Each capsule contains: Proprietary Blend 450 mg: Black Walnut hull, Quassia wood, Wormwood , Gentian root, Clove , fennel seed, Yarrow , Barberry 4:1 extract, Grapefruit seed 4:1 extract, Slippery Elm , Calendula . Other Ingredients: Gelatin Capsule.
Brand name products often contain multiple ingredients. To read detailed information about each ingredient, click on the link for the individual ingredient shown above.
Below is general information about the effectiveness of the known ingredients contained in the product Para Clean. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
Below is general information about the safety of the known ingredients contained in the product Para Clean. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
LIKELY SAFE ...when the fruit (nut) is consumed in amounts normally found in food.
POSSIBLY UNSAFE ...when the bark is used orally or topically, due to its juglone content (2). When applied topically, juglone-containing bark can cause skin irritation. When used orally on a daily basis, the juglone-containing bark of a related species (English walnut) is associated with increased risk of tongue cancer and lip leukoplakia (2,12). There is insufficient reliable information available about the safety of the leaf or hull when used orally as a medicine or when applied topically.
PREGNANCY AND LACTATION: LIKELY SAFE
when the fruit (nut) is consumed in amounts normally found in foods.
PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when the bark is used orally or topically (12); avoid using.
There is insufficient reliable information available about the safety of black walnut leaf or hull when used orally in medicinal amounts during pregnancy or lactation; avoid using.
LIKELY SAFE ...when the flower preparations are used orally or topically and appropriately (4,19779,36931,39503,93552,93557,96647,105088).
PREGNANCY: LIKELY UNSAFE
when used orally; contraindicated due to spermatocide, antiblastocyst, and abortifacient effects.
There is insufficient reliable information available about the safety of calendula when used topically during pregnancy (4).
LACTATION:
Insufficient reliable information available; avoid using.
LIKELY SAFE ...when used orally in amounts commonly found in foods. Clove, clove oil, and eugenol have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912).
POSSIBLY SAFE ...when clove oil is applied topically (272). A clove oil 1% cream has been applied to the anus with apparent safety for up to 6 weeks (43487). A liposome-based product containing clove oil 45% has been applied to the palms with apparent safety for up to 2 weeks (100596).
LIKELY UNSAFE ...when clove smoke is inhaled. Smoking clove cigarettes can cause respiratory injury (17,43599). ...when clove oil is injected intravenously. This can cause pulmonary edema, hypoxemia, and acute dyspnea (16384). There is insufficient reliable information available about the safety of using clove orally in medicinal amounts.
CHILDREN: LIKELY UNSAFE
when clove oil is taken orally.
Ingesting 5-10 mL of undiluted clove oil has been linked to reports of coagulopathy, liver damage, and other serious side effects in infants and children up to 3 years of age (6,17,43385,43395,43419,43457,43652).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts found in foods (4912).
Clove, clove oil, and eugenol have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912). There is insufficient reliable information available about the safety of using clove in medicinal amounts during pregnancy and lactation; avoid using.
LIKELY SAFE ...when the fruit is consumed orally in food amounts (13527). There is insufficient reliable information available about the safety of European barberry when used orally in medicinal amounts or when used topically.
CHILDREN: LIKELY UNSAFE
when used orally in newborns.
The berberine constituent of European barberry can cause kernicterus in newborns, particularly preterm neonates with hyperbilirubinemia (2589). There is insufficient reliable information available about the safety of European barberry when used orally in older children.
PREGNANCY: LIKELY UNSAFE
when used orally.
Berberine is thought to cross the placenta and may cause harm to the fetus. Kernicterus has developed in newborn infants exposed to berberine (2589).
LACTATION: LIKELY UNSAFE
when used orally.
Berberine and other harmful constituents can be transferred to the infant through breast milk (2589).
LIKELY SAFE ...when used orally in amounts commonly found in foods. Fennel has Generally Recognized as Safe (GRAS) status in the US (4912).
POSSIBLY SAFE ...when fennel essential oil or extract is used orally and appropriately, short-term. Twenty-five drops (about 1.25 mL) of fennel fruit extract standardized to fennel 2% essential oil has been safely used four times daily for 5 days (49422). Also, two 100 mg capsules each containing fennel 30% essential oil standardized to 71-90 mg of anethole has been safely used daily for 8 weeks (97498). Powdered fennel extract has been used with apparent safety at a dose of 800 mg daily for 2 weeks (104199). ...when creams containing fennel 2% to 5% are applied topically (49429,92509).
CHILDREN: POSSIBLY SAFE
when combination products containing fennel are used to treat colic in infants for up to one week.
Studied products include up to 20 mL of a fennel seed oil emulsion; a specific product (ColiMil) containing fennel 164 mg, lemon balm 97 mg, and German chamomile 178 mg; and up to 450 mL of a specific tea (Calma-Bebi, Bonomelli) containing fennel, chamomile, vervain, licorice, and lemon balm (16735,19715,49428).
PREGNANCY: POSSIBLY UNSAFE
when used orally.
Observational research has found that regular use of fennel during pregnancy is associated with shortened gestation (100513).
LACTATION: POSSIBLY UNSAFE
when used orally.
Case reports have linked consumption of an herbal tea containing extracts of fennel, licorice, anise, and goat's rue to neurotoxicity in two breast-feeding infants. The adverse effect was attributed to anethole, a constituent of fennel and anise (16744). However, levels of anethole were not measured in breastmilk, and the herbal tea was not tested for contaminants. Furthermore, other adverse effects related to use of fennel during lactation have not been reported. However, until more is known, avoid using.
LIKELY SAFE ...when the root preparations are used in amounts commonly found in foods. Gentian root is categorized by the FDA as a safe food additive flavoring in the US (4912).
POSSIBLY SAFE ...when gentian root is used orally in a specific combination that contains gentian root, elderflower, verbena, cowslip flower, and sorrel (SinuComp, Sinupret) (374,379,95907). There is insufficient reliable information available about the safety of the topical use of gentian.
PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of gentian in medicinal amounts during pregnancy and lactation; avoid using.
LIKELY SAFE ...when used orally in amounts commonly found in foods. Grapefruit has Generally Recognized as Safe status (GRAS) in the US (4912).
POSSIBLY SAFE ...when used orally and appropriately for medicinal purposes. A grapefruit seed extract has been safely used in clinical research (5866). In addition, capsules containing grapefruit pectin 15 grams daily have been used in clinical research for up to 16 weeks (2216).
POSSIBLY UNSAFE ...when used orally in excessive amounts. Preliminary population research shows that consuming a quarter or more of a whole grapefruit daily is associated with a 25% to 30% increased risk of postmenopausal breast cancer (14858). Grapefruit juice is thought to reduce estrogen metabolism resulting in increased endogenous estrogen levels. More evidence is needed to validate this finding.
PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of using medicinal amounts of grapefruit during pregnancy and lactation; avoid using.
LIKELY SAFE ...when used orally in amounts commonly found in foods. Quassia has Generally Recognized as Safe (GRAS) status in the US (4912).
POSSIBLY SAFE ...when used topically and appropriately. A 4% quassia gel has been safely used twice daily for up to 45 days (99995).
POSSIBLY UNSAFE ...when used orally in medicinal amounts. Quassia wood contains cardioactive glycosides (4), but toxicity is likely limited by emetic effects of large doses (4). There is insufficient reliable information available about the safety of rectal use of quassia.
PREGNANCY AND LACTATION: LIKELY UNSAFE
when used orally; avoid using.
Quassia has cytotoxic and emetic properties (4,18,19). There is insufficient reliable information available about the safety of rectal or topical use during pregnancy or lactation; avoid using.
POSSIBLY SAFE ...when used orally and appropriately (4,12,272,512,1740).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
Slippery elm bark has historically been inserted into the cervix to induce abortion. As a result, slippery elm has been reported in some sources to have abortifacient activity. However, there is no reliable information available about whether slippery elm has abortifacient activity when taken orally.
LIKELY SAFE ...when used orally in the amounts commonly found in foods. Wormwood extracts are included in bitters, vermouth, absinthe, and other food or drink products (12814,15007). Wormwood products that are thujone-free have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912); however, products containing thujone might not be safe. Wormwood is described in the pharmacopoeia of various European countries. After being banned for a period of time, it is now allowed in European Union countries; however, beverages must not contain thujone in concentrations greater than 35 mg/kg (12814,15007,86551).
POSSIBLY SAFE ...when wormwood products not containing thujone are used orally in medicinal amounts, short-term (93468,93469). A specific product
POSSIBLY UNSAFE ...when wormwood products containing thujone are used orally. Thujone is a neurotoxin that is present in wormwood oil (12617). Seizures, rhabdomyolysis, and acute kidney failure can occur when as little as 10 mL of wormwood oil is ingested (662,12817).
PREGNANCY:
LIKELY UNSAFE .
.when used orally in amounts greater than those found in foods (662,12817). Some wormwood products contain thujone, a neurotoxin. Theoretically, thujone also has potential uterine and menstrual stimulant effects (12617). There is insufficient reliable information available about the safety of wormwood when used topically during pregnancy.
LACTATION:
Insufficient reliable information available; avoid using.
LIKELY SAFE ...when used orally in amounts commonly found in foods. Yarrow products that are thujone-free have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912); however, products containing thujone might not be safe. Thujone is a chemical that stimulates the central nervous system and is poisonous in large doses.
POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts (2,12,100346). Yarrow whole plant extract has been used with apparent safety at a dose of 250-500 mg daily for 12 months (100346). ...when used intravaginally as a cream containing yarrow extract 2% daily for 7 days (105360). There is insufficient reliable information available about the safety of yarrow when applied topically.
PREGNANCY: LIKELY UNSAFE
when used orally; yarrow is believed to be an abortifacient and affect the menstrual cycle (12).
LACTATION:
Insufficient reliable information available; avoid use.
Below is general information about the interactions of the known ingredients contained in the product Para Clean. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
Theoretically, calendula might have additive effects when used with CNS depressants, although this appears to be unlikely.
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Theoretically, clove oil may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
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Theoretically, concomitant use of clove extracts with antidiabetes drugs might increase the risk of hypoglycemia.
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Clinical and laboratory research suggest that polyphenol extracts from clove flower buds might lower blood glucose levels (100595). Dosing adjustments for insulin or oral hypoglycemic agents may be necessary when taken with clove. Monitor blood glucose levels closely.
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Theoretically, topical application of clove oil with ibuprofen might increase the absorption and side effects of topical ibuprofen.
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Laboratory research shows that topical application of clove oil increases the absorption of topical ibuprofen (98854). This interaction has not been reported in humans.
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Theoretically, taking European barberry with anticholinergic drugs might cause additive effects.
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In vitro evidence suggests that European barberry might have anticholinergic properties (13527).
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Theoretically, European barberry may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
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Theoretically, taking European barberry with antidiabetes drugs might increase the risk of hypoglycemia.
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Preliminary clinical evidence suggests that European barberry juice reduces fasting glucose levels in patients with type 2 diabetes who are also taking antidiabetes drugs (98575). Additionally, some animal studies show that berberine, a constituent of European barberry, has antiglycemic potential (33622,33667). Monitor blood glucose levels closely.
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Theoretically, taking European barberry with antihypertensive drugs might increase the risk of hypotension.
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Theoretically, taking European barberry with cholinergic drugs might decrease the effects of cholinergic drugs.
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In vitro evidence suggests that European barberry might have anticholinergic properties (13527).
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Theoretically, concomitant use with drugs that have sedative properties may cause additive effects.
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Theoretically, concomitant use with cyclosporine may cause additive effects.
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Berberine, a constituent of European barberry, can reduce the metabolism and increase serum levels of cyclosporine. This effect is attributed to the ability of berberine to inhibit cytochrome P450 3A4 (CYP3A4), which metabolizes cyclosporine (13524). Theoretically, European barberry might have a similar effect.
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Theoretically, European barberry might increase the levels and clinical effects of CYP3A4 substrates.
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There is very preliminary evidence suggesting that berberine, a constituent of European barberry, might inhibit the CYP3A4 enzyme (13524). Theoretically, European barberry might have a similar effect.
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Theoretically, fennel might increase the risk of bleeding when used with antiplatelet or anticoagulant drugs.
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Theoretically, fennel might decrease the levels and clinical effects of ciprofloxacin.
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Animal research shows that fennel reduces ciprofloxacin bioavailability by nearly 50%, possibly due to the metal cations such as calcium, iron, and magnesium contained in fennel. This study also found that fennel increased tissue distribution and slowed elimination of ciprofloxacin (6135). |
Theoretically, taking large amounts of fennel might decrease the effects of contraceptive drugs due to competition for estrogen receptors.
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Theoretically, fennel might increase levels of drugs metabolized by CYP3A4.
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Theoretically, taking large amounts of fennel might interfere with hormone replacement therapy due to competition for estrogen receptors.
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Theoretically, taking large amounts of fennel might decrease the antiestrogenic effect of tamoxifen.
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Some constituents of fennel have estrogenic activity (11), which may interfere with the antiestrogenic activity of tamoxifen. |
Theoretically, concurrent use might increase risk of hypotension with drugs that lower blood pressure (13439,13441). These include captopril (Capoten), enalapril (Vasotec), losartan (Cozaar), valsartan (Diovan), diltiazem (Cardizem), Amlodipine (Norvasc), hydrochlorothiazide (HydroDiuril), furosemide (Lasix), and many others.
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Grapefruit juice can decrease blood levels of acebutolol, potentially decreasing the clinical effects of acebutolol.
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Clinical research shows that grapefruit juice can modestly decrease acebutolol levels by 7% and reduce peak plasma concentration by 19% by inhibiting organic anion transporting polypeptide (OATP) (17603,18101). The acebutolol half-life is also extended by 1.1 hours when grapefruit juice is consumed concomitantly (18101). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).
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Grapefruit juice can decrease blood levels of aliskiren, potentially decreasing the clinical effects of aliskiren.
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Clinical research shows that grapefruit juice can decrease aliskiren levels by approximately 60% by inhibiting organic anion transporting polypeptide (OATP) (91428). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).
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Grapefruit juice can increase blood levels of amiodarone, potentially increasing the effects and adverse effects of amiodarone.
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Grapefruit juice might decrease blood levels of amprenavir, although this is not likely to be clinically significant.
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Some clinical research shows that grapefruit juice can slightly decrease amprenavir levels (17673); however, this is probably not clinically significant.
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Grapefruit juice can increase blood levels of oral artemether, potentially increasing the effects and adverse effects of artemether.
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Grapefruit juice might increase blood levels of some oral benzodiazepines, potentially increasing the effects and adverse effects of these drugs.
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Clinical research shows that grapefruit juice can increase plasma triazolam concentrations. Repeated consumption of grapefruit juice greatly increases triazolam concentrations and prolongs the half-life, probably due to inhibition of cytochrome P450 3A4 (CYP3A4) (7776,22118,22131,22133). Some studies show that grapefruit juice, particularly when taken in large quantities, reduces the clearance and increases the maximum blood levels, area under the plasma concentration curve (AUC), and duration of effect of midazolam. However, there is no effect on intravenous midazolam (4300,10159,11275,17601,22117,22119,16711,91427,95978). Grapefruit juice has also been shown to increase the maximum blood levels and duration of effect of diazepam, but the clinical significance of this is not known (3228). This interaction does not appear to occur with alprazolam (17674).
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Grapefruit juice can increase blood levels of blonanserin, potentially increasing the effects and adverse effects of blonanserin.
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Blonanserin is metabolized primarily by cytochrome P450 3A4 (CYP3A4). A small clinical study shows that taking grapefruit juice along with oral blonanserin increases exposure to blonanserin almost 6-fold due to inhibition of intestinal CYP3A4 by grapefruit juice and prolongs the elimination half-life of blonanserin by 2.2-fold due to inhibition of hepatic CYP3A4 by grapefruit juice (96943).
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Grapefruit juice can increase blood levels of budesonide, potentially increasing the effects and adverse effects of budesonide.
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Budesonide is metabolized by cytochrome P450 3A4 (CYP3A4). A small clinical study shows that taking grapefruit juice along with oral budesonide increases the plasma concentration of budesonide. This effect is attributed to grapefruit-induced inhibition of CYP3A4 in both the colon and small intestine (91425).
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Grapefruit juice can increase blood levels of buspirone, potentially increasing the effects and adverse effects of buspirone.
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Clinical research shows that grapefruit juice increases absorption and plasma concentrations of buspirone (3771).
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Grapefruit juice can decrease the clearance of caffeine, potentially increasing the effects and adverse effects of caffeine.
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Clinical research shows that grapefruit juice decreases caffeine clearance (4300).
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Grapefruit juice can increase blood levels of oral calcium channel blockers, potentially increasing the effects and adverse effects of these drugs.
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Clinical research shows that grapefruit juice increases absorption and plasma concentrations of amlodipine (523), nifedipine (528,22114), nisoldipine (529), verapamil (7779,8285), felodipine, nimodipine, nicardipine, diltiazem, pranidipine, nitrendipine, and manidipine (524,528,1388,4300,7780,11276,22136,53338,22138,22139) (22140,22141,22142,22143,22147,22148,22149,53367,22158),
This interaction is likely the result of the inhibition of intestinal metabolism of these drugs by CYP3A4 (7779,7780), although some research suggests grapefruit may alter plasma drug levels by reducing the rate of gastric emptying (22167). Consuming grapefruit juice 1 liter daily increases steady state concentrations of verapamil by as much as 50% (8285). However, some references dispute the clinical relevance of the interactions with amlodipine, diltiazem, and verapamil (3230,4300,22159). Other research in healthy individuals suggests plasma levels of felodipine and nifedipine are not affected when given intravenously (22144,22146). There is considerable interindividual variability in the effect of grapefruit juice on drug metabolism, which might account for inconsistent study results (7777,7779,8285). In healthy older adults, the hemodynamic response to felodipine plus grapefruit juice might be influenced by altered autonomic regulation. In older healthy adults, a single dose of grapefruit juice and felodipine enhanced the blood pressure-lowering effects of felodipine. However, after a week of grapefruit juice and felodipine (steady state), the hypotensive activity was reduced, possibly due to compensatory tachycardia (1392). Research indicates it is necessary to withhold grapefruit juice for as long as 3 days to avoid interactions with felodipine and nisoldipine (5068,5069,6453,22145).
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Grapefruit juice can increase blood levels of carbamazepine, potentially increasing the effects and adverse effects of carbamazepine.
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Clinical research shows that grapefruit juice increases absorption and plasma concentrations of carbamazepine (524).
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Grapefruit juice can increase blood levels of carvedilol, potentially increasing the effects and adverse effects of carvedilol.
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Clinical research shows that grapefruit juice increases the bioavailability of a single dose of carvedilol by 16% (5071).
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Grapefruit juice can decrease blood levels of celiprolol, potentially decreasing the clinical effects of celiprolol.
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In human research, taking grapefruit juice within two hours of celiprolol appears to decrease absorption and blood levels of celiprolol by approximately 85% (91421). This interaction is due to grapefruit-induced inhibition of organic anion transporting polypeptide (OATP) (17603,17604,22161). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).
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Grapefruit juice can increase blood levels of cisapride, potentially increasing the effects and adverse effects of cisapride.
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Theoretically, grapefruit juice might increase blood levels of clomipramine, potentially increasing the effects and adverse effects of clomipramine.
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Case reports have shown that clomipramine trough levels increase significantly after the addition of grapefruit juice to the therapeutic regimen (5064).
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Grapefruit juice can decrease blood levels of the active metabolite of clopidogrel, thereby decreasing the antiplatelet effect of clopidogrel.
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Clopidogrel is an antiplatelet prodrug that is metabolized primarily by cytochrome P450 2C19 (CYP2C19) to form the active metabolite. A small clinical study shows that taking grapefruit juice with clopidogrel decreases plasma levels of the active metabolite by more than 80% and impairs the antiplatelet effect of clopidogrel. This effect is possibly due to grapefruit-induced inhibition of CYP2C19 (91419).
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Theoretically, grapefruit juice might increase blood levels of colchicine, potentially increasing the effects and adverse effects of colchicine.
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Colchicine is an alkaloid that undergoes P-glycoprotein (P-gp) mediated drug efflux in the intestines, followed by metabolism by cytochrome P450 3A4 (CYP3A4). There is concern that grapefruit juice will increase the effects and adverse effects of colchicine due to grapefruit-induced inhibition of P-gp and/or CYP3A4. In vitro evidence shows that grapefruit juice increases absorption of colchicine by inhibiting P-gp (94158). A case of acute colchicine toxicity has been reported for an 8-year-old female who drank grapefruit juice while taking high-dose colchicine, long-term (94157). However, one small clinical study in healthy adults shows that drinking grapefruit juice 240 mL twice daily for 4 days does not affect the bioavailability or adverse effects of a single dose of colchicine 0.6 mg taken on the fourth day (35762).
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Grapefruit juice can increase blood levels of oral cyclosporine, potentially increasing the effects and adverse effects of cyclosporine.
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Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP1A2.
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In vitro research suggests that grapefruit juice might inhibit CYP1A2 enzymes (12479). So far, this interaction has not been reported in humans.
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Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP2C19.
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In vitro research suggests that grapefruit juice might inhibit CYP2C19 enzymes (12479). Also, a small clinical study shows that taking grapefruit juice with clopidogrel, an antiplatelet prodrug that is metabolized primarily by CYP2C19, decreases plasma levels of the active metabolite and impairs the antiplatelet effect of clopidogrel. This effect is likely due to grapefruit-induced inhibition of CYP2C19 (91419).
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Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP2C9.
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In vitro research suggests that grapefruit juice might inhibit CYP2C9 enzymes (12479). So far, this interaction has not been reported in humans.
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Grapefruit juice can increase levels of drugs metabolized by CYP3A4.
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Clinical research shows that grapefruit juice can inhibit CYP3A4 metabolism of drugs, causing increased drug levels and potentially increasing the risk of adverse effects (3227,3774,8283,8285,8286,22129,91427,104190). When taken orally, effects of grapefruit juice on CYP3A4 levels appear to last at least 48 hours (91427). Grapefruit's ability to inhibit CYP3A4 has even been harnessed to intentionally increase levels of venetoclax, which is metabolized by CYP3A4, in an elderly patient with acute myeloid leukemia who could not afford full dose venetoclax. The lower dose of venetoclax in combination with grapefruit juice resulted in serum levels of venetoclax in the therapeutic reference range of full dose venetoclax and positive treatment outcomes for the patient (112287).
Professional consensus recommends the consideration of patient age, existing medical conditions, additional medications, and the potential for additive adverse effects when evaluating the risks of concomitant use of grapefruit juice with any medication metabolized by CYP3A4. While all patients are at risk for interactions with grapefruit juice consumption, patients older than 70 years of age and those taking multiple medications are at the greatest risk for a serious or fatal interaction with grapefruit juice (95970,95972). |
Grapefruit juice can increase blood levels of dapoxetine, potentially increasing the effects and adverse effects of dapoxetine.
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Pharmacokinetic research shows that drinking grapefruit juice 250 mL prior to taking dapoxetine 60 mg can increase the maximum plasma concentration of dapoxetine by 80% and prolong the elimination half-life by 43%. This effect is attributed to the inhibition of both intestinal and hepatic cytochrome P450 3A4 (CYP3A4) by grapefruit (95975).
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Grapefruit juice can increase blood levels of dextromethorphan, potentially increasing the effects and adverse effects of dextromethorphan.
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Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism, causing increased dextromethorphan levels (11362).
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Grapefruit juice can increase blood levels of erythromycin, potentially increasing the effects and adverse effects of erythromycin.
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Clinical research shows that concomitant use of erythromycin with grapefruit can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of erythromycin, increasing plasma concentrations of erythromycin by 35% (8286).
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Grapefruit juice can increase blood levels of estrogens, potentially increasing the effects and adverse effects of estrogens.
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Clinical research shows that grapefruit increases the levels of endogenous and exogenous estrogens by inhibiting cytochrome P450 3A4 (CYP3A4) enzymes (525,526,14858). Grapefruit juice increases exogenously administered 17-beta-estradiol by about 20% in females without ovaries and ethinyl-estradiol in healthy females (525,526,22160).
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Grapefruit juice can decrease blood levels of etoposide, potentially decreasing the clinical effects of etoposide.
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Clinical research shows that grapefruit juice decreases the absorption and plasma concentrations of etoposide. There is some evidence that grapefruit juice co-administered with oral etoposide can reduce levels of etoposide by about 26% (8744). Grapefruit juice seems to inhibit organic anion transporting polypeptide (OATP), which is a drug transporter in the gut, liver, and kidney (7046,17603,17604). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).
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Grapefruit juice can decrease blood levels of fexofenadine, thereby decreasing the clinical effects of fexofenadine.
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Clinical research shows that grapefruit juice can significantly decrease oral absorption and blood levels of fexofenadine. In one study, consuming a drink containing grapefruit juice 25% decreased bioavailability of fexofenadine by about 24%. Consuming a full-strength grapefruit juice drink reduced bioavailability by 67% (7046). In another study, consuming grapefruit juice 300 mL decreased fexofenadine levels by 42%. Consuming 1200 mL of grapefruit juice reduced levels by 64% (17602). Similarly, drinking grapefruit juice 240 mL decreased the oral bioavailability of fexofenadine by 25% in another pharmacokinetic study (112288). Fexofenadine manufacturer data indicates that concomitant administration of grapefruit juice and fexofenadine results in larger wheal and flare sizes in research models. This suggests that grapefruit also reduces the clinical response to fexofenadine (17603).
Grapefruit juice seems to inhibit organic anion transporting polypeptide (OATP), which is a drug transporter in the gut, liver, and kidney (7046,17603,17604,22161). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604). |
Grapefruit juice can increase blood levels of fluvoxamine, potentially increasing the effects and adverse effects of fluvoxamine.
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Clinical research shows that grapefruit juice inhibits metabolism and increases fluvoxamine levels and peak concentration (17675).
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Grapefruit juice can increase blood levels of halofantrine, potentially increasing the effects and adverse effects of halofantrine.
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Clinical research shows that grapefruit juice inhibits cytochrome P450 3A4 (CYP3A4) metabolism, which increases halofantrine levels and peak concentration, as well as a marker of ventricular tachyarrhythmia potential (22129).
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Grapefruit juice can increase blood levels of statins that are metabolized by cytochrome P450 3A4 (CYP3A4), potentially increasing the effects and adverse effects of these statins. Additionally, grapefruit juice might interfere with the bioavailability of statins that are substrates of organic anion transporting polypeptides (OATP).
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Clinical research shows that grapefruit juice inhibits metabolism and increases absorption and plasma concentrations of statins that are metabolized by CYP3A4. These include lovastatin (527,11274), simvastatin (3774,7782,22127), and atorvastatin (3227,12179,22126). Keep in mind that there is considerable variability in the effect of grapefruit juice on drug metabolism, so individual patient response is difficult to predict (7777,7781).
Some statins, including pravastatin, fluvastatin, pitavastatin, and rosuvastatin, are not metabolized by CYP3A4. However, grapefruit juice might still affect the bioavailability of these statins. These statins are substrates of OATP. Grapefruit juice can inhibit OATP. Therefore, grapefruit juice may reduce the bioavailability or increase drug levels of these statins depending on the type of OATP. However, grapefruit juice affects OATP for only a short time. Therefore, separating drug administration by at least 4 hours is likely to avoid this interaction (3227,12179,17601,22126,91420). |
Grapefruit juice can interfere with itraconazole absorption, although the clinical significance of this interaction is unclear.
Details
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Grapefruit juice can decrease blood levels of levothyroxine, potentially decreasing the effectiveness of levothyroxine.
Details
Clinical research shows that grapefruit juice modestly decreases levothyroxine levels by 11% by inhibiting organic anion transporting polypeptide (OATP) (17604,22163). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).
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Grapefruit juice can decrease blood levels of the active metabolite of losartan, potentially decreasing the clinical effects of losartan.
Details
Losartan is an inactive prodrug which must be metabolized to its active form, E-3174, to be effective. In one human study, grapefruit juice reduced losartan metabolism, increased losartan AUC, and reduced the AUC of the major active losartan metabolite, E-3174 (1391).
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Grapefruit juice can increase blood levels of methadone, potentially increasing the effects and adverse effects of methadone.
Details
Clinical research shows that grapefruit juice inhibits the metabolism of methadone, increasing methadone levels and peak concentrations (17676). In one case, a 51-year-old male taking methadone 90 mg daily and no other medications was found unresponsive. The patient reported drinking grapefruit juice 500 mL daily for 3 days prior to the event. Methadone is a substrate of cytochrome P450 3A4 (CYP3A4), and grapefruit juice-induced inhibition of CYP3A4 is the likely cause of this interaction (102056).
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Grapefruit juice can increase blood levels of methylprednisolone, potentially increasing the effects and adverse effects of methylprednisolone.
Details
Clinical research shows that grapefruit juice can increase the plasma concentration of orally administered methylprednisolone. Grapefruit juice 200 mL three times daily given with methylprednisolone 16 mg increased methylprednisolone half-life by 35%, peak plasma concentration by 27%, and total area under the curve by 75% (3123).
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Grapefruit juice might decrease blood levels of nadolol, potentially decreasing the clinical effects of nadolol.
Details
Nadolol is a substrate of organic anion transporting polypeptide 1A2 (OATP1A2) (17603,17604,22161). Some research shows that grapefruit juice and its constituent naringin can inhibit organic anion transporting polypeptides (OATP), which can reduce the bioavailability of OATP substrates (17603,17604,22161,91427). However, preliminary clinical research shows that grapefruit juice containing a low amount of naringin does not significantly affect levels of nadolol (91422). It is not known if grapefruit juice containing higher amounts of naringin reduces the bioavailability of nadolol.
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Grapefruit juice can increase blood levels of nilotinib, potentially increasing the effects and adverse effects of nilotinib.
Details
Clinical research shows that grapefruit juice inhibits metabolism and increases absorption of nilotinib. Grapefruit juice increases nilotinib levels by 29% and peak concentration by 60% (17677).
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Grapefruit juice can decrease levels of drugs that are substrates of OATP.
Details
In vitro and clinical research show that consuming grapefruit juice inhibits OATP, which reduces the bioavailability of oral drugs that are substrates of OATP. Various clinical studies have shown reduced absorption of OATP substrates when taken with grapefruit, including fexofenadine, acebutolol, aliskiren, celiprolol, levothyroxine, nadolol, and pitavastatin (17603,17604,18101,22126,22134,22161,22163,91420,91427,91428,112288). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).
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Grapefruit juice can increase blood levels of oxycodone, potentially increasing the effects and adverse effects of oxycodone.
Details
Oxycodone is metabolized by both cytochrome P450 3A4 (CYP3A4) and cytochrome P450 2D6 (CYP2D6). A small clinical study shows that grapefruit juice can increase plasma levels of oral oxycodone about 1.7-fold by inhibiting CYP3A4. While the analgesic effects of oxycodone do not seem to be affected, taking grapefruit juice along with oxycodone may theoretically increase the adverse effects of oxycodone (91423).
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Grapefruit juice does not seem to affect renal P-glycoprotein (P-gp). Theoretically, it might inhibit intestinal P-gp, but evidence is conflicting.
Details
While most in vitro research shows that grapefruit products inhibit P-gp, (1390,11270,11278,11362,95976), research in humans is less clear. Two small clinical studies in healthy adults using digoxin as a probe substrate show that grapefruit juice does not inhibit P-gp in the kidneys (11277,11282). It is unclear whether this applies to intestinal P-gp, for which digoxin is not considered to be a sensitive probe (105568). Grapefruit juice has been shown to reduce levels of fexofenadine (7046,17602,112288), and increase levels of quinidine (5067,22121). However, as both of these drugs are also substrates of other enzymes and transporters, it is unclear what role, if any, intestinal P-gp has in these findings.
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Grapefruit juice can increase blood levels of pitavastatin, potentially increasing the effects and adverse effects of pitavastatin.
Details
Pharmacokinetic research shows that taking grapefruit juice with pitavastatin 2-4 mg can increase blood levels of pitavastatin by 13% to 14%. Unlike simvastatin and atorvastatin, pitavastatin is not significantly metabolized by cytochrome P450 3A4 (CYP3A4) enzymes. Grapefruit juice appears to increase levels of pitavastatin by inhibiting its uptake by organic anion transporting polypeptide 1B1 (OATP1B1) into hepatocytes for metabolism and clearance from the body (22126,91420). Grapefruit juice seems to increase levels of pitavastatin to a greater degree in patients homozygous for a specific polymorphism (388A>G) in the OATP1B1 gene compared to those heterozygous for this polymorphism (91420).
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Grapefruit juice can decrease blood levels of the active metabolite of prasugrel, thereby decreasing the antiplatelet effect of prasugrel.
Details
Prasugrel is a prodrug that is metabolized by cytochrome P450 3A4 (CYP3A4) into its active metabolite. A small pharmacokinetic study in healthy volunteers shows that drinking grapefruit juice 200 mL three times daily for 4 days and taking a single dose of prasugrel 10 mg with an additional 200 mL of grapefruit juice on day 3, results in a 49% lower peak plasma level and a 26% lower overall plasma exposure to the active metabolite when compared with drinking water. However, despite the reduced exposure, platelet aggregation seems to be reduced by an average of only 5% (105567). The clinical significance of this interaction is unclear.
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Grapefruit juice can increase blood levels of praziquantel, potentially increasing the effects and adverse effects of praziquantel.
Details
Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of praziquantel. Plasma concentrations of praziquantel can increase by as much as 160% when administered with 250 mL of commercially available grapefruit juice (8282).
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Grapefruit juice may increase blood levels of primaquine, potentially increasing the effects and adverse effects of primaquine.
Details
Clinical research shows that grapefruit juice increases the bioavailability of primaquine by approximately 20% (22130). The clinical significance of this interaction is not clear.
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Grapefruit or grapefruit juice, especially if consumed in large amounts, can cause additive QT interval prolongation when taken with QT interval-prolonging drugs, potentially increasing the risk of ventricular arrhythmias.
Details
Clinical research in healthy volunteers shows that drinking 6 liters of grapefruit juice over 6 hours prolonged the QTc by a peak amount of 14 milliseconds (ms). This prolongation was similar to the QT prolongation caused by the drug moxifloxacin. In individuals with long QT syndrome, a smaller dose of grapefruit juice, 1.5 liters, resulted in a greater peak QTc prolongation of about 30 ms (100249). The effect of smaller quantities of grapefruit juice on the QT interval is unclear.
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Grapefruit juice may increase blood levels of quetiapine, increasing the effects and adverse effects of quetiapine.
Details
Quetiapine is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4 (3227,3774,8283,8285,8286,22129,91427,104190). In one case report, a healthy 28-year-old female with bipolar disorder stabilized on quetiapine 800 mg daily presented with quetiapine toxicity considered to be related to consuming a gallon of grapefruit juice over the past 24 hours (108848).
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Grapefruit juice can alter blood levels of quinidine, potentially increasing or decreasing the clinical effects of quinidine.
Details
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Grapefruit juice can increase blood levels of saquinavir, potentially increasing the effects and adverse effects of saquinavir.
Details
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Grapefruit juice can increase blood levels of scopolamine, potentially increasing the effects and adverse effects of scopolamine.
Details
Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of scopolamine, increasing its absorption and plasma concentrations. Oral bioavailability of scopolamine can increase by 30% when administered with 150 mL of grapefruit juice (8284).
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Grapefruit juice can increase blood levels of sertraline, potentially increasing the effects and adverse effects of sertraline.
Details
Clinical research shows that grapefruit juice inhibits the cytochrome P450 3A4 (CYP3A4) metabolism of sertraline, increasing blood levels of sertraline (22122).
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Grapefruit juice can increase blood levels of sildenafil, potentially increasing the effects and adverse effects of sildenafil.
Details
Clinical research shows that grapefruit juice inhibits cytochrome P450 3A4 (CYP3A4) metabolism of sildenafil, increasing its absorption and plasma concentrations. Oral bioavailability of sildenafil can increase by 23% when administered with 500 mL of commercially available grapefruit juice (8283).
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Grapefruit juice may slightly increase blood levels of sunitinib, potentially increasing the effects and adverse effects of sunitinib.
Details
Sunitinib is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit and grapefruit juice can inhibit CYP3A4 and increase levels of some drugs metabolized by this enzyme. One small clinical study shows that drinking 200 mL of grapefruit juice three times daily can increase the bioavailability of sunitinib by 11% (91429). While this effect is unlikely to be clinically significant, patients should use caution when using grapefruit along with sunitinib. Dose adjustments may be necessary.
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Grapefruit juice can increase blood levels of tacrolimus, potentially increasing the effects and adverse effects of tacrolimus.
Details
Clinical research shows that drinking grapefruit juice 200 mL daily while taking tacrolimus 3 mg daily increases the trough blood concentration of tacrolimus by approximately 3-fold in patients with connective tissue diseases (95974). A single case has also reported a 10-fold increase in tacrolimus trough levels after the ingestion of grapefruit juice over 3 days (22122). This effect is attributed to the inhibition of cytochrome P450 3A4 (CYP3A4) by grapefruit (95974).
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Theoretically, grapefruit juice might increase blood levels of tadalafil, potentially increasing the effects and adverse effects of tadalafil.
Details
Animal research shows that grapefruit juice increases tadalafil serum concentrations and overall exposure, likely through inhibition of cytochrome P450 3A4 enzymes (104189).
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Grapefruit juice might decrease blood levels of talinolol, potentially decreasing the clinical effects of talinolol.
Details
Clinical research suggests that grapefruit juice reduces talinolol bioavailability, likely by inhibiting intestinal uptake (22135). The clinical significance of this effect is unclear.
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Grapefruit juice can increase blood levels of terfenadine, potentially increasing the effects and adverse effects of terfenadine.
Details
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Grapefruit juice can decrease blood levels of theophylline, potentially decreasing the effectiveness of theophylline.
Details
Clinical research shows that grapefruit juice seems to modestly decrease theophylline levels when given concurrently with sustained-release theophylline (11013). The mechanism of this interaction is unknown.
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Grapefruit juice can increase blood levels of ticagrelor, thereby increasing the effects and adverse effects of ticagrelor.
Details
Ticagrelor is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4. A small clinical study shows that taking grapefruit juice with ticagrelor increases blood levels of ticagrelor more than two-fold and increases the antiplatelet activity of ticagrelor (91418).
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Grapefruit juice can increase blood levels of tolvaptan, potentially increasing the effects and adverse effects of tolvaptan.
Details
Tolvaptan is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4. A small clinical study shows that grapefruit juice can increase the bioavailability and blood levels of tolvaptan by approximately 1.6-fold for up to 16 hours (91426).
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Theoretically, drinking large amounts of grapefruit juice might increase the effects and adverse effects of warfarin.
Details
In one case report, a patient experienced significantly increased international normalized ratio (INR) associated with consumption of 50 ounces of grapefruit juice daily (12061). However, smaller amounts of grapefruit juice might not be a problem. In a small clinical trial, consumption of 24 ounces of grapefruit juice daily for one week had no effect on INR in males treated with warfarin (12063).
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Theoretically, due to reports that quassia increases stomach acid, quassia might decrease the effectiveness of antacids (19).
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In animals, quassia extract reduced levels of fasting glucose (99998). Theoretically, quassia might have additive effects when used with antidiabetes drugs. This might increase the risk of hypoglycemia in some patients. Monitor blood glucose levels closely.
Details
Some antidiabetes drugs include glimepiride (Amaryl), glyburide (DiaBeta, Glynase PresTab, Micronase), insulin, metformin (Glucophage), pioglitazone (Actos), rosiglitazone (Avandia), and others.
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Quassin and neoquassin, constituents of quassia, have been shown to inhibit cytochrome P450 1A1 (CYP1A1) enzymes in vitro (99996). This effect has not been shown in humans. Theoretically, concomitant use of quassia with drugs metabolized by CYP1A1 may decrease the clearance of these drugs and increase their effects. Some of these drugs include chlorzoxazone, theophylline, and bufuralol.
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Theoretically, concomitant use with cardiac medications might increase the risk of therapeutic and adverse effects (4).
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Overuse of quassia might compound diuretic-induced potassium loss (13). There is some concern that people taking quassia along with potassium depleting diuretics might have an increased risk for hypokalemia. Initiation of potassium supplementation or an increase in potassium supplement dose may be necessary for some patients.
Details
Some diuretics that can deplete potassium include chlorothiazide (Diuril), chlorthalidone (Thalitone), furosemide (Lasix), and hydrochlorothiazide (HCTZ, Hydrodiuril, Microzide), and others.
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Theoretically, due to reports that quassia increases stomach acid, quassia might decrease the effectiveness of H2-blockers (19). The H2 blockers include cimetidine (Tagamet), ranitidine (Zantac), nizatidine (Axid), and famotidine (Pepcid).
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Theoretically, due to reports that quassia increases stomach acid, quassia might decrease the effectiveness of PPIs (19). PPIs include omeprazole (Prilosec), lansoprazole (Prevacid), rabeprazole (Aciphex), pantoprazole (Protonix), and esomeprazole (Nexium).
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Theoretically, slippery elm may slow the absorption and reduce serum levels of oral drugs.
Details
Slippery elm inner bark contains mucilage, which may interfere with the absorption of orally administered drugs (19).
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Theoretically, taking wormwood might interfere with the effects of anticonvulsant drugs.
Details
Thujone, a constituent of wormwood, has convulsant effects (12816).
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Theoretically, taking yarrow with lithium might increase the levels and adverse effects of lithium.
Details
Animal research shows that yarrow has diuretic activity (106018). Theoretically, due to these potential diuretic effects, yarrow might reduce excretion and increase levels of lithium. The dose of lithium might need to be decreased.
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Below is general information about the adverse effects of the known ingredients contained in the product Para Clean. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
General
...Orally, black walnut fruit (nut) is well tolerated.
However, the leaf, bark, and hull of black walnut contain high quantities of tannins, which may cause adverse effects when used orally or topically.
Most Common Adverse Effects:
Orally: The leaf, bark, and hull can cause gastrointestinal upset.
Topically: Hull preparations may cause a temporary yellow or brown discoloration at the site of application. The leaf, bark, and hull can cause skin irritation.
Serious Adverse Effects (Rare):
Orally: The bark may increase the risk for tongue cancer or lip leukoplakia when used long-term.
All routes of administration: Allergic reactions, including anaphylaxis.
Dermatologic ...Topically, black walnut leaf, bark, or hull may have an irritating effect on the skin due to tannin content. Black walnut hull preparations might cause a temporary yellow or brown discoloration of the skin at the site of application (12).
Gastrointestinal ...Orally, black walnut leaf, bark, or hull may cause gastrointestinal upset due to tannin content (12). Also, daily use of the juglone-containing bark of a related species (English walnut) is associated with increased risk of tongue cancer and lip leukoplakia (2,12).
Hepatic ...Orally, black walnut leaf, bark, or hull may cause liver damage if taken for extended periods of time due to tannin content (12).
Immunologic ...Tree nuts, which include black walnuts, can cause allergic reactions in sensitive individuals. Due to the prevalence of this allergy in the general population, tree nuts are classified as a major food allergen in the United States (105410).
Renal ...Orally, black walnut leaf, bark, or hull may cause kidney damage if taken for extended periods of time due to tannin content (12).
General
...Orally and topically, calendula is generally well tolerated.
Serious Adverse Effects (Rare):
All ROAs: Allergic reactions.
Dermatologic ...Topically, a preparation containing calendula powder 0. 1% resulted in inflammation around the wound to which it was applied (96647). Burning sensation, itching, redness, and scaling were reported rarely in patients applying a combination of calendula, licorice, and snail secretion filtrate to the face. The specific role of calendula is unclear (110322).
Immunologic ...Orally, calendula can cause allergic reactions. Topically, calendula can cause eczematous allergic reactions. Calendula-specific patch testing is recommended prior to usage to determine allergenic potential. Testing is particularly necessary in individuals sensitive to the Asteraceae/Compositae family (10691,11458,96647). Members of this family include ragweed, chrysanthemums, marigolds, daisies, and many other herbs. A preparation containing calendula powder 0.1% resulted in hives in a patient with a ragweed allergy (96647). Despite the widespread use of calendula and the occurrence of allergies to other family members, there has been only one report of anaphylaxis (11152).
General
...Orally, clove is well tolerated when consumed as a spice; however, clove oil in doses of only 5-10 mL can be toxic in children.
Topically, clove is generally well tolerated. When inhaled or used intravenously, clove may be unsafe.
Most Common Adverse Effects:
Topically: Burning, contact dermatitis, dental decay, itching, mucous membrane irritation, tingling, ulcers.
Inhaled: Dental decay, hypertension, itching, tachycardia.
Serious Adverse Effects (Rare):
Orally: Liver failure, respiratory distress.
Inhaled: Pneumonitis, pulmonary edema, respiratory distress.
Cardiovascular ...Smoking clove cigarettes increases heart rate and systolic blood pressure (12892).
Dental ...Population research has found that the risk of dental decay is increased in clove cigarette smokers (43332). Repeated topical application of clove in the mouth can cause gingival damage and skin and mucous membrane irritation (4,272,512). Eugenol, a constituent of clove and a material commonly found in dentistry, has been associated with side effects including gum inflammation and irritation (43365,43373,43522).
Dermatologic ...The American Dental Association has accepted clove for professional use, but not nonprescription use, due to potential damage to soft tissue that may be induced by clove application. In clinical research, small aphthous-like ulcers appeared in the area of the mouth where clove gel was applied in four participants (43448). Skin irritation and stinging have been reported with clove oil application (43338,43626). In a 24-year-old, exposure to a clove oil spill resulted in permanent local anesthesia and anhidrosis, or lack of sweating, at the affected area (43626).
Endocrine ...A case of hypoglycemia and metabolic acidosis have been reported after administration of one teaspoon of clove oil to a seven-month-old infant (43457). A case of electrolyte imbalance following accidental ingestion by a seven-month-old has also been reported (6).
Hematologic ...A case of disseminated intravascular coagulation has been reported in a 2-year-old patient after consuming between 5-10 mL of clove oil. The patient was treated with heparin, fresh frozen plasma, protein C, factor VII, and antithrombin III. On the fifth day, the patient started to improve and made a full recovery (43652).
Hepatic ...There are three cases of hepatic failure occurring in children after ingestion of 5-10 mL of clove oil (43395,43419,43652). Liver injury also occurred in a 3-year-old male (96949). These patients were successfully treated with N-acetylcysteine. The course of liver injury seems to be milder and shorter with early N-acetylcysteine treatment (43395,43419,96949). Another patient, who also presented with disseminated intravascular coagulation, was successfully treated with heparin, fresh frozen plasma, protein C, factor VII, and antithrombin III (43652).
Immunologic ...Contact dermatitis and urticaria has been reported following topical exposure to clove oil or eugenol, a constituent of clove oil (12635,43339,43606,43346).
Neurologic/CNS ...CNS depression has been reported in a 7-month-old who was given one teaspoon of clove oil accidentally in place of mineral oil for diarrhea. The patient was successfully treated with supportive care and gastric lavage (43457). A case of confusion and inability to speak has been reported secondary to oral exposure to clove oil and alcohol. The patient required intubation and was successfully treated with thiamine and normal saline (43580). Seizure and coma have been reported in a two-year-old male after ingesting 5-10 mL of clove oil (43652).
Pulmonary/Respiratory
...Clove cigarettes have been associated with throat and chest tightness (43337), pulmonary edema (43618), and fatal aspiration pneumonitis (43599).
The causative factor may be clove alone or clove along with other substances found in cigarettes. Clove cigarettes contain significant amounts of nicotine, tar, and carbon monoxide and increase plasma levels of nicotine and exhaled carbon monoxide, which might cause long-term health effects similar to tobacco smoking (12892). According to the American Medical Association, inhaling clove cigarette smoke has been associated with severe lung injury in a few susceptible individuals with prodromal respiratory infection. Also, some individuals with normal respiratory tracts have apparently suffered aspiration pneumonitis as the result of a diminished gag reflex induced by a local anesthetic action of eugenol, which is volatilized into the smoke (43602).
Intravenous injection of clove oil in a 32-year-old female resulted in hypoxia, acute dyspnea, interstitial and alveolar infiltrates, and non-cardiogenic pulmonary edema. The patient was managed with supplemental oxygen and recovered over the next seven days (16384).
Occupational exposure to eugenol, a constituent of clove, has also been reported to cause asthma and rhinitis (43492).
Renal ...Proteinuria and other urinary abnormalities were observed in a seven-month-old infant given one teaspoon of clove oil accidentally in place of mineral oil for diarrhea. The patient was successfully treated with supportive care and gastric lavage (43457).
General ...European barberry is generally well tolerated when consumed in amounts commonly found in food. A thorough evaluation of safety outcomes has not been conducted for the use of larger, medicinal amounts. Topically, European barberry seems to be well tolerated.
Hepatic ...Orally, a case of hepatitis-associated aplastic anemia is reported in an adult male after consuming European barberry 15 drops and nannari root 15 drops twice a day for 2 weeks. The patient presented with lethargy, loss of appetite, and jaundice that progressed to high-grade fevers, chills, rigors, severe pancytopenia, and abnormal liver function tests. Liver biopsy was suggestive of drug-induced liver injury. The patient was hospitalized for multiple infections and symptomatic thrombocytopenia. Despite receiving supportive care, blood transfusions, and corticosteroids, the patient died 7 weeks after diagnosis (110021). The exact reason for this adverse effect is not clear.
General
...Orally and topically, fennel seems to be well tolerated.
Most Common Adverse Effects:
Orally: Gastrointestinal discomfort, photosensitivity, and allergic reactions in sensitive individuals.
Serious Adverse Effects (Rare):
Orally: Seizures.
Dermatologic ...Advise patients to avoid excessive sunlight or ultraviolet light exposure while using fennel (19). Allergic reactions affecting the skin such as atopic dermatitis and photosensitivity may occur in patients who consume fennel (6178,49507).
Gastrointestinal ...Orally, fennel may cause gastrointestinal complaints, including nausea and vomiting (19146,104196).
Hematologic ...Methemoglobinemia has been reported in four infants following intoxication related to ingestion of a homemade fennel puree that may have been made from improperly stored fennel (49444).
Immunologic ...A case report describes an 11-year-old male who developed an allergy to fennel-containing toothpaste. Immediately after using the toothpaste, the patient experienced sneezing, coughing, itchy mouth, rhinorrhea, nasal congestion, wheezing, difficulty breathing, and palpitations, which resolved within 10 minutes of spitting out the toothpaste and rinsing the mouth. In challenge tests, the patient reacted to chewing fresh fennel root, but not ground fennel seeds (103822).
Neurologic/CNS ...Orally, fennel oil has been associated with tonic clonic and generalized seizures (12868). New-onset cluster headaches are reported in a 24-year-old female while using a toothpaste containing fennel and camphor for 3 months. The headaches resolved upon stopping the toothpaste (112368). It is unclear if this adverse effect can be attributed to fennel, camphor, or the combination.
Pulmonary/Respiratory ...Orally, fennel and fennel seed have been reported to cause bronchial asthma (49478).
General ...Orally, gentian root, in combination with other herbs, seems to be generally well tolerated (95907). Side effects reported in clinical studies include gastrointestinal discomfort and allergic skin reactions (374,379). There is insufficient reliable information available about the adverse effects of gentian when taken as a medicine alone.
Gastrointestinal ...Orally, gentian root, in combination with other herbs, has been reported to cause gastrointestinal adverse effects (374,379). Gastrointestinal intolerance occurred in patients with cancer-associated anorexia who took gentian tincture 1 mL three times daily, in conjunction with turmeric 1 gram and ginger 1 gram twice daily, for 14 days. Six of 17 patients discontinued the regimen due to nausea, 3 due to vomiting, 2 due to diarrhea, and 2 due to bloating. It is unclear if this gastrointestinal intolerance was caused by gentian, the other herbs, or the patients' predisposing conditions (96263).
Immunologic ...Orally, gentian root, in combination with other herbs, has been reported to cause allergic skin reactions (374,379). It is unclear if these reactions were caused by gentian, the other herbs, or the combination.
General
...Orally, grapefruit and grapefruit juice are generally well tolerated.
Serious Adverse Effects (Rare):
Orally: Allergic reactions in sensitive individuals have been reported. When large quantities are consumed, arrhythmias, mineralocorticoid excess, QT prolongation, and pseudohyperaldosteronism have been reported. There is also some concern for increased breast cancer risk with grapefruit consumption.
Cardiovascular ...Orally, consumption of pink grapefruit juice 1000 mL can cause QT prolongation and cause arrhythmias in healthy patients and worsen arrhythmias in cardiomyopathy patients (13031,91424).
Endocrine ...Orally, high doses of grapefruit juice have been observed to cause pseudohyperaldosteronism and mineralocorticoid excess (53340,53346).
Gastrointestinal ...In a case report, grapefruit juice held against the teeth resulted in enamel and tooth surface loss (53368).
Immunologic ...Orally, grapefruit can cause allergic sensitization characterized by eosinophilic gastroenteritis, urticaria, and generalized pruritus (53351,53360).
Oncologic ...Preliminary population research shows that postmenopausal adults who consume a quarter or more of a whole grapefruit daily have a 25% to 30% increased risk of developing breast cancer (14858). Grapefruit is a potent inhibitor of cytochrome P450 3A4, which metabolizes estrogen. Consuming large amounts of grapefruit might significantly increase endogenous estrogen levels and therefore increase the risk of breast cancer. More evidence is needed to validate these findings. Until more is known, advise patients to consume grapefruit in moderation.
Renal ...In population research, consumption of 240 mL/day of grapefruit juice is associated with an increased risk of kidney stones (4216,53372).
General
...Orally, quassia can cause mucous membrane irritation, nausea, and vomiting when used in medicinal amounts (4,18).
Long-term use can cause vision changes and blindness (18).
Topically, quassia seems to be well tolerated (99995). No adverse effects have been reported.
Gastrointestinal ...Orally, quassia has been reported to cause mucous membrane irritation, nausea, and vomiting when used in medicinal amounts (4,18).
Ocular/Otic ...Orally, long-term use of quassia can cause vision changes and blindness (18).
General ...Orally, slippery elm seems to be well tolerated. A thorough evaluation of safety outcomes with topical use of slippery elm has not been conducted.
Dermatologic ...Topically, slippery elm extracts can cause contact dermatitis. The pollen is an allergen (6). Contact dermatitis and urticaria have been reported after exposure to slippery elm or an oleoresin contained in the slippery elm bark (75131).
General
...Wormwood contains thujone, a neurotoxin.
When products containing thujone are used orally in medicinal amounts, wormwood may be unsafe.
Most Common Adverse Effects:
Orally: The oil from wormwood leaves can cause diffuse muscle aches, nausea, and vomiting.
Serious Adverse Effects (Rare):
Orally: The oil from wormwood leaves can cause acute kidney toxicity, rhabdomyolysis, and seizures.
Dermatologic ...Topically, a single case report describes a sensitivity or first degree chemical burn reaction, with facial pain and erythema, after a 50-year-old adult applied a homemade poultice containing wormwood to the face for an unreported length of time (93466).
Gastrointestinal ...Orally, the oil from wormwood leaves can cause nausea and vomiting (662). Use of a home-prepared wormwood extract has been associated with vomiting and severe diarrhea in an infant (93467).
Hematologic ...Orally, use of a home-prepared wormwood extract has been associated with severe metabolic acidosis in an infant (93467).
Immunologic ...Theoretically, wormwood might cause an allergic reaction in people sensitive to the Asteraceae/Compositae family (12815). Members of this family include ragweed, chrysanthemums, marigolds, daisies, and many other herbs.
Musculoskeletal ...Orally, the oil from wormwood leaves can cause diffuse muscle aches and rhabdomyolysis (662).
Neurologic/CNS ...Orally, the oil from wormwood leaves can cause seizures (662).
Renal ...Orally, the oil from wormwood leaves can cause acute kidney toxicity and acute kidney failure (662).
Other ...Chronic ingestion of absinthe, an alcoholic beverage that contains wormwood extract, has been linked to absinthism. Absinthism was first described in the 1800s when absinthe was at its peak levels of consumption. It has been characterized by addiction, gastrointestinal adverse effects, insomnia, auditory and visual hallucinations, tremors, paralysis, epilepsy, and brain damage. There is also increased risk of psychiatric disease and suicide (662,12814,15008). Increasing thujone concentrations of absinthe increases anxiety and decreases attention in healthy individuals (86541). A case of bradyarrhythmias associated with absinthe intoxication has also been reported (86543). However, there is speculation that some of the symptoms of absinthism originally described might be attributed to adulteration with metals or toxic plants such as calamus and tansy, rather than the ingredients usually used in absinthe drinks (15007). Some researchers also suggest that absinthism is not a unique condition and is indistinguishable from alcohol use disorder. In fact, some evidence suggests that the thujone concentrations in the absinthe formulations from the 1800s were too low to cause significant thujone-related toxicities (15008,15009).
General
...Orally and intravaginally, yarrow seems to be well tolerated.
Most Common Adverse Effects:
Topically: Dermatitis.
Dermatologic
...Topically, yarrow can cause atopic or allergic dermatitis or urticaria due to its sesquiterpene lactone content (52558,68385,77007).
Yarrow has also been reported to cause phototoxic and photo-allergic dermatitis and airborne contact dermatitis (68385).
Intravaginally, aggravated facial acne was reported by 1 of 40 patients in a clinical trial (105360).
Endocrine ...Intravaginally, an early menses was reported by 1 of 40 patients in a clinical trial (105360).
Genitourinary ...Intravaginally, aggravated vaginal pruritus and dryness were reported by 1 of 40 patients in a clinical trial (105360).
Immunologic ...Topically, yarrow can cause atopic or allergic dermatitis or urticaria due to its sesquiterpene lactone content (52558,68385,77007,96911). It has also been reported to cause phototoxic and photo-allergic dermatitis and airborne contact dermatitis (68385). In one 44-year-old female, handling yarrow flowers resulted in rhinitis and asthma (96911).