Willow Bark (Herb/Suppl)

Brand and Other Names:basket willow, bay willow, more...brittle willow, osier rouge, purple osier, Salicis cortex, Salix species, Salix spp, violet willow, white willow
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Suggested Dosing

Extract

120-240 mg salicin PO TID-QID

Dried Bark

1-3 g PO TID-QID

Tea

1 cup PO TID-QID; prepared with 1-3 g bark/150 ml water

Liquid Extract

1-3 ml PO qDay; 1:1 25% alcohol

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Suggested Uses

Fever, gouty arthritis, headaches, inflammation, influenza symptoms, muscle/joint aches, pain, rheumatoid arthritis

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Interactions

Interaction Checker

and Willow Bark

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            Contraindicated (0)

              Serious - Use Alternative (2)

              • measles, mumps, rubella and varicella vaccine, live

                willow bark, measles, mumps, rubella and varicella vaccine, live. Mechanism: unspecified interaction mechanism. Avoid or Use Alternate Drug. Risk of Reye's Syndrome with combination; avoid salicylate use for 6 wks after vaccination.

              • varicella virus vaccine live

                willow bark, varicella virus vaccine live. Mechanism: unspecified interaction mechanism. Avoid or Use Alternate Drug. Risk of Reye's Syndrome with combination; avoid salicylate use for 6 wks after vaccination.

              Monitor Closely (17)

              • acetazolamide

                acetazolamide, willow bark. Either increases levels of the other by Other (see comment). Use Caution/Monitor. Comment: Carbonic anhydrase inhibitors (CAIs) and salicylates inhibit each other's renal tubular secretion, resulting in increased plasma levels. CAIs also shift salicylates from plasma to the CNS, leading to potential neurotoxicity.

                acetazolamide, willow bark. Mechanism: passive renal tubular reabsorption due to increased pH. Use Caution/Monitor. Salicylate levels increased at moderate doses; risk of CNS toxicity. Salicylate levels decreased at large doses (d/t increased renal excretion of unchanged salicylic acid).

              • amoxicillin

                amoxicillin, willow bark. Either increases levels of the other by decreasing renal clearance. Use Caution/Monitor.

              • ampicillin

                ampicillin, willow bark. Either increases levels of the other by decreasing renal clearance. Use Caution/Monitor.

              • brinzolamide

                brinzolamide, willow bark. Either increases levels of the other by Other (see comment). Use Caution/Monitor. Comment: Carbonic anhydrase inhibitors (CAIs) and salicylates inhibit each other's renal tubular secretion, resulting in increased plasma levels. CAIs also shift salicylates from plasma to the CNS, leading to potential neurotoxicity.

              • dicloxacillin

                dicloxacillin, willow bark. Either increases levels of the other by decreasing renal clearance. Use Caution/Monitor.

              • griseofulvin

                griseofulvin decreases levels of willow bark by unknown mechanism. Use Caution/Monitor.

              • methazolamide

                methazolamide, willow bark. Either increases levels of the other by Other (see comment). Use Caution/Monitor. Comment: Carbonic anhydrase inhibitors (CAIs) and salicylates inhibit each other's renal tubular secretion, resulting in increased plasma levels. CAIs also shift salicylates from plasma to the CNS, leading to potential neurotoxicity.

              • methotrexate

                willow bark will increase the level or effect of methotrexate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.

              • mycophenolate

                willow bark will increase the level or effect of mycophenolate by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.

              • nafcillin

                nafcillin, willow bark. Either increases levels of the other by decreasing renal clearance. Use Caution/Monitor.

              • oxacillin

                oxacillin, willow bark. Either increases levels of the other by decreasing renal clearance. Use Caution/Monitor.

              • penicillin G aqueous

                penicillin G aqueous, willow bark. Either increases levels of the other by decreasing renal clearance. Use Caution/Monitor.

              • penicillin VK

                penicillin VK, willow bark. Either increases levels of the other by decreasing renal clearance. Use Caution/Monitor.

              • pivmecillinam

                pivmecillinam, willow bark. Either increases levels of the other by decreasing renal clearance. Use Caution/Monitor.

              • probenecid

                willow bark will increase the level or effect of probenecid by acidic (anionic) drug competition for renal tubular clearance. Use Caution/Monitor.

                willow bark decreases effects of probenecid by unknown mechanism. Use Caution/Monitor.

              • temocillin

                temocillin, willow bark. Either increases levels of the other by decreasing renal clearance. Use Caution/Monitor.

              • ticarcillin

                ticarcillin, willow bark. Either increases levels of the other by decreasing renal clearance. Use Caution/Monitor.

              Minor (105)

              • aceclofenac

                aceclofenac will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • acemetacin

                acemetacin will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • acyclovir

                willow bark will increase the level or effect of acyclovir by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • aluminum hydroxide

                aluminum hydroxide, willow bark. Mechanism: passive renal tubular reabsorption due to increased pH. Minor/Significance Unknown. Salicylate levels increased at moderate doses; salicylate levels decreased at large doses (d/t increased renal excretion of unchanged salicylic acid).

              • aminohippurate sodium

                willow bark will increase the level or effect of aminohippurate sodium by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • ascorbic acid

                ascorbic acid will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

                willow bark decreases levels of ascorbic acid by increasing renal clearance. Minor/Significance Unknown.

                ascorbic acid increases levels of willow bark by decreasing renal clearance. Minor/Significance Unknown.

              • aspirin

                aspirin will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

                willow bark increases effects of aspirin by pharmacodynamic synergism. Minor/Significance Unknown. Willow bark contains salicylic acid, which may have additive effects/toxicity with salicylate drugs.

              • aspirin rectal

                willow bark increases effects of aspirin rectal by pharmacodynamic synergism. Minor/Significance Unknown. Willow bark contains salicylic acid, which may have additive effects/toxicity with salicylate drugs.

                aspirin rectal will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • aspirin/citric acid/sodium bicarbonate

                aspirin/citric acid/sodium bicarbonate will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

                willow bark increases effects of aspirin/citric acid/sodium bicarbonate by pharmacodynamic synergism. Minor/Significance Unknown. Willow bark contains salicylic acid, which may have additive effects/toxicity with salicylate drugs.

              • balsalazide

                balsalazide will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

                willow bark increases effects of balsalazide by pharmacodynamic synergism. Minor/Significance Unknown. Willow bark contains salicylic acid, which may have additive effects/toxicity with salicylate drugs.

              • bendroflumethiazide

                bendroflumethiazide will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • budesonide

                budesonide decreases levels of willow bark by increasing renal clearance. Minor/Significance Unknown.

              • bumetanide

                willow bark, bumetanide. Other (see comment). Minor/Significance Unknown. Comment: Salicylates are less likely than other NSAIDs to interact w/bumetanide.

              • calcium carbonate

                calcium carbonate, willow bark. Mechanism: passive renal tubular reabsorption due to increased pH. Minor/Significance Unknown. Salicylate levels increased at moderate doses; salicylate levels decreased at large doses (d/t increased renal excretion of unchanged salicylic acid).

              • cefaclor

                cefaclor will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • cefadroxil

                cefadroxil will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • cefamandole

                cefamandole will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • cefazolin

                cefazolin will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • cefdinir

                cefdinir will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • cefditoren

                cefditoren will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • cefepime

                cefepime will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • cefixime

                cefixime will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • cefotaxime

                cefotaxime will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • cefotetan

                cefotetan will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • cefpirome

                cefpirome will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • cefpodoxime

                cefpodoxime will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • cefprozil

                cefprozil will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • ceftazidime

                ceftazidime will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • ceftibuten

                ceftibuten will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • ceftriaxone

                ceftriaxone will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • celecoxib

                celecoxib will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • cephalexin

                cephalexin will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • chlorothiazide

                chlorothiazide will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • chlorpropamide

                willow bark will increase the level or effect of chlorpropamide by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

                willow bark increases effects of chlorpropamide by plasma protein binding competition. Minor/Significance Unknown. Large dose of salicylate.

              • chlorthalidone

                chlorthalidone will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • choline magnesium trisalicylate

                choline magnesium trisalicylate will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

                willow bark increases effects of choline magnesium trisalicylate by pharmacodynamic synergism. Minor/Significance Unknown. Willow bark contains salicylic acid, which may have additive effects/toxicity with salicylate drugs.

              • cortisone

                cortisone decreases levels of willow bark by increasing renal clearance. Minor/Significance Unknown.

              • cyanocobalamin

                willow bark decreases levels of cyanocobalamin by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

              • cyclopenthiazide

                cyclopenthiazide will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • deflazacort

                deflazacort decreases levels of willow bark by increasing renal clearance. Minor/Significance Unknown.

              • dexamethasone

                dexamethasone decreases levels of willow bark by increasing renal clearance. Minor/Significance Unknown.

              • diclofenac

                diclofenac will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • diflunisal

                diflunisal will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

                willow bark increases effects of diflunisal by pharmacodynamic synergism. Minor/Significance Unknown. Willow bark contains salicylic acid, which may have additive effects/toxicity with salicylate drugs.

              • diltiazem

                diltiazem increases effects of willow bark by unknown mechanism. Minor/Significance Unknown. Enhanced antiplatelet activity.

              • ethanol

                ethanol increases toxicity of willow bark by pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of GI bleeding.

              • etodolac

                etodolac will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • fenoprofen

                fenoprofen will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • fludrocortisone

                fludrocortisone decreases levels of willow bark by increasing renal clearance. Minor/Significance Unknown.

              • flurbiprofen

                flurbiprofen will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • folic acid

                willow bark decreases levels of folic acid by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

              • ganciclovir

                willow bark will increase the level or effect of ganciclovir by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • glimepiride

                willow bark increases effects of glimepiride by plasma protein binding competition. Minor/Significance Unknown. Large dose of salicylate.

              • glipizide

                willow bark increases effects of glipizide by plasma protein binding competition. Minor/Significance Unknown. Large dose of salicylate.

              • glyburide

                willow bark increases effects of glyburide by plasma protein binding competition. Minor/Significance Unknown. Large dose of salicylate.

              • green tea

                green tea, willow bark. Other (see comment). Minor/Significance Unknown. Comment: Use caution when combining green tea with herbs that exhibit antiplatelet effects or anticoagulant activity.

              • hydrochlorothiazide

                hydrochlorothiazide will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • hydrocortisone

                hydrocortisone decreases levels of willow bark by increasing renal clearance. Minor/Significance Unknown.

              • ibuprofen

                ibuprofen will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • ibuprofen IV

                ibuprofen IV will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • indapamide

                indapamide will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • indomethacin

                indomethacin will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • insulin aspart

                willow bark increases effects of insulin aspart by pharmacodynamic synergism. Minor/Significance Unknown. Large dose of salicylate.

              • insulin detemir

                willow bark increases effects of insulin detemir by pharmacodynamic synergism. Minor/Significance Unknown. Large dose of salicylate.

              • insulin glargine

                willow bark increases effects of insulin glargine by pharmacodynamic synergism. Minor/Significance Unknown. Large dose of salicylate.

              • insulin glulisine

                willow bark increases effects of insulin glulisine by pharmacodynamic synergism. Minor/Significance Unknown. Large dose of salicylate.

              • insulin lispro

                willow bark increases effects of insulin lispro by pharmacodynamic synergism. Minor/Significance Unknown. Large dose of salicylate.

              • insulin NPH

                willow bark increases effects of insulin NPH by pharmacodynamic synergism. Minor/Significance Unknown. Large dose of salicylate.

              • insulin regular human

                willow bark increases effects of insulin regular human by pharmacodynamic synergism. Minor/Significance Unknown. Large dose of salicylate.

              • ketoprofen

                ketoprofen will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • ketorolac

                ketorolac will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • ketorolac intranasal

                ketorolac intranasal will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • L-methylfolate

                willow bark decreases levels of L-methylfolate by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

              • lornoxicam

                lornoxicam will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • meclofenamate

                meclofenamate will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • mefenamic acid

                mefenamic acid will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • meloxicam

                meloxicam will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • mesalamine

                mesalamine will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

                willow bark increases effects of mesalamine by pharmacodynamic synergism. Minor/Significance Unknown. Willow bark contains salicylic acid, which may have additive effects/toxicity with salicylate drugs.

              • methyclothiazide

                methyclothiazide will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • methylprednisolone

                methylprednisolone decreases levels of willow bark by increasing renal clearance. Minor/Significance Unknown.

              • metolazone

                metolazone will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • nabumetone

                nabumetone will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • naproxen

                naproxen will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • oxaprozin

                oxaprozin will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • parecoxib

                parecoxib will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • piperacillin

                piperacillin will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • piroxicam

                piroxicam will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • prednisolone

                prednisolone decreases levels of willow bark by increasing renal clearance. Minor/Significance Unknown.

              • prednisone

                prednisone decreases levels of willow bark by increasing renal clearance. Minor/Significance Unknown.

              • rose hips

                rose hips will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

                willow bark decreases levels of rose hips by increasing renal clearance. Minor/Significance Unknown.

                rose hips increases levels of willow bark by decreasing renal clearance. Minor/Significance Unknown.

              • salicylates (non-asa)

                salicylates (non-asa) will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

                willow bark increases effects of salicylates (non-asa) by pharmacodynamic synergism. Minor/Significance Unknown. Willow bark contains salicylic acid, which may have additive effects/toxicity with salicylate drugs.

              • salsalate

                salsalate will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

                willow bark increases effects of salsalate by pharmacodynamic synergism. Minor/Significance Unknown. Willow bark contains salicylic acid, which may have additive effects/toxicity with salicylate drugs.

              • sodium bicarbonate

                sodium bicarbonate, willow bark. Mechanism: passive renal tubular reabsorption due to increased pH. Minor/Significance Unknown. Salicylate levels increased at moderate doses; salicylate levels decreased at large doses (d/t increased renal excretion of unchanged salicylic acid).

              • sodium citrate/citric acid

                sodium citrate/citric acid, willow bark. Mechanism: passive renal tubular reabsorption due to increased pH. Minor/Significance Unknown. Salicylate levels increased at moderate doses; salicylate levels decreased at large doses (d/t increased renal excretion of unchanged salicylic acid).

              • sulfadiazine

                willow bark increases levels of sulfadiazine by unspecified interaction mechanism. Minor/Significance Unknown.

              • sulfamethoxazole

                willow bark increases levels of sulfamethoxazole by unspecified interaction mechanism. Minor/Significance Unknown.

              • sulfasalazine

                sulfasalazine will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

                willow bark increases effects of sulfasalazine by pharmacodynamic synergism. Minor/Significance Unknown. Willow bark contains salicylic acid, which may have additive effects/toxicity with salicylate drugs.

              • sulfisoxazole

                willow bark increases levels of sulfisoxazole by unspecified interaction mechanism. Minor/Significance Unknown.

              • sulindac

                sulindac will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • tolazamide

                willow bark increases effects of tolazamide by plasma protein binding competition. Minor/Significance Unknown. Large dose of salicylate.

              • tolbutamide

                willow bark increases effects of tolbutamide by plasma protein binding competition. Minor/Significance Unknown. Large dose of salicylate.

              • tolfenamic acid

                tolfenamic acid will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • tolmetin

                tolmetin will increase the level or effect of willow bark by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • triamcinolone acetonide injectable suspension

                triamcinolone acetonide injectable suspension decreases levels of willow bark by increasing renal clearance. Minor/Significance Unknown.

              • valganciclovir

                willow bark will increase the level or effect of valganciclovir by acidic (anionic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • verapamil

                verapamil increases effects of willow bark by unknown mechanism. Minor/Significance Unknown. Enhanced antiplatelet activity.

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              Adverse Effects

              Frequency Not Defined

              Blood in stool

              GI complaints

              Hypersensitivity reactions

              Kidney damage

              Liver necrosis

              Nausea/vomiting

              Salicylate toxicity

              Skin rash (topical use)

              Tinnitus

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              Warnings

              Contraindications

              Aspirin hypersensitivity, asthma, diabetes mellitus, gout, hemophilia, hypoprothrombinemia, kidney disease, liver disease, PUD, viral infection (peds)

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              Pregnancy & Lactation

              Pregnancy Category: N/A

              Lactation: unsafe

              Pregnancy Categories

              A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

              B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

              C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

              D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

              X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

              NA: Information not available.

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              Pharmacology

              Mechanism of Action

              Contains salicin, which is converted to salicylic acid

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              Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.