I. Introduction The Dangers of Herbal Supplements



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4/21/04

I. Introduction



  1. The Dangers of Herbal Supplements

1. In the News


This year, the FDA halted the retail sales of the herbal stimulant ephedra after its use was linked to 155 deaths. Among the more serious side effects associated with ephedra were heart attacks and strokes. However, for every ephedra containing supplement banned, there are many more “miracle in a bottle” pills to take its place. With the myriad of herbal and dietary supplements available to American consumers, there are real concerns that these unregulated products present dangers to public health.

One of the more popular ephedra alternatives that has popped up in the marketplace is bitter orange. Bitter orange contains synephrine which is a chemical stimulant similar to ephedra. However, what many people do not realize about bitter orange—a sour “Seville orange”—is that it is closely related to the grapefruit.


Seville Orange Grapefruit




  1. The Healthy Grapefruit

Grapefruit and grapefruit juice have a great health food image—after all, it is a good source of vitamin C, A, and E.

Grapefruit has been classified as a nutritionally dense food, meaning that it contains very few calories but is an excellent source of many vitamins.




Size

Calories

Vitamin A (IU)

Vitamin C (mg)


Potassium (mg)

Folate (mcg)

Grapefruit, pink or red

½ medium

37

318

47

159

15

Grapefruit, white

½ medium

39

12

40

175

12

Grapefruit juice, pink or red, unsweetened

¾ cup

72

815

70

300

19

Grapefruit juice, white, unsweetened

¾ cup

72

18

72

300

18

Table 1: Nutritional content of grapefruit and grapefruit juice

With such a health nutritional profile, it is no wonder that 1 out of every 5 American households (Somerset Medical Center http://www.somersetmedicalcenter.com/18448.cfm US National Library of Medicines–Drug Information

http://www.nlm.nih.gov/ ) have a bottle of grapefruit juice in the refrigerator. Amidst all the diets being advertised in society, there is one called the “Grapefruit Diet,” erroneously credited to the Mayo Clinic. This diet advocates adding a grapefruit or grapefruit juice to every meal to lose weight. However, it is unlikely that simply adding grapefruit to the diet could help reduce weight. Additionally and perhaps more importantly, the so-called “Grapefruit Diet” can be unsafe for some people due to the grapefruit and drug interaction.



    1. The Not so Innocuous Grapefruit




      1. Serendipity

Grapefruit juice was once used in a drug trial for felodipine and ethanol in order to mask the taste of the alcohol. However, the results of the study were surprising since the felodipine concentration found in the patients’ serum were higher than ever observed in other investigations of the same drug. Eventually, the investigators pinpointed the culprit—the grapefruit juice. This single factor enhanced the bioavailability of the administered felodipine, which has the potential to alter the pharmacokinetic and pharmacodynamic parameters of the drug set in previous clinical trials. Ongoing research centers on the various interaction mechanisms of grapefruit juice and drugs as well as the constituents of grapefruit juice responsible for drug interactions.


      1. Why might it matter to you?

Most people do not take the dihydropyridine calcium channel blocker felodipine, but grapefruit’s enhancing effects are not limited to felodipine. Many drugs are now known to interact with grapefruit juice, and the simultaneous intake of grapefruit juice with drugs can lead to markedly elevated levels of drug bioavailability. A single glass of grapefruit juice can produce maximal interactions. The clinical implications, then, of grapefruit drug interactions are profound and has the potential to affect the health of people taking medication.

Interactions with Grapefruit

Table of Drugs

Common Names and Common Side Effects


Common Name or Brand Name

Drug

Grapefruit Juice Influence

Potential Risk

Drug Classification

Plendil

Felodipine

Increased serum plasma levels of drug

Hypotension and irregular heartbeat

Calcium Channel Antagonists

(Used to treat angina, hypertension, arrhythmias )

Sular

Nisoldipine

Increased serum plasma levels of drug

Hypotension and irregular heartbeat




Calan

Verapamil

Increased serum plasma levels of drug

Hypotension and irregular heartbeat



Fortovase

Invirase



Saquinavir

Increased serum plasma levels of drug

Increased adverse effects

HIV Protease Inhibitor

Crixivan

Indinavir

Increased serum plasma levels of drug

Increased adverse effects




Zocor

Simvastatin

Increased serum plasma levels of drug

Acute renal failure, breakdown of muscle fibers

HMG coA reductase inhibitors

Mevacor

Lovastatin

Increased serum plasma levels of drug

Acute renal failure, breakdown of muscle fibers




Lipitor

Atorvastatin

Increased serum plasma levels of drug

Acute renal failure, breakdown of muscle fibers




Sandimmune® Neoral®

Cyclosporine

Increased serum plasma levels of drug

Hypertension, cerebral toxicity, renal toxicity

Immunosupressant


Propulsid®

Cisapride

Increased serum plasma levels of drug

Ventricular arrhythmia, ventricular tachycardia

Prokinetic

(Used to treat constipation, motility stimulant)

Viagra®

Sidenafil

Increased serum plasma levels of drug

Increased adverse effects

Phosphodiesterase-5 inhibitor

(Used to treat erectile dysfunction)

BuSpar®

Buspirone

Increased serum plasma levels of drug

Increased adverse effects

Psychiatric Medication

Atretol® Depitol® Epitol® Tegretol®


Carbamazepine

Increased serum plasma levels of drug

Increased adverse effects




Valium®

Valrelease®



Diazepam

Increased serum plasma levels of drug

Increased depression




Halcion®

Triazolam

Increased serum plasma levels of drug

Increased depression




Zoloft®

Sertraline

Increased serum plasma levels of drug

Increased adverse effects




Seldane®

Terfenadine

Increased unmetabolized drug in plasma

Ventricular arrhythmia, ventricular tachycardia

Antihistamine

Cordarone®


Amiodarone

Blockage of metabolite formation

Arrhythmias

Antiarhythmics

Table 2- Drugs with Grapefruit Drug Interactions


II. Drug Metabolism through Cytochrome P450




Cytochrome P450 from PDB file 1CPT.pdb

A. Cytochrome P-450 Family

Cytochrome P-450s are a group of enzymes present throughout the body, with the highest concentrations and/or diverse isozymes found in the liver and the intestinal walls. The P-450 monooxygenases catalyze metabolism of numerous compounds—everything from biotransformation of natural endogenous compounds like steroids and cholesterol, to detoxification of exogenous compounds such as drugs and pollutants (Dahan et al, 2003). This family of enzymes is responsible for triggering chemical reactions required to metabolize many different drugs. P-450s play a key role in determining both the intensity and duration of a drug’s action.

All P450 enzymes are heme-containing proteins. The heme iron is usually in the ferric state (Fe3+) but is reduced to the ferrous state (Fe2+) upon activity. The basic reaction catalyzed by cytochrome P450s is:

Substrate (RH) + O2 + NADPH + H+  Product (ROH) + H2O + NADP+

One atom of oxygen is often incorporated as a substrate hydroxyl group (RH) and the other, oxygen, is reduced to water with reducing equivalents derived from NADPH. During catalysis, it is believed that cytochrome P450s bind directly to substrates and molecular oxygen, and does not interact directly with either NADPH or NADH.

The catalytic cycle can be seen in more detail in the following figure:


(Schulz-Utermoehl et al)

Figure 1a

In this proposed mechanism, the electron from NADPH is shuttled first through several flavoproteins before entering the P450 enzyme. There, it reduces the central heme group caused by the molecular binding of oxygen. The oxygen is what ultimately attacks the substrate RH forming ROH and regenerating the oxidized heme group.


Figure 1b

A more comprehensive diagram illustrating the enzymatic processes of CYP3A4. A shows the enzyme in its native conformation before binding substrate. B shows the complex formation of CYP3A4 with the alkane. C shows the reduction of the iron from a +3 state to a +2 state. D1 and D2 shows the addition of a diatomic oxygen molecule to the complex. E shows a further reduction reaction changing the overall charge on the complex from –1 to –2. Steps F and G are two protonation reactions. Finally, before steps H1 and H2, water is eliminated from the complex. The final oxidation step that recovers the original enzyme is shown in steps H1 and H2. The processed substrate is released as ROH with the addition of water to the enzyme.

Of cytochrome P-450s, CYP3A4 is the most abundant member in the body and is responsible for metabolizing approximately 60% of all drugs taken (Dahan et al, 2003).

Grapefruit—more specifically compounds in grapefruit that have so far been identified—inhibits the activity of CYP3A4. This means that when grapefruit or grapefruit juice is consumed, a compound within the grapefruit disrupts the intestinal CYP3A4 enzyme’s ability to metabolize a drug. There are two possible scenarios if a drug is not adequately metabolized. First, if it is the unmetabolized form of the drug that is active, then higher levels of the drug may enter the bloodstream since CYP3A4 is no longer able to metabolize the active drug into its inactive metabolite. Second, if it is the metabolized form of the drug that is active, then lower amounts of the drug will enter the body since CYP3A4 will be unable to react with the inactive drug and convert it to its active metabolite. The first situation is equivalent to a drug overdose, while the second situation is equivalent to an under dosing of the drug. Either of these situations is potentially dangerous.

B. Structure CYP 3A4


1. What has been crystallized

Figure 2- Ribbon representation of CYP3A4 with heme group shown in red

What has mutagenesis taught us about the parts likely involved in function?

(Wester et al)

Figure 3
Mutagenesis studies have indicated that the region seen in Figure 5 labeled helices G and H may play a role in substrate entry. It has also been proposed that the movement of the G and F helix (as seen in the superimposed images of substrate bound versus no substrate bound in Figure 5) causes the conformational changes in the enzyme allowing it to interact with the P-450 enzyme.

C. What is the relationship between CYP3A4 and Grapefruit juice


  1. Permanent dismantling of enzyme

Normally, CYP3A4 catalyzes the oxidation of drugs in the small intestine. However, it has been found that four hours after the consumption of grapefruit juice, there is significant reduction of drug presystemic metabolism. A corresponding decrease of 47% in enterocyte (intestinal cell) CYP3A4 protein levels has been observed through immunoblot analysis of duodenal cells before and after drinking grapefruit juice.



(Dahan et al)

Figure 4

Pre grapefruit consumption levels show a strong band for both CYP3A4 concentrations in the intestine. However, after consumption of grapefruit juice, post CYP3A4 levels show a marked decline.

Other studies have indicated that mRNA levels of CYP3A4 remain unchanged after grapefruit juice consumption. These results all show that protein levels of CYP3A4 are reduced in intestinal cells as a direct consequence of grapefruit juice.



(Lown et al)

Figure 5
In this experiment, several patients were analyzed for levels of CYP3A4 mRNA as well as protein before and after consumption of grapefruit juice. The amount of CYP3A4 mRNA remains constant in each patient. However, the Western blot shows that CYP3A4 protein in patients after consumption of grapefruit juice does change a great deal. In fact, the amount of actual CYP 3A4 protein in the patients’ intestinal cells goes down drastically.
Because mRNA levels remain constant, the mechanism of CYP3A4 inhibition by grapefruit juice is probably post-translational. Thus grapefruit juice components most likely responsible for the effect cause degradation of the enzyme in some way.
Because new protein must be synthesized by the cell to replace degraded CYP3A4, it can take up to 72 hours for CYP3A4 protein levels to recover in intestinal cells. The length of time is dependent on the rate of new CYP3A4 enzyme synthesis as determined by transcription and translation in the enterocyte.

II. Drug Transport through the P-glycoprotein




    1. What is the P-glycoprotein, structure?



Figure 6


The overall structure of the P-glycoprotein.

The human P-glycoprotein is a transmembrane protein responsible for actively pumping toxic hydrophobic substances across the cell’s plasma membrane. Of relevance to drug metabolism, the P-glycoprotein transports drugs out of the cell. This is a process that requires the presence of two ATP-binding domains which are circled in Figure 6. These two ATP binding domains are a defining characteristic of a family of transporters known as the ABC (ATP Binding Cassette) family. In addition to the two ATP-binding domains, members of the ABC family are comprised of two homologous subunits, each of which have six transmembrane helices.

While it is known that the P-glycoprotein transports drugs out of the cell, the exact mechanism of drug efflux is not well understood, but might involve either direct transport out of the cytoplasm or redistribution of the drug as it transverses the plasma membrane. The gene that encodes for the P-glycoprotein is the human MDR1 gene.



    1. What is its function and localization in the body?

The P-glycoprotein is localized




    1. How are drugs normally metabolized through it?



    1. What does grapefruit juice do to it?

      1. What are the implications of a MDR- multi drug resistant p-glycoprotein in cancer



  1. Extracts of grapefruit juice involved in pathway




    1. What has been hypothesized to be involved?

1. Peel components

a. bergamottin

1) ID as potential culprit

2) Structural formula

2. Juice components

a. furanocoumarins

1) ID as potential culprit

2) mechanism of action





  1. Specific example of drug interactions

Grapefruit/Drug Interactions: Dangers and Benefits

A large number or orally administered drugs are metabolized via intestinal CYP3A4. Depending on the drug, the resultant metabolites may be active or inactive. Thus, the effective does that results from a given dose can be affected by CYP3A4 inactivation in the gut. The focus of the rest of this report deals primarily with statins, (drugs whose interaction with grapefruit juice may prove to be dangerous) and Saquinavir, an HIV protease inhibitor that might interact favorably with grapefruit juice.

The Statins
Competitive inhibitors that mimic mevalonate, the substrate of HMG-CoA Reductase are commonly known as statins and are prescribed to 12 million Americans each year. These drugs help to reduce plasma cholesterol concentrations and help prevent the onset of atherosclerosis. While there are many types of statins, the chemical structures of Simvastatin (Zocor®), Lovastatin (Mevacor®) and Pravastatin (Pravachol®) are all very similar. The structure of Atorvastatin (Lipitor®) is somewhat different. Each of these structures is shown in Figure #:
Simavastatin Lovastatin Pravastatin



Atorvastatin

As shown in table #, each of the statins, with the exception of Pravastatin, is primarily metabolized (either to a still active or inactive metabolite) by CYP3A4, with very little drug being excreted by the kidneys.




(Martin et al., 2003)


Many studies have been conducted to assess the potential risks involved with grapefruit juice consumption while taking prescribed doses of these statins. What is known about specific interactions between the juice, the statins and the level of danger are discussed next.
High Danger: Simvastatin and Lovastatin

Both Simvastatin and Lovastatin are rapidly metabolized by CYP3A4 in the intestines during absorption through the gut. Metabolization by CYP3A4 yields inactive metabolites of each of these drugs. These inactive metabolites are quickly processed and broken down by the body. Thus, consumption of grapefruit juice and the concomitant loss of CYP3A4 activity in the intestines results in greater bioavailability and serum concentrations of the active, unmetabolized drug. The following data analyses reveal the dangers of combining grapefruit juice and either simvastatin or lovastatin.

(Lilja et al., 2000)




Fig. ?.

These graphs show the mean serum concentrations of simvastatin (upper graph) and simvastatin acid (lower graph) in 10 healthy volunteers after single oral doses of 40 mg simvastatin. Simvastatin was taken with 200 mL water, with 200 mL double-strength grapefruit juice after ingestion of 200 mL grapefruit juice three times daily for 2 days, or with 200 mL water 24 hours, 3 days, or 7 days after last dose of grapefruit juice. The top line shows that the maximum bioavailability of simvastatin is achieved with the maximum dosage of double-strength grapefruit juice.




(Dahan et al., 2003)



Fig. ? These graphs show the serum concentrations of lovastatin and lovastatin acid after a single oral dose of 80 mg lovastatin, after ingestion of large amounts of grapefruit juice () or water ().

Figure # measures the plasma concentration of Simvastatin in treated patients over time following a 40mg dose of Simvastatin. The line indicated by the closed triangles represents those patients that consumed grapefruit juice and the drug together. The measure of bioavailability used most commonly by researchers is to measure the difference in the area under the curve (AUC) of each of the time-dependent graphs. For Simvastatin there was a 16-fold increase in bioavailability and a 7-fold increase in the bioavailability of Simastatin acid as compared to the water control group (open circles). Furthermore, this study indicates that the effects of grapefruit juice can extend for hours or even days. Increased AUC can clearly be seen even 24 hours after consuming grapefruit juice (closed diamonds).

Results for Lovastatin and Lovastatin acid were similar, showing a 15-fold and a 5-fold increase in the AUC respectively. These results can clearly be seen in Figure # where the closed circles represent the group that consumed grapefruit juice with the drug.
Because of these findings, patients taking either of these two medications should avoid drinking grapefruit juice at any time. Due to the increased bioavailability caused by CYP3A4 inactivation, patients combining grapefruit juice with either of these two drugs would receive doses which are far higher than the limits tested during clinical trials.
Moderate Danger: Atorvastatin
Unlike Simvastatin and Lovastatin, when Atorvastatin is processed by CYP3A4, the metabolites remain active and, in fact, account for 70% of the effect of the drug. Given this fact, the exact effects of CYP3A4 inhibition on Atorvastatin are somewhat hard to predict. Studies conducted in Finnish and Japanese populations found that, in general, consuming grapefruit juice with Atorvastatin can increase bioavailability, but not to the same degree as seen in experiments with Simvastatin and Lovastatin. The Finnish study monitored the effects of grapefruit juice consumption on serum concentrations of Atorvastatin and its primary metabolite 2-hydroxyatorvastatin. The details are show in Figure #.


(Lilja et al., 2000)


Fig. ?. Mean ± SEM serum concentrations of atorvastatin acid and lactone (upper panel) and 2-hydroxyatorvastatin acid and lactone (lower panel) in 12 healthy volunteers after a single dose of 40 mg atorvastatin, after ingestion of 200 mL double-strength grapefruit juice (solid circles) or water (open circles) three times a day for 2 days, and on day 3 with atorvastatin and ½ hour and 1 ½ hours after atorvastatin administration. In addition, 200 mL grapefruit juice or water was ingested three times a day on days 4 and 5.

As can be seen from these graphs, grapefruit juice consumption causes an increase in the bioavailability (again measured as the area under the curve) for both Atorvatstatin acid and Atorvastatin lactone. However, because CYP3A4 is inactivated by the grapefruit juice consuming group, the patients’ serum levels of the primary active metabolite are much lower. When these two facts are combined, the overall effects tend to cancel each other out (Figure #).

(Lilja et al., 2000)




Fig. ?. Mean ± SEM serum concentrations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in 12 healthy volunteers after a single dose of 40 mg atorvastatin, after ingestion of 200 mL double-strength grapefruit juice (solid circles)
or water (open circles) three times a day for 2 days, and on day 3 with atorvastatin and ½ hour and 1 ½ hours after atorvastatin administration. In addition, 200 mL grapefruit juice was ingested three times a day on days 4 and 5.
These results show that combining Atorvastatin and grapefruit juice only results in a 2.5-fold increase in overall Atorvastatin bioavailability. Since such an increase falls within dosing norms for this drug, the effects of grapefruit juice consumption would not be as dangerous as combining juice with Simvastatin and Lovastatin in most people. However, individuals sensitive to higher doses may still be affected and caution should be exercised in combining grapefruit juice with Atorvastatin.

Low Danger: Pravastatin

Out of all of the statins discussed thus far, Pravastatin is the only one not directly metabolized by CYP3A4. Though it’s chemical structure is remarkably similar to that of Simvastatin and Lovastatin, it’s chemical properties are quite unique. As seen below, grapefruit juice consumption had little affect on the bioavailability of Pravastatin.

(Lilja et al., 2000)




Fig. ?. Mean ± SEM serum concentrations of unchanged pravastatin in 11 healthy volunteers after a single dose of 40 mg pravastatin, after ingestion of 200 mL double-strength grapefruit juice (solid circles)
or water (open circles) three times a day for 2 days, and on day 3 with pravastatin and ½ hour and 1½ hours after pravastatin administration.
Given these data, Pravastatin might be an effective alternative for those who require statin medication but enjoy drinking grapefruit juice.

HIV Protease Inhibitors: Potential Benefits of Grapefruit Juice Consumption


While most statins react unfavorably with grapefruit juice, increasing serum concentrations of the drugs to dangerous levels, combining grapefruit juice to enhance the bioavailability of certain drugs might actually be beneficial. Saquinavir is an inhibitor of HIV protease and is commonly used in conjunction with reverse transcriptase inhibitors in the treatment of HIV and AIDS. Unfortunately, this drug is highly metabolized by CYP3A4 and as such its bioavailability is generally between 1-4%. Saquinavir is also very expensive to manufacture and so anything that could reduce the necessary dose (usually 600-800mg) would greatly reduce costs for those with HIV. In a study which combined grapefruit juice and oral Saquinavir, it was found that drinking grapefruit juice along with Saquinavir doubled its bioavailability. An additional study, (Figure #), analyzed the affect of a known inhibitor of CYP3A4 on Saquinavir transport across an epithelial monolayer.

(Eagling et al., 1999)


Figure ? The cumulative transport of saquinavir (1 μm; 0.02 μCi) across Caco-2 cell monolayers in the basolateral→apical and apical→basolateral directions: (a) saquinavir alone (b) in the presence of verapamil (500 μm ) and (c) in the presence of ketoconazole (500  μm ). Data represent the mean±s.d. of three individual determinations. () basolateral→apical direction; () apical→basolateral direction.

These results show that reverse transport across the cell (representative of transporting a drug out of the blood and back into the gut lumen) is greatly inhibited by verapamil and ketoconazole, both inhibitors of CYP3A4. Grapefruit juice was expected to produce results similar to those seen in these graphs. Not only does inactivating CYP3A4 prevent retrograde transport of Saquinavir, it also increases the rate at which the drug is pumped into the bloodstream. These findings corroborate other studies that indicate the potential benefit of increased bioavailability derived from combining grapefruit juice and Saquinavir in the treatment of AIDS.


Conclusion


  1. Where do we go from here?




    1. MDR- grapefruit juice could be beneficial in some drugs with low bioavailability

While the consumption of grapefruit juice with a drug may cause toxic levels of that drug in the body, there are some drugs that already have such low bioavailability that grapefruit juice may help increase the metabolic dose a patient receives.


More applicably, substances identified within grapefruit juice that increase the bioavailiability of a drug in the body could be purified and extracted. This chemical could then be incorporated inside the pill for drugs like Saquinavir.

The danger and problem with this approach is that every individual has a unique amount of CYP3A4 and P-glycoprotein. Grapefruit juice may have a rather large effect on someone while having a relatively little effect on another individual. When it comes to perhaps solving the Multi Drug Resistance problems for chemotherapy drugs, grapefruit juice effects may vary from patient to patient. However, these investigations can serve as a good beginning from which to start coming up with better solutions.




    1. Educating the Public

While some members of the public are aware that certain food and drug interactions exist, there is certainly room for the dissemination of more accurate and scientifically correct information. Most of the public remains ignorant to the true gravity of grapefruit juice and drug interactions.


Information regarding the dosing, the timing, and the long term consequences of consuming grapefruit juice along with drugs should perhaps be available on the bottles of juice sold on the shelves. Perhaps the medical community should do a better job of informing patients on medications most likely to have grapefruit drug interactions. A true biochemical explanation regarding CYP3A4 and the P-glycoprotein would perhaps convey the severity of the consequences to drug metabolism that grapefruit juice causes.


    1. A Note about Herbal supplements.

Grapefruit juice and supplements containing grapefruit extracts are not isolated incidents; indeed, these supplements exist amidst a sea of other similar herbal supplements that flood the consumer market. A recent New Yorker article entitled “Miracle in a Bottle” really strikes at the heart of the dietary supplement problem.


“This really is a belief system, almost a religion. Americans believe they have the right to address their health problems in the way that seems most useful to them. Often, that means supplements…they are ready to believe anything if it brings them a little hope.”

These products, these miracles that are offered in a bottle, are cloaked with in what seems like scientific validity. However, not all of these herbal combinations are benign. The significant and wholly unexpected results that are seen with grapefruit juice consumption is just one of numerous examples of herbal drug interactions that are directly pertinent to the average consumer. As seen from the research cited in this website, grapefruit juice seriously disrupts the enzymes found in the small intestine, causing high blood levels of drugs, intensifying side effects, and preventing the efficacy of the drug on the disease being treated.
The dream of wellness and the reality of wellness are oftentimes very different in the world of herbal supplements. There is no doubt that better regulation is necessary to ensure that the thousands of botanical substances currently on the market do not unwittingly harm the thousands of corresponding consumers purchasing them. Later this year, Congress will considers legislation to regulate the dietary supplement agency. Perhaps better labeling and consumer knowledge can prevent the horrible consequences that may ensue should some one take Bitter Orange along with cholesterol lowering agents. If you should find yourself down a grocery aisle filled with little bottles of hope, perhaps a word to the wise would be to remember the mighty grapefruit and the danger hidden beneath the innocence exterior.



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