Known Negative Drug-Vit C Interactions?

Any adverse effects of replacement vitamin C will be discuseed here. Topics include kidney stones, gall stones, oxidation, etc.
We plan to move good discussions from the General Topics forum here for posterity.

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Known Negative Drug-Vit C Interactions?

Post Number:#1  Post by twowheelfree » Sun Jan 09, 2011 11:53 pm

Anybody know of any negative consequences of taking C along with a drug?

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Re: Known Negative Drug-Vit C Interactions?

Post Number:#2  Post by majkinetor » Mon Jan 10, 2011 3:26 am

The most known interaction is with aspirin (easily prevented by not taking them together). Synergic effect may cause an increased bleeding in the digestive tract. Aspirin is one of the drugs that is for instance regularly prescribed to prevent heart attacks, strokes, and blood clot formation. This is especially important since Pauling Therapy may be used in parallel with allophatic therapy for CVD witch might include Aspirin.

Vitamin C may also reverse anticoagulant activity of warfarin.

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Re: Known Negative Drug-Vit C Interactions?

Post Number:#3  Post by pamojja » Mon Jan 10, 2011 1:45 pm

Excuse my bad translation skills of medical terms I don't even understand in my own language.. The following is from:

'Micronutrients'

Mitabolic Tuning - Prevention - Therapy
by Uwe Gröber
2011 edition

Special Interactions:

Acetylsalicylic acid: ASS may lower vitamin C level in blood and white blood-cells.
Bortezomib: In animal-trials oral vitamin C hinders the tumor-destructive effects of protease-inhibitors.
Iron: Vitamin C improves the absorption of non-heme iron through reduction of Fe3+ to Fe2+, as well as through chelation of iron.
Copper: Long-duration high dose vitamin C doses may lower copper absorption and coerulo-plasmin levels.
Selen (Sodiumselenite): Vitamin C may reduce the absorption of Sodiumselenite (take 1-2 hrs apart).
Vitamin E: Intake of vitamin E raises vitamin C needs. In investigations with non-smokers and vitamin E doses > 500mg/day there was an decline of vitamin C plasma-levels of up to 40%.
Zytostatika: In animal-trials the combined intake of Doxorubicin with a peri-enteral application of vitamin C (2g/kg body weight, i.v. or intra-peritoneal) could reduce the cardio-toxic side-effects of Antrazyklins and increase survival-time significantly. Thereby the zytotoxic effect of the Anthorazyklins wasn't reduced. Pharmacological in-vitro studies have further shown, that vitamin C increases the zytotoxic effects of anti-neoplastic substances like Cisplatin, Dacarbazin, Doxorubicin, Gemcitabin, Pactitaxel, Tamoxiflen and 5-Flourouracil (5-FU).

Contra Indications:
Oxalat-Urolithiasis, Iron-storage illnesses (Thalassemia, Hemochromatose); High-dose applications: Glucose-6-P-Dehdrogenase-insufficiency (G6ODG-insufficiency), kidney-insufficiency.

Note:
High vitamin C doses may disturb the determination of clinic parameters in urine (glucose, uric acid, creatinine, inorganic phosphate) and of occult blood in bowel movements.



Though in my own case with about 16 gram daily vitamin C since 2 years serum iron level decreased even further from already low levels (still within references).

Just for completion, here's what 'Natural Standard' has to say, though with their overly critical attitude, take this with a big dose of doubt:

Most herbs and supplements have not been thoroughly tested for interactions with other herbs, supplements, drugs, or foods. The interactions listed below are based on reports in scientific publications, laboratory experiments, or traditional use. You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare provider before starting a new therapy.

Interactions with Drugs

* Vitamin C may increase adverse effects associated with acetaminophen or aluminum-containing antacids such as aluminum hydroxide (Maalox®, Gaviscon®).
* Vitamin C may increase blood levels and adverse effects of aspirin, whereas aspirin may decrease blood levels of vitamin C.
* The effects of vitamin C may be decreased by barbiturates including phenobarbital (Luminal®, Donnatal®), pentobarbital (Nembutal®), or secobarbital (Seconal®).
* Vitamin C supplementation may decrease levels of the drug fluphenazine in the body.
* Concomitant administration of high doses of vitamin C can reduce steady-state indinavir plasma concentrations.
* There is limited case report evidence that high dose vitamin C may reduce side effects of levodopa therapy such as nausea or malcoordination.
* Nicotine products such as cigarettes, cigars, chewing tobacco, or nicotine patches may decrease the effects of vitamin C.
* Oral estrogens may decrease the effects of vitamin C in the body. When taken together, vitamin C may increase blood levels of ethinyl estradiol.
* The effects of vitamin C may be decreased by tetracycline antibiotics such as doxycycline (Vibramycin®), minocycline (Minocin®), or tetracycline (Sumycin®).
* Vitamin C in high doses appears to interfere with the blood thinning effects of warfarin by lowering prothrombin time (PT), as noted in case reports in the 1970s. Complications have not been reported (such as increased blood clots).
* High doses of vitamin C are not recommended in patients with kidney failure. Caution is advised when taking vitamin C and drugs that may damage the kidneys due to an increased risk of kidney failure.

Interactions with Herbs and Dietary Supplements

* When taken together, vitamin C may increase the absorption of iron in the gastrointestinal tract, although this effect appears to be variable and may not be clinically significant.
* Vitamin C may increase absorption of lutein vitamin supplements.
* Large doses of vitamin C may interfere with the absorption and metabolism of vitamin B12.
* In theory, large doses of vitamin C may also interact with herbs and supplements with hormonal, antibacterial and blood thinning (anticoagulant) activity.
* Caution is advised when taking vitamin C and agents that may damage the kidneys due to an increased risk of kidney failure.

Author Information

* This information is based on a systematic review of scientific literature edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (http://www.naturalstandard.com).

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Re: Known Negative Drug-Vit C Interactions?

Post Number:#4  Post by majkinetor » Tue Jan 11, 2011 12:44 am

Almost all of above is not something you should be concerned with.
Also, at least 50% is not about drug-vit C interaction altho that dichotomy (supplement-drug) is artificial - all are chemicals.

About hypothetical deficiencies of other minerals (copper, selenium), although some of that might happen in vivo, I doubt its effect could be big and its certainly easily preventable by taking 1 good multi-mineral-vitamin tablet daily or solo complexes or good diet (for instance Brazil Nut). Keep in mind that there might be chain reaction too. For instance Mg deficiency might be followed by number of symptoms which may drain or over accumulate other nutrients. So this is not big concern IMO and is (probably) totally preventable with 99.9% of people.

Oxalat-Urolithiasis is not true - this is technical name for kidney stones and Vit. C actually prevents them for most people. There seems to be a small subset of population with history of calcium kidney stones that might be at risk but even those people could tolerate higher doses (up to 4g AFAIK). Also, adding Mg should prevent stone formation as Mg has higher affinity to oxalates and will bind before Ca does.

G6ODG-insufficiency concern is important only for IV use. This deficiency is very rare.
Kidney-insufficiency might be concern but some people with history of kidney disease (like Pauling) didn't have a problem taking between 10-30g per day.

B12 caution is not true. This was based on 1 flawed experiment.

Things from animal trials could not be just like that concluded for humans.

My Vit C supplementation regime includes Mg-Citrate (~600mg), Selenium (~100-200mcg), D3 (5000 IU) and K2 (MQ7 or MQ4 variant, 25-100mcg) and 1 multi-mineral-vitamin with higher then usual B complex vitamins (~50mg of most of B vitamins) and good diet including around 1g/kg of protein.
Absorption of Mg depends on D3 and those 2 will also reduce blood pressure which might be concern if you use Sodium Ascorbate, Selenium boosts Glutathion which boosts C and vice-versa, B6 is rate limiting factor in Vitamin C boosted collagen production, L-Lysine & L-Prolyne from protein improve collagen quality. K2 is important for correct Ca metabolism which is boosted by D3 and can not finish correctly without it and furthermore prevents eventual D3 toxicity.
Last edited by majkinetor on Tue Jan 11, 2011 4:41 am, edited 1 time in total.

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Re: Known Negative Drug-Vit C Interactions?

Post Number:#5  Post by majkinetor » Tue Jan 11, 2011 2:38 am

OK, I organised this info you posted a bit and added some additional info so its more clear. I don't know how drug information is accurate.
If interactions with supplements exist they are mild and easily preventable.

Drugs
    Aspirin (aka Acetylsalicylic acid)
    Aspirin may lower vitamin C level in blood, tissue and white blood-cells. Taking an aspirin a day to prevent heart attacks and strokes causes blood loss via the digestive tract on the order of about a tablespoon per day which results in iron loss. A low serum vitamin C level can cause excessive gastric mucosal bleeding. Vitamin C combats aspirin induced hemorrhage and boosts iron absorption.
    Bortezomib (chemotherapy)
    In animal-trials oral vitamin C hinders the tumor-destructive effects of protease-inhibitors.
    Zytostatika (chemotherapy)
    In animal-trials the combined intake of Doxorubicin with a peri-enteral application of vitamin C (2g/kg body weight, i.v. or intra-peritoneal) could reduce the cardio-toxic side-effects of Antrazyklins and increase survival-time significantly. Thereby the zytotoxic effect of the Anthorazyklins wasn't reduced. Pharmacological in-vitro studies have further shown, that vitamin C increases the zytotoxic effects of anti-neoplastic substances like Cisplatin, Dacarbazin, Doxorubicin, Gemcitabin, Pactitaxel, Tamoxiflen and 5-Flourouracil (5-FU).
    Barbiturates (central nervous system depressants)
    The effects of vitamin C may be decreased by barbiturates including phenobarbital (Luminal®, Donnatal®), pentobarbital (Nembutal®), or secobarbital (Seconal®).
    Paracetamol (pain reliever, fever reducer).
    Vitamin C may increase adverse effects associated with acetaminophen or aluminum-containing antacids such as aluminum hydroxide (Maalox®, Gaviscon®).
    Fluphenazine (antipsychotic drug)
    Vitamin C supplementation may decrease levels of the drug fluphenazine in the body.
    Indinavir (anti-retroviral therapy for AIDS)
    Concomitant administration of high doses of vitamin C can reduce steady-state indinavir plasma concentrations.
    Levadopa (Parkinson disease)
    There is limited case report evidence that high dose vitamin C may reduce side effects of levodopa therapy such as nausea or malcoordination.
    Oral estrogens
    Oral estrogens may decrease the effects of vitamin C in the body. When taken together, vitamin C may increase blood levels of ethinyl estradiol.
    Antibiotics
    The effects of vitamin C may be decreased by tetracycline antibiotics such as doxycycline (Vibramycin®), minocycline (Minocin®), or tetracycline (Sumycin®). Concomitant intake of vitamin C. can enhace bioavailability and elevate blood levels of tetracycline. Prolonged use of tetracycline may reduce blood levels of ascorbic acid and can interfere with the activity of vitamin C as well as folic acid, potassium, and vitamins B2, B6, R12, and K. Vitamin C may also protect against hepatic and renal toxicity occasionally associated with tetracycline therapy, as well as the much more common adverse effect of dental and oral discoloration.
    Warfarin (blood thinning agent)
    Data from some, but not all, animal experiments and rare, unqualified case reports indicates that vitamin C, in high doses, might decrease functional level and therapeutic acdtivity of warfarin, but the cumulative body of evidence fails to support a well-founded, consistent, and generalizable conclusion. Findings from the four controlled trials involving large number of subjects indicate a lack of clinically significant interaction between warfarin and ascorbic acid, event at doses as high as 10g vitamin C per day.
    Insulin (diabetes treatment, technically orthomolecular substance)
    The cellular uptake of vitamin C is promoted by insulin and inhibited by hyperglycemia.


Supplements
    Magnesium
    Prolonged use of 20+ grams of Vitamin C may induce slight Magnesium deficiency. Muscle cramps are an obvious sign of magnesium deficiency.
    Iron
    Vitamin C participates in many aspects of iron metabolism, including uptake, transport, regulation, mobilization, utilization, and sequestration.
    Vitamin C improves the absorption of non-heme iron through reduction of Fe3+ to Fe2+, as well as through chelation of iron. This effect appears to be variable and may not be clinically significant. Iron poisoning can become an issue to people with rare iron overload disorders, such as haemochromatosis.
    Copper
    Vitamin C intakes of 1.5g daily for about 2 months resulted in decreased serum copper and ceruloplasmin, a copper-containing protein with oxidase activity; however, despite the decrease, serup copper levels remained within normal range. Human cells treated wtih vitamin C have exhibited enhaced copper uptake from ceruloplasmin. Decreased intestinal absorption of copper by ascorbic acid has been observed in several animal species. The proposed mechanism of interaction for this effect suggests that vitamin C stimulated iron mobilization and the mobilized iron in turn inhibited copper absorption due to well known antagonism between copper and iron. In addition, C may inhibit the binding of copper to metallothionein, a protein found in the intestinal cells and other body cells. Human studies showed mixed results so far. Anemia is a clinical sign of copper deficiency.
    Selenim
    Vitamin C may reduce the absorption of Sodiumselenite (take 1-2 hrs apart).
    Vitamin C increases the absorption of organic selenium-containing yeasts.
    Vitamin E
    Intake of vitamin E raises vitamin C needs. In investigations with non-smokers and vitamin E doses > 500mg/day there was an decline of vitamin C plasma-levels of up to 40%.
    Lutein (carotenoids)
    Vitamin C may increase absorption of lutein vitamin supplements.
    Bioflavonoids
    Bioflavonoids such as Quercetin, Grape Seed Extract, Catechins, citrus bioflavonoids (Narignin, Hesperidin, Rutin...) etc. are considered a factor in enhancing the absorption of Vitamin C, and quite possibly serve to prolong its effectiveness.
    N-Acetyl Cysteine
    When taking N-acetyl cysteine it is recommended that two to three times as much vitamin C be taken at the same time. Failure to do so may result in more harm than good from taking this product because of the prolonged presence of the oxidized form of L-Cysteine. The vitamin C also helps keep the glutathione that is produced from the Cysteine in its reduced form so that it can continue acting as an antioxidant.
    Alpha lipoic acid
    Alpha lipoic acid is incredibly effective when used in addition to vitamin C. DHLA may also reduce the oxidized form of vitamin C.

Contra indications:
  • High doses of vitamin C are not recommended in patients with kidney failure. Caution is advised when taking vitamin C and drugs that may damage the kidneys due to an increased risk of kidney failure.
  • High vitamin C doses may disturb the determination of clinic parameters in urine (glucose, uric acid, creatinine, inorganic phosphate) and of fecal occult blood in bowel movements.
    Vitamin C can change lab test results taken to establish amounts of sugar in the blood and urine and can give a false negative in tests for blood in the stool. There are test kits available that are not affected by Vitamin C.
  • High doses of Vitamin C uptake increase oxalate levels in urine, and it is hypothesized that this could lead to kidney stones. This effect was not observed in-vivo.
  • The daily use of chewable Vitamin C tablets can cause severe dental erosion in a matter of months.
  • Rare G6PD Deficiency ( glucose-6-phosphate dehydrogenase enzyme )must be checked before starting I.V. Vitamin C. High dose intravenous vitamin C (250-350 mg/dl) is a strong pro-oxidant and giving a pro-oxidant to a G6PD-deficient patient can cause hemolysis of their red blood cells.
  • Some people using mega dose therapy of vitamin C may have side effects such as gastrointestinal complaints including diarrhea, nausea and abdominal cramps. These side effects normally stop as soon as high potency intake is reduced or stopped. Dose that causes discomfort is individual and range from 500mg to 25g or more and is usually in range of 5g-15g
Last edited by majkinetor on Fri Jan 28, 2011 1:41 am, edited 17 times in total.

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Re: Known Negative Drug-Vit C Interactions?

Post Number:#6  Post by Dolev » Tue Jan 11, 2011 3:58 am

•Some people using mega dose therapy of vitamin C may have side effects such as gastrointestinal complaints including diarrhea, nausea and abdominal cramps.


I get that from mega dose pizza!
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Re: Known Negative Drug-Vit C Interactions?

Post Number:#7  Post by majkinetor » Tue Jan 11, 2011 4:16 am

You shouldn't mega doze pizzas. It produces carbohydrate and insulin surge :P

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Re: Known Negative Drug-Vit C Interactions?

Post Number:#8  Post by ofonorow » Tue Jan 11, 2011 7:19 am

majkinetor wrote:The most known interaction is with aspirin (easily prevented by not taking them together). Synergic effect may cause an increased bleeding in the digestive tract. Aspirin is one of the drugs that is for instance regularly prescribed to prevent heart attacks, strokes, and blood clot formation. This is especially important since Pauling Therapy may be used in parallel with allophatic therapy for CVD witch might include Aspirin.

Vitamin C may also reverse anticoagulant activity of warfarin.


I know that Irwin Stone and others cited research to the contrary, that because of the risk of bleeding, all doctors should recommend vitamin C be taken with aspirin as a matter of course. In other words, that it was dangerous to take aspirin alone (without vitamin C.) If that is what you meant, I just want to make it clear. The reference is somewhere in the Healing Factor http://www.vitamincfoundation.org/stone/

As far as the idea that vitamin C can counteract the anticoagulant activity of rat poison (warfarin) I would appreciate a reference.

In my mind, the most significant interaction between vitamin C and a drug is with the (from memory) so-called P450 enzyme system (the one grapefruit interferes with). This enzyme system is the major tool the body uses to detoxify (remove toxins.) Vitamin C is important for this enzyme system to function, and thus important for the quick removal of drugs. (Reference Vitamin C: Its Chemistry and Biochemistry, Davies, Austion,Partridge) So, unless the drug (poison) is required to stay in the body longer, vitamin C probably helps rid the body of it.

Vitamin C, Its Chemistry and Biochemistry, Page 89.

"A significant role is played by oxidizing enzymes associated with the microsomal fraction, notably a cytochrome called P450 which is a mixed function oxidase (MFO). This very broad-specificity enzyme, which helps dispose of ethanol, benzene, tetracholromethane, and polychlroinated biphenyls (PCBs) to name but four notorious toxins, may depend for its action on the presence of vitamin C since...."


So the answer to the question is that although we cannot prove a negative, taking vitamin C along with a drug is generally favorable, with few or no known contraindications.
Owen R. Fonorow
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Re: Known Negative Drug-Vit C Interactions?

Post Number:#9  Post by twowheelfree » Tue Jan 11, 2011 8:34 am

Many, many thanks for all your replies and info. All useful. After reading the response, in retrospect, I realize, I would have been more accurate to ask about "contra-indications" to taking Vit C. :lol: That, too, was answered without my directly asking!! :)

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Re: Known Negative Drug-Vit C Interactions?

Post Number:#10  Post by majkinetor » Tue Jan 11, 2011 9:56 am

Owen wrote:As far as the idea that vitamin C can counteract the anticoagulant activity of rat poison (warfarin) I would appreciate a reference.

Walfarin and Related Oral Vitamin K Antagonist Antikoogulants
From "Herb, Nutrient, and Drug Interactions: Clinical Implications and Therapeutic Strategies by Mitchell Bebel Stargrove ND". Data from some, but not all, animal experiments and rare, unqualified case reports indicates that vitamin C, in high doses, might decrease functional level and therapeutic acdtivity of warfarin, but the cumulative body of evidence fails to support a well-founded, consistent, and generalizable conclusion.
Findings from the four controlled trials involving large number of subjects indicate a lack of clinically significant interaction between warfarin and ascorbic acid, event at doses as high as 10g vitamin C per day.

Read...


Owen wrote:I know that Irwin Stone and others cited research to the contrary, that because of the risk of bleeding, all doctors should recommend vitamin C be taken with aspirin as a matter of course.


Nutrition and Environmental Health: The vitamins
Analysis of the urine following aspirin administration showed an increased output of ascorbic acid..... Subsequent in vivo studies with humans revealed that administration of an acute loading dose of 600mg aspirin prevented the uptake of ascorbic acid into leucocytes even at doses of 500 to 2000mg (Loch et al., 1974; Wilson, 1975).

Drug-induced nutritional deficiencies
In patients with reumathoid arthritis aspirin caused ascorbic acid depletion of tissues

The Healing Factor
Even an aspirin should be accompanied by a large does of ascorbic acid to heighten its analgesic effect and lessen its toxic action on the body.

Owen wrote:So the answer to the question is that although we cannot prove a negative, taking vitamin C along with a drug is generally favorable, with few or no known contraindications.

Yes, definitely.

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Re: Known Negative Drug-Vit C Interactions?

Post Number:#11  Post by ofonorow » Wed Jan 12, 2011 5:39 am

I admit I am still a little confused as your reference seem to make my point?
Findings from the four controlled trials involving large number of subjects indicate a lack of clinically significant interaction between warfarin and ascorbic acid, event at doses as high as 10g vitamin C per day.
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Re: Known Negative Drug-Vit C Interactions?

Post Number:#12  Post by majkinetor » Wed Jan 12, 2011 5:49 am

I admit I am still a little confused as your reference seem to make my point?

Yes, I changed the above list after doing some more research about it. After carefully reading about it, I must say that it is embarrassing that some "case reports" are even included in analyses. For instance, in the book mentioned above they write that it is reported that Vitamin C might had caused the interaction with Warfarin, however, nothing is known about the dose and the timing of Vitamin C the woman in question was taking ?! So it was probably guess based on animal studies which were never proven for humans.

I also removed aspirin note that aspirin + C could cause bleeding after you added some more info about it. I searched more about it and while other things mentioned can be found, I couldn't find anything about this in Google books & schoolar, and it doesn't seem reasonable knowing the physiological role of vitamin C. Actually, it seems quite opposite as Irwan Stone talks - bleeding is due to aspirin induced vitamin c deficiency.

Travell & Simons' myofascial pain and dysfunction wrote:VITAMIN C AND ASPIRIN. The increased capillary fragility characteristic of a low serum vitamin C level can cause excessive bleeding in muscles injected for TrPs. Cap illary hemorrhage augments postinjection soreness and leads to unsightly ecchy moses. A frequent source of increased bleeding due to low vitamin C is tobacco. Megadose vitamin C therapy daily for 1 week should correct this deficiency. At least 500 mg of timedrelease vitamin C three times daily is recommended for a minimum of 3 days prior to injection of TrPs. The im portance of vitamin C for smokers was re viewed in Section 12 of this chapter. A daily dose of aspirin increases the susceptibility to bleeding. The patient should take no aspirin for 3 days before TrP injection or needling.

.....
Although megadoses of vitamin C have been identified as theoretically causing cystine and oxalate stones in the urinary
tract , it is becoming apparent that patients with normal renal function can tolerate exceptionally high dosage of vitamin C. One patient took 15 g of vitamin C daily for 4 months without ill effects.



EFFECT OF ASPIRIN ON THE GASTRIC MUCOSA OF GUINEAPIG
Abstract:
Guineapigs were allocated to one of four diets (normal without aspirin, scorbutogenic without aspirin, normal with aspirin, or scorbutogenic with aspirin) for 2 weeks, since guineapigs usually become frankly scorbutic after a scorbutogenic diet for 3-4 weeks. The aim was to determine the influence of a subclinical scorbutic state on the gastric erosions provoked by aspirin. Guineapigs on the scorbutogenic diet bled from the gastric mucosa significantly more often than those on a normal diet. The addition of aspirin to a scorbutogenic diet significantly increased the likelihood of gastric mucosal bleeding. Aspirin thus seems to precipitate gastric mucosal hæmorrhage more readily when guineapigs are in a subclinical scorbutic condition. These results, taken in conjunction with the clinical findings described elsewhere, suggest that aspirin is more likely to cause significant gastric mucosal hæmorrhage when subclinical scurvy is present.

If anyone has some more info or objections to above list let me know. I wish to compile definite vitamin C interaction list.


Rider JA, et al. Double-blind comparison of effects of aspirin and namoxyrate on pH of gastric secretions, fecal blood loss, serum iron and iron-binding capacity in normal volunteers. Curr Ther Res 1965;7:633-8.
Taking an aspirin a day to prevent heart attacks and strokes causes blood loss via the digestive tract on the order of about a tablespoon per day. This results in iron loss.

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Re: Known Negative Drug-Vit C Interactions?

Post Number:#13  Post by majkinetor » Thu Jan 13, 2011 3:42 am

I managed to find this fantastic peace of info everybody should know about various drugs and Vitamin C. The book contains entire chapter devoted to drug - Vitamin C interactions. You can start reading here, I OCR-ed some of the stuff we talked about.

Herb, Nutrient, and Drug Interactions: Clinical Implications and Therapeutic Strategies by Mitchell Bebel Stargrove ND LAc

Aspirin
    Effect and Mechanism of Action

    Vitamin C has been shown to reduce gastric mucosal damage and gastric toxicity induced by ASA-generated reactive oxygen metabolites [55, 56]. After ingestion, both aspirin and salsalate are rapidly converted ro salicylic acid. Aspirin and salicylic acid can increase urinary excretion of vitamin C, lower leukocyte ascorbic acid levels (by 50%), and decrease its metabolic availability [57 - 60]. The gastric mucosa is the largest depot of ascorbic acid in human body, with ascorbic acid concentrations 25 times higher than in plasma [61]. Some data suggest that aspirin may protect endothelial cells from oxidant damage via the nitric oxide (NO) cyclic guanosine monophosphate (cGMP) path way [62,63]. However, gastric epithelial cells require vitamin C to translate inducible heme oxygenase (HO-1) miRNA "into active protein, which then may exert gastroprotection by its antioxidant and vasodilative propertie... Induction of HO-1 is considered to be an adaptive cellular mechanism in response to oxidative stress" [64]. Thus, a significant body of data shows that the oxidative damage caused by aspirin can induce exfoliation of gastric epithelial cells, formation of gastric erosions, and GI hemorrhage. In particular, the gastric mucosa of individuals deficient in vitamin C (and possibly other, synergistic nutrients) might be less able to increase the rate of cell production and therefore susceptible to increased bleeding after aspirin ingestion. Vitamins A, E, and C and bioflavonoids may enhance the "antiaggregative effect of aspirin, prolongate its activity, [and] increase hypocoaguloemia due to reduced releasing of thrombocyte factors 3 and 4 into plasma. [65]

    Research

    Russell. Goldberg, et al published two related studies in The Laneet in 1968 that examined the relationships between leucocitic ascorbic acid levels (L.A.A.) and GI hemorrhage in humans and aspirin and gastric mucosa in vitamin depleted guinea pigs. On measuring leukocyte-ascorbic acid levels in
    60 patients with Cil hemorrhage, they found that the mean value of 14.2 ng/10* white blood cells (WBCs) was "significantly lower than that found in a matched peptic ulcer control group (17.6) and in a healthy control group (23.7) They determined that ascorbic acid levels were "significantly lower in patients in whom aspirin or alcohol might have precipitated bleeding than in those in whom no precipitating factor was present and that "the association of low L.A.A levels with aspirin or alcohol ingestion was present whatever the causation of haemorrhage." they concluded: "Subclinical scurvy may be an additional factor ni maintaining haemorrhage initially precipitated by aspirin or alcohol, and poor dietary intake of vitamin C seems the most probable explanation for the low
    L.A.A. levels observed." This susceptibility to bleeding from acute gastric lesions (erosions) appears greater in elderly indi viduals. In the animal experiment they observed: "Guinea pigs on the scorbutogenic diet bled from the gastric mucosa significantly more often than those on a normal diet.
    The addition of aspirin to a scorbutogenic diet significantly increased the likelikehood of gastric mucosal bleeding." These findings led them to conclude that aspirin "thus seems to precapitate gastric mucosal haemorrhage more readily when guinea pigs ate in a subclinical scorbutic condition." Thus, based on both studies they interpreted their results to "suggest that aspirin is more likely to cause significant gastric mucosal haemorrhage when subclinical scurvy is present." In a subsequent letter, Croft reviewed several studies regarding the impact of malnourishment on compromised gastric mucosa and aspirin-induced loss of epithelial cells and proposed that an "explanation of their finding could be that a low turnover of gastric epithelial cells renders the mucosa particularly susceptible to aspirin."

    Sahud and Cohen compared platelet and plasma levels of ascorbic acid and the effect of aspirin ingestion in 45 healthy individuals and 34 patients with rheumatoid arthritis. They observed that plasma ascorbic acid levels were "abnormally low in all rheumatoid subjects exccpt those taking supplemental vitamin C. Moreover, looking at platelet levels of ascorbic acid, which more accurately reflect tissue stores than plasma levels, they found "significantly low platelet levels of ascorbic acid .. only in those rheumatoid patients receiving high doses of aspirin — i.e., 12 or more tablets per day." Based on these findings, they concluded that "a high dosage of aspirin in patients with rheumatoid arthritis is associated with tissue ascorbic acid depiction" and recommended that "administration of supplemental ascorbic acid to rheumatoid patients receiving a high dosage of aspirin as primary therapy seems
    warranted." Loh et al. examined the effect of aspirin on uptake of ascorbic acid into leukocytes in both in vitro and human studies. First, they compared the uptake of ascorbic acid into leukocytes incubated in a buffered medium of ascorbic acid with that in a medium also containing aspirin and observed that the aspirin completely inhibited absorption of the ascorbic acid. In normal adults, they observed a significant increase in plasma and leukocyte ascorbic acid during the 2 hours alter administration of 500 mg ascorbic acid but found that simultaneous administration of 600 mg aspirin "further increased plasma ascorbic acid concentrations but completely arrested uptake of ascorbic acid into the leukocyics." likewise, administration of ascorbic acid every 6 hours increased urinary excretion of ascorbic acid and produced a concomitant increase in leukocyte ascorbic acid. In contrast, the "simultaneous administration of aspirin with the ascorbic acid resulted in a further significant increase in excretion of ascorbic acid and a simultaneous fall in leukocyte ascorbic acid." Furthcr, administration of aspirin even 6 hours for 7 days "resulted in diminished plasma and leukocyte ascorbic acid concentrations within four days. Thereafter, reduced ascorbic acid levels just in excess of those associated with production of scorbutic symptoms were maintained." The authors concluded that "supplementary ascorbic acid should be administered to individuals receiving aspirin therapy. Not all researchers have demonstrated this adverse effect of
    aspirin on vitamin C levels; at least not in healthy populations, Johansson and Akesson conducted a clinical trial in which healthy adults were given four different diets tor 1 week: "low ascorbic acid diet, low ascorbic acid diet plus acetylsalicvlic acid" (3 g/day), "high ascorbic acid diet" (1 g/day), and high ascorbic acid diet plus acetylsalicylic acid. They observed that "at low ascorbic acid intake, acetylsalicylic acid increased urinary ascorbic acid, but at high ascorbic acid intake, acetylsalicylic acid instead decreased urinary ascorbic acid." They hypothesized that the later effect resulted from inhibited intestinal absorption of ascorbic acid, and the former effect from "decreased protein binding and tissue uptake of ascorbic acid caused by cetylsalicylic acid,". Overall, they reported that in "no instance" did the acetyisalicylic acid affected plasma ascorbic acid levels.

    In a double-blind, randomized, crossover study involving 14 healthy volunteers, McAlindon et al. administered aspirin 900 mg twice daily and either placebo, vitamin C 1 g twice daily, allopurinol 100 mg twice daily, or sulphasalazine 1 g twice daily for days. They demonstrated that aspirin induced gastric injury, as assessed endoseopically and by quantising mucosal reactive oxygen metabolite release by measuring chemiluminescence, but reported that no drug reduced any parameter of gastric injury. Morover, they found that vitamin C reduced duodenal injurs, as assessed bv Lanza score.

    In two studies involving healthy subjects, Oammanu et al. Mid Schulz et al investigated the effects of the interaction between aspirin and ascorbic acid on gastric mucosa and plasma ascorbic acid concentrations. In the first, a randomized, four-told crossover study, they performed serial esophagogastro-duodenoscopy on 17 healthy subjects before and after each course of 4 day dosing and collected gastric aspirates to detect microbleeding. They observed that subjects administered the combination of buffered acetylsalicylic acid and ascorbic acid "yielded the lowest Lanza score, the lowest increase in the number of mucosal petechiac and the lowest increase in the amount of gastric microbleeding." In contrast, those subjects receiving "acetylsalicylic acid plus paracetamol plus caffeine showed the highest Lanza score of all treatments, and a considerably greater sum of pctcchiac in the oesophagus, stomach and duodenum compared with those receiving hulfered acetylsalicylic acid plus ascorbic acid." The authors concluded that this "trial confirms that buffering of acetylsalicylic acid improves local gastric tolerability. In a related prospective, randomized, double-blind study involving three groups of 15 subjects each, these researchers compared concentrations of ascorbic acid in "gastric mucosa, gastric juice, urine and plasma in healthy subjects under steady state and fasted conditions" after 6 days of ascorbic acid (0.48 g/day) with and without concomitant administration of acetylsalicylic acid (0.8 g/dav). Treatments were swindled without any washout, resulting in a 14 day study period overall. Initially, they found that ascorbic acid concentrations were highest in the gastric mucosa, followed by gastric juice, plasma, and urine. Subsequently, on day 7, ascorbic acid concentrations in gastric mucosa, plasma, and unnc had increased to a statistically significant degree in those groups receiving ascorbic acid and decreased significantly in the group receiving aspirin only. During this period, differences in ascorbic acid concentrations in gastric juice, between the treatment groups, were not statistically significant. Thus, in healthy subjects, "clinically relevant doses" of aspirin reduced ascorbic acid concentrations in gastric mucosa "by about 10% within six days resulting from antioxidative defense mechanisms." The authors concluded by recommending, as beneficial, a "protective adjunct administration" of vitamin C, particularly in "patients with long-term ASA treatment or conditions with additional risks such as elderly subjects with unfavorable dietary conditions and impaired antioxidative protection.

    Animal experiments by Bvshchevskil et al. indicate that concomitant administration of aspirin with antioxidants, specifically, vitamins A, E, and C and bioflavonoids, "in balanced diet in doses adequate to therapeutic ones" may potentiate aspirin's atiaggregative effect. They recommended more research and suggested that "administration of [the] vitamin combination studied is likely to diminish thrombocyte aggregative activity to a level needed using lower aspirin doses." More recently, Fiebich et al reported "synergistic inhibitory effect of ascorbic acid and acetylsalicylic acid on prostaglandin E2 release in primary rat microglia." The effects of vitamin C on renal clearance of aspirin suggest another potential interaction from coadministration, although bimodal in its clinical implications. In a review on drug-nutrient interactions among elderly patients, Schumann 2 noted that "high doses of vitamin C" can further reduce renal clearance of acetylsalicylic acid and other acidic drugs among elderly patients, in whom renal clearance is often unpaired. As suggested by the author, and concurrent with the findings of several studies previously diseussed, this possible pattern of interaction indicates an influence of vitamin C on the risk of toxicity inherent to aspirin that is neither inherently adverse nor beneficial. Professional supervision and reasonable monitoring are warranted, with titration of aspirin dose being an advantageous possibility. Such situations can represent risks or opportunities, depending on the characteristics of the patient and the rationale for aspirin administration, and reiterate the preeminent need for inquiry about patient use of supplemental nutrients and comprehensive and coordinated clinical management of the intake of drugs and nutrients among geriatric patients, which is numerous and complex in most cases.

    Nutritional Theropeurics, Clinical Concerns, and Adaptations
    Aspirin and vitamin C may he the most frequently self-pre-scribed medicinal substances in modern culture, and as a result, many individuals forget that adverse elfects are a possibility with any agent. Health care professionals treating patients regularly taking aspirin are advised to educate them regarding the inherent risks of aspirin intake, particularly damage to the GI mucosa and microhemorrhage. In this context, it may also be prudent to suggest the potential protective value of supplementing with 200 to 500 mg vitamin C per day, as typically found in multivitamins. Although not conclusive, the body of available evidence indicates that vitamin C may moderate several of the adverse elfects associated with aspirin intake and may provide some synergistic influence. Further, the populations more likely to use aspirin regularly are also more likely to be elderly, to have aspirin induced gastric mucosal damage and bleeding, and to be on a nutrient-compromised diet, all of which increase the adverse efleets of aspirin on vitamin C status and general health. Professional supervision and periodic monitoring are warranted in such patients, as well as in chose with compromised renal function, to avoid adverse effects of aspirin and an potential added risk that might theoretically derive from coadministration of vitamin C. Although not yet the direct subject of scientific research, the known supportive influence of vitamin C on absorption of nonheme iron might be of benefit in countering the tendency to anemia in those using aspirin on a regular basis. Lastly, chronic use of aspirin, other than as cardiovascular prophylaxis, suggests the need for a more fundamental therapeutic strategy aimed at analyzing and resolving the causes of pain and inflammation.

Antihypertensive Medications (Generally)

    Effect and Mechanism of Action
    The antioxidant activity of vitamin C may play a protective role against the increased production of reactive oxygen species associated with essential hypertension. High dose intraarterial ascorbic acid levels may ameliorate endothelial dysfunction, in individuals with hypertension.

    Research
    In 1 small, randomized, double-blind, placebo-controlled trial, Duftv et al. investigated the effect of ascorbic acid treatment on blood pressure in 45 patients with hypertension who continned conventional antihypertensive medications. Systolic, diastolic, and mean blood pressures in the treatment and placebo groups were similar at baseline and alter acute treatment. They observed that 1 month of ascorbic acid treatment (500 mg/day) significantly decreased systolic blood pressure, in contrast to placebo, which had no effect. Likewise, after I month, ascorbic acid decreased mean blood pressure from 110 (12) to 100 (8) mm Hg, an effect significantly ditferent from placebo. However, whereas 1 month of ascorbic acid decreased diastolic blood pressure, this response was not significant compared with placebo. Based on these findings, the researchers concluded that "the present study suggests that 500 mg of ascorbic acid daily is useful for blood presure control in patients with hypertension" and suggested continued research with larger and longer clinical trials. They also noted: "Epidemiological studies show that dietary intake of ascorbic acid correlate inversely with hypertension and its clinical sequelae."

    Another study on the progression of hypertension produced potentially important findings related to vitamin C usage, but not directly related to an interaction between vitamin C and conventional antihypertensive drugv Kim et al. conducted a double-blind, randomized, controlled trial comparing the effects of 50 or 500 mg daily for 5 years on blood pressure in 224 Japanese subjects in a region with high gastric cancer and stroke mortality levels. Before supplementation, neither systolic nor diastolic blood pressure was significantly related with the serum vitamin C concentration. They found that vitamin C administration failed to produce any signifikant decrease in systolic or diastolic blood pressure. After 5 years, systolic blood pressure significantly increased in groups, regardless of vitamin C dose, compared with baseline, with the increase in low-dose and moderate-dose groups quite similar. Notably, study subjects were slightly less likely to smoke than the general population, but had all been serologically diagnosed with atrophic gastritis.

    Nutritional therapeutics, Clinical Concerns, and Adaptations
    Further research into tihe potential interaction between antihypertensive medications and vitamin C is warranted. Tending substantive findings, physicians might find it prudent to prescribe vitamin C, at a modest dose level, to patients undergoing treatment for hypertension. Proper monitoring at home and during periodic examinations is appropriate, but no substantive research data indicate a significant risk for such individuals with vitamin C administration over an extended period. The importance of a diet emphasizing vegetables and fruits (i.e., rich in nutrients such as vitamin C is fundamental and should be vigorously conveyed to patients.

Chemotherapy and Radiotherapy
    Oxygen radical can act as highly toxic stressors contributing to ontogenesis and other pathological processes. Higher intake of vitamin C and related nutrients through dietary sources is generally associated with reduced risk for many forms of cancer. In particular, vitamin C know for direct activity as a free radical
    scavenger, its central role in supporting intracellular glutathione (GSH) stores, and its synergistic relationship with other antioxidant nutrients and L-acetylcysteine (NAC). Emerging research indicates that pharmacological ascorbic acid concentrations, as attainable through IV administration, selectively kill cancer cells in vitro and act as a prodrug to deliver hydrogen peroxide to tissues.


Corticosteroids
    Physicians prescribing oral corticosteroids, especialy for extended periods of therapy, are advised to consider the potential depleting effects of these medications on the status of vitamin C (and other vital nutrients) and resultant adverse effects on immune and adrenal function. Although conclusive evi
    dence from adequately powered human trials is lacking, the available data indicate that such coadministration of vitamin C may mitigate certain adverse drug effects, particularly impaired healing response, and could enhance treatment eficacy and tolerance. A daily dose of 500 to 1500 mg vitamin C constitutes a typical level of nutrient support and would generally be considered safe in most patients. Ascorbic acid infusions may be appropriate in some cases but require specialized training and monitoring. Further clinical trials focused on reducing adverse elfects and enhancing therapeutic outcomes, as well as safety and protocols for determining the appropriateness of such coadministration, are warranted.

Cyclosporine
    I he use of cyclosporine as an immunosuppressive agent in the treatment of allograft patients presents with a significant incidence of adverse effects, particularly nephrotoxicity. The risk of such events is heightened because the drug is poorly bioavailable (30%). Some individuals are unable to achieve or maintain therapeutic cyclosporinc blood levels. Further, the antioxidant activity of vitamin C may provide protective support against the reactive oxygen species induced by the drug's action and the lipid peroxidation products suspect in its toxic effects within the kidneys. Concomitant administration of vitamin C during cyclosporinc therapy may enhance bioavailability and decrease the clearance and steady state volume of distribution of the drug, as well as enabling a reduction in adverse effects and cost. Such a supportive interaction could potentially allow for decreased dosage levels of the medication. Vitamins C and E have also been used as adjunctive therapy in the context of transplants on the basis that they might slow progression of transplant-associated arteriosclerosis.

    Individuals undergoing immunosuppressive therapy with cyclosporin may benefit from coadministration of vitamin C and possibly other antioxidants such as vitamin E. Such adjutrive therapy may reduce adverse effects but would require vigilant drug level monitoring and drug dosage adjustmentas necessary. Effective care of these patients will require active collaboration among physicians trained and experienced in both conventional pharmacology and nutritional therapeutics within an integrative therapeutic strategy. Given that vitamin C and allied nutrients might alter cyclosporinc absorption and phaimacokinetics and that a wide range in individual responseshas been reported, drug levels should be checked regularly, perhaps more frequently than customary, starting at 2 weeks. Among vitamin c-rich foods, unsupervised intake of grapefruit juice in particular is strongly contraindicated in patients taking cvclosporine because of effects on pharmacokinetics and drug levels.

Desferoxamine and Related Chelating Agents
    In general, vitamin C can slightly to moderately increase absorption ofn onheme iron; it also modulates iron transport and storage in the body. Iron overload may theoretically result from coadministration of iron and vitamin C in patients genetically {hemochromotosis) or medically (frequent IVBC transfusions) predisposed to it. Conversely, high iron levels or iron administration can reduce blood levels of ascorbic acid, a water-soluble antioxidant as well as a reducing agent, through oxidation. Administration of vitamin C can enhance the activity of deferoxamine in excreting iron, even at low levels such as 200 mg daily, but with dose dependent enhancement parricu larly in rhc 750 to 2000 mg dose range". Ascorbic acid is reported to enhance the tovic effects of deferox amine, but no mechanism of action has been confirmed. Ascorbatc has been proposed to induce cytotoxicity from iron-cataluzed oxidation, even in iron-deficient medium, but these in vitro findings of a pro-oxidant action of ascorbate in the context of free metal ions do not correlate with generally accepted observations under physiological conditions inhumans. Complications involving left ventricular dysfunction arc reported to be of particular concern, and its occurrence is purported to be rapid in onset and severe.

    The coadministration of vitamin C with parenteral Agents, especially desferoxamine, may enhance therapeutic efficacy increasing iron excretion, but rarely may also increase risks of left ventricular dysfunction or other significant adverse effects.
    Many clinicians experienced in iron chelation therapy of iron overload states administer 500 mg of vitamin C an hour before beginning each desferal infusion to mobiiize iron from storage sites and render it more available for chelation and subsequent excretion. Clinicians should monitor for cardiac decondensation, particularly in patients with preexisting cardiac disease. Administration of vitamin C after desferal injection may increase toxicity.
    The limited state of the evidence and the mixed outcomes suggest the need for continued research through well-designed clinical trials. Particularly because deferasirox is orally active and a more potent iron chelator than parenteral desferoxamine, clinical studies of potential interactions, both positive and negative, between deferasirox and ascorbatc should be performed.

Disulfiram
    Ethyl alcohol (ethanol) is metabolized through the activity of alcohol dehydrogenase, which is the primary enzyme involved in its oxidation, and the microsomal ethanol-oxidizing system (MKOS), a key metabolic pathway, and manifests its toxic effects throughout the body, but most profoundly in the central nervous system (CNS). Disulfiram is frequently used in the treatment of alcoholism but has a high level of noncompliance and dropout because of adverse effects, especially those attributable to acctaldchydc toxicity. Administration of vitamin C, alone or in combination with nutrients such as t-cysteine, and vitamin B may provide a period of almost complete protection against acetaldehydelethality, although it may not completely abrogate acetaldehydcetoxicity. Moreover, IV vitamin C (typically 1 g) is among the supportive measures possibly indicated to restore blood pressure and treat shock in severe disulllram reactions.

    Vitamin C and other antioxidants (e.g., NAC) can inhibit the cytotoxic effect associated with disultiram. ( hronic admin istration of disulfiram appears to cause axonal degeneration and neurotoxicity, "at least in part, due to the cytotoxic effect of
    the disulliram-Cu(2+) complex formed endogenously."
    The disulfiram-Cu(2+) complex induces apoptosis and perhaps necrosis at a late stage mediated by oxidative stress followed by sequential activation of INK, caspase 3 and poly (ADP-ribose) polymerase degradation" in a time-dependent manner. This "death-signaling pathway' involves" decreased mitochondrial membrane potential, increased free radical production, and depletion of non protein thiols (glutathione). Both disulliram and vitamin C can support abstinence in supervised alcohol abuse program. Gamma glutamyltranspeptidase (GGT) can fall with disulfiram but rise with vitamin C.

    Clincians using disilhram in the treatment of alcohol addiction are advised to investigate the administration of vitamin C for application in situations of complications caused in Antabuse. Research into vitamin C coadministration in a preventive and synergistic role may be warranted.

Erythropoiesis-Stimuloting Aqents
    Resistance to recomobinant human erunropoietin (rHuEpo) is common in hemodialysis patients with functional iron deficiency. Adequate levels of available iron are necessary for optimal response to rHuEpoo, but in some cases, parenteral iron can produce iron overload, thereby increasing morbidity and mortality rates. Functional iron deficiency is a condition in which iron supply is reduced to meet the demands for increased crythropoiesis. Conscquetuly, rHuEpo hyporesponsiveness can occur in patients who are iron-overloaded (ferritin level of 500-800 ug/L.) but also in those with normal iron status.

    Intravenous ascorbic acid improves anemia in iron-overloaded, erythropoietin (rEPO)—hyporesponsivc hemodialysis patients. Vitamin C participates in many aspects of iron metabolism, including uptake, transport, regulation, mobilization, utilization, and sequestration. Patients undergoing hemodialysis tend to develop ascorbic acid deficiency resulting from lack of dietary intake, increased vitamin oxidation catalyzed by iron, and nutrient depletion during dialysis. Although administration of iron can exacerbate hemosiderosis, ascorbic acid can beuelicially alter hemosiderin metabolism and effect hemosiderin deposits. Hemosiderin is
    a pathological deposition of iron in tissues, including the spleen, small intestine, and bone marrow. Ascorbic acid can potentiate the mobilization of ferritin stores from inert tissue stores ami facilitate the incorporation of iron into protoporphyrin in iron-overloaded hemodialysis patients being treated with rHuEpo.
    Thus, ascorbic acid administration, usually IV, not only improves the therapeutic response to rHuEpo but also facilitates elimination of iron from stores without reducing functional iron levels, including risk of rapid decline after discontinuing parenteral maintenance iron.
    Vitamin C is generally thought to reduce oxidative stress generated by iron administration, particularly in compromised patients. However, concerns have been raised that high dose (usually IV) ascorbic acid might act as a pro oxidant.


Statins
    Antioxidants, including vitamin C, may interfere with the high density lipoprotein (HDL)-elevating activity of statin-niacin combinations, although the specific role of ascorbic acid in such potential interference, including possible mechanisms of action, have not been elucidated. Presumably, nutrient rich foods could also impair the activity of such agents, if the hypothesis were to bear out under further investigation.

    Research
    The mixed evidence from clinical trials investigating the use of antioxidant nutrients during statin therapy indicates that scientific knowledge of the mechanisms of action and diverse effects of this common lipid management intervention, as well as its interaction with vitamin ( and other nutrients, is incomplete.
    As part of the HDL Atherosclerosis Treatment Study (MAI'S),Brown, Cheung, and associates reported that coadministration of 1000 mg vitamin C, 500 IU alpha tocopherol, 100 ug selenium, and 25 mg beta-carotene daily diminished the therapeutic activity of a simvastatin-niacin combination. In particular, this antioxidant combination appeared ro interfere with the HDL-elevating activity of the starin-niacin combinations, especially with regard to Lp(A-I), even though statins alone generally lower HDL as well as (with possible exception of atorvastatin). In an accompanying paper focusing on coronary atherosclerotic plaques and the occurrence of a first cardiovascular event, the niacin-simvastatin combination was significantly superior to placebo with regard to average stenosis progression, although in participants also receiving antioxidants, this benefit was significantly attenuated, a finding interpreted as possible interference by antioxidants. Notably, the specific role of vitamin C in such potential interference, including possible mechanisms of action, have not been presented in a precise and substantiated form. Moreover, the HDL increases were probably attributable to the niacin therapy because lowdose simvastatin monotherapy has only limited effects in raising the levels of HDL cholesterol and apolipoprotein (apo)A-I. Thus, one or more of the antioxidants might be interfering with niacin's ability to alter the expression of proteins responsible for the formation of HDL. Further, the findings derived from the population studied may have limited general relevance to individuals who have only elevated LDL cholesterol levels (and normal HDL levels) and to woman who made up only 13% of the cohort. Also, with regard to HDL status, there was no detriment to the antioxidants alone (i.e., given to a group without sinivistatin/niacin) and actually a slight ben-
    efit, which, if involving thousands of patients as in the previous statin and the thrombolytic trials, might have become a trend or even statistically significant. Also of note is that statins block endogenous synthesis of ubiquinone (coenzyme Q10), and thus far no trials in this area have included coadministration of this important mitochondrial protective antioxidant, with or without other antioxidants.
    Subsequently, in a much larger, randomized, controlled trial involving more than 20,000 men and women with coronary array disease (CAD) or diabetes, Collins et al. found that the administration of an antioxidant combination (250 mg vitamin C, 600 mg vitamin E, and 20 mg beta-carotene daily) in conjunction with simvastatin did not impair the cholesterol-lowering effects of simvastatin over a 5-year period. Arad et al. conducted a double blind, placebo controlled, randomizcd clinical trial investigating whether coadministration of conventional lipid-lowering therapy and antioxidants could retard the progression of coronary calcification (as assessed by CT-determined calcium score) and prevent atherosclerotic cardiovascular disease (ASCVD) events. They administered atorvastatin (20 mg daily), vitamin C (1 g daily), and vitamin E (alpha tocopherol, 1000 U daily), versus matching placcbos, to 1005 asymptomatic, apparently healthy men and women age 50 to 70 with coronary calcium scores at or above the 80th percentile for age and gender. Notably, all subjects received concomitant aspirin (81 mg daily). The authors halted the trial prematurely, after more than 4 years, because no statistically significant effect was observed on progression of coronary calcium score. They concluded that the combined treatment "induced substantial and sustained reductions in LDL cholesterol and triglycerides but tailed to achieve conventional levels of statistical significance in the reduction of either all ASCVD events or CAD events."

    Nutritionol Thetopeurics. Clinkal Concerns, and Adaptations
    Physicians prescribing statin therapy for dyslipidemia are advised to ask patients about their intake of vitamin C and other antioxidant nutrients. Monitoring for any adverse impact from high levels of antioxidant intake, including nutrient-rich foods, may be judicious in the event that a niacin-based formulation is used. No scientifically based and clinically useful conclusions have emerged to address the paradox of whether patients should be similarly advised of a potential "risk" from eating fruits and vegetables rich in Mtamin C (as well as E and other antioxidants) as part of supporting cardiovascular health. Further research through well-designed, adequately powered, and clinically relevant trials are necessary to investigate these issues more conclusively. In such research the confounding factors of nutrient dose, source, and combination, as well as controlling for and focusing on food sources of anti-oxidant nutrients, need to be adequately accounted for to produce substantial findings with clinically relevant implications.

Nitrates

    Inorganic nitrates have been used widely in conventional practice for the treatment of both coronary artery disease (CAD) and
    congestive heart failure (CHF), but the tendency of many individuals to build up tolerance to nitrates is an important factor
    limiting their clinical effectiveness. Nitroglycerin and the other organic nitrates are prodrugs that appear to undergo a bio transformation process to yield nitric oxide (NO) or some NO adjunct as their vasoactive metabolite. While providing clear benefits in acute care, nitrate tolerance develops, and these medications rapidly lose some of their hemodynamic activity and clinical effectiveness when applied as sustained therapy. Numerous investigations and ongoing debate have produced no conclusive know ledge of the mechanism(s)
    underlying nitrite tolerance. However, coadministration of vitamin C with nitroglycerin can help maintain the nitroglycerin induced dilation response and changes in the orthostatic blood pressure by one or more possible mechanisms.

    Increased formation of superoxide radicals may play a significant role in the development of nitrate tolerance in certain patients. Coadministration of vitamin ( may help reduce or eliminate vascular tolerance and help maintain the nitroglycerin induced changes in the orthostatic blood pressure during long term nitrate therapy. Some evidence indicates that antioxidant activity and free-radical scavenging produces this beneficial effect, but other data suggest that oxidative stress is not a critical contributor to nitrate tolerance and that
    tolerance reduction by vitamin may be caused by a stabilizing effect oil enzymes involved in the byconversion of glyceryl trinitrate (GTN) to NO. Other research indicates GTN tolerance is "a metabolic syndrome characterized by mitochondrial dysfunction based on evidence that "nitrate tolerance is mediated, at least in significant part. In inhibition of vascular ALDH-2 [aldehyde dehydrogenase ] and that mitochondrial ROS [reactive oxygen species] contribute to this inhibition."

Oral Contraceptives
    Prnysicians prescribing Oral Contraceptives (OC) are advised to consider possible adverse effects associated with such treatment and discuss these potential risks and means of preventing or reversing them with the patient. The available evidence indicates several possible interactions, with permutations ranging from depletion of several key nutrients, including vitamin C, to improbable occurrence of reduced drug efficacy. Dietary intake tissue nutriture status, metabolic stressors, individual pharmacogenomic variability, and numerous other factors influence the probability and character of any potential interaction. In many cases, an actual interaction may not manifest any clinically significant changes, or such changes may be subclinical, subtle, or simply slow to exhibit obvious effects.

    Prophylactic nutritional support may be appropriate for certain individuals, while monitoring over time may elucidate the need for supplementation based on clinical response to OCs. In many patients, nutritional support may relieve symptoms associated with OC use, even though no objective signs of nutrient depletion are evident. In such cases, ascorbic acid in the range of 200 to 500 mg twice daily, along with folic acid, vitamin and magnesium, can be beneficial in preventing or reversing adverse effects of OCs. More comprehensive clinical assessment is appropriate in individuals who develop premenstrual syndrome or other signs of estrogen accumulation, for whom stronger support of hepatic estrogen conjugation functions may be necessary. Although most evidence indicates that vitamin ( supplementation is unlikely to interfere with the intended activity of OCs it is always prudent to be watchful for any indications that vitamin supplementation might be impairing OC activity.

Antibiotics
    Limited evidence suggests that physicians prescribing tetracycline class antibiotics consider the potential benefits of ascorbic acid coadministration, particularly with extended periods of administration and in patients with compromised nutritional status and hepatic or renal function. Nothing in the available data has been interpreted to suggest a significant probability of any adverse effect with coadministration, whereas the general trend in the literature suggests a supportive and possibly protective etfect from concomitant vitamin C. In particular, prudence suggests that the possible protective effect against the discoloration of children's teeth by tetracycline (a relative contraindication for pediatric use) deserves consideration.
    Although controversial, most advocates of vitamin C usage would further, and more fundamentally, recommend high-dose vitamin ( for its direct elfects on bacterial infection and the immune system. A supplemental (or moderate therapeutic) dose of vitamin C is usually in the range of 2000 to 4000 mg per day in divided doses, although higher dosage ascorbic acid therapy is relatively common. Further research into the safety and efficacy of such purposeful coadministration is warranted, especially given the high incidence of self-prescribed vitamin C dosing during acute illnesses and the associated high probability of unsupervised sell administration.
Last edited by majkinetor on Thu Jan 13, 2011 1:04 pm, edited 6 times in total.

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Re: Known Negative Drug-Vit C Interactions?

Post Number:#14  Post by majkinetor » Thu Jan 13, 2011 5:23 am

This is interesting:

Physicians are advised to recommend that individuals increase their consumption of vitamin C rich foods as a means of reducing risk of H. pylori infection and as a possible means of mitigating the effects of infection in those with gastric disease who test positive tor H. priori. However, patients should be further advised to eliminate high-dose vitamin (intake while being treated with LAM triple therapy, to avoid any potential interference with the efficacy of the medication. It is known that low gastric pH is protective of H. pylori, which is why proton pump inhibitors to achieve neutral gastric pH are combined with antibiotics. From this preliminary research, prudent would suggest thai ascorbic acid (and perhaps other organic acids capable of lowering intragastric pH) should be avoided during and H. pylori therapy. Related research indicates that coadministration of probiotic flora to restore gut ecology can enhance clinical outcomes.
---
LAM ( lansoprazole , amoxycillin and metronidazole ) are reported above. However, research with amoxicillin, metronidazole, bismuth and omeprazole here (which was out after the book was written) concludes that Vitamin C is beneficial as addition to the treatment.
Last edited by majkinetor on Thu Jan 13, 2011 1:01 pm, edited 2 times in total.

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Re: Known Negative Drug-Vit C Interactions?

Post Number:#15  Post by pamojja » Thu Jan 13, 2011 5:40 am

What an amazing and informed elaboration! Would be vitamin-wiki ready - too bad this forum's isn't configured properly, for not loosing all valuable posts over time again..

Great work you put into this, very much appreciated!

Herb, nutrient, and drug interactions: clinical implications and therapeutic ...


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