iridoids and isoborneol

Xingnaojing microemulsion (XNJ-M) administered intranasally is used for stroke treatment. In order to decrease the XNJ-M-induced mucosal irritation, XNJ-M modified by mPEG2000-PLA (XNJ-MM) were prepared in a previous work. The present work aimed to assess the impact of mPEG2000-PLA on pharmacokinetic features and brain-targeting ability of XNJ-M. The bioavailability and brain-target effects of borneol and geniposide in XNJ-M and XNJ-MM were compared in mice after intravenous (i.v.) and intranasal (i.n.) administrations. Gas chromatography, high-performance liquid chromatography, and ultra-performance liquid chromatography/tandem mass spectrometry methods were developed for the quantification of borneol and geniposide. Blood and brain samples were collected from mice at different time points after i.v. and i.n. treatments with borneol at 8.0 mg/kg, geniposide at 4.12 mg/kg. In addition, near-infrared fluorescence dye, 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indotricarbocyanine iodide was loaded into microemulsions to evaluate the brain-targeting ability of XNJ-M and XNJ-MM by near-infrared fluorescence imaging in vivo and ex vivo. For XNJ-M and XNJ-MM, the relative brain targeted coefficients (Re) were 134.59% and 198.09% (borneol), 89.70% and 188.33% (geniposide), respectively. Besides, significant near-infrared fluorescent signal was detected in the brain after i.n. administration of microemulsions, compared with that of groups for i.v. administration. These findings indicated that mPEG2000-PLA modified microemulsion improved drug entry into blood and brain compared with normal microemulsion: the introduction of mPEG2000-PLA in microemulsion resulted in brain-targeting enhancement of both fat-soluble and water-soluble drugs. These findings provide a basis for the significance of mPEG2000-PLA addition in microemulsion, defining its effects on the drugs in microemulsion.

Topics: Administration, Intranasal; Animals; Biological Availability; Brain; Camphanes; Drug Delivery Systems; Drugs, Chinese Herbal; Emulsions; Iridoids; Male; Mice; Mice, Inbred ICR; Nasal Cavity; Polyesters; Polyethylene Glycols; Stroke

Geniposide is a bioactive substance derived from gardenia, which has been used in traditional Chinese preparation, such as "Xing-Nao-Jing" (XNJ) for stroke treatment. Stroke and the ingredients of herbal preparation affect the pharmacokinetics of geniposide. A comparative pharmacokinetic study of geniposide in stroke and sham-operated rats after administration of XNJ and geniposide was proceeded to evaluate the effect of stroke on pharmacokinetics of geniposide, while the influence of other components in XNJ was determined by using gardenia extract and geniposide-borneol compounds in rats with stroke to compare.. Stroke was induced by middle cerebral artery occlusion followed by reperfusion 2h later. Plasma concentration of geniposide was determined by HPLC. Various pharmacokinetic parameters were estimated from the plasma concentration versus time data using non-compartmental methods.. The maximum plasma concentration (Cmax) and area under the curve (AUC0-t) in stroke after administration of XNJ were 5.97±3.82 μg/mL, and 570.06±274.32 μg·min/mL, respectively, which were 5 times compared with sham-operated rats or the stroke-afflicted rats given geniposide. In stroke, the Cmax and AUC(0-t) of geniposide-borneol group and gardenia extraction group were close to XNJ group and geniposide group, respectively. The geniposide-borneol group had a higher value.. Stroke improved the absorption of geniposide in XNJ. Borneol may be the key ingredient in XNJ improving the absorption of geniposide.

Topics: Animals; Area Under Curve; Camphanes; Chromatography, High Pressure Liquid; Disease Models, Animal; Drugs, Chinese Herbal; Gardenia; Iridoids; Male; Models, Biological; Rats; Rats, Sprague-Dawley; Stroke

Geniposide is widely used in the treatment of cerebral ischemic stroke and cerebrovascular diseases for its anti-thrombotic and anti-inflammatory effects. Recent studies demonstrated that geniposide could be absorbed promptly and thoroughly by intranasal administration in mice and basically transported into the brain. Here, we explored its transport mechanism and the effect of borneol and muscone on its transport by human nasal epithelial cell (HNEC) monolayer. The cytotoxicity of geniposide, borneol, muscone and their combinations on HNECs was evaluated by the MTT assay. Transcellular transport of geniposide and the influence of borneol and muscone were studied using the HNEC monolayer. Immunostaining and transepithelial electrical resistance were measured to assess the integrity of the monolayer. The membrane fluidity of HNEC was evaluated by fluorescence recovery after photobleaching. Geniposide showed relatively poor absorption in the HNEC monolayer and it was not a P-gp substrate. Geniposide transport in both directions significantly increased when co-administrated with increasing concentrations of borneol and muscone. The enhancing effect of borneol and muscone on geniposide transport across the HNEC may be attributed to the significant enhancement on cell membrane fluidity, disassembly effect on tight junction integrity and the process was reversible. These results indicated that intranasal administration has good potential to treat cerebrovascular diseases.

Topics: Actins; Biological Transport; Camphanes; Cell Membrane Permeability; Cell Survival; Cells, Cultured; Chromatography, High Pressure Liquid; Cycloparaffins; Epithelial Cells; Humans; Iridoids; Microscopy, Fluorescence; Nasal Mucosa

To study the effects of borneol and muscone on membrane fluidity, membrane potential, Na+, K(+)-ATPase activity and calcium ions of blood brain barrier (BBB) model cells (MDCK and MDCK-MDR1) for exploring the mechanism of aromatics.. MDCK and MDCK-MDR1 cells were incubated and the experiment was performed as following. Cells were incubated with aromatic herbs for 3 h. The membrane fluidity were detected by FRAP. The changes of membrane potentials and the concentration of calcium ions were detected by flow cytometer.. Borneol (55.6, 111.2 microg/mL) and muscone (8.34, 16.68 microg/mL) significantly enhanced the cell membrane fluidity. Borneol (27.8, 55.6, 111.2 microg/mL) and muscone (4.17, 8.34, 16.68 microg/mL) made the MDCK and MDCK-MDR1 membrane potentials less negative or depolarized. Borneol increased the concentration of intracellular free calcium in MDCK while decreased the concentration of intracellular free calcium in MDCK-MDR1 cells. Muscone increased the concentration of calcium in MDCK and MDCK-MDR1 cells. Na+, K(+)-ATPase activity was significantly increased in borneol and muscone group.. The regulating effect of membrane fluidity, membrane potential, Na+, K(+)-ATPase activity and calcium ions in MDCK and MDCK-MDR1 cells might be one of the mechanisms of borneol and muscone's BBB opening function.

Topics: Animals; Biological Transport; Blood-Brain Barrier; Calcium; Camphanes; Cell Membrane; Cell Membrane Permeability; Cycloparaffins; Dogs; Dose-Response Relationship, Drug; Drug Interactions; Iridoids; Madin Darby Canine Kidney Cells; Membrane Potentials; Models, Biological; Sodium-Potassium-Exchanging ATPase

It has been verified that borneol could promote the accumulation of other drugs in the whole brain. In this study, a microdialysis sampling system coupled with UPLC-MS was developed to evaluate the delivery of geniposide to four brain regions (cortex, hippocampus, hypothalamus and striatum) of conscious rats in the absence/presence of borneol: rats were administrated with geniposide alone (300mg/kg, iv) or administrated with both geniposide and borneol (0.2g/kg, ig). The dialysate collected from specific brain area was analyzed by a UPLC-MS system: separated on a BEH C18 column (50mm×2.1mm id, 1.7μm) within 1.5min, and detected in positive ion electrospray mode. The calibration curve was in good linearity over the concentration range of 0.009-90μg/mL. The inter- and intra-day accuracies were within ±10%, and the precisions were within 9.13%. The established method was applied to study the brain pharmacokinetics of geniposide and the results demonstrated that borneol markedly facilitated the delivery of geniposide to hippocampus and hypothalamus, but slightly hampered its delivery in cortex.

Topics: Animals; Brain; Camphanes; Cerebral Cortex; Chromatography, High Pressure Liquid; Consciousness; Corpus Striatum; Drug Interactions; Hippocampus; Hypothalamus; Iridoids; Male; Microdialysis; Random Allocation; Rats; Rats, Sprague-Dawley; Spectrometry, Mass, Electrospray Ionization

The objective of this study was (1) to characterize geniposide transport through MDCK and MDCK-MDR1 cell lines to confirm its transport mechanism and (2) to evaluate the effect of borneol and muscone as enhancers of geniposide transport in the BBB models so as to explore the enhancement mechanism. Transport studies of geniposide were performed in both directions, from apical to basolateral and from basolateral to apical sides. Drug concentrations were analyzed by HPLC. Geniposide showed relatively poor absorption in MDCK and MDCK-MDR1 cells, apparent permeability coefficients ranging from 0.323×10(-6) to 0.422×10(-6) cm/s. The in vitro experiments showed that geniposide transport in both directions was not concentration dependent and saturable, indicating purely passive diffusion. The efflux ratio of geniposide was less than 2 in the two cell models, which suggested that geniposide was not P-gp substrates. Geniposide transport in both directions significantly increased when co-administrated with increasing concentrations of borneol and muscone. Actin staining results indicated that borneol and muscone increased geniposide transport in the BBB models may attribute to disassembly effect on tight junction integrity.

Topics: Animals; Biological Transport; Blood-Brain Barrier; Camphanes; Cell Survival; Cycloparaffins; Dogs; Drug Delivery Systems; Iridoids; Madin Darby Canine Kidney Cells; Models, Biological

The purpose of this study was to investigate the effects of natural borneol (NB) on the pharmacokinetics and bioavailability of ophthalmic administered geniposide (Ge) in rabbits. In vitro permeability characteristics of Ge in excised rabbit corneas were evaluated using Franz-type cells. The effect of NB on Ge pharmacokinetic profiles in vivo was studied with microdialysis. Concentrations of Ge were determined with reversed-phase high performance liquid chromatography (HPLC) following ophthalmic administration of Ge alone or with NB (0.01%, 0.02%, and 0.04%) or 0.5% ethylendiaminetetraacetic acid (EDTA). Ocular irritation was evaluated using the Draize method and histological examination. Ge solution alone (control solution) had limited corneal permeability. The ratio of the apparent permeability coefficient (Papp) with respect to the control solution significantly increased by approximately 1.6-, 2.0-, and 2.4-fold at NB concentrations of 0.01, 0.02, and 0.04%, respectively. The Papp for Ge with 0.5% EDTA (positive control) was approximately 1.7-fold higher than that for control solution. Compared to control solution, Ge exhibited a 1.46-, 2.16-, and 2.47-fold greater AUC0-6h, and 2.0-, 3.5-, and 4.4-fold greater Cmax, with 0.01, 0.02, and 0.04% NB, respectively, while Tmax remained unchanged. In conclusion, the ocular bioavailability of Ge significantly increased in the presence of NB.

Topics: Absorption; Animals; Biological Availability; Camphanes; Eye; Iridoids; Ophthalmic Solutions; Rabbits

Both geniposide (Ge) and borneol (Bo) are bioactive substances derived from traditional Chinese medicine. Injections containing co-compound of Gardenia-Borneol are widely used for stroke treatment in China, such as "Xingnaojing" multi-component injection. As more and more adverse reactions (especially drug allergy) were reported, it is urgent to find more effective and safer routes of administration for such kinds of medicines. In this paper, bioavailabilities and brain-target effects of geniposide in Gardenia-Borneol co-compound through different administration routes in mice were investigated. Geniposide concentrations in plasma and in brain of mice were determined by reversed-phase high-performance liquid chromatography. The pharmacokinetics parameters of intranasal (i.n.) and intragastric (i.g.) administration were compared with intravenous (i.v.) administration. The bioavailabilities of Ge were 85.38% and 28.76% for i.n. and i.g. while T(max) were 1 min and 30 min. C(max) were 21.881 ± 5.398, 1.914 ± 0.327 and 42.410 ± 6.268 μg/mL for i.n., i.g. and i.v., respectively. The AUC of Ge in brain were 32413.6 ± 4573.9, 6440.1 ± 863.7 and 37270.5 ± 4160.6 ng/g ·min for i.n., i.g. and i.v., respectively. The drug target indexes (DTI) were 1.02 and 0.60 for i.n. and i.g. The results demonstrated that geniposide could be absorbed promptly and thoroughly by i.n. administration in mice and basically transported into the brain though blood vessel passways.

Topics: Animals; Biological Availability; Brain; Camphanes; Drug Administration Routes; Drugs, Chinese Herbal; Gardenia; Iridoids; Male; Medicine, Chinese Traditional; Mice; Plant Extracts

Both geniposide (Ge) and natural borneol (NB) are bioactive substances derived from traditional Chinese herbs. The effect of NB on the pharmacokinetics of Ge in rat via intranasal administration was investigated. The concentrations of Ge in plasma were determined by reversed-phase high-performance liquid chromatography (HPLC) after intranasal administration of Ge (4 mg/kg) alone and combined with different doses (0.08, 0.8, and 8 mg/kg) of NB. The intravenous administration was given as a reference (4 mg/kg of Ge and 8 mg/kg of NB). Compared with the intravenous administration, the absolute bioavailability of Ge was 76.14% through intranasal administration combined with NB. Compared with the intranasal administration of Ge alone, Ge could be absorbed rapidly in the nasal cavity combined with NB; the peak time of Ge in the plasma became shorter (3-5 min vs. 40 min); the peak concentration became higher (1.32-4.25 μg/ml vs. 0.67 μg/ml); and, the relative bioavailability of Ge combined with NB was 90.3%-237.8%. The enhancing effect was attenuated as the dose of NB decreased. The results indicated that NB can accelerate the absorption of Ge dose-dependently in the nasal cavity.

Topics: Absorption; Administration, Intranasal; Animals; Biological Availability; Camphanes; Drug Synergism; Gardenia; Injections, Intravenous; Iridoids; Male; Nasal Mucosa; Plants, Medicinal; Rats; Rats, Sprague-Dawley

The objective of this research was to study the in situ and in vivo nasal absorption of Geniposide (Ge) co-administered with borneol. A rat in situ nasal perfusion technique with a novel volumeadjusted calculation was used to examine the absorption rate and extent of Ge. The influence of different experimental conditions such as purity of extract, drug concentration, co-administration with synthetic borneol or natural borneol were also investigated. Results indicated nasal absorption of Ge was primarily by passive diffusion that resembled first order kinetics. Following co-administration with borenol, the drug absorption was increased by 1.4 and 1.7 folds for natural borneol and synthetic borneol, respectively. However, the effect of other factors on drug absorption was not significant. In addition, it was also observed that there is a positive correlation between the absorption of water and Ge by the nasal route. In vivo studies carried out in rats where Ge was co-administered with NB and the pharmacokinetic profile obtained following intranasal administration were compared with those after intravenous administration. The bioavailability of Ge by intranasal was 101.5% and T(max) was 2.04 +/- 0.64 min. MRT was 218.7 +/- 74.1 min and 44.4 +/- 8.9 min for intranasal and intravenous, respectively. Combined with the borneol, Ge can be promptly and thoroughly absorbed intranasally in rats.

Topics: Absorption; Administration, Intranasal; Animals; Camphanes; Drug Interactions; Injections, Intravenous; Iridoids; Male; Nasal Mucosa; Random Allocation; Rats; Rats, Sprague-Dawley

To observe the influence of natural borneol and synthetic borneol on mucosal permeability of Gardenia extract.. Taken frog skin as a vitro model to study the vitro mucosal permeation the impacts of the natural borneols and synthetic borneols on the P(app) of the Jasminoidin were studied, and the effect of different borneols on the stability of Jasminoidin were investigated. Compared the 10 h accumulated infiltration rate of each group the effects of influence factors,such as C(Ge), C(B) and rotation speed on P(app) were investigated by using response surface method.. The P(app) of Jasminoidin of natural borneol and synthetic borneol group were 1.44 fold and 1.77 fold of control group (P < 0.01). For two borneol groups, the results also showed a significant difference too (P < 0.05). Jasminoidin began to degrade about 8 h after the effect of frog skin for control group and synthetic borneol group, but was stable within 12 h for natural borneol group. The accumulated permeation rate of 10 h was same for different borneol groups. It was about 1.3 fold of control group. The C(Ge) had a salinence influence on the P(app) (P < 0.01) and C(B) had a salience influence on time-lag (P < 0.01).. Both the natural borneol and synthetic borneol can accelerate the permeation of Jasminoidin and the synthetic borneol has stronger effect on the P(app). Both two different borneol can reduce the degradation effect of frog skin to Jasminoidin, but the natural borneol has a better protect effect on it. By using more natural borneol, the mucosal permeability of Gardenia extract can be increased, the time-lag can be reduced, and Jasminoidin has better stability.

Topics: Administration, Cutaneous; Camphanes; Dosage Forms; Drugs, Chinese Herbal; Gardenia; Iridoids; Mucous Membrane; Nasal Mucosa; Permeability; Skin; Skin Absorption