Comparison of the irritation potentials of Boswellia serrata gum resin and of acetyl-11-keto-beta-boswellic acid by in vitro cytotoxicity tests on human skin-derived cell lines

Indian frankincense is a gum resin from Boswellia serrata of Burseraceae used in Ayurveda and Western medicine for the antinflammatory effects of boswellic acids, particularly 3-O-acetyl-11-keto-beta-boswellic acid (AKBA). We evaluated in vitro cytotoxicities of B. serrata extract and AKBA on differentiated and undifferentiated keratinocytes (HaCaT and NCTC 2544), and foetal dermal fibroblasts (HFFF2), using neutral red uptake (NRU), MTT, and DNA assays. Comparison between NRU and MTT, and between the extract and AKBA, suggested a relatively higher toxicity of both substances on lysosomes respect to mitochondria. Extract cytotoxicity on lysosomes was higher in NCTC and HFFF2 than on the more differentiated HaCaT. DNA assay showed low extract inhibition on HFFF2 proliferation, possibly due to lower growth rate, and a stronger effect on NCTC than on HaCaT, possibly related to higher proapoptotic effect on the less differentiated NCTC, as also suggested by higher AKBA toxicity on NCTC than on HaCaT. In general, gum resin and AKBA toxicities were slightly lower or higher than that of the reference compound SDS. Our in vitro model allowed to compare the sensitivities of different human skin cells to B. serrata, and indicated that the gum resin and AKBA exert moderate to low toxicity on the skin.     

Effect of Boswellia serrata on intestinal motility in rodents: inhibition of diarrhoea without constipation

Clinical studies suggest that the Ayurvedic plant Boswellia serrata may be effective in reducing diarrhoea in patients with inflammatory bowel disease. In the present study, we evaluated the effect of a Boswellia serrata gum resin extract (BSE) on intestinal motility and diarrhoea in rodents. BSE depressed electrically-, acetylcholine-, and barium chloride-induced contractions in the isolated guinea-pig ileum, being more potent in inhibiting the contractions induced by acetylcholine and barium chloride. The inhibitory effect of BSE on acetylcholine-induced contractions was reduced by the L-type Ca(2+) channel blockers verapamil and nifedipine, but not by the sarcoplasmic reticulum Ca(2+)-ATPase inhibitor cyclopiazonic acid, by the phosphodiesterase type IV inhibitor rolipram or by the lipoxygenase inhibitor zileuton. 3-acetyl-11-keto-beta-boswellic acid, one of the main active ingredients of B. serrata, inhibited acetylcholine-induced contractions. BSE inhibited upper gastrointestinal transit in croton oil-treated mice as well as castor oil-induced diarrhoea. However, BSE did not affect intestinal motility in control mice, both in the small and in the large intestine. It is concluded that BSE directly inhibits intestinal motility with a mechanism involving L-type Ca(2+) channels. BSE prevents diarrhoea and normalizes intestinal motility in pathophysiological states without slowing the rate of transit in control animals. These results could explain, at least in part, the clinical efficacy of this Ayurvedic remedy in reducing diarrhoea in patients with inflammatory bowel disease.     

Concentration-dependent potentiating and inhibitory effects of Boswellia extracts on 5-lipoxygenase product formation in stimulated PMNL

Preparations from the gum of Boswellia spec. have been used in the traditional medicine for the treatment of inflammatory diseases. Extracts from B. serrata gum were shown to inhibit leukotriene biosynthesis by impairing the 5-lipoxygenase (5-LO) activity. In order to identify the minimal effective concentrations of extracts in vitro we studied the effects of ethanolic extracts from commercially available resins from two regions (B. serrata gum from India and Olibanum in granis from Arabia) on the 5-LO product formation from endogenous substrate in calcium and ionophore stimulated neutrophils in a defined concentration range. Both extracts inhibited 5-LO product formation in vitro in concentrations greater than 10 to 15 micrograms/ml as reported previously for an ethanolic B. serrata extract. In contrast, lower concentrations of extracts (1 to 10 micrograms/ml) even potentiated 5-LO product formation, especially the biosynthesis of 5(S)-HETE. The in vitro data underline the major importance of drug standardization when Boswellia resin containing preparations are used for the treatment of diseases.     

Boswellia serrata: an overall assessment of in vitro, preclinical, pharmacokinetic and clinical data

Non-steroidal anti-inflammatory drug (NSAID) intake is associated with high prevalence of gastrointestinal or cardiovascular adverse effects. All efforts to develop NSAIDs that spare the gastrointestinal tract and the cardiovasculature are still far from achieving a breakthrough. In the last two decades, preparations of the gum resin of Boswellia serrata (a traditional ayurvedic medicine) and of other Boswellia species have experienced increasing popularity in Western countries. Animal studies and pilot clinical trials support the potential of B. serrata gum resin extract (BSE) for the treatment of a variety of inflammatory diseases like inflammatory bowel disease, rheumatoid arthritis, osteoarthritis and asthma. Moreover, in 2002 the European Medicines Agency classified BSE as an 'orphan drug' for the treatment of peritumoral brain oedema. Compared to NSAIDs, it is expected that the administration of BSE is associated with better tolerability, which needs to be confirmed in further clinical trials. Until recently, the pharmacological effects of BSE were mainly attributed to suppression of leukotriene formation via inhibition of 5-lipoxygenase (5-LO) by two boswellic acids, 11-keto-β-boswellic acid (KBA) and acetyl-11-keto-β-boswellic acid (AKBA). These two boswellic acids have also been chosen in the monograph of Indian frankincense in European Pharmacopoiea 6.0 as markers to ensure the quality of the air-dried gum resin exudate of B. serrata. Furthermore, several dietary supplements advertise the enriched content of KBA and AKBA. However, boswellic acids failed to inhibit leukotriene formation in human whole blood, and pharmacokinetic data revealed very low concentrations of AKBA and KBA in plasma, being far below the effective concentrations for bioactivity in vitro. Moreover, permeability studies suggest poor absorption of AKBA following oral administration. In view of these results, the previously assumed mode of action - that is, 5-LO inhibition - is questionable. On the other hand, 100-fold higher plasma concentrations have been determined for β-boswellic acid, which inhibits microsomal prostaglandin E synthase-1 and the serine protease cathepsin G. Thus, these two enzymes might be reasonable molecular targets related to the anti-inflammatory properties of BSE. In view of the results of clinical trials and the experimental data from in vitro studies of BSE, and the available pharmacokinetic and metabolic data on boswellic acids, this review presents different perspectives and gives a differentiated insight into the possible mechanisms of action of BSE in humans. It underlines BSE as a promising alternative to NSAIDs, which warrants investigation in further pharmacological studies and clinical trials.     

Effects of gum resin of Boswellia serrata in patients with chronic colitis

Patients studied here suffered from chronic colitis characterized by vague lower abdominal pain, bleeding per rectum with diarrhoea and palpable tender descending and sigmoid colon. The inflammatory process in colitis is associated with increased formation of leukotrienes causing chemotaxis, chemokinesis, synthesis of superoxide radicals and release of lysosomal enzymes by phagocytes. The key enzyme for leukotriene biosynthesis is 5-lipoxygenase. Boswellic acids were found to be non-redox, non-competitive specific inhibitors of the enzyme 5-lipoxygenase. We studied the gum resin of Boswellia serrata for the treatment of this disease. Thirty patients, 17 males and 13 females in the age range of 18 to 48 years with chronic colitis were included in this study. Twenty patients were given a preparation of the gum resin of Boswellia serrata (900 mg daily divided in three doses for 6 weeks) and ten patients were given sulfasalazine (3 gm daily divided in three doses for 6 weeks) and served as controls. Out of 20 patients treated with Boswellia gum resin 18 patients showed an improvement in one or more of the parameters: including stool properties, histopathology as well as scanning electron microscopy, besides haemoglobin, serum iron, calcium, phosphorus, proteins, total leukocytes and eosinophils. In the control group 6 out of 10 patients showed similar results with the same parameters. Out of 20 patients treated with Boswellia gum resin 14 went into remission while in case of sulfasalazine remission rate was 4 out of 10. In conclusion, this study shows that a gum resin preparation from Boswellia serrata could be effective in the treatment of chronic colitis with minimal side effects.     

Modulation of Pgp function by boswellic acids

Boswellic acids, the main active ingredients of Boswellia serrata, are gaining more and more importance in the treatment of peritumoural oedema and chronic inflammatory diseases. They may be even considered as alternative drugs to corticosteroids in reducing cerebral peritumoural oedema. An important focus for drugs acting in the central nervous system is achieving a high extent of brain penetration. Today there is increasing evidence for the importance of transporters, especially P-glycoprotein (Pgp), for drug disposition and resulting clinical response. Pharmacokinetic studies revealed that the concentrations of the potent keto derivatives, the 11-keto-beta-boswellic acid (KBA) and the acetyl-11-keto-beta-boswellic acid (AKBA), in proportion to boswellic acids lacking a keto group, like the beta-boswellic acid, are much lower in plasma than in the orally administered extract. Moreover the brain/plasma ratio for KBA and AKBA determined in preliminary experiments on rats was only about 0.51 and 0.81, respectively, in spite of their lipophilicity. Until now little is known about the cerebral pharmacokinetics of boswellic acids and how it may be influenced. Since many drugs are known to interact with Pgp at the level of the intestine and the blood-brain barrier the modulatory potencies of the Boswellia serrata extract of H15(R) and the major boswellic acids on the transport activity of Pgp have been determined in two in vitro assays. A human lymphocytic leukaemia cell line (VLB cells) expressing Pgp was chosen as model for human Pgp, and porcine brain capillary endothelial cells (PBCEC cells) were taken as model for the blood-brain barrier using calcein acetoxymethyl ester (calcein-AM) as Pgp substrate. It was found that the Boswellia extract, as well as the keto-boswellic acids inhibit the transport activity of Pgp in the micromolecular range in both cell types. No modulation was observed using those boswellic acids which have no keto group in their structure. The inhibition of Pgp at the blood-brain barrier by Boswellia extract is probably not relevant for the brain availability of other Pgp substrates, because of the low plasma levels determined for KBA and AKBA. However the presented data could not exclude the possibility of drug interactions caused by modulation of Pgp by extracts of Boswellia serrata on the gastrointestinal level.     

Inhibition of leukotriene B4 formation in rat peritoneal neutrophils by an ethanolic extract of the gum resin exudate of Boswellia serrata.

Suspensions of rat peritoneal polymorphonuclear leukocytes (PMNL) elicited with glycogen were stimulated by calcium and ionophore to produce leukotrienes and 5-HETE from endogenous arachidonic acid (AA). We investigated the effect of ethanolic extracts of the gum resin exudate of Boswellia serrata. A concentration-dependent inhibition of LTB4 and 5-HETE production by different charges of exudate extracts were found. All products of the 5-lipoxygenase (5-LOx) from endogenous arachidonic acid (AA) in PMNL were reduced to the same extent by the extracts tested. The ethanolic extract of the gum resin also decreased 5-LOx mediated metabolisation of exogenously added AA to LTB4 and 5-HETE. Since steroidal-type anti-inflammatory drugs do not exert an immediate effect in the test system used, we conclude that the activity of the 5-LOx itself represents the side of inhibition by the gum resin extract. Therefore, an inhibition of 5-LOx catalysed mediator synthesis might be involved in the previously reported anti-inflammatory activity in vivo.     

3-乙酰基-11-酮-β-乳香酸的抗炎作斥及其衍生物的化学修饰

乳香酸（Bas）是乳香提取物中的活性成分,乳香酸在治疗炎症方面的疾病如类风湿关节炎、慢性支气管炎、哮喘以及慢性发炎性肠道疾病（溃疡性结肠炎和克罗恩病）已经显示出显著的药理活性。数据表明,3-乙酰基-11-酮-β-乳香酸（AKBA）被认为在各种乳香酸中是最强大的。AKBA被发现和确认为5-脂肪氧合酶（5-LOX）强大的抑制剂;AKBA的其他药理活性研究发现,它还充当了p38-MAP激酶强大的抑制剂。为了得到更多的AKBA,它的衍生物BA、KBA、ABA经过一系列化学修饰乙酰化和烯丙基氧化转化为AKBA,从而AKBA的量根据乳香树种和相应树脂质量从0．1％～3．0％上升到25％～35％。     

Complete structural assignment of serratol, a cembrane-type diterpene from Boswellia serrata, and evaluation of its antiprotozoal activity

From the dichloromethane extract obtained from the gum resin of Boswellia serrata Roxb. (Burseraceae), a well-known medicinal plant resin ("Indian Olibanum"), the cembrane-type diterpene serratol was isolated in high yield. Its structure, previously reported without clear specification of double-bond geometry and without specification of stereochemistry, was reanalysed by means of spectroscopic measurements and unambiguously assigned as S(-)-cembra-3E,7E,11E?triene-1-ol. Full assignment of all NMR data is reported for the first time. The compound was found to be identical with a cembrenol previously isolated from B. carteri. Serratolwas tested for in vitro activity against four protozoan human pathogens, namely, Trypanosoma brucei rhodesiense (East African Human Trypanosomiasis, sleeping sickness), T. cruzi (Chagas' disease), Leishmania donovani (Kala-Azar), and Plasmodium falciparum (Tropical Malaria). It was found active against T. brucei and P. falciparum. These activities were 10- to 15-fold higher than its cytotoxicity against rat skeletalmyoblasts. While some reports exist on potential anti-inflammatory activity of Boswellia diterpenes, this is the first report on antiprotozoal activity of such a compound.     

Cytotoxic action of acetyl-11-keto-beta-boswellic acid (AKBA) on meningioma cells

Acetyl-11-keto-beta-boswellic acid (AKBA) is a naturally occurring pentacyclic triterpene isolated from the gum resin exudate of the tree Boswellia serrata (frankincense). Because pentacyclic triterpenes have antiproliferative and cytotoxic effects against different tumor types, we investigated whether AKBA would act in a similar fashion on primary human meningioma cell cultures. Primary cell cultures were established from surgically removed meningioma specimens. The number of viable cells in the absence/presence of AKBA was determined by the non-radioactive cell proliferation assay. The activation status of the proliferative cell marker, extracellular signal-regulated kinase-1 and -2 (Erk-1 and Erk-2) was determined by immunoblotting with the antibody that recognizes the activated form of these proteins. Treatment of meningioma cells by AKBA revealed a potent cytotoxic activity with half-maximal inhibitory concentrations in the range of 2 - 8 microM. At low micromolar concentrations, AKBA rapidly and potently inhibited the phosphorylation of Erk-1/2 and impaired the motility of meningioma cells stimulated with platelet-derived growth factor BB. The cytotoxic action of AKBA on meningioma cells may be mediated, at least in part, by the inhibition of the Erk signal transduction pathway. Because of the central role the Erk pathway plays in signal transduction and tumorigenesis, further investigation into the potential clinical use for AKBA and related boswellic acids is warranted.     

Avoidance of food effect on oral absorption profile of itraconazole by self-micellizing solid dispersion approach

The present study was aimed to avoid pharmacokinetic transitions of itraconazole (ITZ) evoked by high-fat meal intake by employing a self-micellizing solid dispersion (SMSD) approach. The dissolution behavior of SMSD/ITZ was assessed in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). To evaluate the food effect on the oral absorption profile of ITZ, a pharmacokinetic study was conducted on orally-dosed ITZ samples in fasted and high-fat meal-fed rats. Crystalline ITZ showed a 9.0-fold higher dissolution amount of ITZ in fed-state SGF (FeSSGF) than in fasted-state SGF (FaSSGF), whereas there was no significant difference in the dissolution amount of ITZ in SMSD/ITZ between FeSSGF and FaSSGF. In fed- and fasted-state SIF, SMSD/ITZ exhibited reduced variation of ITZ dissolution, possibly leading to suppression of the food effect on the dissolution behavior of ITZ. After the oral administration of crystalline ITZ to high-fat meal-fed rats, the oral bioavailability of ITZ was 14-fold higher than that in fasted rats. In contrast, orally-dosed SMSD/ITZ in fed rats exhibited limited transition of pharmacokinetic behavior regardless of food intake due to the improvement in the dissolution behavior of ITZ even under fasted conditions. SMSD technology could be an efficacious dosage option for the consistent oral absorption and clinical outcomes of ITZ.     

3-Acetoxy group of genuine AKBA (acetyl-11-keto-beta-boswellic acid) is alpha-configurated

The pentacyclic triterpenoid 3-acetyl-11-keto-beta-boswellic acid (AKBA) from the resin of Boswellia spec. is a potent inhibitor of 5-lipoxygenase (5-LO). We noticed discrepancies in the nomenclature and stereochemistry of the 3-acetoxy group of boswellic acids. Isolation of AKBA under mild conditions and the data from the first X-ray crystallography study evidence the 3 alpha-orientation of AKBA's acetoxy function.     

Effect of dietary fat content in meals on pharmacokinetics of quazepam

Dietary fat content in meals has been reported to increase the absorption of several drugs proportionately. However, there is no information about the effects of dietary fat in meals on the sedative hypnotic agent quazepam, although limited data suggest that food intake alters quazepam absorption. Therefore, the authors measured and compared pharmacokinetic parameters of quazepam taken in a fasted state and taken 30 minutes after consuming meals containing different amounts of dietary fat. A three-arm randomized crossover study was conducted. Nine healthy male volunteers took a single oral 20-mg dose of quazepam under the following conditions: (1) after fasting overnight for at least 12 hours, (2) 30 minutes after consuming a low-fat meal (two slices of bread and 200 ml of apple juice), or (3) 30 minutes after consuming high-fat meal (two slices of bread with 30 gm of butter and 200 ml of apple juice). Plasma concentrations of quazepam and its metabolite, 2-oxoquazepam, were monitored up to 48 hours after the dosing. In comparison with corresponding plasma values for quazepam taken in a fasting state, the peak concentrations (Cmax) of quazepam taken 30 minutes after consuming a low-fat meal and high-fat meal were 243% (90% confidence interval [CI] = 161%-325%) and 272% (90% CI = 190%-355%), respectively. Area under the plasma concentration-time curve from 0 to 8 hours (AUC(0-8)) and 0 to 48 hours (AUC(0-48)) of quazepam was increased with the low-fat meal by 2-fold (90% CI = 1.5- to 2.7-fold) and 1.4-fold (90% CI = 1.0- to 1.7-fold), respectively, and with the high-fat meal by 2.2-fold (90% CI = 1.3- to 3-fold) and 1.5-fold (90% CI = 0.7- to 2.4-fold), respectively. The pharmacokinetic change in 2-oxoquazepam to the parent compound was similar. Quazepam was well tolerated, with no significant difference in the Stanford Sleepiness Scale between fasted and fed conditions. These findings show that food intake has an evident effect on quazepam absorption, but further studies are needed to clarify a determinant factor of this alteration (2.5-fold for Cmax and 2.1-fold for AUC(0-8), on average). It might not be necessary to do dose adjustment with meal content because quazepam is well tolerated.     

基于合理给药时间的口服植物药制剂的临床药学调研

目的 促进口服植物药制剂的临床合理使用和科研工作。方法 查阅药品说明书和检索新编临床用药参考软件,找出注明食物-药物相互作用或对服药时间由特殊要求的信息。检索CNKI和PubMed有关进食与植物药制剂疗效或有效成分生物利用度关系的文献。结果 说明书明确要求空腹服用的进口植物药制剂有4种,包括草木犀流浸液片、桃金娘油肠溶胶囊、帕歌斯片和非洲臀果木提取物胶囊。说明书明确要求空腹服用的国产植物药制剂有10种。空腹服用对植物药生物利用度影响的文献涉及绿茶提取物制剂（空腹吸收更好）、齿叶乳香树脂提取物制剂、四物汤和知母皂苷B-II（餐后吸收更好）。植物药有效成分的生物利用度可能与脂溶性大小、胃酸中稳定性以及系统前肠道代谢有关。有12种中成药的服药有时辰要求。结论 植物药制剂说明书中有关食物-药物相互作用信息的标注率低,植物药正确服药时间（特别是空腹还是餐后）还没有引起临床医务人员和科研人员足够的重视,有必要在该领域加强临床药学和科研工作。     

The effects of food on the bioavailability of fenofibrate administered orally in healthy volunteers via sustained-release capsule

OBJECTIVE: To examine the effects of food on plasma concentration and bioavailability of fenofibrate administered as a sustained-release capsule. METHODS: Twenty-four healthy Korean volunteers were enrolled in a randomised, open-label, balanced, three-treatment, three-period, three-sequence, single oral dose, crossover pharmacokinetic study. A single dose of fenofibrate (250 mg sustained-release capsule) was administered on three occasions -- after overnight fasting, after consumption of a standard breakfast and after a high-fat breakfast. Serial blood samples were collected for the next 72 hours. Plasma fenofibric acid concentrations were measured by high-performance liquid chromatography, and pharmacokinetic parameters were calculated. RESULTS: The pharmacokinetic parameters were significantly affected by food intake. The high-fat breakfast affected the rate of absorption of fenofibrate more than the standard breakfast and fasted conditions. Specifically, the area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) and peak plasma concentration (C(max)) increased 2.45-fold and 2.89-fold, respectively, between the fasted and standard-fed conditions (p < 0.01). In addition, the high-fat meal caused 3.34-fold and 3.82-fold increases compared with the fasted condition in AUC(infinity) and C(max), respectively. A one-compartment open model with lag time successfully described the plasma concentrations of fenofibric acid. CONCLUSION: In healthy volunteers, AUC(infinity) and C(max) of fenofibrate, when administered via sustained-release capsules immediately after the consumption of food, was increased significantly from the fasting conditions (p < 0.01). The greatest AUC(infinity) and C(max) occurred when the capsules were taken after a high-fat breakfast.     

The effect of dosing regimen on the pharmacokinetics of risedronate

AIMS: To examine the effect of timing of a risedronate dose relative to food intake on the rate and extent of risedronate absorption following single-dose, oral administration to healthy male and female volunteers. METHODS: A single-dose, randomized, parallel study design was conducted with volunteers assigned to four treatment groups (31 or 32 subjects per group, 127 subjects total). Each subject was orally administered 30 mg risedronate. Group 1 was fasted for 10 h prior to and 4 h after dosing (fasted group); Groups 2 and 3 were fasted for 10 h and were dosed 1 and 0.5 h, respectively, before a high-fat breakfast; and Group 4 was dosed 2 h after a standard dinner. Blood and urine samples were collected for 168 h after dosing. Pharmacokinetic parameters were estimated by simultaneous analysis of risedronate serum concentration and urinary excretion rate-time data. RESULTS: Extent of risedronate absorption (AUC and Ae ) was comparable (P=0.4) in subjects dosed 2 h after dinner and 0.5 h before breakfast; however, a significantly greater extent of absorption occurred when risedronate was given 1 or 4 h prior to a meal (1.4- to 2.3-fold greater). Administration 0.5, 1, or 4 h prior to a meal resulted in a significantly greater rate of absorption (Cmax 2.8-, 3.5-, and 4.1-fold greater, respectively) when compared with 2 h after dinner. CONCLUSIONS: The comparable extent of risedronate absorption when administered either 0.5-1 h before breakfast or 2 h after an evening meal support previous clinical studies where risedronate was found to have similar effectiveness using these dosing regimens. This flexibility in the timing of risedronate administration may provide patients an alternative means to achieve the desired efficacy while maintaining their normal daily routine.     

Novel extended-release formulation of lovastatin by one-step melt granulation: In vitro and in vivo evaluation

The objective of this study was to apply a one-step melt granulation method to develop an extended-release formulation of lovastatin (LOV-ER). We prepared a formulation using PEG 6000 as binder agent in a laboratory scale high-shear mixer. In vitro dissolution studies showed that the release of the drug from the new formulation followed a zero-order kinetic with no differences in the release profile with either the pH media or the agitation rate. The pharmacokinetic of lovastatin and its metabolite lovastatin acid was evaluated after the administration of the new formulation to Beagle dogs in fasted conditions and after a high-fat meal, and compared to the marketed formulation Altoprev®. After the administration of LOV-ER, extended plasma profiles of lovastatin and its active metabolite were achieved in both fasted conditions and after the high-fat meal. Plasma levels of lovastatin and lovastatin acid were always higher when the LOV-ER formulation was administered with the high-fat meal. A high variability in plasma levels and pharmacokinetic parameters was obtained, being this variability higher when the formulation was administered under fasting conditions. Our results suggest that there is an increase in lovastatin bioavailability when the formulation is administered after the high-fat meal. When we compare LOV-ER and Altoprev®, both administered after the high-fat meal, we found significant differences (p < 0.05) in C_max of lovastatin and in AUC_0-∞ and MRT of lovastatin acid. No differences were detected between both formulations in fasting conditions. In this regard, the high-fat meal seems to increase the absorption extent of lovastatin from LOV-ER formulation and to delay the absorption rate of the drug from Altoprev®. In conclusion, we developed a lovastatin formulation that provided extended plasma levels that confirm that one-step melt granulation in high-shear mixer could be an easy and cost-effective technique for extended-release formulation development.     

索磷布韦片在中国健康受试者中的药代动力学和安全性研究

目的：研究中国人群中索磷布韦及其代谢产物GS-331007和GS-566500的主要药代动力学特征和安全性。方法：本试验共入组12例健康受试者,分为四个周期;前三周期为单次给药（低剂量400 mg空腹组、高剂量800 mg空腹组和低剂量400 mg高脂餐组）药代动力学试验;第四周期为多次给药（低剂量400 mg空腹组）药代动力学试验。采用HPLC-MS/MS测定给药前后不同时间点人血浆中索磷布韦及其代谢产物GS-331007和GS-566500的浓度。结果：索磷布韦及其代谢产物GS-566500的暴露与剂量有成比例增加趋势。在多次给药试验中,未观察到明显蓄积现象。与空腹相比,餐后状态下索磷布韦的Cmax变化不大,AUC增加约30%;GS-331007的Cmax和AUC分别减少约30%和10%;GS-566500的Cmax和AUC分别增加约15%和25%。饮食对索磷布韦、GS-331007和GS-56650的Tmax无显著影响。未发生严重不良事件和导致退出的不良事件,所有受试者耐受性良好。结论：在中国健康受试者中,开展的索磷布韦片药代动力学研究结果表明,其药动学特征和安全性与国外研究数据无明显差异,安全性和耐受性良好。