Bacopa monniera is a traditional Ayurvedic herbal medicine used to treat various mental ailments from ancient times. Recently, chemically standardized alcoholic extract of Bacopa monniera (BM) has been developed and currently available as over the counter herbal remedy for memory enhancement in children and adults. However, the consumption of herbal drugs has been reported to alter the expression of drug metabolizing enzymes and membrane transporters. Present study in male Sprague-Dawley rat was performed to evaluate the effect of memory enhancing standardized extract of BM on hepatic and intestinal cytochrome P450 3A and P-glycoprotein expression and activity. The BM (31 mg/kg/day) was orally administered for one week in BM pre-treated group while the control group received the same amount of vehicle for the same time period. The BM treatment decreased the cytochrome P450 3A (CYP3A) mediated testosterone 6β-hydroxylation activity of the liver and intestine by 2 and 1.5 fold, respectively compared to vehicle treated control. Similarly pretreatment with BM extract decreased the expression of intestinal P-glycoprotein (Pgp) as confirmed by Western blot analysis but did not alter the expression of hepatic Pgp. To investigate whether this BM pretreatment mediated decrease in activity of CYP3A and Pgp would account for the alteration of respective substrate or not, pharmacokinetic study with carbamazepine and digoxin was performed in BM pre-treated rats and vehicle treated rats. Carbamazepine and digoxin were used as CYP3A and Pgp probe drugs, respectively. Significant increase in AUC and Cmax of carbamazepine (4 and 1.8 fold) and digoxin (1.3 and 1.2 fold), respectively following the BM pre-treatment confirmed the down regulation of CYP3A and Pgp.
1. For centuries Bacopa monniera (BM) has been used as an herbal drug for the treatment of various mental ailments. A chemically standardized alcoholic extract of BM is clinically available over the counter herbal remedy for memory enhancement in children and adults. Consumption of herbal preparations has been reported to alter the function of membrane transporters, especially P-glycoprotein (P-gp), ATP-dependent drug efflux transporter responsible for the development of herb-drug interactions. 2. In the present study, we evaluated the in vitro effect of BM extract and its five individual active constituents (namely, bacopaside I, bacopaside II and bacopasaponin C, bacoside A and bacoside A3) on P-gp function using luminescent P-gp ATPase assay and Rh123 transport assay across human MDR1 gene transfected LLC-GA5-COL150 cell line. 3. It was observed that BM extract and its five individual constituents inhibited both basal activity as well as verapamil-stimulated ATPase activity, suggesting their affinity towards P-gp. Further, BM and its five active constituents inhibited the rhodamine 123 (Rh123) transport across LLC-GA5-COL150 cell monolayer with bacopaside II being the most potent inhibitor of P-gp, which decreased P-gp efflux ratio of Rh123 by fourfold in comparison to control. 4. Our finding may prove beneficial in predicting the potential herb-drug interactions of BM on concomitant medication with P-gp substrate drugs in clinical settings.
There is an important heterogeneity in generic penetration among EU countries. A North-South gradient in generics market share is often quoted with no reference to policy. Our aim was to compare policies, conditions of penetration and impact of the generics entries in selected countries to represent large and small, Northern and Southern, Eastern and Western EU countries. METHODS: We identified policies and generics market share in volume and value in France, UK, Germany, Poland, Greece, Hungary and Portugal. We browsed websites of EU and national (when applicable) drug agencies, ministry of health, HTA bodies, payers, manufacturer unions etc. We completed our research with literature search and grey reports, as well as Datamonitor reports, IMS data and proprietary pharmavitae database. RESULTS: There is a wide variability between countries concerning generics entry policy. Generics are available from date of their market approval up to 180 days after. Generics prices range from par price to 60% lower than branded product. In some countries, the generics entries impact the price of the whole class by regulatory rules, while it may be company free decision in others. In Hungary, brands are excluded from the market at generic entry. Besides, discount on brands vary from 0 to 50%. Generic substitution is driven by either local mandatory requirements or financial pharmacist incentives. As a consequence, the generic market share varies between 25 to 80% in volume and 20 to 70% in value. The lowest savings are found in Southern EU while UK and Germany have the largest savings. Even though Hungary eliminates brands after generic entry, the mix keeps favouring remaining brands in the same class. CONCLUSIONS: Generics policy varies dramatically from one country to another. This explains the major differences observed across countries on the drug budget associated with generic entry.
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