INTRODUCTION
For many years, warfarin has been the first anticoagulant for the first and secondary prevention of venous and arterial thromboembolic occasions. There may be an intensive quantity of literature that has contributed to the understanding of the complicated pharmacokinetics and pharmacodynamics of warfarin, its interactions with medication and different compounds, its antithrombotic results, and the dangers related to its use. To the authors’ data, nevertheless, there have been no case reviews of an interplay between apple juice and warfarin. The next case report describes elevation of the worldwide normalized ratio (INR) after ingestion of no less than 1 L of home made apple juice each day for two weeks in a affected person who was beforehand steady on warfarin for venous thromboembolism.
CASE REPORT
A 69-year-old lady was referred to the emergency division by her household doctor for supratherapeutic INR.* The affected person denied any minor or main bleeding, regardless of the important INR. Her medical historical past included recurrent deep venous thrombosis requiring lifelong anticoagulation, left parasagittal meningioma, hypertension, obstructive sleep apnea requiring steady constructive airway stress, achalasia, gastroesophageal reflux illness, continual hip ache, despair, stressed leg syndrome, smoking (5 cigarettes/day), and several other distant surgical procedures. The affected person denied any latest alcohol use, new stressors, or latest diseases. Medicines earlier than admission have been nicotine 7-mg patch each day, baclofen 10 mg 3 occasions each day, pantoprazole 40 mg twice each day, salbutamol inhaler 1 or 2 puffs q4h as wanted, gabapentin 600 mg 4 occasions each day, spironolactone 25 mg each day, pramipexole 1 mg each day, zopiclone 7.5 mg at bedtime as wanted, diltiazem CD 120 mg each day, quetiapine 75 mg at bedtime, and warfarin 3 mg each day. The affected person denied use of different over-the-counter medicines, natural medicines, pure well being merchandise, meals dietary supplements, or conventional medicines. She had good medecation adherence. There have been no latest modifications to her medicines, as confirmed by the affected person and by refill dates on the prescription report offered throughout the digital well being report.
The INR had been comparatively steady within the goal vary of two–3 over the earlier 5 months, with 2 remoted supratherapeutic readings (> 3) within the 2 months earlier than the present presentation. The one dietary change was consumption of no less than 1 L of home made pure apple juice each day throughout the 2 weeks earlier than admission. Throughout these 2 weeks, the INR had progressively elevated, with measurements of three.9, 4.0, 6.0, and at last above 9.0, with no change in warfarin dosing (Determine 1).
The outcomes of a bodily examination have been unremarkable. Laboratory assessments on admission included full blood depend, renal perform assessments, and measurement of albumin and liver enzymes, and all the outcomes have been inside regular vary. The INR measured on the time of presentation was once more better than 9. Computed tomography (CT) of the top didn’t present any bleeding, and CT of the stomach and pelvis confirmed no intra-abdominal or retroperitoneal bleeding. Within the emergency division, the affected person obtained 5 mg of oral vitamin Okay, and the warfarin was held. The following day, the affected person’s INR was 3.1, and he or she was discharged from hospital, with a suggestion for follow-up with the anticoagulation administration clinic. The affected person continued all earlier house medicines after discharge and was suggested to discontinue ingesting apple juice. At 6 days after discharge and cessation of apple juice, the INR was 2.2, and a month later it was 2.9 with a warfarin dose of three mg each day.
DISCUSSION
To the authors’ data, this report is the primary to suggest a doable interplay between apple juice and warfarin. On this case, INR elevation was noticed in a affected person who was beforehand steady on warfarin after consumption of huge quantities of apple juice over 2 weeks. The chance of a drug interplay was assessed utilizing the Drug Interplay Chance Scale (DIPS), a software for evaluating the potential of a drug interplay in particular person sufferers.1 The DIPS is predicated on 10 questions referring to the potential drug interplay, with the outcomes getting used to estimate a chance rating. A rating better than 8 suggests {that a} drug interplay is extremely possible, whereas a rating of 5–8 signifies a possible interplay, 2–4 a doable interplay, and fewer than 2 a uncertain interplay. Within the case introduced right here, the DIPS rating was 3, which instructed a doable interplay between warfarin and apple juice.1
A evaluate of varied drug interplay assets and databases2–6 revealed no reviews of an interplay between warfarin and apple juice. A literature search of Embase, Ovid MEDLINE, Google Scholar, Reactions Weekly, and Worldwide Pharmaceutical Abstracts from inception to June 2015 utilizing the search phrases “apple”, “apple juice” and “warfarin” yielded no proof suggesting an interplay between warfarin and apple juice. To the authors’ data, there have been no in vitro or in vivo research investigating the consequences of apple juice on warfarin metabolism.
The mechanism by which apple juice interacts with warfarin could also be just like that of cranberry juice, as each of those juices comprise flavonoids. Actually, apples are a big supply of flavonoids within the human eating regimen.7 In the US, apples signify the most important supply of phenolics, that are non-nutrient plant compounds, together with flavonoids.7 Actually, relative to different fruits, apples comprise one of many largest quantities of whole phenols, primarily based on serving dimension and portion of free phenolics.8,9 Flavonoids might inhibit membrane transporters, cytochrome (CYP) P450 enzymes, and P-glycoprotein.10 Warfarin is extensively metabolized by hepatic cytochrome P450 microsomal enzymes. Warfarin is a racemic combination of two optical isomers, the R and S isomers, with the S isomer being 2 to five occasions stronger than the R isomer. S-Warfarin is metabolized principally by oxidation through the CYP2C9 isoenzyme and, to a lesser extent, the CYP3A4 isozyme. The much less potent R enantiomer can also be metabolized by oxidative metabolism, primarily by CYP1A2 and CYP3A4 and, to a lesser extent, by CYP2C19.11 This means that the rise in INR might have been a results of apple juice inhibiting CYP P450 enzymes, which in flip diminished hepatic clearance of warfarin.
Some in vitro and in vivo research have evaluated the interplay between cranberry and warfarin. Cranberry juice has been proven to inhibit CYP3A4 and CYP2C9.12 A number of research have proven no change in warfarin pharmacokinetics with coadministration of cranberry juice, and most have demonstrated no change in INR.5,12 Nevertheless, many case reviews have described a rise in INR and critical opposed reactions, together with deadly hemorrhage, on account of coadministration of cranberry with warfarin.5,12 Consumption of huge portions of cranberry juice (1–2 L/day) or focus (1000 mg) for longer than 3–4 weeks could also be correlated with altered INR values.12 In vitro research with cranberry juice have instructed that CYP3A4 and CYP2C9 inhibition is concentration-dependent.12 The affected person described right here was consuming no less than 1 L/day of home made pure apple juice, which might be rather more concentrated than commercially out there apple juices and thus would have resulted in better probability of inhibition of CYP enzymes, adopted by diminished warfarin clearance and elevated INR.
Apple juice interacts with different medicines through natural anion transporter polypeptides.5,6,13–15 This mechanism shouldn’t be related to the present case, as natural anion transporter polypeptides don’t affect warfarin pharmacokinetics.5 A evaluate of the affected person’s medicines earlier than admission confirmed pantoprazole as the one treatment that will inhibit natural anion transporters and end in inhibition of renal tubular secretion.5 On this context, pantoprazole is classed as a weak inhibitor.5 About 92% of warfarin is excreted within the urine as metabolites.3 The metabolites of R-warfarin have some anticoagulant exercise however significantly lower than the father or mother compound.3 A small double-blind, randomized, placebo-controlled, crossover research of pantoprazole and warfarin confirmed no clinically vital change within the pharmacokinetics and pharmacodynamics of R- and S-warfarin when coadministered with pantoprazole, and the mix was properly tolerated.16 Pantoprazole has low potential to work together with different medicines, and there are not any clinically vital metabolic interactions when pantoprazole is mixed with warfarin.5,17 Nevertheless, the pantoprazole product monograph states that a couple of remoted circumstances of modifications in INR have been reported throughout concomitant therapy with warfarin within the postmarketing interval.18 The affected person had been receiving pantoprazole concurrently with warfarin for 3 years earlier than the present admission. It’s unlikely {that a} discount in renal tubular secretion through inhibition of natural anion transporters precipitated the elevated INR, as warfarin doesn’t require dosage adjustment in sufferers with renal dysfunction.3
CONCLUSION
Warfarin is thought to work together with many medication and meals. Subsequently, shut monitoring of the INR is necessary to assist forestall supratherapeutic or subtherapeutic ranges of the drug, which may predispose the affected person to extreme bleeding or thromboembolic occasions. To the authors’ data, that is the primary case report of a possible interplay between warfarin and apple juice. On this case, INR grew to become elevated in a affected person who ingested extreme quantities of apple juice for two weeks. One limitation of this research is its reliance on subjective data from the affected person, and though no confounding elements have been recognized, such elements can’t be dominated out. It’s doable that apple interacts with warfarin in a fashion just like cranberry, by way of flavonoids. Extra research are wanted to evaluate this proposed interplay between warfarin and apple juice to grasp the doable mechanism and medical influence.
Footnotes – “apple cider vinegar and warfarin”
References
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