Comparative pharmacokinetic study of paeoniflorin and albiflorin after oral administration of Radix Paeoniae Rubra in normal rats and the acute cholestasis hepatitis rats

A comparative study was designed and conducted to compare the pharmacokinetic difference of paeoniflorin and albiflorin after oral administration of Radix Paeoniae Rubra to normal rats and the acute cholestasis hepatitis rats induced by alpha-naphthylisothiocyanate (ANIT). UPLC-ESI-MS/MS method was employed to determine the level of paeoniflorin and albiflorin in rat plasma using geniposide as the internal standard (IS). Unpaired Student's t-test was used for the statistical comparison. The investigation showed that there were significant differences between the normal rats and the acute cholestasis hepatitis rat groups in calculated parameters, such as AUC(0-t), AUC(0-∞), T(max) and CLz/F. The results indicated that acute liver injury in rats could alter the pharmacokinetics of drug. Since patients are the final users of the drug, it is essential to investigate the pharmacokinetics of the drug in disease status. Therefore, we used normal rats and the acute cholestasis hepatitis rats to study pharmacokinetics of Radix Paeoniae Rubra with the purpose of examining the influence of disease on the metabolic course.     

Pharmacokinetics of brucine after intravenous and oral administration to rats

The toxicity depending on both dose and administration route is the major obstacle to the development of brucine, a bioactive alkaloid from Semen Strychni. In this study, the apparent partition coefficient and plasma protein binding extent of brucine were determined. In addition, the dose-dependency of the pharmacokinetics of brucine was investigated. Three intravenous (2.5, 5 and 10 mg/kg) and three oral (10, 20 and 40 mg/kg) doses were administered to rats. After intravenous administration, the systemic clearance was reduced and AUC was nonlinearly increased as a function of dose. Upon oral administration, brucine was rapidly absorbed (T_max < 0.5 h), which was consistent with previously reported high Caco-2 P_app values. The increase in AUC was proportional to the increase in dose. The oral bioavailability (F) did not vary with the dose (F = 40.31%, 47.15% and 43.02% for 10, 20, 40 mg/kg doses, respectively). However, the dose-proportionality was not observed with C_max. The values of C_max/Dose were calculated to be 92.92 ± 45.83, 55.73 ± 24.01 and 36.29 ± 22.44 μg/L for 10, 20 and 40 mg/kg, respectively. The results of dose-dependent pharmacokinetic behavior under different administration routes may account for the significantly different toxicities of brucine between intravenous and oral administration.     

Hepatoprotective activity of the Indian medicinal plant Polygala arvensis on D-galactosamine-induced hepatic injury in rats

The suspensions of chloroform extract of leaves in 0.3% carboxy methyl cellulose (CMC) was evaluated for hepatoprotective activity in Wistar albino rats by inducing hepatic injury with d-galactosamine (400 mg/kg). The chloroform extract of Polygala arvensis at an oral dose of 200 mg/kg and 400 mg/kg exhibited a significant (P<0.001, P<0.01 and P<0.05) protection effect by normalizing the levels of aspartate amino transferase (ASAT, GOT), alanine amino transferase (ALAT, GPT), alkaline phosphatase (ALP), total bilirubin (TB), lactate dehydrogenase (LDH), total cholesterol (TC), triglycerides (TGL), albumin, total protein (TP) which were significantly (P<0.001) increased in rats by treatment with 400 mg/kg i.p. of d-galactosamine. Silymarin (25 mg/kg), a known hepatoprotective drug used for comparison exhibited significant activity (P<0.001).     

Preparation and evaluation of self-microemulsifying drug delivery system of baicalein

The main object of this work is to prepare self-microemulsifying drug delivery system (SMEDDS) for oral bioavailability enhancement of a poorly water-soluble drug, baicalein. SMEDDS is the mixture of surfactants, cosurfactants, and oils, which are emulsified in aqueous media under conditions of gentle agitation or gastrointestinal motility. Solubility of baicalein was determined in various vehicles. Pseudo-ternary phase diagrams were constructed to identify the efficient self-emulsification region and droplet size distributions of the resultant microemulsions were determined using a particle size analyzer. Optimized SMEDDS formulations for baicalein were Cremophor RH40 (53.57%) as surfactant, Transcutol P (21.43%) as cosurfactant, and Caprylic capric triglyceride (ODO, 25%) as oil. The drug release rate of SMEDDS was significantly higher than that of the baicalein suspension. Comparison of the pharmacokinetics between baicalein-loaded SMEDDS and baicalein suspension was also performed in rats. The plasma concentrations of baicalein and baicalin, its mainly conjugated metabolite, were determined by HPLC method. The in vivo results showed that the absorption of baicalein from SMEDDS resulted in about 200.7% increase in relative bioavailability compared with that of the baicalein suspension. Our studies illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds, such as baicalein by the oral route.     

Hepatoprotective activity of the Leucas lavandulaefolia on D(+)galactosamine-induced hepatic injury in rats

The chloroform extract of Leucas lavandulaefolia at an oral dose of 200 mg/kg and 400 mg/kg exhibited a significant protection on D(+)galactosamine induced liver damage in rats. Silymarin (25 mg/kg), a known hepatoprotective drug used as a standard also exhibited a significant activity.     

Comparative pharmacokinetics of baicalin in plasma after oral administration of Huang-Lian-Jie-Du-Tang or pure baicalin in MCAO and sham-operated rats

A sensitive and specific HPLC method was developed to analyze baicalin in rat plasma. The author had compared the pharmacokinetics of baicalin after oral administration of HLJDT decoction or pure baicalin in MCAO and sham-operated rats. All the rats were divided into two groups, MCAO and sham-operated rats. Each group contained two subgroups: HLJDT decoction and pure baicalin subgroup. The HLJDT subgroup oral administration of HLJDT decoction extract 10.00 g/kg according to body weight (containing baicalin 400.00 mg/kg according to body weight), the pure baicalin subgroup received a gavages at a dosage of baicalin 400.00 mg/kg according to body weight too. The pharmacokinetics parameters were analyzed by kinetica. The results indicated that the pharmacokinetics of baicalin in rat plasma was non-linear and there were significant differences between different groups. No matter in MCAO or sham-operated rats, pure baicalin had shown better absorption than HLJDT decoction. Whether administration of pure baicalin or HLJDT decoction, the MCAO rats show better, quicker absorption of baicalin than sham-operated rats. It was good for baicalin to exert pharmacological effects on healed cerebrovascular diseases. The method had been applied successfully to pharmacokinetics of baicalin in rat plasma after oral administration of pure baicalin or HLJDT decoction.     

Pharmacokinetic study of luteolin,apigenin, chrysoeriol and diosmetin after oral administration of Flos Chrysanthemi extract in rats

Flos Chrysanthemi (the flower of Chrysanthemum morifolium Ramat.) is widely used in China as a food and traditional Chinese medicine for many diseases. Luteolin and apigenin are two main bioactive components in Flos Chrysanthemi, and chrysoeriol and diosmetin are two methylated metabolites of luteolin in vivo by cathechol-O-methyltransferase (COMT). However, there was lack of pharmacokinetic information of chrysoeriol and diosmetin after oral administration of Flos Chrysanthemi extract (FCE). The present study aimed to develop an HPLC-UV method for simultaneous determination of rat plasma concentration of luteolin, apigenin, chrysoeriol and diosmetin and utilize it in pharmacokinetic study of the four compounds after orally giving FCE to rats. The method was successfully validated and applied to the pharmacokinetic study when oral administration of FCE to rats with or without co-giving a COMT inhibitor, entacapone. Chrysoeriol and diosmetin were detected in rat plasma after oral administration of FCE and their concentrations were significantly decreased after co-giving entacapone. Furthermore, AUC of luteolin was significantly increased by entacapone, while that of chrysoeriol was decreased by entacapone, which revealed COMT might play an important role in the disposition of luteolin in rats after dosing of FCE. In conclusion, a sensitive, accurate and reproducible HPLC-UV method for simultaneous determination of luteolin, apigenin, chrysoeriol and diosmetin in rat plasma were developed, pharmacokinetics of chrysoeriol and diosmetin combined with luteolin and apigenin were characterized after oral administration of FCE to rats, which gave us more information on pharmacokinetics and potential pharmacological effects of FCE in vivo.     

Studies on preventive and curative effects of berberine on chemical-induced hepatotoxicity in rodents.

Berberis aristata is an edible plant employed in the South Asian Traditional Medicine, particularly its fruits being used as a tonic remedy for liver and heart. In this investigation, berberine, a known compound from this plant, was studied for its possible antihepatotoxic action in rats. Pretreatment of animals with berberine (4 mg/kg; orally twice daily for 2 days) prevented the acetaminophen- or CCl4-induced rise in serum levels of alkaline phosphatase (ALP) and aminotransaminases (AST and ALT), suggestive of hepatoprotection. Post-treatment with three successive oral doses of berberine (4 mg/kg every 6 h) reduced the hepatic damage induced by acetaminophen, while CCl4-induced hepatotoxicity was not modified, suggesting a selective curative effect against acetaminophen. Pretreatment of animals with a single oral dose of berberine (4 mg/kg) induced prolongation of the pentobarbital (60 mg/kg, i.p.)-induced sleeping time as well as increased strychnine (0.3 mg/kg; i.p.)-induced toxicity, suggestive of inhibitory effect on microsomal drug metabolizing enzymes, cytochrome P450s (CYPs).     

Hypoglycemic effect of Mucuna pruriens seed extract on normal and streptozotocin-diabetic rats

The hypoglycemic effect of the aqueous extract of the seeds of Mucuna pruriens was investigated in normal, glucose load conditions and streptozotocin (STZ)-induced diabetic rats. In normal rats, the aqueous extract of the seeds of Mucuna pririens (100 and 200 mg/kg body weight) significantly (P<0.001) reduced the blood glucose levels after an oral glucose load from 127.5+/-3.2 to 75.6+/-4.8 mg% 2 h after oral administration of seed extract. It also significantly lowered the blood glucose in STZ diabetic rats from 240.5+/-7.2 to 90.6+/-5.6 mg% after 21 days of daily oral administration of the extract (P<0.001). Thus, this study shows that M. pruriens has an anti-hyperglycemic action and it could be a source of hypoglycemic compounds.     

Comparative pharmacokinetics of baicalin in normal and the type 2 diabetic rats after oral administration of the Radix scutellariae extract

Radix scutellariae was used alone or in combination with other medicinal herbs in the treatment of type 2 diabetes mellitus in China. At present, the pharmacokinetics of baicalin in type 2 diabetic rats following oral administration of Radix scutellariae extract was investigated. The results showed that the pharmacokinetics (especially AUC) of baicalin in type 2 diabetic rats after oral administration of Radix scutellariae extract was remarkably different from that in normal rats. Then the mechanism which resulted in the increased AUC of baicalin in diabetic rats was investigated from system clearance and presystemic metabolism. And it was found that the increased AUC of baicalin in diabetic rats at least partly resulted from higher production of baicalein in the intestinal tract of type 2 diabetic rats. Moreover, the activity of β-glucuronidase in intestinal mucosa of type 2 diabetic rats was demonstrated to be higher than that in normal rats, which confirmed the results above. In conclusion, the pharmacokinetic behavior of baicalin was significantly altered in type 2 diabetic rats after orally administrated Radix scutellariae extract, which may partly result from the increased activity of intestinal β-glucuronidase under the pathological state of type 2 diabetes mellitus.     

The novel Sinupret® dry extract exhibits anti-inflammatory effectiveness in vivo

Sinupret® is frequently used as a herbal medicinal product to treat sinusitis, and it was assumed that anti-inflammatory effects might contribute to its overall beneficial properties. Here, we investigated the effects of a Sinupret® drug mixture (SIN) as well as of the novel Sinupret® dry extract (SIN DE) with the latter containing higher concentrations of active ingredients, in an in vivo model of acute inflammation, the carrageenan-induced pleurisy in rats. Both SIN and SIN DE were administered to rats orally at doses of 100 mg/kg (low dose) and 500 mg/kg (high dose) 1 h prior to intrapleural injection of carrageenan. Although both SIN and SIN DE significantly reduced the exudate volume and leukocyte numbers in the pleural exudate at the high and the low dose 4 h after carrageenan injection, the novel SIN DE was more efficient than SIN at the low dose, implying higher efficiency. In parallel, the novel dry extract SIN DE, but not SIN, at 500 mg/kg significantly lowered the levels of prostaglandin (PG)E₂ in the exudates and reduced the amounts of cyclooxygenase (COX)-2 protein in the lungs. Together, SIN and SIN DE exert significant oral anti-inflammatory effects, which rationalize their therapeutic use in the management of sinusitis and other viral/microbial nasal infections that are associated with inflammation. Moreover, our results suggest that based on the higher efficiency and the accompanied reduction of COX-2 expression and PGE₂ formation, the novel dry extract SIN DE might be superior over the former SIN drug mixture.     

Hypoglicemic effect of Leandra lacunosa in normal and alloxan-induced diabetic rats

Leandra lacunosa, popularly known as "erva-do-jabuti", is used in Brazilian folkloric medicine for the treatment of diabetes mellitus. Based on this traditional indication, the aim of this work was to evaluate the hypoglycemic activity of the hydroalcoholic extract of L. lacunosa aerial parts (LLH) in normal and alloxan-induced diabetic rats. Chromatographic fractionation of LLH was also carried out by several techniques, affording isolation of the following major compounds: ursolic acid (1), kaempferol (2), luteolin (3), and quercetin (4). The oral administration of LLH (500 mg/kg) in normal rats caused a significant reduction of 24.7% (P<0.05) in the blood glucose levels after 2 h of treatment, while the administration of chlorpropamide (20 mg/kg, p.o.) led to a reduction of 40.2% (P<0.01). After oral administration of glucose (10 g/kg, p.o.), LLH (500 mg/kg, p.o.) significantly inhibited the increase in blood glucose levels compared with the negative control group. The oral treatment with LLH (500 mg/kg) in alloxan-induced diabetic rats significantly reduced the blood glucose levels in 47.8% after 4 h of treatment, while chlorpropamide resulted in a significant reduction of 71.7% in the 4th hour. Our results showed that LLH, displays hypoglycemic activity, which may be related to the effect of the major compounds identified in the crude extract. This study seems to provide biological evidence for the folkloric use of L. lacunosa in the treatment of diabetes mellitus.     

Long-term treatment with standardized Ginkgo biloba extract (EGb 761) attenuates cognitive deficits and hippocampal neuron loss in a gerbil model of vascular dementia

The standardized extract of Ginkgo biloba EGb 761 has been used to reduce cognitive dysfunction. The present study was designed to evaluate the effect of postischemic oral treatment with EGb 761 in a model of vascular dementia in gerbils. Daily oral posttreatment with EGb 761 led to a significant recovery of spatial memory assessed by the object location test, inhibited the decrease in plasma SOD activity and protected the hippocampal CA1 neurons, even when administered after the insult. These data provide further evidence for the therapeutic potential of EGb 761 in the treatment of vascular dementia.     

Protective effects of echinocystic acid isolated from Gleditsia sinensis Lam. against acute myocardial ischemia

Echinocystic acid (EA), a pentacyclic triterpene, was isolated and identified from the fruits of Gleditsia sinensis Lam. The protective effects of EA were evaluated in rat models with acute myocardial ischemia induced by isoproterenol and vasopressin. In the electrocardiogram of anesthetized rats, EA prevented the ST-segment depression induced by isoproterenol or vasopressin in a dose-dependently manner. Furthermore, the mRNA expression of Bcl-2 was analyzed by RT-PCR. EA shows an elevation of Bcl-2 mRNA level in infarcted tissue induced by isoproterenol in rats. These results demonstrated for the first time EA has a cardioprotective effect and may be a natural drug.     

Comparative pharmacokinetics and bioavailability studies of quercetin, kaempferol and isorhamnetin after oral administration of Ginkgo biloba extracts, Ginkgo biloba extract phospholipid complexes and Ginkgo biloba extract solid dispersions in rats

The aim of this study was to improve the oral bioavailability of Ginkgo biloba extract (GBE) through preparing G. biloba extract phospholipid complexes (GBP) and G. biloba extract solid dispersions (GBS). Firstly we prepared the GBP and GBS and studied their physicochemical properties by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD) and dissolution. Then we studied the pharmacokinetic characteristics and bioavailability in rats. The results showed that the bioavailability of quercetin, kaempferol and isorhamnetin in rats was increased remarkably after oral administration of GBP and GBS comparing with GBE. The bioavailabilities of GBP increased more than that of GBS.     

Behavioral response of Norway rats (<Emphasis Type="Italic">Rattus norvegicus</Emphasis>) to odors of different mammalian species

Behavioral responses to the odors of three predators of rodents (domestic cat (Felis catus), weasel (Mustela sibirica), Eurasian badger (Meles meles)), one non-predator mammal (rabbit (Lepus capensis)), and distilled water (control) were assessed in three types of Norway rats (Rattus norvegicus): wild (WNRs), domestic (DNRs), and albino laboratory Wistar (AWRs). Rats were taken individually to a testing apparatus consisting of a hide box and a testing arena. The behavioral activities, including concealing, heading out, approaching, and feeding behaviors in each trial were videotaped for 3 h. Results revealed that WNRs, DNRs, and AWRs all showed an aversion to the predator odors by spending more time concealing in the hide box: frequencies of approaching and feeding behaviors, as well as the amount of food intake were significantly lower than control group. Our results suggest that the response of DNRs and AWRs were “built-in” or innate in nature as they had never experienced the odors of the tested predators. Moreover, all three types of rats can distinguish between predator and non-predator odors, but the ability of WNRs was the highest, which can distinguish between sympatric and allopatric predators, while the ability of AWRs was the lowest, which spent most time in the hide box. The concealing and approaching behaviors were no significantly different among the five odor exposure groups. Also, the reactions of the three types of rats toward the control group (distilled water) significantly differ. This suggests that the duration of time spent in captivity plays an important role in shaping the response of rats to different predator odors.     

Purgative effect of the methanol extract of Morinda lucida

The purgative effect of a methanol extract of the leaves of Morinda lucida is reported. The oral treatment (12.5–100 mg/kg) caused a pronounced increase in the number of wet faeces in rats and a potentiated castor oil-induced diarrhoea in mice.     

Comparative pharmacokinetics of paclitaxel after oral administration of Taxus yunnanensis extract and pure paclitaxel to rats

Taxus yunnanensis (T. yunnanensis) is endemic to China and has been used in traditional medicine for the treatment of cancer, diabetic ailments and others. Paclitaxel is a representative antitumor compound in the Taxus species. The pharmacokinetic behavior of paclitaxel after oral administration of the crude extract of T. yunnanensis has not been investigated. This study attempts to compare the pharmacokinetics of paclitaxel after an oral administration of the crude extract of the twigs and leaves of T. yunnanensis and pure paclitaxel. A UPLC and a UPLC/MS/MS analysis method were developed for the determination of paclitaxel in T. yunnanensis extract and in the comparative pharmacokinetic study. Caco-2 cells were used to investigate the transport profile of paclitaxel in vitro. In the pharmacokinetic study, rats were randomly grouped and administered with T. yunnanensis extract or pure paclitaxel. The results showed that the AUC and C_max of paclitaxel in rats receiving the T. yunnanensis extract were significantly increased than those receiving the pure paclitaxel, and the in vitro Caco-2 cell monolayer transport study found that the coexisting constituents in the extract of T. yunnanensis could inhibit the efflux of paclitaxel. These findings suggested that the oral absorption and bioavailability of paclitaxel in T. yunnanensis extract were remarkably higher when compared with the pure paclitaxel, and the coexisting constituents in the T. yunnanensis extract might play an important role for the enhancement of the oral absorption and bioavailability of paclitaxel.     

Warfarin resistance test and polymorphism screening in the <Emphasis Type="Italic">VKORC1</Emphasis> gene in <Emphasis Type="Italic">Rattus flavipectus</Emphasis>

The buff-breasted rat (Rattus flavipectus) is a major agricultural pest across China. Warfarin-resistant animals have been found in several major provinces in China, and are hampering effective control. Molecular mechanisms underlying resistance to anticoagulant rodenticides have been determined for other species, but genetic information regarding resistance in R. flavipectus remains unknown. The vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) encoded by VKORC1 gene is the molecular target of coumarin anticoagulants, and amino acid substitutions in VKORC1 coding-regions have been reported as one of the supposed mechanisms of warfarin resistance. Here, lethal feeding test in R. flavipectus (n = 36) was conducted in Zhanjiang, China. Four animals (11%) survived the test period of 25 days and were identified as warfarin resistance. Polymorphism across the whole genome DNA sequence of the VKORC1 gene was screened out and compared with resistant and non-resistant rats. A total of nine single nucleotide polymorphisms (SNPs) were identified including seven SNPs in introns and two SNPs in exons, and the SNP (2317A > G) located in exon 3 led to the amino acid substitution (Tyr139Cys) in VKORC1 protein. Based on the characteristics of Tyr139Cys mutation of VKORC1 in humans or rats and its relationship with warfarin-resistance, Tyr139Cys mutation may be one mutation responsible for anticoagulant resistance in R. flavipectus. Given the low numbers of resistant rats in our feeding test, wider surveillance, tests of resistance development in a larger wild population and further researches on the genetic mechanisms of anticoagulant resistance in R. flavipectus are necessary.     

Effect of Ixora coccinea flowers on dead space wound healing in rats

The alcoholic extract of the flowers of Ixora coccinea was studied for its effect on wound healing, using a dead space wound model in rats. Significant increases in granuloma tissue weight, tensile strength, hydroxyproline and glycosaminoglycan content were observed. The prohealing actions seem to be due to increased collagen deposition as well as better alignment and maturation. The drug induced a hypertropic effect on the thymus gland but had no effect on the adrenals.