Xin-yi-san contains potent human CYP1A2 inhibitors and its combined use with theophylline in treatment increases adverse risks in patients.

BACKGROUND: The Xin-yi-san herbal decoction (XYS) is commonly used to treat patients with allergic rhinitis in Taiwan. Theophylline is primarily oxidized with high affinity by human cytochrome P450 (CYP)1A2, and has a narrow therapeutic index. PURPOSE: This study aimed to investigate the inhibition of human CYP1A2-catalyzed theophylline oxidation (THO) by XYS and its adverse effects in patients. METHODS: Human CYPs were studied in recombinant enzyme systems. The influence of concurrent XYS usage in theophylline-treated patients was retrospectively analyzed. RESULTS: Among the major human hepatic and respiratory CYPs, XYS inhibitors preferentially inhibited CYP1A2 activity, which determined the elimination and side effects of theophylline. Among the herbal components of XYS decoction, Angelicae Dahuricae Radix contained potent THO inhibitors. Furanocoumarin imperatorin was abundant in XYS and Angelicae Dahuricae Radix decoctions, and non-competitively inhibited THO activity with Ki values of 77‒84 nM, higher than those (20‒52 nM) of fluvoxamine, which clinically interacted with theophylline. Compared with imperatorin, the intestinal bacterial metabolite xanthotoxol caused weaker THO inhibition. Consistent with the potency of the inhibitory effects, the docking analysis generated Gold fitness values in the order-fluvoxamine > imperatorin > xanthotoxol. During 2017‒2018, 2.6 % of 201,093 theophylline users consumed XYS. After inverse probability weighting, XYS users had a higher occurrence of undesired effects than non-XYS users; in particular, there was an approximately two-fold higher occurrence of headaches (odds ratio (OR), 2.14; 95 % confidence interval (CI), 1.99‒2.30; p < 0.001) and tachycardia (OR, 1.83; 95 % CI, 1.21‒2.77; p < 0.05). The incidence of irregular heartbeats increased (OR, 1.36; 95 % CI, 1.07‒1.72; p < 0.05) only in the theophylline users who took a high cumulative dose (≥ 24 g) of XYS. However, the mortality in theophylline users concurrently taking XYS was lower than that in non-XYS users (OR, 0.24; 95 % CI, 0.14‒0.40; p < 0.001). CONCLUSION: XYS contains human CYP1A2 inhibitors, and undesirable effects were observed in patients receiving both theophylline and XYS. Further human studies are essential to reduce mortality and to adjust the dosage of theophylline in XYS users.

The role of partial area under the curve and maximum concentrations in assessing the bioequivalence of long-acting injectable formulation of exenatide_A sensitivity analysis.

To ensure therapeutic equivalence between the long-acting injectable (LAI) products, additional PK metrics other than Cmax and AUC were considered necessary. However, regarding the selection of additional PK metrics for bioequivalence (BE) assessment of exenatide LAI, a discrepancy existed between EMA's and USFDA's product-specific guidance. The EMA recommends that both the maximum plasma concentration in the initial-release phase (Cmax,1) and the extended-release phase (Cmax,2) should be determined. Nevertheless, the USFDA recommends the use of the partial area under the curve (i.e., the area under the curve from week 4 to the last sampling point; pAUC4w-t). The focus of this study was to compare the sensitivity of different PK metrics, including Cmax,1, Cmax,2, pAUC4w-t, early and late pAUC metrics truncated at different time points (three, four, five, six and seven weeks), to formulation-related parameters and pharmacodynamic (PD) markers of glycemic control. A sensitivity analysis was conducted using the published PK/PD model of exenatide LAI. The results indicated that Cmax,1 and Cmax,2 exhibited comparable sensitivities. AUC4w-t was sensitive to changes in detecting the differences in formulation-related parameters and PD markers of glycemic control, but did not provide superior sensitivity performance compared to Cmax,1 and Cmax,2. Among all tested PK metrics, AUC7w-t was found to be the most sensitive. The optimal cut-off time point for the pAUC should be set at the time of maximum plasma concentration in the extended-release phase (approximately 6-7 weeks). These results may provide useful insights into the selection of appropriate PK metrics for BE determination of exenatide LAI.

Nalbuphine-6-glucuronide is a potent analgesic with superior safety profiles by altering binding affinity and selectivity for mu-/kappa-opioid receptors.

Although nalbuphine, a semi-synthetic analgesic compound, is less potent than morphine in terms of alleviating severe pain, our recent findings have revealed that nalbuphine-6-glucuronide (N6G), one of the glucuronide metabolites of nalbuphine, promotes a significantly more robust analgesic effect than its parent drug. Nevertheless, despite these promising observations, the precise mechanisms underlying the analgesic effects of nalbuphine glucuronides have yet to be determined. In this study, we aim to elucidate the mechanisms associated with the analgesic effects of nalbuphine glucuronides. Pharmacokinetic and pharmacodynamic studies were conducted to investigate the relationship between the central and peripheral compartments of nalbuphine and its derivatives. The analgesic responses of these compounds were evaluated based on multiple behavioral tests involving thermal and mechanical stimuli. Radioligand binding assays were also performed to determine the binding affinity and selectivity of these compounds for different opioid receptors. The results of these tests consistently confirmed that the heightened analgesic effects of N6G are mediated through its enhanced binding affinity for both mu- and kappa-opioid receptors, even comparable to those of morphine. Notably, N6G exhibited fewer side effects and did not induce sudden death, thereby highlighting its superior safety profile. Additionally, pharmacokinetic studies indicated that N6G could cross the blood-brain barrier when administered peripherally, offering pain relief. Overall, N6G provides great analgesic efficacy and enhanced safety. These findings highlight the potential value of nalbuphine glucuronides, particularly N6G, as promising candidates for the development of novel analgesic drugs.

Human Whole Blood Interactions with Craniomaxillofacial Reconstruction Materials: Exploring In Vitro the Role of Blood Cascades and Leukocytes in Early Healing Events.

The present study investigated early interactions between three alloplastic materials (calcium phosphate (CaP), titanium alloy (Ti), and polyetheretherketone (PEEK) with human whole blood using an established in vitro slide chamber model. After 60 min of contact with blood, coagulation (thrombin-antithrombin complexes, TAT) was initiated on all test materials (Ti > PEEK > CaP), with a significant increase only for Ti. All materials showed increased contact activation, with the KK-AT complex significantly increasing for CaP (p < 0.001), Ti (p < 0.01), and PEEK (p < 0.01) while only CaP demonstrated a notable rise in KK-C1INH production (p < 0.01). The complement system had significant activation across all materials, with CaP (p < 0.0001, p < 0.0001) generating the most pronounced levels of C3a and sC5b-9, followed by Ti (p < 0.001, p < 0.001) and lastly, PEEK (p < 0.001, p < 0.01). This activation correlated with leukocyte stimulation, particularly myeloperoxidase release. Consequently, the complement system may assume a more significant role in the early stages post implantation in response to CaP materials than previously recognized. Activation of the complement system and the inevitable activation of leukocytes might provide a more favorable environment for tissue remodeling and repair than has been traditionally acknowledged. While these findings are limited to the early blood response, complement and leukocyte activation suggest improved healing outcomes, which may impact long-term clinical outcomes.

Identification of the perpetrator imperatorin in Xin-yi-san-theophylline interaction: observed and predicted herb-drug interaction in rats.

OBJECTIVES: Theophylline is a bronchodilator with a narrow therapeutic index and primarily metabolised by cytochrome P450 (CYP) 1A2. Xin-yi-san (XYS) is a herbal formula frequently used to ameliorate nasal inflammation. This study aimed to investigate the effects of XYS and its ingredient, imperatorin, on theophylline pharmacokinetics in rats. METHODS: The kinetics of XYS- and imperatorin-mediated inhibition of theophylline oxidation were determined. Pharmacokinetics of theophylline were analysed. Comparisons were made with the CYP1A2 inhibitor, fluvoxamine. KEY FINDINGS: XYS extract and its ingredient, imperatorin, non-competitively inhibited theophylline oxidation. Fluvoxamine (50 and 100 mg/kg) and XYS (0.5 and 0.9 g/kg) significantly prolonged the time to reach the maximum plasma concentration (tmax) of theophylline by 3-10 fold. In a dose-dependent manner, XYS and imperatorin (0.1-10 mg/kg) treatments significantly decreased theophylline clearance by 27-33% and 19-56%, respectively. XYS (0.9 g/kg) and imperatorin (10 mg/kg) significantly prolonged theophylline elimination half-life by 29% and 142%, respectively. Compared with the increase (51-112%) in the area under curve (AUC) of theophylline by fluvoxamine, the increase (27-57%) by XYS was moderate. CONCLUSIONS: XYS decreased theophylline clearance primarily through imperatorin-suppressed theophylline oxidation. Further human studies are essential for the dose adjustment in the co-medication regimen.

3,4-Desaturation of retinoic acid by cytochrome P450 27C1 prevents P450-mediated catabolism.

Cytochrome P450 (P450, CYP) 27C1 is expressed in human skin and catalyzes the 3,4-desaturation of retinoids. The enzyme has a relatively high specificity constant (kcat/Km), and ∼» of the retinoids in human skin are in the desaturated form but their function is unknown. 3,4-Dehydroretinoic acid (also didehydroretinoic acid, ddRA) has similar affinity as all-trans retinoic acid (atRA) for retinoid X and retinoic acid receptors (RXRs/RAR). The metabolism of ddRA is unknown, and we considered the hypothesis that desaturation might be a protective mechanism in maintaining active retinoid levels in the body. There are limited theoretical products that can result from ddRA oxidation. We optimized conditions for oxidation of atRA by human liver microsomes-a slow loss of atRA was seen due to 4-oxidation but no loss of ddRA was observed under the same conditions. We evaluated the HPLC peaks that were observed in microsomal incubations with ddRA using UV spectroscopy, NaBH4 and NaBD4 reduction, and mass spectrometry. None were potential ddRA oxidation products, and none were increased in the presence of the P450 cofactor NADPH. Known P450 inhibitors had no effects on the levels of these compounds. We conclude that ddRA is not readily oxidized by P450s and that one role of desaturation may be the maintenance of levels of functional retinoids.

Evidence of the need for modified well-stirred model in vitro to in vivo extrapolation.

In vitro to in vivo extrapolation (IVIVE), an approach for hepatic clearance (CLH) prediction used worldwide, remains controversial due to systematic underprediction. Among the various probable factors, the original assumption of the hepatic mathematical model (i.e., the well-stirred model, WSM) may become problematic, leading to the underestimation of drug CLH. Having a similar prerequisite that the well-stirred conditions are homogenous with perfectly mixed reactants, but using a different driving concentration, the modified well-stirred model (MWSM) stands apart from the WSM. However, we believe that both models should coexist so that the entire well-stirred scenario can be completely illustrated. Consequently, we collected published data from the literature and employed a logistic regression method to differentiate the optimal timing of use between WSM and MWSM in drug CLH prediction. Generally, variances adopted in the regression, including partition coefficient (logP), fraction unbound (fu), volumes of distribution at steady-state (Vss), and mean residence time (MRT), corresponded to our assumption when protein-facilitated uptake was considered. Furthermore, a new empirical approach was introduced to allow practical use of the MWSM. The results showed that this model could provide a more precise prediction compared to previous empirical approaches. Therefore, these preliminary results not only delineated a more detailed structure and mechanism of MWSM but also highlighted its necessity and potential.

Effect of repeated Shengmai-San administration on nifedipine pharmacokinetics and the risk/benefit under co-treatment.

Herbal interactions with nifedipine/felodipine through cytochrome P450 (CYP) 3A inhibition is significant in humans. Shengmai-San (SMS), a three-herbal formula of Chinese medicine, is commonly prescribed in Asia populations for cardiovascular disorders. This study aimed to elucidate the impact of SMS on nifedipine/felodipine treatment by the findings from rat pharmacokinetic study of nifedipine to the retrospective cohort study of patients with hypertension. The 3-week SMS treatment increased the systemic exposure to nifedipine by nearly two-fold and decreased nifedipine clearance by 39% in rats. Among the ingredients of SMS component herbs, schisandrin B, schisantherin A, and methylophiopogonanone A, inhibited the nifedipine oxidation (NFO) activities of rat hepatic and intestinal microsomes, as well as human CYP3A4. Methylophiopogonanone A was identified as a time-dependent inhibitor of CYP3A4. After 1:5 propensity score matching, 4,894 patients with nifedipine/felodipine use were analyzed. In patients receiving nifedipine/felodipine, the subgroup with concurrent SMS treatment had a higher incidence of headache (92.70 per 1,000 personyears) than the subgroup without SMS treatment (51.10 per 1,000 person-years). There was a positive association between headache incidence and cumulative doses of SMS (1-60 g SMS: hazard ratio (HR): 1.39; 95% confidence interval (CI): 1.11-1.74; >60 g SMS: HR: 1.97; 95% CI: 1.62-2.39; p < 0.0001). However, patients who had higher cumulative SMS doses had a lower risk of all-cause mortality (1-60 g SMS: HR: 0.67; 95% CI: 0.47-0.94; >60 g SMS: HR: 0.54; 95% CI: 0.37-0.79; p = 0.001). Results demonstrated increased rat plasma nifedipine levels after 3-week SMS treatment and increased headache incidence should be noted in nifedipine/felodipine-treated patients with prolonged SMS administration.

Precisely adjusting the hepatic clearance of highly extracted drugs using the modified well-stirred model.

Hepatic clearance has been widely studied for over 50 yr. Many models have been developed using either theoretical or empirical tests to predict drug metabolism. The well-stirred, parallel-tube, and dispersion metabolic models have been extensively discussed. However, to our knowledge, these models cannot fully describe all relevant scenarios in hepatic clearance. We addressed this issue using the isolated perfused rat liver technique with minor modifications. Diazepam was selected to illustrate different levels of drug plasma-protein binding by changing the added concentration of human serum albumin. The free fractions of diazepam at different albumin concentrations were assayed by rapid equilibrium dialysis. The experimental data provide new insights concerning an accepted formula used to describe hepatic clearance. Regarding drug concentrations passing through the liver, the driving force concentration (CH,ss) in terms of Cin (influx in the liver) or Cout (efflux from the liver) needs to be carefully considered when determining drug hepatic and intrinsic clearances. The newly established model, termed the modified well-stirred model, which was derived from the original formula, successfully estimated hepatic drug metabolism. Using the modified well-stirred model, a theoretical driving force concentration of diazepam passing through the liver was evaluated. The model was further used to assess the predictability of in vitro to in vivo extrapolation. This study was not intended to refute the existing models, but rather to augment them using experimental data. The results stress the importance of proper calculation of dose when the drug clearance deviates from the prediction of the well-stirred model.

Antimicrobial Peptide-Functionalized Mesoporous Hydrogels.

Antimicrobial peptides (AMPs) are seen as a promising replacement to conventional antibiotics for the prevention of skin wound infections. However, due to the short half-life of AMPs in biological environments, such as blood, their use in clinical applications has been limited. The covalent immobilization of AMPs onto suitable substrates is an effective solution to create contact-killing surfaces with increased long-term stability. In this work, an antimicrobial peptide, RRPRPRPRPWWWW-NH2 (RRP9W4N), was covalently attached to amphiphilic and ordered mesoporous Pluronic F127 hydrogels made of cross-linked lyotropic liquid crystals through 1-ethyl-3-(3-(dimethylamino)propyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) chemistry. The AMP-hydrogels showed high antibacterial activity against Staphylococcus epidermidis, Staphylococcus aureus, Pseudomonas aeruginosa, methicillin-resistant S. aureus (MRSA), and multidrug-resistant Escherichia coli for up to 24 h. Furthermore, the AMP-hydrogels did not present any toxicity to human fibroblasts. The AMPs retained their antimicrobial activity up to 48 h in human blood serum, which is a significant increase in stability compared to when used in dissolved state. A pilot in vivo rat model showed 10-100× less viable counts of S. aureus on AMP-hydrogels compared with control hydrogels during the first 3 days of infection. Studies performed on human whole blood showed that blood coagulated more readily in the presence of AMP-hydrogels as compared to hydrogels without AMPs, indicating potential hemostatic activity. Overall, the results suggest that the combination of amphiphilic hydrogels with covalently bonded AMPs has potential to be used as antibacterial wound dressing material to reduce infections and promote hemostatic activity as an alternative to antibiotics or other antimicrobial agents, whose use should be restricted.

Effects of Shengmai San on key enzymes involved in hepatic and intestinal drug metabolism in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Shengmai San (SMS) has been commonly used as a traditional Chinese medicine for the treatment of cardiovascular disorders, of which drug interactions need to be assessed for the safety concern. There is little evidence for the alterations of hepatic and intestinal drug-metabolizing enzymes after repeated SMS treatments to assess drug interactions. AIM OF THE STUDY: The studies aim to illustrate the effects of repeated treatments with SMS on cytochrome P450s (CYPs), reduced nicotinamide adenine dinucleotide (phosphate)-quinone oxidoreductase (NQO), uridine diphosphate-glucuronosyltransferase (UGT), and glutathione S-transferase (GST) using in vivo rat model. MATERIALS AND METHODS: The SMS was prepared using Schisandrae Fructus, Ginseng Radix, and Ophiopogonis Radix (OR) (1:2:2). Chromatographic analyses of decoctions were performed using ultra-performance liquid chromatography (UPLC) and LC-mass spectrometry. Sprague-Dawley rats were orally treated with the SMS and its component herbal decoctions for 2 or 3 weeks. Hepatic and intestinal enzyme activities were determined. CYP3A expression and the kinetics of intestinal nifedipine oxidation (NFO, a CYP3A marker reaction) were determined. RESULTS: Schisandrol A, schisandrin B, ginsenoside Rb1 and ophiopogonin D were identified in SMS. SMS selectively suppressed intestinal, but not hepatic, NFO activity in a dose- and time-dependent manner. Hepatic and intestinal UGT, NQO and GST activities were not affected. A 3-week SMS treatment decreased the maximal velocity of intestinal NFO by 50%, while the CYP3A protein level remained unchanged. Among SMS component herbs, the decoction of OR decreased intestinal NFO activity. CONCLUSIONS: These findings demonstrate that 3-week treatment with SMS and OR suppress intestinal, but not hepatic CYP3A function. It suggested that the potential interactions of SMS with CYP 3A drug substrates should be noticed, especially the drugs whose bioavailability depends heavily on intestinal CYP3A.

Are There Any Experimental Perfusion Data that Preferentially Support the Dispersion and Parallel-Tube Models over the Well-Stirred Model of Organ Elimination?

In reviewing previously published isolated perfused rat liver studies, we find no experimental data for high-clearance metabolized drugs that reasonably or unambiguously support preference for the dispersion and parallel-tube models versus the well-stirred model of organ elimination when only entering and exiting drug concentrations are available. It is likely that the investigators cited here may have been influenced by: 1) the unphysiologic aspects of the well-stirred model, which may have led them to undervalue the studies that directly test the various hepatic disposition models for high-clearance drugs (for which model differences are the greatest); 2) experimental assumptions made in the last century, which are no longer valid today, related to the predictability of in vivo outcomes from in vitro measures of drug elimination and the influence of albumin in hepatic drug uptake; and 3) a lack of critical review of previously reported experimental studies, resulting in inappropriate interpretation of the available experimental data. The number of papers investigating the theoretical aspects of the dispersion, parallel-tube, and well-stirred models of hepatic elimination greatly outnumber the papers that actually examine the experimental evidence available to substantiate these models. When all experimental studies that measure organ elimination using entering and exiting drug concentrations at steady state are critically reviewed, the simple but unphysiologic well-stirred model is the only model that can describe all trustworthy published available data. SIGNIFICANCE STATEMENT: Although the dispersion model of hepatic elimination more adequately reflects physiologic reality, there are no convincing experimental data that unambiguously favor this model. The well-stirred model can describe all well-designed perfusion studies with high-clearance drugs and nondrug substrates, but the field has not recognized this because of hesitation to accept a nonphysiologic model and flawed attempts to utilize in vitro-in vivo extrapolation approaches.

A dual system platform for drug metabolism: Nalbuphine as a model compound.

Reaction phenotyping is a method commonly used for characterizing drug metabolism. It determines the drug metabolic pathways and ratios by measuring the metabolized fractions of individual enzymes. However, currently published results have focused on cytochrome P450s (CYPs), while not considering phase II metabolism. Therefore, the morphinan analgesic, nalbuphine, primarily metabolized in the liver via CYPs and UDP-glucuronosyltransferases (UGTs), was selected as a model drug to establish a dual-phase platform to elucidate its comprehensive metabolic pathway. Enzyme kinetics was studied using 8 common recombinant (r)CYPs, 10 rUGTs, and pooled human liver microsomes. The overall fraction of nalbuphine metabolized by each isozyme was evaluated by determining parent drug depletion. Finally, in vitro-in vivo correlation was validated in animal studies. Fluconazole, a specific UGT2B7 inhibitor, was administered orally to rats to determine the pharmacokinetic effects on nalbuphine and nalbuphine metabolites. Seventy-five percent and 25% of nalbuphine was metabolized by UGTs and CYPs, respectively. UGT2B7, UGT1A3, and UGT1A9 were primarily responsible for nalbuphine glucuronidation; only UGT2B7 produced nalbuphine-6-glucuronide. CYP2C9 and CYP2C19 were the two CYP isozymes that produced 3'-hydroxylnalbuphine and 4'-hydroxylnalbuphine. In vivo, the maximum serum concentration (Cmax) and area under the curve (AUC) of nalbuphine increased 12.4-fold and 13.2-fold, respectively, with fluconazole co-administration. A dual system platform for drug metabolism was successfully established in this study and was used to generate a complete metabolic scheme for nalbuphine. This platform has been verified by in vivo evaluations and can be utilized to study drugs that undergo multisystem metabolism.

Polyvinylalcohol-carbazate (PVAC) reduces red blood cell hemolysis.

BACKGROUND AND OBJECTIVES: The objective of this study was to investigate whether a soluble polymer and aldehyde-scavenger, polyvinylalcohol-carbazate (PVAC), can inhibit hemolysis in the storage of red blood cells (RBC). STUDY DESIGN AND METHODS: The effect of PVAC was assessed over a wide range of concentrations, using absorption spectroscopy to evaluate the level of hemolysis. Moreover, osmotic stability and aldehyde-scavenging potential of RBC were assessed after storage in PVAC. RESULTS: After test tube storage for two weeks, red blood cell hemolysis was lower with PVAC compared to controls (mean difference 23%, 95% CI 16-29%, p < 0.001). A higher level of hemolysis led to a pronounced effect with PVAC. RBC stored in PVAC improved both the binding of free aldehydes (p <0.001) and the osmotic stability (p = 0.0036). CONCLUSION: Erythrocytes stored with PVAC showed less hemolysis, which might be explained by the ability of PVACs to stabilize the cell membrane and decrease oxidative injury.

A practical thrice weekly ertapenem in hemodialysis patients.

Change of ertapenem dosage from 500 mg daily to thrice weekly after each hemodialysis session can maintain the plasma concentration above 2 mg/L, and be practical in hemodialysis patients.

Protein Binding and Hepatic Clearance: Re-Examining the Discrimination between Models of Hepatic Clearance with Diazepam in the Isolated Perfused Rat Liver Preparation.

This study re-examined the hepatic extraction for diazepam, the only drug for which isolated perfused rat liver (IPRL) studies have been reported not to be consistent with the well stirred model of organ elimination when only entering and exiting liver concentration measurements are available. First, the time dependency of diazepam equilibrium fraction unbound measurements from 4 to 24 hours was tested, reporting the continuing increases with time. The results showed that the time dependency of equilibrium protein-binding measurements for very highly bound drugs may be an issue that is not readily overcome. When examining C out/C in (F obs) measurements for diazepam when no protein is added to the incubation media, IPRL outcomes were consistent with previous reports showing marked underpredictability of in vivo clearance from in vitro measures of elimination in the absence of protein for very highly bound drugs, which is markedly diminished in the presence of albumin. F obs for diazepam at additional low concentrations of protein that would allow discrimination of the models of hepatic elimination produced results that were not consistent with the dispersion and parallel-tube models. Therefore, although the outcomes of this study were similar to those reported by Rowland and co-workers, when no protein is added to the perfusion media, these IPRL results for diazepam cannot be reasonably interpreted as proving that hepatic organ elimination is model-independent or as supporting the dispersion and parallel-tube models of organ elimination. SIGNIFICANCE STATEMENT: The only drug experiments for which isolated perfusion rat liver studies do not support hepatic clearance being best described by the well stirred model have been carried out with diazepam at zero protein concentration. This study repeated those studies, confirming the previous results at zero protein concentration, but the addition of low protein-binding conditions capable of differentiating the various models of hepatic elimination are more consistent with the well stirred model of hepatic elimination. These experimental studies do not support the preference for alternate models of hepatic elimination or the proposal that hepatic organ clearance is model-independent.

A novel finding of nalbuphine-6-glucuronide, an active opiate metabolite, possessing potent antinociceptive effects: Synthesis and biological evaluation.

Nalbuphine, a partial agonist/antagonist opioid analgesic, is structurally related to morphine. It is equipotent to morphine and has no serious side effects. In the past few decades, studies focusing on morphine metabolism have indicated that one of its sugar-conjugated metabolites, morphine-6-glucuronide, exerts a higher analgesic effect than its parent drug. Considering that nalbuphine is a morphine analog that follows a similar metabolic scheme, nalbuphine glucuronides were synthesized in this study and their potential analgesic effects were assessed. Nalbuphine-3-glucuronide (N3G) and nalbuphine-6-glucuronide (N6G) were synthesized based on Schmidt's glycosylation with OPiv protections on the glycosyl donor. In a pharmacodynamic study, paw pressure and cold-ethanol tail-flick tests were conducted in rats to evaluate the analgesic response after intracisternal and intraperitoneal administrations of nalbuphine, N3G, or N6G. The antinociceptive response was evaluated for each compound by calculating the area under the curve and the duration spent at greater than 50% maximum possible analgesia. In conclusion, intracisternal administration of N6G exhibited a stronger analgesic response than nalbuphine in the pain tests after both cold and mechanical stimuli, but N3G had no obvious effect. Similar to that of morphine, the glucuronide metabolite of nalbuphine at the 6-O-position exerted at least three-fold higher antinociceptive potency and five-fold longer analgesic duration than nalbuphine.

Thromboinflammation as bioactivity assessment of H2O2-alkali modified titanium surfaces.

The release of growth factors from platelets, mediated by the coagulation and the complement system, plays an important role in the bone formation around implants. This study aimed at exploring the thromboinflammatory response of H2O2-alkali soaked commercially pure titanium grade 2 discs exposed to whole human blood, as a way to assess the bioactivity of the discs. Commercially pure titanium grade 2 discs were modified by soaking in H2O2, NaOH and Ca(OH)2. The platelet aggregation, coagulation activation and complement activation was assessed by exposing the discs to fresh whole blood from human donors. The platelet aggregation was examined by a cell counter and the coagulation and complement activation were assessed by ELISA-measurements of the concentration of thrombin-antithrombin complex, C3a and terminal complement complex. The modified surface showed a statistically significant increased platelet aggregation, coagulation activation and complement activation compared to unexposed blood. The surface also showed a statistically significant increase of coagulation activation compared to PVC. The results of this study showed that the H2O2-alkali soaked surfaces induced a thromboinflammatory response that indicates that the surfaces are bioactive.

Shenmai-Yin decreased the clearance of nifedipine in rats: The involvement of time-dependent inhibition of nifedipine oxidation.

The traditional Chinese herbal formula Shenmai-Yin (SY) and nifedipine have both been used to treat patients with cardiovascular disorders. Nifedipine is primarily oxidized by cytochrome P450 (CYP) 3A. The oxidation and pharmacokinetics of nifedipine were studied in rats in vitro and in vivo to illustrate the interaction of SY with nifedipine. Schisandrol A, schisandrin A and schisandrin B were identified as the main lignans in SY. In the study in vitro, the ethanolic extract of SY was used due to the solubility and the extract inhibited nifedipine oxidation (NFO) activity in a time-dependent manner. Among lignans, schisandrin B caused the most potent inhibition. According to the time-dependent inhibition behavior, rats were treated with SY 1 h before nifedipine administration. After oral treatment with 1.9 g/kg SY, nifedipine clearance decreased by 34% and half-life increased by 142%. SY treatment decreased hepatic NFO activity by 49%. Compared to the change caused by ketoconazole, the SY-mediated reduction of nifedipine clearance was moderate. These findings demonstrate that SY causes a time-dependent inhibition of NFO and schisandrin B contributes to the inhibition. The decreased nifedipine clearance by SY in rats warrants further human study to examine the clinical impact of this decrease.