Borneol acts as an adjuvant agent to enhance the oral absorption of Panax notoginseng saponins in rats: Effect of optical configuration and compatibility ratios.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng saponins (PNS), as the main active component of Panax notoginseng, shows broad pharmacological effects but with low oral bioavailability. Borneol (BO) is commonly used as an adjuvant drug in the field of traditional Chinese medicine, which has been proven to facilitate the absorption of ginsenosides such as Rg1 and Rb1 in vivo. The presence of chiral carbons has resulted in three optical isomers of BO commercially available in the market, all of which are documented by national standards. AIM OF THE STUDY: This study aimed to investigate the role of BO in promoting the oral absorption of PNS from the perspective of optical configuration and compatibility ratios. MATERIALS AND METHODS: In this study, an ultra-performance liquid chromatography coupled with triple quadrupole-linear ion trap tandem mass spectrometry (UPLC-QTRAP-MS/MS) method was validated and applied to determine the concentrations of five main saponins in PNS in rat plasma. The kinetic characteristics of PNS were compared when co-administered with BO based on optical isomerism and different compatibility ratios. RESULTS: The results showed that BO promoted the exposure of PNS in rats. Three forms of BO, namely d-borneol (DB), l-borneol (LB), and synthetic borneol (SB), exhibited different promotion strengths. SB elevated PNS exposure in rats more than DB or LB. It is also interesting to note that under different compatibility ratios, SB can exert a strong promoting effect only when PNS and BO were combined in a 1:1 ratio (PNS 75 mg/kg; BO 75 mg/kg). As a pharmacokinetic booster, the dosage of BO is worthy of consideration and should follow the traditional medication principles of Chinese medicine. CONCLUSIONS: This study shed new light on the compatible use of PNS and BO from the perspective of "configuration-dose-influence" of BO. The results provide important basis for the clinical application and selection of BO.

Multiple regulation and targeting effects of borneol in the neurovascular unit in neurodegenerative diseases.

Efficient delivery of brain-targeted drugs is highly important for the success of therapies in neurodegenerative diseases. Borneol has several biological activities, such as anti-inflammatory and cell penetration enhancing effect, and can regulate processes in the neurovascular unit (NVU), such as protein toxic stress, autophagosome/lysosomal system, oxidative stress, programmed cell death and neuroinflammation. However, the influence of borneol on NVU in neurodegenerative diseases has not been fully explained. This study searched the keywords 'borneol', 'neurovascular unit', 'endothelial cell', 'astrocyte', 'neuron', 'blood-brain barrier', 'neurodegenerative diseases' and 'brain disease' in PubMed, BioMed Central, China National Knowledge Infrastructure (CNKI) and Bing search engines to explore the influence of borneol on NVU. In addition to the principle and mechanism of penetration of borneol in the brain, this study also showed its multiple regulation effects on NVU. Borneol was able to penetrate the blood-brain barrier (BBB), affecting the signal transmission between BBB and the microenvironment of the brain, downregulating the expression of inflammatory and oxidative stress proteins in NVU, especially in microglia and astrocytes. In summary, borneol is a potential drug delivery agent for drugs against neurodegenerative diseases.

Borneol: a Promising Monoterpenoid in Enhancing Drug Delivery Across Various Physiological Barriers.

Incorporation of permeation enhancers is one of the most widely employed approaches for delivering drugs across biological membranes. Permeation enhancers aid in delivering drugs across various physiological barriers such as brain capillary endothelium, stratum corneum, corneal epithelium, and mucosal membranes that pose resistance to the entry of a majority of drugs. Borneol is a natural, plant-derived, lipophilic, volatile, bicyclic monoterpenoid belonging to the class of camphene. It has been used under the names "Bing Pian" or "Long Nao" in Traditional Chinese Medicine for more than 1000 years. Borneol has been incorporated predominantly as an adjuvant in the traditional Chinese formulations of centrally acting drugs to improve drug delivery to the brain. This background knowledge and anecdotal evidence have led to extensive research in establishing borneol as a permeation enhancer across the blood-brain barrier. Alteration in cell membrane lipid structures and modulation of multiple ATP binding cassette transporters as well as tight junction proteins are the major contributing factors to blood-brain barrier opening functions of borneol. Owing to these mechanisms of altering membrane properties, borneol has also shown promising potential to improve drug delivery across other physiological barriers as well. The current review focuses on the role of borneol as a permeation enhancer across the blood-brain barrier, mucosal barriers including nasal and gastrointestinal linings, transdermal, transcorneal, and blood optic nerve barrier.

Preparation, Characterization and in vivo Study of Borneol-Baicalin-Liposomes for Treatment of Cerebral Ischemia-Reperfusion Injury.

PURPOSE: Baicalin (BA) has a good neuroprotective effect, but it is eliminated quickly in the body and does not easily reach the brain. In this experiment, borneol (BO) was used as an auxiliary drug to prepare borneol-baicalin-liposomes (BO-BA-LP) to prolong the efficacy time of BA, synergistically synergize, introduce drugs into the brain, and better exert the therapeutic effect on cerebral ischemia-reperfusion (I/R) injury. METHODS: Through single-factor inspection and response surface optimization analysis, obtained the best preparation process of BO-BA-LP and characterized by various analytical techniques. Validated the long-term effectiveness of BA-BO-LP through pharmacokinetic studies and conducted pharmacodynamic studies on the middle cerebral artery occlusion (MCAO) rat model to verify the therapeutic effect of BO-BA-LP on cerebral I/R injury. RESULTS: The optimum preparation conditions of BO-BA-LP were as follows: the dosage of BO was 9.55 mg, the ratio of phospholipid to drug was 4.02:1, the ratio of phospholipid to cholesterol was 7.25:1, the entrapment efficiency (EE) was 41.49%, and the drug loading (DL) was 4.29%. The particle size range of the liposomes was 167.1 nm, and the polydispersity index (PDI) range was 0.113. The results of pharmacokinetic experiments showed that the combination of BA and BO liposomes effectively improved the pharmacokinetic parameters of BA and prolonged the half-life of BA. Pharmacodynamic studies have found that, compared with BA-LP, BO-BA-LP can significantly improve neurological deficits, cerebral infarction volume, and brain pathological states on MCAO rats. CONCLUSION: These results demonstrated that BO-BA-LP can improve the circulation of drugs in the blood, and the addition of BO can enhance the therapeutic effect of BA and effectively improve cerebral I/R.

Pharmacokinetics, pharmacodynamics, safety, tolerability, and mass balance of single and continuous intravenous infusion of SPT-07A in healthy volunteers.

PURPOSE: SPT-07A is an intravenous injection of (+)-2-borneol being developed for the treatment of acute ischemic stroke. This study aimed to investigate the pharmacokinetics, pharmacodynamics, safety, tolerability, and mass balance of SPT-07A after sequentially administered single and multiple infusions of SPT-07A at 10 mg, 20 mg, or 40 mg. METHODS: This phase I, double-blind, randomized, placebo-controlled, dose-escalation study was conducted in 36 Chinese healthy volunteers. Each cohort enrolled 12 eligible subjects, who were 9:3 randomized to receive SPT-07A or matching placebo during the two study occasions, that is, an initial single-dose occasion followed by a 7-day multiple-dose occasion with a dosing interval of 12 h. Pharmacokinetic, pharmacodynamic assessments regarding effects on the central nervous system (CNS) were performed pre-dose and several times post-dose. Safety and tolerability were evaluated throughout the study for each cohort. RESULTS: Following single intravenous (i.v.) administration of 10 mg to 40 mg SPT-07A, the plasma SPT-07A concentration reached its peak by the end of infusion. Thereafter, the plasma concentration declined in a multiphase exponential manner with an average terminal elimination half-life of 3.85 to 8.93 h. The exposure parameters of SPT-07A increased dose proportionally. Steady state of SPT-07A was reached after 12-hourly i.v. administrations for 4 days with minimal accumulations. No significant difference of change-from-baseline was observed in the pharmacodynamic measurements between each of the three SPT-07A-treated groups and the placebo group. A total of 41 adverse events (AEs) were reported in 77.8% subjects at 10 mg (7/9), 20 mg (7/9), and 40 mg (7/9), respectively. The AE incidence in placebo group was also 77.8% (7/9). All AEs were mild or moderate in severity and self-limited. SPT-07A was mainly excreted in human urine in glucuronic acid conjugate forms. The total urine recovery rate approximated 84.69% of the administered dose. CONCLUSIONS: SPT-07A was safe and well tolerated after single and multiple intravenous administrations of SPT-07A in the range of 10 mg to 40 mg. SPT-07A presented linear pharmacokinetics in human. Based on plasma exposure, the doses of 10-40 mg twice daily resulted in exposure levels comparable with those obtained at doses demonstrating potential efficacy on AIS animal models and were thus recommended as therapeutic exploratory doses in the phase II clinical trial.

Effect of Sunscreen Application Under Maximal Use Conditions on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial.

Importance: The US Food and Drug Administration (FDA) has provided guidance that sunscreen active ingredients with systemic absorption greater than 0.5 ng/mL or with safety concerns should undergo nonclinical toxicology assessment including systemic carcinogenicity and additional developmental and reproductive studies. Objective: To determine whether the active ingredients (avobenzone, oxybenzone, octocrylene, and ecamsule) of 4 commercially available sunscreens are absorbed into systemic circulation. Design, Setting, and Participants: Randomized clinical trial conducted at a phase 1 clinical pharmacology unit in the United States and enrolling 24 healthy volunteers. Enrollment started in July 2018 and ended in August 2018. Interventions: Participants were randomized to 1 of 4 sunscreens: spray 1 (n = 6 participants), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two milligrams of sunscreen per 1 cm2 was applied to 75% of body surface area 4 times per day for 4 days, and 30 blood samples were collected over 7 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, and ecamsule. Results: Among 24 participants randomized (mean age, 35.5 [SD, 1.5] years; 12 (50%] women; 14 [58%] black or African American; 14 [58%]), 23 (96%) completed the trial. For avobenzone, geometric mean maximum plasma concentrations were 4.0 ng/mL (coefficient of variation, 6.9%) for spray 1; 3.4 ng/mL (coefficient of variation, 77.3%) for spray 2; 4.3 ng/mL (coefficient of variation, 46.1%) for lotion; and 1.8 ng/mL (coefficient of variation, 32.1%). For oxybenzone, the corresponding values were 209.6 ng/mL (66.8%) for spray 1, 194.9 ng/mL (52.4%) for spray 2, and 169.3 ng/mL (44.5%) for lotion; for octocrylene, 2.9 ng/mL (102%) for spray 1, 7.8 ng/mL (113.3%) for spray 2, 5.7 ng/mL (66.3%) for lotion, and 5.7 ng/mL (47.1%) for cream; and for ecamsule, 1.5 ng/mL (166.1%) for cream. Systemic concentrations greater than 0.5 ng/mL were reached for all 4 products after 4 applications on day 1. The most common adverse event was rash, which developed in 1 participant with each sunscreen. Conclusions and Relevance: In this preliminary study involving healthy volunteers, application of 4 commercially available sunscreens under maximal use conditions resulted in plasma concentrations that exceeded the threshold established by the FDA for potentially waiving some nonclinical toxicology studies for sunscreens. The systemic absorption of sunscreen ingredients supports the need for further studies to determine the clinical significance of these findings. These results do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.

Preparation, preliminary pharmacokinetic and brain targeting study of metformin encapsulated W/O/W composite submicron emulsions promoted by borneol.

Metformin hydrochloride (Met) is the first-line drug to treat type 2 diabetes and has shown high efficiency in reducing Alzheimer's disease in recent studies. Herein, a borneol W/O/W composite submicron emulsion containing Met (B-Met-W/O/W SE) was prepared, expecting longer in-vivo circulation time, better bioavailability and brain targeting of Met drug. In the optimized formulation, the mean droplets size, polydispersity index and encapsulation efficiency of the composite were 386.5 nm, 0.219 and 87.26%, respectively. FTIR analysis confirmed that Met interacted with carriers in B-Met-W/O/W SE. Compared with Met free drug, in-vitro release of Met in B-Met-W/O/W SE delivery system was much slower. In pharmacokinetic studies in rats, the AUC, MRT and t1/2 of the B-Met-W/O/W SE system were respectively 1.27, 2.49 and 4.02-fold higher than Met free drug system. The drug-targeting index of B-Met-W/O/W SE system to the brain tissue was also higher than that of Met free drug system and Met-W/O/W SE system. These results indicated that B-Met-W/O/W SE drug delivery system is a promising candidate in treating clinical Alzheimer's disease.

Development and validation an LC-MS/MS method to quantify (+)-borneol in rat plasma: Application to a pharmacokinetic study.

(+)-Borneol, a bicyclic monoterpene, has been shown to possess valuable biological properties and potential as a pharmaceutical agent due to anti-inflammatory, anti-oxidant and GABA receptor-enhancing functions; it also enhances the permeability of the blood brain barrier to improve the efficacy of CNS drugs. In this study, we have developed a simple, selective, and rapid liquid chromatography-tandem mass spectrometry method for the assay of (+)-borneol in rat plasma. Verapamil was used as an internal standard. Plasma samples were deproteinized using methanol. The analyte was detected by a mass spectrometer with positive atmospheric pressure chemical ionization by multiple reaction monitoring mode for transitions at m/z [M + H]+ 137.2 → 81.0 for (+)-borneol and 455.2 → 165.1 for verapamil. The method has been fully validated to ensure good selectivity, a satisfactory lower limit of quantification at 10.0 ng/mL, acceptable intra- and inter-day accuracy, and high precision. The method was used for the pharmacokinetic evaluation of (+)-borneol in Sprague-Dawley rats after intravenous, oral, and sublingual administration. The results indicate that oral bioavailability of (+)-borneol was extremely low but sublingual administration yielded rapid absorption and favorable bioavailability of (+)-borneol.

Influence of Orally Administered Borneol on the Expression of Hepatic Transporters in Rats.

BACKGROUND AND OBJECTIVE: Borneol, a traditional Chinese medicine (TCM), is often orally co-administered with other TCM and chemical drugs, but the drug-drug interactions between borneol and the other compounds remains unclear. This work investigates the effect of orally administered borneol on the transcription and expression of hepatic uptake transporters (Ntcp, Oatp2b1, Oatp1a1, Oatp1a4, Oct1, Oct2, Octn2 and Oat2) and efflux transporters (Mdrla, Mrp2, Mrp4 and Mrp5) in rats, aiming to obtain essential information to guide its clinical applications. METHODS: Rats were administered borneol (33, 100 and 300 mg/kg/day, respectively) and vehicle (control) orally via intragastric gavage for 7 consecutive days. The mRNA levels of rat hepatic uptake transporters (Ntcp, Oatp2b1, Oatp1a1, Oatp1a4, Oct1, Oct2, Octn2 and Oat2) and efflux transporters (Mdrla, Mrp2, Mrp4 and Mrp5) were determined using real-time quantitative PCR, while the hepatic Ntcp, Mdrla, Mrp2, Mrp4 and Mrp5 proteins were quantified using western blotting. RESULTS: The oral administration of borneol led to dose-dependent inhibition of mRNA and protein expression of Mrp4 and Mdr1a, dose-independent inhibition of mRNA and protein expression of Mrp2, and inverse dose-dependent inhibition of mRNA and protein expression of Ntcp. No significant effects were observed for mRNA expression of the other transporters tested following borneol administration. CONCLUSIONS: Oral administration of borneol may affect the metabolism of substances that are involved in bile acid enterohepatic circulation and substrates of Ntcp, Mdrla, Mrp2 and Mrp4 transporters.

Tanshinol borneol ester on nanostructured lipid carriers has longer brain and systemic effector retention and better antioxidant activity in vivo.

BACKGROUND: Tanshinol borneol ester (DBZ) is a hybrid of danshensu (DSS) and borneol and has anti-ischemic activity in animals. However, its low water solubility and short half-life limit its clinical application. METHODS: We prepared polyethylene glycol (PEG)-modified and DBZ-loaded nanostructured lipid carriers (DBZ-PEG-NLC) and DBZ-NLC, and examined their physical characteristics, such as particle size, zeta potential, entrapment efficiency and drug loading. The in vitro stability and pharmacokinetics in rats as well as antioxidant activity of DBZ-PEG-NLC and DBZ-NLC in a C57BL/6 mouse model of ischemia/reperfusion-related brain injury were investigated. The levels of DBZ and its hydrolyzed DSS in rat plasma and brain microdialysates were determined by liquid chromatography-mass spectroscopy/mass spectroscopy analysis. RESULTS: We found that the mean particle size and entrapment efficacy of DBZ-PEG-NLC were similar to that of DBZ-NLC. The DBZ-PEG-NLC, like DBZ-NLC, released DBZ in a biphasic manner with initially burst release and then prolonged slow release in vitro. Intravenous injection of DBZ-PEG-NLC resulted in significantly higher levels and longer retention periods of DBZ and DSS in plasma and the brains than DBZ-NLC and DBZ in rats. Finally, treatment with DBZ-PEG-NLC achieved a better antioxidant activity than DBZ or DBZ-NLC in mouse model of ischemia/reperfusion by reducing the levels of brain malondialdehyde, but increasing the levels of brain superoxide dismutase and glutathione. CONCLUSION: DBZ-PEG-NLC is a preferable option to deliver DBZ for sustainable release of DSS and borneol in vivo, and may serve as a promising drug for effective therapy of ischemic cardiovascular and cerebrovascular diseases.

In vivo microdialysis with ultra performance liquid chromatography-mass spectrometry for analysis of tetramethylpyrazine and its interaction with borneol in rat brain and blood.

Tetramethylpyrazine (TMP) has been widely used in the treatment of ischemic cerebrovascular disease. However, the mechanism of TMP and how to increase its bioavailability need to be further explored. In our study, an in vivo microdialysis sampling technique coupled with ultra-performance liquid chromatography-mass spectrometry method was developed to investigate the pharmacokinetic properties of TMP and its interaction with different doses of borneol (BO) in rats. Linearity of TMP in brain and blood dialysates exhibited good linear relationships over the concentration range of 0.991-555.14 ng/mL. The specificity, linearity, accuracy, precision, matrix effect and stability were within acceptable ranges. The results demonstrated that BO had a marked impact on the pharmacokinetic properties of TMP. After co-administration, the areas under the concentration-time curve (AUC) of TMP in brain and blood were significantly increased. Meanwhile, the peak concentration of TMP in brain was also enhanced. The AUCBrain /AUCBlood of TMP, increased from 44% to 56 and 60.8% after co-administration with BO (15 and 30 mg/kg). The pharmacodynamic results showed that TMP co-administration with BO enhanced the cerebral blood flow during the period of ischemia and reduced the infarct volume. Overall, it might be an effective way to treat stroke to use TMP co-administered with BO.

Optimization of the Preparation Conditions of Borneol-Modified Ginkgolide Liposomes by Response Surface Methodology and Study of Their Blood Brain Barrier Permeability.

Ginkgolides (GG), containing ginkgolide A (GA), ginkgolide B (GB) and ginkgolide C (GC), are mainly prescribed for ischemic stroke and cerebral infarction. However, the ginkgolides can hardly pass the blood-brain barrier (BBB) into the brain. The purpose of this study was to prepare borneol-modified ginkgolides liposomes (GGB-LPs) to study whether borneol could enhance the transport of ginkgolides across the BBB. The preparation conditions of GGB-LPs were optimized by a response surface-central composite design. Also, pharmacokinetics and biodistribution studies of GGB-LPs were conducted using UPLC-MS. The optimal preparation conditions for GGB-LP were as follows: ratio of lipid to drug (w/w) was 9:1, ratio of phospholipid to cholesterol (w/w) was 7:1, and hydrate volume was 17.5 mL. Under these conditions, the GGB-LP yield was 89.73 ± 3.45%. With GGB-LPs, borneol significantly promoted the transport of ginkgolide across the BBB. The pharmacokinetic parameters of GGB-LP were significantly improved too, with Tmax of 15 min and a high drug concentration of 3.39 µg/g in brain. Additionally, the drug targeting index and relative uptake rate of GGB-LP was increased. Borneol-modified ginkgolide liposomes can thus potentially be used to improve the BBB permeability of gingkolide formulations.

GC-MS/MS method for the determination and pharmacokinetic analysis of borneol and muscone in rat after the intravenous administration of Xingnaojing injection.

A simple and sensitive gas chromatography with tandem mass spectrometry method was developed and validated for the simultaneous determination of borneol and muscone in rat plasma. The analytes and internal standard, naphthalene, were extracted using a convenient one-step liquid-liquid extraction method with ethyl acetate. The chromatographic separation was realized on a HP-5MS capillary column and detected in multiple reaction monitoring mode. Excellent linearity (R2  ≥ 0.996) was shown over 10.0-5000 ng/mL for borneol and 2.5-250 ng/mL for muscone. The lower limit of quantitation was 10 and 2.5 ng/mL for borneol and muscone, respectively. The intra- and interday precisions were less than 7.52%, and the accuracy values were between  -8.03 and 14.52%. The extraction recovery, matrix effect, and stability were sufficient to meet the Food and Drug Administration criteria. Meanwhile, the assay was successfully applied to the preclinical pharmacokinetic study of borneol and muscone following intravenous administration of Xingnaojing injection, a modern Chinese herbal medicine preparation.

Docking-based design and synthesis of galantamine-camphane hybrids as inhibitors of acetylcholinesterase.

Galantamine (GAL) as an acetylcholinesterase inhibitor (AChEI) is among the main drugs approved for the treatment of Alzheimer's disease. It fits perfectly into acetylcholinesterase (AChE) binding gorge, but it is too short to fill it. The amyloid beta (Aß) peptide binds in the peripheral anionic site (PAS) at the entrance of the binding gorge of AChE and initiates the formation of amyloid plaques. The blockade of PAS prevents from AChE-induced Aß aggregation. In this study, we describe the design of a series of galantamine-camphane hybrids as AChEIs. Camphane (CAM) is a bulky fragment that disposes well on the wide gorge entrance. The designed hybrids have linkers of different length. They were docked into AChE, and the highest scored compounds were synthesized and tested for AChE inhibitory activity. Some of the novel hybrids showed 191- and 369-fold better inhibition than GAL. The CAM fragment of the best binders fits in the same region, proximal to PAS, where the Ω-loop of Aß binds to AChE. The hybrids cross blood-brain barrier by passive diffusion and are non-neurotoxic at the inhibitory concentrations.

Bioavailability of the Phenolic Antioxidant 4-Methyl-2,6-Diisobornylphenol After Oral Administration.

We compared bioavailability of 4-methyl-2,6-diisobornylphenol after single intragastric administration to rats in a dose of 200 mg/kg in starch suspension and in almond oil. Absorption of 4-methyl-2,6-diisobornylphenol in the gastrointestinal tract after administration in almond oil was much more efficient than after administration in aqueous starch mucus.

Albumin-Oxanorbornadiene Conjugates Formed ex Vivo for the Extended Circulation of Hydrophilic Cargo.

Oxanorbornadiene dicarboxylate (OND) reagents were explored for the purpose of binding and releasing chemical cargos from endogenous circulating serum albumins. ONDs bearing gadolinium chelates as model cargos exhibited variable conjugation efficiencies with albumin in rat subjects that are consistent with the observed reactivity of each linker and their observed stability toward serum hydrolases in vitro. The terminal elimination rate from circulation was dependent on the identity of the OND used, and increased circulation time of gadolinium cargo was achieved for linkers bearing electrophilic fragments designed to react with cysteine-34 of circulating serum albumin. This binding of and release from endogenous albumin highlights the potential of OND linkers in the context of optimizing the pharmacokinetic parameters of drugs or diagnostic agents.

Improved blood-brain barrier distribution: effect of borneol on the brain pharmacokinetics of kaempferol in rats by in vivo microdialysis sampling.

ETHNOPHARMACOLOGICAL RELEVANCE: Kaempferol (KA) exists in a variety of herbal medicines. In vitro and in vivo studies have focused on the anti-Alzheimer effect of KA. However, little is known about its brain pharmacokinetic profile. The accumulated amount of KA in brain is very low because of the protection of blood-brain barrier (BBB). Borneol (BO) is a classical aromatic refreshing traditional Chinese medicine and commonly used as an adjuvant component of traditional Chinese medicines (e.g. compound Danshen dropping pills) in the treatment of cardiovascular and cerebrovascular diseases. According to the basic theories of traditional Chinese medicine, BO is called an "upper guiding drug", which can guide other components to the targeting tissues or organs in the upper part of the body, especially in the brain. MATERIALS AND METHODS: The probes for blood and brain sampling were implanted within the jugular vein/right atrium and right hippocampus of SD rats, respectively. Rats were intravenous administered of KA (25 mg/kg) alone or combined with BO (15, 30 mg/kg) via caudal vein. The blood and brain microdialysates were collected every 15 min for 180 min and every 30 min for 180-300 min. A selective and sensitive high performance liquid chromatography-chemiluminescence method was developed for the determination of unbound KA in rat blood and brain microdialysates, which can be converted to their actual free-form concentrations based on the in vivo relative recoveries of KA across microdialysis probes. RESULTS: KA quickly crossed the BBB to enter the extracellular fluid of hippocampus and reached the maximum concentration of 0.11 µg/mL within 30 min. The brain bioavailability and brain delivery of KA evidently increased with the co-administration of 15 and 30 mg/kg of BO. The AUC0-inf of KA in brain increased 1.84 and 2.19 times, and the Cmax of KA in brain increased 2.09 and 3.18 times than that without BO, respectively. In addition, the brain-to-blood distribution ratio of KA increased by 48.68% and 57.97% compared with that without BO. However, no significant difference in the T1/2 of unbound KA in blood aserved between three groups. CONCLUSIONS: BO can enhance the BBB permeability and improve the transportation of KA to brain. The dose-dependent effect of BO on the brain pharmacokinetic parameters of KA was observed. This co-administration strategy can be designed to enhance the brain accumulation of other neuropsychiatric medications.

[Distribution of 4-methyl-2,6-diisobornylphenol in rat tissues].

We have studied the distribution of the new compound 4-methyl-2,6-diisobornylphenol in rats after a single oral administration in a dose of 20 mg/kg. The pharmacokinetic parameters have been estimated by the noncompartmental method. It is established that the drug is nonuniformly distributed in the body and has a high affinity for liver and heart. A low penetration of 4-methyl-2,6-diisobornilphenol has been found in brain tissue. The accumulation of 4-methyl-2,6-diisobornilphenol in adipose tissues has not been found. It been showed that the drug is slowly eliminated from the body, especially from the heart tissues for which the mean retention time is MRT = 45 h.

The effect of borneol on the concentration of meropenem in rat brain and blood.

Meropenem is a carbapenem antibiotic with a wide spectrum of activity against both Gram-positive and Gram-negative bacteria. Because of its clinical efficacy, meropenem is an excellent choice for the treatment of serious infections in both adults and children. The knowledge of tissue concentrations of antibiotic in an infection site is valuable for the prediction of treatment outcome. The aim of the present study is to investigate the effect of borneol on the concentration of meropenem in rat brain and blood and to find the potential relationships of the combined use of medicine and traditional Chinese medicine. Analysis of meropenem in the dialysates was achieved using the microdialysis technique and HPLC. At 40 min after the administration of an intraperitoneal injection of meropenem, the concentration of meropenem in brain in borneol+meropenem group was 2.25 (0.35) µg ml(-1), which was significantly higher than that in meropenem group [1.20 (0.12) µg ml(-1); P < 0.01]. Within 80 min of drug administration, the AUCbrain/AUCblood (area under the curve, AUC) in the borneol+meropenem group was 1.2 times that of the meropenem group. Borneol can increase the concentration of meropenem in the cerebrospinal fluid, but has no influence on its blood concentration. This study represents a successful application of the microdialysis technique, which is an effective method for the study of pharmacokinetics of meropenem.

[Evaluation of the linearity of pharmacokinetics of the phenolic antioxidant 4-methyl-2,6-diisobornylphenol upon intragastric administration].

The linearity of pharmacokinetics of 4-methyl-2,6-diisobornylphenol after single intragastric administration in doses within 10 - 200 mg/kg has been studied in rats. It has been established that pharmacokinetics of 4-methyl-2,6-diisobornilphenol in the indicated dose range is not linear due to a limited absorption of the drug from the intestine.