interactions.

Pharmacokinetics and tissue distribution study of two novel quinazoline PI3K/mTOR dual-inhibitors, potential anticancer agents.

S1 and S2, two structurally similar quinazoline derivatives, are novel anticancer drugs targeting the PI3K/AKT/mTOR signaling pathway channel. However, their pharmacokinetic and tissue distribution characteristics are unknown, which has hindered further development and in-depth studies. In this study, a simple, rapid and sensitive method using high performance liquid chromatography was established and validated to quantitatively study the pharmacokinetics and tissue distribution profiles of S1 and S2 in rats following intravenous injection. The results indicated that after intravenous injection, the elimination of S1 and S2 fit the two-compartment model and linear pharmacokinetics characteristics were observed. Furthermore, S1 and S2 were widely distributed and found in high concentrations in liver and kidney tissues and a small proportion of S1 and S2 could cross the blood-brain barrier and be distributed in the brain. The current findings will contribute to interpretation and understanding the relationship between dosage and pharmacodynamic effects of S1 and S2.

HBV reactivation and its effect on survival in HBV-related hepatocarcinoma patients undergoing transarterial chemoembolization combined with tyrosine kinase inhibitors plus immune checkpoint inhibitors.

Objective: This study aimed to access hepatitis B virus (HBV) reactivation and its effect on survival in HBV-related hepatocarcinoma (HCC) patients who underwent transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs). Methods: In this single-center retrospective study, we enrolled 119 HBV-related unresectable advanced HCC patients receiving TACE combined with TKIs plus ICIs. Risk factors for HBV reactivation were analyzed by logistic regression. Kaplan-Meier method was applied to draw the survival curve, and log-rank test was used to compare survival between patients with and without HBV reactivation. Results: A total of 12 patients (10.1%) encountered HBV reactivation in our study, of which only 4 patients received antiviral prophylaxis. The incidence of HBV reactivation was 1.8% (1/57) in patients with detectable baseline HBV DNA and 4.2% (4/95) in patients with antiviral prophylaxis respectively. Lack of prophylactic antiviral treatment (OR=0.047, 95%CI 0.008-0.273, P=0.001) and undetectable HBV DNA (OR=0.073, 95%CI 0.007-0.727, P=0.026) were independent risk factors for HBV reactivation. The median survival time (MST) for all patients was 22.4 months. No survival difference was observed in patients with or without HBV reactivation. (MST: undefined vs 22.4 months, log-rank test: P=0.614). Conclusion: HBV reactivation could occur in HBV-related HCC patients who treated with TACE in combination with TKIs plus ICIs. Before and during the combination treatment, it is necessary to routinely monitor HBV DNA and to take effective prophylactic antiviral therapy.

Development and validation of a nomogram to predict recompensation in HBV-related cirrhosis with ascites as the single first decompensating event.

BACKGROUND AND OBJECTIVE: Little is known about the influencing factors for recompensation in HBV-related cirrhosis patients with ascites as the single first decompensating event and it's necessary to build a prediction model for these patients. METHODS: Hepatitis B virus-related cirrhosis patients with ascites hospitalized for the first decompensation were included and they were divided into the training cohort (2010.03-2020.03) and the validation cohort (2020.04-2022.04). All patients received antiviral therapy within 3 months before admission or immediately after admission. Recompensation is defined as the patient's ascites disappeared without diuretics, which were maintained for more than 1 year and no other decompensated complications, hepatocellular carcinoma, or liver transplantation occurred. The nomogram was developed from a training cohort of 279 patients and validated in another cohort of 72 patients. RESULTS: Totally, 42.7% of the decompensated patients achieved recompensation. According to the results of logistic regression and competing risk analysis, six independent factors associated with recompensation were found and these factors comprised the nomogram: age, alanine aminotransferase (ALT), albumin (ALB), serum sodium (Na), alpha-fetoprotein (AFP), and maintained virological response (MVR). Through external validation, the area under the receiver operating characteristic curve (AUC) of the nomogram was 0.848 (95% CI: 0.761, 0.936), which was significantly better than CTP, MELD, MELDNa, MELD 3.0, and ALBI grade. CONCLUSIONS: Age, ALT, ALB, Na, AFP, and MVR are closely related to the recompensation. The nomogram developed based on these items can accurately predict the possibility of recompensation in hepatitis B cirrhosis patients with ascites as the single first decompensating event.

Study on the interaction of two quinazoline derivatives as novel PI3K/mTOR dual inhibitors and anticancer agents to human serum albumin utilizing spectroscopy and docking.

Interactions of human serum albumin (HSA) with two structurally similar quinazoline derivatives, S1 and S2 , which are potential anticancer drugs acting on PI3K/mTOR targets, were investigated in vitro utilizing multiple spectroscopy as well as molecular docking. The fluorescence quenching study demonstrated that HSA fluorescence could be statically quenched by S1 and S2 through the formation of an HSA-drug complex. Furthermore, the details of the binding site number, binding constant, as well as the thermodynamic parameters, were estimated at 298, 303, and 310 K. The results revealed that hydrogen bond interactions, as well as van der Waals forces, were the predominant factors responsible for binding HSA to S1 or S2 . Synchronous fluorescence and ultraviolet (UV) absorption spectra suggested that S1 and S2 had little effect on the polarity of the microenvironment and conformation of HSA. Energy transfer from HSA to S1 or S2 most probably occurred. The docking study revealed that S1 and S2 were able to bind to the hydrophobic cavity that was located in the HSA subdomain IIA and formed varying numbers of hydrogen bonds with amino acid residues nearby. Due to the subtle difference in the chemical structure, the binding of S1 and S2 to HSA was slightly different.

Dissolution thermodynamics and preferential solvation of genistein in some (ethanol + water) mixtures at different temperatures.

The solubility of genistein was measured in the binary system of ethanol and water at temperatures ranging from 288.2 to 328.2 K. The obtained data were correlated with the modified Apelblat model, Yalkowsky model, λh model, CNIBS/R-K model, Jouyban-Acree-van't Hoff model, and modified Wilson model and their prediction accuracy was evaluated by calculating the mean relative deviation. The thermodynamic functions, Gibbs energy, enthalpy, and entropy of solution were determined using van't Hoff equation. Moreover, the preferential solvation was analyzed by using the solubility data at 298.2 K. The solubility of genistein in the system increased with an increase in temperature and mole fraction of ethanol in the solvent mixtures. The values for solubility of genistein are ranging from 0.47 obtained in neat water at T = 288.2 K to 5.02 obtained in absolute ethanol at T = 328.2 K. The values of ΔsolnG,0 ΔsolnH0 and ΔsolnH0 for the dissolution of genistein in mixtures are positive, whereas the values of ΔsolnH0 in neat water and absolute ethanol are negative. The thermodynamic properties of dissolution suggest that the dissolution process is non-spontaneous and endergonic. The modified Apelblat model can provide more accurate predictive solubility of genistein in the water and ethanol mixtures, whereas Yalkowsky model calculates solubility of genistein with large deviations. Genistein is preferentially solvated by water in water-rich mixtures (0 < x2 < 0.24) but preferential solvation by ethanol in the region of 0.24 < x2 < 1. Overall, this work could be applied for designing and optimizing the extraction, purification, and crystallization process of genistein.

Investigation on the interaction between myricetin and dihydromyricetin with trypsin, α-chymotrypsin, lysozyme by spectroscopy and molecular docking methods.

The interaction between myricetin and dihydromyricetin with trypsin, α-chymotrypsin and lysozyme was investigated using multispectral and molecular docking methods. The results of fluorescence quenching revealed that myricetin and dihydromyricetin could quench the intrinsic fluorescence of three different proteinases through a static quenching procedure. The binding constant and number of binding sites at different temperatures were measured. The thermodynamic parameters obtained at different temperatures showed van der Waals interactions and hydrogen bonds played the main roles in the interaction of myricetin with trypsin and lysozyme, hydrophobic force was dominant both in myricetin with α-chymotrypsin interaction and dihydromyricetin with trypsin and lysozyme interaction, as for the electrostatic forces, it was mainly the driving force in dihydromyricetin binding to α-chymotrypsin. There was non-radiative energy transfer between three proteinases and myricetin or dihydromyricetin with high probability. The microenvironment of trypsin, α-chymotrypsin and lysozyme is changed. The docking studies revealed that myricetin and dihydromyricetin entered the hydrophobic cavity of three proteinases and formed hydrogen bonds. The binding affinity of myricetin or dihydromyricetin is different with the trypsin, α-chymotrypsin and lysozyme due to the different molecular structure.

Study on the interaction between nimodipine and five proteinases and the effects of naringin and vitamin C on these interactions by spectroscopic and molecular docking methods.

The interaction mechanisms of nimodipine with pepsin, trypsin, α-chymotrypsin, lysozyme and human serum albumin were investigated by multispectral and molecular docking methods. Vitamin C and naringin were the main active components of grapefruit juice, and nimodipine was the typical drug that interacts with this juice. Fluorescence spectroscopy was used to study the interaction of nimodipine with five proteinases (pepsin, trypsin, α-chymotrypsin, lysozyme and human serum albumin) and the effects of vitamin C and naringin on these interactions. The fluorescence quenching results showed that nimodipine can quench the intrinsic fluorescence of these five proteinases by a static quenching procedure. Nimodipine binds to pepsin and α-chymotrypsin, through hydrogen bonding and van der Waals forces, whereas it binds to trypsin, lysozyme and human serum albumin mainly by hydrophobic interactions. The microenvironment of the five proteinases changed. The probability of nonradiative energy transfer between the five proteinases and nimodipine was high. Both vitamin C and naringin reduced the binding constant of nimodipine to the four proteinases (except α-chymotrypsin) and might increase the concentration of free nimodipine. Thus, vitamin C or naringin in fruits or foods could increase the blood concentration of free nimodipine and perhaps a reduction in nimodipine dose was needed.

Quantitative Determination of p-Cymene, Thymol, Neryl Acetate, and ß-Caryophyllene in Different Growth Periods and Parts of Eupatorium fortunei Turcz. by GC-MS/MS.

Eupatorium fortunei Turcz. is a widely used Chinese herbal medicine in China. In this study, a gas chromatography-triple quadrupole mass spectrometry (GC-MS/MS) method was developed and validated to simultaneously determine the contents of p-cymene, thymol, neryl acetate, and ß-caryophyllene in roots, stems, and leaves of Eupatorium fortunei Turcz. harvested at different growth periods. All four constituents could be detected in leaves, three could be detected in stems except ß-caryophyllene, and only thymol could be detected in roots. The order of the total contents of four constituents in different parts was leaves > stems > roots. It indicated that the leaves could be the proper medicinal parts of Eupatorium fortunei Turcz. The content of four constituents in leaves varied a lot among different growth periods and showed an M-shaped change trend with the growth of Eupatorium fortunei Turcz. The four constituents accumulated to the highest values in early July followed by mid-September. Accordingly, the best harvest time of Eupatorium fortunei Turcz. is early July and mid-September.

SIRT6 inhibits inflammatory response through regulation of NRF2 in vascular endothelial cells.

Emerging evidence suggests that inflammation plays a pivotal role in Atherosclerosis. Sirtuin 6 (SIRT6), a member of NAD+-dependent protein lysine deacylases of the sirtuin family, plays an important role in the regulation of metabolism, aging and stress resistance. However, the role of SIRT6 in vascular inflammation and its molecular mechanism is unknown. The present study showed that TNF-α significantly reduced the expression of SIRT6 protein and mRNA in a concentration- and time-dependent manner and increased the expression of monocyte chemotactic protein 1 (MCP-1), interleukin (IL) -6 and IL-1ß in human umbilical vein endothelial cells (HUVECs). Overexpression of SIRT6 but not its catalytically inactive mutant inhibited TNF-α-induced expression of MCP-1, IL-6 and IL-1ß. Knockdown of SIRT6 significantly enhanced TNF-α-induced expression of MCP-1, IL-6 and IL-1ß. Moreover, knockdown of SIRT6 reduced TNF-α-induced nuclear factor erythroid 2 related factor 2 (NRF2) nucleus protein expression, whereas knockdown of NRF2 significantly enhanced TNF-α-induced expression of MCP-1, IL-6 and IL-1ß. In addition, overexpression of SIRT6 increased NRF2 and its target genes expression, and knockdown of SIRT6 decreased NRF2 and its target genes expression. Meanwhile, knockdown of SIRT6 inhibited NRF2 nucleus protein expression. Further, knockdown of SIRT6 decreased phosphorylation of NRF2, overexpression of SIRT6 increased phosphorylation of NRF2. SIRT6 interacted with NRF2. In vivo, the levels of TNF-α and IL-1ß were increased in the serum of hyperlipidemia mice. Hyperlipidemia-induced production of MCP-1, IL-6 and IL-1ß was significantly augmented in the endothelium specific SIRT6 knockout mice. In contrast, the expression of NRF2 and its target genes was reduced. Taken together, these results indicate that SIRT6 protects against vascular inflammation via its deacetylase activity and the NRF2-dependent signaling pathway.

Clinical findings in a group of COVID-19 patients: a single-center retrospective study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) is spreading rapidly across countries and has infected tens of millions of people all over the world. So far, the pandemic is ongoing globally, and the situation is still worsening. METHODS: In this retrospective, single-center cohort analysis, we included 25 adult inpatients with laboratory confirmed COVID-19 disease from the affiliated hospital of Xuzhou Medical University (Xuzhou, China). Epidemiological characterizations, clinical findings, and medical treatments were all reported. In addition, laboratory markers were investigated in terms of course of treatment. RESULTS: Epidemiological features and clinical findings were present for all 25 patients. Laboratory markers were identified due to temporal changes. After medical treatment, all patients were discharged home and recovering from the infection. CONCLUSIONS: This study provides a comprehensive overview of patients with COVID-19 disease in a single hospital. Some of the laboratory markers were statistically different during the course of the disease, which might serve as indicators in identifying patients with COVID-19 disease at an early stage of the infection.

Uptake and Distribution Characteristic and Health Risk Assessment of Heavy Metal(loid)s in Platycodon Grandiflorum (Jacq.) A.DC. with Growth from a Medicinal Herb Garden of Xi'an, China.

The different parts of Platycodon grandiflorum were collected from a medicinal herb garden to determine five heavy metal(loid)s (Pb, Cd, As, Hg, and Cu) contents at different growth stages. The data showed that the plant accumulated varying amounts of metal(loid)s in the order Cu > Hg > Pb > As > Cd. Five heavy metal(loid) concentrations decreased in the early growth stage and then increased in the flowering season. The contents of heavy metal(loid)s except Hg in the stem were relatively lower than other tissues. The flower of Platycodon grandiflorum can highly accumulate heavy metal(loid)s, especially for Cu in the flowering period. Pb, Cd, and Cu contents in stem generally increased with growth time, while Cd and Cu in root decreased during growth time. The average daily intake doses of five heavy metal(loid)s in the root of Platycodon grandiflorum were all below the safety guideline and the target hazard quotient was less than 1.

Asymptomatic and Human-to-Human Transmission of SARS-CoV-2 in a 2-Family Cluster, Xuzhou, China.

We report epidemiologic, laboratory, and clinical findings for 7 patients with 2019 novel coronavirus disease in a 2-family cluster. Our study confirms asymptomatic and human-to-human transmission through close contacts in familial and hospital settings. These findings might also serve as a practical reference for clinical diagnosis and medical treatment.

Fractionation analysis and health risk assessment of heavy metals in six traditional Chinese medicines.

Traditional Chinese medicines (TCMs) are widely used to treat various diseases in China and some countries, and TCM products are becoming increasingly available and popular worldwide. But TCMs are facing the challenge of heavy metal pollution. In this work, we examined the total contents and fractionations of Pb, Cd, Hg, and Cu in six TCMs (Angelicae Sinensis Radix (ASR), Chuanxiong Rhizoma (CR), Polygonati Rhizoma (PR), Astragali Radix (AR), Carthami Flos (CF), and Paeoniae Radix Rubra (PRR)) and evaluated the health risk of four heavy metals in these TCMs. The results showed that Cd, Pb, and Cu contents were considerably high and the amount of Cd in six TCMs, Pb in CR, ASR, AR, and CF, and Hg in ASR, PR, and PRR exceeded the limit values. The predominant fractions of Pb, Cd, and Cu were exchangeable and carbonate fractions in six TCMs; Hg mainly existed in organic and residual fractions. The average daily intake dose (ADD) and target hazard quotient (THQ) of Pb based on total content and total THQ of four heavy metals based on bioaccessible fractions in AR and PRR exceeded the safety guideline. These results indicated that the potential health risk could occur by taking these TCMs.

Comparative pharmacokinetics of verapamil and norverapamil in normal and ulcerative colitis rats after oral administration of low and high dose verapamil by UPLC-MS/MS.

In this study, UC rat model was established by administration of 5% (w/v) dextran sulfate sodium, and the pharmacokinetics of verapamil and norverapamil were evaluated in normal and UC rats using UPLC-MS/MS after oral administration of 5 mg/kg and 50 mg/kg verapamil.The peak concentration (Cmax) and the area under plasma concentration-time curves (AUC) of verapamil in UC rats after oral administration of 5 mg/kg were significantly greater (2.5 times and 2 times, respectively) than those in normal rats, but the clearance rate (Cl) was significantly lower (by 50%). For norverapamil, Cmax and AUC were significantly greater (2.8 times and 2.5 times, respectively), and Cl was significantly lower (by 45%). But, pharmacokinetic parameters of verapamil and norverapamil after oral administration of 50 mg/kg were no significant differences between UC and normal rats.The better absorption and poor excretion for low-dose verapamil may be attributed to down-regulation of P-gp expression in the intestine and kidney. No significant differences of pharmacokinetic parameters for high-dose verapamil may be explained as the saturation of an efflux mechanism.The findings of this study suggested that in UC patients, doses of verapamil should be decreased when low-dose verapamil was orally administrated.

Study on the interaction between lovastatin and three digestive enzymes and the effect of naringin and vitamin C on it by spectroscopy and docking methods.

Lovastatin is a typical drug interacting with grapefruit juice and naringin and vitamin C are main active constituents in fruit juice. It is necessary to study the interaction between lovastatin and digestive enzymes and the effect of naringin and vitamin C on the interaction. Pepsin, trypsin and α-chymotrypsin were selected as representatives of digestive tract enzymes, and fluorescence spectroscopy was employed to study the interaction of lovastatin with three digestive enzymes and the effect of naringin and vitamin C on this interaction. The mechanism of interaction between lovastatin and three digestive enzymes was static quenching. Lovastatin bound to trypsin by electrostatic interaction, while bound to pepsin or α-chymotrypsin mainly by hydrophobic interaction. The conformation of three enzymes changed and non-radiative energy transfer occurred with high probability between three digestive enzymes and lovastatin. Both naringin and vitamin C could reduce the binding stability of lovastatin to pepsin and α-chymotrypsin, increasing concentration of free lovastatin. That is, naringin or vitamin C in the fruit or food may increase the blood concentration of lovastatin; perhaps taking frequency or dosage of lovastatin may be reduced.

Comparison of the Effects of Prophylactic and Therapeutic Administrations on Peripheral Neuropathy in Streptozotocin-Diabetic Rats with Gliclazide or Methylcobalamin.

OBJECTIVE: To observe the differences in curative effects between prophylactic and therapeutic administrations of Gliclazide (GLZ) or Methylcobalamin (MCA) on diabetic peripheral neuropathy in rats. METHODS: GLZ (25 mg/kg/day) or MCA (175 µg/kg/day) was orally administrated prophylactically to streptozotocin-induced diabetic rats for 8 weeks before diabetic peripheral neuropathy developed or administrated therapeutically after diabetic peripheral neuropathy developed, respectively. The motor nerve conduction velocities (MNCV), aldose reductase (AR) activities, the polyol contents and antioxidative enzyme activities in the sciatic never tissues were determined. The morphology of sciatic never tissues was observed. RESULTS: In comparison to vehicle, most of the changes in the sciatic nerves of the diabetic rats (e. g., delayed MNCV, altered/damaged nerve structure, enhanced AR activity, increased polyol contents, altered Cu, Zn-superoxide dismutase, glutathione-peroxidase activities, and elevated malondialdehyde level) were significantly ameliorated by prophylactic administration with either GLZ or MCA. In contrast, only few of above-mentioned parameters were alleviated in DPN rats by therapeutic administration with GLZ or MCA as compared to vehicle. The curative effects of GLZ or MCA prophylactic administration on MNCV, AR activity, polyol contents and antioxidative enzyme activities were markedly stronger than therapeutic administration. CONCLUSION: Prophylactic administration of GLZ or MCA was superior to the therapeutic administration in alleviation of diabetic neuropathy in STZ-rats, suggesting that pharmacotherapy should be initiated at a much earlier stage before diabetic neuropathy developed, but not at a later stage after never damage reached.