Effects of Grapefruit and Pomegranate Juices on the Pharmacokinetic Properties of Dapoxetine and Midazolam in Healthy Subjects.

BACKGROUND: The package leaflet for dapoxetine, an effective treatment for premature ejaculation, includes a strict warning against coadministration with drugs or herbal remedies that strongly induce or inhibit the activity of Cytochrome P450 (CYP) 3A4 enzyme. OBJECTIVE: To assess the effects of multiple daily consumption of grapefruit juice (GFJ) and pomegranate juice (PJ) on the pharmacokinetics of dapoxetine, we conducted an open-label, three-way crossover study in 12 healthy subjects using midazolam as a probe substrate for CYP3A4. METHODS: Participants received a single oral dose of dapoxetine (60 mg) and midazolam (7.5 mg) after pretreatment with 250 ml of either water, undiluted GFJ, or PJ for three consecutive days. All subjects were monitored for adverse effects during the study period. RESULTS: Compared to pretreatment with water, GFJ increased the area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) and peak plasma concentration (C max) of dapoxetine by 60 and 80 %, respectively, and prolonged its elimination half-life (t 1/2) by 43 %. Similar effects of GFJ on the pharmacokinetics of midazolam were observed with a significant increase in AUC0-∞ (75 %), C max (40 %), and t 1/2 (92 %). Slight but not statistically significant changes were observed in the pharmacokinetics of dapoxetine and midazolam after pretreatment with PJ. Time to reach C max (T max) did not differ among the three phases. CONCLUSION: These results suggest that GFJ increases the extent of absorption and reduces clearance of dapoxetine possibly by inhibition of both intestinal and hepatic CYP3A4, whereas PJ has little effect on dapoxetine pharmacokinetics. Although the impact of GFJ on the pharmacokinetics of dapoxetine was mild, a great caution should be considered when they are concomitantly administered.

Pomegranate juice does not affect the disposition of simvastatin in healthy subjects.

Previous in vitro and in vivo investigations reported controversial results for the inhibitory potential of pomegranate on Cytochrome P450 (CYP) 3A activity. This study evaluated the effect of pomegranate juice on the disposition of simvastatin, a CYP3A4 substrate, and simvastatin acid, its active metabolite, compared with grapefruit juice in healthy subjects. A single oral pharmacokinetic study of 40 mg simvastatin was conducted as a three-way crossover (control, pomegranate, and grapefruit juices) in 12 healthy male subjects. The subjects took pomegranate or grapefruit juice three times per day for 3 days (900 mL/day) and on the third day, the pharmacokinetic study was executed. Blood samples were collected to 24 h post-dose and the pharmacokinetic parameters of simvastatin and simvastatin acid were compared among the study periods. In the period of grapefruit juice, the mean C max and AUCinf of simvastatin [the geometric mean ratio (90 % CI) 15.6 (11.6-21.0) and 9.1 (6.0-13.7)] were increased significantly when compared with the control period, whereas they were not significantly different in the period of pomegranate juice [C max and AUCinf 1.20 (0.89-1.62) and 1.29 (0.85-1.94)]. The mean C max and AUCinf of simvastatin acid were increased significantly after intake of grapefruit juice, but not pomegranate juice. These results suggest that pomegranate juice affects little on the disposition of simvastatin in humans. Pomegranate juice does not seem to have a clinically relevant inhibitory potential on CYP3A4 activity.

Potentially significant versus clinically significant drug interactions: pomegranate juice as a case in point.

In vitro and in vivo laboratory data show that pomegranate juice consistently inhibits intestinal CYP2C9 and CYP3A4 enzymes. Pomegranate juice may therefore increase the bioavailability of drugs that are metabolized by these enzymes. However, studies in humans find that pomegranate juice does not increase exposure to either CYP2C9 or CYP3A4 substrates. These contradictory findings suggest that potential drug interactions identified in the laboratory may not necessarily translate into clinically significant drug interactions in humans, and hence that laboratory data are insufficient grounds upon which clinical decisions may be based.

Pomegranate juice exacerbates oxidative stress and nigrostriatal degeneration in Parkinson's disease.

Numerous factors contribute to the death of substantia nigra (SN) dopamine (DA) neurons in Parkinson's disease (PD). Compelling evidence implicates mitochondrial deficiency, oxidative stress, and inflammation as important pathogenic factors in PD. Chronic exposure of rats to rotenone causes a PD-like syndrome, in part by causing oxidative damage and inflammation in substantia nigra. Pomegranate juice (PJ) has the greatest composite antioxidant potency index among beverages, and it has been demonstrated to have protective effects in a transgenic model of Alzheimer's disease. The present study was designed to examine the potential neuroprotective effects of PJ in the rotenone model of PD. Oral administration of PJ did not mitigate or prevent experimental PD but instead increased nigrostriatal terminal depletion, DA neuron loss, the inflammatory response, and caspase activation, thereby heightening neurodegeneration. The mechanisms underlying this effect are uncertain, but the finding that PJ per se enhanced nitrotyrosine, inducible nitric oxide synthase, and activated caspase-3 expression in nigral DA neurons is consistent with its potential pro-oxidant activity.

Possible interaction between pomegranate juice and warfarin.

Pomegranate juice is growing in popularity in the UK. We report a potential interaction between pomegranate juice and warfarin. Laboratory studies have shown that pomegranate juice inhibits cytochrome P450 enzymes involved in warfarin metabolism. As with previous reports of interactions between food and warfarin, this case does not definitively prove the association between pomegranate juice consumption and increased warfarin bioactivity but highlights the importance of taking a complete drug, food and juice history when assessing patients with unstable anticoagulation.

Potential interaction between pomegranate juice and warfarin.

To my knowledge, no published reports have described an interaction between pomegranate juice and warfarin. Investigators from previous animal and in vitro studies have reported a potential for pomegranate juice to inhibit metabolism involving the cytochrome P450 system, an effect that could translate into a clinical drug-diet interaction with warfarin. This case report describes a 64-year-old Caucasian woman who was treated with warfarin for recurrent deep vein thrombosis. She had been receiving a relatively stable dosage of warfarin 4 mg/day for several months, with stable international normalized ratios (INRs). During that time, the patient was consuming pomegranate juice 2-3 times/week. She stopped drinking the juice, and her INRs became subtherapeutic. Her dosage of warfarin was increased to maintain therapeutic anticoagulation. No rechallenge with pomegranate juice was performed. Use of the Drug Interaction Probability Scale indicated a possible relationship between the patient's subtherapeutic INR and the pomegranate juice. Although this potential interaction needs to be explored further, clinicians should be aware of the interaction and thoroughly interview and closely monitor their patients who are receiving warfarin.

Determinação da atividade antibacteriana de româ (Punica granatum L) / Determination of antibacterial activity of punicaceae (Punica granatum L)

Muitas plantas têm sido utilizadas devido às suas características antimicrobianas, as quais se devem aos compostos sintetizados no metabolismo secundário. Estes produtos são conhecidos por suas substâncias ativas, por exemplo, os fenólicos que constituem os óleos essenciais, assim como os taninos. A romã (Punica granatum L.) da família Punicaceae é, provavelmente, originária da Ásia e espalhada em toda a região do Mediterrâneo e cultivada em quase todo o mundo, inclusive no Brasil. A literatura etnofarmacológica se refere ao uso do pericarpo, que é a parte externa do fruto, para tratamento de inflamações na boca e na garganta.(...)O objetivo deste trabalho foi determinar a atividade antibacteriana de romã (Punica granatum L.) empregando-se o método de difusão em gel de agar...

[Fruit and berries--interactions with drugs]. / Frukt og baer--interaksjoner med legemidler.

Diet is one of many factors that could alter the pharmacokinetics of drugs. Several fruits and berries have recently been shown to contain agents that affect drug-metabolizing enzymes. Grapefruit is the most well-known example, but also Sevillian orange, pomelo and star fruit contain agents that inhibit cytochrome P450 3A4 (CYP3A4), which is the most important enzyme in drug metabolism. The present article reviews published information on potential interactions between drugs and fruits/berries, with main focus on inhibition and induction of metabolizing enzymes.

Safety and antioxidant activity of a pomegranate ellagitannin-enriched polyphenol dietary supplement in overweight individuals with increased waist size.

The consumption of pomegranate juice (PJ), a rich source of antioxidant polyphenols, has grown tremendously due to its reported health benefits. Pomegranate extracts, which incorporate the major antioxidants found in pomegranates, namely, ellagitannins, have been developed as botanical dietary supplements to provide an alternative convenient form for consuming the bioactive polyphenols found in PJ. Despite the commercial availability of pomegranate extract dietary supplements, there have been no studies evaluating their safety in human subjects. A pomegranate ellagitannin-enriched polyphenol extract (POMx) was prepared for dietary supplement use and evaluated in two pilot clinical studies. Study 1 was designed for safety assessment in 64 overweight individuals with increased waist size. The subjects consumed either one or two POMx capsules per day providing 710 mg (435 mg of gallic acid equivalents, GAEs) or 1420 mg (870 mg of GAEs) of extracts, respectively, and placebo (0 mg of GAEs). Safety laboratory determinations, including complete blood count (CBC), chemistry, and urinalysis, were made at each of three visits. Study 2 was designed for antioxidant activity assessment in 22 overweight subjects by administration of two POMx capsules per day providing 1000 mg (610 mg of GAEs) of extract versus baseline measurements. Measurement of antioxidant activity as evidenced by thiobarbituric acid reactive substances (TBARS) in plasma were measured before and after POMx supplementation. There was evidence of antioxidant activity through a significant reduction in TBARS linked with cardiovascular disease risk. There were no serious adverse events in any subject studied at either site. These studies demonstrate the safety of a pomegranate ellagitannin-enriched polyphenol dietary supplement in humans and provide evidence of antioxidant activity in humans.

Rhabdomyolysis associated with pomegranate juice consumption.

This 48-year-old man with possible underlying myopathy was successfully treated with ezetimibe 10 mg/day and rosuvastatin 5 mg every other day for 17 months. Three weeks before presentation, he began drinking pomegranate juice (200 ml twice weekly). He presented urgently with thigh pain and an elevated serum creatine kinase level (138,030 U/L, normal < 200 U/L). In conclusion, because both grapefruit and pomegranate juice are known to inhibit intestinal cytochrome P450 3A4, this report suggests that pomegranate juice may increase the risk of rhabdomyolysis during rosuvastatin treatment, despite the fact that rosuvastatin is not known to be metabolized by hepatic P450 3A4.

Anaphylaxis to excipient mannitol: evidence for an immunoglobulin E-mediated mechanism.

BACKGROUND: Anaphylaxis to mannitol present naturally in pomegranate and cultivated mushroom in a sensitized subject has been described recently, and an IgE-mediated mechanism to this sugar alcohol has been proposed. The same subject also experienced severe allergic reactions to a chewable pharmaceutical (cisapride drug). OBJECTIVE: The purpose of the study was to identify allergenic component in the pharmaceutical preparation, and also, to understand the mechanism of immediate hypersensitivity to mannitol. METHODS: Methodology involved skin prick tests (SPTs), high-performance liquid chromatographic (HPLC) analysis of pharmaceutical preparations, separation of mannitol by Ca++-ion-moderated cation-exchange chromatography, preparation of alditol-protein conjugates by reductive amination, SPT using the conjugates, hapten affinity purification of the allergic serum on D-mannitol-keyhole limpet haemocyanin (KLH)-Sepharose CL-6B, and detection of serum mannitol-specific IgE by ELISA. RESULTS: Component testing by SPT, and HPLC analysis of various pharmaceuticals indicated that the excipient mannitol is the causative allergen. Mannitol separated from Cisapid MPS showed allergenic activity by SPT. Among the several conjugates tested by SPT, D-mannitol-bovine serum albumin and D-mannitol-KLH showed positive weal/flare reaction, demonstrating the presence of cell-bound mannitol-specific IgE in vivo. Negative results with D-glucitol, D-galactitol, meso-erythritol, and L-mannitol protein conjugates clearly showed that the mannitol-specific human IgE is very specific to the D-isomer of mannitol. ELISA using the hapten affinity-purified allergic serum was positive, demonstrating the presence of mannitol-specific serum IgE in the allergic subject. CONCLUSION: Mannitol, which is widely used as a food and drug additive (excipient), can rarely cause IgE-mediated anaphylaxis. This study is the first one to demonstrate the presence of mannitol-specific human IgE in a sensitized allergic subject to validate an IgE-mediated hypersensitivity mechanism for mannitol.