Role of P-glycoprotein in the intestinal absorption of tanshinone IIA, a major active ingredient in the root of Salvia miltiorrhiza Bunge

The extracts from the roots of Salvia miltiorrhiza Bunge (Danshen) are widely and traditionally used in the treatment of angina pectoris, acute myocardial infarct, hyperlipidemia and stroke in China and other Asian countries. In this study, we have investigated the role of P-glycoprotein (P-gp) in the intestinal absorption of tanshinone IIA (TSA), a major active constituent of Danshen, using several in vitro and in vivo models. The oral bioavailability of TSA was about 2.9

Role of the ATP-binding cassette drug transporters in the intestinal absorption of tanshinone IIB, one of the major active diterpenoids from the root of Salvia miltiorrhiza

There is an increasing use of herbal medicines worldwide, and the extracts from the root of Salvia miltiorrhiza are widely used in the treatment of angina and stroke. In this study, we investigated the mechanism for the intestinal absorption of tanshinone IIB (TSB), a major constituent of S. miltiorrhiza. The oral bioavailability of TSB was about 3% in rats with less proportional increase in its maximum plasma concentration (C_max) and area under the plasma concentration-time curve (AUC) with increasing dosage. The time to C_max (T_max) was prolonged at higher oral dosage. In a single pass rat intestinal perfusion model, the permeability coefficients (P_app) based on TSB disappearance from the lumen (P_lumen) were 6.2- to 7.2-fold higher (p < 0.01) than those based on drug appearance in mesenteric venous blood (P_blood). The uptake and efflux of TSB in Caco-2 cells were also significantly altered in the presence of an inhibitor for P-glycoprotein (PgP) or for multi-drug resistance associated protein (MRP1/2). TSB transport from the apical (AP) to basolateral (BL) side in Caco-2 monolayers was 3.3- to 5.7-fold lower than that from BL to AP side, but this polarized transport was attenuated by co-incubation of PgP or MRP1/2 inhibitors. The P_app values of TSB in the BL-AP direction were significantly higher in MDCKII cells over-expressing MDR1 or MRP1, but not in cells over-expressing MRP2-5, as compared with the wild-type cells. The plasma AUC_0-24hr in mdr1a and mrp1 gene-deficient mice was 10.2- to 1.7-fold higher than that in the wild-type mice. Furthermore, TSB significantly inhibited the uptake of digoxin and vinblastine in membrane vesicles containing PgP or MRP1. TSB also moderately stimulated PgP ATPase activity. Taken collectively, our findings indicate that TSB is a substrate for PgP and MRP1 and that drug resistance to TSB therapy and drug interactions may occur through PgP and MRP1 modulation.

Transport of cryptotanshinone, a major active triterpenoid in Salvia miltiorrhiza Bunge widely used in the treatment of stroke and Alzheimers disease, across the blood-brain

Cryptotanshinone (CTS), a major constituent from the roots of Salvia miltiorrhiza (Danshen), is widely used in the treatment of coronary heart disease, stroke and less commonly Alzheimer's disease. Our recent study indicates that CTS is a substrate for Pglycoprotein (PgP/MDR1/ABCB1). This study has investigated the nature of the brain distribution of CTS across the brain-blood barrier (BBB) using several in vitro and in vivo rodent models. A polarized transport of CTS was found in rat primary microvascular endothelial cell (RBMVEC) monolayers, with facilitated efflux from the abluminal side to luminal side. Addition of a PgP (e.g. verapamil and quinidine) or multi-drug resistance protein 1/2 (MRP1/2) inhibitor (e.g. probenecid and MK-571) in both luminal and abluminal sides attenuated the polarized transport. In a bilateral in situ brain perfusion model, the uptake of CTS into the cerebrum increased from 0.52 ± 0.1% at 1 min to 11.13 ± 2.36 ml/100 g tissue at 30 min and was significantly greater than that of sucrose. Co-perfusion of a PgP/MDR1 (e.g. verapamil) or MRP1/2 inhibitor (e.g. probenecid) significantly increased the brain distribution of CTS by 35.1-163.6%. The brain levels of CTS were only about 21% of those in plasma, and were significantly increased when coadministered with verapamil or probenecid in rats. The brain levels of CTS in rats subjected to middle cerebral artery occlusion and rats treated with quinolinic acid (a neurotoxin) were about 2- to 2.5-fold higher than the control rats. Moreover, the brain levels in mdr1a(-/-) and mrp1(-/-) mice were 10.9- and 1.5-fold higher than those in the wild-type mice, respectively. Taken collectively, these findings indicate that PgP and Mrp1 limit the brain penetration of CTS in rodents, suggesting a possible role of PgP and MRP1 in limiting the brain penetration of CTS in patients and causing drug resistance to Danshen therapy and interactions with conventional drugs that are substrates of PgP and MRP1. Further studies are needed to explore the role of other drug transporters in restricting the brain penetration of CTS and the clinical relevance.

Effects of Salvia miltiorrhiza after acute myocardial infarction in rats

Acute myocardial infarction (M!) is the commonest cause of death in the developed countries, and it is on the rise in developing countries. Ramipril is a well-knownAngiotensin-converting enzyme (ACE) inhibitorwhich inhibits conversion ofinactive angiotensin I to active angiotensin II. Experimental studies have shown thatACE inhibitors administered chronicallybefore acuteMImight limitmyocardial infarct size, improve cardiac function and prevent cardiac hypertrophy [1, 2]. The Chinese herb, Salvia miltiorrhiza (SM), has been widely and successfully usedmainly for anginapectoris,MI and stroke [3]. Compared to ramipril, however, there is very limited biochemical information availableto demonstrate themechanismsofSMs
cardio-protective effects. This study thus investigates the possible
biochemical and molecularmechanisms ofsuch effects ofSMin Wistar rats in comparison with those oframipril.

Transplantation of artificial gelatin-co-bletillastriata gelatin/Salvia miltiorrhiza Corium promotes dermal repair in rats

Purpose: To evaluate the growth of the composite corium (constructed with fibroblast cells and gelatinco- Bletillastriata gelatin/Salvia miltiorrhiza materials) on rats. Methods: The composite artificial corium was constructed by culturing fibroblast cells in gelatin-co- Bletillastriata gelatin/Salvia miltiorrhiza materials. Full-thickness area of skin was excised from the mice and subsequently, the composite corium was transplanted on the wound. Thereafter, the growth difference of the composite artificial corium and natural corium were compared. In addition, real-time fluorogenic reverse transcription polymerase chain reaction (qRT-PCR) and western blot were performed to determine vascular endothelial growth factor (VEGF) expression at gene and protein levels. Results: The composite artificial corium showed significant repair promoting effect on the skin, and the structure of the repaired skin was similar to that of natural corium. Interestingly, PCR and western blot results showed that the expressions of VEGF were higher in composite artificial corium than in natural corium on days 3 and 7 post-transplantation. Conclusion: The composite artificial corium has some clinical prospects for use in the treatment of wounds on large areas of skin.

Tanshinone IIB, a primary active constituent from Salvia miltiorrhza, exhibits neuro-protective activity in experimentally stroked rats

Tanshinone IIB (TSB) is a major active constituent of the root of Salvia miltiorrhiza (Danshen) used in the treatment of acute stroke. Danshen extracts and TSB have shown marked neuron-protective effects in mouse studies but there is a lack of clinical evidence for the neuron-protective effects of Danshen and its active ingredients. This study investigated the neuron-protective effects of TSB in experimentally stroked rats. TSB at 5 and 25 mg/kg by intraperitoneal injection significantly reduced the focal infarct volume, cerebral histological damage and apoptosis in rats subjected to middle cerebral artery occlusion (MCAO) compared to MCAO rats receiving vehicle. This study demonstrated that TSB was effective in reducing stroke-induced brain damage and may represent a novel drug candidate for further development. Further mechanistic studies are needed for the neuron-protective activity of TSB.

Analysis of cardioprotective effects using purified Saliva miltiorrhiza extract on isolated rat hearts

The purpose of the current study is to evaluate the cardioprotective effects of purified Salvia miltiorrhiza extract (PSME) on myocardial ischemia/reperfusion injury in isolated rat hearts. Hearts were excised and perfused at constant flow (7 – 9 ml · min⁻¹) via the aorta. Non-recirculating perfusion with Krebs-Henseleit (KH) solution was maintained at 37°C and continuously gassed with 95% O₂ and 5% CO₂. KH solution with or without PSME (100 mg per liter solution) was used after 30-min zero-flow ischemia for the PSME and control group, respectively. Left ventricular (LV) developed pressure; its derivatives, diastolic pressure, and so on were continuously recorded via a pressure transducer attached to a polyvinylchloride balloon that was placed in the left ventricle through an incision in the left atrium. PSME treated hearts showed significant postischemic contractile function recovery (developed pressure recovered to 44.2 ± 4.9% versus 17.1 ± 5.7%, P<0.05; maximum contraction recovered to 57.2 ± 5.9% versus 15.1 ± 6.3%, P<0.001; maximum relaxation restored to 69.3 ± 7.3% versus 15.4 ± 6.3%, P<0.001 in the PSME and control group, respectively). Significant elevation in end-diastolic pressure, which indicated LV stiffening in PSME hearts might have resulted from the excess high dose of PSME used. Further study will be conducted on the potential therapeutic value with lower dose of PSME on prevention of ischemic heart disease.

Effects of purified herbal extract of Saliva miltiorrhiza on ischemic rat myocardium after acute myocardial infarction

In the current study, we compared purified Salvia miltiorrhiza extract (PSME) with Angiotensin-converting enzyme inhibitor, Ramipril, in in vitro experiments and also in vivo using animal model of myocardial infarction. PSME was found to have a significantly higher trolox equivalent antioxidant capacity which indicated a great capacity for scavenging free radicals. PSME could also prevent pyrogallo red bleaching and DNA damage.

After 2 weeks treatment with PSME or Ramipril, survival rates of rats with experimental myocardial infarction were marginally increased (68.2% and 71.4%) compared with saline (61.5%). The ratios of infarct size to left ventricular size in both PSME-and Ramipril-treated rats were significantly less than that in the saline-treated group. Activity of cardiac antioxidant enzyme superoxide dismutase (SOD) was significant higher while level of Thiobarbituric acid-reactive substances (TBARs) was lower in the PSME treated group. Purified and standardized Chinese herb could provide an alternative regimen for the prevention of ischemic heart disease.

A mechanistic study of the intestinal absorption of crypotanshinone, the major active constituent of Saliva miltiorrhiza

The nature of intestinal absorption of most herbal medicine is unknown. Cryptotanshinone (CTS) is the principal active constituent of the widely used cardiovascular herb Salvia miltiorrhiza (Danshen). We investigated the oral bioavailability of CTS in rats and the mechanism for its intestinal absorption using several in vitro and in vivo models:1) Caco-2 cell monolayers; 2) monolayers of MDCKII cells overexpressing P-glycoprotein
(PgP); and 3) single-pass rat intestinal perfusion with mesenteric vein cannulation. The systemic bioavailabilities of CTS after oral and intraperitoneal administration at 100 mg/kg were 2.05 and 10.60%, respectively. In the perfused rat intestinal model, permeability coefficients based on CTS disappearance from the luminal perfusate (P_lumen) were 6.7- to 10.3-fold higher than permeability coefficients based on drug appearance in venous blood (P_blood). P_blood significantly increased in the presence of the P-gP inhibitor, verapamil. CTS transport across Caco-2 monolayers was pH-, temperature- and ATP-dependent. The transport from the apical (AP) to the basolateral (BL) side was 3- to 9-fold lower than that from the BL to the AP side. Inclusion of verapamil (50 µM) in both AP and BL sides abolished the polarized CTS transport across Caco-2 cells. Moreover, CTS was significantly more permeable in the BL to AP than in the AP to BL direction in MDCKII and MDR1-MDCKII cells. The permeability coefficients in the BL to AP direction were significantly higher in MDCKII cells overexpressing PgP. These findings indicate that CTS is a substrate for PgP that can pump CTS into the luminal side.

Herb-drug interactions: a literature review

Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations.
Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients.
Piper methysticum (kava) increased the 'off' periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John's wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine).
In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.

Efecto de diferentes densidades de siembra sobre el crecimiento y rendimiento del cultivo de chía (Salvia hispánica L.) Sébaco, Matagalpa, 2015

Este trabajo se realizó con la finalidad de d eterminar la influencia de diferentes densidades de siembra (10, 20, 30 y 40 plantas/m) , sobre el crecimiento, desarrollo y rendimiento de l cultivo de chía ( Salvia hispánica L.) ; se efectuó análisis económico a través de cálculo de costos de producción para determinar la rentabilidad de los tratamientos . Se estableció en el periodo de septiembre 2014 a febrero 2015, en la finca Tamarindo de Oro, de la ciudad de Sébaco, Matagalpa, ubicado a 1 02 km al N orte de Managua. Se utilizó un diseño experimental uní - factorial en arreglos de b loques completos al azar, con 4 tratamientos y 6 repeticiones. Las variables evaluadas fueron, altura de planta, diámetro de tallo, número de ramas primarias y secundarias, número de espigas y r endimiento a la cosecha, presentando en todas ellas diferencia estadística significativa , a excepción de la variable de rendimiento . Para la variable altura de planta, en la densidad más alta (40 plantas/m) , se obtuvo la m ayor altura con un promedio de 1.24 metros. La densidad más baja (10 plantas/m), fue la que logró los mejores resultado en las variables diámetro ( 0.83 mm ) , ramas primarias ( 12 unidad ) , secundarias (15 unidad ) , espigas ( 27 unidad ) y rendimiento (826.46 kg/ha) . El análisis económico demuestra una relación beneficio costos mayor de 1 esto quiere decir que todos los tratamiento s presenta ron una rentabilidad viable, donde el tratamiento a 1 de 10 plantas/m, es mayor en relación a los demás

Przewalskin A: A new C-23 terpenoid with a 6/6/7 carbon ring skeleton from Salvia przewalskii maxim

Przewalskin A (1), a novel C-23 terpenoid with a 6/6/7 carbon ring skeleton, was isolated from Salvia przewalskii. Its structure was determined by comprehensive 1D NMR, 2D NMR, and MS spectroscopic analysis and subsequently confirmed by a single-crystal X

Przewalskin B, a novel diterpenoid with an unprecedented skeleton from Salvia przewalskii maxim

[GRAPHIC] Przewalskin B (1), a novel diterpenoid possessing a unique skeleton, was isolated from a Chinese medicinal plant Salvia przewalskii. Its structure and relative stereochemistry were elucidated by extensive NMR analysis and a single-crystal X-ray

Flower color chimera and abnormal leaf mutants induced by C-12(6+) heavy ions in Salvia splendens Ker-Gawl.

The effect of C-12(6+) heavy ions bombardment on mutagenesis in Salvia splendens Ker-Gawl. was studied. Dose-response studies indicated that there was a peak of malformation frequency of S. splendens at 200 Gy. Abnormal leaf mutants of the bileaf, trileaf and tetraleaf conglutination were selected. Meanwhile, a bicolor flower chimera with dark red and fresh red flower was isolated in M1 generation of S. splendens. Random amplified polymorphic DNA (RAPD) analysis demonstrated that DNA variations existed among the wild-type, fresh and dark red flower shoots of the chimera. The dark red flower shoots of the chimera were conserved and cultivated at a large-scale through micropropagation. MS supplemented with 2.0 mg/L BA and 0.3 mg/L NAA was the optimal medium in which the maximum proliferation ratio (5.2-fold) and rooting rate (88%) were achieved after 6 weeks. Our findings provide an important method to improve the ornamental quality of S. splendens.

Recent national trends in Salvia divinorum use and substance-use disorders among recent and former Salvia divinorum users compared with nonusers.

CONTEXT: Media and scientific reports have indicated an increase in recreational use of Salvia divinorum. Epidemiological data are lacking on the trends, prevalence, and correlates of S. divinorum use in large representative samples, as well as the extent of substance use and mental health problems among S. divinorum users. OBJECTIVE: To examine the national trend in prevalence of S. divinorum use and to identify sociodemographic, behavioral, mental health, and substance-use profiles of recent (past-year) and former users of S. divinorum. DESIGN: Analyses of public-use data files from the 2006-2008 United States National Surveys on Drug Use and Health (N = 166,453). SETTING: Noninstitutionalized individuals aged 12 years or older were interviewed in their places of residence. MAIN MEASURES: Substance use, S. divinorum, self-reported substance use disorders, criminality, depression, and mental health treatment were assessed by standardized survey questions administered by the audio computer-assisted self-interviewing method. RESULTS: Among survey respondents, lifetime prevalence of S. divinorum use had increased from 0.7% in 2006 to 1.3% in 2008 (an 83% increase). S. divinorum use was associated with ages 18-25 years, male gender, white or multiple race, residence of large metropolitan areas, arrests for criminal activities, and depression. S. divinorum use was particularly common among recent drug users, including users of lysergic acid diethylamide (53.7%), ecstasy (30.1%), heroin (24.2%), phencyclidine (22.4%), and cocaine (17.5%). Adjusted multinomial logistic analyses indicated polydrug use as the strongest determinant for recent and former S. divinorum use. An estimated 43.0% of past-year S. divinorum users and 28.9% of former S. divinorum users had an illicit or nonmedical drug-use disorder compared with 2.5% of nonusers. Adjusted logistic regression analyses showed that recent and former S. divinorum users had greater odds of having past-year depression and a substance-use disorder (alcohol or drugs) than past-year alcohol or drug users who did not use S. divinorum. CONCLUSION: S. divinorum use is prevalent among recent or active drug users who have used other hallucinogens or stimulants. The high prevalence of substance use disorders among recent S. divinorum users emphasizes the need to study health risks of drug interactions.